Apr 152014
 

 

Targeted drug delivery is a popular area of research that melds together the disciplines of chemistry, medicine, and materials. The basic idea is to develop ways to give a person adose of medicine and somehow get that medicine to go to exactly the part of the body that needs it most – and preferably nowhere else. An article recently published in JACSdescribes a clever method of antibiotic delivery that involves fat blobs, gold particles, and their interaction with the toxins released by infectious bacteria.

read all

http://icanhasscience.com/bacteria/blinged-out-fat-blob-nanotrucks-for-targeted-drug-delivery/

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Apr 152014
 

Nanosponge attaches to Human Breast Cancer cells

Nanosponge particle attaches to Human Breast Cancer cells

One of the most important applications of nanotechnology in medicine involves use of nanoparticles to deliver drugs, and other therapeutic substances to specific types of cells (such as cancer cells). Nanosized structures and devices are smaller than human cells which are around 10,000 nm in diameter and similar in size to biomolecules such as enzymes, proteins (hemoglobin is 5 nm in diameter). Due to their small size, nanoparticles can also penetrate the blood-brain barrier which is impervious to most therapeutic and imaging agents.

read at

http://trialx.com/curetalk/2012/10/nanotechnology-drug-delivery-systems-an-insight/

Varun AroraVarun Arora

Nanotech drug delivery

 

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Apr 102014
 

GSK744.svg

Cabotegravir, GSK 744,

(3S,11aR)-N-(2,4-Difluorobenzyl)-6-hydroxy-3-methyl-5,7-dioxo-2,3,5,7,11,11a-hexahydro[1,3]oxazolo[3,2-a]pyrido[1,2-d]pyrazine-8-carboxamide

3S, 1 1 aR)- N-[(2,4-difluorophenyl)methyl]-2,3,5,7, 1 1 , 1 1 a-hexahydro-6-hydroxy-3- methyl-5,7- dioxo-oxazolo[3,2-a]pyrido[1 ,2-d]pyrazine-8-carboxamide

 

read at

http://newdrugapprovals.org/2014/04/10/cabotegravir-gsk-744-in-phase-2-for-hiv-infection/

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Apr 082014
 

 

 

LM11A-31-BHS

(2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide

2-Amino-3-methyl-N-[2-(4-morpholinyl)ethyl]-pentanamide dihydrochloride

  • CAS Number 1214672-15-7
  • Empirical Formula C12H25N3O2 · 2HCl
  • Molecular Weight 316.27

LM11A-31 is a non-peptide ligand of the p75 neurotrophin receptor (p75NTR). LM11A-31 blocks pro-NGF induced cell death in neuronal cultures, and protects neuronal cells from the the cytotoxic effects of cisplatin or methotrexate. Oral administration of LM11A-31 promotes the survival of oligodendrocytes and myelinated axons in a mouse spinal cord injury model and improves function in both weight-bearing and non-weight bearing tests.Inhibits death of hippocampal neurons at 100–1,000 pM

http://amcrasto.wix.com/anthony-melvin-crasto/apps/blog/lm11a-31-new-drug-can-help-paralyzed

PharmatrophiX

Figure 2.

 

LM11A-31, C12 H25 N3 O2, Pentanamide, 2-amino-3-methyl-N-[2-(4-morpholinyl)ethyl]- WO 2010102212 TO LONGO FRANK, PUB 10.09.2010 THE UNIVERSITY OF NORTH CAROLINA AT CHAPEL HILL

PATENT LINK

http://patentscope.wipo.int/search/en/WO2010102212

Scientists have developed a pill which they claim could help paralyzed people walk again.

The new drug allowed mice with no movement in their lower limbs to walk with ‘well-coordinated steps’ and even to replicate swimming motions, researchers said.

The experimental drug, called LM11A-31, was developed by Professor Frank Longo, of Stanford University, California.

The researchers gave three different oral doses of LM11A-31, as well as a placebo, to different groups of mice beginning four hours after injury and then twice daily for a 42 day experimental period, the ‘Daily Mail’ reported.

In tests, the experimental medication did not increase pain in the mice and showed no toxic effects on the animals.

It also efficiently crossed the blood brain barrier, which protects the central nervous system from potentially harmful chemicals carried around in the rest of the bloodstream.

An injury to the spinal cord stops the brain controlling the body and this is the first time an oral drug has been shown to provide an effective therapy.

“This is a first to have a drug that can be taken orally to produce functional improvement with no toxicity in a rodent model,” Professor Sung Ok Yoon, of Ohio State University, Columbus, said.

“So far, in the spinal cord injury field with rodent models, effective treatments have included more than one therapy, often involving invasive means. Here, with a single agent, we were able to obtain functional improvement,” Yoon said.

The small molecule in the study was tested for its ability to prevent the death of cells called oligodendrocytes.

These cells surround and protect axons, long projections of a nerve cell, by wrapping them in a myelin sheath that protect the fibres.

In addition to functioning as axon insulation, myelin allows for the rapid transmission of signals between nerve cells.

The drug preserved oligodendrocytes by inhibiting the activation of a protein called p75. Yoon’s lab previously found p75 is linked to the death of these specialised cells after a spinal cord injury. When they die, axons that are supported by them degenerate.

“Because we know oligodendrocytes continue to die for a long period of time after an injury, we took the approach that if we could put a brake on that cell death, we could prevent continued degeneration of axons,” she said.

FULL TEXT – JOURNAL OF NEUROSCIENCE

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death  in Journal of neuroscience, 26(20): 5288-5300; doi: 10.1523/​JNEUROSCI.3547-05.2006 by SM Massa – 2006 - Cited by 51 - Related articles
17 May 2006 – At 5 nm, LM11A-24 and -31 inhibit TUNEL staining to a degree  We further prioritized LM11A-31, because preliminary studies

Small, Nonpeptide p75NTR Ligands Induce Survival Signaling and Inhibit proNGF-Induced Death

Figure 1.

2010 SLIDE PRESENTATION RE P75 (E.G. LM11A-31) BY PHARMATROPHIX’S 

investorvillage.com/smbd.asp?mb=160&mn=440341…

3 Nov 2010 – 2010 slide presentation re p75 (e.g. LM11A-31) by PharmatrophiX’s founder. Longo is PharmatrophiX’s founder.

The experimental drug was developed by Prof Frank Longo from Stanford UniversityThe experimental drug was developed by Prof Frank Longo from Stanford University

Prof Frank Longo from Stanford University publications

http://med.stanford.edu/profiles/cancer/frdActionServlet?choiceId=showFacPublications&fid=7249&

Patents

1 US2013005731  (A1) ― 2013-01-03

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2013005731A1&KC=A1&FT=D&ND=3&date=20130103&DB=worldwide.espacenet.com&locale=en_EP

2 WO2011150347  (A2) ― 2011-12-01

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=WO&NR=2011150347A2&KC=A2&FT=D&ND=3&date=20111201&DB=worldwide.espacenet.com&locale=en_EP

3 US2011230479  (A1) ― 2011-09-22

http://worldwide.espacenet.com/publicationDetails/originalDocument?CC=US&NR=2011230479A1&KC=A1&FT=D&ND=3&date=20110922&DB=worldwide.espacenet.com&locale=en_EP

<a href=”http://www.bloglovin.com/blog/4674983/?claim=hj3e8pdf2nd”>Follow my blog with Bloglovin</a>

………………..

http://www.google.com.mx/patents/US7723328

TABLE I
Structures of Compounds 1-6
Compound Name
Figure US07723328-20100525-C00018
Compound 1 (also referred to herein as “LM11A-28”)
Figure US07723328-20100525-C00019
Compound 2 (also referred to herein as “LM11A-7”)
Figure US07723328-20100525-C00020
Compound 3 (also referred to herein as “LM11A-24”, “24”, and “C24”)
Figure US07723328-20100525-C00021
Compound 4 (also referred to herein as “LM11A-31” and “31”)
Figure US07723328-20100525-C00022
Compound 5 (also referred to herein as “LM11A-36”, “36”, and “C36”)
Figure US07723328-20100525-C00023
Compound 6 (also referred to herein as “LM11A-38” and “C38”)
Figure US07723328-20100525-C00024
Compound 7

 

…………………….

http://www.google.co.in/patents/WO2010102212A2?cl=en

Table I. Structures of Compounds i-vii

 

Figure imgf000050_0001
Figure imgf000051_0001

Example 32: Preparation of enantiomerically pure 2-amino-3-methyl-N-(2- morpholino-ethyϊ)-pentanamide

[00332] 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by a method shown in Scheme 4 below. First, 2-aminoethanol (Compound IE) is transformed to its derivative with a leaving group (Compound 2E). Examples of the leaving group include halides and alkoxy or other activated hydroxyl group. Second, Compound 2E reacts with morpholine at a neutral or basic condition to yield 2-morpholinoethanamine (Compound 3E). The aforementioned two steps may also be performed continuously as one step with Compound 2E being generated in situ. For example, Compound 3 E can be prepared from Compound IE directly through a Mitsunobu reaction wherein the hydroxyl group of Compound IE is activated by diethyl azodicarboxylate (DEAD) before morpholine is added. The final product, 2-amino-3-methyl-N-(2-moipholinoethyl)-pentanamide (Compound 5E), can be obtained by coupling 2-morpholinoethanamine with 2-amino-3- methylpentanoic acid (Compound 4E) via a peptide coupling agent. Examples of the peptide coupling agent include l,r-carbonyldiimidazole (CDI), hydroxybenzotriazole (HOBT), 1,3-dicyclohexylcarbodiimide (DCC), 1- hydroxybenzo-7-azatriazole (HOAt), and the like. Scheme 4:

H2N^0H — H2N^ / LG , p , .

1 Ot= LG: a leaving group

1E zt

 

Figure imgf000099_0001

[00333] A chiral 2-amino-3-methyl-N-(2-moφholinoethyl)-pentanamide (Compound 5E) can be obtained by using the corresponding chiral 2-amino-3- methylpentanoic acid (Compound 4E) in the above coupling step. For example, (2S,3S)-2-amino-3-methyl-N-(2-moφholinoethyl)-pentanamide; (2R,3R)-2-amino- 3 -methyl-N-(2-morpholinoethyl)-pentanamide; (2R,3 S)-2-amino-3 -methyl-N-(2- moφholinoethyl)-pentanamide; and (2S,3R)-2-ammo-3-methyl-N-(2- morpholinoethyl)-pentanamide can be obtained by using (2S,3S)-2-amino-3- methylpentanoic acid, i.e., L-isoleucine; (2R,3R)-2-amino-3-methylpentanoic acid, i.e., D-isoleucine; (2R,3S)-2-amino-3-methylpentanoic acid, i.e., D-alloisoleucine; and (2S,3R)-2-amino-3-methylpentanoic acid, i.e., L-alloisoleucine, respectively. [00334] The chiral purity, also known as, enantiomeric excess or EE, of a chiral Compound 5E can be determined by any method known to one skilled in the art. For example, a chiral Compound 5E can be hydrolyzed to Compound 3E and the corresponding chiral Compound 4E. Then, the chiral Compound 4E obtained through hydrolysis can be compared with a standard chiral sample of Compound 4E to determine the chiral purity of the chiral Compound 5E. The determination can be conducted by using a chiral HPLC.

……………….

http://www.google.co.in/patents/EP2498782A1?cl=en

Scheme A shows the chemical structures of the present compounds.

 

Figure imgf000013_0001

(2S,3S)-2-amino-3-methyl-/V-(2-mor holinoethyl)pentanamide

 

Figure imgf000013_0002

(2R,3R)-2-amin -3-methyl-A/-(2-morpholinoethyl)pentanamide

 

Figure imgf000013_0003

(2S,3R)-2-amino-3-meth l-A/-(2-morpholinoethyl)pentanamide

 

Figure imgf000013_0004

] Q (2R,3S)-2-amino-3-methyl-/ /-(2-morpholinoethyl)pentanamide

The free base compound of 2-amino-3-niethyl- -(2-morpholinoethyl)-pentanamide can be prepared from isoleucine by synthetic methods known to one skilled in the art.

Standard procedures and chemical transformation and related methods are well known to one skilled in the art, and such methods and procedures have been described, for example, in standard references such as Fiesers’ Reagents for Organic Synthesis, John Wiley and Sons, New York, NY, 2002: Organic Reactions, vols, 1-83, John Wiley and Sons, New York, NY, 2006; March J, and Smith M,, Advanced Organic Chemistry, 6th ed., John Wiley and Sons, New York, NY; and Larock R.C., Comprehensive Organic Transformations, Wiley-VCH Publishers, New York, 1999. All texts and references cited herein are incorporated by reference in their entirety. Other related synthetic methods can be found in U.S. Patent Application Publication Nos. 2006/024072 and 2007/0060526, the contents of which are herein incorporated by reference in their entirety for all purposes. The amorphous dihydrochloride (di-HCl) salt of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide can be prepared by mixing two molar ecjuivalents of HC1 with one molar equivalent of 2-amino- 3-methyl-N-(2-morpholinoethyl)~pentanamide in appropriate solvent(s) and then separating the di-HCl salt from the solvent(s) mixture.

The amorphous di-HCl salt of 2-aniino-3-methyl-N-(2-moi holinoethyl)-pentariamide was analyzed via the methods as described above. The XRD analysis indicated it was amorphous/low ordered as shown in Figure 1 , The DSC thermogram exhibited a broad endotherm with onset temperature 37 °C and peak temperature 74 °C and an enthalpy value of ΔΗ = 80 J/g. The TGA thermogram indicated the di-HCl salt is anhydrous and starts to decompose after about 200°C. An overlay of DSC and TGA thermograms are shown in Figure 2. The moisture sorption-desorpiion isotherm of the di-HC! salt (Figures 3 A and 3 B ) was collected using dynamic vapor sorption (DVS) analysis. The material did not adsorb much moisture from 0% to 20% RH, then it showed steady sorption up to 140 wt% moisture at 95% RH (likely deliquescence). This sample showed rapid desorption from 95% to 70% RH and then continues desorbing at a relatively slower pace to a mass about 5 wt% greater than the original value at 0% RH. This sample shows a small hysteresis between the sorption and desorption phase. O verall this material is quite hygroscopic. The crude solubility of the di-HCl salt in water was >30 mg/niL. The proton N MR spectrum of the amorphous di-HCl salt is shown in Figure 4. Example 2. Preparation of 2-amino-3-methyl- -(2-morpholinoethy[)-pentanamide (free base):

Five grams of 2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide di-HCl salt was dissolved in 150 mL of ethanol. Sodium bicarbonate (5.3 g), dissolved in 100 mL of HPLC water, was added to this solution. The mixed solution was sonicated for ~10 minutes. This solution was concentrated using a rotovap, and the residue was dissolved in 300 mL of methylene chloride. This solution was passed through a short plug of carbonate bonded silica gel. This solution was concentrated using rotovap and the residue was lyophilized to dry, resulting in 3.6 g of the free base as a white solid. Proton NMR, C-13 NMR and LC/MS confirmed the structure of this material as the free base of 2-amino-3-methyl-N-(2- morpholmoethyl)-pentanamide.

In the process of converting the di-HCl salt to free base, the sample was lyophilized to avoid formation of oil. XRD analysis of the lyophilized free base surprisingly re vealed it was crystalline, as shown in Figure 5. The DSC thermogram exhibited an endotherm with extrapolated onset temperature 51 °C and peak temperature 53 °C and an enthalpy value of Δ¾= 104 J/g. The TGA thermogram shows less than 0.6 wt% loss at 105 °C, suggesting it was solvent free. An overlay of the DSC and TGA thermograms can be seen in Figure 6. The crude solubility of free base in water was >30 mg/mL. The proton NMR was consistent with the free base. The NMR and Raman spectra are shown in Figures 7 and 8A and 8B, respectively. The moisture sorption-desorption isotherm (Figures 9 A and 9B) was collected using dynamic vapor sorption (DVS) analysis. The sample did not adsorb much moisture content from 0% to 45% RH under the experimental conditions. Above 45 %RH the sample appears to adsorb moisture of – 10 wt% from 45% to 50% RH followed by rapid sorption up to 96 wt% moisture at 95% RH. In the desorption phase, the free base shows a rapid desorption from 95% to 80°/» RH, then the sample desorbs at a relatively slow pace to the original weight at 0% RH. The sample may form a hydrate near 45 %>RH, The putative hydrate appears to deliquesce resulting in an amorphous glass by the end of the scan.

……………

new patent

WO-2014052659

Crystalline forms of neurotrophin mimetic compounds and their salts

Type II TNF receptor agonist; NGF receptor modulator

Crystalline forms of (2S,3S)-2-amino-3-methyl-N-(2-morpholinoethyl)-pentanamide (LM11A-31-BHS), useful for the treatment of neurodegenerative disorders such as Alzheimer’s disease (AD), Parkinson’s disease and multiple sclerosis. See WO2011066544 claiming deuterated compounds of LM11A-31-BHS, useful for treating neurodegenerative diseases. PharmatrophiX is investigating the p75 neutrophin receptor ligand, LM11A-31-BHS, for the oral treatment of AD. By March 2013, a phase I trial was planned. The drug was formerly being investigated in collaboration with Elan Corp and the deal was terminated by the fourth quarter of 2010.

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Apr 082014
 

2D chemical structure of 737789-87-6

Relugolix (TAK-385)

1-[4-[1-(2,6-Difluorobenzyl)-5-(dimethylaminomethyl)-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl]-3-methoxyurea

N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N’-methoxyurea

CAS NO 737789-87-6

  • C29-H27-F2-N7-O5-S
  • 623.6383

Synonyms

  • N-(4-(1-((2,6-Difluorophenyl)methyl)-5-((dimethylamino)methyl)-1,2,3,4-tetrahydro-3-(6-methoxy-3-pyridazinyl)-2,4-dioxothieno(2,3-d)pyrimidin-6-yl)phenyl)-N’-methoxyurea
  • TAK-385
  • UNII-P76B05O5V6

Systematic Name

  • Urea, N-(4-(1-((2,6-difluorophenyl)methyl)-5-((dimethylamino)methyl)-1,2,3,4-tetrahydro-3-(6-methoxy-3-pyridazinyl)-2,4-dioxothieno(2,3-d)pyrimidin-6-yl)phenyl)-N’-methoxy-

TAK-385 is a luteinizing hormone-releasing hormone (LH-RH) receptor antagonist administered orally. By preventing LH-RH from binding with the LH-RH receptor in the anterior pituitary gland and suppressing the secretion of luteinizing hormone (LH)  and follicle stimulation hormone (FSH) from the anterior pituitary gland, TAK-385 controls the effect of LH and FSH on the ovary, reduces the level of estrogen in blood, which is known to be associated with the development of endometriosis and uterine fibroids, and is expected to improve the symptoms of these disorders.

TAK-385 in Japan for the treatment of endometriosis and uterine fibroids. TAK-385 is a luteinizing hormone-releasing hormone (LH-RH) *1 receptor antagonist administered orally. By preventing LH-RH from binding with the LH-RH receptor in the anterior pituitary gland and suppressing the secretion of luteinizing hormone (LH) *2 and follicle stimulation hormone (FSH) *3 from the anterior pituitary gland, TAK-385 controls the effect of LH and FSH on the ovary, reduces the level of estrogen in blood, which is known to be associated with the development of endometriosis and uterine fibroids, and is expected to improve the symptoms of these disorders. The safety and efficacy of TAK-385 in subjects with endometriosis and uterine fibroids will be evaluated in two individual phase 2, double-blind, comparative studies. There are medical needs which cannot be met by the current therapies in the treatment of endometriosis and uterine fibroids. We are committed to the rapid development to deliver the oral LH-RH antagonist TAK-385, which could become a new treatment option for patients with these conditions.

  • *1 The hormone that controls the secretion of LH and FSH, gonadotropic hormones, secreted from the anterior pituitary gland.
  • *2 A hormone that is secreted from the anterior pituitary gland by the action of LH-RH and encourages follicular maturation, ovulation and luteinization by acting on the ovaries.
  • *3 A hormone that is secreted from the anterior pituitary gland by the action of LH-RH and encourages follicular maturation by stimulating the ovaries.

TAK-385, an oral antagonist of gonadotropin-releasing hormone (GnRH), was originated by Takeda. It is in phase II clinical trials for the treatment of endometriosis and for the treatment of uterine fibroids (myoma). Phase I clinical trials are also underway for the treatment of prostate cancer.

TAK-385 (relugolix) is a novel, non-peptide, orally active gonadotropin-releasing hormone (GnRH) antagonist, which builds on previous work with non-peptide GnRH antagonist TAK-013. TAK-385 possesses higher affinity and more potent antagonistic activity for human and monkey GnRH receptors compared with TAK-013. Both TAK-385 and TAK-013 have low affinity for the rat GnRH receptor, making them difficult to evaluate in rodent models. Here we report the human GnRH receptor knock-in mouse as a humanized model to investigate pharmacological properties of these compounds on gonadal function. Twice-daily oral administration of TAK-013 (10 mg/kg) for 4 weeks decreased the weights of testes and ventral prostate in male knock-in mice but not in male wild-type mice, demonstrating the validity of this model to evaluate antagonists for the human GnRH receptor.
The same dose of TAK-385 also reduced the prostate weight to castrate levels in male knock-in mice. In female knock-in mice, twice-daily oral administration of TAK-385 (100 mg/kg) induced constant diestrous phases within the first week, decreased the uterus weight to ovariectomized levels and downregulated GnRH receptor mRNA in the pituitary after 4 weeks. Gonadal function of TAK-385-treated knock-in mice began to recover after 5 days and almost completely recovered within 14 days after drug withdrawal in both sexes. Our findings demonstrate that TAK-385 acts as an antagonist for human GnRH receptor in vivo and daily oral administration potently, continuously and reversibly suppresses the hypothalamic–pituitary–gonadal axis. TAK-385 may provide useful therapeutic interventions in hormone-dependent diseases including endometriosis, uterine fibroids and prostate cancer.

Relugolix (TAK-385)

…………….

http://www.google.co.in/patents/EP1591446A1?cl=en

 

(Production Method 1)

  • Figure 00120001
    (Production method 2)

  • Figure 00130001

 

      Example 83
      http://www.google.co.in/patents/EP1591446A1?cl=en
    Production of N-(4-(1-(2,6-difluorobenzyl)-5-((dimethylamino)methyl)-3-(6-methoxy-3-pyridazinyl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl)phenyl)-N’-methoxyurea
  • Figure 01690002
  • The similar reaction as described in Example 4 by using the compound (100 mg, 0.164 mmol) obtained in Reference Example 54 and methyl iodide (0.010 ml, 0.164 mmol) gave the title compound (17.3 mg, 17 %) as colorless crystals.
    1 H-NMR(CDCl3) δ: 2.15 (6H, s), 3.6-3.8 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.2-7.65 (7H, m), 7.69 (1H, s).

……………

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2011, 54(14): 4998. http://pubs.acs.org/doi/full/10.1021/jm200216q

1-{4-[1-(2,6-Difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (16b)

Compound 16b was prepared in 44% yield from 15j by a procedure similar to that described for16a as colorless crystals, mp 228 °C (dec). 1H NMR (CDCl3): δ 2.15 (6H, s), 3.60–3.80 (2H, m), 3.82 (3H, s), 4.18 (3H, s), 5.35 (2H, s), 6.92 (2H, t, J = 8.2 Hz), 7.12 (1H, d, J = 8.8 Hz), 7.20–7.65 (7H, m), 7.69 (1H, s). LC–MS m/z: 624.0 [M + H+], 621.9 [M + H]. Anal. (C29H27F2N7O5S) C, H, N.

Abstract Imagetak 385

 

http://pubs.acs.org/doi/suppl/10.1021/jm200216q/suppl_file/jm200216q_si_001.pdf

…………………….

 

new patent

WO-2014051164

Method for the production of TAK-385 or its salt and crystals starting from 6-(4-aminophenyl)-1-(2,6-difluorobenzyl)-5-dimethylaminomethyl-3-(6-methoxypyridazin-3-yl) thieno[2,3-d] pyrimidine-2,4 (1H,3H)-dione or its salt. Takeda Pharmaceutical is developing relugolix (TAK-385), an oral LHRH receptor antagonist analog of sufugolix, for the treatment of endometriosis and uterine fibroids. As of April 2014, the drug is in Phase 2 trails. See WO2010026993 claiming method for improving the oral absorption and stability of tetrahydro-thieno[2,3-d]pyrimidin-6-yl]-phenyl)-N’-methoxy urea derivatives.

references

Discovery of TAK-385, a thieno[2,3-d]pyrimidine-2,4-dione derivative, as a potent and orally bioavailable nonpeptide antagonist of gonadotropin releasing hormone (GnRH) receptor
238th ACS Natl Meet (August 16-20, Washington) 2009, Abst MEDI 386

 

Discovery of 1-{4-[1-(2,6-difluorobenzyl)-5-[(dimethylamino)methyl]-3-(6-methoxypyridazin-3-yl)-2,4-dioxo-1,2,3,4-tetrahydrothieno[2,3-d]pyrimidin-6-yl]phenyl}-3-methoxyurea (TAK-385) as a potent, orally active, non-peptide antagonist of the human gonadotropin-releasing hormone receptor
J Med Chem 2011, 54(14): 4998. http://pubs.acs.org/doi/full/10.1021/jm200216q

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Apr 062014
 

Sucrose 2D NMR Spectra

The sugar sucrose can be used to illustrate  homonuclear 2D NMR experiment: the TOCSY.

Sucrose

Sucrose

Table sugar

Sucrose (“table sugar”) is a disaccharide derived from glucose and fructose.

The interesting element from an NMR spectroscopy viewpoint is that the two monomer units are completely separate spin systems and this can be visualised in the TOCSY spectrum.

HH COSY

HH COSY

The HH COSY shows the coupling network within the molecule.

HH TOCSY

HH TOCSY

The HH TOCSY spectrum shows correlations that belong together in contiguous spin systems: in the sucrose example, this means that the protons in the respective glucose and fructose units can be assigned.

HMQC

HMQC

In the HMQC spectrum the one-bond direct HC couplings can be viewed as cross-peaks between the proton and carbon projections.

HMBC

HMBC

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Apr 062014
 

A multistep single-crystal-to-single-crystal bromodiacetylene dimerization

http://www.nature.com/nchem/journal/v5/n4/fig_tab/nchem.1575_F6.html

Nature Chemistry5,327–334 
doi:10.1038/nchem.1575
2D NMR spectroscopy for the structural elucidation of 4.

The heteronuclear multiple bond correlation NMR spectrum (400 MHz, CDCl3) of dimer 4 with the corresponding 1D 1H NMR and 13C NMR traces exhibited ten acetylene carbon resonances, a duplication of the propargyl methylene proton resonances that coupled with four and six acetylene carbons, respectively, as well as two new olefin carbon resonances that coupled only with the propargyl methylene protons on the ‘shorter’ side of the molecule. The inset is a magnified view of the region of the acetylene cross-peaks. For a more detailed discussion, see the Supplementary Information.

SEE

http://www.nature.com/nchem/journal/v5/n4/extref/nchem.1575-s1.pdf

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1H-1H COSY (COrrelated SpectroscopY) is a useful method for determining which signals arise from neighboring protons (usually up to four bonds). Correlations appear when there is spin-spin coupling between protons, but where there is no coupling, no correlation is expected to appear.

This method is very useful when the multiplets overlap or when is extensive second order coupling complicates the 1D spectrum.

There are many variants on the COSY pulse sequence. The most popular one in our laboratory is the gradient enhanced double quantum coherence (DQF-COSY) version. The ratio of gradient strengths is usually set to two to yield all COSY signals but may be set to three to yield only those correlations involving three protons, e.g., CH-CH2. We use the gradient enhanced DQF-COSY pulse sequence shown in fig. 1.

Fig. 1. Pulse sequence for gradient DQF-COSY

cholesteryl acetate

The COSY spectrum as shown in fig. 2 for ethylbenzene (fig. 3) contains a diagonal and cross peaks (signals that are not on the diagonal and correspond to other signals on the same horizontal and vertical projections). The cross peaks indicate couplings between two mutliplets up to three, or occasionally four, bonds away. The diagonal consists of the 1D spectrum with single peaks suppressed.

The most apparent cross-peak in the spectrum is between H1′ and H2′ at 2.65 and 1.24 ppm. A much weaker four-bond correlation (see the figure below) appears between H1′ and H2 at 2.65 and 7.20 ppm. All the desired signals are antiphase. Half the multiplet is positive and half negative. In addition, artifacts (undesired signals) appear in the spectrum as vertical streaks (interference and f1 noise) and along the inverted ‘V’ (fig. 4) whose tip is on the top axis of the sepctrum. These artifacts are rarely in phase with the desired signals and appear in specific locations.

Fig. 2. 2D COSY spectrum of ethylbenzene

COSY of ethylbenzene

Fig. 3. Structure of ethylbenzene

Ethylbenzene

Fig. 4. Artifacts in the COSY spectrum of ethylbenzene

COSY artifacts

For example, in 12,14-ditbutylbenzo[g]chrysene (fig. 5), only a partial analysis of the regular 1H-NMR spectrum is possible. COSY (fig. 6) provides extra information about the connectivity. No correlations (cross-peaks) are seen to the tbutyls because they are too many bonds away from the ring system.

Fig. 5. Structure of 12,14-ditbutylbenzo[g]chrysene

12,14-ditbutylbenzo[g]chrysene

Fig. 6. Artifacts in the COSY spectrum of ethylbenzene

COSY of 12,14-ditbutylbenzo[g]chrysene

The aromatic region of the spectrum (fig. 7) shows three bond correlations strongest. These can be used to determine which protons are neighbors. For example the proton at 8.17 ppm is next to the proton at 7.34 ppm, a fact that could not be easily determined from the 1D spectrum.

Fig. 7. Aromaric region of the 2D COSY spectrum of 12,14-ditbutylbenzo[g]chrysene showing mostly three-bond correlations (a four-bond correlation between H10 and H11 is also visible)

Aromatic region of COSY of 12,14-ditbutylbenzo[g]chrysene

Four-bond and five-bond correlations are apparent when plotted to lower contours (fig. 8). These separate the spectrum into four groups of protons in a manner that is much clearer than the 1D spectrum.

Fig. 8. Aromaric region of the 2D COSY spectrum of 12,14-ditbutylbenzo[g]chrysene showing three, four and five-bond correlations

Aromatic region of COSY of 12,14-ditbutylbenzo[g]chrysene

Using horizontal and vertical lines, it is possible to separate each group and follow its connectivity (fig. 9). The blue group of four protons is connected in the order 8.62 ppm to 7.55 to 7.59 to 8.56, the green group of four protons in the order 8.54 to 7.34 to 7.44 to 8.17 and the red group or two protons, that correspond to H9 and 10 because they are the only group of two protons expected to have a three-bond coupling constant (8.9 Hz), are at 7.76 and 8.32 ppm. The yellow group of two protons correspond to H11 and 13 because the coupling constant is small (1.9 Hz) and consistent with a four bond correlation.

Fig. 9. Aromaric region of the 2D COSY spectrum of 12,14-ditbutylbenzo[g]chrysene showing connectivity and separation into four color-coded proton groups

Aromatic region of COSY of 12,14-ditbutylbenzo[g]chrysene in color

The multiplet structures in COSY are anti-phase for active couplings which leads to different patterns that for pure phase. A pure singlet (A) will not appear in a DQF-COSY spectrum because it is purely single quantum and a double-quantum filter is applied. This is true for deuterated solvent signals and for some protiated solvents such as water. Advantage of this is often taken for solvent suppression. A simple doublet appears in anti-phase. Many other combinations exist. The more common ones are listed in the table below and a few examples are shown.

Table 1. multiplicities often seen in COSY spectra compared with their pure phase counterparts.a

Multiplicity Pure phase Anti-phase
A 1 0
AX 1 1 1 -1
AX2 1 2 1 1 0 -1
AXY 1 1 1 1 1 1 -1 -1
AYX 1 1 1 1 1 -1 1 -1
AX3 1 3 3 1 1 1 -1 -1
AX2Y 1 2 1 1 2 1 1 0 -1 1 0 -1
AY2X 1 2 1 1 2 1 1 2 1 -1 -2 -1
AXY2 1 1 2 2 1 1 1 -1 2 -2 1 -1
AYX2 1 1 2 2 1 1 1 -1 0 0 1 -1
AYX2JAY=2JAX 1 2 2 2 1 1 0 0 0 -1
AXYZ 1 1 1 1 1 1 1 1 1 1 1 1 -1 -1 -1 -1
AYXZ 1 1 1 1 1 1 1 1 1 1 -1 -1 1 1 -1 -1
AYZX 1 1 1 1 1 1 1 1 1 -1 1 -1 1 -1 1 -1
AXYZ, JAX=JAY+JAZ 1 1 1 2 1 1 1 1 1 1 0 -1 -1 -1
AXYZ, JAY=JAX+JAZ 1 1 1 2 1 1 1 1 1 -1 0 1 -1 -1
AXYZ, JAZ=JAX+JAY 1 1 1 2 1 1 1 1 -1 1 0 -1 1 -1
AX6 1 6 15 20 15 6 1 1 2 1 0 -1 -2 -1

aThe active coupling is from A to X. The coupling constant decreases from left to right, e.g., for AXYZ, JAX > JAY > JAZ.

Figs. 10-13 show expansions of COSY multiplets. The red contours are negative and the black ones are positive. The 1D projections are only representations (in practice the sum of the projection is zero).

Fig. 10. Anti-phase AX correlation between doublets H9 and 10 of 12,14-ditbutylbenzo[g]chrysene

Antiphase AX signal

Higher multiplicities in which all the couplings are active yield the patterns shown in table 1. For example the correlation between the CH3 and CH2 protons in ethylbenzene yield a 1 0 1 pattern in one direction and a 1 1 -1 – 1 pattern in the other direction (fig. 11).

Fig. 11. Anti-phase A2X3 correlation between the ethyl protons of ethylbenzene

Antiphase AX signal

When there are more than two multiplets coupled, then only one coupling is active in each cross-peak. This can be used to determine which coupling constant relates to which correlation, something that may not be obvious from the 1D spectrum. In figs. 12 and 13 for ditbutylbenzo[g]chrysene, the active couplings are labeled. The top cross-peak between the protons at 7.34 and 8.17 ppm shows the largest active coupling of 8.1 Hz. The coupling pattern in the vertical (f1) direction is 1 1 1 0 -1 -1 -1 and in the horizontal (f2) direction it is 1 1 1 1 -1 -1 -1 -1. The multiplet below it has the smallest active coupling of 1.4 Hz. The f1 coupling pattern is 1 -1 1 0 -1 1 -1 and the f2 coupling pattern is 1 1 -1 -1 1 1 -1 -1. The bottom multiplet displays an active coupling of 7.0 Hz and the coupling pattern in both directions is 1 1 -1 0 1 -1 -1.

Figs. 12, 13. Comparison of three AXYZ correlations showing different active couplings (from the COSY of 12,14-ditbutylbenzo[g]chrysene)

Antiphase AXYZ signalsAntiphase AYXZ signal

EXAMPLE

COSY spectra

  • The information on the H that are coupling with each other is obtained by looking at the peaks inside the grid.  These peaks are usually shown in a contour type format, like height intervals on a map.
  • In order to see where this information comes from, let’s consider an example shown below, the COSY of ethyl 2-butenoate 
  • First look at the peak marked A in the top left corner.  This peak indicates a coupling interaction between the H at 6.9 ppm and the H at 1.8 ppm.  This corresponds to the coupling of the CH3 group and the adjacent H on the alkene.
  • Similarly, the peak marked B indicates a coupling interaction between the H at 4.15 ppm and the H at 1.25 ppm.  This corresponds to the coupling of the CH2 and the CH3 in the ethyl group.
  • Notice that there are a second set of equivalent peaks, also marked A and Bon the other side of the diagonal.

 

 

COSY spectra of ethyl 2-butenoate

 

The (H,H) COSY experiment establishes the connectivity of a molecule by giving cross peaks (these are the off diagnonal peaks) for pairs of protons that are in close proximity. For the example of Glutamic acid below, we obtain cross peaks for the proton pairs (2,3) and (3,4). We do not observe a crosspeak for the pair (2,4), because these protons are not directly adjacent.

relayed COSY experiment goes one step beyond a COSY experiment by showing cross peaks not just for pairs of adjacent protons, but for triples as well. As a result, we observe additional cross peaks like the one for the pair 2,4 in Glutamic acid below. Relayed COSY experiments can give cross peaks for protons that are too distant to show coupling in the 1D NMR spectrum.500 MHz H-relayed (H,H) COSY Spectrum of Glutamic acid. 1-D spectra left and top. 10 mg of compound in 0.5 mL of D2O, 5 mm sample tube, 256 spectra, digital resolution of 2.639 Hz/data point. Total measurement time ca. 3h.

 

500 MHz H-relayed (H,H) COSY Spectrum of Glutamic acid. 1-D spectra left and top. 10 mg of compound in 0.5 mL of D2O, 5 mm sample tube, 256 spectra, digital resolution of 2.639 Hz/data point. Total measurement time ca. 3h.

With present hardware and pulse sequences, it is possible to repeat the relay step up to three times. This allows the correlation of of protons that are separated by up to six bonds (d-protons). The relaying nucleus is typically 1H, but high abundance I =1/2 hetero-elements like 31P or 19F can be used as well.

 

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File:Prulifloxacin.png

PRULIFLOXACIN

(RS)-6-Fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid

6-Fluoro-1-methyl-7-(4-(5-methyl-2-oxo-1,3-dioxelen-4-yl)methyl-1-piperazinyl)-4-oxo-4H-(1,3)thiazeto(3,2-a)quinoline-3-carboxylic acid

123447-62-1 CAS NO

NM 441, Quisnon, Pruvel, Sword, Prulifloxacin [INN], 123447-62-1, NM-441, CCRIS 7686, NCGC00164615-01NAD-441A
OPT-99
Molecular Formula: C21H20FN3O6S
Molecular Weight: 461.463403

Launched – 2002 BY NIPPON SHINYAKU

SYNTHESIS…….http://www.drugfuture.com/synth/syndata.aspx?ID=151640

Prulifloxacin is an older synthetic chemotherapeutic antibiotic of the fluoroquinolone drug class[1][2] undergoing clinical trials prior to a possible NDA (New Drug Application) submission to the U.S. Food and Drug Administration (FDA). It is a prodrug which is metabolized in the body to the active compound ulifloxacin.[3][4] It was developed over two decades ago by Nippon Shinyaku Co. and was patented in Japan in 1987 and in the United States in 1989.[5][6]

It has been approved for the treatment of uncomplicated and complicated urinary tract infections, community-acquired respiratory tract infections in Italy and gastroenteritis, including infectious diarrheas, in Japan.[3][7] Prulifloxacin has not been approved for use in the United States.

Prulifloxacin is a novel fluoroquinolone antibiotic that was launched pursuant to a collaboration between Meiji Seika and Nippon Shinyaku in 2002 for the oral treatment of systemic bacterial infections, including acute upper respiratory tract infection, bacterial pneumonia, prostatitis, cholecystitis, bacterial enteritis, internal genital infections, otitis media, sinusitis and others. It is currently marketed in a tablet formulation. A once-daily formulation to be taken over a three-day period is in phase III clinical trials at Optimer Pharmaceuticals to be used in the treatment of bacterial gastroenteritis, including traveler’s diarrhea. The formulation had been in phase II trials at the company for the treatment of urinary tract infections, however, no recent development for this indication have been reported. The drug has also been studied at Optimer for the treatment of community-acquired respiratory tract infections, but recent progress reports for this indication have not been made available.

Prulifloxacin has in vitro activity against a wide range of gram-negative and gram-positive microorganisms. Its antibacterial action results from inhibition of DNA gyrase and topoisomerase IV, both Type II isomerases. DNA gyrase is an essential enzyme that is involved in the replication, transcription, and repair of bacterial DNA. Topoisomerase IV is an enzyme known to play a key role in the partitioning of the chromosomal DNA during bacterial cell division. Together, the Type II topoisomerases remove the positive supercoils that accumulate ahead of a translocating DNA polymerase, allowing DNA replication to continue unhindered by topological strain. Fluoroquinolones may be active against pathogens that are resistant to penicillins, cephalosporins, aminoglycosides, macrolides and tetracyclines, as they possess a distinct mechanism of action from these antibiotics.

Prulifloxacin was discovered by Nippon Shinyaku and codeveloped with Meiji Seika in Japan. Nippon Shinyaku granted Angelini a manufacturing and marketing license for Italy in 1993. Exclusive Korean manufacturing and commercialization rights were acquired by Yuhan from Nippon Shinyaku in March 2003. In June 2004, Optimer was granted exclusive development and commercialization rights to prulifloxacin in the U.S. from Nippon Shinyaku. Finally, Recordati signed a nonexclusive licensing agreement with Angelini for the marketing and sale of prulifloxacin in Spain in October 2004. In March 2009, the product was licensed to Lee’s Pharmaceuticals by Nippon Shinyaku for marketing in China as an oral treatment of bacterial infection. In 2010, prulifloxacin was licensed to Algorithm by Nippon Shinyaku in North Africa and the Middle East for the development and marketing for the treatment of bacterial infections.

History

In 1987 a European Patent (EP 315828) for prulifloxacin (Quisnon ) was issued to the Japanese based pharmaceutical company, Nippon Shinyaku Co., Ltd (Nippon). Ten years after the issuance of the European patent, marketing approval was applied for and granted in Japan (March 1997). Subsequent to being approved by the Japanese authorities in 1997 prulifloxacin (Quisnon) was co-marketed and jointly developed in Japan with Meiji Seika as licensee (Sword).[6]

In more recent times, Angelini ACRAF SpA, under license from Nippon Shinyaku, has fully developed prulifloxacin, for the European market.[8] Angelini is the licensee for the product in Italy. Following its launch in Italy, Angelini launched prulifloxacin in Portugal (January 2007) and it has been stated that further approvals will be sought in other European countries.[9][10]

Prulifloxacin is marketed in Japan and Italy as Quisnon (Nippon Shinyaku); Sword (Meiji); Unidrox (Angelini) and generic as Pruquin.

In 1989 and 1992 United States patents (US 5086049) were issued to Nippon Shinyaku for prulifloxacin. It was not until June 2004, when Optimer Pharmaceuticals acquired exclusive rights to discover, develop and commercialize prulifloxacin (Pruvel) in the U.S. from Nippon Shinyaku Co., Ltd., that there were any attempts to seek FDA approval to market the drug in the United States. Optimer Pharmaceuticals expects to file an NDA (new drug application) for prulifloxacin some time in 2010. As the patent for prulifloxacin has already expired, Optimer Pharmaceuticals has stated that this may have an effect on the commercial prospects of prulifloxacin within the United States market.[11]

Licensed uses

Prulifloxacin has been approved in Italy ,Japan,China,India and Greece (as indicated), for treatment of infections caused by susceptible bacteria, in the following conditions:

Italy
  • Acute uncomplicated lower urinary tract infections (simple cystitis)
  • Complicated lower urinary tract infections
  • Acute exacerbation of chronic bronchitis
Japan
  • Gastroenteritis, including infectious diarrheas
Other countries
  • Prulifloxacin has not been approved for use in the United States, but may have been approved in other Countries, other than that which is indicated above.

Availability

Prulifloxacin is available as:

  • Tablets (250 mg, 450 mg or 600 mg)

In most countries, all formulations require a prescription.

Prulifloxacin is chemically known as 6-fluoro-1-methyl-7-{4-[(5-methyl-2-oxo-1 ,3-dioxol- 4-yl)methyl]piperazin-1-yl}-4-oxo-4H-[1 ,3]-thiazeto-[3,2-a]-quinoline-3-carboxylic acid, and it has the structure as shown below as formula I:

 

Figure imgf000002_0001

FORMULA I

Prulifloxacin has significant antibacterial activity and has been marketed as a synthetic antibacterial agent.

Prulifloxacin was first disclosed in US 5,086,049. The patent discloses a process for the preparation of prulifloxacin by the condensation of ulifloxacin with a 4-halomethyl-5- methyl-1 ,3-dioxolen-2-one of formula III

Figure imgf000002_0002

wherein X is halo selected form chloro, bromo or iodo, in the presence or absence of an aprotic solvent and a base to obtain prulifloxacin free base which is recrytallised with chloroform-methanol. In an exemplified process, ethyl 6,7-difluoro-1-methyl-4-oxo-4H- (1 ,3)-thiazeto-(3,2-a)-quinoline-3-carboxylate is condensed with piperazine in the presence of dimethyl formamide and purified by column chromatography followed by basic hydrolysis to give ulifloxacin, which is then converted to prulifloxacin.

The above process involves column chromatography. Prulifloxacin prepared by this method has a purity of 60-65% containing impurities in unacceptable levels. Removal of these impurities by usual purification procedures, such as recrystallisation, distillation and washing, is difficult and requires extensive and expensive multiple purification processes. This further decreases the overall yield. A method involving column chromatographic purifications and multiple purifications cannot be used for large-scale operations, thereby making the process commercially non-viable.

European Patent No. 315828 disclosed a variety of quinoline carboxylic acid derivatives and pharmaceutically acceptable salts thereof. These compounds are exhibiting antibacterial activity and useful as remedies for various infectious diseases. Among them prulifloxacin, chemically (+)-6-Fluoro- 1 -methyl-7-[4-(5-methyl-2-oxo-1 ,3-dioxolen-4-ylmethyl)-1 -piperazinyl]-4-oxo-4H- [1 ,3]thiazeto[3,2-a]quinoline-3-carboxylic acid is a fluoroquinolone antibacterial prodrug which shows potent and broad-spectrum antibacterial activity both in vitro and in vivo. Prulifloxacin also showed superior activity against strains of Enterobacteriaceae and Pseudomonas aeruginosa. Prulifloxacin is represented by the following structure:

 

Figure imgf000002_0001

Processes for the preparation of prulifloxacin and related compounds were disclosed in European Patent No. 315828 and UK Patent Application No. GB 2190376.

In – the preparation of prulifloxacin, 6-fluoro-1-methyl-4-oxo-7-(1- piperazinyl)-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylic acid of formula I:

 

Figure imgf000003_0001

is a key intermediate. According to the UK Patent Application No. GB 2190376, the compound of the formula I was prepared by the reaction of 3,4-difluroaniline with carbon disulfide and triethylamine to give triethylammonium N-(3,4- difluorophenyl)dithio carbamate, which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate, followed by reaction with diethyl malonate and KOH in dioxane affords the potassium salt, which is then treated with methoxymethyl chloride in dimethylformamide to give diethyl 1-(3,4-difluorophenylamino)-1- (methoxymethylthio)-rnethylene-rnalonate. The cyclization of the thio compound at 2400C in diphenyl ether affords ethyl 6,7-difluoro-4-hydroxy-2- methoxymethylthioquinoline-3-carboxylate, which by treatment with HCI in ethanol gives ethyl δy-difluoro^-hydroxy^-mercaptoquinoline-S-carboxylate. The cyclization of the mercapto compound with 1,1-dibromoethane by means of potassium carbonate and potassium iodide in hot dimethylformamide yields ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate, which is condensed with piperazine in dimethylformamide to afford ethyl 6- fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]thiazeto[3,2-a]quinoline-3- carboxylate, which is then subjected to hydrolysis with potassium hydroxide in hot tert-butanol to give the compound of formula I.

The compound of formula I obtained by the process described in the UK Patent Application No. GB 2190376 is not satisfactory from purity point of view, the reaction between ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2- a]quinoline-3-carboxylate and piperazine requires longer time about 48 hours to complete, the yield obtained is not satisfactory, and the process also involves column chromatographic purifications. Methods involving column chromatographic purifications cannot be used for large-scale operations, thereby making the process commercially not viable. According to the European Patent No. 315828, prulifloxacin is prepared by reacting 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]thiazeto[3,2-a] quinoline-3-carboxylic acid with 4-bromomethyl-5-methyl-1 ,3-dioxolen-2-one in presence of potassium bicarbonate in dimethylformamide. However, a need still remains for an improved and commercially viable process of preparing pure prulifloxacin that will solve the aforesaid problems associated with process described in the prior art and will be suitable for large- scale preparation, in terms of simplicity, purity and yield of the product.

Prulifloxacin is chemically 6-fluoro-l-methyl-7-{4-[(5-methyl-2-oxo-l,3-dioxol-4- yl)methyl]piperazin-l-yl}-4-oxo-4H-[l,3]thiazeto[3,2-α]quinoline-3-carboxylic acid of Formula I having the structure as depicted below:

 

Figure imgf000002_0001

FORMULA I

Prulifloxacin has significant antibacterial activity and has been marketed as a synthetic antibacterial agent. U.S. Patent No. 5,086,049 provides a process for the preparation of prulifloxacin by reacting 6-fluoro-l-methyl-4-oxo-7-piperazin-l-yl-4H- [l,3]thiazeto[3,2-α]quinoline-3-carboxylic acid of Formula II,

 

Figure imgf000002_0002

FORMULA II and 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III,

Figure imgf000003_0001

FORMULA III using N,N-dimethylformamide as a solvent. 4-(Bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III is used in excess to one mole of the compound of Formula II. The process provided in U.S. Patent No. 5,086,049 further involves concentrating the reaction mixture, pouring the residue into water and isolating prulifloxacin by filtration. The resulting prulifloxacin is recrystallized from chloroform-methanol.

However, U.S. Patent No. 5,086,049 does not provide any method to remove the unreacted or the excess of 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one of Formula III used as a starting material. The present inventors have observed that it is difficult to obtain prulifloxacin with pharmaceutically acceptable purity by following the process provided in U.S. Patent No. 5,086,049, which is typically contaminated by process related impurities including 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one

A need still remains for an improved and commercially-viable process for preparing pure prulifloxacin that will solve the aforesaid problems associated with the process described in the prior art and that will be suitable for large-scale preparation, in terms of simplicity, purity and yield of the product.

EP1626051 A1 mentions that Type I, Type II and Type III crystals of prulifloxacin are obtained by crystallization from acetonitrile as reported in lyakuhin Kenkyu, Vol. 28 (1), (1997), 1-11. However, the conditions of crystallization from acetonitrile for preparing Type I, Type II and Type III crystals are not disclosed in lyakuhin Kenkyu, Vol. 28 (1), (1997), 1-11. EP1626051A1 further mentions that Type III crystals have been marketed by considering the solubility, absorbability, therapeutic effect and the like of the respective crystal forms.

US 2007/0149540 discloses a crystal of prulifloxacin acetonitrile solvate (Compound B) which is an intermediate for producing preferentially the type III crystal of prulifloxacin. A crystal of Compound B can be preferentially precipitated by controlling the supersaturation concentration in crystallization using acetonitrile as a solvent, subsequently; the type III crystal of Compound A can be produced by performing desolvation of the crystal.

WO 2008/111018 discloses processes for the preparation of Type I, Type II and Type III crystals of prulifloxacin. There is disclosed a process for preparing Type I crystals by controlled cooling over a period of 7 to 9 hours and prolonged drying over 24 hours. The inventors of the present invention have found that Type I and Type III crystals prepared according to the WO 2008/111018 process are unstable and the process is non-reproducible.

WO 2010/0084508 discloses processes for the preparation of Type I, Type II and Type III crystals of prulifloxacin.

WO 2008/059512 discloses a process for the preparation of prulifloxacin using novel intermediates.

WO 2008/111016 discloses a process for the preparation of prulifloxacin having purity of about 99% or above. It would be a significant contribution to the art to provide a crystalline form of prulifloxacin, which is consistent and to provide industrially viable methods of preparation, pharmaceutical formulations, and methods of use thereof.

 

…………………

SYNTHESIS

http://www.google.com/patents/WO2012001357A1?cl=en

Scheme 1.

 

Figure imgf000020_0001

 

Figure imgf000020_0002

Formula I

[PRULIFLOXACIN]

Example 1

Preparation of ethyl-6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-(1 ,3)-thiazeto-[3,2-a]- quinoline-3-carboxylate (formula III)

5,6-difluoro-1-methyl-4-oxo-4H-[1 ,3]-thiazeto-[3,2-a]-quinoline-3-carboxylic acid ethyl ester of formula (II) (100 gms, 0.321 moles) was stirred in 500 ml of DMF at room temperature. Piperazine (76 gms, 0.882 moles) was added at room temperature and stirred for 10 minutes. The temperature was slowly raised to 50-55°C and the reaction mass was stirred at 50-55°C for 5 hours. After completion of the reaction, the reaction mass was cooled to 25-30°C and stirred for 2 hours. The reaction mass was further chilled to 10-15°C and stirred for 2 hours. The precipitated solid was filtered, washed of chilled DMF (2 x 50 ml). The solid was slurry washed with water (300 ml), filtered, washed with water ( 2 x 100 ml) and dried under vacuum at 70-75°C to yield the title compound [90 gms, 74 % yield, 95% HPLC purity].

Example 2

Preparation of 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]-thiazeto-[3,2-a]- quinoline-3-carboxylic acid (formula IV)

Ethyl-6-fluoro-1 -methyl-4-oxo-7-(1 -piperazinyl)-4H-(1 ,3)-thiazeto-[3,2-a]-quinoline-3- carboxylate (100 gms, 0.265 moles) was stirred in water (600 ml) at 25-30°C. To this potassium hydroxide solution (50 gms of potassium hydroxide flakes is dissolved in 200 ml of water) was added and the reaction mass was heated to 80-85°C. The contents were stirred for 1 hour and after completion of reaction, the reaction mass was cooled to 25-30°C. The pH of the reaction mass was adjusted to 6.5-7.0 using 1:1 aqueous acetic acid solution. The contents were stirred at room temperature for 1 hour. The precipitated solid was filtered, washed with water (2 x 100 ml). The solid was slurried in methanol (300 ml) for 1 hour at 25-30°C, filtered, washed with methanol (2 x 50 ml) and dried under vacuum at 70-75°C to yield the title compound [90 gms, 97% yield, 96% HPLC purity]. Example 3

Preparation of prulifloxacin

To a solution of 4-(chloromethyl)-5-methyl-1,3-dioxol-2-one (55 gms, 0.371 moles) in 50 ml of DMF at 25-30°C, sodium bromide (77 gms, 0.748 moles) was added and the reaction mass was slowly heated to 40-45°C. The contents were stirred at 40-45°C for 2 hours, acetone ( 500 ml) was added at 40-45°C and stirred for 3 hours. The reaction mass was filtered over hyflo, and the bed washed with acetone (100 ml). The solvent was completely distilled off under vacuum below 45°C to yield 4-(bromomethyl)-5- methyl-1 ,3-dioxol-2-one (formula V).

To a solution of 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]-thiazeto-[3,2-a]- quinoline-3-carboxylic acid of formula IV (100 gms, 0.286 moles) in 4.0 It of acetonitrile, DIPEA (70 ml , 0.402 moles)) was added at room temperature, stirred for 10 minutes. The reaction mass was cooled to 10-15°C and a solution of 4-(bromomethyl)-5-methyl- 1 ,3-dioxol-2-one (formula V) in 500 ml of acetonitrile was slowly added at 10-15°C over a period of 1 hour. The contents were stirred at 25-30°C for 20 hour, filtered over hyflo, and the bed washed with 200 ml of acetonitrile. The solvent was distilled off completely under vacuum below 50°C. Acetonitrile (100 ml) was added at 50°C and the contents were stirred for 30-60 minutes. The reaction mass was slowly chilled to 0-5°C and the precipitated solid was filtered, washed with acetonitrile (25 ml) and dried to yield 65 gms of prulifloxacin. Example 4

Preparation of Type I crystals of prulifloxacin

Prulifloxacin (65 gms) was added to 200 ml of DMF at 25-30°C and heated to 80-85°C for 1 hour. The mixture was then slowly cooled to 25-30°C, stirred for 2 hours, chilled to 0-5°C for 2 hours. The precipitated solid was filtered and dried under vacuum at 70- 75°C to yield Type I crystals of prulifloxacin (55 gms, 99.5 % HPLC purity).

Example 5

Preparation of prulifloxacin

(55 gms, 0.371 moles) of 4-(chloromethyl)-5-methyl-1 ,3-dioxol-2-one is taken in 5.0 ml of DMF at 25-30°C. (77 gms, 0.748 moles) of sodium bromide is added and slowly heated the reaction mass to 40-45°C. The contents are stirred at 40-45°C for 2 hours, 500 ml of acetone is added at 40-45°C and stirred for 3 hours. The reaction mass is clarified over hyflo, and the bed washed with 100 ml of acetone to yield a solution of 4- (bromomethyl)-5-methyl-1 ,3-dioxol-2-one (formula V).

To a solution of 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]-thiazeto-[3,2-a]- quinoline-3-carboxylic acid of formula IV (100 gms, 0.286 moles) in 3.5 Its of acetone was at room temperature DIPEA (70 ml, 0.402 moles) and stirred for 10 minutes. The reaction mass was cooled to 10-15°C and a solution of 4-(bromomethyl)-5-methyl-1 ,3- dioxol-2-one (formula V) in acetone was slowly added to the reaction mass at 10-15°C over a period of 1 hour. The contents were further stirred at 25-30°C for 20 hour, filtered over hyflo and the bed washed with 200 ml of acetone. The solvent was distilled off completely under vacuum below 50°C. Acetonitrile (100 ml) was added at 50°C and the contents were stirred for 30-60 minutes. The reaction mass was further chilled to 0- 5°C and stirred for 2 hours. The precipitated solid was filteredand dried to yield prulifloxacin.

………………….

http://www.google.com/patents/WO2008059512A1?cl=en

novel process for preparing 6-fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]thiazeto [3,2-a]quinoline-3-carboxylic acid of formula I:

 

Figure imgf000004_0001

which comprises: a) reacting the difluoro-quinoline compound of formula

 

Figure imgf000004_0002

wherein R represents hydrogen atom or alkyl containing 1 to 4 carbon atoms; with boric acid of formula III:

Figure imgf000005_0001

in presence of acetic anhydride and acetic acid to give borane compound of formula IV:

 

Figure imgf000005_0002

b) reacting the borane compound of formula IV with piperazine of formula V:

HN NH V

to give piperazine compound of formula Vl:

 

Figure imgf000005_0003

c) treating the compound of formula Vl with an alkaline metal hydroxide, carbonate or bicarbonate to obtain the compound of formula I.

Prulifloxacin and pharmaceutically acceptable acid addition salts of prulifloxacin can be prepared by using the compound of formula I by known methods for example as described in the European Patent No. 315828. Borane compound of the formula IV and Vl are novel and forms part of the invention. Preferably the reaction in step (a) is carried out at about 300C to reflux temperature more preferably at about 800C to reflux temperature and still more preferably at reflux temperature.

Example 1 Step-I:

Acetic anhydride (24 ml) and acetic acid (11 ml) are added to boric acid (3.5 gm) under stirring at 25 – 300C, the contents are heated to reflux and then stirred for 3 hours at reflux. The reaction mass is cooled to 1000C, ethyl 6,7- difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate (20 gm) is added at 1000C, the contents are heated to reflux and then refluxed for 2 hours. The reaction mass is cooled to 25 – 350C, toluene (200 ml) is added under stirring, the reaction mass is cooled to 50C and then stirred for 1 hour at 5 – 100C. Filtered the solid, washed with 20 ml of toluene and then dried to give 25.5 gm of 6,7-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate -O3,04/bis/acetato-0/-borone. Step-I I: Acetonitrile (125 ml), dimethylsulfoxide (125 ml) and piperazine (13.8 gm) are added to 6,7-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3- carboxylate-03,04/bis/acetato-0/-borone (25.5 gm, obtained in step-l) under stirring at 25 – 350C, the contents are heated to 850C and then stirred for 3 hours at 80 – 850C to form a clear solution. The solution is cooled to 100C and then stirred for 1 hour at 10 – 150C. Filtered the solid, washed with 25 ml of acetonitrile and then dried to give 26 gm of 6-fluoro-1-methyl-4-oxo-7-(1- piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate-03,04/bis/acetato-0/- borone. Step-Ill: Water (155 ml), potassium hydroxide (17 gm) are added to 6-fluoro-1- methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate- O3,O4/bis/ acetato-0/-borone (26 gm, obtained in step-ll) under stirring at 25 – 350C, the contents are heated to 650C and then stirred for 4 hours at 60 – 650C. The reaction mass is cooled to 250C, filtered the undesired solid on hi-flow bed and then pH of the resulting filtrate is adjusted to 7 – 7.5 with 50% HCI solution at 25 – 300C. The separated solid is stirred for 1 hour at 25 – 300C, filtered the solid, washed with 35 ml of water and then dried to give 17 gm of 6-fluoro-1- methyl-4-oxo-7-(1 -piperazinyl)-4H-[1 ,3]thiazeto [3,2-a]quinoline-3-carboxylic acid (HPLC Purity: 98.5%). Example 2 Step-I:

Acetic anhydride (12 ml) and acetic acid (5.5 ml) are added to boric acid (1.25 gm) under stirring at 25 – 300C, the contents are heated to reflux and then stirred for 3 hours at reflux. The reaction mass is cooled to 1000C, 6,7-difluoro-1- methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylic acid (10 gm) is added at 1000C, the contents are heated to reflux and then refluxed for 3 hours. The reaction mass is cooled to 500C, toluene (100 ml) is added under stirring at 500C, the resulting mass is cooled to 100C and then stirred for 1 hour at 10 – 150C. Filtered the solid, washed with 20 ml of toluene and then dried to give 10 gm of 6,7-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate -O3 , 04/bis/acetato-0/-borone . Step-I I:

Acetonitrile (50 ml), dimethylsulfoxide (50 ml) and piperazine (5.5 gm) are added to 6,7-difluoro-1-methyl-4-oxo-4H-[1 ,3]thiazeto[3,2-a]quinoline-3- carboxylate-03,04/bis/acetato-0/-borone (10 gm, obtained in step-l) under stirring at 25 – 350C, the contents are heated to 850C and then stirred for 3 hours at 80 – 850C to form a clear solution. The solution is cooled to 100C and then stirred for 1 hour at 10 – 150C. Filtered the solid, washed with 10 ml of acetonitrile and then dried to give 10.4 gm of 6-fluoro-1-methyl-4-oxo-7-(1- piperazinyl)-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate-03,04/bis/acetato-0/- borone. Step-Ill :

Water (62 ml), potassium hydroxide (7 gm) are added to 6-fluoro-1-methyl-4- oxo-7-(1-piperazinyl)-4H-[1 ,3]thiazeto[3,2-a]quinoline-3-carboxylate-03,04/bis/ acetato-OAborone (10.4 gm, obtained in step-ll) under stirring at 25 – 350C, the contents are heated to 650C and then stirred for 4 hours at 60 – 650C. The reaction mass is cooled to 250C, filtered the undesired solid on hi-flow bed and then pH of the resulting filtrate is adjusted to 7 – 7.5 with 50% HCI solution at 25 – 300C. The separated solid is stirred for 30 minutes at 25 – 300C, filtered the solid, washed with 20 ml of water and then dried to give 68 gm of 6-fluoro-1- methyl-4-oxo-7-(1-piperazinyl)-4H-[1 ,3]thiazeto [3,2-a]quinoline-3-carboxylic acid (HPLC Purity: 98.6%). Example 3

Acetonitrile (560 ml) and potassium bicarbonate (8 gm) are added to 6- fluoro-i-methyM-oxo-y-CI-piperazinyO^H-CI .SKhiazetofS^-alquinoline-S- carboxylic acid (14 gm, obtained as per the processes described in examples 1 and 2) under stirring at 25 – 300C, the contents are cooled to 150C and then the solution of 4-bromomethyl-5-methyl-1 ,3-dioxolen-2-one (10 gm) in acetonitrile (140 ml) is added at 15 – 200C for 30 to 45 minutes. The contents are stirred for 25 hours at 25 to 300C, filtered and the resulting filtrate is distilled under vacuum. To the residue added acetonitrile (70 ml), cooled the mass to 200C and then stirred for 1 hour to 1 hour 30 minutes at 20 – 250C. Filtered the solid, washed the solid with 15 ml of chilled acetonitrile and then dried to give 16 gm of prulifloxacin crude (HPLC Purity: 98.8%).

To the prulifloxacin crude (obtained above) added acetonitrile (200 ml) at 25 – 300C, the contents are heated to reflux and then refluxed for 30 minutes. To the reaction mass added activated carbon (5 gm) and refluxed for 15 minutes. The reaction mass is filtered on hi-flo bed, the resulting filtrate is cooled to 200C and then stirred for 3 – 4 hours at 20 – 250C. Filtered the solid, washed with 20 ml of acetonitrile and then dried to give 14 gm of prulifloxacin (HPLC Purity: 99.9%).

 

…………………

http://www.google.com/patents/WO2008111016A1?cl=en

In a first aspect, a process for the preparation of prulifloxacin is provided, the process comprising: a) reacting a compound of Formula II with a compound of Formula III to obtain prulifloxacin;

 

Figure imgf000004_0001
Figure imgf000004_0002

FORMULA III

FORMULA II

b) contacting the prulifloxacin obtained in step a) with an acid in a biphasic solvent system, wherein the biphasic solvent system comprises water and a water- immiscible organic solvent; c) separating the aqueous layer from the reaction mixture obtained in step b); d) treating the aqueous layer with a base; and e) isolating prulifloxacin.

The process described in steps b – e above may be carried out with prulifloxacin made from any process however.

The compounds of Formula II and Formula III may be prepared according to the methods provided in U.S. Patent No. 5,086,049.

Example 1: Process for the Preparation of Prulifloxacin:

 

Step A): A solution of 4-(bromomethyl)-5-methyl-l,3-dioxol-2-one (35.5 g, 0.184 mole) in N,N-dimethylformamide (200 ml) was added dropwise at 0 to 5° C to a stirred solution of 6-fluoro-l-methyl-4-oxo-7-piperazin-l-yl-4H-[l,3]thiazeto[3,2-α]quinoline-3- carboxylic acid (50 g, 0.143 mole and potassium bicarbonate (15.8 g, 0.1578 mole) in N,N-dimethylformamide (200 ml). The resulting mixture was stirred at 25° to 28°C for 3 to 4 hours. After the completion of the reaction, the reaction mixture was poured into water (1250 ml). The solid obtained was filtered, washed with water (100 ml), and subsequently dissolved in a mixture of chloroform: methanol (7:3; 1250 ml). The lower organic layer was separated and water (500 ml) was added to the organic layer. A dilute aqueous solution of hydrochloric acid was added to the biphasic reaction mixture to adjust pΗ to 0.8 to 1.0. The reaction mixture was stirred for 15 minutes, allowed to settle and the upper aqueous layer was separated. The process was repeated twice and the aqueous layers were combined. Activated charcoal (10%) was added to the combined aqueous layer and stirred for 30 minutes, filtered and cooled to 20° to 25° C. The pΗ of the reaction mixture was adjusted to 6.5 to 7.0 by adding an aqueous solution of sodium bicarbonate. The solid obtained was extracted with chloroform (375 ml), stirred for 15 minutes and the organic layer was separated. The aqueous layer was further extracted with a mixture of chloroform: methanol (7:3 ratio; 50 ml). The combined organic layer was distilled under vacuum at 35° to 40° C to recover the solvent up to 125 ml. The reaction mass so obtained was stirred for 3 to 4 hours at 28° to 30° C, filtered and washed with chilled chloroform (50 ml). The wet cake obtained was dried at 45° C for 12 hours to obtain the title compound. Step B): The prulifloxacin (30 g) obtained in Step A) was suspended in a mixture of chloroform: ethanol (10:1, v/v, 585 ml: 58.5 ml) and heated to reflux temperature. Activated carbon (3.9 gm) was added to the partially cleared solution and refluxed for 30 minutes, followed by filtration through Celite bed. The bed was further washed with chloroform: ethanol (10:1, v/v, 585 ml: 58.5 ml). The filtrate so obtained was distilled at atmospheric pressure till to partially remove the solvent. The concentrate so obtained was stirred at about 25° C for 1 hour, and filtered. The solid obtained was washed with chloroform: ethanol (39 ml X 2), dried under vacuum at 45° C for 12 hours to obtain the title compound. Yield: 22 g

HPLC Purity: 99%

………………………….

SEE

Studies on pyridonecarboxylic acids. 1. Synthesis and antibacterial evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto[3, 2-a]quinoline-3-carboxylic acids
J Med Chem 1992, 35(25): 4727

http://pubs.acs.org/doi/pdf/10.1021/jm00103a011

 

 

The reaction of 3,4-difluoroaniline (I) with carbon disulfide and triethylamine gives triethylammonium N-(3,4-difluorophenyl)dithiocarbamate (II), which by reaction with ethyl chloroformate and triethylamine in chloroform is converted into 3,4-difluorophenyl isothiocyanate (III). The reaction of (III) with diethyl malonate and KOH in dioxane affords the potassium salt (IV), which is treated with chloromethyl methyl ether in DMF to give the corresponding methoxymethylsulfanyl compound (V). The cyclization of (V) at 240 C in diphenyl ether affords 6,7-difluoro-4-hydroxy-2-(methoxymethylsulfanyl)quinoline-3-carboxylic acid ethyl ester (VI), which by treatment with HCl in ethanol gives the corresponding mercapto compound (VII). The cyclization of (VII) with 1,1-dibromoethane by means of K2CO3 and KI in hot DMF yields 5,6-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid ethyl ester (VIII), which is condensed with piperazine (IX) in DMF to afford the corresponding piperazino-derivative (X). The hydrolysis of (X) with KOH in hot tert-butanol gives the corresponding free acid (XI) , which is finally condensed with 4-(bromomethyl)-5-methyl-1,3-dioxol-2-one (XII) by means of KHCO3 in DMF.

………………….

Treatment of 3,4-difluoroaniline (I) with CS2 and Et3N gives triethylammonium dithiocarbamate (II), which reacts with ethyl chloroformate in chloroform to yield (III). Isothiocyanate (III) is converted into the potassium salt (IV) by reaction with diethyl malonate and KOH in dioxane and then transformed into methoxymethyl thioether (VI) by means of reagent (V) and Et3N in toluene. Cyclization of (VI) by heating in diphenyl ether affords quinoline (VII), which then reacts with benzoyl chloride (VIII) in pyridine to furnish (IX). Benzoyloxy derivative (IX) is converted into (X) by means of HCl in EtOH, and its reaction with 1-bromo-2-fluoroethane (XI) and NaHCO3 yields compound (XII). Chlorination of (XII) with SO2Cl2 in hexane provides (XIII), which by simultaneous hydrolysis and intramolecular cyclization by means of Et3N /H2O in THF provides the mixture of isomers (XIV). (+)-(XV) is obtained by HPLC chromatography of (XIV) on a chiral stationary phase. Treatment of (+)-(XV) with 1-methylpiperazine (XVI) in DMF provides ethyl ester (+)-(XVII), which is finally hydrolyzed by means of H2SO4 in H2O.

INTERMEDIATES

154330-67-3

Ethyl 6,7-difluoro-2-ethylmercapto-4-hydroxyquinoline-3-carboxylate

154330-68-4

Ethyl 4-acetoxy-6,7-difluoro-2-(ethylthio)quinoline-3-carboxylate

 

113046-72-3

Ethyl 6,7-difluoro-1-methyl-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate

 

113028-17-4

Ethyl 6-fluoro-1-methyl-4-oxo-7-(1-piprazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate

 

112984-60-8

6-Fluoro-1-methyl-4-oxo-7-(1-piperazinyl)-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid

 

REFERENCES

  1.  Nelson, Jennifer M.; Chiller, Tom M.; Powers, John H.; Angulo, Frederick J. (2007). “Food Safety: Fluoroquinolone‐Resistant Campylobacter Species and the Withdrawal of Fluoroquinolones from Use in Poultry: A Public Health Success Story”. Clinical Infectious Diseases 44 (7): 977–80. doi:10.1086/512369PMID 17342653.
  2.  Kawahara S (1998). “[Chemotherapeutic agents under study]“. Nippon Rinsho (in Japanese) 56 (12): 3096–9. PMID 9883617.
  3.  Fritsche, T. R.; Biedenbach, D. J.; Jones, R. N. (2008). “Antimicrobial Activity of Prulifloxacin Tested against a Worldwide Collection of Gastroenteritis-Producing Pathogens, Including Those Causing Traveler’s Diarrhea”Antimicrobial Agents and Chemotherapy 53 (3): 1221–4. doi:10.1128/AAC.01260-08PMC 2650572.PMID 19114678.
  4.  Giannarini, Gianluca; Tascini, Carlo; Selli, Cesare (2009). “Prulifloxacin: clinical studies of a broad-spectrum quinolone agent”. Future Microbiology 4 (1): 13–24.doi:10.2217/17460913.4.1.13PMID 19207096.
  5.  JP patent 1294680, Kise Masahiro; Kitano Masahiko; Ozaki Masakuni; Kazuno Kenji; Matsuda Masato; Shirahase Ichiro; Segawa Jun, “Quinolinecarboxylic Acid Derivative”, issued November 28, 1989
  6.  Prulifloxacin. Drugfuture.com. Retrieved on 2010-11-03.
  7. Anonymous (2002). “Prulifloxacin ['Quisnon'; Nippon Shinyaku] has been approved in Japan”Inpharma 1 (1362): 22.
  8.  Research and Development Department of Angelini. Angelinipharma.com. Retrieved on 2010-11-03.
  9.  Nippon Shinyaku, Annual Report 2007
  10.  ”Prulifloxacin. NAD-441A, NM 441, Quisnon”. Drugs in R&D 3 (6): 426–30. 2002.PMID 12516950.
  11.  Annual Report 2008, p. 34

Segawa,J,Mashiko kitano, Kenji Kazuno et al, Studies on Pyridonecarboxylic acids,1.Sythesis and antibacterial Evaluation of 7-substituted-6-halo-4-oxo-4H-[1,3]thiazeto [3,2-]quionoline- 3-caroboxylic acids[J].J Med  Chem. 1992,35(25):4727-4738.

Masato Matsuoka, Jun Segawa, Yoshihiko.et al, Studies on Pyridone Carb oxylic acids. V.A Practial synthesis of Ethyl 6,7–Difuoro-1-methyl-4-oxo-[1,3] Thiazeto [3,2-a]quinoline-3- Caroboxylate a   key  intermediate for the new tricyclic quinolone, prulifloxacin (NM441) and Versatile new  syntheses of the 2-thioquinoline Skeleton[J].J Heterocyclic Chem.1997,34,1773-1779.

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7(4-(5 METHYL-2-OXO-1,3-DIOXALEN-4-YL)METHYL 1-PIPERZINYL)-4-OXO-4H-(1,3)THIAZETO(3,2-A)QUINOLINE-3-CARBOXYLIC ACIDS
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WO2008059512A1 Nov 17, 2006 May 22, 2008 Hetero Drugs Ltd Process for preparation of prulifloxacin using novel intermediates
WO2008111016A1 Mar 14, 2008 Sep 18, 2008 Ranbaxy Lab Ltd Process for the preparation of pure prulifloxacin
WO2008111018A2 Mar 14, 2008 Sep 18, 2008 Ranbaxy Lab Ltd Process for the preparation of crystals of prulifloxacin
WO2010084508A2 Dec 10, 2009 Jul 29, 2010 Elder Pharmaceuticals Ltd. Process for the preparation of type i, type ii and type iii crystalline prulifloxacin
EP0315828A1 * Oct 26, 1988 May 17, 1989 Nippon Shinyaku Company, Limited Quinolinecarboxylic acid derivatives
EP1626051A1 Apr 28, 2004 Feb 15, 2006 Nippon Shinyaku Co., Ltd. Crystals of quinolinecarboxylic acid derivative solvate
US5086049 Apr 8, 1991 Feb 4, 1992 Nipponshinyaku Co., Ltd. 7[4-(5 methyl-2-oxo-1,3-dioxalen-4-yl)methyl 1-piperzinyl]-4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acids
US20070149540 Apr 28, 2004 Jun 28, 2007 Nippon Shinyaky Co., Ltd. Crystals of quinolinecarboxylic acid derivative solvate

EXTRA INFO

http://www.google.com/patents/EP2524922A1?cl=en

  •  formula 1 is S-(-)-6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl]-4-oxo-4H-[1,3]thiazet o[3,2-α]quinoline-3-carboxylic acid (levo-prulifloxacin for short); its stereo configuration is S configuration; it has optical property of levorotatory polarized light:
  • Figure imgb0001
    S-(-) ulifloxacin (as shown in formula 2 below) as raw material and the compound as shown in the following formula 3 are reacted in organic solvent in the presence of alkaline material. The reaction formula is shown below:

    Figure imgb0002
    • S-(-)-ulifloxacin and R-(+)-ulifloxacin are prepared according to the method disclosed in CN101550142A .
    • Japanese scholars Masato Matsuoka et al. have proved the absolute configuration of optically pure prulifloxacin. The study (see the publication Chem. Pharm. Bull. 43(7) 1238-1240 (1995)) verifies that (-)-ulifloxacin is S configuration while (+)-ulifloxacin is the enantiomer of R configuration by applying chemical methods together with single-crystal X-ray diffraction.

     

    • Accordingly, R-prulifloxacin can be prepared from R-(+)-ulifloxacin and the compound of formula 3 by the method described hereinbefore.
    • [0022]
      The reaction formula is depicted below:

      Figure imgb0003
    • S-prulifloxacin prepared in accordance with the present invention is determined to be laevorotatory by optical rotation measurement, so it is S-(-)-prulifloxacin. R-prulifloxacin prepared in accordance with the present invention is determined to be dextrorotatory by optical rotation measurement, so it is R-(+)-prulifloxacin.
    • The present invention studied the absorption features of S-(-)-prulifloxacin and R-(+)-prulifloxacin on circular polarized light by circular dichroism spectroscopy. The two spectrograms are mirror images of each other, which proves that S-(-)-prulifloxacin and R-(+)-prulifloxacin are enantiomer of each other.
    • Comparing the circular dichroism spectrogram as depicted in figure 4 with the circular dichroism spectrogram of analogue of the similar structure with known absolute configuration as disclosed in the publication Chem. Pharm. Bull. 47(12) 1765-1773 (1999), it is found that (-)-prulifloxacin has similar Cotton effect to the two analogues reported in the publication, ethyl S-(-)-6,7-difluoro-1-methyl-4-oxo-4H-[1,3] thiazeto[3,2-α]quinoline-3-carboxylate and ethyl S-(-)-6, 7-difluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-α]quinoline-3-carboxylate; so does (+)-prulifloxacin. The results also verify on the other hand that the absolute configuration of levo-prulifloxacin of the present invention is S type while the absolute configuration of dextro-prulifloxacin is R type.
    • The compound of the present invention and physiologically acceptable acid can be prepared to salts: dissolving or suspending S-(-)-prulifloxacin in solvent such as chloroform, DMF and the like; adding into acid or acid solution (for example, hydrochloric acid or hydrogen chloride-methanol solution and the like) while stirring; precipitating and filtering to obtain solid salt from the solvent solution, or alternatively removing solvent from the salt solution directly by concentration, spray drying and the like to obtain the salt of S-(-)-prulifloxacin. The obtained solid may be further recrystallized.

    Example 1 Preparation of (S)-(-)-uliflourxacin

    • 105 g of racemic uliflourxacin was dissolved in 1,500 mL of dimethyl sulfoxide. 27 g of D-tartaric acid was dissolved in 405 mL of dimethyl sulfoxide dropwise while stirring. After stirring at room temperature for 20 hours, the precipitate was filtrated. The collected solid was dried under vacuum to obtain 86 g solid, which was recrystallized in dimethyl sulfoxide to obtain 37 g of levoulifloxacin-D-tartrate, with C49.08%, H5.06%, N9.50%, S7.44% shown by elemental analysis (molecular formula: C16H16FN3O3S·1/2C4H6O6·H2O, calculated values: C48.86%, H4.78, N9.50%, S7.25%). Said salt was added into water to obtain a suspension, and the pH value was adjusted to 7-8 with 2% NaOH aqueous solution while stirring. After precipitation, filtration, and drying, 24.5 g of (S)-uliflourxacin was obtained, having a chemical name (S)-(-)-6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H,4H-[1,3]thiazeto [3,2-α]quinoline-3-carboxylic acid.
    • Specific rotation [α]20 D= -133° (c=0.5, 0.1 mol/L methanesulfonic acid); 1H-NMR (DMSO-d6δ2.11 (3H, d, j=6.2 Hz), 2.87 (4H, m), 3.19 (4H, m), 6.40 (1H, q, j=6.2 Hz), 6.89 (1H, d, j=7.4Hz), 7.79 (1H, d, j=13.9Hz), optical purity e.e. 96%.

    Example 2 Preparation of (R)-(+)-uliflourxacin

    • 105 g of racemic uliflourxacin was dissolved in 1,500 mL of DMSO. 27 g of L-tartaric acid was dissolved in 405 mL dimethyl sulfoxide dropwise while stirring to allow that the solution became turbid and the precipitation occurred. The solution was stirred at room temperature for 20 hours and then filtered. The collected solid was dried under vacuum to obtain 82 g solid which was recrystallized in dimethyl sulfoxide to obtain 34 g of dextrouliflourxacin-L-tartarte. Said salt was added into water to obtain a suspension, and the pH value was adjusted to 7-8 with 2% NaOH aqueous solution while stirring. After filtration and drying, 22 g of (R)-uliflourxacin was obtained, having a chemical name (R)-(+)-6-fluoro-1-methyl-4-oxo-(1-piperazinyl)-1H,4H-[1,3]thiazeto[3,2-a]quinoline -3-carboxylic acid.
    • Specific rotation [α]20 D= +132.4° (c=0.5, 0.1 mol/L methanesulfonic acid), optical purity e.e. 96%.

    Example 3 Preparation of S-(-)-prulifloxacin

    • 3.49 g (0.01 mol) of S-(-)-uliflourxacin prepared in Example 1, 2.02 g (0.02 mol) of triethylamine and 20 ml of dimethylformamide (hereinafter referred to as DMF) were mixed and stirred. After the solution was cooled to -5∼5 °C, 0.012 mol of 4-bromomethyl-5-methyl-1,3-dioxolen-2-one (hereinafter referred to as DMDO-Br) in DMF (5 ml) solution was added thereinto, followed by stirring at -5∼5 °C for 3 hours. The reaction solution was poured into 100 ml of ice water, stirred for 30 minutes, and then filtered. The filter residue was washed with water. The solid was collected and dried under vacuum. After recrystallization from acetonitrile, 2.9 g of S-(-)-prulifloxacin was obtained, having a chemical name: S-(-)-6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl ]-4-oxo-4H-[1,3]thiazeto[3,2-α]quinoline-3-carboxylic acid, with a purity of 98% and a yield rate of 63%. Specific rotation [α]20 D= -108° (c=0.5, 0.1 mol/L methanesulfonic acid)

    Example 4 Preparation of R-(+)-prulifloxacin

    • R-(+)-prulifloxacin prepared in Example 2 was used as raw material to prepare 2.7 g of target product R-(+)-prulifloxacin in accordance with the method as described in Example 3, with a yield rate of 60.7% and a purity of 98%. Specific rotation [α]20 D= +108° (c=0.5, 0.1 mol/L methanesulfonic acid).

     

    • Comparing the circular dichroism spectrogram as depicted in Figure 4 with the circular dichroism spectrogram of analogue of the similar structure with known absolute configuration as disclosed in the publication Chem. Pharm. Bull. 47(12) 1765-1773 (1999), it was found that (-)-prulifloxacin has similar Cotton effect with the two analogues reported in the publication, ethyl S-(-)-6,7-difluoro-1-methyl-4-oxo-4H-[1,3] thiazeto[3,2-α]quinoline-3-carboxylate and ethyl S-(-)-6, 7-difluoro-1-fluoromethyl-4-oxo-4H-[1,3]thiazeto[3,2-α]quinoline-3-carboxylate; so does (+)-prulifloxacin. The results also verify on the other hand that the absolute configuration of levo-prulifloxacin of the present invention is S type while the absolute configuration of dextro-prulifloxacin is R type.
    • Conclusion: The absolute configuration of the sample prepared in Example 3 is S configuration, as shown in the formula below:

      Figure imgb0009

    Example 5 Preparation of S-(-)-prulifloxacin

    • 3.49 g (0.01 mol) of S-(-)-uliflourxacin, 1.2 g (0.012 mol) of anhydrous potassium bicarbonate and 20 ml of dimethylsulfoxide were mixed and stirred. 0.012 mol of DMDO-Br in DMSO (5 mL) solution was added dropwise at -20 °C. Stirring proceeded at -20 °C for 3 hours. The reaction solution was poured into 100 ml of ice water, and the pH value was adjusted to 7 with 20% acetic acid. The solution was filtered after stirring for 30 minutes. The filter residue was washed with water. The solid was collected and dried under vacuum. After recrystallization from acetonitrile, 2.5 g of the target product levo-prulifloxacin was obtained with a purity of 98% and a yield rate of 54%.
      Specific rotation [α]20 D= -108° (c=0.5, 0.1 mol/L methanesulfonic acid)

    Example 6 Preparation of S-(-)-prulifloxacin

    • 3.49 g (0.01 mol) of S-(-)-uliflourxacin, 1.04 g (0.008 mol) of N,N-diisopropylethylamine and 20 mL of N,N-dimethylformamide (DMF) was mixed and stirred, 0.008 mol of DMDO-Br in DMF (5 mL) solution was added thereinto. The solution was heating to 60 °C and reacted for 15 minutes. The reaction solution was poured into 100 ml of ice water, and the pH value was adjusted to 7 with 20% acetic acid. The solution was filtered after stirring for 30 minutes. The filter residue was washed with water. The solid was collected and dried under vacuum. After recrystallization from acetonitrile, 2.0 g of the target product levo-prulifloxacin was obtained with a purity of 98% and a yield rate of 43%.
      Specific rotation [α]20 D= -108° (c=0.5, 0.1 mol/L methanesulfonic acid)

    Example 7 Preparation of S-(-)-prulifloxacin

    • 10 g (0.029 mol) of S-(-)-uliflourxacin, 30 ml of N,N-dimethylacetylamide and 14.7 g (0.145mol) of triethylamine was mixed and cooled to 5~10 °C. 8.5 g (0.03 mol) 4-(p-toluenesulfonic acid-1-methyl ester)-5-methyl-1,3-dioxolen-2-one in 25 ml of N,N-dimethylacetylamide solution was added dropwise while stirring. After addition, the solution was reacted at room temperature for 10 hours. The reaction solution was poured into 200 ml of ice water, and the pH value was adjusted to 7 with 20% acetic acid. The solution was filtered after stirring for 30 minutes. The filter residue was washed with water. The solid was collected and dried under vacuum. After recrystallization from acetonitrile, 7.46 g of the target product levo-prulifloxacin was obtained with a purity of 98% and a yield rate of 57%. Specific rotation [α]20 D= -108° (c=0.5, 0.1 mol/L methanesulfonic acid).

    Example 8 Preparation of S-(-)-prulifloxacin

    • 3.49 g (0.01 mol) of S-(-)-uliflourxacin, 0.79 g (0.05 mol) of potassium carbonate and 20 ml of dimethylformamide (DMF) was mixed and stirred. 0.012 mol of DMDO-Br in DMF (5ml) solution was added at -10 °C. At the same temperature, the solution was reacted for 2 hours. The reaction solution was poured into 100 ml of ice water, and the pH value was adjusted to 7 with 20% acetic acid. The solution was filtered after stirring for 30 minutes. The filter residue was washed with water. The solid was collected and dried under vacuum. After recrystallization from acetonitrile, 2.2 g of the target product levo-prulifloxacin was obtained with a purity of 98% and a yield rate of 48%. Specific rotation [α]20 D= -108° (c=0.5, 0.1 mol/L methanesulfonic acid).

    Example 9 Preparation of S-(-)-prulifloxacin

    • 3.49 g (0.01 mol) of S-(-)-uliflourxacin, 0.79 g (0.02 mol) of diisopropylamine and 20 ml of dimethylformamide (DMF) was mixed and stirred. 0.02 mol of DMDO-Br in DMF (5ml) solution was added at 0 °C. At the same temperature, the solution was reacted for 2 hours. The reaction solution was poured into 100 ml of ice water, and the pH value was adjusted to 7 with 20% acetic acid. The solution was filtered after stirring for 30 minutes. The filter residue was washed with water. The solid was collected and dried under vacuum. After recrystallization from acetonitrile, 2.5 g of the target product levo-prulifloxacin was obtained with a purity of 98% and a yield rate of 54%. Specific rotation [α]20D= -108° (c=0.5, 0.1 mol/L methanesulfonic acid).

    Example 10 Preparation of R-(+)-prulifloxacin

    • In accordance with the method as described in Example 5, the raw material R-(+)-prulifloxacin was prepared to 2.5 g of the target product R-(+)-prulifloxacin with a purity of 98% and a yield rate of 54%. Specific rotation [α]20 D= +108° (c=0.5, 0.1 mol/L methanesulfonic acid).

    Example 11 Preparation of levo-prulifloxacin hydrochloride

      S-(-)-6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl] -4-oxo-4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylic acid hydrochloride

    • 0.5 g of S-(-)-prulifloxacin was dissolved in 15 mL of chloroform and then 0.5 mL of 33% (v/v) hydrochloric acid- methanol solution was added while stirring. The solution was filtered and the filtration residue was washed with methanol. The collected solid was dried to obtain 450 mg said compound with a yield rate of 83%. The melting point of the product is higher than 220 °C (the sample became darker during the test).

    Example 12 Preparation of levo-prulifloxacin mesylate

      S-(-)-6-fluoro-1-methyl-7-[4-(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl-1-piperazinyl] -4- oxo-4H-[1,3]thiazeto[3,2-α]quinoline-3-carboxylic acid mesylate

    • 0.5 g of S-(-)-prulifloxacin was dissolved in 15 mL of chloroform and then 0.5 mL of 50% methanesulfonic acid- methanol solution was added while stirring. The solution was filtered and the filtration residue was washed with methanol. The collected yellow solid was dried with calcium chloride under vacuum for 24 hours and further dried with calcium chloride at 80 °C under vacuum for 5 hours to obtain 470 mg said compound with a yield rate of 78%. The melting point of the product is higher than 220 °C (the sample became darker during the test).

    Example 13 Preparation of levo-prulifloxacin hydrochloride

    • 0.5 g of S-(-)-prulifloxacin was dissolved in 15 mL of chloroform and then 0.5 mL of 33% (v/v) hydrochloric acid- methanol solution was added while stirring. The solution was dried by evaporation. Methanol was added to the residue and stirred for 10 minutes. The solution was filtered and the filtration residue was washed with methanol. The collected solid was dried to obtain 460 mg said compound with a yield rate of 85%.
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Apr 052014
 

File:Clinafloxacin.png

Clinafloxacin

7-(3-Aminopyrrolidin-1-yl)-8-chloro-1-cyclopropyl-6-fluoro-4-oxoquinoline-3-carboxylic acid

7-(3-Amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid

(±)-7-(3-Amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid

105956-99-8  cas no

Clinafloxacin (INN) is a fluoroquinolone antibiotic. Its use is associated with phototoxicity and hypoglycaemia.[1]

Clinafloxacin is a novel quinolone with wide activity against the plethora of microorganisms encountered in intraabdominal infections.

Clinafloxacin is a chlorofluoroquinolone with excellent bioavailability and activity against gram-positive, gram-negative, and anaerobic pathogens . Typical MICs for α-streptococci are 0.06–0.12 µg/mL . MIC90 values for methicillin-resistant Staphylococcus aureus (MRSA) average 1.0 µg/mL. The MIC90 for enterococci is typically 0.5 µg/mL . Both intravenous and oral formulations have been developed . Several studies have demonstrated the efficacy of clinafloxacin monotherapy for serious infections  Clinafloxacin was also active in animal models of endocarditis, including endocarditis due to ciprofloxacin-resistant S. aureus infection .

Clinafloxacin HCl, CI-960 HCl, 105956-99-8, Clinafloxacin hydrochloride (USAN), Clinafloxacin hydrochloride [USAN], AC1L1SJB,
Molecular Formula: C17H18Cl2FN3O3   Molecular Weight: 402.247523
……………………………………..
EP 0195316
http://www.google.com/patents/EP0195316A1?cl=en
preparation process for the compound of the invention.

Figure imgb0002
    Example 28 7-(3-Amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid

  • A mixture of 8-chloro-1-cyclopropyl-6,7-difluoro-1,4-di- hydro-4-oxo-3-quinolinecarboxylic acid (0.6 g), anhydrous acetonitrile (6 ml), 3-aminopyrrolidine (0.35 g) and DBU (0.31 g) was refluxed for an hour. Then, 3-aminopyrrolidine (0.2 g) was more added and further refluxed for 2 hours. After cooling, the resulting precipitate was collected by filtration, dissolved in water (9 ml) containing sodium hydroxide (0.12 g) and neutralized with acetic acid. The resulting precipitate was collected by filtration and washed with water and acetonitrile successively to give the title compound (0.52 g) as colorless powder, mp 237-238 °C (decompd.).
  • Analysis (%) for C17H17ClFN3O3·H2O, Calcd. (Found): C, 53.20 (52.97); H, 4.99 (4.62); N, 10.95 (10.83).

Example 29 7-(3-Amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid hydrochloride

  • To a suspension of 7-(3-amino-1-pyrrolidinyl)-8-chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid (100 mg) in ethanol (2 ml) was added 0.2 ml of ethanol solution of hydrogen chloride (7.0 mmol HC1/ml) and then the mixture was concentrated. The resulting residue was recrystallized from methanol to give the title compound (79 mg) as light yellow prisms, mp 263-265 °C (decompd.).
  • Analysis (%) for C17H17ClFN3O3.HCl, Calcd. (Found): C, 50.76 (50.50); H, 4.51 (4.44); N, 10.45 (10.38).

…………………..

J. Med. Chem., 23, 1358 (1980)

Figure imgb0024
  • structural formula D

    Figure imgb0028

    may be readily prepared from the known starting material methyl 5-oxo-l-(phenylmethyl)-3-pyrrolidinecarboxylate, A, [J. Org. Chem., 26, 1519 (1961)] by the following reaction sequence.

    Figure imgb0029
  • The compound wherein R3 is hydrogen, namely 3-pyrrolidinemethanamine, has been reported in J. Org. Chem., 26, 4955 (1961).
Journal of Medicinal Chemistry, 1988 ,  vol. 31, p. 983 – 991

 

References

  1. Rubinstein, E. (2001). “History of quinolones and their side effects.”. Chemotherapy. 47 Suppl 3: 3–8; discussion 44–8.doi:10.1159/000057838PMID 11549783.

 

EP0106489A2 * Sep 6, 1983 Apr 25, 1984 Warner-Lambert Company Antibacterial agents
EP0153163A2 * Feb 15, 1985 Aug 28, 1985 Warner-Lambert Company 7-Substituted-1-cyclopropyl-6,8-difluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acids; 7-substituted-1-cyclopropyl-1,4-dihydro-6-fluoro-4-oxo-1,8-naphthyridine-3-carboxylic acids; their derivatives; and a process for preparing the compounds
BE899399A1 * Title not available
GB2057440A * Title not available

 

 

Examples of
reported trade
names for products
containing the 6-
6-Fluoroquinolin- fluoroquinolin-
4(1H)-one 4(1H)-one Structure
amifloxacin
Figure US20120046259A1-20120223-C00019
balofloxacin
Figure US20120046259A1-20120223-C00020
ciprofloxacin Cipro®, Ciprobay, & Ciproxin
Figure US20120046259A1-20120223-C00021
clinafloxacin
Figure US20120046259A1-20120223-C00022
danofloxacin Advocin & Advocid
Figure US20120046259A1-20120223-C00023
difloxacin Dicural® & Vetequinon
Figure US20120046259A1-20120223-C00024
enrofloxacin Baytril®
Figure US20120046259A1-20120223-C00025
fleroxacin Megalone
Figure US20120046259A1-20120223-C00026
flumequine Flubactin
Figure US20120046259A1-20120223-C00027
garenoxacin
Figure US20120046259A1-20120223-C00028
gatifloxacin Tequin® & Zymar®
Figure US20120046259A1-20120223-C00029
grepafloxacin Raxar
Figure US20120046259A1-20120223-C00030
ibafloxacin
Figure US20120046259A1-20120223-C00031
levofloxacin Levaquin®, Gatigol, Tavanic, Lebact, Levox, & Cravit
Figure US20120046259A1-20120223-C00032
lomefloxacin Maxaquin®
Figure US20120046259A1-20120223-C00033
marbofloxacin Marbocyl® & Zenequin
Figure US20120046259A1-20120223-C00034
moxifloxacin Avelox® & Vigamox®
Figure US20120046259A1-20120223-C00035
nadifloxacin Acuatin, Nadoxia, & Nadixa
Figure US20120046259A1-20120223-C00036
norfloxacin Noroxin®, Lexinor, Quinabic, & Janacin
Figure US20120046259A1-20120223-C00037
ofloxacin Floxin®, Oxaldin, & Tarivid
Figure US20120046259A1-20120223-C00038
orbifloxacin Orbax® & Victas
Figure US20120046259A1-20120223-C00039
pazufloxacin
Figure US20120046259A1-20120223-C00040
pefloxacin
Figure US20120046259A1-20120223-C00041
pradofloxacin
Figure US20120046259A1-20120223-C00042
prulifloxacin
Figure US20120046259A1-20120223-C00043
rufloxacin Uroflox
Figure US20120046259A1-20120223-C00044
sarafloxacin Floxasol, Saraflox, Sarafin
Figure US20120046259A1-20120223-C00045
sitafloxacin
Figure US20120046259A1-20120223-C00046
sparfloxacin Zagam
Figure US20120046259A1-20120223-C00047
temalioxacin Omniflox
Figure US20120046259A1-20120223-C00048

 

 

enoxacin Penetrex & Enroxil
Figure US20120046259A1-20120223-C00061
gemifloxacin Factive
Figure US20120046259A1-20120223-C00062
tosufloxacin
Figure US20120046259A1-20120223-C00063
trovafloxacin Trovan
Figure US20120046259A1-20120223-C00064
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