AUTHOR OF THIS BLOG

DR ANTHONY MELVIN CRASTO, WORLDDRUGTRACKER
Feb 082016
 

 

 

Dapagliflozin structure.svg

(S) – propylene glycol and water, 1: 1 crystalline complex

PATENT

WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME

HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)

KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)

The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.

long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.
Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.
In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.
Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.
[Formula 1]
While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.
In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.
[Formula 2]
Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).
However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.
In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.
However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.

Best Mode for Carrying out the Invention

Hereinafter, the present invention will be described in detail.
Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).
[Formula 3]

The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.
It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.
The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.
In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.
It describes a method for producing crystalline complex according to the present invention;
Step 1: Mannitol solution prepared
Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.
The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.
The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.
The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.
The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .
Step 2: Preparation of an alcohol solution
Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.
In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.
The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C 1 ~ C 4 alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .
The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.
Step 3: heat-up phase
Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.
The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.
The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.
Step 4: obtained crystalline complexes
Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.
The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.
Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.
The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.

Mode for the Invention

Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.
Example 1. Preparation of the crystalline complex
The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).
Experimental Example 1. Structural analysis
Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using 1 yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.
1 H NMR (400㎒, DMSO-d 6 ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)
The first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).
[Formula 4]

Experimental Example 2. OK crystalline crystalline complexes
By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.
Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .
Experimental Example 3. HPLC analysis
To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.

TABLE 1

column Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
The mobile phase A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)
Test Solution Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
Column temperature 25 ℃
Wavelength detector UV, 220nm
Dose 3 ㎕
Flow rate 0.7 mL / min
Operating hours 40 min

Table 2

Gradient systems
Time (min) Mobile phase A (%) Mobile phase B (%)
0 75 25
0-25 35 65
25-26 30 70
26-29 30 70
29-35 75 25
35-40 75 25
As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.

Claims

To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]

According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.

According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.
1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]
[Claim 5]
According to claim 4, wherein the solvent is the production of water, the crystalline complex.
According to claim 4, wherein the alcohol is a C 1 ~ C 4, a method of producing a crystalline complex comprising at least one kind of alcohol.
According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.

According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.

FIGURES

Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.
2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.
3 is of the crystalline complex in accordance with an embodiment of the present invention 1 shows the H-NMR measurement results.
[Figure 1]

[Figure 2]

[Figure 3]

CEO, YOUNG KIL CHANG

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Jan 132016
 
Abstract Image

The revolution in synthetic biology has enabled innovative manufacture of biofuels and the development of biological processes for the manufacture of bulk and fine chemicals. This short review gives some examples of recent progress.

 

Facts, Growth, and Opportunities in Industrial Biotechnology

Industrial Biotechnology and Environmental, Biotechnology Industry Organization (BIO), 1201 Maryland Avenue, SW, Suite 900, Washington, DC 20024, United States
Org. Process Res. Dev., 2011, 15 (1), pp 175–179
DOI: 10.1021/op100312a
Publication Date (Web): December 7, 2010
Copyright © 2010 American Chemical Society
This article is part of the Biocatalysis special issue.

http://pubs.acs.org/doi/abs/10.1021/op100312a

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Jan 132016
 
Abstract Image

Process validation includes laboratory optimization, pilot-plant introduction, and process implementation on manufacturing scale, as well as monitoring batches after implementation and continuously improving the manufacturing processes. There are many opportunities to change and optimize operations. The background information in this contribution describes current guidance and terminology for validation, including the integration of validation over the development lifecycle of drug substances. Various examples illustrate challenges and success stories of implementation as part of the overall approach to process validation.

 

Current Practices of Process Validation for Drug Substances and Intermediates

Anderson’s Process Solutions, 7400 Griffin Lane, Jacksonville, Oregon 97530, United States, Creative Innovation Partners, 1971 Western Avenue, Albany, New York 12203, United States, and Rib-X Pharmaceuticals Inc., 300 George Street, New Haven, Connecticut 06511, United States
Org. Process Res. Dev., 2011, 15 (1), pp 162–172
DOI: 10.1021/op1002825
Publication Date (Web): December 21, 2010
Copyright © 2010 American Chemical Society
* To whom correspondence should be addressed: E-mail: nganderson@dishmail.net., †

Creative Innovation Partners., ‡Rib-X Pharmaceuticals Inc.

http://pubs.acs.org/doi/abs/10.1021/op1002825

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Jan 092016
 

 

Twelve Principles for Drug Optimization
1. Increasing Potency
In the analogue class of the histamine H2-receptor antagonists (cimetidine, nizatidine, ranitidine, roxatidine, and famotidine), an increasing potency of the drug analogues can be observed. Famotidine is the most potent member of this class.
2. Improving the Ratio of the Main Activity to Adverse Affects
The pioneer drug of the adrenergic β-blockers is propranolol, which blocked both β1– and β2-receptors. However, blocking β2-receptors in asthma is harmful. Several selective blockers were developed and used in cardiology, such as atenolol, metoprolol, etc.

3. Improving the Physicochemical Properties with the Help of Analogues
Benzylpenicillin (penicillin G) was a pioneer antibiotic molecule, which could be administered only by intramuscular injection because of its acid-sensitivity. Through analogues, stable molecules were obtained and they could be given orally (e.g., ampicillin).

4. Decreasing Resistance to Anti-Infective Drugs
Resistance to anti-infective drugs has become an increasing problem all over the world. The widespread use of penicillin G led to an alarming increase of penicillin-G resistant Staphylococcus aureus infections in 1960. A solution to the problem was the design of penicillinase-resistant penicillins. Several examples show that analogues can also overcome the resistance to antifungal and antiviral drugs.

5 .Decreasing Resistance to Anticancer Agents
Imatinib is the pioneer drug for the treatment of chronic myelogenous leukemia. However, a significant number of patients develop resistance to imatinib. New analogues, such as dasatinib and nilotinib, have been introduced recently and it is hoped that these analogues will be effective in imatinib-resistant cases.

6. Improving Oral Bioavailability
A good oral bioavailability is necessary in most cases because the oral application of a drug is preferred to an injection therapy. Enalaprilat is an angiotensin-converting enzyme inhibitor which is used in intravenous administration for the treatment of hypertensive emergencies. Its ester prodrug has an excellent oral bioavailability, but it requires hydrolysis by esterases. Analogue-

based drug research afforded the lysylproline analogue, lisinopril, which has an acceptable bioavailability and it does not require metabolic activation.

7. Long-Acting Drugs for Chronic Diseases
Quaternary antimuscarinics are important drugs for the treatment of chronic obstructive pulmonary disease. Ipratropium bromide is a very active bronchodilator that is used several times daily. Its analogue is tiotropium with a longer duration of action which enables a once-daily dosing.

8. Ultrashort-Acting Drugs in Emergency Cases
Esmolol is an adrenergic β1-selective blocker with a very short duration of action. It is used when β-blockade of very short duration is desired in emergency situations.

9. Decreasing Interindividual Pharmacokinetic Differences
Omeprazole is a pioneer proton pump inhibitor that shows interindividual variability. Analogue-based drug discovery afforded pantoprazole with a linear, highly predictable pharmacokinetic property.

10. Decreasing Systemic Activities
For intranasal and inhalation applications of corticosteroids in the treatment of asthma and rhinitis, it is important to decrease the systemic availability of these drugs to avoid their adverse effects. Analogue research afforded budenoside and fluticasone with a low oral bioavailability.

11. Decreasing Drug Interactions with the Help of Analogues
Cimetidine inhibits CYPs, an important class of drug-metabolizing enzymes. This interaction inhibits the metabolism of certain drugs, such as propranolol, warfarin, diazepam, thus producing effects equivalent to an overdose of these medicines. These effects are avoided by analogues such as ranitidine and famotidine.

12. Synergistic Interactions between Analogues
Analogue-based drug research starting from ritonavir, which is an HIV-1 protease inhibitor, afforded the more potent lopinavir. However, it has a low plasma half- life. A combination of ritonavir and lopinavir is very successful, because ritonavir inhibits the P-450-mediated metabiolism of lopinavir.

 

Standalone Drugs Can Be Starting
Points for Drug Optimizations

We analyzed the Top 100 most frequently used drugs and nine standalone drugs were identified, that is, pioneer drugs for which there are no effective analogues. These are the following drugs: acetaminophen, acetylsalicylic acid, aripiprazole, bupropion, ezetimibe, lamotrigine, metformin, topiramate, and valproate semisodium.

Acetaminophen is one of the oldest drugs, which even nowadays has a broad application as an analgesic and antipyretic agent. However, acute overdose can cause severe hepatic damage.

Acetylsalicylic acid (aspirin) is also one of the oldest drugs and, contrary to acetaminophen, its mechanism of action is partly known: it irreversibly inhibits the cyclooxygenase-1 enzyme. A more potent derivative with a better adverse effect profile would be advantageous.

Aripiprazole is a relatively new antipsychotic drug which acts as a dopamine partial agonist for the treatment of schizophrenia. A more effective drug is needed for the treatment of refractory patients, to improve treatment of negative symptoms and cognitive dysfunction.

Bupropion is a unique antidepressant drug. It is the first non-nicotine medication for the treatment of smoking cessation.
Ezetimibe is a relatively new cholesterol absorption inhibitor. Its mechanism of action was discovered only recently (2005). Analogue-based drug research is underway.

Lamotrigine, topiramate, and valproate are widely used anticonvulsant drugs, whose mechanism of action is not known. Several efforts have been made to find better analogues, so far without positive results.

Metformin is already an old standalone drug for the treatment of type 2 diabetes. It is used alone or in combination with new antidiabetic agents. Its mechanism of action is not known which makes it difficult to conduct an analogue-based drug research.

 

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Jan 052016
 

 

Abstract Image

Recently, application of the flow technologies for the preparation of fine chemicals, such as natural products or Active Pharmaceutical Ingredients (APIs), has become very popular, especially in academia. Although pharma industry still relies on multipurpose batch or semibatch reactors, it is evident that interest is arising toward continuous flow manufacturing of organic molecules, including highly functionalized and chiral compounds. Continuous flow synthetic methodologies can also be easily combined to other enabling technologies, such as microwave irradiation, supported reagents or catalysts, photochemistry, inductive heating, electrochemistry, new solvent systems, 3D printing, or microreactor technology. This combination could allow the development of fully automated process with an increased efficiency and, in many cases, improved sustainability. It has been also demonstrated that a safer manufacturing of organic intermediates and APIs could be obtained under continuous flow conditions, where some synthetic steps that were not permitted for safety reasons can be performed with minimum risk. In this review we focused our attention only on very recent advances in the continuous flow multistep synthesis of organic molecules which found application as APIs, especially highlighting the contributions described in the literature from 2013 to 2015, including very recent examples not reported in any published review. Without claiming to be complete, we will give a general overview of different approaches, technologies, and synthetic strategies used so far, thus hoping to contribute to minimize the gap between academic research and pharmaceutical manufacturing. A general outlook about a quite young and relatively unexplored field of research, like stereoselective organocatalysis under flow conditions, will be also presented, and most significant examples will be described; our purpose is to illustrate all of the potentialities of continuous flow organocatalysis and offer a starting point to develop new methodologies for the synthesis of chiral drugs. Finally, some considerations on the perspectives and the possible, expected developments in the field are briefly discussed.

Two examples out of several in the publication discussed below……………

 

1  Diphenhydramine Hydrochloride

Figure
Scheme 1. Continuous Flow Synthesis of Diphenhydramine Hydrochloride
Diphenhydramine hydrochloride is the active pharmaceutical ingredient in several widely used medications (e.g., Benadryl, Zzzquil, Tylenol PM, Unisom), and its worldwide demand is higher than 100 tons/year.
In 2013, Jamison and co-workers developed a continuous flow process for the synthesis of 3minimizing waste and reducing purification steps and production time with respect to existing batch synthetic routes (Scheme 1). In the optimized process, chlorodiphenylmethane 1 and dimethylethanolamine 2 were mixed neat and pumped into a 720 μL PFA tube reactor (i.d. = 0.5 mm) at 175 °C with a residence time of 16 min. Running the reaction above the boiling point of 2and without any solvent resulted in high reaction rate. Product 3, obtained in the form of molten salt (i.e., above the melting point of the salt), could be easily transported in the flow system, a procedure not feasible on the same scale under batch conditions.
The reactor outcome was then combined with preheated NaOH 3 M to neutralize ammonium salts. After quenching, neutralized tertiary amine was extracted with hexanes into an inline membrane separator. The organic layer was then treated with HCl (5 M solution in iPrOH) in order to precipitate diphenhydramine hydrochloride 3 with an overall yield of 90% and an output of 2.4 g/h.

2 Olanzapine

Figure
Scheme 2. Continuous Flow Synthesis of Olanzapine
Atypical antipsychotic drugs differ from classical antipsychotics because of less side effects caused (e.g., involuntary tremors, body rigidity, and extrapyramidal effects). Among atypical ones, olanzapine 10, marketed with the name of Zyprexa, is used for the treatment of schizophrenia and bipolar disorders.
In 2013 Kirschning and co-workers developed the multistep continuous flow synthesis of olanzapine 10 using inductive heating (IH) as enabling technology to dramatically reduce reaction times and to increase process efficiency.(16) Inductive heating is a nonconventional heating technology based on the induction of an electromagnetic field (at medium or high frequency depending on nanoparticle sizes) to magnetic nanoparticles which result in a very rapid increase of temperature.As depicted in Scheme 2 the first synthetic step consisted of coupling aryl iodide 4 and aminothiazole 5 using Pd2dba3 as catalyst and Xantphos as ligand. Buchwald–Hartwig coupling took place inside a PEEK reactor filled with steel beads (0.8 mm) and heated inductively at 50 °C (15 kHz). AcOEt was chosen as solvent since it was compatible with following reaction steps. After quenching with distilled H2O and upon in-line extraction in a glass column, crude mixture was passed through a silica cartridge in order to remove Pd catalyst. Nitroaromatic compound 6 was then subjected to reduction with Et3SiH into a fixed bed reactor containing Pd/C at 40 °C. Aniline 7 was obtained in nearly quantitative yield, and the catalyst could be used for more than 250 h without loss of activity. The reactor outcome was then mixed with HCl (0.6 M methanol solution) and heated under high frequency (800 kHz) at 140 °C. Acid catalyzed cyclization afforded product 8 with an overall yield of 88%. Remarkably, the three step sequence did not require any solvent switch, and the total reactor volume is about 8 mL only.
The final substitution of compound 8 with piperazine 9 was carried out using a 3 mL of PEEK reactor containing MAGSILICA as inductive material and silica-supported Ti(OiPr)4 as Lewis acid. Heating inductively the reactor at 85 °C with a medium frequency (25 kHz) gave Olanzapine 10 in 83% yield.

SEE MORE IN THE PUBLICATION…………..

 

Flow Chemistry: Recent Developments in the Synthesis of Pharmaceutical Products

Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00325
Publication Date (Web): November 26, 2015
Copyright © 2015 American Chemical Society

ACS Editors’ Choice – This is an open access article published under an ACS AuthorChoice License, which permits copying and redistribution of the article or any adaptations for non-commercial purposes.

Riccardo Porta

Riccardo Porta

 PhD Student
Dipartimento di Chimica, Università degli Studi di Milano Via Golgi 19, I-20133 Milano, Italy

Map of milan italy

 

 

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Jan 022016
 

Graphical abstract: Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters.

Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.

image file: c5gc00402k-s2.tif.

Scheme 2 Synthetic routes to 2-fluoromalonate esters.

There are three realistic, low-cost synthetic strategies available for the large scale manufacture of diethyl 2-fluoromalonate ester (Scheme 2) which involve reaction of ethanol with hexafluoropropene (HFP), halogen exchange (Halex)and selective direct fluorination processes. Other syntheses of fluoromalonate esters using electrophilic fluorinating agents such as Selectfluor™ are possible, but are not sufficiently commercially attractive to be considered for manufacture on the large scale.
A growing number of patents utilising fluoromalonate as a substrate for the synthesis of a range of biologically active systems have been published  For example, Fluoxastrobin (Fandango®), a fungicide marketed by Bayer CropScience that has achieved global annual sales of over €140 m since its launch in 2005, and TAK-733, an anti-cancer drug candidate, employ 2-fluoromalonate esters as the key fluorinated starting material (Scheme 1).
image file: c5gc00402k-s1.tif
Scheme 1 2-Fluoromalonate esters used in the synthesis of Fluoxastrobin and TAK-733.

 Before a comparison of the green metrics between the three possible, economically viable large scale processes for the synthesis of fluoromalonate esters (Scheme 2) could be carried out, some primary goals for the optimisation of the process were targeted: complete conversion of the starting material is essential because it can be difficult to separate the starting material from the desired monofluorinated product by simple distillation; fluorine gas usage should be minimised because neutralisation of excess reagent could potentially generate significant amounts of waste; reduction in volumes of solvents used to reduce waste streams and overall intensification of the fluorination process and replacement and/or reduction of all environmentally harmful solvents used.
Conventional batch direct fluorination reactions of malonate esters were carried out in glassware vessels by introduction of fluorine gas, as a 10% or 20% mixture in nitrogen (v/v), at a prescribed rate via a gas mass flow controller into a solution of malonate ester and copper nitrate catalyst in acetonitrile using equipment described previously.
To better understand the relationship between fluorine gas introduction and rate of conversion, real time IR spectroscopic monitoring of the reaction was chosen as the most suitable technique. The use of the ReactIR technique was enabled by a sufficient difference in the carbonyl group stretching frequencies (1734 cm−1 for diethyl malonate and 1775 cm−1 for diethyl 2-fluoromalonate) and provided an in situ reaction profile (Fig. 1).
image file: c5gc00402k-f1.tif
Fig. 1 IR spectra of the fluorination reaction at 0% (light blue), 50% (dark blue) and 100% (red) conversions.
The real time reaction monitoring (Fig. 1 and 2) revealed that the reaction begins instantly upon initiation of fluorine introduction and the reaction conversion is directly proportional to the amount of fluorine gas passed into the reaction vessel. When the intensity of the fluoromalonate carbonyl peak (1775 cm−1) reached a maximum, the introduction of fluorine gas was stopped and the crude reaction mixture was analysed by 1H and 19F NMR spectroscopy. Complete conversion of the starting material was observed and diethyl fluoromalonate was formed with 93% selectivity after introducing 1.1 equivalents of fluorine into the reaction mixture. The small excess of fluorine explains the unexpectedly small amount of difluorinated side products B and C (4.5 and 2.5% respectively) which were the major impurities (6.5 and 9% respectively) when larger excess of fluorine gas (1.8 eq.) was used.
image file: c5gc00402k-f2.tif
Fig. 2 In situ monitoring of the fluorination of diethyl malonate.
The effect of concentration of fluorine in nitrogen, reaction temperature, copper nitrate catalyst loading and concentration of malonate substrate in acetonitrile were varied to optimise the fluorination process (Table 1). Additionally, reactions described in Table 1 allowed an assessment of various factors that have a major influence on the environmental impact of the process such as solvent usage, reaction temperature and the amount and composition of waste generated. In each case 20 mmol (3.20 g) of diethyl malonate was used as substrate and the isolated mass balance of crude material obtained after work-up was recorded along with the conversion of starting material and yield of fluorinated products (Table 1).
Table 1 Fluorination of diethyl malonate ester using fluorine gas catalysed by Cu(NO3)2·2.5H2O
image file: c5gc00402k-u1.tif
Entry no. T/°C C malonate (mol L−1) Catalyst (mol%) F 2 in N2 (% v/v) Conversion (1H NMR) A/B/C ratio (19F NMR) Isolated weight
1 0–5 1.0 10 10 100% 93.5/4.5/2 3.37 g
2 0–5 1.5 10 10 100% 94/4/2 3.30 g
3 0–5 1.0 5 10 97% 95/4/1 3.53 g
4 0–5 1.0 2.5 10 82% 95/4/1 3.51 g
5 RT 1.0 10 10 56% 97.5/1.5/1 3.33 g
6 0–5 1.0 10 15 85% 97.5/1.5/1 3.47 g
7 0–5 1.0 10 20 100% 94/3/3 3.50 g
8 0–5 2.0 5 20 52% 92/5/3 3.40 g

In all cases, small quantities of side products were formed which were identified by 19F NMR and these originate from two different processes: 3,3-difluoromalonate is produced from enolisation of diethyl fluoromalonate which is much slower than enolisation of the diethyl malonate substrate, while the fluoroethyl fluoromalonate is postulated to form via an electrophilic process.
The data in Table 1 suggest that the concentration of the malonate ester substrate in acetonitrile has no apparent effect on the outcome of the reaction although solvent is required for these reactions because diethyl malonate does not dissolve the catalyst. Additionally, the use of high dielectric constant media, such as acetonitrile, have been found to be beneficial for the control of selectivity of electrophilic direct fluorination processes. For convenience, a 1.5 M concentration of malonate in acetonitrile was chosen as the optimal conditions which is approximately 5 mL solvent per 1 mL of diethyl malonate.
The concentration of fluorine gas, between 10–20% v/v in nitrogen, does not affect the selectivity of the reaction and the quality of the product either, as exemplified by the product mixtures obtained from reactions 1, 2 and 7 which have identical compositions. In contrast, carrying out fluorination reactions at room temperature rather than cooling the reaction mixture to 0–5 °C leads to increased catalyst decomposition which results in an insoluble copper species that on occasion blocked the fluorine gas inlet tube. In addition, without cooling, the exothermic nature of this fluorination reaction led to a slight reaction temperature increase (from 20 to 29 °C in a small scale laboratory experiment) resulting in loss of some solvent and some decomposition of the catalyst and product degradation.
Lowering the concentration of the copper nitrate catalyst led to a significantly slower reaction as would be expected and required the use of a larger excess of fluorine gas to enable sufficiently high conversion. For example, the reaction proceeded in the presence of only 2.5 mol% catalyst, but in this case 40% excess fluorine was required to reach 100% conversion.
Typical literature work-up procedures for direct fluorination reactions involve pouring the reaction mixture into 3 to 5 volumes of water and extracting the resulting mixture three times with dichloromethane. The combined organic fraction is typically washed with water, saturated sodium bicarbonate solution and dried over sodium sulfate before evaporation of the solvent to give the crude reaction product. We sought to improve the work-up to enable recycling of the reaction solvent and substitute the use of environmentally harmful dichloromethane in the reaction work-up stage. Upon completion of fluorine gas addition, acetonitrile was evaporated for reuse and then the residue was partitioned between ethyl acetate and water, the organic phase was washed with water, saturated Na2CO3 solution and saturated brine and dried prior to evaporation under reduced pressure. Modification of the workup procedure in this manner enables the recovery of acetonitrile and ethyl acetate and significantly reduces the amount of aqueous waste generated. When direct reuse of the recovered acetonitrile was attempted, a copper containing precipitate was formed presumably because of the high HF content of the solvent (0.63 M by titration). Therefore, before reuse of the solvent, HF must be removed. Stirring the recovered reaction solvent with solid Na2CO3 lowered the acid content to an acceptable level (0.04 M) and when a second fluorination reaction was carried out in the recovered, neutralised acetonitrile, no change in the fluorination reaction profile was observed.
Upon completion of these optimisation studies, selective fluorination reactions of malonate esters were scaled up to 40 g scale in the laboratory without experiencing any change in product profile. Isolation of significant quantities of monofluoromalonate A crude product (99% yield, 95% purity) was achieved which could be used in the subsequent cyclisation processes described below without further purification or, if high purity material was required, could be purified by fractional vacuum distillation (bp. 102–103 °C, 18 mbar) to produce 99% pure material in 77% yield.
Related malonate esters were also subjected to direct fluorination using the optimised conditions established above. In the case of di-tert-butyl malonate, fluorination was carried out on 12 g scale. 100% conversion was reached after the introduction of 1.2 equivalents of fluorine gas and the desired product was isolated in 96% yield. The purity of the crude product was higher than 97% by 1H and 19F NMR spectroscopy without any further purification and as expected, the only side product was the 2,2-difluorinated product (Scheme 3).
image file: c5gc00402k-s3.tif
Scheme 3 Fluorination of di-methyl and di-tert-butyl malonates.

Diethyl fluoromalonate large scale fluorination

Diethyl malonate (40.0 g, 0.25 mol) and copper nitrate hydrate (Cu(NO3)2·2.5H2O; 5.81 g, 25 mmol) were dissolved in acetonitrile (200 mL) and placed in 500 mL fluorination vessel, cooled to 0–5 °C and stirred at 650 rpm using an overhead stirrer. After purging the system with N2 for 5 minutes, fluorine gas (20% v/v in N2, 80 mL min−1, 265 mmol) was introduced into the mixture for 6 hours and 30 minutes. The reactor was purged with nitrogen for 10 minutes, the solvent removed in vacuo and the residue partitioned between water (50 mL) and ethyl acetate (50 mL). The aqueous phase was extracted once more with ethyl acetate (50 mL) and the combined organic layers were washed with saturated NaHCO3 (25 mL) and brine (20 mL). After drying over sodium sulfate, the solvent was evaporated to leave diethyl 2-fluoromalonate (44.4 g, 99% yield, 95% purity) as a light yellow, transparent liquid. This crude product was distilled to afford high purity fluoromalonate (34.7 g, 77% yield, 99%+ purity) as a colourless liquid, bp. 102–103 °C (18 mbar), (lit.: 110–112 °C, 29 mbar), spectroscopic data as above………N. Ishikawa, A. Takaoka and M. K. Ibrahim, J. Fluorine Chem., 1984, 25, 203–212 CrossRef CAS.

PAPER
 REF

Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters

Antal Harsanyi and Graham Sandford *
Department of Chemistry, Durham University, South Road, Durham, DH1 3LE, UK. E-mail: graham.sandford@durham.ac.uk
Received 19th February 2015 , Accepted 17th March 2015
First published on the web 17th March 2015

Optimisation and real time reaction monitoring of the synthesis of 2-fluoromalonate esters by direct fluorination using fluorine gas is reported. An assessment of green metrics including atom economy and process mass intensity factors, demonstrates that the one-step selective direct fluorination process compares very favourably with established multistep processes for the synthesis of fluoromalonates.
Paper

Fluorine gas for life science syntheses: green metrics to assess selective direct fluorination for the synthesis of 2-fluoromalonate esters

*Corresponding authors
aDepartment of Chemistry, Durham University, South Road, Durham, UK
E-mail: graham.sandford@durham.ac.uk
Green Chem., 2015,17, 3000-3009

DOI: 10.1039/C5GC00402K

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Dec 302015
 
File:Sofosbuvir structure.svgSOFOSBUVIR

NEW PATENT WO2015188782,

(WO2015188782) METHOD FOR PREPARING SOFOSBUVIR

CHIA TAI TIANQING PHARMACEUTICAL GROUP CO., LTD [CN/CN]; No. 8 Julong North Rd., Xinpu District Lianyungang, Jiangsu 222006 (CN)

Sofosbuvir synthesis routes currently used include the following two methods:



https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015188782&redirectedID=true

Preparation Example 1 sofosbuvir implementation

 

 

Step (a):

 

At 0 ℃, dichloro-phenyl phosphate (6.0g, 28.4mmol) in dry dichloromethane (30ml) and stirred added alanine isopropyl ester hydrochloride (4.8g, 28.4mmol), the mixture After stirring and cooling to -55 ℃, was slowly added dropwise triethylamine (6.5g, 64mmol) and dichloromethane (30ml) mixed solution, keeping the temperature during at -55 ℃, dropping was completed, stirring was continued for 60 minutes, after liters to -5 ℃ stirred for 2 hours, TLC monitored the reaction was complete. To remove triethylamine hydrochloride was filtered and the filtrate evaporated under reduced pressure to give compound 3-1 as a colorless oil (Sp / Rp = 1/1).

 

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ8.25 & 7.94 (1: 1);

 

1 HNMR (CDCl 3 , 300 MHz): δ7.39-7.34 (m, 2H), 7.27-7.18 (m, 3H), 5.10-5.02 (m, 1H), 4.51 (br, 1H), 4.11 (m, 1H ), 1.49 (d, 3H), 1.29-1.24 (m, 6H);

 

13 C NMR (CDCl 3 , 300 MHz): δ172.1 (Rp), 196.3 (Sp), 129.8,129.6 (d), 125.9,120.5 (d), 69.7 (d), 50.7 (d), 21.6 (d), 20.4 (d).

 

Step (b):

 

At 5 ℃, the compound of formula 2 (5.20g, 20.0mmol) in dry THF (30ml) and stirred at t-butyl chloride (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise the compound 3-1 (approximately 28.4mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 4: 1). Toluene was added (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (2.6g, yield 25%, HPLC purity measured 98.8%).

 

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 as internal standard): δ3.54ppm;

 

13 C NMR (CDCl 3 , 300 Hz): δ173.1 (d), 162.7 (s), 150.2 (d), 139.3 (d), 129.6 (q);

 

MS (M + H): 530.1.

 

Preparation of compounds of formula 2 shown in Example 3-2

 

 

(1) a nucleophilic reagent as NaSCN, the phase transfer catalyst is TBAB

 

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added dropwise It was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

 

1 HNMR (CDCl 3 , 500Hz): δ7.32-7.13 (m, 3H), 7.08-7.02 (m, 2H), 5.0-4.9 (m, 1H), 3.92 (m, 1H), 1.49 (m, 3H ), 1.23-1.17 (m, 6H);

 

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-18.16 / -18.26.

 

(2) nucleophile NaSCN, phase transfer catalyst is 18-crown-6 ether

 

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in ethyl acetate (20ml) was added 18-crown -6 (2.8mmol), the NaSCN (35mmol) was added to the above the reaction mixture. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

 

(3) nucleophile NaSCN, phase transfer catalyst is TBAB and 18-crown-6

 

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol) and 18-crown -6 (2.8mmol), the NaSCN (35mmol) in water (2.0ml) was added to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = SCN).

 

(4) nucleophile as NaN 3 , phase transfer catalyst is TBAB

 

The compound (product of Example 1, step (a)) is represented by the formula 3-1 is dissolved in dichloromethane (20ml) was added TBAB (2.8mmol), the NaN 3 (35 mmol) in water (2.0ml) solution of was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure, to obtain a compound of formula 3-2 as (where X = N 3 ).

 

1 HNMR (CDCl 3 , 500Hz): δ7.30-7.33 (m, 2H), 7.27-7.21 (m, 3H), 5.10-5.05 (m, 1H), 4.12-4.00 (m, 1H), 1.43 (d , 3H), 1.28-1.17 (m, 6H);

 

31 PNMR- (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ2.04 / 2.19.

 

(5) the nucleophilic reagent is KCN, the phase transfer catalyst is TBAB

 

The compound was dissolved in methylene chloride as in formula 3-1 (20ml), was added TBAB (2.8mmol), the KCN (35mmol) in water (2.0ml) was added dropwise to the reaction solution. Dropping was completed, stirring was continued for 60 minutes, the solid was removed by filtration. The filtrate was washed with water, add MgSO 4 dried for 24 hours. Filtered, and the filtrate was evaporated under reduced pressure to remove the solvent to give a compound as shown in Formula 3-2 (where X = CN).

 

1 HNMR (CDCl 3 , 300 Hz): δ7.22-7.13 (m, 3H), 7.09-7.02 (m, 2H), 5.01-4.95 (m, 1H), 4.08-3.93 (m, 1H), 1.43-1.35 (m, 3H), 1.20-1.17 (m, 6H);

 

31 PNMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ-2.71 / -2.93.

 

Preparation Example 3 sofosbuvir implementation

 

 

(1) X is SCN

 

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 (Preparation Example 2 28.4 mmol, obtained) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. After dropping was completed, the mixture was stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (3.6g, yield 34%, HPLC purity measured 98.7%).

 

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

 

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

 

(2) X is N 3

 

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. Was added lithium chloride (21.0mmol), was slowly added dropwise after the compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 7: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.2g, yield 40%, HPLC purity measured 98.8%).

 

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

 

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

 

(3) X is CN

 

Under 5 ℃, the compound (5.20g, 20.0mmol) as shown in Equation 2 in dry THF (30ml) in. T-butyl chloride was added with stirring (1.0M THF solution, 42ml, 42.0mmol). The reaction temperature was raised to 25 ℃, and the mixture was stirred for 30 minutes. After addition of lithium chloride (21.0mmol), was slowly added dropwise a compound of formula 3-2 obtained in Preparation Example 2 (about 28.4 mmol) and THF (30ml) mixed solution, keeping the temperature during at 5 ℃. Bi drops, stirred for 15 hours. With aqueous 1N HCl (25ml) The reaction solution was quenched (HPLC assay Sp: Rp ratio of 6: 1). After further addition of toluene (100ml), temperature was raised to room temperature. The organic layer was washed with 1N HCl, water, 5% Na 2 CO 3 and washed with brine, dried over anhydrous magnesium sulfate, filtered, and the solvent was distilled off under reduced pressure to a solid, was added methylene chloride (20ml), stirred for 5 minutes plus isopropyl ether, stirring was continued for 2 hours, the precipitated solid was filtered off. The solid was dissolved by heating in dichloromethane (60ml), slowly cooled to room temperature and the precipitated crystalline solid. Repeat if necessary obtain pure crystalline sofosbuvir (4.02g, yield 40%, HPLC purity measured 98.8%).

 

1 HNMR (CDCl 3 , 300 MHz): [delta] 8.63 (s, 1H, NH), 7.46 (d, 1H, C6-H), 7.36 (t, 2H, O-aromatic), 7.18-7.24 (m, 3H, m, P-aromatic), 6.20-6.14 (d, 1H, Cl’-H), 5.70-5.68 (d, 1H, C5-H), 5.05-4.97 (m, 1H, CH- (CH 3 ) 2 ) , 4.57-4.41 (m, 2H, C5′-H2), 4.12-4.09 (d, 1H, C3′-H), 4.06-3.79 (m, 3H, C3′-OH, C4′-H, Ala-CH -CH 3 ), 3.79 (s, 1H, Ala-NH), 1.44 (d, 3H, C2′-H3), 1.36-1.34 (d, 3H, Ala-CH 3 ), 1.25-1.23 (t, 6H, CH- (CH 3 ) 2 );

 

P 31 NMR (CDCl 3 , 300 Hz, H 3 PO 4 internal standard): δ3.56.

File:Sofosbuvir structure.svg


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Abstract Image

The safe use of diazo reagents for the preparation of a key structure in the synthesis of milnacipran analogues is described herein. Using continuous flow technology, the diazo reagent is synthesized, purified, dried, and subsequently used in semi-batch mode for an intramolecular cyclopropanation. Side products formed in the reaction are isolated and rationalized to optimize the process. Different separation techniques in flow are compared with regard to their ability to produce pure and dry diazo reagents. The studies yield a scalable process to a key intermediate in the syntheses of milnacipran and its possible substituted analogues.

 

Toward a Large-Scale Approach to Milnacipran Analogues Using Diazo Compounds in Flow Chemistry

School of Chemistry, Cardiff University, Park Place, Cardiff CF10 3AT, U.K.
Institut de Recherche Pierre Fabre, 81603 Gaillac, France
§ Pierre Fabre Médicament, Parc Industriel de la Chartreuse, 81106 Castres, France
Org. Process Res. Dev., Article ASAP
DOI: 10.1021/acs.oprd.5b00308
Publication Date (Web): October 29, 2015
Copyright © 2015 American Chemical Society
*E-mail: wirth@cf.ac.uk.

http://pubs.acs.org/doi/abs/10.1021/acs.oprd.5b00308

 

 

 

 

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An immobilised monolithic iridium hydrogen transfer catalyst has been developed for use in flow based processing. The monolithic construc thas been used for several redox reductions demonstrating excellent recyclability, good turnover numbersand high chemical stability giving negligible metal leaching over extended periods of use.

A FlowSyn Auto-LF system was employed to automatically process a library of 40 aldehydes and ketones.

 

An immobilised iridium hydrogen transfer catalyst has been developed for use in flow based processing by incorporation of a ligand into a porous polymeric monolithic flow reactor. The monolithic construct has been used for several redox reductions demonstrating excellent recyclability, good turnover numbers and high chemical stability giving negligible metal leaching over extended periods of use.

 

Graphical abstract: A monolith immobilised iridium Cp* catalyst for hydrogen transfer reactions under flow conditions
*Corresponding authors
aDepartment of Chemistry, University of Cambridge, Lensfield Road, Cambridge, UK
E-mail: mavirm@hotmail.com
bDepartment of Chemistry, University of Durham, South Road, Durham, UK
Org. Biomol. Chem., 2015,13, 1768-1777
DOI: 10.1039/C4OB02376E

http://pubs.rsc.org/en/content/articlelanding/2015/ob/c4ob02376e#!divAbstract

 

 

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