Solvates, Salts, and Cocrystals: A Proposal for a Feasible Classification System

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May 132016

The design of pharmaceutical cocrystals has initiated widespread debate on the classification of cocrystals. Current attempts to classify multicomponent crystals suffer from ambiguity, which has led to inconsistent definitions for cocrystals and for multicomponent crystals in general. Inspired by the work of Aitipamula et al. (Cryst. Growth Des. 2012, 12, 2147–2152), we present a feasible classification system for all multicomponent crystals. The present classification enables us to analyze and classify multicomponent crystal structures present in the Cambridge Structural Database (CSD). This reveals that all seven classes proposed are relevant in terms of frequency of occurrence. Lists of CSD refcodes for all classes are provided. We identified over 5000 cocrystals in the CSD, as well as over 12 000 crystals with more than two components. This illustrates that the possibilities for alternative drug formulations can be increased significantly by considering more than two components in drug design.

READ ………….http://pubs.acs.org/doi/full/10.1021/acs.cgd.6b00200

Solvates, Salts, and Cocrystals: A Proposal for a Feasible Classification System

E. Grothe^†, H. Meekes^†, E. Vlieg^†, J. H. ter Horst^‡, and R. de Gelder^*^†

^† Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

^‡ EPSRC Centre for Innovative Manufacturing in Continuous Manufacturing and Crystallisation, Strathclyde Institute of Pharmacy and Biomedical Sciences, Technology and Innovation Centre, University of Strathclyde, 99 George Street, Glasgow G1 1RD, United Kingdom

Cryst. Growth Des., Article ASAP

DOI: 10.1021/acs.cgd.6b00200

Publication Date (Web): April 21, 2016

*E-mail: r.degelder@science.ru.nl.

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.

Synopsis

A classification system for multicomponent crystals is applied to the organic crystals in the Cambridge Structural Database (CSD) in an attempt to reveal the population of structures within each subclass. Seven subclasses of multicomponent crystals are presented, each illustrated by an example of an isonicotinamide crystal structure that can be found in the CSD.

//////////Solvates, Salts, Cocrystals, Proposal, Feasible Classification System

Teslaphoresis of Carbon Nanotubes

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May 132016

This paper introduces Teslaphoresis, the directed motion and self-assembly of matter by a Tesla coil, and studies this electrokinetic phenomenon using single-walled carbon nanotubes (CNTs). Conventional directed self-assembly of matter using electric fields has been restricted to small scale structures, but with Teslaphoresis, we exceed this limitation by using the Tesla coil’s antenna to create a gradient high-voltage force field that projects into free space. CNTs placed within the Teslaphoretic (TEP) field polarize and self-assemble into wires that span from the nanoscale to the macroscale, the longest thus far being 15 cm. We show that the TEP field not only directs the self-assembly of long nanotube wires at remote distances (>30 cm) but can also wirelessly power nanotube-based LED circuits. Furthermore, individualized CNTs self-organize to form long parallel arrays with high fidelity alignment to the TEP field. Thus, Teslaphoresis is effective for directed self-assembly from the bottom-up to the macroscale.

SEE………..http://pubs.acs.org/doi/full/10.1021/acsnano.6b02313

Teslaphoresis of Carbon Nanotubes

^†Department of Chemistry, ^‡Department of Materials Science and NanoEngineering, ^§Smalley-Curl Institute, Rice University, 6100 Main Street, Houston, Texas 77005, United States

^∥ Department of Chemistry and Physics, University of Tennessee—Chattanooga, 615 McCallie Avenue, Chattanooga, Tennessee 37403, United States

^⊥ Department of Biomedical Engineering, Texas A&M University, 101 Bizzell Street, College Station, Texas 77843,United States

^# Second Baptist School, 6410 Woodway Drive, Houston, Texas 77057, United States

ACS Nano, 2016, 10 (4), pp 4873–4881

DOI: 10.1021/acsnano.6b02313

Publication Date (Web): April 13, 2016

*E-mail: paul.cherukuri@rice.edu.

Keywords:

dielectrophoresis, directed self-assembly, carbon nanotubes, Tesla, wireless energy

/////////

Dihydrobenzofuran Neolignans

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May 132016

Figure 1 Structures of dihydrobenzofuran neolignans 2a and 2b.

Scheme 1 (i) Ag₂O, (CH₃)₂CO:C₆H₆ 3:5, r.t., 20 h (2a: 36% yield; 2b: 43% yield).

Figure 3 Main nuclear Overhauser effect (NOE) correlations observed in the nuclear Overhauser effect spectroscopy (NOESY) spectra of compounds 2a and 2b.

Table 1 ¹H and ¹³C NMR data assignments for compound 2a (400 MHz, CDCl₃)

	δ_Ca	δ_H (integral, multiplicityb), J/ Hz
1	132.0 (C)	−
2=6	127.5 (CH)	7.27 (2H, ddd, J_2,5 = J_6,3 0.3, J_2,7 = J_6,7 0.6, J_2,3 = J_6,5 8.3)
3=5	115.7 (CH)	6.84 (2H, dd, J_3,6 = J_5,2 0.3, J_3,2 = J_5,6 8.3)
4	156.1 (C)	−
7	87.7 (CH)	6.09 (1H, dt, J_7,2 = J_7,6 0.6, J_7,8 7.2)
8	55.1 (CH)	4.27 (1H, dd, J_8,6′ 1.4, J_8,7 7.2)
9	170.9 (C)	−
10	52.9 (CH₃)	3.83 (3H, s)
1′	127.8 (C)	−
2′	130.8 (CH)	7.43 (1H, ddd, J_2′,7‘ 1.1, J_2′,6′ 2.0, J_2′,3′ 8.3)
3′	110.3 (CH)	6.89 (1H, dd, J_3′,6′ 0.4, J_3′,2′8.3)
4′	161.2 (C)	−
5′	125.1 (C)	−
6′	124.9 (CH)	7.55 (1H, dddd, J_6′,3′ 0.4, J_6′,7′ 0.7, J_6′,8 1.4, J_6′,2′2.0)
7′	144.7 (CH)	7.66 (1H, ddd, J_7′,6′ 0.7, J_7′,2′ 1.1, J_7′,8′ 15.9)
8′	115.2 (CH)	6.32 (1H, d, J_8′,7′ 15.9)
9′	167.9 (C)	−
10′	51.7 (CH₃)	3.81 (3H, s)

^aMultiplicities assigned on the basis of distortionless enhancement by polarization transfer (DEPT) 135 experiments;

^bmultiplicities and coupling constant values measured within ¹H NMR and J-resolved spectra with the help from¹H-¹H correlation spectroscopy (COSY) results.

Table 2 2D NMR data for compound 2a (400 MHz, CDCl₃)

C	H	gCOSYa	gHMBCb	gHMQCc	NOESYd
1	–	–	H₃ =H₅, H₇, H₈	–	–
2=6	2=6	H₃, H₅, H₇	H₃ =H₅, H₇	H₂=H₆	H₇, H₈
3=5	3=5	H₂, H₆	H₅	H₃=H₅	–
4	–	–	H₃ =H₅, H₂ =H₆	–	–
7	7	H₂=H₆, H₈	H₆, H₈	H₇	H₂=H₆*
8	8	H₇, H_6′	H₇, H_6′	H₈	H₂=H₆, H_6′*
9	–	–	H₇, H₈, H₁₀	–	–
10	10	–	−	H₁₀	–
1′	–	–	H_3′, H_8′	–	–
2′	2′	H_3′, H_6′, H_7′	H_6′, H_7′	H_2′	H_7′, H_8′*
3′	3′	H_2′, H_6′	−	H_3′	–
4′	–	–	H_2′, H_3′, H_6′, H₇, H₈	–	–
5′	–	–	H₈, H_3′	–	–
6′	6′	H_2′, H_3′, H_7′, H₈	H_2′, H_7′, H₈	H_6′	H_8′, H_7′, H₈*
7′	7′	H_2′, H_8′, H_6′	H_2′, H_6′, H_8′	H_7′	H_6′*, H_2′
8′	8′	_H7′	H_7′	H_8′	H_6′*, H_2′
9′	–	–	H_7′, H_8′, H_10′	–	–
10′	10′	–	–	H_10′	–

^bgradient-selected heteronuclear multiple bond coherence;
^cgradient-selected heteronuclear multiple quantum coherence;
^dnuclear Overhauser effect spectroscopy.
^*mean weak correlation.

^aGradient-selected correlation spectroscopy;

Table 3 ¹H and ¹³C NMR data assignments for compound 2b (400 MHz, acetone-d₆)

	δ_Ca	δ_H (integral, multiplicityb); J/ Hz
1	132.5 (C)	–
2	111.2 (CH)	7.10 (1H, ddd, J_2,5 0.3, J_2,7 0.8, J_2,6 2.1)
3	149.1 (C)	–
4	148.5 (C)	–
5	116.3 (CH)	6.84 (1H, dd, J_5,2 0.3, J_5,6 8.3)
6	120.7 (CH)	6.92 (1H, ddd, J_6,7 0.6, J_6,2 2.1, J_6,5 8.3)
7	88.8 (CH)	6.04 (1H, ddd, J_7,6 0.6, J_7,2 0.8, J_7,8 7.3)
8	57.0 (CH)	4.47 (1H, dd, J_8,6′ 1.4, J_8,7 7.3)
9	172.1 (C=O)	–
10	53.5 (CH₃)	3.81 (3H, s)
11	56.4 (CH₃)	3.84 (3H, s)
1′	129.9 (C)	–
2′	113.9 (CH)	7.33 (1H, dd, J_2′,7′ 0.4, J_2’6′ 2.6)
3′	146.3 (C)	–
4′	151.5 (C)	–
5′	127.8 (C)	–
6′	119.5 (CH)	7.29 (1H, ddd, J_6′,7′ 0.8, J_6′,8 1.4, J_6′,2′ 2.6)
7′	145.9 (CH)	7.63 (1H, ddd, J_7′,2′ 0.4, J_7′,6′ 0.8, J_7′,8′ 15.8)
8′	116.8 (CH)	6.44 (1H, d, J_8′,7′ 15.8)
9′	168.2 (C)	–
10′	52.1 (CH₃)	3.73 (3H, s)
11′	56.8 (CH₃)	3.92 (3H, s)

^aMultiplicities assigned on the basis of distortionless enhancement by polarization transfer (DEPT) 135 experiments;
^bmultiplicities and coupling constant values measured within ¹H-NMR and J-resolved spectra with the help from¹H-¹H correlation spectroscopy (COSY) results.

Table 4 2D NMR data for compound 2b (400 MHz, acetone-d₆)

C	H	gCOSYa	gHMBCb	gHMQCc	NOESYd
1	–	–	H₂, H₆, H₇, H₈	–	–
2	2	H₅, H₆, H₇	H₅, H₆, H₇	H₂	H₇, H₈, H₁₁
3	–	–	H₂, H₅, H₁₁	H₃	–
4	–	–	H₂, H₅, H₆	–	–
5	5	H₂, H₆	H₆	H₅	–
6	6	H₂, H₅, H₇	H₂, H₅	H₆	H₇, H₈
7	7	H₂, H₆, H₈	H₂, H₆, H₈	H₇	H₆*, H₂
8	8	H_6′, H₇	H₂, H_6′	H₈	H_6′*, H₂, H₆
9	–	–	H₇, H₈, H₁₀	H₉	–
10	10	–	−	H₁₀	–
11	11	–	−	H₁₁	H₂
1′	–	–	H_7′, H_8′	H_1′	–
2′	2′	H_6′, H_7′	H_6′, H_7′	H_2′	H_7′, H_8′*, H_11′
3′	–	–	H_11′	–	–
4′	–	–	H_2′, H_6′, H₇, H₈	–	–
5′	–	–	H₇, H_8′	–	–
6′	6′	H_7′, H_2′, H₈	H_2′, H_7′, H₈	H_6′	H_8′, H_7′, H₈*
7′	7′	H_2′, H_6′, H_8′	H_2′, H_6′, H_8′	H_7′	H_6′, H_2′,
8′	8′	H_7′	H_7′	H_8′	H_6′, H_2′
9′	–	–	H_8′, H_10′	–	–
10′	10′	–	–	H_10′	–
11′	11′	–	–	H_11′	H_2′

^aGradient-selected correlation spectroscopy;
^bgradient-selected heteronuclear multiple bond coherence;
^cgradient-selected heteronuclear multiple quantum coherence;
^dnuclear Overhauser effect spectroscopy.
^*mean weak correlation.

¹H and ¹³C NMR data previously reported for compound2a and 2b were obtained in CDCl₃ or acetone-d₆. Most of the signals in the ¹H NMR spectrum were between δ_H 6.0 and δ_H 8.0, but the hydrogen signal multiplicities are ambiguous. In this work, we found that for compound2a in acetone-d₆, the signals at δ_H 7.6-7.7 are referred to four hydrogen atoms and their overlapping precluded their correct assignment (Figure 2). Therefore, CDCl₃ provided much clearer spectra for 2a, but not for 2b, due to the solvent influence on chemical shifts. For compound 2b, three hydrogen atoms resonate at δ_H 6.91 in the ¹H HMR spectrum in CDCl₃. On the other hand, the ¹H NMR signals of 2b were resolved by using acetone-d₆ as solvent, which allowed verification of the multiplicities, observation of the chemical shifts and measurement of the coupling constants.

Figure 2 Expansions of the ¹H NMR spectrum of compounds 2a and 2b obtained in CDCl₃ and acetone-d₆.

Journal of the Brazilian Chemical Society

On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.27 no.1 São Paulo Jan. 2016

http://dx.doi.org/10.5935/0103-5053.20150262

ARTICLES

Detailed ¹H and ¹³C NMR Spectral Data Assignment for Two Dihydrobenzofuran Neolignans

Talita C. T. Medeiros^a^#, Herbert J. Dias^a^#, Eliane O. Silva^a, Murilo J. Fukui^b, Ana Carolina F. Soares^b, Tapas Kar^c, Vladimir C. G. Heleno^b, Paulo M. Donate^a, Renato L. T. Parreira^b, Antônio E. M. Crotti^a^*

^{^a}Departamento de Química, Faculdade de Filosofia, Ciências e Letras de Ribeirão Preto, Universidade de São Paulo, 14040-901 Ribeirão Preto-SP, Brazil

^{^b}Núcleo de Pesquisas em Ciências Exatas e Tecnológicas, Universidade de Franca, 14404-600 Franca-SP, Brazil

^{^c}Department of Chemistry and Biochemistry, Utah State University, 84322-0300 Logan-UT, United States

ABSTRACT

In this work we present a complete proton (1H) and carbon 13 (¹³C) nuclear magnetic resonance (NMR) spectral analysis of two synthetic dihydrofuran neolignans (±)-trans-dehydrodicoumarate dimethyl ester and (±)-trans-dehydrodiferulate dimethyl ester. Unequivocal assignments were achieved by ¹H NMR, proton decoupled ¹³C (¹³C{¹H}) NMR spectra, gradient-selected correlation spectroscopy (gCOSY), J-resolved, gradient-selected heteronuclear multiple quantum coherence (gHMQC), gradient-selected heteronuclear multiple bond coherence (gHMBC) and nuclear Overhauser effect spectroscopy (NOESY) experiments. All hydrogen coupling constants were measured, clarifying all the hydrogen signals multiplicities. Computational methods were also used to simulate the ¹H and ¹³C chemical shifts and showed good agreement with the transconfiguration of the substituents at C₇ and C₈.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000100136&lng=en&nrm=iso&tlng=en

Key words: neolignans, oxidative coupling, J-resolved, benzofurans

see……….0103-5053-jbchs-27-01-0136-suppl01.pdf

//////////////

Buthionine Sulphoximine

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May 112016

Buthionine Sulphoximine

A gamma-glutamylcysteine synthetase inhibitor potentially for the treatment of solid tumors.

NSC-326231; BSO

CAS No. 5072-26-4

BUTHIONINE SULFOXIMINE; DL-Buthionine-[S,R]-sulfoximine; 5072-26-4; Buthionine sulfoxamine; Buthionine-S,R-sulfoximine; Buthione sulfoximine;

Molecular Formula:	C₈H₁₈N₂O₃S
Molecular Weight:	222.30512 g/mol

Buthionine sulfoximine (BSO) is a sulfoximine which reduces levels of glutathione and is being investigated as an adjunct withchemotherapy in the treatment of cancer.^[1] The compound inhibits gamma-glutamylcysteine synthetase, the enzyme required in the first step of glutathione synthesis. Buthionine sulfoximine may also be used to increase the sensitivity of parasites to oxidativeantiparasitic drugs.^[2]

Buthionine sulphoximine is an oncolytic agent in early clinical development at the National Cancer Institute (NCI) for the treatment of neuroblastoma in pediatric patients in combination with melphalan and bone marrow or peripheral stem cell transplantation.

DATA

1H NMR

13C NMR

Synthesis

Methionine and buthionine sulfoximines: Syntheses under mild and safe imidation/oxidation conditions
Advanced Synthesis&Catalysis (2014), 356, (10), 2209-2213

Abstract

Methionine and buthionine sulfoximines (MSO and BSO) are non-natural amino acids known to inhibit the biosynthesis of glutathione (GSH). The current syntheses of these biologically active molecules involve harsh reaction conditions and the use of hazardous reagents for the sulfur imidation. Here, improved syntheses of MSO and BSO are presented including safe and mild one-pot imidation/oxidation sequences and single-step deprotections of three different functionalities.

Methionine and Buthionine Sulfoximines: Syntheses under Mild and Safe Imidation/Oxidation Conditions

Laura Buglioni,
Vincent Bizet and
Carsten Bolm^*

DOI: 10.1002/adsc.201400354

http://onlinelibrary.wiley.com/doi/10.1002/adsc.201400354/abstract

References

Defty, CL; Marsden, JR (2012). “Melphalan in regional chemotherapy for locally recurrent metastatic melanoma.”. Current topics in medicinal chemistry 12 (1): 53–60. PMID 22196271.
“Definition of buthionine sulfoximine – National Cancer Institute Drug Dictionary”.

BUTHIONINE SULFOXIMINE.png

Buthionine sulfoximine
Names


IUPAC name 2-amino-4-(butylsulfonimidoyl)butanoic acid
Other names BSO
Identifiers
CAS Number	5072-26-4
ChEBI	CHEBI:28714
ChemSpider	19896
Jmol 3D model	Interactive image
MeSH	Buthionine+sulfoximine
PubChem	21157
InChI [show]
SMILES [show]
Properties
Chemical formula	C₈H₁₈N₂O₃S
Molar mass	222.305 g/mol
Density	1.29 g/mL
Melting point	215 °C (419 °F; 488 K)
Boiling point	382.3 °C (720.1 °F; 655.5 K)
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////NSC-326231, BSO, 5072-26-4, Butionine sulfoximine, Neuroblastoma

CCCCS(=N)(=O)CCC(C(=O)O)N

Multibiphenyl A, New biphenyls from Garcinia multiflora.

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May 112016

Figure 2 Selected HMBC (H→C) and ¹H-¹H correlation spectroscopy (COSY) (–) correlations of 1.

Compound 1 was obtained as a pale yellow gum. The molecular formula was determined to be C₂₀H₂₂O₆ from the molecular ion peak [M]⁺ at m/z 358.1408 in the EI-HRMS. The IR spectrum indicated that 1 possesses hydroxy (3422 cm^-1), phenyl (2939, 1498 cm^-1), and carbonyl (1721 cm^-1) functional groups. The ¹H and ¹³C NMR spectra (Table 1) revealed the signals for a 1,2,3,4,5-pentasubstituted benzene ring [d_H 6.26 (1H, s, H-6); δ_C 129.6 (C-1), 119.7 (C-2), 144.9 (C-3), 135.0 (C-4), 147.2 (C-5), 105.9 (C-6)], one p-substituted benzene ring [d_H 7.00 (2H, dd, J 8.8, 2.4 Hz, H-8, H-12), 6.74 (2H, dd, J 8.8, 2.4 Hz, H-9, H-11); δ_C 133.8 (C-7), 131.7 (C-8, C-12), 115.7 (C-9, C-11), 157.1 (C-10)], one acetoxyprenyl group [d_H 3.21 (2H, d, J 6.7 Hz, H-1′), 5.44 (1H, d, J6.7 Hz, H-2′), 4.33 (2H, s, H-4′), 1.39 (3H, s, H-5′), and 1.99 (3H, s, H-OAc); δ_C 26.8 (C-1′), 130.7 (C-2′), 134.6 (C-3′), 71.5 (C-4′), 14.0 (C-5′), 172.9, 20.8 (OAc)], and one methoxy group [d_H 3.76 (3H, s, OMe-5); δ_C 56.5 (OMe)], which implied that compound1 was a biphenyl derivative. This conclusion was confirmed by the heteronuclear multiple bond correlation (HMBC) correlations of H-6 with C-7, and of H-8 and H-12 with C-1 (Figure 2). HMBC correlations of H-1′ with C-1, C-2, and C-3, and of H-2′ with C-1 suggested the acetoxyprenyl group at C-2. The methoxy group was located at C-5 from the HMBC correlations of δ_H 3.76 (OMe) with C-5. Considering the signal for quarternary C-3, C-4, C-10 and the molecular formula of 1, three hydroxy groups were located at C-3, C-4, C-10, respectively. Thus, the structure of 1 was determined as shown (Figure 1), and named multibiphenyl A.

Figure 1 New biphenyls from Garcinia multiflora.

Multibiphenyl A (1)

Pale yellow gum; [α]_D –11.0 (c 0.07, MeOH); UV (MeOH) l_max / nm (log ε) 570 (2.16), 205 (4.71); IR (KBr) n / cm^-1 3422, 2939, 1721, 1611, 1589, 1498, 1443, 1357, 1266, 1172, 1102, 1045, 1023, 838; ¹H and ¹³C NMR data (400 and 100 MHz, CD₃OD), see Table 1; ESI-MS (positive mode) m/z 381 [M + Na]⁺; EI-HRMS (M⁺) calcd.: 358.1416; found: 358.1408 (C₂₀H₂₂O₆).

Table 1 ¹H and ¹³C NMR data for compounds 1-3 (d in ppm, 1 and 2 in CD₃OD, 3 in CDC1₃, 100 and 400 MHz)

No.	1		2		3
No.	δ_C (m) / ppm	δ_H (m, J , Hz) / ppm	δ_C (m) / ppm	δ_H (m, J , Hz) / ppm	δ_C (m) / ppm	δ_H (m, J , Hz) / ppm
1	129.6 s		132.4 s		132.3 s
2	119.7 s		114.2 s		112.4 s
3	144.9 s		142.0 s		141.5 s
4	135.0 s		131.9 s		132.7 s
5	147.2 s		149.6 s		144.8 s
6	105.9 d	6.26 (s, 1H )	106.6 d	6.44 (s, 1H)	105.5 d	6.43 (s, 1H)
7	133.8 s		134.6 s		132.7 s
8	131.7 d	7.00 (dd, 1H, J 8.8 Hz, 2.4)	131.8 d	7.11 (dd, 1H, J 8.4 Hz, 1.9)	130.3 d	7.16 (d, 1H, J 8.6 Hz)
9	115.7 d	6.74 (dd, 1H, J 8.8 Hz, 2.4)	116.0 d	6.82 (dd, 1H, J 8.4 Hz, 1.9)	114.8 d	6.86 (d, 1H, J 8.6 Hz)
10	157.1 s		157.7 s		155.5 s
11	115.7 d	6.74 (dd, 1H, J 8.8 Hz, 2.4)	116.0 d	6.82 (dd, 1H, J 8.4 Hz, 1.9)	114.8 d	6.86 (d, 1H, J 8.6 Hz)
12	131.7 d	7.00 (dd, 1H, J 8.8 Hz, 2.4)	131.8 d	7.11 (dd, 1H, J 8.4 Hz, 1.9)	130.3 d	7.16 (d, 1H, J 8.6 Hz)
1′	26.8 t	3.21 (d, 2H, J 6.7 Hz, CH₂)	124.7 d	6.41 (d, 1H, J 10.1 Hz)	21.1 t	2.59 (t, 2H, J 6.6 Hz, CH₂)
2′	130.7 d	5.44 (t, 1H, J 6.7 Hz)	124.4 d	5.48 (d, 1H, J 10.1 Hz)	33.0 t	1.72 (t, 2H, J 6.6 Hz, CH₂)
3′	134.6 s		77.6 s		74.7 s
4′	71.5 t	4.33 (s, 3H, CH₃)	69.0 t	4.27 (d, 1H, J 11.5 Hz, CH₂)	26.7 q	1.39 (s, 3H, CH₃)
				4.14 (d, 1H, J 11.5 Hz, CH₂)
5′	14.0 q	1.39 (s, 3H, CH₃)	23.4 q	1.47 (s, 3H, CH₃)	26.7 q	1.39 (s, 3H, CH₃)
3-OMe	56.5 q	3.76 (s, 3H, OCH₃)	56.5 q	3.85 (s, 3H, OCH₃)	56.1 q	3.86 (s, 3H, OCH₃)
5′- OAc	172.9 s		172.6 s
	20.8 q	1.99 (s, 3H, COCH₃)	20.7 q	2.00 (s, 3H, COCH₃)

Journal of the Brazilian Chemical Society

On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.27 no.1 São Paulo Jan. 2016

http://dx.doi.org/10.5935/0103-5053.20150235

ARTICLES

New Biphenyls from Garcinia multiflora

Xue-Mei Gao^a^b, Bing-Kun Ji^a^b, Yin-Ke Li^a^c, Yan-Qing Ye^a, Zhi-Yong Jiang^a, Hai-Ying Yang^a, Gang Du^a, Min Zhou^a, Xiao-Xia Pan^a, Wen-Xing Liu^a, Qiu-Fen Hu^a^*

^{^a}Key Laboratory of Chemistry in Ethnic Medicinal Resources, State Ethnic Affairs Commission & Ministry of Education, Kunming, P. R. China

^{^b}Joint Research Centre for International Cross-Border Ethnic Regions Biomass Clean Utilization in Yunnan, Yunnan Minzu University, 650031 Kunming, P. R. China

^{^c}College of Resource and Environment, Yuxi Normal University, 653100 Yuxi, P. R. China

ABSTRACT

Three new biphenyls were isolated from Garcinia multiflora. The structures of these biphenyls were elucidated by spectroscopic methods, and their rotavirus activity was evaluated.

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000100010&lng=en&nrm=iso&tlng=en

Key words: Garcinia multiflora, biphenyls, anti-rotavirus activity

///////

Lupin to co-market Novartis’ asthma drug in India

Uncategorized Comments Off

May 112016

Lupin to co-market Novartis’ asthma drug in India

BS B2B Bureau | Mumbai April 12, 2016 Last Updated at 10:27 IST

Novartis Healthcare will continue to market Sequadra (indacaterol/glycopyrronium inhaler), while Lupin will promote the inhaler under the brand name Loftair in India

read original article at

http://www.business-standard.com/content/b2b-pharma/lupin-to-co-market-novartis-asthma-drug-in-india-116041200249_1.html

/////inhaler, Novartis Healthcare, Sequadra, indacaterol, glycopyrronium inhaler, Lupin, inhaler, brand name, Loftair, India

Ixorine, a New Cyclopeptide Alkaloid from the Branches of Ixora brevifolia

Uncategorized Comments Off

May 102016

Figure 2 Selected key HMBC (¹H ¹³C) and NOESY (¹H ¹H) correlations for ixorine (1).

Figure 1 Structures of compounds 1–4 isolated from the branches of I. brevifolia.

Ixorine (1)

HRESIMS m/z, calcd.: C₃₀H₄₀N₄O₄ [M + H]⁺: 521.3044; found: 521.3049; [α]_D²⁰ = -292.3 (c 0.001, CHCl₃); ¹H NMR (300 MHz, CDCl₃) and ¹³C NMR (75 MHz, CDCl₃), see Table 1.

Table 1 NMR spectroscopic data (300 MHz, CDCl3) for ixorine (1)

Position	δ_C	δ_H (mult., J in Hz)	HMBC	COSY
1	156.3	−	H-14, H-16	−
2	−	−	−	−
3	81.7	4.91 (dd, 8.0, 2.1)	H-4, H-18, H-19	H-4
4	55.6	4.44 (dd, 9.0, 8.0)	−	H-20 (NH)
5	171.6	−	H-6 (NH)	−
6	−	5.94 (d, 6.3, NH)	−	−
7	55.2	4.30 (m)	H-28	H-28
8	167.2	−	H-28	−
9	−	6.20 (sl, NH)	−	−
10	125.7	6.56 (m)	−	−
11	118.4	6.40 (d, 6.6)	H-13	−
12	131.8	−	H-14	−
13	131.7	7.03 (m)	−	H-14
14	121.9	7.15 (m)	−	−
15	122.7	7.03 (m)	−	H-16
16	130.2	6.92 (m)	−	−
17	29.3	2.00 (m)	H-18, H-19	H-18, H-19
18	20.4	1.25 (d, 7.2)	H-17, H-19	−
19	15.2	1.00 (d, 6.6)	H-17	−
20	−	6.94 (m, NH)	−	−
21	172.4	−	H-22, H-23	−
22	75.2	2.40 (d, 4.2)	H-24, H-25, H-26, H-27	H-26, H-27
23	27.8	2.05 (m)	H-24, H-25	H-24, H-25
24	21.0	1.05 (d, 6.9)	−	−
25	17.6	0.93 (d, 6.6)	−	−
26	43.1	2.14 (s)	H-27	−
27	43.1	2.14 (s)	−	−
28	37.1	2.76 (dd, 13.8, 4.5)/3.07 (m)	H-30, H-30’	H-28
29	135.7	−	H-7, H-28, H-31, H-31’	−
30, 30’	129.6	7.15 (m)	−	H-31, H-31’
31, 31’	129.0	7.34 (m)	−	−
32	127.4	7.24 (m)	−	H-30, H-30’

Journal of the Brazilian Chemical Society

On-line version ISSN 1678-4790

J. Braz. Chem. Soc. vol.27 no.4 São Paulo Apr. 2016

http://dx.doi.org/10.5935/0103-5053.20150326

ARTICLES

Ixorine, a New Cyclopeptide Alkaloid from the Branches of Ixora brevifolia

Rebeca P. Medina^a, Ivânia T. A. Schuquel^a, Armando M. Pomini^a, Cleuza C. Silva^a, Cecília M. A. Oliveira^b, Lucília Kato^b, Celso V. Nakamura^c, Silvana M. O. Santin^*^a

^{^a}Departamento de Química, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá-PR, Brazil

^{^b}Instituto de Química, Universidade Federal de Goiás, Campus II, Samambaia, 74001-970 Goiânia-GO, Brazil

^{^c}Departamento de Análises Clínicas e Biomedicina, Universidade Estadual de Maringá, Av. Colombo 5790, 87020-900 Maringá-PR, Brazil

ABSTRACT

The isolation and structure determination of new cyclic peptide alkaloid ixorine, along with five known constituents frangulanine, syringaresinol, cinnamtannin B-1, daucosterol and mannitol from the branches of Ixora brevifolia are described. The cyclic peptide frangulanine is being described for the first time in the Rubiaceae family. The structures were elucidated on their spectral data basis, mainly one- (¹H, ¹³C, DEPT) and two-dimensional (COSY, NOESY, HSQC and HMBC) nuclear magnetic resonance (NMR) and by comparison with data from the literature. The mixture of two cyclopeptide alkaloids showed weak activity against Leishmania amazonensis……..http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0103-50532016000400753&lng=en&nrm=iso&tlng=en

Key words: Ixora brevifolia, Rubiaceae, cyclopeptide alkaloids, Leishmania

see……….http://www.scielo.br/pdf/jbchs/v27n4/0103-5053-jbchs-27-04-0753-suppl01.pdf

SUPPLEMENTARY INFORMATION

1D and 2D NMR spectra for compounds 1–2 are available free of charge online

0103-5053-jbchs-27-04-0753-suppl01.pdf

^*e-mail: smoliveira@uem.br

////

Arbaclofen

Uncategorized Comments Off

May 102016

Arbaclofen placarbil

(3R)-3-(4-chlorophenyl)-4-[[(1S)-2-methyl-1-(2-methylpropanoyloxy)propoxy]carbonylamino]butanoic acid

A GABA (B) receptor agonist potentially for the treatment of muscle spasticity.

AGI-006; STX-209; OS-440

CAS No. 69308-37-8 free

847353-30-4 placarbil

Arbaclofen placarbil (ar-bac-loe-fen pla-kar-bil, also known as XP19986) is a prodrug of R–baclofen. Arbaclofen placarbil possesses more favorable pharmacokinetic profile than baclofen, with less fluctuations in plasma drug levels. It was being developed as a potential treatment for patients with GERD and spasticity due to multiple sclerosis; however, in May 2013 XenoPort announced the termination of development because of unsuccessful results in phase III clinical trials.^[1]

Arbaclofen Placerbil is a prodrug of Arbaclofen, which is a selective gamma-amino-butyric acid type B receptor agonist and the R-enantiomer of baclofen. It was discovered, and has been patented by XenoPort as a new chemical entity with an improved pharmacokinetic profile compared to baclofen, which allows for sustained release properties. ArbaclofenPlacerbil was believed to have therapeutic potential in treating gastroesophogeal reflux disease (GERD) and plasticity; however due to discouraging clinical trial results, the drug was abandoned by XenoPort in 2011 for the treatment of GERD. On May 20th, 2013, XenoPort announced plans to terminate the development of Arbaclofen Placerbil for the treatment of multiple sclerosis.

Autism spectrum disorder (ASD) is a behaviorally defined disorder which has increased in prevalence over the last two decades. Despite decades of research, no effective treatment is currently available. Animal models, as well as other lines of evidence, point to abnormalities in the balance of cortical excitation to inhibition in individuals with ASD, with this imbalance resulting in an overall increase in cortical excitation. To reduce cortical excitatory glutamate pathways, arbaclofen, a selective agonist of the gamma aminobutyric acid receptor type B, has been developed. This article reviews the evidence for this treatment for ASD using a systematic review methodology. Overall, a systematic search of the literature revealed 148 relevant references with the majority of these being review papers or news items that mentioned the potential promise of arbaclofen. Five original studies were identified, four of which used STX209, a form of arbaclofen developed by Seaside Therapeutics, Inc., and one which used R-baclofen. In an animal model, treatment of Fragile X, a genetic disease with ASD features, demonstrated a reversal of behavioral, neurological, and neuropathological features associated with the disease. One double-blind, placebo-controlled study treated children and adults with Fragile X. Results from this study were promising, with signs of improvement in social function, especially in the most severely socially impaired. Two studies, one open-label and one double-blind, placebo-controlled, were conducted in children, adolescents, and young adults with ASD. These studies suggested some improvements in socialization, although the effects were limited and may have been driven by individuals with ASD that were higher-functioning. These studies and others that have used arbaclofen for the treatment of gastroesophageal reflux suggest that arbaclofen is safe and well-tolerated. Clearly, further clinical studies are needed in order to refine the symptoms and characteristics of children with ASD that are best treated with arbaclofen.

Arbaclofen placarbil.png

Fig. 1.

The Structures of R-baclofen (1), arbaclofen placarbil (2), R-baclofen lactam (3), and the potential γ-hydroxy metabolite of R-baclofen (4).

Route 2

Reference：1. Chem. Pharm. Bull. 1995, 43, 1302-1306.

Route 3

Reference：1. Tetrahedron Lett. 1997, 38, 1195-1196.

Route 4

Reference：1. J. Am. Chem. Soc. 2005, 127, 119-125.

2. WO2007066828A1 / US2009137819A1.

Route 5

Reference：1. US2012029230A1

Route 1

Reference：1. Tetrahedron-Asymmetr. 1992, 3, 1213-1221.

2. Tetrahedron Lett. 1991, 32, 6949-6952.

References

http://investor.xenoport.com/releasedetail.cfm?ReleaseID=765868

Arbaclofen placarbil
Systematic (IUPAC) name

(3R)-3-(4-chlorophenyl)-4-[[[(1S)-2-methyl-1-[(2-methylpropanoyl)oxy]propoxy]carbonyl]amino]butanoic acid
Clinical data
Pregnancy category	N/A
Legal status
Legal status	Development terminated
Identifiers
CAS Number	847353-30-4
ATC code	none
PubChem	CID 11281011
ChemSpider	9456008
KEGG	D08861
ChEMBL	CHEMBL2107312
Chemical data
Formula	C₁₉H₂₆ClNO₆
Molar mass	399.86 g/mol

///////AGI-006, STX-209, OS-440, Arbaclofen, autism spectrum disorder, Fragile X, gamma-aminobutyric acid, arbaclofen, R-baclofen, STX209

CC(C)[C@@H](OC(=O)C(C)C)OC(=O)NC[C@H](CC(=O)O)C1=CC=C(C=C1)Cl

DISCLAIMER

I , Dr A.M.Crasto is writing this blog to share the knowledge/views, after reading Scientific Journals/Articles/News Articles/Wikipedia. My views/comments are based on the results /conclusions by the authors(researchers). I do mention either the link or reference of the article(s) in my blog and hope those interested can read for details. I am briefly summarising the remarks or conclusions of the authors (researchers). If one believe that their intellectual property right /copyright is infringed by any content on this blog, please contact or leave message at below email address amcrasto@gmail.com. It will be removed ASAP

Nolatrexed Dihydrochloride

Uncategorized Comments Off

May 092016

Nolatrexed

A thymidylate synthase inhibitor potentially for the treatment of hepatocellular carcinoma and nasopharyngeal cancer.

AG-337

CAS No. 147149-76-6 (free)

free form data

(eluents: CH₃CN−H₂O = 10−90, pH 4.94; R_t = 11.8 min); R_f = 0.31 [ethyl acetate/(0.63 M NH₃ in ethanol) = 6/4]; Mp 300−302 °C (lit.:(J. Med. Chem. 1993, 36, 733– 746) a tan solid; Mp 301−302 °C); MS (ESI⁺) m/z: 285.1 [M + 1]⁺; the major impurity: 3.0% (R_t = 13.0 min); Mp 73−77 °C; ¹H NMR (DMSO-d₆): δ 7.95 (d, J = 6.4 Hz, 4 H), 8.81 (d, J = 6.4 Hz, 4 H);

MS (ESI⁺) m/z: 219.2 [M − 1]⁺;

Nolatrexed dihydrochloride.png

152946-68-4(Nolatrexed Dihydrochloride)

2-amino-6-methyl-5-pyridin-4-ylsulfanyl-1H-quinazolin-4-one;dihydrochloride

Nolatrexed dihydrochloride; Thymitaq; 152946-68-4; Nolatrexeddihydrochloride; AG 337; AG-337;

Molecular Formula:	C₁₄H₁₄Cl₂N₄OS
Molecular Weight:	357.25816 g/mol

diHCl data

IR (KBr cm⁻¹):ṽ 3401, 3058, 2929, 1701, 1621, 1471, 799;

¹H NMR (DMSO-d₆): δ 2.43 (s, 3H, −CH₃), 7.53 (d,J = 6.9 Hz, 2H, Pyr-H), 7.67 (d, J = 8.5 Hz, 1H, Ar−H), 7.92 (d, J = 8.5 Hz, 1 Hz, Ar−H), 8.30 (br s, 3H, NH₃), 8.52 (d, J = 6.9 Hz, 2H, Pyr-H); MS (ESI⁺) m/z: 285 [M − 1−2Cl]⁺; (ESI⁺) m/z: 283 [M − 1− 2HCl]⁺.

Pfizer (Originator) , Gilead,LG Life Sciences,北京康辰药业

Nolatrexed is a thymidylate synthase inhibitor.^[1]^[2]

Phase I studies of p.o. administered nolatrexed dihydrochloride (AG337, THYMITAQ), a nonclassical thymidylate synthase inhibitor, were performed to establish the maximum tolerated dose and a recommended dose for Phase II studies. The bioavailability and pharmacokinetic and pharmacodynamic properties of oral nolatrexed were also studied. Forty-five patients were treated with oral nolatrexed every 6 h for 5 days at doses of 288-1000 mg/m2/day. The bioavailability of the oral preparation was determined, and the effect of a standard meal on nolatrexed absorption was investigated at a dose of 800 mg/m2/day. Nolatrexed plasma concentrations were analyzed by high-performance liquid chromatography. Nolatrexed was rapidly absorbed with a median bioavailability of 89% (range 33-116%), with 88% of patients above 70%. The dose-limiting toxicities were gastrointestinal, and the recommended Phase II oral dose was 800 mg/m2/day. After a standard meal, the peak plasma nolatrexed concentration achieved was lower (median, 8.3 microg/ml versus 15.0 microg/ml; P = 0.001), and the time taken to reach the peak was longer (median, 180 min versus 45 min; P = 0.00003), but the trough concentration was higher (median, 3.6 microg/ml versus 2.1 microg/ml; P = 0.004) when compared with the fasted state. The area under the nolatrexed plasma concentration versus time curve was not affected by food. Average trough nolatrexed concentration, but not dose, was significantly related to the % decrease in both thrombocytes (r2 = 0.58; C50 = 6.0 microg/ml, where C50 is the plasma concentration associated with a 50% decrease in thrombocytes) and neutrophils (r2 = 0.63; C50 = 0.6 microg/ml). Nolatrexed can be safely administered as an oral preparation at a dose of 800 mg/m2/day for 5 days. Bioavailability was close to 100% and, because inhibition of thymidylate synthase by nolatrexed is rapidly reversible, the slower absorption after a standard meal may result in a shorter duration of noninhibitory concentrations between doses.

Catalytic hydrogenation of 2-bromo-4 -nitrotoluene (I) over Raney-Ni provided aniline (II). Reaction of (II) with chloral hydrate and hydroxylamine gave rise to the isonitrosoacetanilide (III), which was subsequently cyclized to the isatin (IV) by heating in concentrated H2SO4. Oxidative cleavage of isatin (IV) produced the anthranilic acid (V). This was converted to the benzoxazinone (VI) upon refluxing with acetic anhydride. Ring opening of benzoxazinone (VI) with MeOH, followed by acidic hydrolysis of the acetamide function, yielded the anthranilate ester (VII). The quinazoline derivative (VIII) was then obtained by treatment of anthranilate (VII) with chloroformamidine hydrochloride in refluxing diglyme. Finally, displacement of the bromide group of (VIII) with the sodium thiolate of 4-mercaptopyridine (IX) under Ullmann conditions afforded the title pyridyl sulfide.

Dissertation title	[BT] A New Method for Synthesis of Nolatrexed Dihydrochloride

Hangul title	Nolatrexed dihydrochloride Synthesis Process Development

Author	Xueqing Zhao, Fei Li, Weiping Zhuang, Xiaowen Xue, Yuanyang Lian, Jianhui Fan and Dongsheng Fang

Japjimyeong	ORG PROCESS RES DEV	Issue year	2010

Gwonho details	14 (2)	The surface	346-350

ABSTRACT	A new synthetic method for nolatrexed dihydrochloride (thymitaq) has been developed. The synthesis was accomplished in three steps featuring the direct conversion of the starting 4-bromo-5-methylisatin into the methyl anthranilate by potassium peroxydisulfate / sodium methoxide. In the final Ullmann reaction potassium carbonate was employed in place of sodium hydride, and the amount of copper catalysts was significantly reduced. Moreover, sodium sulfide solution was utilized to efficiently remove copper under approximately neutral conditions instead of hydrogen sulfide / methanol under strongly acidic conditions. By means of these modifications, nolatrexed dihydrochloride was ensured to be prepared in good yield and high purity.

Contents	Nolatrexed dihydrochloride (2-Amino-6-methyl-5-(4-pyridylthio) -3 H-quinazolin-4-one dihydrochloride, thymitag, 1) is the HCC cancer therapeutic agent to the TS (thymidylate synthase) folate binding site on the TS inhibitor as DNA replication inhibition, DNA damage, S-phase cell cycle arrest, and caspase-dependent apoptosis induction and clinical 2 on theresults look HCC patients, the survival benefit of showing the current phase III study is in progress in it. under scheme 1 is conducted in a number of synthesis team Nolatrexedillustrates the development process Scheme 1. Synthetic routes A-F from 4-bromo-5-methylisatin (2) to nolatrexed dihydrochloride (1) The scheme 1 When the complex first synthesis process but is A : 2 – 3 – 4 – 5 – 7 · HCl – 1 or in part, 6 pass through a B step ( 2 – 3 – 6 – 5 ) to obtain the desired compound with, but However, these processes are of the desired product quality control had a disadvantage unfulfilled this . after C, D, E process was developed during the E step is a step wherein compound 8 from the first to the one-pot is the most superior process consists in the process also drug of the compound for use as a quality control has difficulty in . more recentlyWennerberg is a new process F compounds were reported for 3 compound directly from the 7fully in the process I scored quality control could be the place . in the process, each reactionstep partially changed by the use of a reagent zoom impurity to minimize the formation of .However, this process also work-up, and purification there have difficulties to process the authors reported a new efficient way . Scheme 2. Synthetic route G from 4-bromo-5-methylisatin (2) to nolatrexed dihydrochloride (1) Scheme 2 The process reported to also have specifically not a new process only takes the best features from several processes previously reported , significant differences that the author is proud director teen two direct compound from 5 will get the , also reported in other processes already advanced mercaptopyridine introducing Ullmann reaction in the processimpurity , to reduce the formation of NaH , instead of K2CO3 were used the copper catalyst in order to minimize the amount of copper scavenge used to H2S instead of Na2S was used . the compound obtained in the process 1 of the purity is 96.6% and 3% with impurities of the 4,4′-dithiodipyridine this was confirmed copper impurity is 20 ppm was below . last Nolatrexed dihydrochloride in the process to obtain a 99.7% purity I scored the desired product , 0.3% ofunidentified impurity, and 10 ppm less than copper because it contains should think very advanced process compared to the previous number of ways . Fortunately Ullmann key contained in the reaction impurity in 4,4′-dithiodipyridine was automatically removed from the crystallization process of the last reaction. Korea Research Institute of Chemical Technology provides incurable disease treatment and research center, Dr. jaedu

View original	http://pubs.acs.org/doi/full/10.1021/op9002517

Route 1

Reference：1. J. Med. Chem. 1993, 36, 733-746.

2. WO9320055A1.

Route 2

Reference：1. Org. Process Res. Dev. 2008, 12, 1195-1200.

Route 3

Reference：1. Org. Process Res. Dev. 2010, 14, 346-350.

2. CN1335307A.

Route 4

Ref Chemical Reagents 2011, 33, 1131-1134..

References

Hughes AN, Rafi I, Griffin MJ, et al. (January 1999). “Phase I studies with the nonclassical antifolate nolatrexed dihydrochloride (AG337, THYMITAQ) administered orally for 5 days”. Clin. Cancer Res. 5 (1): 111–8. PMID 9918208.
“Nolatrexed”. PubChem.gov. Pub Chem. Retrieved 12 August 2014.

Nolatrexed
Names

IUPAC name 2-Amino-6-methyl-5-(4-pyridylthio)-1H-quinazolin-4-one
Identifiers
CAS Number	147149-76-6
ChemSpider	97268
Jmol 3D model	Interactive image
PubChem	108189
UNII	K75ZUN743Q
InChI [show]
SMILES [show]
Properties
Chemical formula	C₁₄H₁₂N₄OS
Molar mass	284.34 g/mol
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////Nolatrexed, thymidylate synthase inhibitor, AG337, THYMITAQ,

CC1=C(C2=C(C=C1)NC(=NC2=O)N)SC3=CC=NC=C3.Cl.Cl

CADROFLOXACIN

NDA, Uncategorized Comments Off

May 092016

Cadrofloxacin Structure

Cadrofloxacin , CS 940

3-Quinolinecarboxylic acid, 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-1,4-dihydro-7-[(3S)-3-methyl-1-piperazinyl]-4-oxo-, hydrochloride (1:1)

UNII-1YOQ7J9ACY; 153808-85-6; CADROFLOXACIN HYDROCHLORIDE; 1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[(3s)-3-methylpiperazin-1-yl]-4-oxo-1,4-dihydroquinoline-3-carboxylic acid;

1-cyclopropyl-8-(difluoromethoxy)-6-fluoro-7-[(3S)-3-methylpiperazin-1-yl]-4-oxoquinoline-3-carboxylic acid

Molecular Formula:	C₁₉H₂₀F₃N₃O₄
Molecular Weight:	411.37501 g/mol

Company：HengRui (Originator), Daiichi Sankyo (Originator), UBE (Originator)

A quinolone antibiotic potentially for the treatment of bacterial infections.

Research Code CS-940

CAS No. 153808-85-6(FREE)

Cas 128427-55-4(Cadrofloxacin HCl)

HYDROCHLORIDE

Molecular Weight	447.84
Formula	C19H20F3N3O4 • HCl

OriginatorSankyo; Ube Industries
DeveloperSankyo
ClassAntibacterials; Quinolones; Small molecules
Mechanism of ActionType II DNA topoisomerase inhibitors
- 20 Jun 1996An animal study has been added to the Bacterial infections pharmacodynamics section
- 24 Mar 1995Phase-II clinical trials for Bacterial infections in Japan (PO)

Cadrofloxacin hydrochloride was studied for the treatment of bacterial infections.The compound was originally developed by UBE and Daiichi Sankyo. However, this study was discontinued. The compound currently was developed by Hengrui.

SYNTHESIS

Decarboxylation of 3,5,6-trifluoro-4- hydroxyphthalic acid (I) upon heating at 140 C in an autoclave furnished 2,4,5-trifluoro-3-hydroxybenzoic acid (II). This was converted to ethyl ester (III) by refluxing in EtOH in the presence of H2SO4. Condensation of (III) with chlorodifluoromethane and NaH in hot DMF produced the corresponding difluoromethyl ether, and subsequent basic hydrolysis of the ethyl ester yielded 3- (difluoromethoxy) -2, 4,5-trifluorobenzoic acid (IV). Alternatively, acid (II) was converted to acid chloride with SOCl2 and subsequently condensed with ammonia to give amide (V). After formation of the difluoromethyl ether (VI) under similar conditions as above, acid (IV) was obtained by diazotization of the amide function of (VI) in hot sulfuric acid. The difluoromethoxy acid (IV) was also prepared by direct alkylation of hydroxy acid (II) with chlorodifluoromethane in the presence of NaOH in hot DMF. acid (IV) was activated as the corresponding acid chloride (VII) with SOCl2. Condensation of acid chloride (VII) with the magnesium salt of diethyl malonate gave rise to the benzoylmalonate (VIII). Further decarbethoxylation of (VIII) by heating in the presence of p-toluenesulfonic acid yielded keto ester (IX). This was condensed with triethyl orthoformate in the presence of Ac2O to give the ethoxyacrylate (X), which was converted to enamine (XII) by treatment with cyclopropylamine (XI). The target quinolone system (XIII) was then obtained by intramolecular cyclization of (XII) in the presence of NaH. Then, ethyl ester (XII) cleavage using boron trifluoride etherate provided the key quinolonecarboxylic acid boron chelate (XIV)

Route

US5073556A / US5348961A.

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Patent ID	Date	Patent Title
US2011159049	2011-06-30	PHARMACEUTICAL COMPOSITION
US2010330165	2010-12-30	USE OF CHEMOTHERAPEUTIC AGENTS
US2007196504	2007-08-23	PHARMACEUTICAL COMPOSITION
US2007197501	2007-08-23	Use Of Chemotherapeutic Agents
US2007148235	2007-06-28	PHARMACEUTICAL COMPOSITION
US2005152975	2005-07-14	Pharmaceutical composition
US2004022848	2004-02-05	Medicinal composition
US2003045544	2003-03-06	Use of chemotherapeutic agents