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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 AFRICURE PHARMA, ROW2TECH, NIPER-G, Department of Pharmaceuticals, Ministry of Chemicals and Fertilizers, Govt. of India as ADVISOR, earlier assignment was with GLENMARK LIFE SCIENCES LTD, as CONSUlTANT, Retired from GLENMARK in Jan2022 Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 32 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, 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 32 PLUS year tenure till date Feb 2023, 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 100 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 100 Lakh plus views on dozen plus blogs, 227 countries, 7 continents, 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 38 lakh plus views on New Drug Approvals Blog in 227 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 He has total of 32 International and Indian awards

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Lefucoxib (乐福昔布)

December 3, 2015 7:26 am / Leave a comment

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

冉允章, 梅世昌

梅世昌, 冉允章

CHINA FLAG

PATENT

CN 1468854

http://www.google.com/patents/CN1468854A?cl=en

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)

References

Cheng, Feixiong, Edited by Lee, Philip W, From Handbook of Metabolic Pathways of Xenobiotics (2014), 4, 1655-1656

Bi, X.; Meng, Z.; Chen, H.; Zhu, X.; Dou, G.
In vivo and in vitro metabolism of lefucoxib in rats, J Pharm Biomed Anal. 2008 Sep 10;48(1):134-9. doi: 10.1016/j.jpba.2008.04.024. Epub 2008 Apr 30.

Bi, X.; Meng, Z.; Dou, G. Determination of lefucoxib in rat plasma, urine, and feces by high-performance liquid chromatography with fluorescence detection: Application in pharmacokinetic studies
J Chromatogr B Anal Technol Biomed Life Sci 2007, 850(1-2): 199

Talanta (2011), 85(1), 8-27

Jiefangjun Yaoxue Xuebao (2009), 25(6), 496-498.

Yaowu Fenxi Zazhi (2006), 26(9), 1222-1224.

Zhongguo Yaolixue Yu Dulixue Zazhi (2007), 21(2), 147-151.

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

China PLA General Hospital

//////////c1c(ccc(c1C)C)c2n(nc(c2)C(F)(F)F)c3ccc(cc3)S(=O)(=O)C

CC1=C(C=C(C=C1)C2=CC(=NN2C3=CC=C(C=C3)S(=O)(=O)C)C(F)(F)F)C

Beijing Shenogen Granted Fast Track Status for Novel Cancer Drug, Icaritin

September 21, 2015 3:14 am / Leave a comment

Icaritin; 118525-40-9; AC1NSXIV; UNII-UFE666UELY;

3,5,7-trihydroxy-2-(4-methoxyphenyl)-8-(3-methylbut-2-enyl)chromen-4-one

C₂₁H₂₀O₆
Molecular Weight:	368.3799 g/mol

The roots of Epimedium brevicornu Maxim

Beijing Shenogen Granted Fast Track Status for Novel Cancer Drug

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

Beijing Shenogen Biomedical announced that Icaritin, a China Class I cancer drug, was granted Fast Track Review status after the company filed its New Drug Approval submission to the Beijing Food & Drug Administration. Icaritin is an oral traditional Chinese medicine, derived from barrenwort, which targets the estrogen receptor α36. Shenogen has conducted clinical trials of Icaritin in patients with liver cancer, though it expects the drug will also prove effective in breast cancer and other estrogen-related cancers as well. More details…. http://www.chinabiotoday.com/articles/20150917

Antiproliferative agent (IC₅₀values are 8,13 and 18 μM for K562, CML-CP and CML-BC cells respectively). Inhibits H/R-induced PTK activation. Induces G(2)/M cell cycle arrest and mitochondrial transmembrane potential drop. Modulates MAPK/ERK/JNK and JAK2/STAT3 /AKT signaling. Inhibits PPAR-g. Modulates differentiation. Inhibits cytochrome P450 in vivo. Orally active.

Cardiovascular function improvement, hormone regulation and antitumor activity.
2. The anti-MM activity of Icaritin was mainly mediated by inhibiting IL-6/JAK2/STAT3 signaling.
3. The inhibitory activity of Icariside II on pre-osteoclast RAW264.7 growth was synergized by Icaritin, which maybe contribute to the efficiency of Herba Epimedii extract on curing bone-related diseases, such as osteoporosis.
4. The Icaritin at low concentration (4 or 8 μmol/L) can promote rat chondrocyte proliferation and inhibit cell apoptosis, while the effect of Icaritin on rat chondrocyte at high concentration was reversed.
5. Icaritin might be a new potent inhibitor by inducing S phase arrest and apoptosis in human lung carcinoma A549 cells.
6. Icaritin dose-dependently inhibits ENKL cell proliferation and induces apoptosis and cell cycle arrest at G2/M phase. Additionally, Icaritin upregulates Bax, downregulates Bcl-2 and pBad, and activates caspase-3 and caspase-9.

What is Epimedium ?

Herba epimedii (Epimedium, also called bishop’s hat, horny goat weed or yin yang huo), a traditional Chinese medicine, has been widely used as a kidney tonic and antirheumatic medicine for thousands of years. It is a genus of about 60 flowering herbs, cultivated as a ground cover plant and an aphrodisiac. The bioactive components in herba epimedii are mainly prenylated flavonol glycosides, end-products of the flavonoid pathway. Epimedium species are also used as garden plants due to the colorful flowers and leaves. Most of them bloom in the early spring, and the leaves of some species change colors in the fall, while other species retain their leaves year round.

Figure 1 Epimedium

Epimedium Raw Material

The herbs we used to extract icariin is one species of Epimedium, which name is Epimedium brevicornum Maxim. This kind of epimedium only can be abundantly found in Gansu province of China. And because of the growth habit of this kind of herb, which only grows under trees, it can’t to be planted, only can harvest the wild one.

This wild epimedium contains quite a bit of active components, depending on its long growth time and rich nutrient. Usually the content of the icariin is not lower than 1%.

Below photo is the herb specimen which we use. Picking in the epimedium full-bloom stage. And the medicinal value of the herb is the best at this time. The herb we select contains roots, stems, leaves and flowers. And we extract with the whole herb.

Figure 2 Epimedium for extract

Epimedium Extract

Epimedium extract is a herbal supplement claimed to be beneficial for the treatment of sexual problems such as impotence. It is believed to contain a number of active components, including plant compounds that may have antioxidant activity and estrogen-like compounds. The major components of Epimedium brevicornum are icariin, epimedium B and epimedium C. It is reported to have anti-inflammatory, anti-proliferative, and anti-tumor effects. It is also reported to have potential effects on the management of erectile dysfunction.

Figure 3 HPLC spectrum of icariin

Our specification available is Icariin HPLC 50%- 98%. Below please see the the information for reference:

Figure 4 Epimedium Extract(Icariin)

Derivatives

The plant extracts of epimedium traditionally used for male impotence, and the individual compounds is icariin, were screened against phosphodiesterase-5A1 (PDE5A1) activity. Human recombinant PDE5A1 was used as the enzyme source. The E. brevicornum extract and its active principle icariin were active. To improve its inhibitory activity, some derivatives ware subjected to various structural modifications, which include icaritin, icariside II and 3,7-bis(2-hydroxyethyl) icaritin. There have some scientific papers report that the improved pharmacodynamic profile and lack of cytotoxicity on human fibroblasts make such compounds a promising candidate for further development. We hope that our new products can help you to find more commercial opportunity.

In this way, we can introduce those products as below, and we can also provide more details about the products according to your demand. The 1H-NMR of icaritin and 3,7-bis(2-hydroxyethyl) icaritin is as below.

Product Name	Specification	CAS No.
Icariin	HPLC 50%-98%	489-32-7
icaritin	HPLC 98%	118525-40-9
icariside II	HPLC 98%	113558-15-9
3,7-bis(2-hydroxyethyl) icaritin	HPLC 98%	1067198-74-6

Figure 4 1H-NMR of icaritin and 3,7-bis(2-hydroxyethyl) icaritin

Main Function of Epimedium Extract

horny goat weed; epimedium; Icariin; penis medicine;epimedium p.e;epimedium brevicornum; shorthorned epimedium herb; Icariins; Icaritin; 3,7-Bis(2-Hydroxyethyl)Icaritin; icariin 60%; icariin 98%; epimedium graepimedium; icarisides II;epimedium sagittatum;epimedium leaf; barrenwort.powder extract

Epimedium has been used to treat male erectile dysfunction in Traditional Chinese Medicine for many centuries. The main functions of Epimedium brevicornum in ancient Chinese books focused on the nourishment of kidney viscera and reinforcement of ‘yang’, resulting in the restoration of erectile function in males.

Epimedium contains chemicals which might help increase blood flow and improve sexual function. It also contains phytoestrogens, chemicals that act somewhat like the female hormone estrogen that might reduce bone loss in postmenopausal women.

Figure 5 some products from epimedium extract

………..

PAPER

The novel total synthesis of icaritin (1), naturally occurring with important bioactive 8-prenylflavonoid, was performed via a reaction sequence of 8 steps including Baker-Venkataraman reaction, chemoselective benzyl or methoxymethyl protection, dimethyldioxirane (DMDO) oxidation, O-prenylation, Claisen rearrangement and deprotection, starting from 2,4,6-trihydroxyacetophenone and 4-hydroxybenzoic acid in overall yields of 23%. The key step was Claisen rearrangement under microwave irradiation. MS, ¹H and ¹³C NMR techniques have been used to confirm the structures of all synthetic compounds. – See more at: http://www.eurekaselect.com/124334/article

…….

PAPER

Figure 1: Structures of icariin (1), icariside I (2) and icaritin (3).

Synthesis of icariin from kaempferol through regioselective methylation and para-Claisen–Cope rearrangement

Qinggang Mei^1,2, Chun Wang¹, Zhigang Zhao³, Weicheng Yuan² and Guolin Zhang¹

¹Chengdu Institute of Biology, Chinese Academy of Sciences, Chengdu 610041, China
²Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
³College of Chemistry and Environmental Protection Engineering, Southwest University for Nationalities, Chengdu 610041, China…http://www.beilstein-journals.org/bjoc/single/articleFullText.htm?publicId=1860-5397-11-135

http://www.beilstein-journals.org/bjoc/content/supplementary/1860-5397-11-135-S1.pdf

Scheme 1: Reagents and conditions: (a) Ac₂O, pyridine, 94%; (b) BnBr, KI, K₂CO₃, acetone, 85%; (c) Me₂SO₄, K₂CO₃, acetone, MeOH, 82%; (d) MOMCl, N,N-diisopropylethylamine (DIPEA), CH₂Cl₂, 93%; (e) 3,3-dimethylallyl bromide, 18-crown-6, K₂CO₃, acetone, 86%; (f) Eu(fod)₃, NaHCO₃, PhCl, 85 °C, 61%; (g) MeOH, 3 M HCl (aq), reflux, 95%; (h) Pd/C, 1,4-cyclohexadiene, MeOH, 84%.

Scheme 2: Decomposition of 8.

Scheme 3: Claisen rearrangement of flavonol 8.

Scheme 4: Reagents and conditions: (a) 15, DMF/CHCl₃, Ag₂CO₃, molecular sieves (4 Å, powder); (b) 16, CH₂Cl₂, Ag₂O, molecular sieves (4 Å powder), 31% for 2 steps; (c) NH₃ (g), MeOH, 94%; (d) NH₃ (g), MeOH, 63% for 2 steps.

3 Nguyen, V.-S.; Shi, L.; Li, Y.; Wang, Q.-A. Lett. Org. Chem. 2014, 11, 677–681.

4. Dell’Agli, M.; Galli, G. V.; Dal Cero, E.; Belluti, F.; Matera, R.; Zironi, E.; Pagliuca, G.; Bosisio, E. J. Nat. Prod. 2008, 71, 1513–1517.

1H NMR

13C NMR

HMBC

NOESY

………….

The present invention relates to compositions comprising icariside I, and to a novel, one step method of preparing such compositions, comprising converting specific prenylated flavonol glycosides such as epimedium A, epimedium B, epimedium C, icariin, and their corresponding acetate derivatives contained in an Epimedium plant extract to a single compound, namely icariside I shown below as compound I, which was surprisingly discovered to be a strong PDE-5 inhibitor.

This invention further comprises compositions enriched for anhydroicaritin, and to methods of preparing such compositions. One method of this invention for preparing compositions enriched for anhydroicaritin comprises a one-step method of converting prenylated flavonol glycosides, specifically the sagittatoside compounds A, B, and C, and the corresponding acetate derivatives, present in Epimedium plant extracts to a single compound, namely anhydroicaritin shown below as compound II, which was also discovered to be a strong PDE-5 inhibitor.

http://www.google.com/patents/US6399579

EXAMPLES Example 1 Acid Hydrolysis of a 50% EtOH Extract and Purification by Reversed Phase ChromatographyWhole Epimedium grandiflorum leaves were extracted with a 1:1 mixture of ethanol and water at 55° C. The resulting extract (referred to as a “50% EtOH extract”) was filtered and the filtrate concentrated at 40-50° C. under vacuum and then dried under vacuum at 60° C. to a dry solid. The dried extract (131 g) containing approximately 5.8 g of total PFG’s was placed in a 2 liter round bottom flask and 1 L of 90% ethanol was added. The mixture was heated to reflux to help dissolve the solids. Concentrated sulfuric acid (28 mL) was added. The mixture refluxed for 2 hr, cooled to room temperature, and 900 mL of water added with stirring. Next the mixture was filtered using vacuum to remove insoluble sulfate salts and other solids and loaded on a 2.5×56 cm (275 mL) column packed with 250-600 micron divinylbenzene cross-linked polystyrene resin (Mitsubishi Chemical). The column was washed with 2 column volumes (CVs) of 60% ethanol and the icariside I was eluted with 2 CVs of 95% ethanol. The product pool was air-dried producing 11.3 g of brown solids. HPLC analysis (FIG. 5) showed that the solids contained 18% icariside I (peak 15.27 min) and 12% anhydroicaritin (peak 25.15 min). The recovery of the icariside I in the product pool was 87% of the amount present in the hydrolyzate.

Example 2 Purification of a Hydrolyzate by Liquid/liquid ExtractionThe ethanolic hydrolyzate (25 mL) prepared in Example 1 was mixed with 62.5 mL of de-ionized water and the pH was adjusted to 7.0 using 50% (w/w) sodium hydroxide solution. The resulting mixture was extracted with three 25 mL portions of ethyl acetate and the combined ethyl acetate extracts were back extracted with 150 mL of water. The ethyl acetate layers were combined, dried, and assayed for icariside I. HPLC analysis (FIG. 6) showed that the dried EtOAc fractions contained 22% icariside I (peak 15.29 min) and 11% anhydroicaritin (peak 25.27 min), and icariside I recovery into the ethyl acetate was 97% of the amount present in the hydrolyzate. The partition coefficient for icariside I between ethyl acetate and water was found to be 16, indicating that the icariside I has a high affinity for ethyl acetate over water.

Example 3 Acid Hydrolysis of a 50% EtOH Extract and Purification by PrecipitationThe dried extract (204 g) described in Example 1 was mixed with 1 L of 90% EtOH and then heated to reflux to help dissolve the solids. Sulfuric acid (25 ML) was added slowly with swirling. The mixture was refluxed 90 minutes and immediately chilled to stop the reaction. After cooling to room temperature, the mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials, and the cake was washed with about 350 mL of 90% ethanol. The resulting ethanolic hydrolyzate (1.34 L) contained 4.1 g of icariside I.

The ethanolic hydrolyzate prepared above (1.32 L) was placed in a 10 L container and 40 g of 50% (w/w) sodium hydroxide solution was added followed by 20 mL of phosphoric acid. Next 3.3 L of deionized water was added with stirring. The pH of this mixture was 2.4. Sodium hydroxide solution (50% w/w ) was added until the pH was 8.25. The mixture was heated to 65° C. to assist with the coagulation of the precipitate. The mixture was cooled to room temperature and stirred for 0.5 hr at room temperature before filtering through a cellulose filter using vacuum. The resulting brown solids were washed with 715 mL of 10% ethanol and dried either under vacuum at room temperature or in air at 55° C. to yield brown solids. HPLC analysis (FIG. 7) showed the solids contained 20% icariside I (peak 15.27 min) and 10% anhydroicaritin. Recovery of icariside I using this precipitation procedure was 94% of the amount present in the hydrolyzate.

Example 4 Acid Hydrolysis of a Water Extract and Purification by PrecipitationGround Epimedium grandiflorum leaves (0.40 kg) were mixed with 5 L water in a 10 L round bottom flask. The flask was placed on a rotary evaporator for two hours at a rotation speed of 120 rpm and a water bath temperature of 90° C. The extract was filtered under reduced pressure through cellulose paper. The resulting filtrate (3.2 L) was evaporated using the rotary evaporator to a volume of 100 mL and dried under vacuum at 50° C.

The dark brown solids prepared above (40.4 g) were mixed with 200 mL of 90% ethanol and 6.0 mL of sulfuric acid in a 500 mL round bottom flask. The mixture was refluxed for 90 minutes and immediately chilled to stop the reaction. This mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials. The cake was washed with 15 mL of 90% ethanol. The resulting ethanolic hydrolyzate (215 mL) contained 0.53 g of icariside I.

The hydrolyzate prepared above (50 mL) was transferred to a 250 mL beaker and 2.5 mL of 50% (w/w) sodium hydroxide solution was added with stirring to adjust the pH of the solution to pH 9, followed by 1.5 mL of concentrated phosphoric acid. Deionized water (125 mL) was added, and the mixture was adjusted to pH 8.2 using 1.5 mL of 50% sodium hydroxide solution. The mixture was heated to 65° C. to assist with coagulation of the precipitate and cooled to room temperature. The mixture was allowed to sit undisturbed at room temperature for 30 minutes prior to filtration under reduced pressure through cellulose paper. The resulting olive-green solids were washed with 25 mL of de-ionized water and dried under vacuum at room temperature or in air at 80° C. to produce olive-green solids. HPLC analysis (FIG. 8) showed the solids contained 60% icariside I (peak 15.33 min) and 2.4% anhydroicaritin (peak 25.40 min). Recovery of icariside I using this precipitation procedure was 92% of the amount present in the hydrolyzate.

Example 5 Enzymatic Hydrolysis of Icariside Ia) The substrate was a partially purified icariside I product with 20% icariside I and 11% anhydroicaritin. About 50 mg was dissolved in 10 mL of ethanol, and water or buffer was added until the mixture became cloudy (about 20% ethanol). The following dry enzymes were added to separate samples: α-amylase, α-glucosidase, β-amylase, β-glucosidase, hesperidinase, lactase, and pectinase. The samples were incubated overnight at 40 ° C. and analyzed by HPLC. The results were only semi-quantitative due to the difficulty in dissolving the anhydroicaritin that precipitated from the samples. However, several of the chromatograms did show a definite reduction in icariside I and increase in the ratio of anhydroicaritin to icariside I. The best results were obtained using hesperidinase, lactase, β-glucosidase and pectinase.

A larger scale experiment was done using hesperidinase in order to isolate pure anhydroicaritin for characterization. Pure icariside I (20 mg )was dissolved in 10 mL of ethanol and 50 mL of water and 200 mg of hesperidinase enzyme was added and the mixture was incubated for 24 hr at 40 ° C. Crude anhydroicaritin was collected via filtration and purified on a 2.5×30 cm semi-prep C-18 HPLC column using a gradient of 50:50 (MeCN/H₂O) to 80:20 (MeCN/H₂O) in 20 min. The pure anhydroicaritin was analyzed by LC/MS and proton NMR.

b) Enzymatic Hydrolysis of PFG’s: The purified PFG solids (55.3%, purified by reversed-phase chromatography of a 50% EtOH extract) were subjected to enzymatic hydrolysis with the same enzymes and conditions described in part (a). Hesperidinase, lactase, β-glucosidase and pectinase appeared to convert the mixture of PFG’s to a mixture of sagittatosides, but no icariside I or anhydroicaritin were observed. This indicated that these enzymes were specific for the 7-β-glucosyl group and did not hydrolyze the 3-position sugar(s).

Example 6 Preparation of a High Anhydroicaritin-containing ProductA high sagittatosides Epimedium sagittatum extract containing 24.7% total sagittatosides (assayed as icariin) and 8.1% icariin and other expected prenylated flavonol glycosides was obtained from China. A 50 g portion of this extract was mixed with 250 mL of 90% ethanol and 7.5 mL of concentrated sulfuric acid in a 500 mL round bottom flask. The mixture was refluxed for 90 minutes, then allowed to cool to room temperature. The hydrolyzed mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials. The cake was washed with approximately 20 mL of 90% ethanol. The resulting filtered ethanolic hydrolyzate (305 mL) contained 3.75 g of anhydroicaritin and 2.50 g of icariside I.

The filtered hydrolyzate prepared above (200 mL) was transferred to a 1000 mL container and 8.0 mL of 50% (w/w) sodium hydroxide solution was added with stirring, followed by 4.0 mL of phosphoric acid. De-ionized water (500 mL) was then added. This mixture was adjusted to pH 4.9 using 50% sodium hydroxide solution. The mixture was allowed to sit undisturbed at room temperature for 24 hours prior to decanting off the liquid. The resulting solids were macerated using de-ionized water and filtered under reduced pressure through cellulose paper. The resulting dark brown solids (11.9 g) were washed with de-ionized water and dried in air overnight. The dark brown solids contained 20% anhydroicaritin and 12% icariside I and an anhydroicaritin/icariside I ratio of 1.66. The recovery of anhydroicaritin in the precipitation procedure was 94% from the hydrolyzate.

Example 7 Recrystallization of Icariside IIcariside 1 (30 mg) obtained by a method described in Example 1 was dissolved in a minimum of hot tetrahydrofuran (THF). Hot methanol (approximately 10 mL) was then added. The hot THF/MeOH solution was filtered through a PTFE filter into a vial and allowed to evaporate at room temperature to about 5 mL, whereupon crystals began to form, and then placed in a 4° C. refrigerator for 24 hours. The crystals were filtered and washed with cold methanol and dried in a vacuum. Icariside I (21 mg) was isolated as yellow crystals and had a chromatographic purity of 97.4%.

Example 8 Large Scale Acid Hydrolysis of an Epimedium extractAn 800 g portion of an Epimedium sagittatum powder extract obtained from China containing about 13% total prenylflavonol glycosides as icariin was mixed with 4.0 L of 90% ethanol and 120 mL of sulfuric acid in a 10 L round bottom flask. The mixture was refluxed for 90 minutes and immediately chilled to stop the reaction. This mixture was filtered under reduced pressure through cellulose paper to remove insoluble sulfates and other materials. The cake was washed with approximately 200 mL of 90% ethanol. The resulting ethanolic hydrolyzate (4.0 L) contained 33.7 g of icariside I.

The ethanolic hydrolyzate prepared above was transferred to a 34 L container and 200 mL of 50% (w/w) sodium hydroxide solution was added with stirring, followed by 120 mL of phosphoric acid. De-ionized water (10 L) was then added. This mixture was adjusted to pH 8.2 using 120 mL of 50% sodium hydroxide solution. The mixture was stirred for 10 minutes and allowed to sit undisturbed at room temperature for 60 minutes prior to filtration under reduced pressure through cellulose paper. The resulting olive-green solids were washed with 750 mL of de-ionized water and dried under vacuum at 50° C. or in air at 80° C. The olive-green solids contained 44.6% icariside I. Recovery of icariside I in the precipitation procedure was 96% from the hydrolyzate.

Example 9 Large Scale Purification of an Epimedium Extract Containing Prenylflavonoid GlycosidesA 3.7 kg portion of an Epimedium sagittatum powdered extract obtained from China containing approximately 10% total prenylflavonol glycosides (PFG’s) assayed as icariin was stirred with 35 L of 85/15 acetone/water (v/v) in a 50 L mixing tank. The mixture was stirred vigorously for 30 minutes and allowed to sit for 5 minutes. The acetone extract layer (36 L) was decanted from the tank and contained 362 g of PFG’s. Recovery of the PFG’s in this extraction procedure was 96%.

A portion (about 500 mL) of the acetone extract was dried under reduced pressure at 50° C. or less, providing 16.1 g of brown solids which were analyzed to contain 28.6% total PFG’s when assayed as icariin.

TABLE 1

			PDE-5
			IC₅₀
Entry	Sample description	% PFG’s	(μg/mL)


1	Vat extraction of Epimedium leaves,	8.0	5.78
	refluxing for 17 hours with methanol
2	Extract prepared by extracting Epimedium	7.2	4.24
	leaves with 50% ethanol
3	Extract prepared by extracting Epimedium	10.2	12.50
	leaves with 90% ethanol
4	Extract prepared by extracting Epimedium	16.30	5.27
	leaves with 50% EtOH and then purifying
	the extract (after removal of EtOH) by
	liq/liq extraction with butanol. Sample
	tested was the butanol fraction.
5	Extract prepared by extracting Epimedium	19.3	3.97
	leaves with 50% EtOH and purifying by
	liquid/liquid extraction. Sample tested was
	the aqueous fraction of the liq/liq extraction.
6	Purification of a 90% ethanol extract on	65.60	1.87
	a HP-20 reversed phase column

TABLE 2

			PDE-5
		%	IC₅₀
Entry	Sample description	icarside I	(μg/mL)


7	Crude hydrolyzate composition obtained	2.1	24.30
	from a 50% EtOH extract of Epimedium
	leaves
8	Crude hydrolyzate composition obtained	5.3	9.39
	from a 90% EtOH extract of Epimedium
	leaves
9	Icariside I fraction obtained from	21.4	1.50
	purifying hydrolyzate Sample No. 7 on a
	SP-70 reversed-phase column and
	eluting icariside I with alcohol
10	Pure (recrystallized) icariside I	100	0.33
11	Pure anhydroicaritin	0	1.50
12	icariside I hydrate	0	21.50
13	sildenafil	0	0.031

Liang DL & Zheng SL Effects of icaritin on cytochrome P450 enzymes in rats. Pharmazie 69:301-5 (2014).Read more (PubMed: 24791596) »
Guo Y et al. An anticancer agent icaritin induces sustained activation of the extracellular signal-regulated kinase (ERK) pathway and inhibits growth of breast cancer cells. Eur J Pharmacol 658:114-22 (2011). Read more (PubMed: 21376032) »
Zhu Jf et al. Icaritin shows potent anti-leukemia activity on chronic myeloid leukemia in vitro and in vivo by regulating MAPK/ERK/JNK and JAK2/STAT3 /AKT signalings. PLoS One 6:e23720 (2011). Read more (PubMed: 21887305) »
The roots of Epimedium brevicornu Maxim

Patent	Submitted	Granted
Compositions comprising icariside I and anhydroicaritin and methods for making the same [US6399579]		2002-06-04
COSMETIC COMPOSITION CONTAINING HYDROLYSATES OF ICARIIN [US2009170787]	2009-07-02
COMPOUNDS AND METHODS FOR TREATING ESTROGEN RECEPTOR-RELATED DISEASES [US8252835]	2008-06-19	2012-08-28

/////////Beijing Shenogen, Granted Fast Track Status, Novel Cancer Drug, Icaritin, New Drug Approval submission, Beijing Food & Drug Administration, oral traditional Chinese medicine, barrenwort

China Generic Drugmakers Poaching Indian Execs

September 7, 2015 3:21 am / Leave a comment

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

///////////

MORINIDAZOLE 吗啉硝唑

August 11, 2015 10:05 am / 1 Comment on MORINIDAZOLE 吗啉硝唑

Stockhausen's Mai 1.1 of the innovative spirit of antimicrobial agents (morpholine metronidazole) chemical structure

MORINIDAZOLE

吗啉硝唑

(迈灵达^®

1- [3- (4-morpholinyl) -2-hydroxypropyl] -2-methyl-5- nitro -1H- imidazole

CAS 92478-27-8

Jiangsu Hansoh Pharmaceutical Co., Ltd.

Morinidazole was approved by China Food and Drug Administration (CFDA) on February 24, 2014. It was developed and marketed as a step Lingda ® by Hansoh Pharmaceutical.

A nitroimidazoles antibiotic used to treat bacterial infections including appendicitis and pelvic inflammatory disease.

Morinidazole is a nitroimidazoles antibiotic indicated for the treatment of bacterial infections including appendicitis and pelvic inflammatory disease (PID) caused by anaerobic bacteria.

str1

PATENT

WO2006058457A1.

http://www.google.com/patents/WO2006058457A1?cl=en

……………………….

PATENT
CN1981764A.

https://www.google.com/patents/CN1981764A?cl=en

1- (2,3-epoxypropoxy yl) -2-methyl-5-nitro-imidazole (10g), morpholino (10g), 100ml of acetonitrile under reflux for 2 hours, vacuum recovery of acetonitrile, water was added 100ml, heating to the whole solution, filtered hot, let cool, filtering, washing and drying to obtain an off-white solid (11g).

Proton nuclear magnetic resonance data: 1HNMR (CD3Cl) δ2.39 ~ 2.73 (6H, m) δ2.61 (3H, s) δ3.71 ~ 3.81 (4H, m) δ4.10 ~ 4.17 (2H, m) δ4 .63 ~ 4.66 (1H, m) δ8.00 (1H, s)

CN 102199147

http://www.google.com/patents/CN102199147A?cl=en

CN 1605586

https://www.google.com/patents/CN1605586A?cl=en

Example 7 Preparation of α- (morpholino-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol according to Example 4 the same manner as in Preparation α- (morpholino-1-yl) methyl-2-methyl-5-nitroimidazole-1-ethanol, except for using morpholine instead of 4-hydroxypiperidine, prepared by the present invention Compound 7. Proton nuclear magnetic resonance data: 1HNMR (CD3Cl) δ2.39 ~ 2.73 (6H, m) δ2.61 (3H, s) δ3.71 ~ 3.81 (4H, m) δ4.10 ~ 4.17 (2H, m) δ4

Jiangsu Hansoh Pharmaceutical Co., Ltd.

NMR PREDICT

1H NMR PREDICT

13C NMR PREDICT

COSY

CN1810815B	Mar 8, 2006	Mar 16, 2011	陕西合成药业有限公司	Nitroimidazole derivative for treatment
CN1903846B	Aug 15, 2006	Jul 13, 2011	杨成	Ornidazole derivative used for therapy, its preparation method and use
CN100387233C	Jun 9, 2006	May 14, 2008	南京圣和药业有限公司	Use of levo morpholine nidazole for preparing medicine for antiparasitic infection
CN100427094C	Dec 13, 2005	Oct 22, 2008	江苏豪森药业股份有限公司	Usage of alpha-(Morpholin-1-base) methyl-2-methyl-5-azathio-1-alcohol in preparation of anti-trichomoniasis and anti-ameba medicines
CN100540549C	Dec 15, 2005	Sep 16, 2009	南京圣和药业有限公司	Alpha-substituted-2-methyl-5-nitro-diazole-1-alcohol derivative with optical activity
WO2007079653A1 *	Dec 25, 2006	Jul 19, 2007	Junda Cen	OPTICALLY PURE α-SUBSTITUTED 2-METHYL-5-NITROIMIDAZOLE-1-ETHANOL DERIVATIVES

Harbin Gloria to Commercialize Constipation Drug in China

May 18, 2015 6:52 am / 1 Comment on 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

CHINESE MEDICINE-Xuezhikang , A blood lipid regulator

November 22, 2013 10:46 am / 6 Comments on CHINESE MEDICINE-Xuezhikang , A blood lipid regulator

Xuezhikang

Xuezhikang, the extract of red yeast rice, has been widely used as a Chinese traditional medicine for the therapy of patients with cardiovascular diseases. It contains natural Lovastatin and its homologues, as well as unsaturated fatty acids, flavonoids, plant sterols and other biologically active substances

The product is a world-recognized blood lipid regulator, which is made by extracting from “specially-made red yeast rice”. It combines modern high-tech biotechnology with traditional Chinese medicine, which can safely and effectively regulate blood lipids in a comprehensive way with proven curative effects and reliable safety.

Pharmacological Effects: the product can reduce blood cholesterol, triglycerides, low density lipoprotein cholesterol, improve high density lipoprotein cholesterol, inhibit atherosclerotic plaque formation, and protect vascular endothelial cells; and inhibit lipid deposition in the liver. The large-scale evidence-based research has proven that long-term use of XUEZHIKANG can greatly reduce the risk of CHD occurrence and decrease the mortality. XUEZHIKANG is the only Chinese medicine with blood lipids regulating function which is listed into the National Basic Medicine List.

Beijing Peking University WBL Biotech (WPU) has developed and launched Xuezhikang, a capsule formulation of Monascus purpureus-fermented rice, for the oral treatment of hyperlipidemia and cardiovascular disease

CLINICAL TRIAL, NCT01327014 PHASE 2

The data had shown that Xuezhikang significantly reduced the level of low density lipoprotein cholesterin (LDL-C) in patients in a similar manner to statins and increased the level of the beneficial high density lipoprotein cholesterin (HDL-C). It had a good safety profile with no significant liver enzyme abnormal events observed. Besides regulation of dyslipidemia, the drug also signifcantly reduced cardiovascular events and general mortality rate of patients

NCT01686451 PHASE 4

Both XueZhiKang and Statins are cholesterol-lowering medications that are often prescribed for individuals with high cholesterol and who are at risk for cardiovascular disease (CVD). Several studies, including one randomized, double-blind, placebo-controlled clinical trial, have suggested that the use of statins is more frequently associated with fatigue. And XueZhiKang may be not. The purpose of this study is to compare the effect of these two medications on fatigue in persons who are at moderate to low CVD risk based on the risk estimation system in ESC(European Society of Cardiology)/ESA(European Atherosclerosis Society) guidelines (2011) for the management of dyslipidemias.

Those of you with high cholesterol will be happy to learn that there are some legitimate options to your statin pills. Many people cannot tolerate the extremely popular statin pills, especially from side effects of muscle aches. But there’s now some very strong evidence that herbal medicines, including red yeast rice, can be at least as effective as a statin, and without the side effects. Too good to be true? Maybe not…

Red yeast rice is a bright reddish purple fermented rice, which acquires its colour from being cultivated with the mold Monascus purpureus. Red yeast rice is known as Zhi Tai when in powdered form but is called Xue Zhi Kang in alcohol extract form. This has been used in China for many centuries for many reasons, but researchers have been very interested in its effectiveness in lowering cholesterol and preventing heart disease (similar benefits from statins). It seems that the main active ingredient is indeed the natural form of a common statin, lovastatin — but researchers feel that other ingredients inside may add more protective effects. There is an official patented Chinese TCM formulation, called Xue Zhi Kang (xue2 zhi1 kang2 jiao nang 血脂康胶囊), which has the equivalent of 10mg of lovastatin. The ScienceDaily website has a nice 2008 review of a well-designed study, printed in American Journal of Cardiology, which followed 5,000 persons after their first heart attack, and divided them into two groups taking either xuezhikang or placebo. After 5 years:

Frequencies of the primary end point were 10.4% in the placebo group and 5.7% in the XZK-treated group, with absolute and relative decreases of 4.7% and 45%, respectively. Treatment with XZK also significantly decreased CV and total mortality by 30% and 33%, the need for coronary revascularization by 1/3, and lowered total and low-density lipoprotein cholesterol and triglycerides, but raised high-density lipoprotein cholesterol levels. In conclusion, long-term therapy with XZK significantly decreased the recurrence of coronary events and the occurrence of new CV events and deaths, improved lipoprotein regulation, and was safe and well tolerated.

This is impressive data, and the study design is very well done, which means the evidence is quite strong. One co-author, Dr Capuzzi, has a nice summary:

“It’s very exciting because this is a natural product and had very few adverse side effects including no abnormal blood changes,” said Capuzzi. “People in the Far East have been taking Chinese red yeast rice as food for thousands of years, but no one has ever studied it clinically in a double-blind manner with a purified product against a placebo group until now and we are pleased with the results. However, people in the United States should know that the commercially available over-the-counter supplement found in your average health food store is not what was studied here. Those over-the-counter supplements are not regulated, so exact amounts of active ingredient are unknown and their efficacy has not been studied yet.”

: XueZhiKang

In another randomized trial study, printed last year in the Annals of Internal Medicine, patients who had previously failed treatment of statins due to side effects were given 1800mg of red yeast rice twice a day versus placebo. The red yeast rice group had a significant improvement in cholesterol numbers — with no major reports of severe muscle aches they previously had on the statins.

There are other studies that also show similar benefits. In fact, the evidence is so strong that it is classified as Grade A evidence: “Strong scientific evidence for use”. This is the highest grade that any therapy can get. There are a number of good reviews of red yeast rice in Western literature, including from Medscape; the Mayo Clinic; WebMD; MedlinePlus; and NCCAM. There’s also more informal information from the TCM blog Qi Spot. You can find more scholarly information in the 2008 review from Chinese Medical Journal.

http://www.hindawi.com/journals/ecam/2012/636547/

(U.S. patent #6,046,022), ethanol extract of red yeast rice, with a total monacolins content of approx. 0.8%.

1 Heber D et al. Cholesterol-lowering effects of a proprietary Chinese red-yeast-rice dietary supplement. American Journal of Clinical Nutrition 1999;69(2): 231-236
2) SoRelle R. Appeals court says Food and Drug Administration can regulate cholestin. Circulation 200;102 (7): E9012?E9013.
3) Li, C et al. Monascus purpureus-fermented rice (red yeast rice): a natural food product that lowers blood cholesterol in animal models of hypercholesterolemia. Nutrition Research 1998;18 (1): 71-81
4) Becker DJ et al. Red yeast rice for dyslipidemia in statin-intolerant patients: a randomized trial.Ann Intern Med. 2009 Jun 16;150(12):830-9, W147-9
5) Lu Z et al.Effect of Xuezhikang, an extract from red yeast Chinese rice, on coronary events in a Chinese population with previous myocardial infarction. Am J Cardiol. 2008 Jun 15;101(12):1689-93.

Hypochol is the same product. Xuezhikang is the brand name marketed in China. Hypochol, is manufactured by a Singapore comapany who have a joint venture agreement with Peking University who perfected the processing and quality control of the Red Yeast Rice Extract Product. You can order directly from: http://www.hypocol.com/wbm.html
or thru their New Zealand distributor (very good service) at: http://www.hypocol.co.nz/

Dried grain red yeast rice

Red yeast rice (simplified Chinese: 红曲米; traditional Chinese: 紅麴米); pinyin: hóng qū mǐ; literally “red yeast rice”), red rice koji (べにこうじ, lit. ‘red koji‘) or akakoji (あかこぎ, also meaning ‘red koji‘), red fermented rice, red kojic rice, red koji rice, anka, or ang-kak, is a bright reddish purple fermented rice, which acquires its colour from being cultivated with the mold Monascus purpureus.

Red yeast rice is what is referred to, in Japanese, as a koji, meaning ‘grain or bean overgrown with a mold culture’, a food preparation tradition going back to ca. 300 BC.^[1] In both the scientific and popular literature in English that draws principally on Japanese, it is most often known as “red rice koji“. English works favoring Chinese sources may prefer the translation “red yeast rice”.

In addition to its culinary use, red yeast rice is also used in Chinese herbology and traditional Chinese medicine. Its use has been documented as far back as the Tang Dynasty in China in 800 AD. It is taken internally to invigorate the body, aid in digestion, and revitalize the blood. A more complete description is in the traditional Chinese pharmacopoeia, Ben Cao Gang Mu-Dan Shi Bu Yi, from the Ming Dynasty (1378–1644).

What other names is Red Yeast known by?

Arroz de Levadura Roja, Cholestin, Hong Qu, Koji Rouge, Levure de Riz Rouge, Monascus, Monascus purpureus, Monascus Purpureus Went, Red Rice, Red Rice Yeast, Red Yeast Rice, Red Yeast Rice Extract, Riz Rouge, Xue Zhi Kang, XueZhiKang, XZK, Zhibituo, Zhi Tai.

What is Red Yeast?

Red yeast is the product of rice fermented with Monascus purpureus yeast. Red yeast supplements are different from red yeast rice sold in Chinese grocery stores. People use red yeast as medicine.

Possibly Effective for…

High cholesterol.
High cholesterol and triglyceride levels caused by human immunodeficiency virus (HIV) disease (AIDS).

Insufficient Evidence to Rate Effectiveness for…

Indigestion, diarrhea, improving blood circulation, spleen and stomach problems, and other conditions.

In the late 1970s, researchers in the United States and Japan were isolating lovastatin from Aspergillus and monacolins fromMonascus, respectively, the latter being the same fungus used to make red yeast rice but cultured under carefully controlled conditions. Chemical analysis soon showed that lovastatin and monacolin K are identical. The article “The origin of statins” summarizes how the two isolations, documentations and patent applications were just months apart.^[5] Lovastatin became the patented, prescription drug Mevacor for Merck & Co. Red yeast rice went on to become a contentious non-prescription dietary supplement in the United States and other countries.

Lovastatin and other prescription “statin” drugs inhibit cholesterol synthesis by blocking action of the enzyme HMG-CoA reductase. As a consequence, circulating total cholesterol and LDL-cholesterol are lowered. In a meta-analysis of 91 randomized clinical trial of ≥12 weeks duration, totaling 68,485 participants, LDL-cholesterol was lowered by 24-49% depending on the statin. Different strains ofMonascus fungus will produce different amounts of monacolins. The ‘Went’ strain of Monascus purpureus (purpureus = dark red in Latin), when properly fermented and processed, will yield a dried red yeast rice powder that is approximately 0.4% monacolins, of which roughly half will be monacolin K (identical to lovastatin). Monacolin content of a red yeast rice product is described in a 2008 clinical trial report.

Bristol-Myers Squibb to Market Japanese Hypertension Drug in China

November 4, 2013 4:05 am / 2 Comments on Bristol-Myers Squibb to Market Japanese Hypertension Drug in China

Bristol-Myers Squibb licensed exclusive China rights to market Coniel, a calcium channel blocker treatment for hypertension and angina pectoris, from Kyowa Hakko Kirin Co. BMS said the transaction, its first China-specific in-licensing deal, demonstrated the company’s long-term commitment to China. Previously, Kyowa Hakko Kirin handled China marketing of the product itself.

O5-methyl O3-[(3R)-1-(phenylmethyl)piperidin-3-yl] 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate

Benidipine (INN), also known as Benidipinum or benidipine hydrochloride, is a dihydropyridine calcium channel blocker for the treatment of high blood pressure (hypertension).

Molecular Structure of 105979-17-7 (3,5-Pyridinedicarboxylicacid, 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-, 3-methyl5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester, (4R)-rel-)

Dosing

Benidipine is dosed as 2–4 mg once daily.^[1]

Benidipine is sold as Coniel by Kyowa Hakko Kogyo.

Benidipine is only licensed for use in Japan and selected Southeast Asian countries, where it is sold as 4 mg tablets.

Also known as: 105979-17-7, NCGC00185768-01, Benidipene, AC1LCVDP, SureCN24516, CTK8E8626, AKOS015895389, H007

Molecular Formula: C₂₈H₃₁N₃O₆ Molecular Weight: 505.56224

Hi-Eisai Pharmaceutical, Inc. “Coniel (benidipine) package insert (Philippines)”.MIMS Philippines. CMPMedica. Retrieved 2008-03-31.
Hirayama, N. and Shimizu, E.: Acta Cryst., C47, 458 (1991)

Benidipine hydrochloride, A calcium channel protein inhibitor

Benidipine hydrochloride C28H31N3O6.HCl [91599-74-5]

Alternative Name: KW 3049

Chemical Name: (4R)-rel-1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid 3-methyl 5-[(3R)-1-(phenylmethyl)-3-piperidinyl] ester hydrochloride

Biological Activity

Orally active antihypertensive agent which displays a wide range of activities in vitro and in vivo. Inhibits L-, N- and T-type Ca²⁺ channels. Also inhibits aldosterone-induced mineralocorticoid receptor activation. Exhibits cardioprotective and antiartherosclerotic effects.

Technical Data

M.Wt:

542.02

Formula:

C₂₈H₃₁N₃O₆.HCl

Solubility:

Soluble to 75 mM in DMSO and to 10 mM in ethanol

Storage:

Desiccate at RT

CAS No:

91599-74-5

References

Yao et al (2006) Pharmacological, pharmacokinetic, and clinical properties of benidipine hydrochloride, a novel long-acting calcium channel blocker. J.Pharmacol.Sci. 100 243. PMID: 16565579.

Kosaka et al (2010) The L-, N-, T-type triple calcium channel blocker benidipine acts as an antagonist of mineralocorticoid receptor, a member of nuclear receptor family. Eur.J.Pharmacol. 635 49. PMID: 20307534.

Benidipine hydrochloride, whose chemical name is (±)-(R*)- 1 ,4-dihydro-2,6-dimethyl-4-(meta-nitrophenyl)-3 ,5-pyridinedica rbolate methyl ester [(R*)-l-benzyl-3-piperidine alcohol ester], belongs to dihydropyridine receptor antagonist. It can bind to dihydropyridine receptors at the binding site with high affinity and high specificity, and shows a strong inhibitory effect on Ca channel. Benidipine not only has an inhibitory effect on muscular (L-type) Ca channel, but also has an inhibitory effect on voltage-dependent N- and T-type Ca channels. It is, up to now, the only calcium antagonist that can inhibit all the three Ca channels mentioned above. Furthermore, benidipine has highly affinity with cell membrane, has vascular selectivity and renal protection effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina.

There are two chiral atoms in the molecule of benidipine hydrochloride, which locate on site 4 of the dihydropyridine ring and site 3′ of the side chain piperidine ring. Accordingly, benidipine hydrochloride has 4 optical isomers: (S)-(S)-(+)-a, (R)-(R)-(-)-a, (R)-(S)-(+)^ and (S)-(R)-(-)^, and the active ingredients for drug are the mixture of (S)-(S)-(+)-a and (R)-(R)-(-)-0L Therefore, it is necessary to separate a and β isomers during the post- treatment stage of benidipine hydrochloride preparation.

Based on the order of synthesis of dihydropyridine main ring, there mainly are two groups of total 5 synthesis routes of benidipine hydrochloride. Among them, there are two routes which involve synthesis of the main ring first: 1) acylchloridizing the main ring of dihydropyridine and then linking the side chain to synthesize directlybenidipine hydrochloride; 2) After acylchloridizing the main ring of dihydropyridine, 3-piperidinol and then benzyl is added. The routes involve the synthesis of the main ring later includes the following; 1) synthesizing the main ring via β-aminocrotonate; 2) synthesizing the main ring via acetylacetate ester; 3) the One-pot’ method involving 3-nitrobenzaldehyde, β-aminocrotonate and acetylaceate ester.

Several synthetic routes of benidipine hydrochloride and its analogues have been disclosed in EP0063365A1, EP0161877A2, JP57-171968A, EP0106275 A2, etc. Among them, EP0106275 A2 gave a summary of the synthetic pathways ofbenidipine hydrochloride. In all of the above references, it was mentioned to separate the benidipine hydrochloride prepared through column chromatography and spit it into its a and β isomers, thus obtain the therapeutically active (±)-a-benidipine hydrochloride.

In order to obtain a highly purified benidipine hydrochloride meeting pharmaceutical use, it is necessary to perform multiple recrystallization with acetone and/or ethanol. Moreover, the crystallization condition is relatively strict since it should be performed below freezing point or even below -20 ^°C . Furthermore, the crystallization process usually need a relatively long time (more than 24 hours).

JP2007-8819A thus disclosed a method for preparing highly purified benidipine hydrochloride meeting pharmaceutical use by first preparing the monohydrate of benidipine hydrochloride.

Because benidipine hydrochloride has a very low solubility, for dissolving in a solvent quickly, benidipine hydrochloride is often grounded into nanoparticles. CN 1794993 A provided a method to grind benidipine hydrochloride into particles of 1.0^50.0 μπι. The mechanical grinding method is performed by grinding larger particles of crystals into desired smaller size of crystals. This method consumes large amount of energy and time, and results in a widely distribution of the crystal particle size.

PEOPLE found the desired sizes of benidipinehydrochloride nanoparticles could be obtained by ultrasonic crystallization technology. Unlike the method of CN 1794993 A, the method according to the present invention obtains crystals from smaller to larger sizes. The distribution of particle sizes in the method of the present invention is relatively narrower since the solvent crystalizes rapidly and steadily in the solution. Overall, the present invention can save time and energy, and is readily for preparation. Summary of the invention

benidipine preparation are disclosed in EP0106275, after JP 2007008819 discloses the industrial preparation methods, Kyowa Hakko Kogyo Co., Japan Institute of Pharmacology at Arzneimittelforschung magazine published a hydrochloric Benidipine physical and chemical properties and stability studies Japanese Pharmacopoeia 15th edition reproduces the drug. Benidipine given above literature its infrared spectrum (IR) in 3170cm “\ 3066 cm-1, 2950cm-1, 2523cm-1, 1694cm-1, 1666cm-1, 1642cm_ \ l533cm_ \ l491cm_ \ l432cm_ \ l348cm_ \ l299cm_ \ l218cm_ \ lll6cm_ \ l088cm_ \

HPLC

Purity test of benidipine hydrochloride (area normalization method): Chromatography conditions

Detector: ultraviolet absorption detector (detection wavelength: 237nm)

Chromatography column: stainless steel column: 4.6 mm x 10 cm, with octadecylsilyl (ODS) silica as filler.

Column temperature: constant, about 25 ^°C

Mobile phase: mixed solution of 0.05 mol/L potassium dihydrophosphate solution (pH 3.0): methanol : tetrahydrofuran (65:27:8) Flow rate: adjusted to render the retention time of benidipine hydrochloride to be about 20 min.

Chromatogram record time: about 2 times of the peak time of benidipine hydrochloride

CLINICAL TRIALS

http://clinicaltrials.gov/show/NCT00135551

Benidipine-based Comparison of Angiotensin Receptors, Î²-blockers, or Thiazide Diuretics in Hypertensive Patients

Completed

Cardiovascular Disease

February 19, 2012

Title: Benidipine

CAS Registry Number: 105979-17-7

CAS Name: (4R)-rel-1,4-Dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridinedicarboxylic acid methyl (3R)-1-(phenylmethyl)-3-piperidinyl ester

Additional Names: (±)-(R*)-3-[(R*)-1-benzyl-3-piperidyl] methyl 1,4-dihydro-2,6-dimethyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate; (±)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl) ester-5-methyl ester

Molecular Formula: C28H31N3O6

Molecular Weight: 505.56

Percent Composition: C 66.52%, H 6.18%, N 8.31%, O 18.99%

Literature References: Dihydropyridine calcium channel blocker. Prepn (stereochemistry unspecified): K. Muto et al., EP 63365;eidem, US 4448964 (1982, 1984 both to Kyowa). Prepn: eidem, EP 106275 (1984 to Kyowa); and toxicity data: eidem, Arzneim.-Forsch. 38, 1662 (1988). Structural studies: N. Hirayama, E. Shimizu, Acta Crystallogr. C47, 458 (1991). Series of articles on properties, pharmacology, determn and clinical evaluation: Arzneim.-Forsch. 38, 1666-1763 (1988). Review: H. Suzuki, T. Saruta,Cardiovasc. Drug Rev. 7, 25-38 (1989).

Derivative Type: Hydrochloride

CAS Registry Number: 91599-74-5

Manufacturers’ Codes: KW-3049

Trademarks: Coniel (Kyowa)

Molecular Formula: C28H31N3O6.HCl

Molecular Weight: 542.02

Percent Composition: C 62.05%, H 5.95%, N 7.75%, O 17.71%, Cl 6.54%

Properties: Yellow crystalline powder, mp 199.4-200.4°. uv max (ethanol): 238, 359 nm (e 2.80 ´ 104, 6.68 ´ 103). Soly at 25° (%): methanol 6.9; ethanol 2.2; water 0.19; chloroform 0.16; acetone 0.13; ethyl acetate 0.0056; toluene 0.0019; n-heptane 0.00009. pKa 7.34. Partition coefficient (n-octanol/water): 1230 (pH 6.4, 22°). LD50 orally in male mice: 218 mg/kg (Muto, 1988).

Melting point: mp 199.4-200.4°

pKa: pKa 7.34

Log P: Partition coefficient (n-octanol/water): 1230 (pH 6.4, 22°)

Absorption maximum: uv max (ethanol): 238, 359 nm (e 2.80 ´ 104, 6.68 ´ 103)

Toxicity data: LD50 orally in male mice: 218 mg/kg (Muto, 1988)

Therap-Cat: Antihypertensive.

Keywords: Antihypertensive; Dihydropyridine Derivatives; Calcium Channel Blocker; Dihydropyridine Derivatives.

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

October 15, 2013 7:18 am / 2 Comments on 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

September 23, 2013 3:27 am / 42 Comments on EFAVIRENZ – Huahai Pharma China-Approved to Produce AIDS Treatment

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

Sustiva (USA, Bristol-Myers Squibb)
Stocrin (EU, MSD)
Aspen Efavirenz (Sub-Saharan Africa, Aspen Pharmacare)

Generic brands India:

E.F (McNeil & Argus)
Efavir (Cipla)
Efcure (Emcure Pharmaceuticals)
Efferven (Ranbaxy Laboratories)
Estiva (Hetero)
Evirenz (Alkem Laboratories)
Viranz (Aurobindo Pharma)

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 Sustiva, Stocrin, Efavir 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

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.

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

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

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

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)

CLIPS

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

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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
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WO1995020389A1 *	Jan 24, 1995	Aug 3, 1995	Merck & Co Inc	Benzoxazinones as inhibitors of hiv reverse transcriptase
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WO1998052570A1 *	May 14, 1998	Nov 26, 1998	David Walter Barry	Antiviral combinations containing the carbocyclic nucleoside 1592u89

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Röder, CS; Heinrich, T; Gehrig, AK; Mikus, G (2007). “Misleading results of screening for illicit drugs during efavirenz treatment”. AIDS (London, England) 21 (10): 1390–1. doi:10.1097/QAD.0b013e32814e6b3e. PMID 17545727.
10
Ren J, Bird LE, Chamberlain PP; et al. (2002). “Structure of HIV-2 reverse transcriptase at 2.35-A resolution and the mechanism of resistance to non-nucleoside inhibitors”. Proc Natl Acad Sci USA 99 (22): 14410–15. doi:10.1073/pnas.222366699. PMC 137897. PMID 12386343.
11
Sustiva (efavirenz) capsules and tablets. Product information (April 2005)
12
Simen AA, Ma J, Svetnik V, Mayleben D, Maynard J, Roth A, Mixson L, Mogg R, Shera D, George L, Mast TC, Beals C, Stoch A, Struyk A, Shire N, Fraser I (2014). “Efavirenz modulation of sleep spindles and sleep spectral profile”. J Sleep Res 24: 66–73. doi:10.1111/jsr.12196. PMID 25113527.
13
Gatch MB, Kozlenkov A, Huang RQ, Yang W, Nguyen JD, González-Maeso J, Rice KC, France CP, Dillon GH, Forster MJ, Schetz JA (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.
14
Dabaghzadeh F, Ghaeli P, Khalili H, Alimadadi A, Jafari S, Akhondzadeh S, Khazaeipour Z (2013). “Cyproheptadine for prevention of neuropsychiatric adverse effects of efavirenz: a randomized clinical trial”. AIDS Patient Care STDS 27 (3): 146–54. doi:10.1089/apc.2012.0410. PMID 23442031.
15
Dabaghzadeh F, Khalili H, Ghaeli P, Dashti-Khavidaki S (2012). “Potential benefits of cyproheptadine in HIV-positive patients under treatment with antiretroviral drugs including efavirenz”. Expert Opin Pharmacother 13 (18): 2613–24. doi:10.1517/14656566.2012.742887. PMID 23140169.
16
Price listed on http://drugstore.com website, 4/20/2008
17
“Merck & Co., Inc., Again Reduces Price of Stocrin (efavirenz) for Patients in Least Developed Countries and Countries Hardest Hit by Epidemic – Drugs.com MedNews”.
18
IndiaDaily – A new trend in emerging nations – Brazil opts for Indian generic drug ignoring US pharmaceutical giant Merck’s patent on AIDS drug Efavirenz
19
http://www.cipla.com
20
Patrick Lumumba Osewe; Yvonne Korkoi Nkrumah; Emmanuel K. Sackey (15 June 2008). Improving Access to HIV/AIDS Medicines in Africa: Trade-Related Aspects of Intellectual Property Rights (TRIPS) Flexibilities Utilization. World Bank Publications. pp. 35–39. ISBN 978-0-8213-7544-0. Retrieved 30 June 2012.
21
http://www.sustiva.com/
22
http://www.medsafe.govt.nz/consumers/cmi/s/stocrin.pdf
23
Drugsupdate.com generic brands list: http://www.drugsupdate.com/brand/generic/Efavirenz/87
24
http://mcneilargusindia.com/
25
http://www.alkemlabs.com/
26
“Regast® (efavirenz) film-coated tablets.”. http://www.pharmasyntez.com (in Russian). Pharmasyntez, 2011. Retrieved 28 June 2015. External link in |website= (help)
27
IOL: Thugs get high on stolen Aids drugs IOL News May 12, 2007
28
Getting high on HIV drugs in S Africa. BBC News, 8 December 2008.
29
‘No Turning Back’: Teens Abuse HIV Drugs. ABC News, April 6, 2009.
30
Getting High On HIV Medication Vice 7.04.2014.
31

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
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
ATC code	J05AG03 (WHO)
PubChem	CID 64139
DrugBank	DB00625
ChemSpider	57715
UNII	JE6H2O27P8
KEGG	D00896
ChEBI	CHEBI:119486
ChEMBL	CHEMBL223228
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

SEE………..http://www.ijppsjournal.com/Vol6Issue1/8170.pdf IR MASS HPLC ETC

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

FC([C@@]1(C#CC2CC2)OC(=O)Nc2c1cc(Cl)cc2)(F)F

Diet Pill Dilemma: Why Is FDA Approving Drugs When Europe Isn’t?

September 4, 2013 12:14 pm / 1 Comment on Diet Pill Dilemma: Why Is FDA Approving Drugs When Europe Isn’t?

We’ve all dreamt of popping a pill to help us safely lose weight, or at least eat that chocolate cake without guilt. But alas, even though the Food and Drug Administration has approved two new diet drugs in recent months, that dream probably isn’t any closer to reality.

In the current issue of the BMJ (formerly the British Medical Journal), Sidney Wolfe, founder of the advocacy group Public Citizen, slams the FDA for approving the drugs – lorcaserin (US brand name Belviq) and topiramate (called Qsymia). The FDA’s European counterpart rejected both of them because of heart risks that turned up during preliminary trials.

read all this at

http://commonhealth.wbur.org/2013/08/diet-pill-dilemma-why-is-fda-approving-drugs-when-europe-isnt

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