New Drug Approvals

Home » Posts tagged 'china' (Page 2)

Tag Archives: china

Advertisements
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO .....FOR BLOG HOME CLICK HERE

Blog Stats

  • 2,622,268 hits

Flag and hits

Flag Counter

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,416 other followers

Follow New Drug Approvals on WordPress.com

Categories

Flag Counter

ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

Enter your email address to follow this blog and receive notifications of new posts by email.

Join 2,416 other followers

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK PHARMACEUTICALS LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 year tenure till date Dec 2017, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 50 Lakh plus views on dozen plus blogs, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 19 lakh plus views on New Drug Approvals Blog in 216 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

Personal Links

Verified Services

View Full Profile →

Categories

Flag Counter
Advertisements

Lefucoxib (乐福昔布)


CID 16730197.pngC3

 

Lefucoxib (乐福昔布)

5-(3,4-dimethyl-phenyl)-1-methanesulfonyl-3-trifluoromethol-pyrazole

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole

CAS 849048-84-6

Molecular Formula: C19H17F3N2O2S
Molecular Weight: 394.41069 g/mol

IND FILED

Prostaglandin G/H Synthase 2 (PTGS2; COX-2) Inhibitors

A COX-2 inhibitor potentially for the treatment of rheumatoid arthritis.

cyclooxygenase-2 (COX-2) inhibitor

National Center of Biomedical Analysis

Example 1

1 [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1)

1- (3,4- two toluene-yl) -4,4,4-trifluoro-methyl – D-1,3-dione (IV1) of sodium metal was weighed 2.3g (0.1mol) was added 50ml of anhydrous toluene to prepare a sodium sand. After cooling, ethanol was added dropwise 12ml, and then heated at 60 ℃, complete reaction of sodium metal. After cooling to room temperature, was added 3,4-dimethylphenyl ethanone 23.8g (0.1mol) and trifluoroacetic ethyl acetate 20ml (0.2mol), reacted at 100 ℃ 5 hours. Toluene was distilled off under reduced pressure, a 10% aqueous hydrochloric acid was added, the pH was adjusted to 2-3, extracted with ethyl acetate, washed with water, dried over anhydrous MgSO4, ethyl acetate was distilled off under reduced pressure. Then under reduced pressure, distillation, collecting fractions 105-107 ℃ / 0.7mmHg, was 14.6g, 60% yield.

1- [4- (methylsulfonyl) phenyl] -3-trifluoromethyl-5- (3,4-dimethylphenyl) – pyrazole (I1) take the above-prepared substituted (IV1) 2.38g (0.01mol ), 15ml of ethanol, then added p-methanesulfonyl phenyl hydrazine salt alkoxide 2.3g (0.01ml). Was refluxed for 15 hours. Place the refrigerator overnight, the crystals were collected by filtration, recrystallized from ethanol, mp 129-31 ℃, to give 3.1 g.

Elemental analysis: C19H17F3N2O2S Calculated: C, 57.86; H, 4.34; N, 7.10 Found: C, 57.97; H, 4.29; N, 7.20MS (m / z): 395 (M + 1)

C4

 

CN101497585B Jan 31, 2008 Jan 12, 2011 中国科学院理化技术研究所 Method for photocatalytic synthesis of 1,3,5-trisubstituted-2-pyrazole derivative
Advertisements

China Generic Drugmakers Poaching Indian Execs


China Generic Drugmakers Poaching Indian Execs

Written by Richard Daverman, PhD, Executive Editor, Greg B. Scott.

In the competition between China and India pharmas, China’s generic drug industry leads in the supply of APIs to global drugmakers, but India supplies more finished generic drugs to the world’s marketplace. That may be changing. According to press reports,

China drugmakers have begun hiring experienced Indian pharma execs, offering them two to three times their present salaries.

The China companies are willing to pay at these levels because the Indian professionals have two skills the Chinese want: drug formulation experience and English.

China’s drugmakers want help as they target the western world’s lucrative generic drug market.

More details…. http://www.chinabiotoday.com/articles/20150903

 

///////////

Harbin Gloria to Commercialize Constipation Drug in China


Harbin Gloria to Commercialize Constipation Drug in China

Harbin Gloria Pharma in-licensed China rights to Amitiza, a novel anti-constipation drug from Sucampo Pharma of the US. Amitiza is a chloride channel activator, approved for US use in 2006, which acts in the small intestine. Gloria will be responsible for obtaining CFDA approval of the drug and then commercializing it in China. Gloria paid $1 million upfront and will be liable for additional milestone payments. More details….

– See more at: http://www.chinabiotoday.com/articles/20150512_1#sthash.YbauZ6qM.dpuf

http://www.chinabiotoday.com/articles/20150512_1

AMITIZA (lubiprostone)

 

 

Harbin Gloria Pharmaceuticals Co., Ltd. engages in the research, development, production, and sale of pharmaceutical products primarily in the People’s Republic of China. The company offers orthopedic medicines, antineoplastic products, medical-nutrition products, rheumatology drugs, digestive and respiratory system medicines, cardiovascular medicines, liver disease medications, gynecology medications, and antibiotics. It also provides circulatory system, pediatrics, uropoiesis and reproduction, immune regulation, and other products. Harbin Gloria Pharmaceuticals Co., Ltd. was founded in 2000 and is based in Harbin, the People’s Republic of China.

No. 29, Beijing Road

Limin Economic & Technological Development Zone

Harbin,  150025

China

Founded in 2000

Phone:

86 451 5735 1368

Fax:

86 451 5735 1992

www.gloria.cc

Harbin

Map of harbin china

 

 

 

 

 

Allisartan isoproxil


 

Figure US20100292286A1-20101118-C00007

 

Allisartan isoproxil

CAS: 947331-05-7

553.01, C27 H29 Cl N6 O5

An angiotensin II receptor antagonist used to treat mild to moderate essential hypertension.

Approved china, cfda July 1 2012

Shanghai Allist Pharmaceutical, Inc.

Allist Shanghai Pharmaceutical Co., Ltd.

2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-methyl]-imidazole-5-carboxylic acid, 1-[(isopropoxy)-carbonyloxy] methyl ester,

2-Butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid isopropoxycarbonyloxymethyl ester

2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester

Allisartan is an orally-available angiotensin AT1 antagonist in phase II clinical trials at Shanghai Allist Pharmaceutical for the treatment of mild to moderate essential hypertension.

Shanghai Allist Pharmaceutical PHASE 2 for Hypertension

 

The prior art discloses Arleigh medoxomil illiquid, low bulk density, electrostatic phenomena evident. Chinese patent discloses a CN200710094131.0 Alicante medoxomil polymorph and method of preparation. Allie medoxomil based crystal prepared by the method has high stability characteristics, but relatively small bulk density of the crystal clear after the electrostatic phenomenon and poor liquidity dried, crushed and used for easy dispensing generate dust, operating the site clean and labor protection inconvenience, on the other hand also for accurate weighing and packaging products inconvenience.

CN200710094021.4 and CN201110289695.6 disclose the preparation of Alicante medoxomil, the inventor repeated, the proceeds of crystal and Chinese patent CN200710094131.0 consistent disclosed.

 

Figure US20100292286A1-20101118-C00002

Allisartan isoproxil

Angiotensin II AT-1 receptor antagonist

Essential hypertension

Amorphous form of allisartan isoproxil is claimed in WO 2015062498. Useful for treating hypertension. Shenzhen Salubris Pharmaceuticals, in collaboration with Allist, has developed and launched allisartan isoproxil. In October 2012, Shenzhen Salubris signed a strategic cooperation framework agreement with Allist Pharmaceutical for the production and marketing of allisartan isoproxil. Family members of the product case of allisartanWO2007095789, expire in the EU and in the US in 2026. For a prior filing see WO2009049495 (assigned to Allist Pharmaceuticals), claiming the crystalline form of allisartan and its method of preparation.

The compound of formula (I) is an Ang II receptor antagonist. Its chemical name is 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)-1,1′-biphenyl-methyl]-imidazole-5-carb-oxylic acid, 1-[(isopropoxy)-carbonyloxy] methyl ester. Chinese Patent CN101024643A describes the structure, and its use as antihypertensive drugs.

Figure US20100292286A1-20101118-C00001

As regards to the solid physical properties of the compound of formula (I), the patent document of CN101024643A discloses that it is a white solid, and its melting point is 134.5-136° C. However, CN101024643A dose not disclose the crystalline structure of the compound of formula (I).

Figure US20100292286A1-20101118-C00003

CHINA

 

 

 

NEW PATENT

WO-2015062498

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015062498

2-butyl-4-chloro -1- [2 ‘- (1H- tetrazol-5-yl) -1,1’-biphenyl- – methyl] – imidazole-5-carboxylic acid, 1 – [(isopropoxy) – oxy] -, methyl ester, is a novel angiotensin Ⅱ receptor antagonist. China Patent CN200680000397.8 disclosed structural formula Alicante medoxomil compound. Allie medoxomil toxicity, blood pressure better than the same type of products (such as losartan), which by generating active metabolite (EXP3174) in vivo metabolism, and thus play its antihypertensive effect.

 

The prior art discloses Arleigh medoxomil illiquid, low bulk density, electrostatic phenomena evident. Chinese patent discloses a CN200710094131.0 Alicante medoxomil polymorph and method of preparation. Allie medoxomil based crystal prepared by the method has high stability characteristics, but relatively small bulk density of the crystal clear after the electrostatic phenomenon and poor liquidity dried, crushed and used for easy dispensing generate dust, operating the site clean and labor protection inconvenience, on the other hand also for accurate weighing and packaging products inconvenience.
CN200710094021.4 and CN201110289695.6 disclose the preparation of Alicante medoxomil, the inventor repeated, the proceeds of crystal and Chinese patent CN200710094131.0 consistent disclosed.

……………………..

PATENT

http://www.google.com/patents/CN103965171A?cl=en

Hypertension is a major disease threat to human health, looking for efficiency, low toxicity anti-hypertensive drugs can help relieve social pressures and family responsibilities, with good social and economic benefits.

 Angiotensin II (Ang II) is the renin – angiotensin – aldosterone system (RAAS) main vasoconstrictor hormone, which plays an important role in the pathobiology of many chronic diseases, particularly its the role of blood pressure regulation is particularly prominent, and therefore Ang II receptor is believed to be a good target for the development of anti-hypertensive drugs.

EP0253310 discloses a series of imidazole derivatives, DuPont declared and obtained by the study of losartan potassium-listed in 1994, was the first non-peptide Ang II receptor antagonist anti-hypertensive drugs. Thereafter, he listed a series of losartan antihypertensive drugs: candesartan cilexetil, valsartan, irbesartan, telmisartan and olmesartan medoxomil, etc. (EP0253310, W02005049587, GB2419592, EP1719766, US5196444) .

The losartan potassium in the body, the active metabolite EXP3174 has a stronger antihypertensive effect than losartan potassium, but EXP3174 polar molecular structure, is difficult to form passive absorption by diffusion through the cell membrane. US5298915 discloses five carboxyl ester group transformation EXP3174 is a series of derivatives, focusing on the compound HN-65021, and discloses hypotensive test results HN-65021 administered by the oral route, its hypotensive activity with chlorine Similar losartan potassium (BritishJouurnal ofClinical Pharmacology, 40,1995,591).

CN200680000397.8 _5_ discloses a class of imidazole carboxylic acid derivatives, namely Alicante medoxomil compound 8 has a good blood pressure lowering effect, the structure of formula I, the preparation method disclosed in this patent document follows the route A, losartan potassium by oxidation, the protecting group into an ester, deprotected to give a compound of formula I, the route step oxidation process of hydroxyl to carboxyl groups, will be reduced to very fine granular potassium permanganate, manganese dioxide, filtration This manganese mud time-consuming, inefficient, polluting; the second step conversion was about 70%, and post-processing cumbersome; byproducts and produced the first two steps more. This makes the high cost of the entire route, not suitable for the production of amplification.

 

Figure CN103965171AD00061

CN200710094021.4 discloses another method for preparing the compounds of formula I, the following route B, the starting material by nucleophilic substitution, oxidation, an ester, a tetrazole ring to obtain a compound of formula I, the first step of the method nucleophilic substitution easy to generate an imidazole ring -3 para isomer impurities difficult to remove; the last step into the ring to use sodium azide, operating dangerous.

 

Figure CN103965171AD00071

CN201210020174.5 disclosed a series of anti-hypertensive compound and preparation method, the following line C, the temperature control in the first step of its preparation O ~ 5 ° C, a mixed solution of acetone and water, with a 5% aqueous solution of sodium hypochlorite oxidation, yield 70%, the second step use of potassium permanganate, manganese dioxide will produce the same, and a yield of only 40%, the first two steps total yield of 28%, is very low, and the post-treatment methods are by column separation, the first two steps are used are organic and inorganic mixed solvent is not conducive to recovery, not suitable for scale-up.

 

Figure CN103965171AD00081

 

Figure CN103965171AC00021

 

Figure CN103965171AC00022

 

Figure CN103965171AC00023

 

Figure CN103965171AC00031

 

Figure CN103965171AC00032

Example 8 2-Butyl-4-chloro _1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole

5-carboxylic acid, 1 – [(isopropoxy) carbonyl] -L-methoxy ester (Alicante medoxomil crude)

 

Figure CN103965171AD00162

To a 20L reactor 9800ml of methanol, stirring was started, the rotational speed is added at 200r / min 1225.3g solid compound of formula II, and heated to reflux. The reaction 8-10h evacuation HPLC detection, the formula II compound residue <1.0% seen as a response endpoint. After reaching the end of the reaction the heating was stopped, continued stirring speed of 180r / min. About 3_4h fell 20_25 ° C, colorless transparent crystalline solid precipitated. The reaction mixture was cooled to continue to 15-20 ° C, to maintain 15-20 ° C with stirring 3h, the reaction mixture was filtered to give a pale yellow clear filtrate. The filtrate was concentrated under reduced pressure to move 20L flask, vacuum degree of 0.075MPa, 40_45 ° C methanol distilled off under until no distillate. 800ml of absolute ethanol was added, a vacuum degree of 0.075MPa, 40-45 ° C under distillation until no distillate.

900ml of absolute ethanol was added, heated to reflux. N-heptane was added slowly 1100ml, reflux 15min, to -10 ° c / h speed cooled to 15 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = 1 mixture of filter cake was washed / 3, the back pressure dry vacuum filtration lh, was Allie medoxomil crude (800.lg, yield 93.8%).Purification was used directly in the next step without drying.

 Example 9 2-butyl-4-chloro-_1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole-5-carboxylic acid, 1 – [(isopropylamino oxy) carbonyl] -L-methoxy ester (Alicante medoxomil)

 

Figure CN103965171AD00171

850ml of absolute ethanol was added to the 3L reaction vessel was charged with crude Alicante medoxomil (800.lg, 1.45mol), heated to reflux. After completely dissolved clear, slow addition of n-heptane 1300ml, reflux 15min, to -10 ° C / h speed cooled to 10 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = 1 mixture of filter cake was washed / 3, the back pressure dry vacuum filtration, the purified Alicante medoxomil (780.9g, 97.6% yield).

Example 10 2-butyl-4-chloro _1- [2 ‘- (1-tetrazol-5-yl biphenyl – methyl] imidazole

5-carboxylic acid, 1 – [(isopropoxy) carbonyl] -L-methoxy ester (Alicante medoxomil)

 

Figure CN103965171AD00172

950ml of absolute ethanol was added to the 5L reaction vessel was charged with crude Alicante medoxomil (549.9g, 1.72mol), heated to reflux. After completely dissolved clear, slow addition of n-heptane 1200ml, reflux 15min, to -10 ° C / h speed cooled to 10 ± 2 ° C, keep stirring 3h. Filtered under reduced pressure, ethanol / n-heptane = cake was washed with a mixture of 1/3, and dried under reduced pressure after filtration to obtain a purified Alicante medoxomil (540.0g, 98.2% yield).

……………….
PATENT

Example 122-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester (compound 8)

Figure US20090036505A1-20090205-C00031

To a 100 ml of one-necked flask, 0.523 g of material, 0.124 g of potassium carbonate, 5 ml of N,N-dimethylacetamide were added in turn. The solution was stirred at room temperature for 20 minutes. Then 0.562 g of 1-chloromethyl isopropyl carbonate was added and the mixture was reacted at 45-50° C. for 16 hours. After the reaction was completed, the mixture solution was filtered, and 30 ml of water was added into the filtrate. The resulting mixture was extracted with 30 ml of ethyl acetate twice. The organic phase was dried and concentrated to give 1.724 g of oil, which was directly used in the next reaction without purification.

10 ml of dioxane and 5 ml of 4 mol/L HCl were added, and the resulting mixture was reacted at room temperature for 16 hours. The reaction was stopped and the solution was adjusted to pH 6-7 using aqueous sodium bicarbonate solution. The solution went turbid, and was extracted with ethyl acetate. The organic phase was washed with saturated brine, dried, concentrated to give 0.436 g of 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester.

In addition, the following reaction condition can be used to deprotect the protecting group. To 1.7 g of oily product, 5 ml absolute methanol was added and the mixture was heated slowly to reflux and stirred for 8 hours. When the insoluble solid disappeared totally, the mixture was discontinued to heating and cooled to 5° C. The white solid precipitated, and was separated by filtration, and the filter cake was washed with a small quantity of methanol. The combined filtrate was concentrated to dryness to give 2-butyl-4-chloro-1-[2′-(1H-tetrazol-5-yl)1,1′-biphenyl-methyl]imidazole-5-carboxylic acid, 1-[(isopropoxycarbonyl)oxy]methyl ester with the yield of 70%.

1H-NMR (CDCl3) δ H (ppm): 0.89 (t, 3H, J=14.6), 1.24 (d, 6H, J=6.3), 0.37 (m, 2H, J=22.1), 1.69 (m, 2H, J=30.5), 2.64 (t, 2H, J=15.5), 4.81 (m, 1H, J=12.4), 5.54 (s, 2H), 5.86 (s, 2H), 6.95-7.64 (8H), 8.08 (d, 1H, J=7.42)

ESI(+) m/z: 552.7

Mp: 134.5-136° C.

 str1
 USE CTRLand + Key, or click on picture
str1
str1
 
WO2005011646A2 * 20 Jul 2004 10 Feb 2005 Nicoletta Almirante Nitrooxy derivatives of losartan, valsatan, candesartan, telmisartan, eprosartan and olmesartan as angiotensin-ii receptor blockers for the treatment of cardiovascular diseases
Citing Patent Filing date Publication date Applicant Title
US8455526 * 6 Jun 2008 4 Jun 2013 Shanghai Allist Pharmaceuticals, Inc. Therapeutic use of imidazole-5-carboxylic acid derivatives
US20100168193 * 6 Jun 2008 1 Jul 2010 Shanghai Allist Pharmaceuticals, Inc. Therapeutic use of imidazole-5-carboxylic acid derivatives
USRE44873 31 Jul 2006 29 Apr 2014 Salubris Asset Management Co., Ltd. Imidazole-5-carboxylic acid derivatives, the preparation method therefor and the uses thereof
CN101024643A 20 Feb 2006 29 Aug 2007 上海艾力斯医药科技有限公司 Imidazo-5-carboxylic-acid derivatives, its preparing method and use
US5298519 * 24 Sep 1992 29 Mar 1994 Chemish Pharmazeutische Forschungsgesellschaft M.B.H. Acylals of imidazole-5-carboxylic acid derivatives, and their use as angiotensin (II) inhibitors

……………….

 

update……………..

WO 2015192722

Example 1

Weigh 25g 2- butyl-4-chloro-1- [2 ‘- (1-trityl–1H- tetrazol-5-yl) -1,1’-biphenyl – methyl] – imidazole 5-carboxylic acid, 1 – [(isopropoxy) – carbonyloxy] -, methyl ester, was added to a 500ml three-necked flask, methanol was added 200ml, refluxed for 9h, methanol was distilled off under reduced pressure to give crude Alicante medoxomil .


To the residue (i.e., medoxomil crude Alicante) were added 33ml of isopropanol and 66ml of n-heptane, heated to 76 ℃ stirred for 2h. After cooling to 60 ℃ stirring for 1h, and then the system was slowly cooled to 0 ℃, stirring was continued for 3h. Filtered, the filter cake was washed with n-heptane. At 40 ℃ 8 hours and dried in vacuo to give 15.3g Alicante medoxomil (purity 99.3%) as a XRD spectrum as shown in Figure, the main peak of the diffraction peaks as shown in the following table, the DSC spectrum shown in figure II . Compared with the published crystal, the crystal obtained by the absence of significant electrostatic phenomena.

 

 

 

Shanghai , CHINA

 

 

What is SMU-B?


Figure CN101851237BD00291

cas 1253286-89-3

Spiro[3H-​indole-​3,​4′-​piperidin]​-​2(1H)​-​one, 5-​[6-​amino-​5-​[(1R)​-​1-​(2,​6-​dichloro-​3-​fluorophenyl)​ethoxy]​-​3-​pyridinyl]​-​1′-​methyl-

SMU-B

or is it

china 1

1253286-90-6

Spiro[3H-​indole-​3,​4′-​piperidin]​-​2(1H)​-​one, 6-​[6-​amino-​5-​[(1R)​-​1-​(2,​6-​dichloro-​3-​fluorophenyl)​ethoxy]​-​3-​pyridinyl]​-​1′-​methyl-

SMU-B

Abstract Image

A series of novel aminopyridyl/pyrazinyl-substituted spiro[indoline-3,4′-piperidine]-2-ones were designed, synthesized, and tested in various in vitro/in vivo pharmacological and antitumor assays. 6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (compound 5b or SMU-B) was identified as a potent, highly selective, well-tolerated, and orally efficacious c-Met/ALK dual inhibitor, which showed pharmacodynamics effect by inhibiting c-Met phosphorylation in vivo and significant tumor growth inhibitions (>50%) in GTL-16 human gastric carcinoma xenograft models.

see..http://pubs.acs.org/doi/abs/10.1021/ml400203d

ACS Med. Chem. Lett., 2013, 4 (8), pp 806–810
DOI: 10.1021/ml400203d

cas 1253286-90-6

6-[6-Amino-5-[(1R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy]-3-pyridyl]-1′-methylspiro[indoline-3,4′-piperidine]-2-one (compound 5b or SMU-B)

SEE

CN 101851237

南方医科大学

Figure CN101851237BD00142

1_4,3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-nitro-approved P set

 

Figure CN101851237BD00251

  obtained in Step 1-3 (IS) -I- (2,6- dichloro-3-fluorophenyl) ethanol (2. 09g, IOmmol) was dissolved in dry THF (80 ml). Then, at room temperature under a nitrogen atmosphere, a solution of 3-hydroxy-2-nitro-pyridine (1.54g, llmmol) and triphenylphosphine (3. 409g, 13mmol), and so is completely dissolved, cooled to 0 ° C, was added Diisopropyl azodicarboxylate (DIAD, 2.63g, 13mmol), After the addition, the mixture was stirred at 0 ° C for 16 hours, the solvent was removed by rotary evaporation and the oily residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate : 4/1) to give the desired product as a white solid (3. 046g, yield: 92%) o 1H-NMR (CDClySOOMHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), 6 . 10 (q, J = 6. 4Hz, 1H), 7. 09 (dd, J = 7. 6,8. 8Hz, 1H), 7. 21 (dd, J = 8. 4, I. 2Hz, 1H ), 7. 31 (dd, J = 4. 8,8. 8Hz, 1H),

7. 37 (dd, J = 4. 8,8. OHz, 1H), 8. 04 (dd, J = L 6,4. 4Hz, 1H). Mass spectrum m / z:. 330 94 [M + H, 35C1,35Cl], 332. 92 [M + H, 35Cl, 37Cl].

  1_5,3_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -2_ atmosphere based grant given P

 

Figure CN101851237BD00252

to take steps 1-4 to get the 3 – [(lR) _l- (2,6_ dichloro-3-fluorophenyl) ethoxy] -2_ nitro than Li Jie (2. 649g, 8mmol) was dissolved in ethanol (15mL) was added iron powder (3. 575g, 64mmol) were mixed under nitrogen with vigorous stirring at 90 ° C oil bath, was added via syringe 0.8mL IM HCl (aq), after 10 minutes, was added 0. 8mL IMHCl (aq). Stirring was continued for 30 minutes, TLC showed the reaction. Cooled to room temperature, filtered through Celite, the filter residue washed with ethanol (3X IOmL). The combined organic phase was removed by rotary evaporation of the solvent gave the desired product as a light brown solid (2. 41g, yield: 100%) o 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 81 (d, J = 6. 8Hz, 3H ), 5. 03 (s, br, 2H), 6. 01 (q, J = 6. 8Hz, 1H), 6. 47 (dd, J = 4. 8,7. 6Hz, 1H), 6. 70 (d, J = 8. OHz, 1H), 7. 05 (t, J = 8. 8Hz, 1H), 7. 28 (dd, J = 4. 0,8. 0Hz, 1H), 7. 57 ( d, J = 5.2Hz, lH). Mass spectrum m / z:. 301 00 [M + H, 35Cl, 35Cl], 302. 77 [M + H, 35Cl, 37Cl].

  l-6,5_ desert _3_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -2_ atmosphere base than Li Jie

 

Figure CN101851237BD00261

The steps 1-5 obtained 3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-yl atmosphere than Li Jie (1.506g, 5mmol) dissolved in acetonitrile (20mL) in. Then, at 0 ° C and the degree of stirring in added portionwise N- bromosuccinimide (0.908g, 5. Lmmol), After the addition, stirring was continued for 30 minutes. The solvent was removed by rotary evaporation, the crude product was obtained as a white solid was the desired product (1.045g, yield: 55%) was purified by column chromatography on silica gel. 1H-NMR (⑶Cl3,500MHz): 8 (ppm) I. 81 (d, J = 6. 8Hz, 3H), 4 85 (s, br, 2H), 6 98 (q, J = 6. 8Hz.. , 1H), 6. 82 (d, J =

2. 0Hz, 1H), 7. 08 (t, J = 8. 4Hz, 1H), 7. 31 (dd, J = 4. 8,8. 8Hz, 1H), 7. 65 (d, J = 2 . OHz, 1H). Mass spectrum m / z:… 378 84 [M + H, 35Cl, 35Cl, 79Br], 380 82 [M + H, 35Cl, 35Cl, 81Br or 35Cl, 37Cl, 79Br], 382 80 [M + H, 35Cl , 37Cl, 81Bror 37Cl, 37Cl, 79Br].

Step 2, I ‘- methyl-5- (4,4,5,5-tetramethyl -I, 3,2- dioxolane boron-2-yl) spiro [indoline Spray – 3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00262

  2-1,5- bromo -I ‘- methyl-spiro [indoline-3,4’ – piperidin] _2_ one

 

Figure CN101851237BD00263

[0300] 5-bromo – indol-2-one (I. 272g, 6mmol) was suspended THF (15mL) at, and cooled to -78 ° C, added dropwise with stirring IM NaN (SiMe3) THF solution of 2 (30mL, 30mmol). After the addition was stirred at _78 ° C 30 min, then 2-chloro -N- (2- chloro-ethyl) -N- methyl-ethylamine hydrochloride solid (I. 155g, 6mmol). After the addition stirring was continued for 30 minutes, then warmed to room temperature and stirred for two days. TLC showed the reaction was completed, to the pink suspension was carefully added aqueous 4M hydrochloric acid (IOmL), and then adjusted with concentrated aqueous ammonia to pH ^ 9, and extracted with DCM (3 X 80mL). The organic phases were combined, dried (Na2SO4), and concentrated to give the crude product was purified by silica gel column chromatography (7M NH3 in methanol solution / DCM: 5/95) to give the desired product (I. 38g, yield: 78%) was purified. 1H-NMR (CD3ODjOOMHz):. 8 (ppm) I. 86-1 92 (m, 2H), I 94-1 98 (m, 2H), 2 44 (s, 3H), 2 62-…. 2. 68 (m, 2H), 2. 86-2. 91 (m, 2H), 6. 76 (d, J = 7. 6Hz, 1H), 7. 33 (dd, J = I. 2,7 . 6Hz, 1H), 7. 44 (d, J = I. 6Hz, 1H), 7. 81 (s, br, 1H). Mass spectrum m / z:. 294 99 [M + H, 79Br], 296 82 [M + H, 81Br]..

2-2, V – methyl-5- (4,4,5,5-tetramethyl–1,3,2_ dioxolane Borane _2_ yl) spiro [indoline – 3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00271

Under nitrogen, obtained in Step 2-1 to 5-bromo -I ‘- methyl-spiro [indoline-_3,4’ – piperidin] _2_ one (147. 6mg, 0. 5mmol) , the United pinacols drop acid unitary purpose (140mg, 0. 55mmol) and acetic acid Bell (147mg, I. 5mmol) in DMSO (0. 2ml) was added in PdCl2 (dppf) • CH2Cl2 (20. 4mg, 0. 025mmol ), to the resulting solution was bubbled with nitrogen for 2 minutes, and then stirred at 80 ° C of 16 hours. LC-MS showed completion of the reaction, after cooling to room temperature, water (2mL), extracted with DCM (3X5mL). The organic phases were combined, dried (Na2SO4), and concentrated to give the desired product (170mg, yield: 100%) o MS m / z:. 342 07 [M + H], 343. 08 [M + H, 100%], 344. 11 [M + H].

  Step 3,5_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3_ batch P fixed base] -I ‘- A group spiro [indoline-3,4 ‘- piperidin] -2_ one

The steps 1-6 5_ desert obtained _3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] -2-yl batch atmosphere pyridine (75. 8mg , 0. 2mmol), I’- step 2_2 obtained methyl 5- (4,4,5,5-tetramethyl-l, 3,2-dioxolane Borane 2-yl) spiro [ indoline-3,4′-piperidin] -2-one (82mg, 0. 24mmol) and potassium carbonate (82. 9mg, 0. 6mmol) was dissolved in DME / water mixture solution (4 / 1,2. Oml ). Then, under nitrogen, was added Pd (PPh3) 4 (II. 6mg, 0. Olmmol), to the resulting mixture was bubbled with nitrogen for 2 minutes, and then stirred at 80 ° C of 18 hours. LC-MS showed completion of the reaction, after cooling to room temperature, water (5mL), extracted (3 X IOmL) with DCM. The organic phases were combined, dried (Na2SO4), and concentrated to give the crude product was purified by silica gel column chromatography (7M NH3 in methanol solution / DCM: 5/95) to give the desired product (88. 6mg, yield: 86%) was purified. 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), I 93-2 02 (m, 4H), 2 44 (s, 3H),…

2. 66-2. 72 (m, 2H), 2. 89-2. 93 (m, 2H), 4. 87 (s, br, 2H), 6. ll (q, J = 6. 4Hz, 1H ), 6. 88 (d, J =

8. OHz, 1H), 6. 94 (d, J = I. 2Hz, 1H), 7. 06 (t, J = 8. 4Hz, 1H), 7. 19 (dd, J = I. 2,8 . OHz, 1H),

7. 31 (m, 1H), 7. 36 (s, 1H), 7. 66 (s, br, 1H), 7. 80 (d, J = 2. OHz, 1H). Mass spectrum m / z:.. 515 05 [M + H, 35Cl, 35Cl], 517 03 [M + H, 35Cl, 37Cl].

  Example 2: 6_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3_ than Li Jie base] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00281

Step I, I ‘- methyl-6- (4,4,5,5-tetramethyl–I, 3,2- dioxolane boron-2-yl) spiro [indoline Spray – 3,4 ‘- piperidin] -2_ one

  1-1,6- bromo -I ‘- methyl-spiro [indoline-3,4’ – piperidin] -2_ one

 

Figure CN101851237BD00282

  As described in Example I steps 2-1 of the method from the commercially available 6-bromo – indol-2-one was prepared, Yield: 82%. Analysis of the data obtained the desired product are = 1H-Nmr (Cd3OdJOOmHz): 8 (ppm) 1.90-1.98 (m, 4H),

2. 44 (s, 3H), 2. 64-2. 68 (m, 2H), 2. 86-2. 92 (m, 2H), 7. 05 (d, J = 2. 0Hz, 1H), 7. 16-7. 21 (m, 2H), 7. 91 (s, br, 1H). Mass spectrum m / z: 295 00 [M + H, 79Br], 296 78 [M + H, 81Br]… [0312] 1-2, 1 ‘- methyl-6- (4,4,5,5-tetramethyl-_1,3,2_ dioxolane Borane _2_ yl) spiro [indoline – 3,4 ‘- piperidin] -2_ one

 

Figure CN101851237BD00283

In the step 1-1 of the obtained 6-bromo -I ‘- methyl-spiro [indoline-_3,4’ – piperidin] -2_ ketone and commercially available linking pinacol boronic ester material, the method of Example I was prepared in accordance with steps 2-2, Yield: 95%. Analysis of the data obtained of the target product are as follows: Mass spectrum m / z:. 342 06 [M + H], 343 04 [M + H, 100%], 344. 12 [M + H]..

  Step 2,6_ [6_ atmosphere base _5_ [(IR) -I- (2,6_ two gas -3- gas phenyl) ethoxy] -3 ratio Li Jie base] -I ‘- methyl-spiro [indoline-3,4 ‘- piperidin] -2_ one

  Example I steps 1-6 to obtain 5-bromo -3 – [(IR) -I- (2,6- dichloro-3-fluorophenyl) ethoxy] -2-amino- pyridine, I obtained in Example 1-2 of the present embodiment in step ‘- methyl-6- (4,4,5,5-tetramethyl-l, 3,2-dioxolane-2-yl borane) spiro [indoline-_3,4 ‘- piperidin] -2-one, prepared as in Example I Step 3. Yield: 82%. 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 86 (d, J = 6. 4Hz, 3H), I. 91-1 95 (m, 2H), I 97-2 03 (m, 2H… ), 2. 45 (s, 3H), 2. 65-2. 72 (m, 2H), 2. 89-2. 95 (m, 2H), 5. 12 (s, hr, 2H),

6. 12 (q, J = 6. 4Hz, 1H), 6. 94-7. 00 (m, 3H), 7. 06 (t, J = 8. 4Hz, 1H), 7. 31 (m, 1H ), 7. 35 (d, J = 7. 2Hz, 1H), 7. 90 (d, J = 2. 0Hz, 1H), 9. 28 (s, br, 1H). Mass spectrum m / z:.. 515 05 [M + H, 35Cl, 35Cl], 517 03 [M + H, 35Cl, 37Cl].

5- [6-amino-5 – [(2,6-dichloro-3-fluorophenyl) methoxy] _3_ pyridinyl] -I’–methyl-spiro [indole: 3 [0317] Example morpholine-3,4 ‘- piperidin] -2-one

 

H2N N

 

Figure CN101851237BD00291
Figure CN101851237BD00292
Figure CN101851237BD00293

Step I, 5_ desert _3_ (2,6_ two gas -3- integrity oxy) _2_ atmosphere based grant given P

  1-1,2,6_ two gas acid gas _3_

 

Cl OF

Sodium hydroxide (13g, 325mmol) in water (IlOmL) was cooled to _5 ° C was added dropwise under vigorous stirring of liquid bromine (12. 5g, 78. 2mmol), added after the addition of pre-cooled to 10 ° C dioxane (75mL). The above mixture under vigorous stirring was added dropwise a pre-cooled to 5 ° C of I- (2,6- dichloro-3-fluorophenyl) ethanone (5g, 21. 2mmol) in dioxane (330mL) and water (90mL) was added. After the addition, at room temperature for 2 hours Lan Xiang, Xiang Lan then 90 C for 30 minutes. TLC was not shown with the S starting material disappeared, and was acidified with concentrated hydrochloric acid to PH~9. The resulting mixture was rotary evaporated to dryness, added water (20mL), and extracted with diethyl ether (2X80mL), the organic phases were combined, dried (Na2SO4), and concentrated to give an oily product solidified after cooling to a transparent, slightly yellow solid (3. 4g, Yield: 67%). 1H-Nmr (Cdci3AOOmHz):. 8 (ppm) 7. 21 (. Dd, J = 8. 0,8 8Hz, 1H), 7 35 (. Dd, J = 4. 4,9 2Hz, 1H), 9 . 79 (s, br, 1H). Mass spectrum m / z (ES “:. 207 11 [M_H, 35Clj35Cl], 209 10 [MH, 35Cl, 37Cl]..

  1-2,2,6–dichloro-3-fluoro-benzyl alcohol

 

^ Coh

F

[0325] To be filled with 2,6-dichloro-3-fluoro benzoic acid (3g, 14. 35mmol) added dropwise to the flask IM BH3. THF (43mL, 43mmol), added after the mixture was stirred under reflux for 24 hours. TLC showed the reaction was complete, methanol (50mL) to destroy excess borane, and the solvent was distilled off under reduced pressure and the resulting trimethyl borate, the process is repeated twice more to give a viscous product 2. I g, yield: 75% . 1H-Nmr (Cdci3JOOmHz): 8 (ppm) 2. 09 (t, J = 6. 4Hz, 1H), 4. 97 (d, J = 6. 4Hz, 2H), 7 09 (t, J = 8. . 8Hz, 1H), 7. 32 (dd, J = 4. 8,9. 1Hz, 1H). Mass spectrum m / z (ES-):.. 193 08 [M_H, 35Cl, 35Cl], 195 12 [MH, 35Cl, 37Cl].

  1-3,3_ (2,6-gas _3_ integrity oxy) _2_ nitro grant given P

 

Figure CN101851237BD00301

Following the procedure of steps 1-4 of Example I, was prepared from 2,6-dichloro-3-fluoro-benzyl alcohol and 3-hydroxy-2-nitropyridine prepared in yield (in this example embodiment steps 1_2) : 90%. 1H-Nmr (Cdci3AOOmHz): 8 (ppm) 5. 45 (s, 2H), 7 20, 7 37 (dd, J = 4. 8. (Dd, J = 8. 0,9 2Hz, 1H.). , 9. 2Hz, 1H), 7. 59 (dd, J = 4. 4,8. 4Hz, 1H),

7. 74 (dd, J = L 2,8. 4Hz, 1H), 8. 17 (dd, J = L 6,4. 4Hz, 1H). Mass spectrum m / z:. 316 89 [M + H, 35Cl, 35Cl], 318. 89 [M + H, 35Cl, 37Cl].

  1_4,3_ (2,6-gas _3_ integrity oxy) _2_ atmosphere based grant given P

 

Figure CN101851237BD00302

The method according to Example I step 1_5 from 3- (2,6-gas -3- integrity oxy) _2_ nitro Jie ratio 唳 preparation (in this case, steps 1-3), that Yield: 95% o 1H-Nmr (Cdci3JOOmHz):. 8 (ppm) 4 65 (s, br, 2H), 5 31 (s, 2H), 6 66 (dd, J = 5. 2,8.. . 0Hz, 1H), 7. 14 (dd, J = I. 2,8. 0Hz, 1H), 7. 18 (dd, J =

8. 4,9. 2Hz, 1H), 7. 37 (dd, J = 4. 8,8. 8Hz, 1H), 7. 73 (dd, J = I. 6,5. 6Hz, 1H). Mass spectrum m / z:. 286 95 [M + H, 35Cl, 35Cl], 288 85 [M + H, 35Cl, 37Cl]..

  1-5,5_ desert -3- (2,6-gas -3_ integrity oxy) ~ 2 ~ atmosphere based grant given P

 

Figure CN101851237BD00303

Following the procedure of Example I step 1_6 embodiment, starting from 3- (2,6-gas _3_ integrity yloxy) _2_ atmosphere group given the preparation of the batch P (in the example of the present embodiment in step 1-4), Yield: 60% o 1H-Nmr (Cdci3JOOmHz):. 8 (ppm) 4 68 (s, br, 2H), 5 28 (s, 2H), 7 21 (dd, J = 8. 0,8.. . 8Hz, lH), 7. 24 (dd, J = 2. OHz, 1H), 7. 39 (dd, J = 4. 8,

9. 2Hz, 1H), 7. 78 (d, J = 2. OHz, 1H). Mass spectrum m / z:. 364 83 [M + H, 35Cl, 36Cl, 79Br], 366 77 [M + H], 368 69 [M + H]…

  Step 2,5_ [6_ atmosphere base _5_ [(2,6_ two gas -3- gas) methoxy] -3_ than Li Jie base] -I-methyl-spiro [indoline _ 3,4 ‘- piperidin] -2-one

The present embodiment 5_ desert steps 1_5 obtained _3_ (2,6_ two gas _3_ integrity yloxy) pyridine ~ 2 ~ atmosphere, Examples 2-2 obtained in step I I ‘- methyl-5- (4,4,5,5-tetramethyl-borane _1,3,2- dioxolane-2-yl) spiro [indoline-_3,4’ – piperidine ] -2-one, prepared as in Example I Step 3. Yield: 85 V0o 1H-Nmr (Cdci3JOOmHz):.. 8 (ppm) I. 92-2 02 (m, 4H), 2. 43 (s, 3H), 2. 65-2 71 (m, 2H) , 2. 90-2. 91 (m, 2H), 4. 92 (s, br, 2H), 5. 52 (s, 2H), 6. 89 (d, J = 8. 4Hz, 1H), 6 . 90 (d, J = L 2Hz, 1H), 7. 06 (t, J = 8. OHz, 1H), 7. 21 (dd, J = L 2,8. OHz, 1H), 7. 31 ( m, 1H),

7. 37 (s, 1H), 7. 79 (s, br, 1H), 7. 80 (d, J = 2.0Hz, lH). MS m / z:. 501 06 [M + H, 35Cl, 35Cl], 503 04 [M + H, 35Cl, 37Cl]..

6- [6-amino-5 – [(2,6-dichloro-3-fluorophenyl) methoxy] _3_ pyridinyl] -I’- methyl-spiro [indole: 4 [0337] Example morpholine _3,4 ‘- piperidin] -2-one

 

Figure CN101851237BD00311
Figure CN101851237BD00312
Figure CN101851237BD00313

H2N N

  Following the procedure in Example I step of Example 3, the procedure of Example 3 to give 5-bromo-1-5 _3_ (2,6-dichloro-3-fluoro-benzyloxy) -2-amino-pyridine and Step 2 in Example I to give the embodiment 1-2 ‘- methyl-6- (4,4,5,5-tetramethyl-1,3,2-dioxolane Borane 2-yl) spiro [ indoline-3,4 ‘- piperidine] _2_ ester -one, yield:. 78 V0o 1H-Nmr (Cdci3JOOmHz): 8 (ppm) I. 96-2 00 (m, 2H), 2. 01 -2. 12 (m, 2H), 2. 46 (s, 3H), 2. 66-2. 73 (m, 2H), 2. 90-2. 96 (m, 2H), 5. 30 (s , hr, 2H), 6. 94-7. 01 (m, 3H), 7. 07 (t, J =

8. 4Hz, 1H), 7. 30 (m, 1H), 7. 34 (d, J = 7. 2Hz, 1H), 7. 89 (d, J = 2. OHz, 1H), 8. 56 ( s, br, 1H). MS m / z:. 501 06 [M + H, 35Cl, 35Cl], 503 04 [M + H, 35Cl, 37Cl]..

  Example 5: 5_ [5_ atmosphere base -6- [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Batch-2-yl] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2-one

 

J0A = o

. | J: too

[0342] Step 1,5_ desert _2_ atmosphere base _3_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Jie than exposure

 

Cl 6, / ISL / Br

xy

H2N N

  In at 0 ° C, NaH (80mg of NaH in mineral oil, 2mmol) force the mouth (1R) -1_ (2,6- dichloro-3-fluorophenyl) ethanol (418mg, 2mmol. See example Example I Step 1_3) in anhydrous THF (6mL) and stirred for half an hour, a solution of 2-amino-3,5-dibromo-pyrazine (506mg, 2mmol) in THF (6mL) was added. The resulting mixture was warmed to room temperature, heated under reflux for 20 hours. TLC showed the reaction was substantially complete. After cooling to room temperature, water was added (IOmL), the mixture was extracted three times with ethyl acetate (3x20mL), the organic phases were combined, dried, concentrated, and the residue to give 594mg product was purified by column chromatography (l-3Me0H inhexanes), yield: 78%. 1H-NMR (O) Cl3, 500MHz):. 8 (ppm) I. 83 (d, J = 7. 2Hz, 3H), 5. 12 (s, br, 2H), 6 73 (q, J = 6 . 8Hz, 1H), 7. 05 (t, J = 8. OHz, 1H), 7. 28 (dd, J = 4. 8,

8. 8Hz, 1H), 7. 58 (s, 1H). Mass spectrum m / z:. 379 83 [M + H, 35Cl, 35Cl, 79Br], 381. 81 [M + H, 35Cl, 35Cl, 81Br], 383 79 [M + H, 35Cl, 37Cl, 81Br]..

Step 2,5_ [5_ atmosphere base _6_ [(IR) -I- (2,6_ two gas _3_ gas phenyl) ethoxy] Batch-2-yl] -I ‘- A group spiro [indoline-3,4 ‘- piperidin] -2-one

  5_ bromide present embodiment obtained in step I _2_ amino _3_ [(IR) -I- (2,6_ dichloro _3_ fluorophenyl) ethoxy] pyrazine, implemented I’- methyl step 2-2 obtained in Example I-5 (4,4,5,5-tetramethyl -I, 3,2- dioxolane boron

2-yl) spiro [indoline-3,4 ‘- piperidin] -2-one, prepared as in Example I Step 3. Yield: 54%. 1H-NMR (CD3ODjOOMHz): 8 (ppm) I. 85 (d, J = 6. 8Hz, 3H), I 85-1 88 (m, 2H), I 97-2 04 (m, 2H…. ), 2. 46 (s, 3H), 2. 76-2. 82 (m, 2H), 2. 97-3. 02 (m, 2H), 6. 74 (q, J = 6. 4Hz, 1H ), 6. 85 (d, J = 8. OHz, 1H), 7. 15 (t, J = 8. 4Hz, 1H), 7. 41 (dd, J = 4. 8,9. 2Hz, lH) , 7. 54 (dd, J = I. 6,

8. OHz, 1H), 7. 69 (d, J = I. 8Hz, 1H), 7. 81 (dt, J = 2. 0,8. 0Hz, 1H), 7. 87 (s, 1H). Mass spectrum m / z:. 515 92 [M + H, 35Cl, 35Cl], 517. 90 [M + H, 35Cl, 37Cl].

Example 6: 6- [5-amino -6 – [(lR) -l_ (2,6- dichloro _3_ fluorophenyl) ethoxy] pyrazin-2-yl] -I ‘ – methyl-spiro [indoline-3,4 ‘- piperidin] -2-one

 

Figure CN101851237BD00321

The embodiment of Example 5, 5_ bromo obtained in step I _2_ amino _3_ [(IR) -I- (2,6_ dichloro _3_ fluorophenyl) ethoxy] pyrazine, Example I’- methyl-2 obtained in steps 1-2 6- (4,4,5,5-tetramethyl–I, 3,2- dioxolane boron-2-yl) spiro [indole morpholine -3,4’_ piperidin] -2-one, prepared as in Example I Step 3. Yield: 67% 0

1H-NMR (CD3ODjOOMHz): 8 (ppm) I. 85 (d, J = 6. 8Hz, 3H), I 88-1 96 (m, 4H), 2 48 (s… , 3H), 2. 76-2. 82 (m, 2H), 2. 98-3. 05 (m, 2H), 6. 75 (q, J = 6. 4Hz, 1H), 7. 16 (t , J = 8. 8Hz, 1H), 7. 31 (d, J = 2. OHz, 1H), 7. 36-7. 43 (m, 3H), 7. 88 (s, 1H).

Mass spectrum m / z:. 515 99 [M + H, 35Clj35Cl], 517 90 [M + H, 35Cl, 37Cl]..

SEE

Bioorganic & Medicinal Chemistry Letters (2014), 24(16), 3673-3682.

School of Pharmaceutical Sciences, Southern Medical University,

P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.




COCK WILL TEACH YOU NMR
COCK SAYS MOM CAN TEACH YOU NMR
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE
Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK
Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

         

 amcrasto@gmail.com

 

SWEDEN
A golden medallion with an embossed image of Alfred Nobel facing left in profile. To the left of the man is the text
A black and white photo of a bearded man in his fifties sitting in a chair.
Alfred Nobel had the unpleasant surprise of reading his own obituary, titled The merchant of death is dead, in a French newspaper.
Map of sweden europe
Nyköping (Sweden)-houses.
Fjallbacka, a colorful fishing Village along the west coast of Sweden
Knights Island, Stockholm, Sweden
Stockholm, Sweden
Sweden Stockholm
Europe Örby Änger – Sweden
Despite the cold weather, public came and enjoyed different activities. The famous chef, Paul Svensson who works in one of the fanciest and most famous …

 

ANTHONY CRASTO VENTURES INTO CHINA…..MY KAIXIN BLOG 开心网 ON MEDICINAL CHEMISTRY


KAIXIN



MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

CHINA

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878

MY EASTERN VENTURE TO PROPAGATE CHEMISTRY……………http://www.kaixin001.com/home/?_profileuid=159073878\

 

 
DRUG APPROVALS BY DR ANTHONY MELVIN CRASTO …..FOR BLOG HOME CLICK HERE

Join me on Linkedin

View Anthony Melvin Crasto Ph.D's profile on LinkedIn

Join me on Facebook FACEBOOK

Join me on twitterFollow amcrasto on Twitter
Join me on google plus Googleplus

 amcrasto@gmail.com

KHAJURAHO INDIA

Khajuraho Group of Monuments is located in India

Khajuraho Group of Monuments
Location of Khajuraho Group of Monuments in India.

Location in Madhya PradeshLocation in Madhya Pradesh

  1. Khajuraho Group of Monuments – Wikipedia, the free …

    en.wikipedia.org/wiki/Khajuraho_Group_of_Monuments

    The Khajuraho Group of Monuments are a group of Hindu and Jain temples in Madhya Pradesh, India. About 620 kilometres (385 mi) southeast of New Delhi, …

Hotel Chandela – A Taj Leisure Hotel

Zifaxaban, TY-602, Zhifeishaban 知非沙班……Tianjin Institute of Pharmaceutical Research China


 

zifa

 

Zifaxaban

Figure CN102464658AD00081

Zifaxaban

cas 1378266-98-8

rotation (-)

C20 H16 Cl N3 O4 S

C20H16ClN3O4 S, M = 429.87

Tianjin Institute of Pharmaceutical Research

Deep vein thrombosis; Lung embolism

Factor Xa antagonist

TY-602; zhifeishaban; zifaxaban

天津药物研究院

Chinese J Struc Chem. 2014, 33 (7), 1091-1095.

(S) -5- chloro -N- ((2- oxo _3_ (4_ (2_ oxo _2H_-1-yl) phenyl) oxazolidin-5 -1,3_ yl) methyl) thiophene-2-carboxamide

5-Chloro-N-(5S)-2-oxo-3-[4-(2-oxopyridin-1(2H)-yl)phenyl]oxazolidin-5-ylimethyllthiophene-2-carboxamide]

 

The title compound(zifaxaban 2, C20H16ClN3O4 S, Mr = 429.87) was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900(12), b = 13.086(3), c = 12.889(3) A, β = 100.86(3)°, V = 959.1(3) A3, Z = 2, Dc = 1.489 g/cm3, F(000) = 444, μ = 0.342 mm-1, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections(I > 2σ(I)).

The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation.

Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.

zifaxaban (first disclosed in CN102464658), useful for treating thromboembolic disorders. Zifaxaban, a factor Xa antagonist, is being developed by Tianjin Institute of Pharmaceutical Research, for treating deep vein thrombosis and pulmonary embolism (preclinical, as of November 2014). In May 2014, an IND was filed in China. In June 2014, the institute was seeking to outlicense this product.

In vivo within the cardiovascular, blood coagulation or blood analysis some have formed out of the process of forming a solid mass with the aggregation, called thrombosis, the formation of a solid mass called a thrombus blocks. Thrombosis is an abnormal flow of blood coagulation status due to platelet activation and coagulation factors are activated in accordance therewith.

The blood coagulation was originally a protective mechanism of the organism, there is a mutual antagonism in blood coagulation system and the anti-clotting system. Under physiological conditions, blood clotting factors continue to be activated to produce thrombin, fibrin formation trace, calm on the vascular endothelium, but these traces of fibrin and constantly being activated fibrinolytic system dissolution, while being activated coagulation factors are constantly mononuclear phagocyte system swallowed. The dynamics of the coagulation system and fibrinolysis system, which ensures the blood coagulation potential can also always ensure that the fluid state of the blood.

 Sometimes, however, in certain factors can promote the coagulation process, breaking the above dynamic balance triggered the coagulation process, the blood can form a thrombosis or embolism, such as leading to myocardial infarction, stroke, deep vein thrombosis, pulmonary embolism and other thromboembolic disease.

Thromboembolic disease is cardiovascular disease against the most serious diseases, is the first killer of human health. In China, with the improvement and increased aging of the population’s living standards, the incidence of such diseases, mortality, morbidity is increasing every year.

The existing anti-thromboembolic diseases into anti-platelet drugs, anticoagulants and fibrinolytic drugs. Among them, the anti-clotting drugs are the main contents of antithrombotic therapy, mainly thrombin inhibitors and vitamin K antagonists. Heparin and low molecular weight heparin, represented by the presence of oral thrombin inhibitor invalid, non-selective inhibition and high risk of bleeding and other shortcomings. Although warfarin is representative of vitamin K antagonists can be administered orally, but there are narrow therapeutic index, high risk of bleeding and other shortcomings.

Studies have shown that the coagulation process is usually divided into intrinsic coagulation pathway and the extrinsic coagulation pathway. Coagulation process involves a lot of coagulation factors, coagulation factor activated are each the next inactive clotting factor precursor is converted into the activated form. Endogenous, exogenous pathway final summary, the blood coagulation factor X is converted to Xa.

Therefore, theoretically, the direct inhibition of ¾ factor activity should produce effective anti-clotting effect, without the side effects of thrombin inhibitors with. As direct inhibition) (a factor activity on normal hemostasis reaction / adjustment process produces minimal impact. For example, platelets remain low catalytic activity of thrombin on the ability to respond to, and thus does not affect the formation of platelet thrombi, so bleeding integrated minimize the risk of the levy.

  research also proved this point. Recently reported a variety of compounds can selectively inhibit efficient Xa, which play a preventive and / or treatment of thromboembolic disease effect (W003000256A1; CN00818966; US2007259913A1; US2007259913A1). Among them, rivaroxaban (Rivaroxaban) was listed in 2008 for hip or knee replacement surgery prophylaxis and treatment of venous thrombosis, with oral, fixed dose and other advantages.

  rivaroxaban drawback is the high price of raw materials, low yield preparation, purification of the product is difficult, high production costs. Patent CN00818966 8 reported rivaroxaban synthetic routes as follows:

4

Figure CN102464658AD00051

where the first reaction (Preparation of 4- (4-morpholino-3-yl) nitrobenzene) yield of only 17.6%, and rivaroxaban difficult purification.

 

Figure CN102464658AD00061

 

………………………………

Patent

http://www.google.com/patents/CN103232446A?cl=en

(S) -5- chloro -N- ((2- oxo-3- (4- (2_ oxo -2H- pyridin-1-yl) phenyl) -1, 3_ oxazolidine -5 – yl) methyl) thiophene-2-carboxamide.

[0011] Meanwhile, patent CN201110337461.4 described formula (I) Preparation of the compound:

[0012]

Figure CN103232446AD00041

 

……………………………………..

Patent

CN102464658

http://www.google.com/patents/CN102464658B?cl=en

Example 1

[0046] (S) -5- chloro -N- ((2- oxo-3- (4_ (2_ Batch oxo _2H_ piperidinyl) phenyl) _1,3_ oxazolidin-5-yl) methyl ) thiophene-2-carboxamide (II)

 

Figure CN102464658AD00081

[0048] A, 1- (4- amino-phenyl) -IH- pyridin _2_ -one (Compound VII) is

[0049] The reaction flask was charged with 104g of pyridine -2 (IH) – one (Compound IX), 200g of iodoaniline (compound VIII), 26gCuI, 151g of potassium carbonate, 18g8- hydroxyquinoline, 500mlDMF, nitrogen, heated to reflux, Insulation reaction was stirred 10h. Filtered hot, the filtrate evaporated under reduced pressure to make the solvent, the residue was added ethyl acetate, IL, 0 ° C incubated with stirring lh, filtered and the solid dried, 2L acetonitrile and purified to give 98g dark red solid. Refined liquor was concentrated to 500ml, the ice bath was stirred lh, filtered to give a dark red solid 19g. Total product were 117g, yield 68.9%.

[0050] 1H-NMR (DMSO-Cl6), δ (ppm):… 5 306 (s, 2H), 6 236 (d, 1H), 6 406 (d, 1H), 6 601 (d,. 2H), 6. 977 (d, 2H), 7. 459 (m, 2H).

[0051] B, (R) -2- (2- hydroxy-3- ((2-oxo–2H- pyridin-1-yl) phenyl) amino) propyl) isoindoline-1,3- -dione (Compound V) is

[0052] The reaction flask was added 40gl_ (4- aminophenyl) -IH- pyridin-2-one (Compound VII), 45g (S) _N_ glycidyl phthalimide (Compound VI), 300ml95% ethanol, heating to reflux, the gradual emergence of solid insulation mixing IOh, cooled to room temperature, filtered, and the filter cake washed with ethanol (150ml X 2), and dried to give an off-white solid 38g.

[0053] The mother liquor was taken, evaporated to dryness under reduced pressure, was added 15g (Q-N_ glycidyl phthalimide (Compound VII), 150ml95% ethanol, heated to reflux, stirred incubated 10h, concentrated under reduced pressure, cooled to room temperature , stirred at room temperature for 2h, washed with ethanol and dried to give an off-white solid 33g.

[0054] A total of an off-white solid 71g, yield of 84.8%, without purification, was used directly in the next step.

[0055] 1H-NMR (DMS0_d6), δ (ppm):… 3 053 (m, 1H), 3 194 (m, 1H), 4 644 (m, 2H), 4 020 (m, 1H). , 5. 168 (d, 1H), 5. 851 (t, 1H), 6. 230 (m, 1H), 6. 404 (d, 1H), 6. 665 (d, 2H), 7. 041 ( d, 2H), 7. 435 (m, 1H), 7. 537 (m, 1H), 7. 855 (m, 4H).

[0056] C, ⑶-2- ((2- oxo-3- (4- (2_ oxo _2H_ pyridyl) phenyl) oxazolidin _5_ -1,3_ yl) methyl ) Preparation of isoindoline-1,3-dione (Compound IV) of the

[0057] The reaction flask was charged 50g Compound V, 27gN, N’- carbonyldiimidazole (⑶I), 4_ catalytic amount of dimethylaminopyridine (DMAP), 150mlN, N- dimethylformamide (DMF), stirred for 90 temperature ° C, the reaction was kept for 8 hours to make the solvent was evaporated under reduced pressure, added to IL of water, stirred and dispersed, filtered, washed with water (150mlX “, washed with ethanol (100ml X 1), dried to give a white solid 48g, yield of 90%.

[0058] 1H-NMR (DMSo-CI6), δ (ppm):…. 3 984 (m, 3H), 4 251 (t, 1H), 4 968 (m, 1H), 6 301 (m, 1H), 6. 459 (d, 1H), 7. 423 (d, 2H), 7. 514 (m, 1H), 7. 615 (m, 3H), 7. 892 (m, 4H).

[0059] D, (S) -5- (aminomethyl) -3- (4- (2_ oxo _2H_-1-yl) phenyl) oxazolidin _2_ -1,3_ one hydrochloride (compound III) Synthesis of

[0060] The reaction flask was charged 50g compound IV, 200ml of ethanol, 60ml aqueous methylamine (40%), heated to reflux, stirred incubated 2h, cooled, evaporated under reduced pressure to make the solvent to give a sticky solid.

[0061] added to 300ml of ethanol, 20ml of hydrochloric acid, heated to reflux, stirred incubated lh, cooled to room temperature, incubated with stirring 2h, filtered, washed with ethanol, and dried to obtain;. 34 5g of white solid, yield 88.7%.

 1H-NMR (DMS0_d6), δ (ppm):…. 3 240 (m, 2H), 3 980 (m, 1H), 4 255 (m, 1H), 5 028 (m, 1H) , 6. 321 (m, 1H), 6. 475 (d, 1H), 7. 504 (m, 3H), 7. 634 (m, 3H), 8. 561 (s, 1H).

 Ε, (S) -5- chloro -N – ((2- oxo-3- (4- (2-oxo–2Η- pyridin-1-yl) phenyl) oxazolidin _1,3_ 5-yl) methyl) thiophene-2-carboxamide Preparation of thiophene (II) of

The reaction flask was charged 15g Compound III, 200ml of tetrahydrofuran, 40ml of water was added with stirring 6. 2g of sodium carbonate was added dropwise 10g5- chloro-thiophene-2-carbonyl chloride (Compound II-1) in tetrahydrofuran IOOml, 30~35 ° C insulation stirred 5h, point board to control the reaction was complete.

 to make the solvent was distilled off under reduced pressure, 50ml of water was added, stirring was filtered, the filter cake washed with water and dried to give 18. 5g of white solid.

 200ml of acetic acid and purified room temperature overnight, filtered, and the filter cake washed with ethanol and dried to give a white solid 16g, 80% yield.

Melting point: 204 8 ~205 8 ° C;

 1H-NMR (DMSo-CI6), δ (ppm):…. 3 623 (t, 2H), 3 893 (m, 1H), 4 230 (t, 1H), 4 871 (m, 1H), 6. 308 (t, 1H), 6. 468 (d, 1H), 7. 193 (d, 1H), 7. 426 (m, 2H), 7. 500 (m, 1H), 7. 637 (m, 4H), 8. 967 (t, 1H);

 MS (ESI): m / z = 430 (M + H);

 HPLC: rt (%) = 14. 38 (99. 62);

 [a] 20d = -37 6 ° (c 0. 3004, DMS0);

 

WO-2014183667Acetic acid solvate of oxazolidinone derivative, preparation method for the solvate, and application thereof

 

WO-2014183665Oxazolidinone derivative crystal form I and preparation method and use thereof

 

WO-2014183666Oxazolidinone derivate crystal form II, preparation method therefor, and application thereo

 

SEE ABAN SERIES AT…………http://organicsynthesisinternational.blogspot.in/p/aban-series.html

/////////

 

The US FDA has issued a Warning Letter to Tianjin Zhongan Pharmaceutical Co. Ltd. in Tianjin, China.


 

FDA issues Warning Letter for API Facility

http://www.gmp-compliance.org/enews_4367_FDA%20issues%20Warning%20Letter%20for%20API%20Facility_8509,S-WKS_n.html
The US FDA has issued a Warning Letter to Tianjin Zhongan Pharmaceutical Co. Ltd. in Tianjin, China. The company produces APIs and failed to establish adequate GMP procedures at the facility. Read more about the FDA Warning Letter.


FDA issues Warning Letter for API Facility
The US FDA has issued a Warning Letter to Tianjin Zhongan Pharmaceutical Co. Ltd. in Tianjin, China. The company produces APIs and failed to establish adequate GMP procedures at the facility.

For quite some time India was in the center of attention and very little was heard about GMP problems in China (see also RAPS article). This is a bit surprising because a number of non-compliant facilities have been detected in the past. Also the facilities which caused the Heparin Scandal were located in China. The last enforcement action from FDA which became public referred to Import Alerts for the manufacturer Zhejiang Jiuzhou Pharmaceutical and for Zhejiang Zonebanne in China.

The new Warning Letter for Tianjin Zhongan Pharmaceutical lists a number of different non compliance findings. These findings refer to equipment cleaning (risk of cross contamination), not adequate Change Control procedures and failure to adequately review and investigate product deviations. However, in difference to the Warning Letters sent to Indian manufacturers recently data integrity issues have not been detected.

Interestingly the API manufacturer Tianjin Zhongan Pharmaceutical is not listed in EudraGMDP the inspection database in the EU. No entry for GMP Certificates or GMP Non-Compliance Report are available.

Source: FDA Warning Letter to Tianjin Zhongan Pharmaceutical

Tianjin Zhong’an Pharmaceutical Company Ltd. locates in the southwest of Tianjin. Set up in 1988, the company underwent operation mechanism reform in 2002 and acquired the present name.

The company covers an area of 82,000 square meters, with a construction area of 31,600 square meters and an afforested area of 13,300 square meters. It has over 600 staff members, more than 50 of whom have been conferred intermediate or advanced titles of technical post. The company produces 10 major chemical bulk pharmaceuticals, including Caffeine, Theophylline, Aminophylline, Metronidazole, Metronidazole Benzoate, Nifedipine, Secnidazole and Xanthinol Nicotinate. Its annual production capacity amounts to 4000 ton, with a sales volume of approximately RMB 250 million. Two leading products in the company are Caffeine and Metronidazole.

Zhong’an Pharmaceutical enjoys a self-management power over import and export., 90% of its products are aimed at international market, with 60% of which sold directly to world-renowned pharmaceutical and beverage enterprises. It has established a sales network which covers more than 30 countries and regions, including some European and American countries, Hong Kong, Taiwan and Macao, countries in Southeast and Midwest Asia, and Russia.

Zhong’an Pharmaceutical has set up a full set of quality assurance system, and owns a central laboratory with advanced analyse instruments that has got the title of Export Enterprise Lab and approved by Tianjin entry-exit inspection and quarantine bureau. All workshops of the company are dedicated to avoid the issue of cross pollution. Every stage of production strict complies with the cGMP, which led to the products has been enjoying a high reputation both domestic and overseas market.

Since 2000, the company has obtained GMP and ISO9001certificates, and conferred the title of Tianjin High-new Tech Enterprise and Municipal-level Key Technical Center. Both of leading products Metronidazole and Caffeine have got COS issued by EDQM and DMF register number from US FDA. Also Caffeine has got “Foreign Manufacturer Validation Certificate” from Japan Health Ministry and KOF-K and Halal certificates.

 

Sihuan Pharma’s clinical study application for oncology drug Pirotinib accepted by CFDA


The China Food and Drug Administration (CFDA) has accepted Sihuan Pharmaceutical’s application for clinical trial approval for its Pirotinib, a Category 1.1 innovative oncology drug developed by the company’s drug R&D team.

By developing Pirotinib, Sihuan Pharma has demonstrated its capability for the oncology products market. The company holds the largest cardio-cerebral vascular (CCV) drug franchise in China’s prescription market.

The new drug is a second generation (pan-HER) inhibitor intended to treat patients with lung and breast cancer.http://www.pharmaceutical-technology.com/news/newssihuan-pharmas-clinical-study-application-oncology-drug-pirotinib-accepted-cfda?WT.mc_id=DN_News

EFAVIRENZ – Huahai Pharma China-Approved to Produce AIDS Treatment


File:Efavirenz skeletal.svg

Efavirenz

DMP 266

Efavirenz, L-743725((+)-enantiomer), DMP-266, L-741211(racemate), L-743726, Stocrin, Sustiva
(S)-(-)-6-Chloro-4-(cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
154598-52-4

Generic brands India:

Zhejiang Huahai Pharma received CFDA approval to produce efavirenz, an oral non-nucleoside reverse transcriptase inhibitor (NNRTI) used to control the symptoms of AIDS. Huahai is the first China drugmaker approved to make the drug. Huahai produced efavirenz API for Merck, which marketed the drug under the name Stocrin

read at

http://www.sinocast.com/readbeatarticle.do?id=99634

Efavirenz (EFV), sold under the brand names Sustiva among others, is a non-nucleoside reverse transcriptase inhibitor (NNRTI). It is used as part of highly active antiretroviral therapy (HAART) for the treatment of a human immunodeficiency virus (HIV) type 1. For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines currently recommends the use of efavirenz in combination with tenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents.[1] Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz was combined with the HIV medications tenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications under the brand name Atripla, provides HAART in a single tablet taken once a day.

Efavirenz was discovered at Merck Research Laboratories. It is on the WHO Model List of Essential Medicines, the most important medication needed in a basic health system.[2] As of 2015 the cost for a typical month of medication in the United States is more than 200 USD.[3]

 

Efavirenz (EFV, brand names SustivaStocrinEfavir etc.) is a non-nucleoside reverse transcriptase inhibitor (NNRTI) and is used as part of highly active antiretroviral therapy(HAART) for the treatment of a human immunodeficiency virus (HIV) type 1.

For HIV infection that has not previously been treated, the United States Department of Health and Human Services Panel on Antiretroviral Guidelines currently recommends the use of efavirenz in combination with tenofovir/emtricitabine (Truvada) as one of the preferred NNRTI-based regimens in adults and adolescents.

Efavirenz is also used in combination with other antiretroviral agents as part of an expanded postexposure prophylaxis regimen to reduce the risk of HIV infection in people exposed to a significant risk (e.g. needlestick injuries, certain types of unprotected sex etc.).

The usual adult dose is 600 mg once a day. It is usually taken on an empty stomach at bedtime to reduce neurological and psychiatric adverse effects.

Efavirenz was combined with the popular HIV medication Truvada, which consists oftenofovir and emtricitabine, all of which are reverse transcriptase inhibitors. This combination of three medications approved by the U.S. Food and Drug Administration(FDA) in July 2006 under the brand name Atripla, provides HAART in a single tablet taken once a day. It results in a simplified drug regimen for many patients.

 

doi:10.1016/0040-4039(95)01955-H

Merck synthesis of Efavirenz

 

 

History

Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

  •  Efavirenz is a non-nucleoside reverse trancriptase inhibitor being studied clinically for use in the treatment of HIV infections and AIDS.
  • Efavirenz chemically known as (-) 6-Chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1 , 4- dihydro-2H-3, 1-benzoxa zin-2-one, is a highly potent non-nucleoside reverse transcriptase inhibitor (NNRTI).A number of compounds are effective in the treatment of the human immunodeficiency virus (HIV) which is the retrovirus that causes progressive destruction of the human immune system. Effective treatment through inhibition of HIV reverse transcriptase is known for non- nucleoside based inhibitors. Benzoxazinones have been found to be useful non-nucleoside based inhibitors of HIV reverse transcriptase.(-) β-chloro^-cyclopropylethynyM-trifluoromethyl-l ,4-dihydro-2H-3,l -ben zoxazin-2-one (Efavirenz) is efficacious against HIV reverse transcriptase resistance. Due to the importance of (-)6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-l,4-dihydro-2H-3,l-ben zoxazin-2- one, economical and efficient synthetic processes for its production needs to be developed.The product patent US5519021. discloses the preparation of Efavirenz, in Example-6, column-29, involving cyclisation of racemic mixture of 2-(2-amino-5-chlorophenyl)-4- cyclopropyl-l,l,l-trifluoro-3-butyn-2-ol using l ,l ‘-carbonyldiimidazole as carbonyl delivering agent to give racemic Efavirenz. Further, resolution of the racemic Efavirenz is carried out using (-) camphanic acid chloride to yield optically pure Efavirenz. However, research article published in the Drugs of the future, 1998, 23(2), 133-141 discloses process for manufacture of optically pure Efavirenz. The process involves cyclisation of racemic 2-(2-amino-5-chlorophenyl)-4-cyclopropyl-l, 1, l-trifluoro-3-butyn-2- ol using 1, 1-carbonyldiimidazole as carbonyl delivering agent to give racemic Efavirenz and further resolution by (-) camphanic acid chloride.Similarly research article published in Synthesis 2000, No. 4, 479-495 discloses stereoselective synthesis of Efavirenz (95%yield, 99.5%ee), as shown below
    Figure imgf000003_0001

    Even though many prior art processes report method for the preparation of Efavirenz, each process has some limitations with respect to yield, purity, plant feasibility etc. Hence in view of the commercial importance of Efavirenz there remains need for an improved process.

  • US 6 028 237 discloses a process for the manufacture of optically pure Efavirenz.
  • The synthesis of efavirenz and structurally similar reverse transcriptase inhibitors are disclosed in US Patents 5,519,021, 5,663,169, 5,665,720 and the corresponding PCT International Patent Application WO 95/20389, which published on August 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 8937-8940, as well as the PCT publication, WO 96/37457, which published on November 28, 1996.
  • Additionally, several applications have been filed which disclose various aspects of the synthesis of(-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one including: 1) a process for making the chiral alcohol, U.S.S.N. 60/035,462, filed 14 January 1997; 2) the chiral additive, U.S.S.N. 60/034,926, filed 10 January 1997; 3) the cyclization reaction, U.S.S.N. 60/037,059, filed 12 February 1997; and the anti-solvent crystallization procedure, U.S.S.N. 60/037,385 filed 5 February 1997 and U.S.S.N. 60/042,807 filed 8 April 1997.

Efavirenz has been obtained by two related ways: 1) The acylation of 4-chloroaniline (I) with pivaloyl chloride (II) by means of Na2CO3 in toluene gives the expected anilide (III), which is acylated with ethyl trifluoroacetate by means of butyllithium in THF yielding, after hydrolysis with HCl, 2′-amino-5′-chloro-2,2,2-trifluoroacetophenone (IV). The benzylation of (IV) with 4-methoxybenzyl chloride (V) in basic alumina affords the protected acetophenone (VI), which is regioselectively condensed with cyclopropylacetylene (VII) [obtained by cyclization of 5-chloro-1-pentyne (VIII) by means of butyllithium in cyclohexane] by means of butyllithium in THF in the presence of (1R,2S)-1-phenyl-2-(1-pyrrolidinyl)-1-propanol (IX) giving the (S)-isomer of the tertiary alcohol (X) exclusively. The cyclization of (X) with phosgene and triethylamine or K2CO3 in toluene/THF yields the benzoxazinone (XI), which is finally deprotected with ceric ammonium nitrate in acetonitrile/water. 2) The condensation of 2′-amino-5′-chloro-2,2,2-trifluoroacetophenone (IV) with cyclopropylacetylene (VIII) by means of butyllithium or ethylmagnesium bromide in THF gives (?-2-(2-amino-5-chlorophenyl)-4-cyclopropyl-1,1,1-trifluoro-3-butyn-2-ol (XII). The cyclization of (XII) with carbonyldiimidazole (XIII) in hot THF yields the racemic benzoxazinone (XIV). Compound (XIV) is submitted to optical resolution by condensation with (S)-(-)-camphanoyl chloride by means of dimethylaminopyridine (DMAP) in dichloromethane to give the acyl derivative (XVI) as a diastereomeric mixture that is resolved by crystallization and finally decomposed with HCl in ethanol or butanol.
Corley, E.G.; Thompson, A.S.; Huntington, M.F.; Grabowski, E.J.J.; Use of an ephedrine alkoxide to mediate enantioselective addition of an acetylide to a prochiral ketone: Asymmetric synthesis of the reverse transcriptase inhibitor L-743,726.
Tetrahedron Lett1995,36,(49):8937-40
EP 1332757 A1
Clips
When a commercial market already exists for the RMs used in synthesizing an API, their cost can be rather modest. When RMs used in synthesizing an API have no other commercial use, however, they can contribute very substantially to API cost. With a continued growth of volume demand, improved chemistry and competition from multiple suppliers, however, the cost of API RMs can greatly decrease over time. The inhibitor of HIV-1 RT, EFV, provides an illustration of this situation. Cyclopropylacetylene (CPA) is an RM for the synthesis of EFV (Figure 4). During clinical trials, when the demand for CPA was only a few metric tons, this material was produced at a price of USD800–1,350/kg. When the drug was first approved in 1998, and demand for CPA was about 50 metric tons per year, the price of CPA had fallen to USD350/kg. Today, with global demand for EFV at greater than 1,000 metric tons/year, CPA can be purchased for about USD50–60/kg. In the earliest stages of production, nearly 1 kg of CPA was needed to produce a kilogram of EFV. Current production processes are more efficient; roughly 3 kg of EFV is now produced for each 1 kg of CPA used. From this it can be roughly estimated that the contribution of CPA to the cost of EFV API production has fallen from as high as USD425/kg to about USD17–20/kg today.
https://i1.wp.com/www.intmedpress.com/journals/avt/iframePopup_fig.cfm
The most recent chemistry for asymmetric alkynylation of manufacturing EFV uses inexpensive, safe reagents and processing at ambient temperature to reach EFV pricing that would have been thought impossible when the drug was launched by Dupont Pharmaceuticals in 1998
Biao J, Yugui S. inventors; Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, assignee. Amino alcohol ligand and its use in preparation of chiral propargylic tertiary alcohols and tertiary amines via enantioselective addition reaction. US Patent 7,439,400. 2008 October 21.
Bollu RB, Ketavarapu NR, Indukuri VSK, Gorantla SR, Chava S. inventors; Laurus Labs Private Limited, assignee. Efficient process to induce enantioselectivity in procarbonyl compounds. US Patent Application 2012/0264933 A1. 2012 October 18.
FPPs for adult ART are usually capsules or tablets. A general rule-of-thumb is that an FPP as a conventional, solid oral dosage formulation costs about 33–40% more than the corresponding API in a competitive market. It has been widely quoted, conversely, that APIs contribute about 60–80% of the cost of an FPP. The API contribution to FPP cost increases with the complexity of synthesis and API cost per kilogram. Although marketing is a substantial incremental cost for originator pharmaceutical companies, generic producers do not incur high marketing costs for ART.

Syntheses of EFV API; different routes of manufacturingAPI, active pharmaceutical ingredient; EFV efavirenz. BELOW

https://i1.wp.com/www.intmedpress.com/journals/avt/iframePopup_fig.cfmhttps://i1.wp.com/www.intmedpress.com/journals/avt/iframePopup_fig.cfm

Related substances and degradants (partial listing) in EFVAPI, active pharmaceutical ingredient; CPA, cyclopropylacetylene; EFV, efavirenz

Syntheses of EFV API; different routes of manufacturingAPI, active pharmaceutical ingredient; EFV efavirenz.

illustrates the great effect of new routes of synthesis on API costs. The manufacturing cost of route 1 for the launch of EFV in 1998 was about USD1,800/kg [31,41]. EFV API was priced at about USD1,100/kg for the first generic launch in 2005. At this time the price of CPA was about USD250/kg. The best prices for EFV API in 2012–2013 are USD120–130/kg prepared under GMP. This drastic 89% reduction in generic API pricing is due in part to volume demand – the LMIC use of generic EFV in 2012 exceeded 750 metric tons and was estimated to exceed 900 metric tons in 2013. Reductions in the cost of RMs have also had a significant effect. More efficient processes for producing the final intermediate SD 573, have contributed the largest part to price reductions [42]. The route 1 synthesis requires five steps while routes 2 through 4 require only two steps from the same starting materials for the commercial production of EFV.

Chemical properties

Efavirenz is chemically described as (S)-6-chloro-(cyclopropylethynyl)-1,4-dihydro-4-(trifluoromethyl)-2H-3,1-benzoxazin-2-one. Its empirical formula is C14H9ClF3NO2. Efavirenz is a white to slightly pink crystalline powder with a molecular mass of 315.68 g/mol. It is practically insoluble in water (<10 µg/mL).

History

Efavirenz was approved by the FDA on September 21, 1998, making it the 14th approved antiretroviral drug.

Society and culture

Pricing information

A one-month supply of 600 mg tablets cost approximately $550 in April 2008.[16] Merck provides efavirenz in certain developing countries at cost, currently about $0.65 per day.[17] Some emerging countries have opted to purchase Indian generics[18] such as Efavir by Cipla Ltd.[19] In Thailand, one month supply of efavirenz + truvada, as of June 2012, costs THB 2900 ($90), there’s also a social program for poorer patients who can’t afford even this price. In South Africa, a license has been granted to generics giant Aspen Pharmacare to manufacture, and distribute to Sub-Saharan Africa, a cost-effective antiretroviral drug.[20]

 PATENT

http://www.google.com/patents/WO1999061026A1?cl=en

EXAMPLE 1

Cl

1a

To a solution of trifluoroethanol and (IR, 2S)-N-pyrrolidinyl norephedrine in THF (9 L) under nitrogen is added a solution of diethylzinc in hexane at 0 °C slowly enough to keep the temperature below 30 °C. The mixture is stirred at room temperature for 0.5 ~ 1 h. In another dry flask a solution of chloromagnesium cyclopropyl acetylide is prepared as follows: To neat cyclopropyl acetylene at 0 °C is added a solution of rc-butylmagnesium chloride slowly enough to keep the internal temperature < 30 °C. The solution is stirred at 0 °C for ~ 40 min and transfered to the zinc reagent via cannula with 0.36 L of THF as a wash. The mixture is cooled to -10 °C and ketoaniline la is added. The mixture is stirred at -2 to -8 °C for 35 h, warmed to room temperature, stirred for 3 h, and quenched with 30% potassium carbonate over 1.5 h. The mixture is stirred for 4 h and the solid is removed by filtration and washed with THF (2 cake volume). The wet solid still contains -18 wt% of pyrrolidinyl norephedrine and is saved for further study. The filtrate and wash are combined and treated with 30% citric acid. The two layers are separated. The organic layer is washed with water (1.5 L). The combined aqueous layers are extracted with 2.5 L of toluene and saved for norephedrine recovery. The toluene extract is combined with the organic solution and is concentrated to ~ 2.5 L. Toluene is continuously feeded and distilled till THF is not detectable by GC. The final volume is controlled at 3.9 L. Heptane (5.2 L) is added over 1 h. The slurry is cooled to 0 °C, aged for 1 h, and filtered. The solid is washed with heptane (2 cake volume) and dried to give 1.234 Kg (95.2% yield) of amino alcohol 3 as a white crystalline. The material is 99.8 A% pure and 99.3% ee.

EXAMPLE 2

To a three necked round bottom flask, equipped with a mechanical stirrer, nitrogen line, and thermocouple, was charged the solid amino alcohol 3, MTBE (500 L), and aqueous KHCO3 (45 g in 654 mL H2O). Solid 4-nitrophenyl chloroformate was added, in 4 batches, at 25°C. During the addition the solution pH was monitored. The pH was maintained between 8.5 and 4 during the reaction and ended up at 8.0. The mixture was stirred at 20-25°C for two hours. Aqueous KOH (2N) was added over 20 minutes, until the pH of the aqueous layer reached 11.0.

The layers were separated and 500 mL brine was added to the MTBE layer. 0.1 N Acetic acid was added until the pH was 6-7. The layers were separated and the organic phase was washed with brine (500 mL). At this point the mixture was solvent switched to EtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 3

To a three necked round bottom flask, equipped with a mechanical stirrer, nitrogen line, and thermocouple, was charged the solid amino alcohol 3a, toulene (500 mL), and aqueous KHCO3 (86.5 g in 500 L H2O). Phosgene solution in toulene was added at 25°C, and the mixture was stirred at 20-25°C for two hours.

The layers were separated and the organic phase was washed with brine (500 mL). At this point the mixture was solvent switched to EtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 4

To a three necked round bottom flask, equipped with a mechanical stirrer, nitrogen line, and thermocouple, was charged the solid amino alcohol 3a, MTBE (500 mL), and aqueous KHCO3 (86.5 g in 500 mL H2O). Phosgene gas was slowly passed into the solution at 25°C, until the reaction was complete.

The layers were separated and the organic phase was washed with brine (500 mL). At this point the mixture was solvent switched to EtOH/IPA and crystallized as recited in Examples 5 and 6.

EXAMPLE 5

Crystallization of efavirenz from 30% 2-Propanol in Water using a ratio of 15 ml solvent per gram efavirenz Using Controlled Anti-Solvent Addition on a 400 g Scale.

400 g. of efavirenz starting material is dissolved in 1.8 L of 2- propanol. The solution is filtered to remove extraneous matter. 1.95 L of deionized (DI) water is added to the solution over 30 to 60 minutes. 10 g. to 20 g. of efavirenz seed (Form II wetcake) is added to the solution. The seed bed is aged for 1 hour. The use of Intermig agitators is preferred to mix the slurry. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet-milled for 15 – 60 seconds. 2.25 L of DI water is added to the slurry over 4 to 6 hours. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet- milled for 15 – 60 seconds during the addition. The slurry is aged for 2 to 16 hours until the product concentration in the supernatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 30 % 2-propanol in water and then twice with 1 bed volume of DI water each. The washed wet cake is dried under vacuum at 50°C.

EXAMPLE 6

Crystallization of efavirenz from 30% 2-Propanol in Water using a ratio of 15 ml solvent per gram efavirenz Using a Semi-Continuous Process on a 400 g Scale.

400 g. of efavirenz starting material is dissolved in 1.8 L of 2- propanol. A heel slurry is produced by mixing 20 g. of Form II efavirenz in 0.3 L of 30 % (v/v) 2-propanol in water or retaining part of a slurry froma previous crystallization in the crystallizer. The dissolved batch and 4.2 L of DI water are simultaneously charged to the heel slurry at constant rates over 6 hours to maintain a constant solvent composition in the crystallizer. Use of Intermig agitators during the crystallization is preferred. During this addition the slurry is wet-milled when the crystal lengths become excessively long or the slurry becomes too thick. The slurry is aged for 2 to 16 hours until the product concentration in the supernatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 30 % 2-propanol in water and then twice with 1 bed volume of DI water each. The washed wet cake is dried under vacuum at 50°C.

EXAMPLE 7 Preparation of Amino Alcohol 3 and ee Upgrading— Through Process

1a

A solution of diethyl zinc in hexane was added to a solution of trifluoroethanol (429.5 g, 4.29’mol) and (IR, 2S)-N-pyrrolidinyl norephedrine (1.35 kg, 6.58 mol) in THF (9 L), under nitrogen, at 0 °C. The resulting mixture was stirred at room temperature for approx. 30 min. In another dry flask a solution of chloromagnesium- cyclopropylacetylide was prepared as follows. To a solution of n- butylmagnesium chloride in THF (2 M, 2.68 L, 5.37 mol) was added neat cyclopropylacetylene at 0 °C keeping the temperature < 25 °C. The solution was stirred at 0 °C for 1 ~ 2 h. The solution of chloromagnesiumcyclopropylacetylide was then warmed to room temperature and was transferred into the zinc reagent via cannula over 5 min followed by vessel rinse with 0.36 L of THF. The resulting mixture was aged at ~ 30 °C for 0.5 h and was then cooled to 20 °C. The ketoaniline 1 (1.00 kg, 4.47 mol) was added in one portion as a solid, and the resulting mixture was stirred at 20-28 °C for 3 h.

The reaction was quenched with 30% aq. potassium carbonate (1.2 L) and aged for 1 h. The solid waste was filtered and the cake was washed with THF (3 cake volumes). The filtrate and wash were combined and solvent switched to IP Ac.

The IPAc solution of product 3 and pyrrolidinyl norephedrine was washed with citric acid (3.5 L) and with water (1.5 L). The combined aqueous layers were extracted with IPAc (2 L) and saved for norephedrine recovery. To the combined organic layers was added

12N HC1 (405 mL, 4.88 mol), to form a thin slurry of the amino alcohol-

HC1 salt. The mixture was aged for 30 min at 25 °C and was then dried azeotropically. The slurry was aged at 25 °C for 30 min and filtered. The cake was washed with 2.5 L of IPAc and dried at 25 °C under vacuum/nitrogen for 24 h to give 1.76 kg of the wet HC1 salt.

The salt was dissolved in a mixture of MTBE (6 L) and aq Na2Cθ3 (1.18 kg in 6.25 L water). The layers were separated and the organic layer was washed with 1.25 L of water. The organic layer was then solvent switched into toluene.

Heptane (5 L) was added over 1 h at 25 °C. The slurry was cooled to 0 °C, aged for 1 h, and filtered. The solid was washed with heptane (2 cake volumes) and was dried to give 1.166 kg (90% overall yield) of amino alcohol 3 as a white crystalline solid. Norephedrine recovery

The aqueous solution was basified to pH13 using 50% aq NaOH, and extracted with heptane (2 L). The heptane solution was washed with water (1 L) and concentrated to remove residual IPAc and water. The final volume was adjusted to about 3 L. The heptane solution was cooled to -20 °C, aged for 2 h, and filtered. The solid was washed with cold heptane (1 cake volume) and dried to give 1.269 kg solid (94% recovery)

 

https://i2.wp.com/dmd.aspetjournals.org/content/27/11/1319/F1.medium.gif

 

 

CLIPS

http://www.mdpi.com/1420-3049/21/2/221/htm

Molecules 21 00221 g003 1024

Molecules 21 00221 g004 1024

 

 

 

 

 

WO2007013047A2 * Jul 31, 2006 Feb 1, 2007 Ranbaxy Lab Ltd Water-dispersible anti-retroviral pharmaceutical compositions
WO2007013047A3 * Jul 31, 2006 May 31, 2007 Ranbaxy Lab Ltd Water-dispersible anti-retroviral pharmaceutical compositions
WO2007052289A2 * Jul 24, 2006 May 10, 2007 Rubicon Res Pvt Ltd Novel dispersible tablet composition
WO2007052289A3 * Jul 24, 2006 Dec 27, 2007 Rubicon Res Pvt Ltd Novel dispersible tablet composition
WO2011131943A2 Apr 20, 2011 Oct 27, 2011 Cipla Limited Pharmaceutical compositions
WO2012048884A1 Oct 14, 2011 Apr 19, 2012 Lonza Ltd Process for the synthesis of cyclic carbamates
WO2012048886A1 Oct 14, 2011 Apr 19, 2012 Lonza Ltd Process for the synthesis of cyclic carbamates
WO2015059466A1 Oct 22, 2014 Apr 30, 2015 Cipla Limited Pharmaceutical compositions comprising efavirenz
EP1448170A2 * Nov 26, 2002 Aug 25, 2004 Bristol-Myers Squibb Company Efavirenz tablet formulation having unique biopharmaceutical characteristics
EP2441759A1 Oct 14, 2010 Apr 18, 2012 Lonza Ltd. Process for the synthesis of cyclic carbamates
EP2447255A1 Oct 14, 2010 May 2, 2012 Lonza Ltd. Process for the synthesis of cyclic carbamates
US6238695 Apr 6, 1999 May 29, 2001 Dupont Pharmaceuticals Company Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants
US6555133 Apr 2, 2001 Apr 29, 2003 Bristol-Myers Squibb Company Formulation of fast-dissolving efavirenz capsules or tablets using super-disintegrants
US8871271 Jul 29, 2013 Oct 28, 2014 Gilead Sciences, Inc. Method and composition for pharmaceutical product
US8957204 Oct 14, 2011 Feb 17, 2015 Lonza Ltd. Process for the synthesis of cyclic carbamates
US8969550 Oct 14, 2011 Mar 3, 2015 Lonza Ltd. Process for the synthesis of cyclic carbamates
US9018192 Oct 10, 2013 Apr 28, 2015 Bristol-Myers Squibb & Gilead Sciences, Inc. Unitary pharmaceutical dosage form
US9198862 Jul 24, 2006 Dec 1, 2015 Rubicon Research Private Limited Dispersible tablet composition
WO1995020389A1 * Jan 24, 1995 Aug 3, 1995 Merck & Co Inc Benzoxazinones as inhibitors of hiv reverse transcriptase
WO1996037457A1 * May 21, 1996 Nov 28, 1996 Merck & Co Inc Asymmetric synthesis of (-) 6-chloro-4-cyclopropyl-ethynyl-4-trifluoromethyl-1,4-dihydro-2h-3,1-benzoxazin-2-one
WO1998052570A1 * May 14, 1998 Nov 26, 1998 David Walter Barry Antiviral combinations containing the carbocyclic nucleoside 1592u89

References

  1. Gatch, M. B.; Kozlenkov, A.; Huang, R. Q.; Yang, W.; Nguyen, J. D.; González-Maeso, J.; Rice, K. C.; France, C. P.; Dillon, G. H.; Forster, M. J.; Schetz, J. A. (2013). “The HIV Antiretroviral Drug Efavirenz has LSD-Like Properties”. Neuropsychopharmacology 38 (12): 2373–84. doi:10.1038/npp.2013.135. PMC 3799056. PMID 23702798.
  • Sütterlin, S.; Vögele, C.; Gauggel, S. (2010). “Neuropsychiatric complications of Efavirenz therapy: suggestions for a new research paradigm”. The Journal of Neuropsychiatry and Clinical Neurosciences 22 (4): 361–369. doi:10.1176/jnp.2010.22.4.361.

External links

Efavirenz
Efavirenz.svg

 

 

Efavirenz.svg

Efavirenz ball-and-stick model.png
Systematic (IUPAC) name
(4S)-6-chloro-4-(2-cyclopropylethynyl)-4-(trifluoromethyl)-2,4-dihydro-1H-3,1-benzoxazin-2-one
Clinical data
Trade names Sustiva, Stocrin, others
AHFS/Drugs.com monograph
MedlinePlus a699004
Pregnancy
category
  • US: D (Evidence of risk)
Routes of
administration
By mouth (capsules, tablets)
Legal status
Legal status
  • UK: POM (Prescription only)
  • US: ℞-only
  • ℞ (Prescription only)
Pharmacokinetic data
Bioavailability 40–45% (under fasting conditions)
Protein binding 99.5–99.75%
Metabolism Hepatic (CYP2A6 and CYP2B6-mediated)
Onset of action 3–5 hours
Biological half-life 40–55 hours
Excretion Urine (14–34%) and feces (16–61%)
Identifiers
CAS Number 154598-52-4 Yes
ATC code J05AG03 (WHO)
PubChem CID 64139
DrugBank DB00625 Yes
ChemSpider 57715 Yes
UNII JE6H2O27P8 Yes
KEGG D00896 Yes
ChEBI CHEBI:119486 Yes
ChEMBL CHEMBL223228 Yes
NIAID ChemDB 032934
PDB ligand ID EFZ (PDBe, RCSB PDB)
Chemical data
Formula C14H9ClF3NO2
Molar mass 315.675 g/mol
1H NMR spectrum of C14ClF3H9NO2 in CDCL3 at 400 MHz
//////////////
FC([C@@]1(C#CC2CC2)OC(=O)Nc2c1cc(Cl)cc2)(F)F
Figure 1
%d bloggers like this: