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Ambrisentan, أمبريسنتان , 安立生坦 ,アンブリセンタン

August 18, 2018 10:05 am / Leave a comment

ChemSpider 2D Image | ambrisentan | C22H22N2O4

Ambrisentan

BSF-208075; LU-208075

(+)-(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid

Molecular FormulaC₂₂H₂₂N₂O₄
Average mass378.421 Da

(2S)-2-[(4,6-dimethylpyrimidin-2-yl)oxy]-3-methoxy-3,3-diphenylpropanoic acid

177036-94-1 [RN]

8128

HW6NV07QEC

أمبريسنتان [Arabic] [INN]

安立生坦 [Chinese] [INN]

QA-7701

UNII:HW6NV07QEC

BSF208075

Letairis

Letairis®

LU208075

Trade Name：Letairis^® / Volibris^®

MOA：Type A endothelin receptor (ETA) antagonist

Indication：Pulmonary arterial hypertension

Company：Abbott (Originator) , Gilead,GlaxoSmithKline

アンブリセンタン
Ambrisentan

C₂₂H₂₂N₂O₄ : 378.42
[177036-94-1

Ambrisentan (U.S. trade name Letairis; E.U. trade name Volibris; India trade name Pulmonext by MSN labs) is a drug indicated for use in the treatment of pulmonary hypertension.

The peptide endothelin constricts muscles in blood vessels, increasing blood pressure. Ambrisentan, which relaxes those muscles, is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ET_A).^[1] Ambrisentan significantly improved exercise capacity (6-minute walk distance) compared with placebo in two double-blind, multicenter trials (ARIES-1 and ARIES-2).^[2]

Ambrisentan was approved by the U.S. Food and Drug Administration (FDA) and European Medicines Agency, and designated an orphan drug, for the treatment of pulmonary hypertension.^[3]^[4]^[5]^[6]^[7]

Ambrisentan is an endothelin receptor antagonist used in the therapy of pulmonary arterial hypertension (PAH). Ambrisentan has been associated with a low rate of serum enzyme elevations during therapy, but has yet to be implicated in cases of clinically apparent acute liver injury.

Ambrisentan was first approved by the U.S. Food and Drug Administration (FDA) on Jun 15, 2007, then approved by the European Medicines Agency (EMA) on Apr 21, 2008 and approved by Pharmaceuticals and Medical Devices Agency of Japan (PMDA) on Jul 23, 2010. In 2000, Abbott, originator of ambrisentan, granted Myogen (acquired by Gilead in 2006) a license to the compound for the treatment of PAH. In 2006, GlaxoSmithKline obtained worldwide rights to market the compound for PAH worldwide, with the exception of the U.S. It is marketed as Letairis^® by Gilead in US.

Ambrisentan is an endothelin receptor antagonist, and is selective for the type A endothelin receptor (ETA). It is indicated for the treatment of pulmonary arterial hypertension (PAH) (WHO Group 1) to improve exercise ability and delay clinical worsening. Studies establishing effectiveness included predominantly patients with WHO Functional Class II-III symptoms and etiologies of idiopathic or heritable PAH (64%) or PAH associated with connective tissue diseases (32%).

Letairis^® is available as film-coated tablet for oral use, containing 5 or 10 mg of free Ambrisentan. The recommended starting dose is 5 mg once daily with or without food, and increase the dose to 10 mg once daily if 5 mg is tolerated.

Recent Developments and Publications

Last Updated 9/2/2015
8/15/2015Reprod. Toxicol.	Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. As such, endothelin receptor antagonists such as Ambrisentan are teratogenic.^[8]
8/27/2015NEJM	Ambrisentan when used in combination therapy with Tadalafil was found to be more efficacious in treating treatment naive patients with WHO class II or III Pulmonary Arterial Hypertension than monotherapy using either drug.^[9]

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2007-06-15	Marketing approval	Letairis	Pulmonary arterial hypertension	Tablet, Film coated	5 mg/10 mg	Gilead	Priority; Orphan

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2008-04-21	Marketing approval	Volibris	Pulmonary arterial hypertension	Tablet, Film coated	5 mg/10 mg	GlaxoSmithKline	Orphan

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2010-07-23	Marketing approval	Volibris	Pulmonary arterial hypertension	Tablet, Film coated	2.5 mg	GlaxoSmithKline

Approval Date	Approval Type	Trade Name	Indication	Dosage Form	Strength	Company	Review Classification
2010-10-19	Marketing approval	凡瑞克/Volibris	Pulmonary arterial hypertension	Tablet	5 mg	GlaxoSmithKline
2010-10-19	Marketing approval	凡瑞克/Volibris	Pulmonary arterial hypertension	Tablet	10 mg	GlaxoSmithKline

Clinical uses

Ambrisentan is indicated for the treatment of pulmonary arterial hypertension (WHO Group 1) in patients with WHO class II or III symptoms to improve exercise capacity and delay clinical worsening.

Image result for ambrisentan

Birth defects

Endothelin receptor activation mediates strong pulmonary vasoconstriction and positive inotropic effect on the heart. These physiologic effects are vital for the development of the fetal cardiopulmonary system. In addition to this, endothelin receptors are also known to play a role in neural crest cell migration, growth, and differentiation. As such, endothelin receptor antagonists such as Ambrisentan are known to be teratogenic.

Ambrisentan has a high risk of liver damage, and of birth defects if a woman becomes pregnant while taking it. In the U.S., doctors who prescribe it, and patients who take it, must enroll in a special program, the LETAIRIS Education and Access Program (LEAP), to learn about those risks. Ambrisentan is available only through specialty pharmacies.

External links

Letairis website run by Gilead Sciences
Prescribing information
Information on the LETAIRIS Education and Access Program (LEAP)

PATENT

WO9611914A1 / US7109205B2.

WO2010070658A2 / US2011263854A1.

WO2011004402A2 / US2012184573A1.

WO2013030410A2 / US2014011992A1.

CN103709106A.

CN103420811A.

PATENT

https://patents.google.com/patent/WO2012167406A1/en

Ambrisentan and darusentan first reported in U. Med. Chem. 1996, 39, 2123-2128), as a selective antagonist of endothelin receptor A, followed by their pharmacological properties have been studied further, published in J. Med. Chem. 1996, 39, 2123-2128), US patent US 5932730, WO 2009/017777 A2 in. The formula (I), when R is methyl, Chinese name is (+) – ambrisentan, Chinese chemical name is (+) – (2S) -2 – [(4, 6- dimethyl-pyrimidine 2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid; English name is (+) – ambrisentan, English name: (S) -2- (4,6-dimethylpyrimidin -2-yloxy) -3-methoxy-3,3-diphenylpropanoic acid; when R is methoxy, Chinese as (+) – darusentan, Chinese chemical name is (+) – (2S) -2- [ (4,6-dimethoxypyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid; English name is (+ darusentan, English name: (S) – . 2- (4,6-dimethoxypyrimidin-2-yloxy) -3-methoxy-3,3-diphenylpropanoic acid ambrisentan now been approved by the FDA in the United States, the trade name Letairis, for the oral treatment of pulmonary hypertension; up Lu bosentan new drugs may be resistant hypertension (Resistant hypertension) of.

Existing ambrisentan or darusentan synthetic techniques include benzophenone Darzens reaction of an epoxy compound and a racemic methyl chloroacetate, the racemic epoxide opening catalyst in a solution of boron trifluoride diethyl ether ring to give the chiral alcohol latent after substitution reaction and then after hydrolysis reaction ambrisentan or darusentan. Existing obtained optically pure (+) – ambrisentan or (+) – darusentan methods rely mainly on resolution techniques. For example, the split is by a latent chiral alcohol or R- L- proline methyl phenethylamine, see WO 2010/070658 A2, WO 2011/004402 A2. It is well known as chiral utilization of raw materials is not high, resulting in increased costs, limiting industrial-scale applications.

Example 1, (+) – ambrisentan ((2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl propionic acid) of

Preparation of 3,3-diphenyl-2,3-epoxy-propionate (1) (2S)

As indicated above Formula Scheme, wherein, Ph is phenyl; Ac is acetyl;

To a 50 L reactor equipped with a mechanical stirrer was added 3.0 L of acetonitrile was dissolved in 3,3-diphenyl acrylate (0.536 mol, 135.0 g), was dissolved in 1.5 L of acetonitrile to give a concentration of 0.12 M ⁴ M ethylenediamine of formula (IV) shown fructose derived chiral ketones and tetra-n-butylammonium hydrogen sulfate (36 mmol, 12.2 g), was then added containing 3.0 L Ι χ ΙΟ “an aqueous solution of disodium ; cooling liquid into the reaction vessel dissection, the kettle temperature adjusted to -5 ° C- + 5 ° C; was added in batches with stirring pulverized with the pulverizer medicine through a 1.85 kg potassium hydrogen sulfate complex salt mixture (Oxone®), and 0.78 kg NaHCO ₃ (9.29mol), and takes about 4.5 hours complete addition of the above mixture, after the addition the reaction mixture was continued stirring the reaction under this condition (in the system, 3,3- diphenyl acrylate, over a potassium bisulfate salts and complexes of formula molar ratio of fructose derived chiral ketone (IV) is shown in h 5: 0.34), and the timing detection reactions by gas chromatography; the end of the reaction after 5 hours , 5.0 L of water was added to dilute the reaction solution, and extracted with 5.0 L of ethyl acetate; the aqueous phase was added 2.5 L of acetic Extracted with ethyl; organic phases were combined and concentrated to remove the solvent to give homogeneous Qing 162.56 g (2S) -3,3- diphenyl-2,3-epoxy-propionate, crude yield greater than 99%, No purification processing the next reaction, nuclear magnetic conversion was 92%, measured by HPLC enantiomeric excess of 86.9%, Analytical conditions: column model Chiralcel OD-H, n has a volume ratio of the embankment and isopropanol 98: 2 analysis of wavelength 210 nm, the mobile phase flow rate of 1 mL / min, t! = 9.5 min, t 2 = 13.01 min, 86.9% ee.

IR (fi lm) 1760, 1731 cm- 1; ¾ NMR [400 MHz, CDC1 3] δ 7.46-7.44 (m, 2H), 7.36-7.31 (m, 8H), 3.99 (m, 3H), 0.96 (t , J = 7.2Hz, 3H); 13 C NMR [100 MHz, CDC1 3] δ 166.99, 138.98, 135.62, 128.67, 128.53, 128.36, 128.13, 127.04, 66.57, 62.16, 61.43, 13.96.

(2) (2S) -2-phenyl-3,3-hydroxy-3-methoxy propionate

The step (1) 162.56 g obtained in unpurified (2S) – 3,3-diphenyl acrylate epoxy crude compound was dissolved in 100 mL of methanol, 1 mL of boron trifluoride etherate ((2S ) – mole fraction of ethylene-3,3-diphenyl acrylate and boron trifluoride diethyl ether ratio of 1: 0.013) for the epoxy ring opening reaction; after controlling the reaction temperature is 20 ° C, reacted for 8 hours , the reaction solution was concentrated, ethyl acetate and aqueous extraction of the reaction solution after the ethyl acetate was concentrated to give 166.0 g of intermediate (2S) -2- hydroxy-3-methoxy-3,3-diphenyl acetic acid ester, crude yield of 92%, measured by high performance liquid enantiomeric excess of 86.9%, Analytical conditions: column model Chiralcel OD-H, n-and isopropyl alcohol embankment has a volume ratio of 98: 2, the wavelength analysis 210 nm, mobile phase flow rate of 1 mL / min,

_{min, t 2 = 14.51 min,} 85.8% ee .;

IR (film) 1769, 1758 cm “1; 1H NMR [400 MHz, CDC1 3] δ 7.50-7.28 (m, 10H), 5.18 (s, 1H), 4.10 (t, 2H), 3.20 (s, J = 7.2Hz, 3H), 3.03 (s , 1H), 1.17 (t, J = 7.2Hz, 3H); 13 C NMR [100 MHz, CDC1 3] δ 172.48, 141.13, 140.32, 128.97, 128.73, 128.99, 127.81, 127.76, 127.62, 85.01, 77.42, 61.76, 52.62, 14.07.

-3-methoxy-3,3-diphenyl propionate (3) (2S) -2- [- oxo – dimethyl-pyrimidin-2-yl)]

Step (2) obtained in 166.0 g of intermediate (2S) -2- hydroxy-3-methoxy-3,3-diphenyl-propionate were added N, N- dimethylformamide 750 mL , potassium carbonate 45.54 g, was added 4,6-dimethyl after stirring for about half an hour 2-methanesulfonyl-pyrimidin nucleophilic substitution reaction at 80 ° C in an oil bath, the system, (2S) -2- hydroxy -3-methoxy-3,3-diphenyl-ethyl, 4,6-dimethyl-2 molar fraction ratio methylsulfonylpyrimidine and potassium carbonate is 1: 1.2: 0.6; nuclear magnetic after complete consumption of starting material was monitored after about 3 hours, water was added and the reaction solution was extracted with ethyl acetate, the ethyl acetate layer was concentrated to give 237.70 g of intermediate (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl ) – oxy] -3-methoxy-3,3-diphenyl propionate, crude yield greater than 99%, measured by HPLC enantiomeric excess of 85.9%, Analytical conditions: column Chiralcel OD model volume -H, isopropanol and n has embankment ratio of 98: 2, analysis wavelength was 210 nm, the mobile phase flow rate of 1 mL / min, t ^ lO.15 min, t 2 = 11.87 min, 85.9% ee .

IR (film) 1750cm “VH NMR [400 MHz, CDC1 3] δ 7.45 (d, J = 7.2 Hz, 2H), 7.39 (d, J = 7.2 Hz, 2H), 7.33-7.19 (m, 7H), 6.70 (s, 1H), 6.12 ( s, 1H), 4.01-3.85 (m, 2H), 3.50 (s, 3H) 2.38 (s, 6H), 0.93 (t, J = 6.8 Hz, 3H); 13 C NMR _{[100 MHz, CDC1 3] δ} 169.51, 168.70, 163.86, 142.50, 141.29, 128.54, 128.03, 127.97, 127.94, 127.47, 127.40, 115.03, 83.76, 79.23, 77.43, 60.66, 53.92, 23.99, 13.93;. Anal Calcd For _{C 24 H 26 N 2 O 4}: C, 70.92; H, 6.45; N, 6.89 Found:. C, 70.72; H, 6.47; N, 6.83.

(4) (28) -2 – [(4,6-dimethyl-2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid ((+) – Abe Students Tanzania) preparation

To step (3) 237.7 g of the intermediate obtained (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl propionate was dissolved in 1.2 L of organic solvent is 1,4-dioxane was added 600 mL of an aqueous solution containing 92.3 g of sodium hydroxide (wherein, (2S) -2 – [(4,6- dimethyl pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl propionate and sodium hydroxide molar fraction ratio of 1: 4), the reaction temperature was 80 ° C, the reaction after 8 hours, the reaction solution was concentrated, using (1 L, 0.5 L, 0.5 L) and extracted with ether to remove organic impurities, the aqueous phase was extracted after addition of hydrochloric acid to adjust pH 3, large amount of solid appears; then the aqueous phase was added 1.0 L ethyl acetate, filtered to remove insolubles (insolubles which was found after analysis racemic ambrisentan, 23.37 g), the organic layer was concentrated, i.e., optically pure can be obtained 103.9 g (+) – ambrisentan, from 3 , 3-diphenyl acrylate departure, the optically pure (+) – ambrisentan, a yield of 52.3%. A small amount of the obtained reaction with ambrisentan diazo embankment derived (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3 methyl diphenyl measured enantiomeric excess ambrisentan. (2S) -2 – [(4,6- dimethyl-pyrimidin-2-yl) – oxy] -3-methoxy-3,3-diphenyl-propionic acid methyl ester: HPLC measured enantiomer excess of 99.1%, Analytical conditions: column model Chiralcel OD-H, n has a volume ratio of isopropanol embankment 98:! 2, analysis wavelength was 210 nm, the mobile phase flow rate of 1 mL / min, t = _{11.61 min, t 2 = 14.05 min} , 99.1% ee.

_{^{[a] D 25 = + 174.2}}(c = 0.5, MeOH); mp> 150 ° C turns yellow,> 180 ° C into a black, 182 ° C melt; 1H NMR [400 MHz, CDC1 3] δ 7.43 ( d, J = Hz, 2H) , 7.29-7.19 (m, 8H), 6.63 (s, 1H), 6.30 (s, 1H), 3.26 (s, 3H) 2.31 (s, 6H); 13 C NMR [100 _{MHz, CDC1 3] δ 178.98,}170.54, 169.70, 163.48, 139.91, 138.91, 128.77, 128.67, 128.22, 128.08, 115.34, 84.67, 77.55, 53.49, 23.93; 1H NMR [400 MHz, DMSO] δ 12.53 (s, 1H ), 7.34-7.20 (m, 10H) , 6.95 (s, 1H), 6.14 (s, 1H), 3.37 (s, 3H) 2.34 (s, 6H); 13 C NMR [100 MHz, DMSO] δ 169.01, 163.14, 142.59, 141.41, 127.80, 127.68, 127.64, 127.19, 126.95, 114.72, 83.12, 77.55, 52.99, 23.30.

CLIP

SEE https://www.pharmacodia.com/yaodu/html/v1/chemicals/a01610228fe998f515a72dd730294d87.html

CLIP

http://www.orgsyn.org/demo.aspx?prep=v89p0350#ref68

Image result for ambrisentan

Shi and coworkers recently obtained 120 g of virtually enantiopure (+)-ambrisentan (97) without the need for column chromatography (Scheme 23).⁶⁸ (+)-Ambrisentan, an endothelin-1 receptor antagonist, is currently used to treat hypertension. Ketone 2-catalyzed epoxidation afforded 96 in 90% conversion and 85% ee. Compound 97 was further enriched via precipitation and filtration of the racemate.

Peng, X.; Li, P.; Shi, Y. J. Org. Chem. 2012, 77, 701-703.

Clip

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00184

Process Research for (+)-Ambrisentan, an Endothelin-A Receptor Antagonist

Wei-Dong Feng^†, Song-Ming Zhuo^‡, Jun Yu^§, Chuan-Meng Zhao^§, and Fu-Li Zhang *^†^§

^† Collaborative Innovation Center of Yangze River Delta Region Green Pharmaceuticals, Zhejiang University of Technology, 18 Chaowang Road, Hangzhou 310014, China

^‡ Department of Pharmaceutial Engineering, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China

^§ Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmacetical Industry, 285 Gebaini Road, Pudong, Shanghai 201203, China

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00184

Publication Date (Web): August 6, 2018

*E-mail: zhangfuli1@sinopharm.com.

An efficient and robust synthetic route to (+)-ambrisentan ((+)-AMB) was designed by recycling the unwanted isomer from the resolution mother liquors. The racemization of AMB in the absence of either acid or base in the given solvents was reported. The recovery process was developed to produce racemates with purities over 99.5%. The mechanism of the formation of the process-related impurities of (+)-AMB is also discussed in detail. (+)-AMB was obtained in 47% overall yield with >99.5% purity and 99.8% e.e. by chiral resolution with only one recycling of the mother liquors on a 100-g scale without column purification.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00184/suppl_file/op8b00184_si_001.pdf

PaPER

https://pdfs.semanticscholar.org/3801/d5a98a526a4386c431e25d3ac99a328bfae2.pdf

CHEMICAL ENGINEERING TRANSACTIONS VOL. 46, 2015 A publication of The Italian Association of Chemical Engineering Online at http://www.aidic.it/cet Guest Editors: Peiyu Ren, Yancang Li, Huiping Song Copyright © 2015, AIDIC Servizi S.r.l., ISBN 978-88-95608-37-2; ISSN 2283-9216

Improved Synthesis Process of Ambrisentan and Darusentan Jian Lia , Lei Tian*b, c a School of Environmental Science, Nanjing Xiaozhuang University, 3601 Hongjing Road, Nanjing, Jiangsu, 211171, China b School of Petroluem Engineer, Yangtze University, Wuhan, Hubei, 430100, P. R. China c Key Laboratory of Exploration Technologies for Oil and Gas Resources (Yangtze University), Ministry of Education tianlei4665@163.com

2-hydroxy-3-phenoxy-3, 3-diphenylpropinate (5) was prepared from benzophenone via Darzens, methanolysis and hydrolysis reaction. The compound (5) was salified with (S)-dehydroabietylamine (7) and diasterotropic resolution was carried out to provide the key intermediate (S)-2-hydroxy-3-methoxy-3, 3-diphenylpropionic acid (6). Compound (6) was condensed with 2-methylsulfonyl-4, 6-dimethylpyrimidine and 2-methoxysulfonyl4, 6-dimethylpyrimidine to afford ambrisentan (1) and darusentan (7), respectively. Two products were with excellent charity and chemical purity. The total yield of the synthesis was 30.1% and 29.6%, respectively.

Synthesis of methyl 3, 3-diphenyloxirane-2-carboxylate (3) To a solution of sodium methanolate (4.3 g, 79.6 mmol) in dry THF (25 mL) was added the solution of benzophenone (7.2 g, 39.5 mmol) and methyl chloroacetate (6.6 g, 60.8 mmol) in dry THF (15 mL) and stirred at -10 °C for 2 h. The mixture was quenched with water (50 mL). The solution was extracted with diethyl ether (80 mL×3). The organic phases were combined and washed with saturated NaCl. The solution was dried over Na2SO4, filtered, and evaporated under reduced pressure to afford a light yellow oil. The residue (3) can apply in next step without further purification (8.24 g, 82.1%). 1H-NMR (CDCl3): δ 3.52 (s, 3H), 3.99 (s, 1H), 7.32-7.45 (m, 10H).

Synthesis of 2-hydroxy-3-methoxy-3, 3-diphenylpropanoic acid (5)

To a solution of compound (3) (8.2 g, 31.6 mmol) in methanol (40 mL) was added p-toluene sulfonic acid (0.5 g) and stirred at for 0.5 h to afford the solution containing compound (4). Aqueous solution of NaOH (10% wt.) (60 mL) was added to the solution of compound (4) and the mixture was stirred at refluxed for 1h (ester disappeared by TLC). The solution was evaporated in order to remove a lot of methanol. The residue was acidified to pH 2 by conc. HCl. The solution was stirred for overnight and white solid stayed at the aqueous layer. The precipitate was filtered and deeply dried under vacuum to afford (5). (7.34 g, 85.3%). 1H-NMR (CDCl3): δ 3.22 (s, 3H), 5.14 (br, 1H), 5.20 (d, 1H), 7.18-7.37 (m, 10H), 12.30 (1H, br). Synthesis of (S)-2-hydroxy-3-methoxy-3, 3-diphenylpropanoate (6) The solution of compound (5) (14 g, 51.4 mmol) in methyltertiarybutylether (140 mL) was stirred and refluxed for 0.5 h. Dehydroabietylamine (7) (14.7 g, 51.4 mmol) in methyltertiarybutylether (50 mL) was added dropwise in 10 min. After addition, the reaction mixture was stirred for 1 h under reflux temperature. The reaction mixture was cooled to 0 °C and continued to stir for 2 h. The solid ((R, S)-diastereoisomers) was precipitated from the solution, filtered, washed with acetonitrile. The filtrate was diluted with water (100 mL) and acidified to pH 2 by conc. HCl. The aqueous solution was extracted with methylteriarybutylether (50 mL×4). The organic phases were combined and washed with water (80 mL). The organic phase was separated, dried over anhydrous Na2SO4 and evaporated under reduced pressure to afford white residue. The residue was recystallized from toluene to afford (6) as a white solid. (5.53 g, 39.5%). 1H-NMR (CDCl3): δ 3.22 (s, 3H), 5.14 (br, 1H), 5.20 (d, 1H), 7.18-7.37 (m, 10H), 12.30 (1H, br). [α] 20 D =12.3°(c=1.8% in ethanol).

Synthesis of (+)-ambrisentan (1) To a solution of compound (6) (3.6 g, 13.1 mmol) and NaNH2 (1.0 g, 25.6 mmol) in DMF (20 mL) was added 4, 6-dimethyl-2-(methylsulfonyl) pyrimidine (3.63 g, 19.6 mmol) in DMF (10 mL) slowly. After addition, the reaction was stirred for 5 h at room temperature. The solution was quenched with water (20 mL) and acidified to pH 2 by 10% H2SO4 aqueous solution. The mixture was extracted with ethyl acetate (50 mL ×4). The combined organic layers were washed with water (30 mL) and saturated NaCl solution (30 mL). The organic layer was dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting residue was recrystallized from iso-propyl alcohol (30 mL) and water (40 mL), and precipitate formed was filtered off. The cake was deeply dried under vacuum to afford (1) as a white solid. (4.27 g, 86.1%). 1H-NMR (CDCl3): δ 2.39 (s, 6H), 3.32 (s, 3H), 6.43 (s, 1H), 6.70 (s, 1H), 7.28-7.40 (m, 8H), 7.53-7.56 (d, 2H). MS-EI (m/z): 377(M-H). HPLC (XDB-C18, CH3OH/10mmol/L NaH2PO4 + 0.1% H3PO4 = 70/30, 1.0 mL/min): tR 5.2 min (>99.0%); ee= 99.0%.

Patent EP2547663A1

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Title: Ambrisentan

CAS Registry Number: 177036-94-1

CAS Name: (aS)-a-[(4,6-Dimethyl-2-pyrimidinyl)oxy]-b-methoxy-b-phenylbenzenepropanoic acid

Manufacturers’ Codes: BSF-208075; LU-208075

Molecular Formula: C22H22N2O4

Molecular Weight: 378.42

Percent Composition: C 69.83%, H 5.86%, N 7.40%, O 16.91%

Literature References: Nonpeptide endothelin ETA receptor antagonist. Prepn: H. Riechers et al., WO 9611914; eidem, US5932730 (1996, 1998 both to BASF); H. Riechers et al., J. Med. Chem. 39, 2123 (1996). Pharmacology: H. Vatter et al., Clin. Neuropharmacol. 26, 73 (2003). Clinical evaluation in pulmonary arterial hypertension: N. Galié et al., J. Am. Coll. Cardiol. 46, 529 (2005). Review of development and therapeutic potential: G. E. Billman, Curr. Opin. Invest. Drugs 3, 1483-1486 (2002).

Derivative Type: (±)-Form

CAS Registry Number: 713516-99-5

Properties: Crystals from diethylether, mp 190-191°.

Melting point: mp 190-191°

Therap-Cat: Antihypertensive.

Keywords: Antihypertensive; Endothelin Receptor Antagonist.

References

Jump up^ Vatter H, Seifert V (2006). “Ambrisentan, a non-peptide endothelin receptor antagonist”. Cardiovasc Drug Rev. 24 (1): 63–76. doi:10.1111/j.1527-3466.2006.00063.x. PMID 16939634.
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Jump up^ “FDA Approves New Orphan Drug for Treatment of Pulmonary Arterial Hypertension” (Press release). Food and Drug Administration. 2007-06-15. Archived from the original on 23 June 2007. Retrieved 2007-06-22.
Jump up^ “GlaxoSmithKline’s Volibris (ambrisentan) receives authorisation from the European Commission for the treatment of Functional Class II and III Pulmonary Arterial Hypertension” (Press release). GlaxoSmithKline. 2008-04-25. Archived from the original on 30 April 2008. Retrieved 2008-04-29.
Jump up^ Waknine, Yael (2005-05-09). “International Approvals: Ambrisentan, Oral-lyn, Risperdal”. Medscape. Retrieved 2007-06-16.
Jump up^ de Raaf MA, Beekhuijzen M, Guignabert C, Vonk Noordegraaf A, Bogaard HJ (2015). “Endothelin-1 receptor antagonists in fetal development and pulmonary arterial hypertension”. Reproductive Toxicology. 56: 45–51. doi:10.1016/j.reprotox.2015.06.048. PMID 26111581.
Jump up^ Galiè, Nazzareno; Barberà, Joan A.; Frost, Adaani E.; Ghofrani, Hossein-Ardeschir; Hoeper, Marius M.; McLaughlin, Vallerie V.; Peacock, Andrew J.; Simonneau, Gérald; Vachiery, Jean-Luc; Grünig, Ekkehard; Oudiz, Ronald J.; Vonk-Noordegraaf, Anton; White, R. James; Blair, Christiana; Gillies, Hunter; Miller, Karen L.; Harris, Julia H.N.; Langley, Jonathan; Rubin, Lewis J. (2015). “Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension”. New England Journal of Medicine. 373 (9): 834–44. doi:10.1056/NEJMoa1413687.

US5703017
CA2201785
US5840722
US7601730
US8377933
US7109205
USRE42462
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WO2003066614A1 *2002-02-042003-08-14Colorado State University Research FoundationAsymmetric epoxidation of electron deficient olefins

WO2010070658A2 *2008-11-052010-06-24Msn Laboratories LimitedImproved process for the preparation of endothelin receptor antagonists

CN102276536A *2011-06-102011-12-14中国科学院化学研究所An optically pure (+) – ambrisentan and optically pure (+) – darusentan preparation

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Non-Patent Citation

Title

WANG, BIN ET AL.: ‘A Diacetate Ketone-Catalyzed Asymmetric Epoxidation of Olefins’ J. ORG. CHEM. vol. 74, 23 April 2009, pages 3986 – 3989 *

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CN102276536B *2011-06-102015-04-29中国科学院化学研究所Preparation method of optically pure (+)-ambrisentan and optically pure (+)-darusentan

CN103420811B *2012-05-182015-04-15上海医药工业研究院Intermediate compound used for preparing Ambrisentan, preparation method thereof, and preparation of Ambrisentan

CN103524425A *2012-07-042014-01-22天津药物研究院Crystal form V of ambrisentan as well as preparation method and application thereof

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Ambrisentan
Clinical data

AHFS/Drugs.com	Monograph
License data	EU EMA: by INN US FDA: Ambrisentan
Pregnancy category	AU: X (High risk) US: X (Contraindicated)
Routes of administration	Oral
ATC code	C02KX02 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	Undetermined
Protein binding	99%
Elimination half-life	15 hours (terminal)
Identifiers
IUPAC name [show]
CAS Number	177036-94-1
PubChem CID	6918493
IUPHAR/BPS	3951
ChemSpider	5293690
UNII	HW6NV07QEC
ChEMBL	CHEMBL1111
ECHA InfoCard	100.184.855
Chemical and physical data
Formula	C₂₂H₂₂N₂O₄
Molar mass	378.421 g/mol
3D model (JSmol)	Interactive image

/////////////Ambrisentan, أمبريسنتان , 安立生坦 , BSF-208075, LU-208075, アンブリセンタン

CC1=CC(=NC(=N1)OC(C(=O)O)C(C2=CC=CC=C2)(C3=CC=CC=C3)OC)C

Tesirine

August 16, 2018 10:18 am / Leave a comment

2D chemical structure of 1595275-62-9

Tesirine

Molecular Formula:	C₇₅H₁₀₁N₉O₂₃
Molecular Weight:	1496.673 g/mol

UNII-8DVQ435K46;

CAS 1595275-62-9

(11S,11aS)-4-((2S,5S)-37-(2,5-Dioxo-2,5-dihydro-1H-pyrrol-1-yl)-5-isopropyl-2-methyl-4,7,35-trioxo-10,13,16,19,22,25,28,31-octaoxa-3,6,34-triazaheptatriacontanamido)benzyl 11-hydroxy-7-methoxy-8-((5-(((S)-7-methoxy-2-methyl-5-oxo-5,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepin-8-yl)oxy)pentyl)oxy)-2-methyl-5-oxo-11,11a-dihydro-1H-benzo[e]pyrrolo[1,2-a][1,4]diazepine-10(5H)-carboxylate

SG3249, Tesirine

[4-[[(2S)-2-[[(2S)-2-[3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxopyrrol-1-yl)propanoylamino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]-3-methylbutanoyl]amino]propanoyl]amino]phenyl]methyl (6S,6aS)-3-[5-[[(6aS)-2-methoxy-8-methyl-11-oxo-6a,7-dihydropyrrolo[2,1-c][1,4]benzodiazepin-3-yl]oxy]pentoxy]-6-hydroxy-2-methoxy-8-methyl-11-oxo-6a,7-dihydro-6H-pyrrolo[2,1-c][1,4]benzodiazepine-5-carboxylate

PATENT

WO 2014057074

In 2012, tesirine (SG3249) was developed by Spirogen, as a drug linker combining a set of desired properties: fast and straightforward conjugation to antibody cysteines by maleimide Michael addition, good solubility in aqueous/DMSO (90/10) systems, and a traceless cleavable linker system delivering the highly potent pyrrolobenzodiazepine (PBD) DNA cross-linker SG3199

Image result for tesirine

CLIP

Image result for tesirine

CLIP

Scale-up Synthesis of Tesirine

Arnaud C. Tiberghien *^†

, Christina von Bulow^†, Conor Barry^†, Huajun Ge^§, Christian Noti^∥, Florence Collet Leiris^#, Marc McCormick^‡, Philip W. Howard^†, and Jeremy S. Parker^‡

^† Spirogen, QMB Innovation Centre, 42 New Road, E1 2AX London, United Kingdom

^§ Pharmaron, No. 6, Taihe Road, BDA, Beijing, 100176, People’s Republic of China

^∥ Lonza AG, Rottenstrasse 6, CH – 3930 Visp, Switzerland

^# Novasep Ltd, 1 Rue Démocrite, 72000 Le Mans, France

^‡ Early Chemical Development, Pharmaceutical Sciences, IMED Biotech Unit, AstraZeneca, Macclesfield, United Kingdom

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00205

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00205

*E-mail: tiberghiena@medimmune.com.

This work describes the enabling synthesis of tesirine, a pyrrolobenzodiazepine antibody–drug conjugate drug-linker. Over the course of four synthetic campaigns, the discovery route was developed and scaled up to provide a robust manufacturing process. Early intermediates were produced on a kilogram scale and at high purity, without chromatography. Midstage reactions were optimized to minimize impurity formation. Late stage material was produced and purified using a small number of key high-pressure chromatography steps, ultimately resulting in a 169 g batch after 34 steps. At the time of writing, tesirine is the drug-linker component of eight antibody–drug conjugates in multiple clinical trials, four of them pivotal

CLIP

https://cdn-pubs.acs.org/doi/10.1021/acsmedchemlett.6b00062

Design and Synthesis of Tesirine, a Clinical Antibody–Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

Arnaud C. Tiberghien ^*, Jean-Noel Levy †, Luke A. Masterson, Neki V. Patel, Lauren R. Adams, Simon Corbett, David G. Williams, John A. Hartley, and Philip W. Howard ^*

QMB Innovation Centre, Spirogen, 42 New Road, E1 2AX London, U.K.

ACS Med. Chem. Lett., 2016, 7 (11), pp 983–987

DOI: 10.1021/acsmedchemlett.6b00062

Publication Date (Web): May 24, 2016

*E-mail: tiberghiena@medimmune.com., *E-mail: philip.howard@spirogen.com.

This article is part of the Antibody-Drug Conjugates and Bioconjugates special issue.

Pyrrolobenzodiazepine dimers are an emerging class of warhead in the field of antibody–drug conjugates (ADCs). Tesirine (SG3249) was designed to combine potent antitumor activity with desirable physicochemical properties such as favorable hydrophobicity and improved conjugation characteristics. One of the reactive imines was capped with a cathepsin B-cleavable valine-alanine linker. A robust synthetic route was developed to allow the production of tesirine on clinical scale, employing a flexible, convergent strategy. Tesirine was evaluated in vitro both in stochastic and engineered ADC constructs and was confirmed as a potent and versatile payload. The conjugation of tesirine to anti-DLL3 rovalpituzumab has resulted in rovalpituzumab-tesirine (Rova-T), currently under evaluation for the treatment of small cell lung cancer.

https://cdn-pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.6b00062/suppl_file/ml6b00062_si_001.pdf

SG3249 (tesirine) (860 mg, 73% over 2 steps). LC/MS, method 2, 2.65 min (ES+) m/z (relative intensity) 1496.78 ([M+H] +. , 20). [] 24 D = +262 (c = 0.056, CHCl3).

1H NMR (400 MHz, DMSO-d6) δ 9.95 (s, 1H), 8.20 (d, J = 7.0 Hz, 1H), 8.03 (t, J = 5.6 Hz, 1H), 7.97 – 7.84 (m, 2H), 7.55 (d, J = 8.1 Hz, 2H), 7.32 (s, 1H), 7.18 (d, J = 8.0 Hz, 2H), 7.10 – 6.96 (m, 3H), 6.84 (s, 1H), 6.79 – 6.57 (m, 4H), 5.59 (d, J = 9.4 Hz, 1H), 5.16 (d, J = 12.7 Hz, 1H), 4.81 (d, J = 12.4 Hz, 1H), 4.38 (t, J = 7.1 Hz, 1H), 4.32 – 4.17 (m, 2H), 4.17 – 4.07 (m, 1H), 4.07 – 3.87 (m, 3H), 3.80 (d, J = 14.2 Hz, 6H), 3.74 – 3.62 (m, 1H), 3.59 (t, J = 7.2 Hz, 4H), 3.55 – 3.42 (m, 28H), 3.35 (d, J = 5.2 Hz, 2H), 3.21 – 3.11 (m, 2H), 3.11 – 2.98 (m, 2H), 2.98 – 2.83 (m, 1H), 2.49 – 2.28 (m, 5H), 2.03 – 1.88 (m, 1H), 1.87 – 1.65 (m, 10H), 1.64 – 1.47 (m, 2H), 1.29 (t, J = 5.9 Hz, 3H), 0.85 (dd, J = 17.1, 6.7 Hz, 6H).

13C NMR (126 MHz, DMSO-d6) δ 171.55, 171.29, 171.16, 170.78, 169.91, 164.80, 162.52, 155.03, 150.25, 139.27, 134.99, 128.84, 123.13, 122.67, 121.76, 119.28, 111.93, 110.93, 86.05, 70.21, 70.16, 70.02, 69.95, 69.46, 68.93, 68.79, 67.39, 57.94, 56.16, 54.03, 49.49, 38.97, 38.89, 36.39, 34.53, 34.40, 31.04, 28.69, 28.65, 22.72, 19.60, 18.55, 18.37, 13.88, 13.82. HRMS (ESI) m/z Calc. C75H101N9O23 1495.70831 found 1495.70444.

FT-IR (ATR, cm‐1 ) 3311, 2911, 2871, 1706, 1643, 1623, 1601, 1512, 1435, 1411, 1243, 1213, 1094, 1075, 946, 827, 747, 695, 664.

Patent ID	Title	Submitted Date	Granted Date
US2015297746	PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES	2013-10-11	2015-10-22
US2017267778	HUMANIZED ANTI-TN-MUC1 ANTIBODIES AND THEIR CONJUGATES	2015-04-15

Patent ID	Title	Submitted Date	Granted Date
US2015283258	PYRROLOBENZODIAZEPINE – ANTI-PSMA ANTIBODY CONJUGATES	2013-10-11	2015-10-08
US2015283262	PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES	2013-10-11	2015-10-08
US2015283263	PYRROLOBENZODIAZEPINE-ANTIBODY CONJUGATES	2013-10-11	2015-10-08
US2016106861	AXL ANTIBODY-DRUG CONJUGATE AND ITS USE FOR THE TREATMENT OF CANCER	2014-04-28	2016-04-21
US2014127239	PYRROLOBENZODIAZEPINES AND CONJUGATES THEREOF	2013-10-11	2014-05-08

Patent ID	Title	Submitted Date	Granted Date
US2017320960	NOVEL ANTI-MFI2 ANTIBODIES AND METHODS OF USE	2015-09-04
US2016015828	NOVEL ANTIBODY CONJUGATES AND USES THEREOF	2014-02-21	2016-01-21
US2015265722	PYRROLOBENZODIAZEPINE-ANTI-CD22 ANTIBODY CONJUGATES	2013-10-11	2015-09-24
US2015273077	PYRROLOBENZODIAZEPINE-ANTI-HER2 ANTIBODY CONJUGATES	2013-10-11	2015-10-01
US2015273078	PYRROLOBENZODIAZEPINE-ANTI-PSMA ANTIBODY CONJUGATES	2013-10-11	2015-10-01

.//////////Tesirine, SG3249, SG 3249

CC1=CN2C(C1)C=NC3=CC(=C(C=C3C2=O)OC)OCCCCCOC4=C(C=C5C(=C4)N(C(C6CC(=CN6C5=O)C)O)C(=O)OCC7=CC=C(C=C7)NC(=O)C(C)NC(=O)C(C(C)C)NC(=O)CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN8C(=O)C=CC8=O)OC

BMS-978587

July 19, 2018 10:30 am / Leave a comment

BMS-978587

Molecular Formula:	C₂₆H₃₅N₃O₃	CAS	1629125-65-0
Molecular Weight:	437.582

US9675571 PATENT

Inventor James Aaron Balog Audris Huang Bin Chen Libing Chen Steven P. Seitz Amy C. Hart Jay A. Markwalder

AssigneeBristol-Myers Squibb Co Priority date 2013-03-15

IDO-IN-4; 1629125-65-0; SCHEMBL17456163; AKOS030526622; ZINC521836543; CS-5086

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid

(1R,2S)-2-[4-[bis(2-methylpropyl)amino]-3-[(4-methylphenyl)carbamoylamino]phenyl]cyclopropane-1-carboxylic acid

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

BMS-978587 was discovered and developed within Bristol-Myers Squibb as a potent small molecule IDO inhibitor

Tryptophan is an amino acid which is essential for cell proliferation and survival. Indoleamine-2,3-dioxygenase is a heme-containing intracellular enzyme that catalyzes the first and rate-determining step in the degradation of the essential amino acid L-tryptophan to N-formyl-kynurenine. N-formyl-kynurenine is then metabolized by mutliple steps to eventually produce nicotinamide adenine dinucleotide (NAD+). Tryptophan catabolites produced from N-formyl-kynurenine, such as kynurenine, are known to be preferentially cytotoxic to T-cells. Thus an overexpression of IDO can lead to increased tolerance in the tumor microenvironment. IDO overexpression has been shown to be an independent prognostic factor for decreased survival in patients with melanoma, pancreatic, colorectal and endometrial cancers among others. Moreover, IDO has been found to be implicated in neurologic and psychiatric disorders including mood idsorders as well as other chronic diseases characterized by IDO activation and tryptophan depletiion, such as viral infections, for example AIDS, Alzheimer’s disease, cancers including T-cell leukemia and colon cancer, autimmune diseases, diseases of the eye such as cataracts, bacterial infections such as Lyme disease, and streptococcal infections.

Accordingly, an agent which is safe and effective in inhibiting production of IDO would be a most welcomed addition to the physician’s armamentarium

SYNTHESIS

PATENT

https://patents.google.com/patent/US9675571

Figure US09675571-20170613-C00026

Figure US09675571-20170613-C00027

Example 1 Method A Enantiomer 1 and Enantiomer 2 Enantiomer 1: (1R,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

PATENT

WO2014/150677

https://patents.google.com/patent/WO2014150677A1/en

Example 1- Method A

Enantiomer 1 and Enantiomer 2

Enantiomer 1 : (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

1A. 4-bromo-N,N-diisobutyl-2-nitroaniline

4-bromo-l-fluoro-2 -nitrobenzene (7 g, 31.8 mmol) and diisobutylamine (12.23 ml, 70.0 mmol) were heated at 130 °C for 3 h. It was then cooled to RT, purification via flash chromatography gave 1A (bright red solid, 8.19 g, 24.88 mmol, 78 % yield) LC-MS Anal. Calc’d for Ci₄H₂iBrN₂0₂ 328.08, found [M+3] 331.03, T_r = 2.63 min (Method A).

IB. N,N-diisobutyl-2-nitro-4-vinylaniline

To a solution of 1 A (1 g, 3.04 mmol) in ethanol (15.00 mL) and toluene (5 mL) (sonication to break up the solid) was added 2,4,6-trivinyl- 1 ,3 ,5 ,2,4,6-trioxatriborinane pyridine complex (0.589 g, 3.64 mmol) followed by K3PO₄ (1.289 g, 6.07 mmol) and water (2.000 mL). The reaction mixture was purged with Argon for 2 min and then Pd (PPh₃)₄(0.351 g, 0.304 mmol) was added. It was then heated at 80 °C in an oil bath for 8 h. LC-MS indicated completion. It was diluted with EtOAc (10 mL) and water (5 mL) and filtered through a pad of Celite, rinsed with EtOAc (2×30 mL). Aqueous layer was further extracted with EtOAc (2×30 mL), the combined extracts were washed with water, brine, dried over MgS0₄, filtered and concentrated. Purification via fiash chromatography gave IB (orange oil, 800 mg, 2.89 mmol, 95 % yield). LC-MS Anal. Calc’d for

Ci₆H₂₄N₂0₂ 276.18, found [M+H] 277.34, T_r = 2.41 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 7.73 (d, J=2.2 Hz, 1H), 7.44 (dd, J=8.8, 2.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 6.60 (dd, J=17.5, 10.9 Hz, 1H), 5.63 (dd, J=17.6, 0.4 Hz, 1H), 5.20 (d, J=11.2 Hz, 1H), 3.00 – 2.89 (m, 4H), 1.99 – 1.85 (m, 2H), 0.84 (d, J=6.6 Hz, 12H) IC. Racemic (lR,2S)-ethyl 2-(4-(diisobutylamino)-3 nitrophenyl)

cyclopropanecarboxylate

To a solution of IB (800 mg, 2.61 mmol) in DCM (15 mL) was added rhodium(II) acetate dimer (230 mg, 0.521 mmol) followed by a slow addition of a solution of ethyl diazoacetate (0.811 mL, 7.82 mmol) in CH2CI2 (5.00 mL) over a period of 2 h via a syringe pump. The reaction mixture turned into a dark red solution and it was stirred at RT for extra 1 h. LC-MS indicated the appearance of two peaks with the desired molecular mass, the solvent was removed in vacuo and purification via flash

chromatography gave 1C (cis isomer) (yellow oil, 220 mg, 0.607 mmol, 23.30 % yield) and trans isomer (yellow oil, 300 mg, 0.828 mmol, 31.8 % yield). LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.27, T_r = 2.34 min (cis), 2.42 min (trans) (Method A), cis isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=1.8 Hz, 1H), 7.30 – 7.25 (m, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.86 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.53 – 2.44 (m, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.37 – 1.30 (m, 1H), 0.99 (t, J=7.0 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H) trans isomer: 1H NMR (400MHz, CHLOROFORM-d) δ 7.43 (d, J=2.2 Hz, 1H), 7.17 – 7.11 (m, 1H), 7.08 – 7.03 (m, 1H), 4.18 (q, J=7.3 Hz, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.46 (ddd, J=9.2, 6.4, 4.2 Hz, 1H), 1.94 – 1.80 (m, 3H), 1.62 – 1.54 (m, 1H), 1.34 – 1.23 (m, 4H), 0.83 (d, J=6.6 Hz, 12H)

ID. Racemic (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

To a stirred solution of 1C (cis isomer) (220 mg, 0.607 mmol) in EtOAc (6 mL) was added palladium on carbon (64.6 mg, 0.061 mmol) and the suspension was hydrogenated (1 atm, balloon) at RT for 1 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×30 mL). Combined filtrate and rinses were evaporated in vacuo. Purification via flash chromatography gave ID (light yellow oil, 140 mg, 0.421 mmol, 69.4 % yield). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.34, T_r= 2.22 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=2.0 Hz, 1H), 6.64 – 6.59 (m, 1H), 4.06 (s, 2H), 3.87 (qd, J=7.1, 0.9 Hz, 2H), 2.56 (d, J=7.0 Hz, 4H), 2.47 (q, J=8.6 Hz, IH), 2.01 (ddd, J=9.4, 7.8, 5.7 Hz, IH), 1.78 – 1.61 (m, 3H), 1.24 (ddd, J=8.6, 7.9, 5.1 Hz, IH), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Racemic example 1. Racemic (lR,2S)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

To a solution of ID (140 mg, 0.421 mmol) in THF (4mL) was added 1- isocyanato-4-methylbenzene (0.079 mL, 0.632 mmol). The resulting solution was stirred at RT for 3 h. LC-MS indicated completion. The reaction mixture was concentrated and used without purification in the next step. The crude ester (180 mg, 0.387 mmol) was dissolved in THF (4 mL), NaOH (IN aqueous) (1.160 mL, 1.160 mmol) was added. Then MeOH (1 mL) was added to dissolve the precipitate and it turned into a clear yellow solution. After 60 h, reaction was complete by LC-MS. Most MeOH and THF was removed in vacuo and the crude was diluted with 2 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×10 mL) and the combined organic phase was washed with brine, dried over Na₂S0₄ and concentrated. Purification via flash chromatography gave racemic example 1 (yellow foam, 110 mg, 0.251 mmol, 65.0 % yield), LC-MS Anal. Calc’d for CzeHssNsOs 437.27, found [M+H] 438.29, T_r = 4.22 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 10.15 (br. s., IH), 7.42 – 7.35 (m, 3H), 7.22 – 7.14 (m, 2H), 7.10 (d, J=8.1 Hz, 2H), 3.22 (d, J=6.6 Hz, 4H), 2.54 (q, J=8.6 Hz, IH), 2.31 (s, 3H), 2.16 – 1.98 (m, 3H), 1.61 (dt, J=7.3, 5.6 Hz, IH), 1.40 (td, J=8.3, 5.3 Hz, IH), 1.01 (br. s., 12H)

Example 1, Enantiomer 1 and Enantiomer 2. Chiral separation of racemic example 1 (Method H) gave enantiomer 1 T_r = 9.042 min (Method J). [a]²⁴ _D = -11.11 (c 7.02 mg/mL, MeOH) and enantiomer 2 T_r = 10.400 min (Method J). [a]²⁴ _D = + 11.17 (c 7.02 mg/mL, MeOH) as single enantiomers. Absolute stereochemistry was confirmed in example 1 method B.

Enantiomer 1 : LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.25, T_r= 4.19 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.12 (d, J=1.3 Hz, IH), 7.97 (s, IH), 7.20 (d, J=8.4 Hz, 2H), 7.14 – 7.07 (m, 2H), 7.02 (t, J=7.7 Hz, 2H),

6.89 (dd, J=8.1, 1.5 Hz, IH), 2.60 (q, J=8.6 Hz, IH), 2.50 (d, J=7.0 Hz, 4H), 2.32 (s, 3H), 2.13 – 2.04 (m, 1H), 1.71 – 1.55 (m, 3H), 1.35 (td, J=8.3, 5.1 Hz, 1H), 0.76 (dd, J=6.6, 2.2 Hz, 12H)

Enantiomer 2: LC-MS Anal. Calc’d for C26H35N3O3 437.27, found [M+H] 438.24, T_r= 4.18 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 8.11 (d, J=1.5 Hz, 1H), 7.96 (s, 1H), 7.23 – 7.16 (m, 2H), 7.13 – 7.07 (m, 2H), 7.05 – 6.98 (m, 2H), 6.89 (dd, J=8.3, 1.7 Hz, 1H), 2.59 (q, J=8.7 Hz, 1H), 2.49 (d, J=7.3 Hz, 4H), 2.32 (s, 3H), 2.12 – 2.03 (m, 1H), 1.70 – 1.53 (m, 3H), 1.34 (td, J=8.2, 5.0 Hz, 1H), 0.75 (dd, J=6.6, 2.0 Hz, 12H) Example 1 – Method B

Enantiomer 1 and Enantiomer 2

Enantiomer 2: (lS,2R)-2-(4-(diisobutylamino)-3-(3-(p- tolyl)ureido)phenyl)cyclopropanecarboxylic acid

IE. 4-(5,5-dimethyl-l,3,2-dioxaborinan-2-yl)-N,N-diisobutyl-2-nitroaniline

1A (10 g, 30.4 mmol), 5,5,5′,5′-tetramethyl-2,2′-bi(l,3,2-dioxaborinane) (7.55 g, 33.4 mmol), PdCl₂(dppf)- CH₂C1₂ adduct (0.556 g, 0.759 mmol) and potassium acetate

(8.94 g, 91 mmol) were combined in a round bottom flask, and DMSO (100 mL) was added. It was vacuated and back-filled with N₂ three times, then heated at 80 °C for 8 h. Reaction was complete by LC-MS. Cooled to RT and passed through a short plug of silica gel, rinsed with a mixture of Hexane/EtOAc (5: 1) (3×100 mL). After removing the solvent in vacuo, purification via flash chromatography gave IE (orange oil, 9 g, 22.36 mmol, 73.6 % yield), LC-MS Anal. Calc’d for C19H31BN2O4 362.24, found [M+H] 295.18 (mass of boronic acid), T_r = 3.65 min (Method A). 1H NMR (400MHz,

CHLOROFORM-d) δ 8.13 (d, J=1.8 Hz, 1H), 7.73 (dd, J=8.4, 1.5 Hz, 1H), 7.04 (d, J=8.6 Hz, 1H), 3.75 (s, 4H), 3.00 – 2.92 (m, 4H), 1.93 (dquin, J=13.5, 6.8 Hz, 2H), 1.02 (s, 6H), 0.93 – 0.79 (m, 12H)

IF. (lS,2R)-ethyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To IE (9 g, 22.36 mmol) in a 500 mL round bottom flask was added 1,4-dioxane (60 mL). After it was dissolved, cesium carbonate (15.30 g, 47.0 mmol) was added. To the suspension was then added water (30 mL) slowly. It became an homogeneous solution. Enantiopure (lR,2R)-ethyl 2-iodocyclopropanecarboxylate (5.90 g, 24.59 mmol) (For synthesis see Organic Process Research & Development 2004, 8, 353-359 ) was then added. The resulting mixture was purged with nitrogen for 25 min. Then PdCl₂(dppf)-

CH₂C1₂ adduct (1.824 g, 2.236 mmol) was added. The reaction mixture was purged with nitrogen for another 10 min. It became dark brown colored solution. This mixture was then stirred under nitrogen at 87 °C for 22 h. LC-MS indicated product formation and depletion of starting material. It was then cooled to RT. After removing solvent under reduced pressure, it was diluted with EtOAc (50 mL) and water (50 mL). Organic layer was separated and the aqueous layer was further extracted with EtOAc (3x 30 mL). The combined organic layers were washed with brine, dried over MgS0₄, filtered and concentrated. Purification via flash chromatography gave IF (dark orange oil, 3.2 g, 8.83 mmol, 39.5 % yield), LC-MS Anal. Calc’d for C20H30N2O4 362.22, found [M+H] 363.3, T_r = 3.89 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) 57.65 – 7.60 (m, 1H), 7.29 (d, J=2.2 Hz, 1H), 7.02 (d, J=8.6 Hz, 1H), 3.95 – 3.84 (m, 2H), 2.89 (d, J=7.3 Hz, 4H), 2.48 (q, J=8.6 Hz, 1H), 2.07 (ddd, J=9.2, 7.9, 5.7 Hz, 1H), 1.87 (dquin, J=13.5, 6.8 Hz, 2H), 1.67 (dt, J=7.3, 5.5 Hz, 1H), 1.38 – 1.28 (m, 1H), 0.99 (t, J=7.2 Hz, 3H), 0.82 (d, J=6.6 Hz, 12H

IG. (lS,2R)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of IF (5.5 g, 15.17 mmol) in EtOAc (150 mL) was added palladium on carbon (1.615 g, 1.517 mmol) and the suspension was hydrogenated (1 atm, balloon) for 1.5 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (2×50 mL). Combined filtrate and rinses were concentrated under reduced pressure. Purification via flash chromatography gave 1G (yellow oil, 4.5 g, 13.53 mmol, 89 % yield). LC-MS Anal. Calc’d for

C20H32N2O2 332.25, found [M+H] 333.06, T_r = 2.88 min (Method A). 1H NMR

(400MHz, CHLOROFORM-d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H)

Example 1 enantiomer 2 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 2 T_r = 10.646 min (Method J). Absolute stereochemistry was confirmed by referring to reference: Organic Process Research & Development 2004, 8, 353-359.

Enantiomer 1 Method B: (lR,2S)-2-(4-(diisobutylamino)-3

tolyl)ureido)phenyl)cyclopropanecarboxylic acid

1H. Single enantiomer (lR,2S)-ethyl 2-(3-amino-4-(diisobutylamino)phenyl) cyclopropanecarboxylate

1H was prepared following procedures in example 1 enantiomer 2 method B utilizing enantiopure (l S,2S)-ethyl 2-iodocyclopropanecarboxylate. This was obtained through chiral resolution modifying the procedure in Organic Process Research & Development 2004, 8, 353-359, using (i?)-(+)-N-benzyl-a-methylbenzylamine instead of (S)-(-)-N-benzyl-a-methylbenzylamine). LC-MS Anal. Calc’d for C20H32N2O2 332.25, found [M+H] 333.06, T_r = 2.88 min (Method A). 1H NMR (400MHz, CHLOROFORM- d) δ 6.95 (d, J=7.9 Hz, 1H), 6.68 – 6.58 (m, 2H), 4.06 (s, 2H), 3.93 – 3.81 (m, 2H), 2.57 (d, J=7.3 Hz, 4H), 2.47 (q, J=8.6 Hz, 1H), 2.01 (ddd, J=9.4, 7.8, 5.5 Hz, 1H), 1.78 – 1.59 (m, 3H), 1.30 – 1.18 (m, 1H), 0.92 (t, J=7.2 Hz, 3H), 0.89 (dd, J=6.6, 0.9 Hz, 12H).

Note: 1H was also made through chiral separation (Method I) of racemic (1R,2S)- ethyl 2-(3-amino-4-(diisobutylamino)phenyl)cyclopropanecarboxylate. Chiral analytical analysis (Method K) showed 1H as a single enantiomer (99 % ee).

Example 1 enantiomer 1 was prepared following the reduction, urea formation and basic saponification procedures in racemic example 1 method A using 1H except that saponification was carried out at 50 °C for 8 h instead of at RT. Chiral analytical analysis verified it was enantiomer 1 with 97.8% ee (Method J).

Example 1 – Method C

Enantiomer 1

(lR,2S)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

II. Diastereomer 1: (R)-4-benzyl-3-((lR,2S)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one

Diastereomer 2: (R)-4-benzyl-3-((l S,2R)-2-(4-(diisobutylamino)-3- nitrophenyl)cyclopropanecarbonyl)oxazolidin-2-one: 1C (1.2 g, 3.31 mmol) was dissolved in THF (20 mL), NaOH (IN aqueous) (8.28 mL, 8.28 mmol) was added. Saw precipitate formed, then MeOH (5.00 mL) was added and it turned into a clear yellow solution. The reaction was monitored by LC-MS. After 24 h, reaction was complete. Most MeOH and THF was removed in vacuo and the crude was diluted with 10 mL of water, the pH was adjusted to ca. 2 using IN aqueous HC1. The aqueous phase was then extracted with EtOAc (3×30 mL) and the combined organic phase was washed with brine, dried over Na₂S0₄ , filtered and concentrated to give 1.1 g of desired acid as an orange foam. This was used without purification in the subsequent step. To a solution of the crude acid from the previous step (1132 mg, 3.39 mmol) in THF (15 mL) cooled in an ice-water bath was added N-methylmorpholine (0.447 mL, 4.06 mmol) followed by slow addition of pivaloyl chloride (0.500 mL, 4.06 mmol). After stirring in an ice-water bath for 30 min, the reaction mixture was then cooled to -78 °C. In a separate reaction flask, ftBuLi (1.354 mL, 3.39 mmol) was added dropwise to a solution of (R)-4- benzyloxazolidin-2-one (600 mg, 3.39 mmol) in THF (15.00 mL). After 45 min at -78 °C, the solution was cannulated into the -78 °C anhydride mixture. After 30 min, the cooling bath was removed and the solution was allowed to warm to RT. After 1 h, LC-MS indicated completion. The reaction was quenched by addition of saturated aqueous NH₄C1. The solution was then partitioned between EtOAc and water. The organic phase was further extracted with EtOAc (2×30 mL). The combined organic extracts were washed with water, brine, dried over MgS0₄, filtered and concentrated. Purification via flash chromatography gave II Diastereomer 1 (yellow oil, 600 mg, 1.216 mmol, 35.9 % yield). Diastereomer 2 (yellow oil, 450 mg, 0.912 mmol, 26.9 % yield) LC-MS Anal. Calc’d for C₂8H3₅N₃0₅ 493.26, found: [M+H] 494.23, T_r = 5.26 min (Diastereomer 1). T_r = 5.25 min (Diastereomer 2) (Method A). Diastereomer 1 : 1H NMR (400MHz,

CHLOROFORM-d) δ 7.56 (d, J=1.8 Hz, 1H), 7.35 – 7.23 (m, 4H), 7.18 – 7.12 (m, 2H), 7.03 (d, J=8.8 Hz, 1H), 4.37 (ddt, J=9.6, 7.3, 3.6 Hz, 1H), 4.11 – 4.06 (m, 2H), 3.48 – 3.40 (m, 1H), 3.22 (dd, J=13.4, 3.5 Hz, 1H), 2.89 (d, J=7.3 Hz, 4H), 2.77 – 2.66 (m, 2H), 1.97 – 1.81 (m, 3H), 1.52 – 1.44 (m, 1H), 0.82 (d, J=6.6 Hz, 12H); Diastereomer 2: 1H NMR (400MHz, CHLOROFORM-d) δ 7.62 (d, J=2.0 Hz, 1H), 7.36 – 7.19 (m, 4H), 7.09 – 6.97 (m, 3H), 4.45 (ddt, J=10.2, 7.2, 3.0 Hz, 1H), 4.14 – 4.05 (m, 2H), 3.45 – 3.36 (m, 1H), 2.80 (d, J=7.3 Hz, 4H), 2.52 (dd, J=13.3, 3.2 Hz, 1H), 2.19 (dd, J=13.2, 10.3 Hz, 1H), 2.03 (dt, J=7.2, 5.8 Hz, 1H), 1.72 (dquin, J=13.4, 6.8 Hz, 2H), 1.45 (ddd, J=8.3, 7.3, 5.3 Hz, 1H), 0.64 (dd, J=6.6, 2.0 Hz, 12H) 1 J. (lR,2S)-methyl 2-(4-(diisobutylamino)-3-nitrophenyl)

cyclopropanecarboxylate

To a solution of II Diastereomer 1 (460 mg, 0.932 mmol) in THF (6mL) at 0 °C was added hydrogen peroxide (0.228 mL, 3.73 mmol). Then a solution of lithium hydroxide monohydrate (44.6 mg, 1.864 mmol) in water (2.000 mL) was added to the cold THF solution and stirred for 6 h. LC-MS indicated completion, then 2 mL of saturated aqueous Na₂S0₃ was added followed by 3 mL of saturated aqueous NaHC0₃. The mixture was concentrated to remove most of the THF. The solution was then diluted with 5 mL of water. The aqueous solution was acidified with 1 N aqueous HC1 and extracted with EtOAc (3×20 mL). The combined organic extracts was washed with water, brine, dried over MgS0₄, filtered and concentrated to give 300 mg acid. To a solution of the crude acid from previous step (300 mg, 0.897 mmol) in MeOH (10 mL) was added 6 drops of concentrated H₂SO₄. The resulting solution was stirred at 50 °C for 6 h. After LC-MS indicated completion, solvent was removed under reduced pressure. It was then diluted with 5 mL of water, the aqueous layer was then extracted with EtOAc (3×20 mL) and the combined organic extracts were washed with water, brine, dried with Na₂S0₄, filtered and concentrated. Purification via flash chromatography gave 1J (orange oil, 260 mg, 0.746 mmol, 83 % yield). LC-MS Anal. Calc’d for Ci₉H₂₈N₂0₄ 348.20, found:

[M+H] 349.31 , T_r = 3.87 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ

7.66 – 7.61 (m, 1H), 7.31 – 7.25 (m, 1H), 7.04 (d, J=8.8 Hz, 1H), 3.47 (s, 3H), 2.90 (d, J=7.3 Hz, 4H), 2.54 – 2.44 (m, 1H), 2.14 – 2.04 (m, 1H), 1.89 (dquin, J=13.5, 6.8 Hz, 2H),

1.67 (dt, J=7.5, 5.5 Hz, 1H), 1.42 – 1.31 (m, 1H), 0.83 (dd, J=6.6, 1.1 Hz, 12H)

IK. (lR,2S)-methyl 2-(3-amino-4-(diisobutylamino)phenyl)

cyclopropanecarboxylate

To a stirred solution of 1 J (100 mg, 0.287 mmol) in EtOAc (5mL) was added palladium on carbon (30.5 mg, 0.029 mmol) and the suspension was hydrogenated (1 atm, balloon) for 2 h. LC-MS indicated completion. The suspension was filtered through a pad of Celite and the filter cake was rinsed with EtOAc (20 mL). Combined filtrate and rinses were concentrated. Purification via flash chromatography gave IK (yellow oil, 90 mg, 0.287 mmol, 99 % yield). LC-MS Anal. Calc’d for Ci₉H₃oN₂0₂ 318.23, found:

[M+H] 319.31 , T_r = 2.72 min (Method A). 1H NMR (400MHz, CHLOROFORM-d) δ 6.95 (d, J=8.1 Hz, 1H), 6.65 (d, J=1.8 Hz, 1H), 6.60 (dd, J=8.1 , 1.5 Hz, 1H), 4.08 (br. s., 2H), 3.42 (s, 3H), 2.58 (d, J=7.0 Hz, 4H), 2.52 – 2.42 (m, 1H), 2.09 – 1.98 (m, 1H), 1.79 – 1.59 (m, 3H), 1.32 – 1.22 (m, 1H), 0.94 – 0.84 (m, 12H)

Enantiomer 1 was prepared following the urea formation and saponification procedure in racemic example 1 method A. Chiral analytical analysis verified it was enantiomer 1 with 98.1% ee (Method J).

Example 1 – Method C Enantiomer 2

(lS,2R)-2-(4-(diisobutylamino)-3-(3-(p-tolyl)ureido)phenyl)cyclopropanecarboxylic acid

Example 1 Enantiomer 2 was prepared following the procedure for Example 1 enantiomer 1 method C using diastereomer 2 instead of diastereomer 1. Chiral analytical analysis verified it was enantiomer 2 with 94.0% ee (Method J).

PAPER

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00171

Development of a Scalable Synthesis of BMS-978587 Featuring a Stereospecific Suzuki Coupling of a Cyclopropane Carboxylic Acid

Prantik Maity^†, V. V. Ramana Reddy^†, Jayaraj Mohan^†, Satish Korapati^†, Harishkumar Narayana^†, Nagesh Cherupally^†, Sathishkumar Chandrasekaran^†, Ravikumar Ramachandran^†, Chris Sfouggatakis^‡, Martin D. Eastgate^‡

, Eric M. Simmons^‡

, and Rajappa Vaidyanathan *^†

^† Chemical Development and API Supply, Biocon Bristol-Myers Squibb Research and Development Center, Biocon Park, Jigani Link Road, Bommasandra IV, Bangalore-560099, India

^‡ Chemical and Synthetic Development, Bristol-Myers Squibb, 1 Squibb Drive, New Brunswick, New Jersey 08903, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00171

*E-mail: vaidy@bms.com.

A modified synthetic route to BMS-978587 was developed featuring a chemoselective nitro reduction and a stereospecific Suzuki coupling as the key bond formation steps. A systematic evaluation of the reaction conditions led to the identification of a robust catalyst/ligand/base combination to reproducibly effect the Suzuki reaction on large scale. The modified route avoided several challenges with the original synthesis and furnished the API in high overall yield and purity without recourse to chromatography.

(1R,2S)-2-[4-(Di-isobutylamino)-3-(3-(p-tolyl)ureido)phenyl] Cyclopropanecarboxylic Acid (1)

………… afford 1 as a white solid (510 g, 99.05 HPLC area % purity, 96.0% potency, 60% yield; Pd content: <10 ppm).

¹H NMR (300 MHz, DMSO-d₆) 11.83 (br s, 1H), 9.30 (s, 1H), 7.90 (d, 1H, J = 1.5 Hz), 7.82 (s, 1H), 7.35–7.37 (d, 2H, J = 8.1 Hz), 7.06–7.10 (q, 3H, J = 2.1, 6.3, and 2.1 Hz), 6.78–6.80 (t, 1H, J = 6.3 and 1.8 Hz), 2.50–2.72 (m, 4H), 2.25 (s, 3H), 1.934–2.01 (m, 1H), 1.59–1.65 (m, 2H), 1.20–1.41 (m, 2H), 0.81(m, 13H);

¹³C NMR (100 MHz, DMSO-d₆) 172.2, 153.0, 139.0, 137.8, 135.2, 133.1, 131.2, 129.6, 123.0, 122.1, 121.4, 119.4, 63.6, 26.3, 25.3, 21.9, 21.6, 20.8, 11.4.

HRMS (ESI) m/zcalcd for C₂₆H₃₆N₃O₃ [M + H]⁺ 438.2757, found 438.2714.

REF

(a) Balog, J. A.; Huang, A.; Chen, B.; Chen, L.; Seitz, P.; Hart, A. C.; Markwalder, J. A. Preparation of cycloalkylaryl amide compounds as indoleamine 2,3-dioxygenase and therapeutic uses thereof, PCT Int. Appl. 2014, WO 2014150677A1 20140925.

(b) Balog, J. A.; Cherney, E. C.; Guo, W.; Huang, A.; Markwalder, J. A.; Seitz, S. P.; Shan, W.; Williams, D. K.; Murugesan, N.; Nara, S.Jethanand; Preparation of benzenediamine derivatives as inhibitors of indoleamine 2,3-dioxygenase for the treatment of cancer, PCT Int. Appl. 2016, WO 2016161269A1 20161006.

(c) Markwalder, J. A.; Seitz, S. P.; Hart, A.; Nation, A.; Balog, A.; Vite, G.; Borzilleri, R.; Jure-Kunkel, M.; Chen, B.; Chen, L.; Newitt, J.; Lu, H.; Abell, L.; Lin, T.-A.; Covello, K.; Hunt, J.; D’Arienzo, C.; Fargnoli, J.; Ranasinghe, A.; Traeger, S. C. Manuscript in preparation.

Swift, E. C.; Jarvo, E. R. Asymmetric transition metal-catalyzed cross-coupling reactions for the construction of tertiary stereocenters. Tetrahedron 2013, 69, 5799– 5817, DOI: 10.1016/j.tet.2013.05.001

Proceedings of the National Academy of Sciences of the United States of America2018vol. 115 13p. 3249 – 3254

////////////BMS-978587, IDO-IN-4, 1629125-65-0, CS-5086, BMS978587, BMS 978587

OC(=O)[C@@H]3C[C@@H]3c2cc(NC(=O)Nc1ccc(C)cc1)c(cc2)N(CC(C)C)CC(C)C

Mercaptamine bitartrate, システアミン , меркаптамин , 巯乙胺

July 18, 2018 10:43 am / Leave a comment

Cysteamine bitartrate.png Image result for mercaptamine bitartrate

Image result for mercaptamine bitartrate

Mercaptamine bitartrate

2-aminoethanethiol;2,3-dihydroxybutanedioic acid

Molecular Formula:	C₆H₁₃NO₆S
Molecular Weight:	227.231 g/mol

Cystagon; Cysteamine – Mylan/Orphan Europe; Cysteamine bitartrate

Procysbi; CYSTEAMINE BITARTRATE; 27761-19-9; CHEBI:50386; (+/-)-Tartaric Acid

INGREDIENT	UNII	CAS
Cysteamine Bitartrate	QO84GZ3TST	27761-19-9
Cysteamine Hydrochloride	IF1B771SVB	156-57-0

Cysteamine bitartrate is a mercaptoethylamine compound that is endogenously derived from the COENZYME A degradative pathway. The fact that cysteamine is readily transported into LYSOSOMES where it reacts with CYSTINE to form cysteine-cysteamine disulfide and CYSTEINE has led to its use in CYSTINE DEPLETING AGENTS for the treatment of CYSTINOSIS.

Cysteamine Bitartrate is an aminothiol salt used in the treatment of nephropathic cystinosis. Cysteamine bitartrate enters the cell and reacts with cystine producing cysteineand cysteine–cysteamine mixed disulfide compound, both of which, unlike cystine, can pass through the lysosomal membrane. This prevents the accumulation of cystinecrystals in the lysosomes of patients with cystinosis, which can cause considerable damage and eventual destruction of the cells, particularly in the kidneys. (NCI05)

Cysteamine is a simple aminothiol molecule that is used to treat nephropathic cystinosis, due to its ability to decrease the markedly elevated and toxic levels of intracellular cystine that occur in this disease and cause its major complications. Cysteamine has been associated with serum enzyme elevations when given intravenously in high doses, but it has not been shown to cause clinically apparent acute liver injury.

Given intravenously or orally to treat radiation sickness. The bitartrate salts (Cystagon® and Procysbi) have been used for the oral treatment of nephropathic cystinosis and cystinurea. The hydrochloride salt (Cystaran™) is indicated for the treatment of corneal cystine crystal accumulation in cystinosis patients.

OriginatorMylan
DeveloperAlphapharm; Mylan
ClassMercaptoethylamines; Small molecules; Sulfhydryl compounds
Mechanism of ActionGlutathione synthase stimulants

Highest Development Phases

MarketedNephropathic cystinosis
DiscontinuedUnspecified

Most Recent Events

09 Apr 2018Mercaptamine bitartrate licensed to Recordati worldwide
26 Oct 2017Chemical structure information added
31 Dec 2008Mercaptamine bitartrate oral is still in phase II/III trials for Undefined indication in European Union

DESCRIPTION: CYSTAGON® (cysteamine bitartrate) Capsules for oral administration, contain cysteamine bitartrate, a cystine depleting agent which lowers the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport. CYSTAGON® is the bitartrate salt of cysteamine, an aminothiol, beta-mercaptoethylamine. Cysteamine bitartrate is a highly water soluble white powder with a molecular weight of 227 and the molecular formula C2H7NS · C4H6O6. It has the following chemical structure:

Cysteamine is a medication intended for a number of indications, and approved by the FDA to treat cystinosis.

It is stable aminothiol, i.e., an organic compound containing both an amine and a thiol functional groups. Cysteamine is a white, water-soluble solid. It is often used as salts of the ammonium derivative [HSCH₂CH₂NH₃]⁺^[1] including the hydrochloride, phosphocysteamine, and bitartrate.^[2]

Cysteamine molecule is biosynthesized in mammals, including humans, by the degradation of coenzyme A. The intermedia pantetheineis broken down into cysteamine and pantothenic acid.^[2] It is the biosynthetic precursor to the neurotransmitter hypotaurine.^[3]^[4]

Medical uses

Cysteamine is used to treat cystinosis. It is available by mouth (capsule and extended release capsule) and in eye drops.^[5]^[6]^[7]^[8]^[9]

Adverse effects

Topical use

The most important adverse effect related to topical use might be skin irritation.

Oral use

The label for oral formulations of cysteamine carry warnings about symptoms similar to Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms including seizures, lethargy, somnolence, depression, and encephalopathy, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension that can cause headache, tinnitus, dizziness, nausea, double or blurry vision, loss of vision, and pain behind the eye or pain with eye movement.^[6]

The main side effects are Ehlers-Danlos syndrome, severe skin rashes, ulcers or bleeding in the stomach and intestines, central nervous symptoms, low white blood cell levels, elevated alkaline phosphatase, and idiopathic intracranial hypertension (IIH). IIH can cause headache, ringing in the ears, dizziness, nausea, blurry vision, loss of vision, and pain behind the eye or with eye movement.

Additional adverse effects of oral cysteamine include bad breath, skin odor, vomiting, nausea, stomach pain, diarrhea, and loss of appetite.^[6]

The drug is in pregnancy category C; the risks of cysteamine to a fetus are not known but it harms babies in animal models at doses less than those given to people.^[7]^[8]

For eye drops, the most common adverse effects are sensitivity to light, redness, and eye pain, headache, and visual field defects.^[8]

Interactions

There are no drug interactions for normal capsules or eye drops,^[7]^[8] but the extended release capsules should not be taken with drugs that affect stomach acid like proton pump inhibitors or with alcohol, as they can cause the drug to be released too quickly.^[6] It doesn’t inhibit any cytochrome P450 enzymes.^[6]

Pharmacology

People with cystinosis lack a functioning transporter (cystinosin) which transports cystine from the lysosome to the cytosol. This ultimately leads to buildup of cystine in lysosomes, where it crystallizes and damages cells.^[5] Cysteamine enters lysosomes and converts cystine into cysteine and cysteine-cysteamine mixed disulfide, both of which can exit the lysosome.^[6]

Biological function

Cysteamine also promotes the transport of L-cysteine into cells, that can be further used to synthesize glutathione, which is one of the most potent intracellular antioxidants.^[4]

Cysteamine is used as a drug for the treatment of cystinosis; it removes cystine that builds up in cells of people with the disease.^[10]

History

First evidence regarding the therapeutic effect of cysteamine on cystinosis dates back to 1950s. Cysteamine was first approved as a drug for cystinosis in the US in 1994.^[6] An extended release form was approved in 2013.^[11]

Society and culture

It is approved by FDA and EMA.^[5]^[6]

In 2013, the regular capsule of cysteamine cost about $8,000 per year; the extended release form that was introduced that year was priced at $250,000 per year.^[11]

Research

It was studied in in vitro and animal models for radiation protection in the 1950s, and in similar models from the 1970s onwards for sickle cell anemia, effects on growth, its ability to modulate the immune system, and as a possible inhibitor of HIV.^[2]

In the 1970s it was tested in clinical trials for Paracetamol toxicity which it failed, and in clinical trials for systemic lupus erythematosus in the 1990s and early 2000s, which it also failed.^[2]

Clinical trials in Huntington’s disease were begun in the 1990s and were ongoing as of 2015.^[2]^[12]

As of 2013 it was in clinical trials for Parkinson’s disease, malaria, radiation sickness, neurodegenerative disorders, neuropsychiatric disorders, and cancer treatment.^[10]^[2]

It has been studied in clinical trials for pediatric nonalcoholic fatty liver disease^[13]

Horizon Pharma , following the acquisition of Raptor Pharmaceuticals (previously through its Bennu Pharmaceuticals subsidiary, and following its acquisition of Encode Pharmaceuticals , which licensed the drug from the University of California )) has developed and launched DR Cysteamine (EC Cysteamine; Procysbi), a methyl-CpG binding protein 2 (MECP2) gene modulating, oral delayed-release (DR), enteric-coated (EC), bitartrate salt formulation of mercaptamine (cysteamine).

PRODUCT PATENT, WO2007089670 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2007089670

hold SPC protection in most of the EU states until September 2028, and expire in the US in July 2037. In July 2018, the US FDA’s Orange Book was seen to list a patent covering product ( US8026284 and US9173851 ) of cysteamine bitartrate, that is due to expire in September 2027 and December 2034, respectively.

Cystinosis is a rare, autosomal recessive disease caused by intra-lysosomal accumulation of the amino acid cystine within various tissues, including the spleen, liver, lymph nodes, kidney, bone marrow, and eyes. Nephropathic cystinosis is associated with kidney failure that
necessitates kidney transplantation. To date, the only specific treatment for nephropathic cystinosis is the sulfhydryl agent, cysteamine. Cysteamine has been shown to lower intracellular cystine levels, thereby reducing the rate of progression of kidney failure in children.
[0004] Cysteamine, through a mechanism of increased gastrin and gastric acid production, is ulcerogenic. When administered orally to children with cystinosis, cysteamine has also been shown to cause a 3 -fold increase in gastric acid production and a 50% rise of serum gastrin levels. As a consequence, subjects that use cysteamine suffer
gastrointestinal (GI) symptoms and are often unable to take cysteamine regularly or at full dose .

[0005] To achieve sustained reduction of leukocyte cystine levels, patients are normally required to take oral cysteamine every 6 hours, which invariably means having to awaken from sleep. However, when a single dose of
cysteamine was administered intravenously the leukocyte cystine level remained suppressed for more than 24 hours, possibly because plasma cysteamine concentrations were higher and achieved more rapidly than when the drug is administered orally. Regular intravenous administration of cysteamine would not be practical. Accordingly, there is a need for formulations and delivery methods that would result in higher plasma, and thus intracellular, concentration as well as decrease the number of daily doses and therefore improve the quality of life for patients.

PATENT

US-20180193292

Process for the preparation of cysteamine bitartrate . Represents the first patenting to be seen from Lupin Limited on cysteamine bitartrate.

Cysteamine bitartrate (I) is a cystine depleting agent which lower the cystine content of cells in patients with cystinosis, an inherited defect of lysosomal transport, it is indicated for the management of nephropathic cystinosis in children and adults. Cysteamine bitartrate (I) is simplest stable aminothiol salt and has the following structural formula:

The application WO 2014204881 provides pharmaceutical composition of cysteamine bitrate and another application WO 2007089670 provides method of administrating cysteamine and pharmaceutically salts and method of treatment thereof.

Examples

1. Preparation of Cysteamine Bitartrate.

A mixture of ethanol (1000 ml), butylated hydroxy anisole (1 g) and cysteamine hydrochloride (100 g) was stirred and cooled to 5 to 10° C. To this mixture a solution of ethanol (500 ml) and sodium hydroxide (352 g) was added over a period of 30 minutes.

The mixture was stirred at a temperature of 10 to 15° C. for 45 minutes. The mixture was filtered through celite. The filtrate was added to a mixture of ethanol (1250 ml), butylated hydroxy anisole (1 g) and L-(+)-tartaric acid (132 g) at a temperature of 55-60° C. The reaction mixture was stirred at 70-75° C. for 45 minutes. The mixture was cooled to 20-30° C. The solid was filtered, washed with ethanol and dried under vacuum.

2. Purification of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (100 g) and ethanol (5000 ml) was heated to a temperature of 77-82° C. The solution was filtered and the filtrate was cooled to 20 to 30° C. and stirred for 40 minutes. The solid was filtered, washed with ethanol and dried under vacuum. Yield: 80 g; HPLC purity: 99.90%.

3. Preparation of Crystalline Form L1 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −5 to −25° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and dried under vacuum. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 1 was obtained.

4. Preparation of Crystalline Form L2 of Cysteamine Bitartrate.

A mixture of cysteamine bitartrate (50 g), butylated hydroxy anisole (1.3 g) and methanol (600 ml) was heated to a temperature of 35-45° C. The solution was filtered and the filtrate was cooled to 5 to 10° C. Cysteamine bitartrate (0.25 g) seed material was added to the filtrate. The slurry was cooled to −25 to −30° C. and stirred for 40 minutes. The solid was filtered, washed with precooled methanol and the solid was dried under 800-900 mm/Hg of vacuum at 35-40° C. for 5 hours. Yield: 40 g. Cysteamine bitartrate with X-ray powder diffraction pattern as depicted in FIG. 2 was obtained.

PATENT

WO 2014204881

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2014204881

PATENTS

EP3308773A1 *2016-10-112018-04-18Recordati Industria Chimica E Farmaceutica SPAFormulations of cysteamine and cysteamine derivatives

Family To Family Citations

JP2016523364A *2013-06-172016-08-08ラプターファーマシューティカルズインコーポレイテッドシステアミン組成物の分析方法

WO2017087532A1 *2015-11-162017-05-26The Regents Of The University Of CaliforniaMethods of treating non-alcoholic steatohepatitis (nash) using cysteamine compounds

WO2017157922A12016-03-182017-09-21Recordati Industria Chimica E Farmaceutica S.P.A.Prolonged release pharmaceutical composition comprising cysteamine or salt thereof,

KR20167000255A2014-06-17서방성 시스테아민 비드 투약 형태

JP2016521489A2014-06-17

CN 2014800346472014-06-17延迟释放型半胱胺珠粒调配物，以及其制备及使用方法

EP201408131322014-06-17Delayed release cysteamine bead formulation

CA 29147702014-06-17Delayed release cysteamine bead formulation, and methods of making and using same

References

Jump up^ Reid, E. Emmet (1958). Organic Chemistry of Bivalent Sulfur. 1. New York: Chemical Publishing Company, Inc. pp. 398–399.
^ Jump up to:^a ^b ^c ^d ^e ^f Besouw, M; Masereeuw, R; van den Heuvel, L; Levtchenko, E (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today. 18 (15–16): 785–92. doi:10.1016/j.drudis.2013.02.003. PMID 23416144.
Jump up^ Singer, Thomas P (1975). “Oxidative Metabolism of Cysteine and Cystine”. In Greenberg, David M. Metabolic pathways Vol. 7. Metabolism of sulfur compounds (3rd ed.). New York: Academic Press. p. 545. ISBN 9780323162081.
^ Jump up to:^a ^b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today. 18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003. ISSN 1878-5832. PMID 23416144.
^ Jump up to:^a ^b ^c Nesterova, Galina; Gahl, William A. (October 6, 2016). “Cystinosis”. GeneReviews. University of Washington, Seattle.
^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h “US Label: Cysteamine bitartrate delayed-release capsules” (PDF). FDA. August 2015.
^ Jump up to:^a ^b ^c “US Label: Cysteamine bitartrate capsules” (PDF). FDA. June 2007.
^ Jump up to:^a ^b ^c ^d “US Label: Cysteamine ophthalmic solution” (PDF). FDA. October 2012.
Jump up^ Shams, F; Livingstone, I; Oladiwura, D; Ramaesh, K (10 October 2014). “Treatment of corneal cystine crystal accumulation in patients with cystinosis”. Clinical ophthalmology (Auckland, N.Z.). 8: 2077–84. doi:10.2147/OPTH.S36626. PMC 4199850 . PMID 25336909.
^ Jump up to:^a ^b Besouw, Martine; Masereeuw, Rosalinde; van den Heuvel, Lambert; Levtchenko, Elena (August 2013). “Cysteamine: an old drug with new potential”. Drug Discovery Today. 18(15–16): 785–792. doi:10.1016/j.drudis.2013.02.003. ISSN 1878-5832. PMID 23416144.
^ Jump up to:^a ^b Pollack, Andrew (30 April 2013). “F.D.A. Approves Raptor Drug for Form of Cystinosis”. The New York Times.
Jump up^ Shannon, KM; Fraint, A (15 September 2015). “Therapeutic advances in Huntington’s Disease”. Movement disorders : official journal of the Movement Disorder Society. 30 (11): 1539–46. doi:10.1002/mds.26331. PMID 26226924.
Jump up^ Mitchel, EB; Lavine, JE (November 2014). “Review article: the management of paediatric nonalcoholic fatty liver disease”. Alimentary pharmacology & therapeutics. 40 (10): 1155–70. doi:10.1111/apt.12972. PMID 25267322.

ysteamine
Clinical data

Skeletal formula (top) Ball-and-stick model of the cysteamine
Synonyms	2-Aminoethanethiol β-Mercaptoethylamine 2-Mercaptoethylamine Decarboxycysteine Thioethanolamine Mercaptamine
License data	EU EMA: by Mercaptamine bitartrate
Identifiers
IUPAC name [show]
CAS Number	60-23-1
PubChemCID	6058
IUPHAR/BPS	7440
DrugBank	DB00847
ChemSpider	5834
UNII	5UX2SD1KE2
KEGG	D03634
ChEBI	CHEBI:17141
ChEMBL	CHEMBL602
ECHA InfoCard	100.000.421
Chemical and physical data
Formula	C₂H₇NS
Molar mass	77.15 g·mol⁻¹
Melting point	95 to 97 °C (203 to 207 °F)

Title: Cysteamine

CAS Registry Number: 60-23-1

CAS Name: 2-Aminoethanethiol

Additional Names: mercaptamine; b-mercaptoethylamine; 2-aminoethyl mercaptan; thioethanolamine; decarboxycysteine; MEA; mercamine

Manufacturers’ Codes: L-1573

Trademarks: Becaptan (Labaz); Lambratene (formerly) (Cilag Italiano)

Molecular Formula: C2H7NS

Molecular Weight: 77.15

Percent Composition: C 31.14%, H 9.15%, N 18.16%, S 41.56%

Line Formula: HSCH2CH2NH2

Literature References: A sulfhydryl compound with a variety of biological effects. Prepn: Gabriel, Leupold, Ber. 31, 2837 (1898); Knorr, Rössler, ibid. 36, 1281 (1903); Mills, Jr., Bogart, J. Am. Chem. Soc. 62, 1173 (1940); Wenker, ibid. 57, 2328 (1935); D. A. Shirley, Preparation of Organic Intermediates (Wiley, New York, 1951) p 189. Use in treatment of paracetamol (acetaminophen) poisoning: L. F. Prescott et al., Lancet 2, 109 (1976); A. L. Harris, Br. Med. J. 284, 825 (1982). Effects in nephropathic cystinosis: M. Yudkoff et al., N. Engl. J. Med. 304, 141 (1981). Radioprotective effects: R. P. Bird, Radiat. Res. 72, 290 (1980); C. J. Koch, R. L. Howell, ibid. 87, 265 (1981). Cysteamine has been shown to be a duodenal ulcerogen in rats: H. Selye, S. Szabo, Nature 244,458 (1973); S. Szabo, Am. J. Pathol. 93, 273 (1978); P. Kirkegaard et al., Scand. J. Gastroenterol. 15, 621 (1980). Review: S. Szabo, Lab. Invest. 51, 121 (1984). It has also been found to deplete somatostatin concentration: S. Szabo, S. Reichlein, Endocrinology 109, 2255 (1981); S. M. Sagar et al., J. Neurosci. 2, 225 (1982). In pituitary tissue, cysteamine is a potent depletor of prolactin concentrations in vivo and in vitro: W. J. Millard et al., Science 217, 452 (1982). Toxicity studies: E. Beccari et al.,Arzneim.-Forsch. 5, 421 (1955); D. L. Klayman et al., J. Med. Chem. 12, 510 (1969); P. K. Srivastava, L. Field, ibid. 18, 798 (1975).

Properties: Crystals by sublimation in vacuo. Disagreeable odor. mp 97-98.5°. Oxidizes to cystamine on standing in air. Freely sol in water, alkaline reaction. LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field).

Melting point: mp 97-98.5°

Toxicity data: LD50 in mice (mg/kg): 625 orally; 250 i.p. (Klayman); (Srivastava, Field)

Derivative Type: Hydrochloride

Molecular Formula: C2H7NS.HCl

Molecular Weight: 113.61

Percent Composition: C 21.14%, H 7.10%, N 12.33%, S 28.22%, Cl 31.21%

Properties: Crystals from alc, mp 70.2-70.7°. Sol in water, alcohol. LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari).

Melting point: mp 70.2-70.7°

Toxicity data: LD50 (cg/kg): 23.19 i.p. in rats; 14.95 i.v. in rabbits (Beccari)

Use: Experimentally as a radioprotective agent and to produce acute and chronic duodenal ulcers in rats.

Therap-Cat: Antidote to acetaminophen.

Keywords: Antidote (Acetaminophen Poisoning)

///////////Mercaptamine bitartrate, Cystagon, Cysteamine, Cysteamine bitartrate, Mercaptamine,, システアミン , меркаптамин , 巯乙胺

C(CS)N.C(C(C(=O)O)O)(C(=O)O)O

Acamprosate calcium, アカンプロセート

July 10, 2018 11:09 am / Leave a comment

ChemSpider 2D Image | Acamprosate | C5H11NO4S Image result for Acamprosate synthesis

Acamprosate calcium

Molecular Formula:	C₁₀H₂₀CaN₂O₈S₂
Molecular Weight:	400.474 g/mol

3-acetamidopropane-1-sulfonic acid

Campral [Trade name]

Ethanimidic acid, N-(3-sulfopropyl)-, (1Z)- [ACD/Index Name]

N4K14YGM3J

N-Acetylhomotaurine

アカンプロセート

INGREDIENT	UNII	CAS	fre form Cas 77337-76-9 181.21 C₅H₁₁NO₄S
Acamprosate Calcium	59375N1D0U	77337-73-6

INGREDIENT

UNII

CAS

fre form

Cas 77337-76-9

181.21

C₅H₁₁NO₄S

Acamprosate Calcium

59375N1D0U

77337-73-6

Acamprosate, sold under the brand name Campral, is a medication used along with counselling to treat alcohol dependence.^[1]^[2]

Acamprosate, also known by the brand name Campral™, is a drug used for treating alcohol dependence. Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. Reports indicate that acamprosate only works with a combination of attending support groups and abstinence from alcohol. Certain serious side effects include allergic reactions, irregular heartbeats, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence. Acamprosate should not be taken by people with kidney problems or allergies to the drug.

Acamprosate is thought to stabilize chemical signaling in the brain that would otherwise be disrupted by alcohol withdrawal.^[3] When used alone, acamprosate is not an effective therapy for alcoholism in most individuals;^[4] however, studies have found that acamprosate works best when used in combination with psychosocial support since it facilitates a reduction in alcohol consumption as well as full abstinence.^[2]^[5]^[6]

Serious side effects include allergic reactions, abnormal heart rhythms, and low or high blood pressure, while less serious side effects include headaches, insomnia, and impotence.^[7] Diarrhea is the most common side-effect.^[8] Acamprosate should not be taken by people with kidney problems or allergies to the drug.^[9]

Until it became a generic in the United States, Campral was manufactured and marketed in the United States by Forest Laboratories, while Merck KGaA markets it outside the US.

Medical uses

Acamprosate is useful when used along with counselling in the treatment of alcohol dependence.^[2] Over three to twelve months it increases the number of people who do not drink at all and the number of days without alcohol.^[2] It appears to work as well as naltrexone.^[2]

Contraindications

Acamprosate is primarily removed by the kidneys and should not be given to people with severely impaired kidneys (creatinine clearance less than 30 mL/min). A dose reduction is suggested in those with moderately impaired kidneys (creatinine clearancebetween 30 mL/min and 50 mL/min).^[1]^[10] It is also contraindicated in those who have a strong allergic reaction to acamprosate calcium or any of its components.^[10]

Adverse effects

The US label carries warnings about increased of suicidal behavior, major depressive disorder, and kidney failure.^[1]

Adverse effects that caused people to stop taking the drug in clinical trials included diarrhea, nausea, depression, and anxiety.^[1]

Other frequent adverse effects include headache, stomach pain, back pain, muscle pain, joint pain, chest pain, infections, flu-like symptoms, chills, heart palpitations, high blood pressure, fainting, vomiting, upset stomach, constipation, increased appetite, weight gain, edema, sleepiness, decreased sex drive, impotence, forgetfulness, abnormal thinking, abnormal vision, distorted sense of taste, tremors, runny nose, coughing, difficulty breathing, sore throat, bronchitis, and rashes.^[1]

Pharmacology

Acamprosate calcium

Pharmacodynamics

The pharmacodynamics of acamprosate is complex and not fully understood;^[11]^[12]^[13] however, it is believed to act as an NMDA receptor antagonist and positive allosteric modulator of GABA_A receptors.^[12]^[13]

Ethanol and benzodiazepines act on the central nervous system by binding to the GABA_A receptor, increasing the effects of the inhibitory neurotransmitter GABA (i.e., they act as positive allosteric modulators at these receptors).^[12]^[4] In chronic alcohol abuse, one of the main mechanisms of tolerance is attributed to GABA_A receptors becoming downregulated (i.e. these receptors become less sensitive to GABA).^[4] When alcohol is no longer consumed, these down-regulated GABA_A receptor complexes are so insensitive to GABA that the typical amount of GABA produced has little effect, leading to physical withdrawal symptoms;^[4] since GABA normally inhibits neural firing, GABA_A receptor desensitization results in unopposed excitatory neurotransmission (i.e., fewer inhibitory postsynaptic potentialsoccur through GABA_A receptors), leading to neuronal over-excitation (i.e., more action potentials in the postsynaptic neuron). One of acamprosate’s mechanisms of action is the enhancement of GABA signaling at GABA_A receptors via positive allosteric receptor modulation.^[12]^[13] It has been purported to open the chloride ion channel in a novel way as it does not require GABA as a cofactor, making it less liable for dependence than benzodiazepines. Acamprosate has been successfully used to control tinnitus, hyperacusis, ear pain and inner ear pressure during alcohol use due to spasms of the tensor tympani muscle.^{[medical citation needed]}

In addition, alcohol also inhibits the activity of N-methyl-D-aspartate receptors (NMDARs).^[14]^[15] Chronic alcohol consumption leads to the overproduction (upregulation) of these receptors. Thereafter, sudden alcohol abstinence causes the excessive numbers of NMDARs to be more active than normal and to contribute to the symptoms of delirium tremensand excitotoxic neuronal death.^[16] Withdrawal from alcohol induces a surge in release of excitatory neurotransmitters like glutamate, which activates NMDARs.^[17] Acamprosate reduces this glutamate surge.^[18] The drug also protects cultured cells from excitotoxicity induced by ethanol withdrawal^[19] and from glutamate exposure combined with ethanol withdrawal.^[20]

Pharmacokinetics

Acamprosate is not metabolized by the human body.^[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.^[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.^[13]

History

Acamprosate was developed by Lipha, a subsidiary of Merck KGaA.^[21] and was approved for marketing in Europe in 1989.^{[citation needed]}

In October 2001 Forest Laboratories acquired the rights to market the drug in the US.^[21]^[22]

It was approved by the FDA in July 2004.^[23]

The first generic versions of acamprosate were launched in the US in 2013.^[24]

As of 2015 acamprosate was in development by Confluence Pharmaceuticals as a potential treatment for fragile X syndrome. The drug was granted orphan status for this use by the FDA in 2013 and by the EMA in 2014.^[25]

Society and culture

“Acamprosate” is the INN and BAN for this substance. “Acamprosate calcium” is the USAN and JAN. It is also technically known as N-acetylhomotaurine or as calcium acetylhomotaurinate.

It is sold under the brand name Campral.^[1]

Research

In addition to its apparent ability to help patients refrain from drinking, some evidence suggests that acamprosate is neuroprotective (that is, it protects neurons from damage and death caused by the effects of alcohol withdrawal, and possibly other causes of neurotoxicity).^[18]^[26]

References

^ Jump up to:^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j ^k ^l ^m “Campral label” (PDF). FDA. January 2012. Retrieved 27 November2017. For label updates see FDA index page for NDA 021431
^ Jump up to:^a ^b ^c ^d ^e Plosker, GL (July 2015). “Acamprosate: A Review of Its Use in Alcohol Dependence”. Drugs. 75 (11): 1255–68. doi:10.1007/s40265-015-0423-9. PMID 26084940.
Jump up^ Williams, SH. (2005). “Medications for treating alcohol dependence”. American Family Physician. 72 (9): 1775–1780. PMID 16300039.
^ Jump up to:^a ^b ^c ^d Malenka RC, Nestler EJ, Hyman SE, Holtzman DM (2015). “Chapter 16: Reinforcement and Addictive Disorders”. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (3rd ed.). New York: McGraw-Hill Medical. ISBN 9780071827706. It has been hypothesized that long-term ethanol exposure alters the expression or activity of specific GABAA receptor subunits in discrete brain regions. Regardless of the underlying mechanism, ethanol-induced decreases in GABAA receptor sensitivity are believed to contribute to ethanol tolerance, and also may mediate some aspects of physical dependence on ethanol. … Detoxification from ethanol typically involves the administration of benzodiazepines such as chlordiazepoxide, which exhibit cross-dependence with ethanol at GABAA receptors (Chapters 5 and 15). A dose that will prevent the physical symptoms associated with withdrawal from ethanol, including tachycardia, hypertension, tremor, agitation, and seizures, is given and is slowly tapered. Benzodiazepines are used because they are less reinforcing than ethanol among alcoholics. Moreover, the tapered use of a benzodiazepine with a long half-life makes the emergence of withdrawal symptoms less likely than direct withdrawal from ethanol. … Unfortunately, acamprosate is not adequately effective for most alcoholics.
Jump up^ Mason, BJ (2001). “Treatment of alcohol-dependent outpatients with acamprosate: a clinical review”. The Journal of Clinical Psychiatry. 62 Suppl 20: 42–8. PMID 11584875.
Jump up^ Nutt, DJ (2014). “Doing it by numbers: A simple approach to reducing the harms of alcohol”. JOURNAL OF PSYCHOPHARMACOLOGY. 28: 3–7. doi:10.1177/0269881113512038. PMID 24399337.
Jump up^ “Acamprosate”. drugs.com. 2005-03-25. Archived from the original on 22 December 2006. Retrieved 2007-01-08.
Jump up^ Wilde, MI; Wagstaff, AJ (June 1997). “Acamprosate. A review of its pharmacology and clinical potential in the management of alcohol dependence after detoxification”. Drugs. 53(6): 1038–53. doi:10.2165/00003495-199753060-00008. PMID 9179530.
Jump up^ “Acamprosate Oral – Who should not take this medication?”. WebMD.com. Retrieved 2007-01-08.
^ Jump up to:^a ^b Saivin, S; Hulot, T; Chabac, S; Potgieter, A; Durbin, P; Houin, G (Nov 1998). “Clinical Pharmacokinetics of Acamprosate”. Clinical Pharmacokinetics. 35 (5): 331–345. doi:10.2165/00003088-199835050-00001. PMID 9839087.
Jump up^ “Acamprosate: Biological activity”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017. Due to the complex nature of this drug’s MMOA, and a paucity of well defined target affinity data, we do not map to a primary drug target in this instance.
^ Jump up to:^a ^b ^c ^d “Acamprosate: Summary”. IUPHAR/BPS Guide to Pharmacology. International Union of Basic and Clinical Pharmacology. Retrieved 26 November 2017. Acamprosate is a NMDA glutamate receptor antagonist and a positive allosteric modulator of GABAA receptors.
Marketed formulations contain acamprosate calcium
^ Jump up to:^a ^b ^c ^d ^e ^f “Acamprosate”. DrugBank. University of Alberta. 19 November 2017. Retrieved 26 November 2017. Acamprosate is thought to stabilize the chemical balance in the brain that would otherwise be disrupted by alcoholism, possibly by blocking glutaminergic N-methyl-D-aspartate receptors, while gamma-aminobutyric acid type A receptors are activated. … The mechanism of action of acamprosate in maintenance of alcohol abstinence is not completely understood. Chronic alcohol exposure is hypothesized to alter the normal balance between neuronal excitation and inhibition. in vitro and in vivostudies in animals have provided evidence to suggest acamprosate may interact with glutamate and GABA neurotransmitter systems centrally, and has led to the hypothesis that acamprosate restores this balance. It seems to inhibit NMDA receptors while activating GABA receptors.
Jump up^ Malenka RC, Nestler EJ, Hyman SE (2009). “Chapter 15: Reinforcement and Addictive Disorders”. In Sydor A, Brown RY. Molecular Neuropharmacology: A Foundation for Clinical Neuroscience (2nd ed.). New York: McGraw-Hill Medical. p. 372. ISBN 9780071481274.
Jump up^ Möykkynen T, Korpi ER (July 2012). “Acute effects of ethanol on glutamate receptors”. Basic & Clinical Pharmacology & Toxicology. 111 (1): 4–13. doi:10.1111/j.1742-7843.2012.00879.x. PMID 22429661.
Jump up^ Tsai, G; Coyle, JT (1998). “The role of glutamatergic neurotransmission in the pathophysiology of alcoholism”. Annual Review of Medicine. 49: 173–84. doi:10.1146/annurev.med.49.1.173. PMID 9509257.
Jump up^ Tsai, GE; Ragan, P; Chang, R; Chen, S; Linnoila, VM; Coyle, JT (1998). “Increased glutamatergic neurotransmission and oxidative stress after alcohol withdrawal”. The American Journal of Psychiatry. 155 (6): 726–32. doi:10.1176/ajp.155.6.726. PMID 9619143.
^ Jump up to:^a ^b De Witte, P; Littleton, J; Parot, P; Koob, G (2005). “Neuroprotective and abstinence-promoting effects of acamprosate: elucidating the mechanism of action”. CNS Drugs. 19 (6): 517–37. doi:10.2165/00023210-200519060-00004. PMID 15963001.
Jump up^ Mayer, S; Harris, BR; Gibson, DA; Blanchard, JA; Prendergast, MA; Holley, RC; Littleton, J (2002). “Acamprosate, MK-801, and ifenprodil inhibit neurotoxicity and calcium entry induced by ethanol withdrawal in organotypic slice cultures from neonatal rat hippocampus”. Alcoholism: Clinical and Experimental Research. 26 (10): 1468–78. doi:10.1097/00000374-200210000-00003. PMID 12394279.
Jump up^ Al Qatari, M; Khan, S; Harris, B; Littleton, J (2001). “Acamprosate is neuroprotective against glutamate-induced excitotoxicity when enhanced by ethanol withdrawal in neocortical cultures of fetal rat brain”. Alcoholism: Clinical and Experimental Research. 25(9): 1276–83. doi:10.1111/j.1530-0277.2001.tb02348.x. PMID 11584146.
^ Jump up to:^a ^b Berfield, Susan (27 May 2002). “A CEO and His Son”. Bloomberg Businessweek.
Jump up^ “Press release: Forest Laboratories Announces Agreement For Alcohol Addiction Treatment”. Forest Labs via Evaluate Group. October 23, 2001.
Jump up^ “FDA Approves New Drug for Treatment of Alcoholism”. FDA Talk Paper. Food and Drug Administration. 2004-07-29. Archived from the original on 2008-01-17. Retrieved 2009-08-15.
Jump up^ “Acamprosate generics”. DrugPatentWatch. Retrieved 27 November 2017.
Jump up^ “Acamprosate – Confluence Pharmaceuticals – AdisInsight”. AdisInsight. Retrieved 27 November 2017.
Jump up^ Mann K, Kiefer F, Spanagel R, Littleton J (July 2008). “Acamprosate: recent findings and future research directions”. Alcohol. Clin. Exp. Res. 32 (7): 1105–10. doi:10.1111/j.1530-0277.2008.00690.x. PMID 18540918.

Title: Acamprosate Calcium

CAS Registry Number: 77337-73-6

CAS Name: 3-(Acetylamino)-1-propanesulfonic acid calcium salt (2:1)

Additional Names: calcium acetyl homotaurinate; Ca-AOTA; calcium bisacetyl homotaurine

Trademarks: Aotal (Merck KGaA); Campral (Merck Sant?

Molecular Formula: C10H20CaN2O8S2

Molecular Weight: 400.48

Percent Composition: C 29.99%, H 5.03%, Ca 10.01%, N 6.99%, O 31.96%, S 16.01%

Literature References: GABA (g-aminobutyric acid, q.v.) agonist. Prepn: J. P. Durlach, DE 3019350; idem, US 4355043 (1980, 1982 both to Lab. Meram). Physicochemical and pharmacological study: C. Chabenat et al., Methods Find. Exp. Clin. Pharmacol.10, 311 (1988). Pharmacology: J. Durlach et al., ibid. 437; A. Guiet-Bara et al., Alcohol 5, 63 (1988). Suppression of ethanol intake in rats: F. Boismare et al., Pharmacol. Biochem. Behav. 21, 787 (1984); J. Le Magnen et al., Alcohol 4, 97 (1987). Evaluation of abuse potential: K. A. Grant, W. L. Woolverton, Pharmacol. Biochem. Behav. 32, 607 (1989). HPLC determn in plasma: C. Chabenat et al., J. Chromatogr. 414, 417 (1987). Clinical evaluation in relapse prevention in weaned alcoholics: J. P. L’Huintre et al., Lancet 1, 1014 (1985); J. P. L’Huintre et al., Alcohol Alcohol. 25, 613 (1990). Review of clinical efficacy in maintenance of abstinence in alcoholics: L. J. Scott et al., CNS Drugs 19, 445-464 (2005); of mechanism of action: P. De Witte et al., ibid. 517-537.

Properties: Colorless crystalline powder, mp 270°. uv max (water): 192 nm (e 7360). Freely sol in water. Practically insol in absolute ethanol, dichloromethane. LD50 i.p. in male mice: 1.87 g/kg (Durlach, 1982).

Melting point: mp 270°

Absorption maximum: uv max (water): 192 nm (e 7360)

Toxicity data: LD50 i.p. in male mice: 1.87 g/kg (Durlach, 1982)

Therap-Cat: In treatment of alcoholism.

Keywords: Alcohol Dependence Treatment.

Acamprosate calcium

- ATC:N07BB03
Use:alcohol-abuse deterrent
Chemical name:3-(acetylamino)-1-propanesulfonic acid calcium salt (2:1)
Formula:C₁₀H₂₀CaN₂O₈S₂

MW:400.49 g/mol
CAS-RN:77337-73-6
EINECS:278-665-3
LD₅₀:>10 g/kg (M, p.o.)

Derivatives

free acid

Formula:C₅H₁₁NO₄S
MW:181.21 g/mol
CAS-RN:77337-76-9
EINECS:278-667-4

Substance Classes

Acetamides, acetylamino substituted acids and their amides
Amino sulfonic acids
Calcium salts

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
3687-18-1	C₃H₉NO₃S	3-aminopropane-1-sulfonic acid	1-Propanesulfonic acid, 3-amino-
156-87-6	C₃H₉NO	3-amino-1-propanol	1-Propanol, 3-amino-

Trade Names

Country	Trade Name	Vendor
D	Campral	Merck
F	Aotal	Merck Lipha
GB	Campral EC	Merck Serono
USA	Campral	Forest

Formulations

tabl. 50 mg, 100 mg, 333 mg

References

- DE 3 019 350 (Lab. Meram; appl. 21.5.1980; F-prior. 23.5.1979).
- US 4 355 043 (Lab. Meram; 19.10.1982; F-prior. 23.5.1979).

synthesis of 3-aminopropane-1-sulfonic acid:
- Fujii, A. et al.: J. Med. Chem. (JMCMAR) 18, 502 (1975).
- JP 46 002 012 (Kowa; appl. 19.1.1971).
- WO 8 400 958 (Mitsui; appl. 15.3.1984; J-prior. 7.9.1982, 19.7.1983, 8.9.1982).

Acamprosate
Clinical data


Trade names	Campral EC
Synonyms	N-Acetyl homotaurine, Acamprosate calcium (JAN JP), Acamprosate calcium (USANUS)
Pregnancy category	C^[1]> (US) B2 (AU)
Routes of administration	Oral ^[1]
ATC code	N07BB03 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Bioavailability	11%^[1]
Protein binding	Negligible^[1]
Metabolism	Nil^[1]
Elimination half-life	20 h to 33 h^[1]
Excretion	Renal^[1]
Identifiers
IUPAC name [show]
CAS Number	77337-76-9
PubChem CID	155434
IUPHAR/BPS	7106
DrugBank	DB00659
ChemSpider	136929
UNII	N4K14YGM3J
KEGG	D07058
ChEBI	CHEBI:51042
ChEMBL	CHEMBL1201293
ECHA InfoCard	100.071.495
Chemical and physical data
Formula	C₅H₁₁NO₄S
Molar mass	181.211 g/mol
3D model (JSmol)	Interactive image
SMILES [hide] [Ca+2].O=C(NCCCS(=O)(=O)[O-])C.[O-]S(=O)(=O)CCCNC(=O)C
InChI [hide] InChI=1S/2C5H11NO4S.Ca/c21-5(7)6-3-2-4-11(8,9)10;/h22-4H2,1H3,(H,6,7)(H,8,9,10);/q;;+2/p-2 Key:BUVGWDNTAWHSKI-UHFFFAOYSA-L
(what is this?) (verify)

Open Babel bond-line chemical structure with annotated hydrogens.<br>Click to toggle size. Image result for Acamprosate nmr

////////////////Acamprosate calcium, アカンプロセート

CC(=O)NCCCS(O)(=O)=O

CC(=O)NCCCS(=O)(=O)[O-].CC(=O)NCCCS(=O)(=O)[O-].[Ca+2]

DOCONEXENT, доконексен, دوكونيكسانت , 二十二碳六烯酸

July 9, 2018 9:46 am / Leave a comment

ChemSpider 2D Image | Docosahexaenoic acid | C22H32O2 (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid.png

Image result for doconexent Docosahexaenoic Acid

Doconexent

CAS 6217-54-5

WeightAverage: 328.4883
Chemical FormulaC₂₂H₃₂O₂

4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-

Doconexent sodium

295P7EPT4C

81926-93-4

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
22:6-4, 7,10,13,16,19
22:6(n-3)
4,7,10,13,16,19-docosahexaenoic acid
4,7,10,13,16,19-Docosahexaenoic acid
all-cis-4,7,10,13,16,19-docosahexaenoic acid
all-cis-DHA
cervonic acid
DHA
docosa-4,7,10,13,16,19-hexaenoic acid
Docosahexaenoic acid
Ropufa 60
S.Presso
all-Z-Docosahexaenoic acid
all-cis-4,7,10,13,16,19-Docosahexaenoic acid
Δ^{4,7,10,13,16,19}-Docosahexaenoic acid
4,7,10,13,16,19-Docosahexaenoic acid, (all-Z)- (8CI)
Docosahexaenoic acid (6CI)
- (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid
- (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid
- (4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexenoic acid
- (all-Z)-4,7,10,13,16,19-Docosahexaenoic acid
- 4-cis,7-cis,10-cis,13-cis,16-cis,19-cis-Docosahexaenoic acid

Docosahexaenoic acid (22:6(n-3))

ZAD9OKH9JC

доконексент [Russian] [INN]

دوكونيكسانت [Arabic] [INN]

二十二碳六烯酸 [Chinese] [INN]

(4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid [ACD/IUPAC Name]

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosa-4,7,10,13,16,19-hexaenoic acid

(4Z,7Z,10Z,13Z,16Z,19Z)-Docosahexaenoic acid

(all-Z)- 4,7,10,13,16,19-Docosahexaenoic Acid

(all-Z)-4,7,10,13,16,19-Docosahexaenoic acid

4,7,10,13,16,19-Docosahexaenoic acid, (4Z,7Z,10Z,13Z,16Z,19Z)-

all-Z-Docosahexaenoic acid

cis-4, cis-7, cis-10, cis-13, cis-16, cis-19-docosahexaenoic acid

cis-4,7,10,13,16,19-Docosahexaenoic acid

D4,7,10,13,16,19-Docosahexaenoic Acid

A mixture of fish oil and primrose oil; used as a high-docosahexaenoic acid fatty acid supplement.

A mixture of fish oil and primrose oil, doconexent is used as a high-docosahexaenoic acid (DHA) supplement. DHA is a 22 carbon chain with 6 cis double bonds with anti-inflammatory effects. It can be biosythesized from alpha-linolenic acid or commercially manufactured from microalgae. It is an omega-3 fatty acid and primary structural component of the human brain, cerebral cortex, skin, and retina thus plays an important role in their development and function. The amino-phospholipid DHA is found at a high concentration across several brain subcellular fractions, including nerve terminals, microsomes, synaptic vesicles, and synaptosomal plasma membranes

Image result for doconexent

Synthesis , By Farmer, Ernest H.; Van den Heuvel, Frantz A., From Journal of the Chemical Society (1938), 427-30.

ALSO

Title: Docosahexaenoic Acid

CAS Registry Number: 6217-54-5

CAS Name: (4Z,7Z,10Z,13Z,16Z,19Z)-4,7,10,13,16,19-Docosahexaenoic acid

Additional Names: cervonic acid; doconexent; DHA

Molecular Formula: C22H32O2

Molecular Weight: 328.49

Percent Composition: C 80.44%, H 9.82%, O 9.74%

Literature References: Omega-3 fatty acid found in marine fish oils and in many phospholipids. Major structural component of excitable membranes of the retina and brain; synthesized in the liver from a-linolenic acid, q.v. Isoln from oil of Sardina ocellata J. and structure: J. M. Whitcutt, Biochem. J. 67, 60 (1957). Improved isoln from cod liver oil: S. W. Wright et al., J. Org. Chem. 52,4399 (1987). Effect on brain and behavioral development: P. E. Wainwright, Neurosci. Biobehav. Rev. 16, 193 (1992). Review of uptake and metabolism by retinal cells: N. G. Bazan, E. B. Rodriguez de Turco, J. Ocul. Pharmacol. 10, 591-603 (1994). Review of clinical studies in infant formula supplementation: M. Makrides et al., Lipids 31, 115-119 (1996).

Properties: Clear, faintly yellow oil, mp -44.7 to -44.5°. n26D 1.5017.

Melting point: mp -44.7 to -44.5°

Index of refraction: n26D 1.5017

Use: Nutritional supplement.

Docosahexaenoic acid (DHA) is an omega-3 fatty acid that is a primary structural component of the human brain, cerebral cortex, skin, and retina. It can be synthesized from alpha-linolenic acid or obtained directly from maternal milk (breast milk), fish oil, or algae oil.^[1]

DHA’s structure is a carboxylic acid (-oic acid) with a 22-carbon chain (docosa- derives from the Ancient Greek for 22) and six (hexa-) cis double bonds (-en-);^[2] with the first double bond located at the third carbon from the omega end.^[3] Its trivial name is cervonic acid, its systematic name is all-cis-docosa-4,7,10,13,16,19-hexa-enoic acid, and its shorthand name is 22:6(n−3) in the nomenclature of fatty acids.

Most of the DHA in fish and multi-cellular organisms with access to cold-water oceanic foods originates from photosynthetic and heterotrophic microalgae, and becomes increasingly concentrated in organisms the further they are up the food chain. DHA is also commercially manufactured from microalgae: Crypthecodinium cohnii and another of the genus Schizochytrium.^[4] DHA manufactured using microalgae is vegetarian.^[5]

In strict herbivores, DHA is manufactured internally from α-linolenic acid, a shorter omega-3 fatty acid manufactured by plants (and also occurring in animal products as obtained from plants), while omnivores and carnivores primarily obtain DHA from their diet.^[6] Limited amounts of eicosapentaenoic and docosapentaenoic acids are possible products of α-linolenic acid metabolism in young women^[7] and men.^[6] DHA in breast milk is important for the developing infant.^[8] Rates of DHA production in women are 15% higher than in men.^[9]

DHA is a major fatty acid in brain phospholipids and the retina. While the potential roles of DHA in the mechanisms of Alzheimer’s disease are under active research,^[10] studies of fish oil supplements, which contain DHA, have failed to support claims of preventing cardiovascular diseases.^[11]^[12]^[13]

Image result for doconexent

Central nervous system constituent

DHA is the most abundant omega-3 fatty acid in the brain and retina. DHA comprises 40% of the polyunsaturated fatty acids (PUFAs) in the brain and 60% of the PUFAs in the retina. Fifty percent of the weight of a neuron‘s plasma membraneis composed of DHA.^[14]

DHA modulates the carrier-mediated transport of choline, glycine, and taurine, the function of delayed rectifier potassium channels, and the response of rhodopsin contained in the synaptic vesicles, among many other functions.^[15]

DHA deficiency is associated with cognitive decline.^[16] Phosphatidylserine (PS) controls apoptosis, and low DHA levels lower neural cell PS and increase neural cell death.^[17] DHA levels are reduced in the brain tissue of severely depressed patients.^[18]^[19]

Image result for DOCONEXENT NMR

Metabolic synthesis

In humans, DHA is either obtained from the diet or may be converted in small amounts from eicosapentaenoic acid (EPA, 20:5, ω-3) via docosapentaenoic acid (DPA, 22:5 ω-3) as an intermediate.^[7]^[6] This synthesis had been thought to occur through an elongation step followed by the action of Δ4-desaturase.^[6] It is now considered more likely that DHA is biosynthesized via a C24 intermediate followed by beta oxidation in peroxisomes. Thus, EPA is twice elongated, yielding 24:5 ω-3, then desaturated to 24:6 ω-3, then shortened to DHA (22:6 ω-3) via beta oxidation. This pathway is known as Sprecher’s shunt.^[20]^[21]

In organisms such as microalgae, mosses and fungi, biosynthesis of DHA usually occurs as a series of desaturation and elongation reactions, catalyzed by the sequential action of desaturase and elongase enzymes. A common pathway in these organisms involves:

a desaturation at the sixth carbon of alpha-linolenic acid by a Δ6 desaturase to produce stearidonic acid,
elongation of the stearidonic acid by a Δ6 elongase to produce to eicosatetraenoic acid,
desaturation at the fifth carbon of eicosatetraenoic acid by a Δ5 desaturase to produce eicosapentaenoic acid,
elongation of eicosapentaenoic acid by a Δ5 elongase to produce docosapentaenoic acid, and
desaturation at the fourth carbon of docosapentaenoic acid by a Δ4 desaturase to produce DHA.^[22]

Metabolism

DHA can be metabolized into DHA-derived specialized pro-resolving mediators (SPMs), DHA epoxides, electrophilic oxo-derivatives (EFOX) of DHA, neuroprostanes, ethanolamines, acylglycerols, docosahexaenoyl amides of amino acids or neurotransmitters, and branched DHA esters of hydroxy fatty acids, among others.^[23]

The enzyme CYP2C9 metabolizes DHA to epoxydocosapentaenoic acids (EDPs; primarily 19,20-epoxy-eicosapentaenoic acid isomers [i.e. 10,11-EDPs]).^[24]

Potential health effects

Neurological research

While one human trial of 402 subjects lasting 18 months concluded that DHA did not slow decline of mental function in elderly people with mild to moderate Alzheimer’s disease,^[25] a similar trial of 485 subjects lasting 6 months concluded that algal DHA of 900 mg per day taken decreased heart rate and improved memory and learning in healthy, older adults with mild memory complaints.^[26]

In another early-stage study, higher DHA levels in middle-aged adults was related to better performance on tests of nonverbal reasoning and mental flexibility, working memory, and vocabulary.^[27]

One study found that the use of DHA-rich fish oil capsules did not reduce postpartum depression in mothers or improve cognitive and language development in their offspring during early childhood.^[28] Another systematic review found that DHA had no significant benefits in improving visual field in individuals with retinitis pigmentosa.^[29] A 2017 pilot study found that fish oil supplementation reduced the depression symptoms emphasizing the importance of the target DHA levels.^[30]

Pregnancy and lactation

It has been recommended to eat foods which are high in omega-3 fatty acids for women who want to become pregnant or when nursing.^[31] A working group from the International Society for the Study of Fatty Acids and Lipids recommended 300 mg/day of DHA for pregnant and lactating women, whereas the average consumption was between 45 mg and 115 mg per day of the women in the study, similar to a Canadian study.^[32] Despite these recommendations, recent evidence from a trial of pregnant women randomized to receive supplementation with 800 mg/day of DHA versus placebo, showed that the supplement had no impact on the cognitive abilities of their children at up to seven years follow-up.^[33]

Other research

In one preliminary study, men who took DHA supplements for 6–12 weeks had lower blood markers of inflammation.^[34]

Nutrition

Algae-based DHA supplements

Ordinary types of cooked salmon contain 500–1500 mg DHA and 300–1000 mg EPA per 100 grams.^[35] Additional rich seafood sources of DHA include caviar (3400 mg per 100 grams), anchovies (1292 mg per 100 grams), mackerel (1195 mg per 100 grams), and cooked herring(1105 mg per 100 grams).^[35] Brains from mammals are also a good direct source, with beef brain, for example, containing approximately 855 mg of DHA per 100 grams in a serving.^[36]

Discovery of algae-based DHA

In the early 1980s, NASA sponsored scientific research on a plant-based food source that could generate oxygen and nutrition on long-duration space flights. Certain species of marine algae produced rich nutrients, leading to the development of an algae-based, vegetable-like oil that contains two polyunsaturated fatty acids, DHA and arachidonic acid,^[37] present in some health supplements.

Use as a food additive

DHA is widely used as a food supplement. It was first used primarily in infant formulas.^[38] In 2004, the US Food and Drug Administration endorsed qualified health claims for DHA.^[39]

Some manufactured DHA is a vegetarian product extracted from algae, and it competes on the market with fish oil that contains DHA and other omega-3s such as EPA. Both fish oil and DHA are odorless and tasteless after processing as a food additive.^[40]

Studies of vegetarians and vegans

Vegetarian diets typically contain limited amounts of DHA, and vegan diets typically contain no DHA.^[41] In preliminary research, algae-based supplements increased DHA levels.^[42]While there is little evidence of adverse health or cognitive effects due to DHA deficiency in adult vegetarians or vegans, breast milk levels remain a concern for supplying adequate DHA to the developing fetus.^[41]

DHA and EPA in fish oils

Fish oil is widely sold in capsules containing a mixture of omega-3 fatty acids, including EPA and DHA. Oxidized fish oil in supplement capsules may contain lower levels of EPA and DHA.^[43]^[44]

Hypothesized role in human evolution

An abundance of DHA in seafood has been suggested as being helpful in the development of a large brain,^[45] though other researchers claim a terrestrial diet could also have provided the necessary DHA.^[46]

Patent

CN 106190872

https://patents.google.com/patent/CN106190872A/zh

PATENT

WO 2017038860

https://patents.google.com/patent/WO2017038860A1/en

[Example 1]
The raw EPA ethyl ester 1 of Comparative Example 1 containing EPA 96.7%, except for changing the temperature of the alkaline hydrolysis in 6 ° C., in the same manner as in Comparative Example 1 was alkaline hydrolysis.
That is, the starting EPA ethyl ester 1 2.50 g, ethanol 6.25 mL (4.92 g, 14.11 equivalents relative fatty acid), water 1.00 mL, 48 wt% sodium hydroxide aqueous solution 0.76 g ( 1.20 equivalents of base) was added a sample solution 3 was prepared against fatty acids. In sample liquid 3, moisture 1.40 g, i.e., was 10.27 equivalents relative fatty acid. The sample liquid 3, stirred for 24 hours 6 ° C., was subjected to hydrolysis treatment. Confirmed the completion of the reaction of the hydrolysis treatment, returned to the sample liquid 3 after treatment at room temperature, after transferred to a separatory funnel, and hexane was added 3.13 mL, purified water 2.50mL the sample liquid 3. When further adding 2.25g of hydrochloric acid, the sample solution 3 was separated into two layers of hexane and aqueous layers. The pH of the aqueous layer was 1.0.

The sample liquid 3 was stirred, then the mixture was allowed to stand, after removing the aqueous layer from the sample liquid 3, was further stirred with purified water 3.75mL the sample liquid 3 after removal. Hydrochloric acid was added small amount to adjust the pH of the aqueous layer to 1.0. Thereafter, the aluminum plate was washed with the same amount of purified water as rinsing liquid. Rinsing liquid is recovered after washing with water was repeatedly washed with water until neutral pH 6.0 ~ 7.0. The hexane layer was recovered from the sample liquid 3 after washing with water, the recovered hexane layer, the hexane was removed with an evaporator and vacuum, the EPA3 a composition containing free EPA was obtained 2.14 g.
Against EPA3, it was evaluated in the same manner as EPA1. The results are shown in Table 1 and Table 4.
The recovery was 93.8%. The resulting Gardner color of EPA3 is 2-, AnV 1.3, ethyl ester (EE) content 2790Ppm, conjugated diene acid content was 0.47%. Conjugated unsaturated fatty acids other than the conjugated diene acid was not detected. These physical property values are shown in Table 1. Note that the conjugated unsaturated fatty acids, only the conjugated diene acid shown in Table 1.

PATENT

WO-2018120574

Process for production of docosahexaenoic acid (DHA), by microbial fermentation of Schizochytrium limacinum . Discloses use of DHA for treating cardiovascular diseases, infertility or neurological diseases. See CN106635405 , claiming method for separating DHA from powder DHA grease by supercritical extraction method. Kingdomway lists that it produces DHA by microorganism fermentation.

DHA, the full name doc-4,7,10,13,16,19-docosahexaenoic acid, DHA, is a polyunsaturated fatty acid. The human body is difficult to synthesize itself and must be taken from the outside world. DHA is one of the essential fatty acids in the human body. It has important physiological regulation functions and health care functions. When it is lacking, it will cause a series of diseases, including growth retardation, skin abnormalities, scales, infertility, mental retardation, etc. In addition, there are cardiovascular diseases. Special preventive and therapeutic effects. Studies have also shown that DHA can act on many different types of tissues and cells, inhibit inflammation and immune function, including reducing the production of inflammatory factors, inhibit lymphocyte proliferation, etc. DHA also has multiple effects in preventing Alzheimer’s disease and neurological diseases. .

The current commercial sources of DHA are mainly fish oil and microalgae. DHA extracted from traditional deep-sea fish oil is unstable due to the variety, season and geographical location of fish, and the content of cholesterol and other unsaturated fatty acids is high. The difference in length and degree of unsaturation of fatty acid chains is large, resulting in limited production and content of DHA. It is not high, it is difficult to separate and purify, and the cost is high. With the growing shortage of fish oil raw materials, it is difficult to achieve the widespread use of DHA, a high value-added product in the food and pharmaceutical industries. The production of DHA by microbial fermentation can overcome the defects of traditional fish oil extraction, can be used for mass production of DHA, continuously meet people’s needs, has broad application prospects, and has attracted the attention of scholars at home and abroad. The microbial fermentation method uses fermented microorganisms such as fungi and microalgae to produce DHA-containing algal oil, and refined to obtain essential oil with high DHA content. DHA-producing strains approved by the Ministry of Health include Schizochytrium sp., Ulkenia amoeboida, and Crypthecodinium cohnii.

The market share of DHA produced by microbial fermentation is increasing rapidly year by year. There is a trend to replace DHA of fish oil, improve the production technology and quality of microalgae DHA, and the prospect of entering the microalgae DHA market is broad.

The publication No. CN103882072A discloses a method for producing docosahexaenoic acid by using Schizochytrium, and the highest yield disclosed is a cell dry weight of 61.2 g/L, a DHA content of 55.07%, and a DHA yield of 22.17 g. /L. The publication No. CN101812484A discloses a method for fermenting DHA by high-density culture of Schizochytrium, which discloses a dry cell weight of 120-150 g/L and a DHA yield of 26-30 g/L, which is also reported. The highest production level of DHA produced by Schizochytrium sp. Although the DHA productivity has been greatly improved compared with the previous research, the industrial production of docosahexaenoic acid by using microalgae greatly reduces the production cost, increases the unit yield, and enables the method of microbial fermentation to produce DHA. Promotion and popularization are still far from enough.

There are three main methods for extracting DHA from the fermentation liquid of Schizochytrium, one is centrifugation, the other is organic solvent extraction, and the third is supercritical extraction. Centrifugation, such as the publication No. CN101817738B, discloses a method for extracting DHA from algae and fungal cells by separating the microalgae or fungal fermentation broth after fermentation by a separation system, and adjusting the pH of the sludge with an acid. 2.0-4.0, then control the temperature of the slime at 10 °C-20 °C, add anti-oxidant in the slime, and then carry out high-pressure homogenization and breaking through the high-pressure homogenizer; add the broken mud to the water, stir and feed The liquid was separated by a three-phase separator to obtain DHA grease. The invention adopts physical wall breaking and physical extraction methods, has simple process, high cell breakage, low temperature treatment of bacteria sludge and antioxidant treatment, can effectively protect the biological activity of algae and fungal cells, and the product is green and non-toxic. Residue. However, the quality of the oil layer after centrifugation of the invention is poor. In addition to the oil, it also contains impurities such as water, medium components and cell debris, which is not conducive to subsequent refining. In addition, the wastewater layer after centrifugation contains a large amount of slag and has a high COD. Difficult to handle or process is extremely costly. The organic solvent extraction method, such as the publication No. CN101824363B, discloses a method for extracting docosahexaenoic acid oil: the fermentation liquid containing docosahexaenoic acid is subjected to enzymatic breaking, and then an organic solvent is used first. The first stage water is divided, the cells are enriched, and the organic solvent is used for secondary extraction to obtain a crude oil. The method is simple in operation and low in equipment investment, but the method uses organic solvent for extraction, and the final product may have solvent residue, and the extraction process has safety hazards such as flammability and explosion. The supercritical extraction method, as disclosed in the publication No. CN102181320B, discloses a method for extracting bio-fermented DHA algae oil, comprising the following steps: a) drying the solid matter obtained by solid-liquid separation of the microalgae fermentation liquid to obtain a dried bacterial cell; b) extracting the dried cells with supercritical carbon dioxide as an extractant to obtain a carbon dioxide fluid; c) separating the carbon dioxide fluid under reduced pressure to obtain DHA algae oil. Experiments show that the DHA content of DHA algae oil obtained by the method provided by the invention is more than 40%, the extraction yield is only 85.23%, and the need to add ethanol as the extracting agent has certain safety risks and supercritical. The equipment is expensive and the extraction yield is not high.

In the prior art, the refining of DHA hair oil is mostly carried out by chemical refining technology, and the DHA hair oil is degummed, alkali refining, decolorized and deodorized to obtain DHA essential oil. Inevitably, there are some problems in the process technology. For example, in order to achieve the requirement of controlling low acid value, alkali refining usually adds excessive alkali, and some triglycerides are inevitably saponified; high COD wastewater produced by alkali refining will pollute the environment; Alkali refining requires high temperature treatment for a long time, which is easy to cause the product’s peroxide value and anisidine value to increase; the deodorization temperature is high, and the long time is easy to produce trans fatty acids.

Currently, there is still a need to develop new DHA production processes.

Fermentation culture

In the following Examples 1-13, unless otherwise specified, the seed medium formulations used were: glucose 3%, peptone 1%, yeast powder 0.5%, sea crystal 2%, and pH natural (the rest being water). The fermentation medium formula is: glucose 12%, peptone 1%, yeast powder 0.5%, sea crystal 2% (the rest is water).

Example 1

The Schizochytrium sp. ATCC 20888, Schizochytrium limacinum Honda et Yokochi ATCCMYA-1381, and Schizochytrium sp. CGMCC No. 6843 slope-preserved strains were respectively inserted into 400 mL of medium. The 2L shake flask was cultured at a temperature of 25 ° C at a rotation speed of 200 rpm for 24 hours to complete the activated culture of the strain. According to the inoculation amount of 0.4%, the shake flask seed solution was connected to the first-stage seed tank containing the sterilized medium, and the culture temperature was 28 ° C, the aeration amount was 1 vvm, the tank pressure was 0.02 MPa, and the stirring speed was 50 rpm for 30 hours to complete the first stage. Seeds are expanded and cultured. The seed liquid of the primary seed tank was connected to the secondary seed tank containing the sterilized medium according to the inoculation amount of 3%, and the culture temperature was 28 ° C, the aeration amount was 1 vvm, the tank pressure was 0.02 MPa, and the stirring speed was 75 rpm for 24 hours. Complete secondary seed expansion culture. The seed solution of the secondary seed tank was connected to a fermentor containing the sterilized medium according to a 3% inoculum.

The fermentation process has a culture temperature of 28 ° C, aeration of 1 vvm, a can pressure of 0.02 MPa, a stirring speed of 75 rpm, a carbon source containing 30% of the pretreated crude glycerin, a glucose concentration of 5 g/L, and a nitrogen source. Fermentation culture. During the fermentation process, the glucose concentration, pH, bacterial biomass, crude oil production and DHA yield of the fermentation broth were measured.

After 96 hours of culture, the fermentation was terminated. Table 1 below shows the biomass, crude oil production, DHA production and DHA productivity of the three strains cultured in the original culture mode. Table 2 below shows the mixed fat and fatty acid composition of the gas obtained after fermentation. Analysis results. The biomass, crude oil production and DHA production of CGMCC No.6843 are also shown in Figure 3.

Table 1: Fermentation results of different strains in the original culture mode

Table 2: 100m ³ fermenter original culture method

It can be seen from Table 1 and Table 2 that the yield and fatty acid composition of the three strains are different in the original culture mode, and the Schizochytrium sp. CGMCC No. 6843 is superior to the other two strains. Schizochytrid sp. (Schizochytrium sp. CGMCC No. 6843) was used as the starting strain to optimize the different culture methods.

PATENT

CN106635405

https://patents.google.com/patent/CN106635405A/zh

PATENT

WO2012153345

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2012153345

PAPER

NMR

Organic Chemistry 2014 vol. 2014 21 pg. 4548 – 4561

Patent

WO 2015162265

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015162265&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

¹ H NMR (500 MHz; CDCI₃) δ_Η 5.43-5.30 (m, 12H, CH=CH), 2.85-2.80 (m, 10H, CH₂ bis-allylic), 2.42-2.40 (m, 4H, CH₂-C=0, CH₂ allylic), 2.07 (quint, J = 7.5 Hz, 2H, CH₂ allylic), 0.98 (t, J = 7.5 Hz, 3H, CH₃)

¹ H NMR (500 MHz; CDCI₃) δ_Η 5.43-5.30 (m, 12H, CH=CH), 2.85-2.80 (m, 10H, CH₂ bis-allylic), 2.42-2.40 (m, 4H, CH₂-C=0, CH₂ allylic), 2.07 (quint, J = 7.5 Hz, 2H, CH₂ allylic), 0.98 (t, J = 7.5 Hz, 3H, CH₃)

Image result for doconexent

Patent

Publication numberPriority datePublication dateAssigneeTitle

JPS60133094A *1983-12-211985-07-16Nisshin Oil Mills LtdManufacture of high purity eicosapentaenoic acid

JPH07242895A *1993-03-161995-09-19Ikeda Shiyotsuken KkEicosapentaenoic acid of high purity and isolation and purification of lower alcohol ester thereof

JPH09238693A *1996-03-071997-09-16Maruha CorpPurification of highly unsaturated fatty acid

JPH10139718A *1996-11-071998-05-26Kaiyo Bio Technol Kenkyusho:KkProduction of eicosapentaenoic acid

JP2004089048A *2002-08-302004-03-25National Institute Of Advanced Industrial & TechnologyNew labyrinthulacese microorganism and method for producing 4,7,10,13,16-docosapentaenoic acid therewith

JP2007089522A *2005-09-292007-04-12Hisahiro NagaoMethod for producing fatty acid composition containing specific highly unsaturated fatty acid in concentrated state

WO2013172346A1 *2012-05-142013-11-21日本水産株式会社Highly unsaturated fatty acid or highly unsaturated fatty acid ethyl ester with reduced environmental pollutants, and method for producing same

Family To Family Citations

CA2930897A1 *2013-12-042015-06-11Nippon Suisan Kaisha, Ltd.Dihomo-gamma-linolenic acid-containing microbial oil and dihomo-gamma-linolenic acid-containing microbial biomass

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External links

DHA / EPA Omega-3 Institute – Recent studies, overviews, and objective science.
Docosahexaenoic acid (DHA) – University of Maryland Medical Center (UMMC)
Docosahexaenoic acid – DHA ChemSub Online

REFERENCE

Calder PC: Omega-3 fatty acids and inflammatory processes. Nutrients. 2010 Mar;2(3):355-74. doi: 10.3390/nu2030355. Epub 2010 Mar 18. [PubMed:22254027]
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Kelley DS, Siegel D, Fedor DM, Adkins Y, Mackey BE: DHA supplementation decreases serum C-reactive protein and other markers of inflammation in hypertriglyceridemic men. J Nutr. 2009 Mar;139(3):495-501. doi: 10.3945/jn.108.100354. Epub 2009 Jan 21. [PubMed:19158225]
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Docosahexaenoic acid

Names

IUPAC name

(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenoic acid

Other names

cervonic acid
DHA
doconexent (INN)

Identifiers

CAS Number

6217-54-5

3D model (JSmol)

Interactive image

ChEBI

CHEBI:28125

ChEMBL

ChEMBL367149

ChemSpider

393183

ECHA InfoCard

100.118.398

IUPHAR/BPS

1051

PubChem CID

445580

UNII

ZAD9OKH9JC

Properties

C₂₂H₃₂O₂

328.488 g/mol

0.943 g/cm³

−44 °C (−47 °F; 229 K)

Boiling point

446.7 °C (836.1 °F; 719.8 K)

Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

///////////Docosahexaenoic acid (22:6(n-3)), ZAD9OKH9JC, доконексен, دوكونيكسانت , 二十二碳六烯酸 , Doconexent, 6217-54-5, cervonic acid, DHA, doconexent, 81926-93-4

all-Z-Docosahexaenoic acid
AquaGrow Advantage
CCRIS 7670
Cervonic acid
DHA
Doconexent
Doconexento
Doconexento [INN-Spanish]
Doconexentum
Doconexentum [INN-Latin]
Docosahexaenoic acid (all-Z)
Doxonexent
Efalex
Marinol D 50TG
Martek DHA HM
Monolife 50
Ropufa 60
UNII-ZAD9OKH9JC

CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O

Promega
308064-99-5

MW: 644.9746

4,7,10,13,16,19-Docosahexaenoic acid, (4E,7E,10E,13E,16E,19E)-
391921-09-8

MW: 328.4928

Algal DHA

MW: 328.4928

Omega-3 Fatty Acids

MW: 909.3808

4,7,10,13,16,19-Docosahexaenoic acid
2091-24-9

MW: 328.493

Doconexent [INN]
6217-54-5

MW: 328.4928

Docosahexaenoic acid, (Z,Z,Z,Z,Z,Z)-
32839-18-2

MW: 328.493

Doconexent sodium
81926-93-4

MW: 350.4749

(14C)Docosahexaenoic acid
93470-46-3

MW: 328.493

CH4630808

July 2, 2018 9:32 am / Leave a comment

CH4630808, CH-4630808, NA-808

(2S)-2-[(E,2S)-1-[[(1S)-2-(4-but-2-ynoxyphenyl)-1-carboxyethyl]amino]-1,11-dioxooctadec-3-en-2-yl]-2-hydroxybutanedioic acid

Molecular Formula:	C₃₅H₄₉NO₁₀
Molecular Weight:	643.774 g/mol

Cas 827034-92-4 DOUBLE BOND E, SP ROT (-)

CAS 744208-75-1 E Z NOT DEFINED

D-erythro-Pentonic acid, 5-[[(1S)-2-[4-(2-butynyloxy)phenyl]-1-carboxyethyl]amino]-3-C-carboxy-2,4,5-trideoxy-5-C-oxo-4-[(1E)-9-oxo-1-hexadecenyl]- (9CI)
5-[[(1S)-2-[4-(2-Butyn-1-yloxy)phenyl]-1-carboxyethyl]amino]-3-C-carboxy-2,4,5-trideoxy-5-C-oxo-4-[(1E)-9-oxo-1-hexadecen-1-yl]-D-erythro-pentonic acid
D-erythro-Pentonic acid, 5-[[(1S)-2-[4-(2-butyn-1-yloxy)phenyl]-1-carboxyethyl]amino]-3-C-carboxy-2,4,5-trideoxy-5-C-oxo-4-[(1E)-9-oxo-1-hexadecen-1-yl]-

Chugai Pharmaceutical (Originator)

Trisodium Der ,CAS 1799542-36-1, SP ROT (-), MW 709.7097, MF C35 H46 N O10 . 3 Na, Trisodium (2S)-2-[(2S,3E)-1-([(1S)-2-[4-(but-2-yn-1-yloxy)phenyl]-1-carboxylatoethyl]amino)-1,11-dioxooctadec-3-en-2-yl]-2-hydroxybutanedioate

SIMILAR

PAPER

https://www.sciencedirect.com/science/article/pii/S0960894X12013741

Bioorganic & Medicinal Chemistry Letters

Volume 23, Issue 1, 1 January 2013, Pages 336-339

Image result for CH4630808.

Image result for CH4630808

Scheme 3. Reagents and conditions: (a) TBDPSCl, imidazole, DMF, rt; (b) n-BuLi, (CH2O)n, THF; (c) Red-Al, 0 C, then I2, THF 40 C; (d) DHP, PPTS, DCM, rt; (e) n-BuLi, (CH2O)n, THF, 78 C to 0 C; (f) TBDPSCl, imidazole, DMF, rt; (g) PPTS, EtOH. 28.6% over 7 steps; (h) L-(+)-DET, Ti(Oi-Pr)4, TBHP, DCM, 97%, >95% ee; (i) Terminal alkyne 7 in Scheme 2, Cp2ZrClH, MeMgCl, CuI, THF, 20 C, 91% yield⁄ ; (j) 2,2-dimethoxypropane, PPTS, DCM, 85% yield⁄ ; (k) TBAF, AcOH, THF, 89% yield⁄ ; (l) oxalyl chloride, DMSO, triethylamine, DCM, 78 C; (m) NaClO2, NaH2PO4, 2-methyl-2-butene, t-BuOH-H2O; (n) N,N-dimethylformamide di-tert-butyl acetal, 58% yield in 3 steps⁄ ; (o) 80% AcOH, THF, rt, 90% yield⁄ ; (p) Jones reagent, aqueous acetone, 10 C, 80% yield⁄ ; (q) the corresponding amine, HATU, Hunig base, 85% yield⁄ ; (r) TFA, anisole, DCM, 90% yield⁄ ; (s) H2-Pd/C, EtOH, 80%; (t) NaBH4, THF, MeOH, 93% yield. ⁄ yields when n = 5 and R1 = n-C7H15.

Paper

Development of a Kilogram-Scale Synthesis of a Novel Anti-HCV Agent, CH4930808

CH4630808 corrected

Tsuyoshi Haneishi ^*^†

, Yoshiaki Kato^‡, Hiroshi Fukuda^†, Tomoyuki Shimamura^‡, Takemi Tanokura^‡, Akira Hiraide^‡, Kaichiro Koyama^‡, Masato Fudesaka^‡, Kenji Maeda^‡, Nobuyuki Nakata^‡, Masahiro Nagase^‡, Takahiko Yabuzaki^‡, Hiroaki Takao^‡, Masaharu Kigawa^‡, Hitoshi Shimizu^‡, and Makoto Shimizu^§

^† Research Division, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan

^‡ Pharmaceutical Technology Division, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-ku, Tokyo 115-8543, Japan

^§ Department of Chemistry for Materials, Graduate School of Engineering, Mie University, Tsu, Mie 514-8507, Japan

Org. Process Res. Dev., 2018, 22 (2), pp 236–240

DOI: 10.1021/acs.oprd.7b00383

*E-mail: haneishitys@chugai-pharm.co.jp. Tel.: +81-550-87-9102. Fax: +81-550-87-5326.

Abstract

Herein, we report the kilogram-scale synthesis of CH4930808 (1) CH 4630808 CORRECTED, a novel anti-hepatitis C virus agent. While pursuing improved productivity using many through-process strategies, we conducted scrupulous impurity control. Finally, we successfully developed a practical and scalable process for the synthesis of (1·1.5Na·2.5H₂O), by which we prepared 3.28 kg of the active pharmaceutical ingredient for clinical studies

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00383/suppl_file/op7b00383_si_001.pdf

1H-NMR and 13C-NMR spectra of compound 5·HCl S 3– S 4

1H-NMR spectra of compound 1·1.5 Na·2.5 H2O S 5

13C-NMR spectra compound 1·1.5 Na·2.5 H2O S 6

1H-COSY spectra of compound 1·1.5 Na·2.5 H2O S 7 – S 8

DEPT spectra of compound 1·1.5 Na·2.5 H2O S 9 – S 10

HMBC spectra of compound 1·1.5 Na·2.5 H2O S 11 – S 17

MASS

PATENT

WO 2004071503

WO 2005005372

WO 2006016657

WO 2006088071

WO 2007000994

WO 2007132882

WO 2009154248

WO 2014027696

PAPER

Angewandte Chemie, International Edition (2012), 51(17), 4218-4222, S4218/1-S4218/77.

Bioorganic & Medicinal Chemistry Letters (2013), 23(1), 336-339

PAPER

Organic & Biomolecular Chemistry (2017), 15(31), 6632-6639.

http://pubs.rsc.org/en/Content/ArticleLanding/2017/OB/C7OB01608E#!divAbstract

10.1039/C7OB01608E

Stereoselective synthesis of the viridiofungin analogue NA808 from a chiral tetrahydrofuran-carboxylic acid

Masatoshi Murakata*^a and Takuma Ikeda^a

Author affiliations

*Corresponding authors

^aAPI Process Development Department, Chugai Pharmaceutical Co., Ltd., 5-5-1 Ukima, Kita-Ku, Japan
E-mail: murakatamst@chugai-pharm.co.jp

Abstract

The viridiofungin analogue NA808 was synthesized by the stereoselective Ireland–Claisen rearrangement of dienylmethyl ester, regioselective bromolactonization of β-divinylpropanoic acid and retro-bromolactonization.

http://www.rsc.org/suppdata/c7/ob/c7ob01608e/c7ob01608e1.pdf

PATENT

https://patents.google.com/patent/WO2004071503A1/ar

The number of people infected with hepatitis C virus (HCV) is estimated at 1 to 200 million people worldwide, and over 2 million people in Japan. Approximately 50% of these patients migrate to chronic hepatitis, of which approximately 20% become liver cirrhosis, liver cancer after more than 30 years after infection. About 90% of liver cancer is said to be hepatitis C cause. In Japan, more than 20,000 patients die every year from liver cancer associated with HCV infection.

HCV was discovered in 1989 as a major causative virus of non-A non-B hepatitis after transfusion. HCV is an enveloped RNA virus whose genome

It consists of single-stranded (+) RNA and is classified as a genus Hepacivirus of Flaviviridae.

Since HCV avoids the immune mechanism of the host due to a cause which is still unclear, persistent infection is often established even when infected with an adult with developed immune mechanism, progresses to chronic hepatitis, liver cirrhosis, hepatocellular carcinoma, surgery It is also known that many patients have liver cancer recurrence due to inflammation that continues to occur in non-cancerous areas.

Therefore, establishment of an effective therapy for hepatitis C is desired, and among them, apart from coping therapy that suppresses inflammation by anti-inflammatory agents, development of a drug that reduces or eradicates HCV in the affected liver It is strongly desired.

Interferon treatment is currently known as the only effective treatment for HCV elimination. However, the number of patients with interferon effective is about one third of all patients. In particular, interferon response to HCV genotype 1 b is very low. Therefore, development of anti-HCV drugs that can replace or be used in combination with interferon is strongly desired.

In recent years, Ribavirin (1 – 3 – D – lipofuranosyl – 1 H – 1, 2, 4 – triazole – 3 – carboxamide) is commercially available as a therapeutic agent for hepatitis C by combining with interferon, Is still low, further new treatment for hepatitis C is desired. In addition, attempts have been made to eliminate viruses by enhancing the immune system of patients, such as interferon agonists, interleukin-12 agonists, etc. However, no effective drug has yet been found.

Since the HCV gene has been cloned, molecular biological analysis of the mechanism and function of viral genes, functions of proteins of each virus and the like has been accompanied by rapid development of forces, replication of virus in host cells, persistent infection, pathogenesis The mechanism such as sexuality has not been sufficiently elucidated, and at the present time, an HCV infection experiment system using reliable cultured cells has not been constructed. Conventionally, when evaluating anti-HCV drugs, alternative alternative virus method using other closely related viruses had to be used.

In recent years, however, it became possible to observe in vitro HCV replication using the nonstructural region part of HCV, so that anti-HCV drugs could be easily evaluated by the replicon assay method (Non-Patent Document 1). The mechanism of H CV RN A replication in this system is believed to be identical to the replication of the full-length HCV RNA genome infected with hepatocytes. Therefore, this system can be said to be a cell-based approach system useful for identifying compounds that inhibit the replication of HCV.

The compounds claimed in this patent are compounds that inhibit the replication of HCV found by the replicon astrocyte method. These inhibitors are considered highly likely to be therapeutic agents for HCV.

Non-Patent Document 1

B. Roman et al., Science (Science), 1999, 285, 110 – 113

Example 14

– 1 (Step 1 1)

According to the method described in the literature (J. Org. Chem. 1989, 45, 5522, BE Marron, et al)

TBDPSO.

a on

Of compound a (7.0 1 g) was synthesized, and anhydrous ethyl ether of this compound a

(700 ml) was cooled to 0 ° C. and bis (2-methoxyethoxy) aluminum hydride (414 mmol, 218 ml, 70% toluene solution) was added slowly. Five minutes after adding the reagent, the ice bath was removed and stirring was continued for 1 hour at room temperature. The reaction solution was cooled to 0 ° C and anhydrous ethyl acetate (1 9.8 ml, 203 mmol) was added slowly. After stirring at the same temperature for 10 minutes, it was cooled to 1 78 ° C., and iodine (76.1 g,

300 thigh ₀ 1) was added. The temperature was gradually raised to room temperature over 2 hours to complete the reaction. To the reaction solution was added aqueous sodium bisulfite solution, and ethyl acetate was added. The reaction solution was filtered with suction through celite, the organic layer was separated, and the aqueous layer was extracted again with ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude title compound (100 g) as a light brown oily substance. The obtained crude product was directly used for the next reaction.

Physicochemical properties of compound b

Molecular weight 466

FAB-MS (positive mode, matrix m-NBA) 467 (M + H ⁺ ).

Chemical shift value of ^X H-NMR (in heavy chloroform) δ:

J = 6 Hz), 3.80 (2H, t, J = 6 Hz), 4.18 (2H, t, J = 5 Hz), 2.73 (2H, t, J = 6 Hz), 1.49 Hz, 5.91 (1 H, t, J = 5 Hz), 7.35 – 7.46 (6 H, m), 7.65 – 7.69 (4 H, m)

1 -2 (Step 1 – 2)

TBDPS

Dichloro port methane solution of compound b obtained in the above reaction (300 ml) was cooled to 0 ° C, dihydropyran (22. 7 ml, 248删₀ plus 1). Pyridinium paratoluenesulfonic acid (260 mg, 1 mol) was added to this solution. After 1 hour sodium bicarbonate water was added to stop the reaction. The separated organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude compound c (108 g) thus obtained was directly used for the next reaction.

Physicochemical properties of compound c

Molecular weight 550

FAB-MS (positive mode, matrix m-NBA) 551 (M + H ⁺ )

Chemical shift value of ¹ H – NMR (in heavy mouth formium) δ:

3.46-3.58 (2H, m), 3.76 (2H, t, J = 6 Hz), 3.82 (2H, t, J = 6 Hz), 1.04 (9H, s), 1.49-1.91 J = 13, 6 Hz), 4.65 (1 H, t, J = 3 Hz), 5.91 (1 H, t (s)), 4.93 (1 H, m), 4.06 (1 H, dd, J = 13, 6 Hz) , J = 5 Hz) 7.35 – 7.43 (6 H, m), 7.65 – 7.69 (4 H, m)

1-3 (Step 1- 3)

The crude compound c (4. 73 g) was dissolved in anhydrous ethyl ether (30 ml) and cooled to 1 78 ° C. Tert-butyllithium (1 7. 2 mol, 1 0.7 ml, 1.6 N pentane solution) was added slowly. After stirring at the same temperature for 1 hour, paraformaldehyde (1 8.9 mraol, 570 mg) was added and the mixture was warmed to 0 ° C. for 30 minutes at the same temperature and stirred for 1 hour. An aqueous solution of salthyanmonium was added to stop the reaction, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The crude product obtained by concentration under reduced pressure was purified by column chromatography (silica gel, hexane-ethyl acetate 9: 1 to 4: 1) to give compound d (1. 635 g) as a colorless oily substance.

Physicochemical properties of compound d

Molecular weight 454

FAB-MS (positive mode, matrix m-NBA) 455 (M + H ⁺ )

^ – NMR (chemical shift value in heavy chloroform) δ:

J = 6 Hz), 3.03 (1 H, t, J = 6 Hz), 3.47 – 3.58 (2 H, m), 3.75 – 3.92 (2 H, (3 H, m), 4.08 – 4.26 (4 H, m), 4.68 (1 H, t, 3 Hz),

5.53 (1 H, t, J = 7 Hz) 7.35 – 7.47 (6 H, m), 7.64 – 7.68 (4 H, m)

1 -4 (Step 1 – 4)

An anhydrous N, N-dimethylformamide solution (2 ml) of the compound d (34 mg, 0. 76 mmol) and imidazole (71 mg, 1.14 mmol) was cooled to 0 ° C and tert- Chlorosilane (0: 2 ml, 0. 76 mmol) was capped and stirred for 2 hours. An ammonium chloride aqueous solution was added to stop the reaction, and the mixture was extracted with hexane. The organic layer was washed with water twice, followed by saturated brine and dried over anhydrous sodium sulfate. And concentrated under reduced pressure to obtain crude compound e (554 mg) as a colorless oily substance.

Physicochemical properties of compound e

FAB-MS (positive mode, matrix m-NBA) 715 (M + Na ⁺ )

Chemical shift value of ‘1 H-NMR (in heavy mouth formium) δ:

(4H, m), 1.00 J = 7 Hz), 5.43 (1 H, t, J = 7 Hz), 7.29 – 7.48 (12 H, m), 4.00 – 4.09 (1 H, m), 4.14 , 7.57 – 7.78 (8 H, m)

1-5 (Step 1- 5)

Pyridinium paratoluenesulfonic acid (9 O mg, 0.36 mmol) was added to an ethanol solution (6 ml) of the compound e (1. 16 g, 1. 67 mmol), and the mixture was stirred at 60 ° C. for 3.5 hours. After cooling the solution to room temperature, a saturated aqueous sodium bicarbonate solution was added and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane / ethyl acetate 20: 1) to give compound f (825 mg, 81%) as a colorless oily substance.

Physicochemical properties of compound f

Molecular weight 608

FAB-MS (positive mode, matrix m-NBA) 631 (M + Na ⁺ )

^ – NMR (chemical shift value in heavy chloroform) δ:

(2H, t, J = 7 Hz), 3.75 (2H, t, J = 7 Hz), 3.90 (2H, t, J = 7 Hz), 1.01 (9H, s), 1.01 , 7.59-7.47 (12 H m), 7.57-7.75 (8 H, m), 4.14 (2 H, s), 5 47 (1 H, t, J =

1-6 (Step 1-6)

The round bottom flask containing the rotor was heated and dried under reduced pressure and then purged with nitrogen, and anhydrous

Dichloromethane (60 ml) was added and cooled to _20 ° C. Titanium tetraisopropoxide (2.3 3 ml, 7.8 8 mmol), L 1 (+) – Jetyl tartrate (1.6 2 ml, 9. 4 6 min. ₀ 1) was added successively, and after stirring for 15 minutes, compound f (4.80 g, 7. 88 mmol) in dichloromethane (30 ml), and the mixture was stirred for 15 minutes. Cool to _ 25 ° C and add tert-butyl hydroperoxide (5. 25 ml,

15. 8 mmol, 3 N dichloromethane solution) was slowly added dropwise. After completion of the dropwise addition, the mixture was stirred at 20 ° C. for 2 hours, dimethylsulfide (1.1 ml) was added, and the mixture was further stirred at the same temperature for 1 hour. A 10% aqueous solution of tartaric acid was added to the reaction solution and the mixture was stirred for 30 minutes, and then stirred at room temperature for 1 hour. The organic layer was separated, the aqueous layer was extracted with a small amount of dichloromethane and the combined organic layers were dried over anhydrous sodium sulfate. The crude product obtained was concentrated under reduced pressure, and purified by force RAM chromatography (silica gel, hexane / monoacetic acid ethyl 9: 1). Compound g (4. 78 g, 97%) was obtained as a colorless oily substance. The asymmetric yield (> 95% ee) was determined by NMR analysis of the corresponding MT PA ester.

Physicochemical properties of compound g

Molecular weight 624

F AB-MS (positive mode, matrix m-NBA) 647 (M + Na ⁺ )

– Chemical shift value of NMR (in heavy chloroform) δ:

J = 14, 7 Hz), 2.23 (1 H, dt, J = 14, 1 H), 1.02 (9 H, s), 1.03 (9 H, s), 1.72 (6H, m), 7.32-7.45 (12H, m), 7.60- 7.65 (8H, m), 6.5 Hz), 3.17 (1H, dd, J = 6, 5 Hz), 3.55-3.79

1 – 7 (Step 1 – 7)

To a solution (100 ml) of the compound α (10. 45 g, 37.2 mmol) produced in the step 2-3 of Production Example 1 described below in an anhydrous tetrahydrofuran solution (100 ml) under a nitrogen atmosphere was added biscyclopentadienylzirconium hydride chloride (10. lg, 37.2 mol) was added at room temperature and stirred for 30 minutes. The resulting solution was cooled to 1780C and methyl magnesium chloride (24.7 ml, 74 mmol, 3 N tetrahydrofuran

Furan solution), and the mixture was stirred for 5 minutes. Monovalent copper iodide (500 mg, 7.2 mM) was added to this solution and the temperature was gradually raised to _ 30 ° C. An anhydrous tetrahydrofuran solution (70 ml) of the compound g (4. 49 g) was added over 20 minutes, and after completion of the dropwise addition, the mixture was stirred at 25 ° C. overnight. The saturated ammonium chloride aqueous solution was slowly added, the reaction was stopped, and the temperature was gradually raised to room temperature. The mixture was stirred at room temperature for 10 hours and the resulting white solid was filtered off through celite. The celite was washed thoroughly with ethyl acetate and the organic layer was separated. The aqueous layer was extracted with a small amount of ethyl acetate and the combined organic layer was washed with saturated aqueous ammonium chloride solution and then dried over anhydrous sodium sulfate. Concentrated under reduced pressure and the obtained crude product was purified by column chromatography (silica gel, hexyl acetate

20: 1 to 9: 1) to give compound h (5. 96 g, 91%) as a pale yellow oily substance.

Physicochemical properties of compound h

Molecular weight 907

F AB – MS (negative mode, matrix πι – Α Β A) 906 (Μ – Η ⁺ )

Chemical shift value of ¹ H-NMR (in heavy chloroform) δ:

0.88 (3H, t,
0.99 (9H, s), 1.04 (9H, s), 1.18-1.63 (22H, m), 1.78-2.01 (4H, m), 2.44-2.57 (1H, m), 3.00 (1H, t, J = 6 Hz), 3.59-3.92 (10H, m), 4.28 (1H, s), 5.37-5.55 (2H, m), 7.29-7.65 (20H, m)

1-8 (Step 1-8)

Compound h (5.30 g, 5.84 dragon ol) was dissolved in dichloromethane (200 ml) and 2, 2-dimethoxypropane (150 ml), pyridinium paratoluenesulfonic acid (15 mg, 0.058 mmol) was added , And the mixture was stirred at room temperature overnight. The reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted twice with dichloromethane. After drying over anhydrous sodium sulfate, the mixture was concentrated under reduced pressure, and the resulting crude product was purified by column chromatography (silica gel, hexane-ethyl acetate 20: 1). Compound i (4. 69 g, 86%) was obtained as a pale yellow oily substance.

Physicochemical properties of Compound i

Molecular weight 947

F AB-MS (negative mode, matrix m-NBA) 946 (M – H ⁺ )

Chemical shift value of ¹ H – NMR (in heavy mouth formium) δ:

(1 H, m), 0.88 (3H, t, J = 6 Hz), 1.02 (9H, s), 1.05 (9H, s), 1.14-1.63 (28H, m), 1. 2.16 (2H, m), 7.28 – 7.47 (12H, m), 7.61 – 7.69 (1H, d, J = 10 Hz), 3.64-3.86 (6H, m 3.92 (s, 4H), 5.36-5.42 8 H, m) 1 – 9 (Step 1 – 9)

A tetrahydrofuran solution (50 ml) of the compound i (4. 39 g, 4. 64 mmol) was cooled to 0 ° C., tetrabutylammonium fluoride (10. 2 ml, 10, 2 difficulty, 1 M tetrahydrofuran solution) and Acetic acid (0. 53 ml, 9. 27 mmol) was added. The temperature was gradually raised to room temperature and stirred for 2 days. A saturated ammonium chloride aqueous solution was added and the mixture was extracted twice with dichloromethane. The combined organic layer was washed with aqueous sodium bicarbonate and dried over anhydrous sodium sulfate. The crude product was purified by column chromatography (silica gel, hexane-ethyl acetate 9: 1 to 3: 2) to obtain the compound〗 (1. 73 g, 81%) Was obtained as a pale yellow oily substance.

Physicochemical properties of compound j

Molecular weight 470

F AB-MS (positive mode, matrix m-NBA) 493 (M + Na ⁺ )

Chemical shift value of ^X H-NMR (in heavy chloroform) δ:

2.73 (1H, dt, J = 6, 10 Hz), 2.95 (3H, t, J = 6 Hz), 1.17-1.73 (26H, m), 1.91-2.16 (4H, m), 2.4 J = 15, 7 Hz (1 H, dt, J = 15 Hz), 3.48 (1 H, d, J = 1 Hz), 3.63-4.01 (m, 10 H), 5.15 )

1-10 (Step 1- 10)

Under an atmosphere of nitrogen, a solution of oxalyl chloride (0. 575 ml, 6. 6 mol) in anhydrous dichloromethane (17 ml) was cooled to 178 ° C. and dimethyl sulfoxide

(0. 9 36 ml, 1 3 2 minol) in dichloromethane (1 ml) was added dropwise and the mixture was stirred for 15 minutes. Dichloromethane solution (5 ml) of compound j (388 mg, 0. 824 aura) was slowly added dropwise. The mixture was stirred at the same temperature for 1 hour, then terethylamine (3 ml, 21.4fflmol) was added and the mixture was stirred for 30 minutes. The cooling bath was removed and a low-boiling compound was removed by blowing a nitrogen gas stream to the solution, followed by drying under reduced pressure. Jether ether (15 ml) was added to the residue, and insoluble matter was filtered off and concentrated. After this operation was carried out twice, the obtained residue was immediately used for the next reaction.

The crude dialdehyde was dissolved in 2-methyl-2-propanol (24 ml) and 2-methyl-2-butene (6 ml) and cooled to about 5 to 7 ° C. To this solution was added sodium chlorite (745 mg, 8. 24 mmol) and sodium dihydrogenphosphate

(745 mg, 6. 2 l mmol) in water (7. 45 ml) was slowly added dropwise. After 2 hours the mixture was cooled to 0 ° C. and aqueous sodium hydrogenphosphate solution was added to adjust PH to approximately 5. The mixture was extracted three times with dichloromethane, and the combined organic layer was washed with saturated brine and then dried over anhydrous sodium sulfate. After filtration, concentration under reduced pressure afforded a pale yellow oily residue which was immediately used for the next reaction without further purification.

The crude dicarboxylic acid was dissolved in N, N-dimethylformamide di tert-butylacetal (4. 5 ml) and stirred at 70 ° C. for 1 hour. The low boiling point compound was distilled off under reduced pressure. The residue was purified by column chromatography (silica gel, hexane / ethyl acetate 20: 1) to give compound k (340 mg, 60%) as a pale yellow oily substance.

Physicochemical properties of compound k

Molecular weight 6 10

FAB-MS (positive mode, matrix m-NBA) (M + H ⁺ ) 611, (M + Na ⁺ ) 633

^ – NMR (chemical shift value in heavy chloroform) δ:

(2H, ABq, J = 15, 18 Hz), 2.93 (1 H, q, J = 6 Hz), 1.18 J = 7 Hz), 3.82-3.88 (2H, m), 3.92 (4H, s), 5.51-5.69 (2H, m)

1- 11 (Step 1 – 1 1)

Compound k (34 mg, 0. 556 mmol) was dissolved in tetrahydrofuran (1 ml), 80% acetic acid aqueous solution (10 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. The mixture was slowly added into a saturated aqueous solution of sodium bicarbonate to neutralize acetic acid and then extracted twice with ethyl acetate. Drying over anhydrous sodium sulfate, followed by filtration and concentration under reduced pressure to give compound t

(290 mg, 99%) as a pale yellow oil.

Physicochemical properties of compound f

Molecular weight 526

FAB – MS (positive mode, matrix m – NBA) (M + H ⁺ ) 527,

(M + Na ⁺ ) 549

Chemical shift value of iH-NMR (in heavy chloroform) δ:

(2H, Q
, 2.25-2.41 (5H, m), 1.99 (1H, d, J = 7 Hz), 2.04 (1H, d (1H, t, 7 Hz), 1.18- 1.68 (36H, ra), 2.01 J = 7 Hz), 5.58 (1 H, dt, J = 16, 6 Hz), 3.62 (3H, m), 3.99 (1H, s), 5.42

1-12 (Step 1 – 12)

Acetone (45 ml) was cooled to 0 ° C. and Jyones reagent (0.48 ml, 0.9 mmol, 1.8 9 N) was added. An acetone solution (3 ml) of the compound (216 mg, 0, 41) was slowly added dropwise to this mixture. Stirring at the same temperature for 1 hour

After stirring, the reaction was stopped by adding an aqueous sodium bisulfite solution until the yellow color of the reaction disappeared and a dark green precipitate appeared. A saturated saline solution (20 ml) was added thereto, and the mixture was extracted twice with dichloromethane, and the combined organic layer was dried over anhydrous sodium sulfate. The mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (dichloromethane monomethanol 50: 1 to 20: 1) to give compound m (198 mg, 89%) as a pale yellow oily substance.

Physicochemical properties of compound m

Molecular weight 541

ESI (L CZMS positive mode) (M + H ⁺ ) 542

Chemical shift value of ¹ H – NMR (in heavy mouth formium) δ:

J = 8 Hz), 2.70 (1 H, t, J = 6 Hz), 1.16 – 1.67 (36 H, m), 1.99 (2 H, J = 15, 5 Hz), 2.68 (1 H, d, J = 9 Hz), 3.28 )

1 – 13 (Step 1 – 13)

A solution of the compound m (6. 4 mg, 0.12 mmol), a solution of (S) -4- (2-butynyloxy) phenylalanine t-butyl ester hydrochloride (4.6 mg, 0.114 mmol) in N, N-dimethylformamide lml) was cooled to 110 ° C and N, N-diisopropylethylamine (0 ° 5 ml, 0.026 mmol), O- (7-azobenzotriazole 1- 1, N, N, N ‘, N’ – tetramethyluronium hexafluorophosphate (7.0 mg, 0.17 mmol) was added sequentially. The temperature was raised to room temperature with stirring and stirred overnight. An aqueous ammonium chloride solution was added to terminate the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed twice with water and then with saturated brine, and then dried over anhydrous sodium sulfate. After filtration and concentration under reduced pressure, the residue was purified by thin layer silica gel thin layer chromatography (hexane / ethyl acetate 7: 3) to obtain compound n

(8. 4 mg, 88%) as a colorless solid.

Physicochemical properties of compound n

^ – NMR (chemical shift value in heavy chloroform) δ:

J = 1.9 Hz), 1.90-2.03 (2H, m), 2.29 – 2.43 (4H, t, J = 6.9 Hz), 1 .12-1.68 (45H, m), 1.85 (3H, m), 4.22 (1 H, s), 4.57 – 4.74 (3H, d, J = 16.5 Hz) J = 8.6 Hz), 7.01 (1 H, d, J = 8.6 Hz), 5.46 (1 H, dd J = 9.2, 15.2 Hz), 5.64 (1 H, dt, J = 6.6, 15.2 Hz) 7.9 Hz), 7.13 (2H, d, J – 8.6 Hz)

1-14 (Step 1 – 14)

Dichloromethane solution (3 ml) of compound n (8.4 mg) was cooled to 0 ° C and anisanol (0.01 ml) and trifluoroacetic acid (1 ml) were sequentially added. Slowly warmed to room temperature and stirred overnight. After concentrating the reaction solution under reduced pressure and azeotropically twice with benzene, the residue was purified with megabond-1-butanediol (500 mg, Parian) (dichloromethane-methanol = 20: 1) to obtain Compound 21 (5. 3 mg, 80% As a colorless solid.

Physicochemical properties of compound 21 ‘

Molecular weight 643

ESI (LC / MS positive mode) 644 (M + H +)

Chemical shift value of ¹ H – NMR (in methanol d – 4) δ:

0.90 (3 H, t, J = 7 Hz), 1.19 – 1.38 (1 m), 1.42 – 1.60 (cm), 1.82 (3 H, t,

J = 2 Hz), 2.8 – 2.98 (2 H, m), 3.09 – 3.23 (2 H, m), 2.8 (2H, d, J = 9 Hz) 7 7.13 (2H, d, J = 9 Hz), 4.53 – 4.67 (3H, m), 5.39-5.61 (2H, m), 6.83

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US2010152457	Intermediate compound for synthesis of viridiofungin a derivative	2010-06-17
US8030496	Intermediate compound for synthesis of viridiofungin a derivative	2010-06-17	2011-10-04
US7897783	Intermediate compound for synthesis of viridiofungin a derivative	2008-11-27	2011-03-01

Patent ID	Patent Title	Submitted Date	Granted Date
US2011160252	PHARMACEUTICAL COMPOSITIONS FOR TREATMENT OR PREVENTION OF HBV INFECTION	2011-06-30
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References

Discovery of NA808: A novel host targeting anti-HCV agent
237th Am Chem Soc (ACS) Natl Meet (March 22-26, Salt Lake City) 2009, Abst MEDI 14

///////////////CH4630808, CH 4630808, NA 808

Viridiofungin A.png

Viridiofungin A

CCCCCCCC(=O)CCCCCCC=CC(C(=O)NC(CC1=CC=C(C=C1)O)C(=O)O)C(CC(=O)O)(C(=O)O)O

TITLE COMPD

O=C(O)[C@](O)(CC(=O)O)[C@H](\C=C\CCCCCCC(=O)CCCCCCC)C(=O)N[C@@H](Cc1ccc(OCC#CC)cc1)C(=O)O

BMS-986169

July 1, 2018 10:17 am / Leave a comment

BMS-986169

CAS 1801151-08-5 Related CAS : 1801151-09-6 1801151-08-5
Chemical Formula: C23H27FN2O2
Molecular Weight: 382.4794
Elemental Analysis: C, 72.23; H, 7.12; F, 4.97; N, 7.32; O, 8.37

(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

(3R)-3-[(3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl]-1-[(4-methylphenyl)methyl]pyrrolidin-2-one

Preclinical

BMS-986169 is a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate 2B Receptor Negative Allosteric Modulator with Potential in Major Depressive Disorder. BMS-986169 showed high binding affinity for the GluN2B subunit allosteric modulatory site (Ki = 4.03-6.3 nM) and selectively inhibited GluN2B receptor function in Xenopus oocytes expressing human N-methyl-d-aspartate receptor subtypes (IC50 = 24.1 nM). BMS-986169 weakly inhibited human ether-a-go-go-related gene channel activity (IC50 = 28.4 μM) and had negligible activity in an assay panel containing 40 additional pharmacological targets.

Chemical structures of BMS-986169 and the phosphate prodrug BMS-986163.

PAPER

Evolution of a Scale-Up Synthesis to a Potent GluN2B Inhibitor and Its Prodrug

James Kempson *^†

, Huiping Zhang^†, Michael K. Y. Wong^†, Jianqing Li^†

, Peng Li^†, Dauh-Rurng Wu^†, Richard Rampulla^†, Michael A. Galella^‡, Marta Dabros^‡, Sarah C. Traeger^†, Vetrichelvan Muthalagu^§, Anuradha Gupta^§, Pirama Nayagam Arunachalam^§, and Arvind Mathur^†

^† Discovery Chemistry and Molecular Technologies, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08540, United States

^‡ Drug Product Science & Technology, Materials Science & Engineering, Bristol-Myers Squibb Research and Development, Princeton, New Jersey 08540, United States

^§ Department of Discovery Synthesis, Biocon Bristol-Myers Squibb Research Center (BBRC), Bangalore 560099, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00120

*E-mail: james.kempson@bms.com.

This paper describes the efficient scale-up synthesis of the potent negative allosteric glutamate N2B (GluN2B) inhibitor 1 (BMS-986169), which relies upon a stereospecific S_N2 alkylation strategy and a robust process for the preparation of its phosphate prodrug 28 (BMS-986163) from parent 1 using POCl₃. A deoxyfluorination reaction employing bis(2-methoxyethyl)aminosulfur trifluoride (Deoxo-Fluor) is also used to stereospecifically introduce a fluorine substituent. The optimized routes have been demonstrated to provide APIs suitable for toxicological studies in vivo.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.8b00120/suppl_file/op8b00120_si_001.pdf

PAPER

https://pubs.acs.org/doi/abs/10.1021/acsmedchemlett.8b00080

BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder

Lawrence R. Marcin *^†

, ET AL

^† Bristol-Myers Squibb Research and Development, 5 Research Parkway, Wallingford, Connecticut 06492, United States

^‡ Biocon Bristol-Myers Squibb Research Center, Bangalore, India

^§ Bristol-Myers Squibb Research and Development, 3551 Lawrenceville Road, Princeton, New Jersey 08648, United States

ACS Med. Chem. Lett., 2018, 9 (5), pp 472–477

DOI: 10.1021/acsmedchemlett.8b00080

*Phone 203-677-6701. E-mail: lawrence.marcin@bms.com.

There is a significant unmet medical need for more efficacious and rapidly acting antidepressants. Toward this end, negative allosteric modulators of the N-methyl-d-aspartate receptor subtype GluN2B have demonstrated encouraging therapeutic potential. We report herein the discovery and preclinical profile of a water-soluble intravenous prodrug BMS-986163 (6) and its active parent molecule BMS-986169 (5), which demonstrated high binding affinity for the GluN2B allosteric site (K_i = 4.0 nM) and selective inhibition of GluN2B receptor function (IC₅₀ = 24 nM) in cells. The conversion of prodrug 6 to parent 5 was rapid in vitro and in vivo across preclinical species. After intravenous administration, compounds 5 and 6 have exhibited robust levels of ex vivo GluN2B target engagement in rodents and antidepressant-like activity in mice. No significant off-target activity was observed for 5, 6, or the major circulating metabolites met-1 and met-2. The prodrug BMS-986163 (6) has demonstrated an acceptable safety and toxicology profile and was selected as a preclinical candidate for further evaluation in major depressive disorder.

Image result for BMS-986169

(S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-
methylbenzyl)pyrrolidin-2-one (compound 23) and (R)-3-((3S,4S)-3-fluoro-4-(4-
hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (BMS-986169, compound
5)……https://pubs.acs.org/doi/suppl/10.1021/acsmedchemlett.8b00080/suppl_file/ml8b00080_si_001.pdf

Analytical data for BMS-986169 (compound 5): LCMS (C23H27FN2O2, MW 382.2, ESAPI),
observed 383.2 m/z (M+H)+; []D20 = +6.09 (c = 1.15, MeOH); Anal. Calcd for
C23H27FN2O2 (382.21): C, 72.22; H, 7.12; N, 7.32. Found: C, 72.26; H, 7.05; N, 7.31; HRMS
(ESI) Calcd for C23H27N2O2, 383.2118. Found, 383.2129;

13C NMR (126 MHz, chloroformd)
172.4, 155.0, 137.5, 133.0, 132.8, 129.4, 128.6, 128.2, 115.6, 91.6 (d, J=173.5 Hz),
65.0, 54.5 (d, J=25.4 Hz), 48.3, 47.7 (d, J=17.3 Hz), 46.7, 43.6, 31.5, 21.1, 19.2;(500 MHz, chloroform-d) 7.23 – 7.11 (m, 5H), 6.92 (d, J=8.5 Hz, 2H), 6.18 (br. s., 1H),
4.79 – 4.55 (m, 1H), 4.57 – 4.33 (m, 2H), 3.72 (t, J=8.7 Hz, 1H), 3.46 – 3.30 (m, 1H), 3.30 –
3.09 (m, 2H), 2.82 (d, J=8.5 Hz, 1H), 2.73 – 2.56 (m, 2H), 2.49 (d, J=2.5 Hz, 1H), 2.36 (s,
3H), 2.21 – 1.98 (m, 2H), 1.87 (br. s., 2H). The corresponding 1H NMR spectrum for
compound 5 is shown below

1H NMR

PATENT

https://patents.google.com/patent/US9221796B2/und

InventorDalton King Lorin A. Thompson, III Jianliang Shi Srinivasan Thangathirupathy Jayakumar Sankara Warrier Imadul Islam John E. Macor

Current Assignee Bristol-Myers Squibb Co

https://patents.google.com/patent/WO2015105772A1/und

N-Methyl-D-aspartate (NMDA) receptors are ion channels which are gated by the binding of glutamate, an excitatory neurotransmitter in the central nervous system. They are thought to play a key role in the development of a number of neurological diseases, including depression, neuropathic pain, Alzheimer’s disease, and Parkinson’s disease. Functional NMDA receptors are tetrameric structures primarily composed of two NRl and two NR2 subunits. The NR2 subunit is further subdivided into four individual subtypes: NR2A, NR2B, NR2C, and NR2D, which are differentially distributed throughout the brain. Antagonists or allosteric modulators of NMDA receptors, in particular NR2B subunit-containing channels, have been investigated as therapeutic agents for the treatment of major depressive disorder (G. Sanacora, 2008, Nature Rev. Drug Disc. 7: 426-437).

The NR2B receptor contains additional ligand binding sites in additon to that for glutamate. Non-selective NMDA antagonists such as Ketamine are pore blockers, interfering with the transport of Ca⁺⁺ through the channel. Ketamine has demonstrated rapid and enduring antidepressant properties in human clinical trials as an i.v. drug. Additionally, efficacy was maintained with repeated, intermittent infusions of Ketamine (Zarate et al., 2006, Arch. Gen. Psychiatry 63: 856-864). This class of drugs, though, has limited therapeutic value because of its CNS side effects, including dissociative effects.

An allosteric, non-competitive binding site has also been identified in the N-terminal domain of NR2B. Agents which bind selectively at this site, such as

Traxoprodil, exhibited a sustained antidepressant response and improved side effect profile in human clinical trials as an i.v. drug (Preskorn et al., 2008, J. Clin.

PsychopharmacoL, 28: 631-637, and F. S. Menniti, et al, 1998, CNS Drug Reviews, 4, 4, 307-322). However, development of drugs from this class has been hindered by low bioavailability, poor pharmacokinetics, and lack of selectivity against other pharmacological targets including the hERG ion channel. Blockade of the hERG ion channel can lead to cardiac arrythmias, including the potentially fatal Torsades de pointe, thus selectivity against this channel is critical. Thus, in the treatment of major depressive disorder, there remains an unmet clinical need for the development of effective NR2B-selective negative allosteric modulators which have a favorable tolerability profile.

NR2B receptor antagonists have been disclosed in PCT publication WO 2009/006437.

The invention provides technical advantages, for example, the compounds are novel and are ligands for the NR2B receptor and may be useful for the treatment of various disorders of the central nervous system. Additionally, the compounds provide advantages for pharmaceutical uses, for example, with regard to one or more of their mechanism of action, binding, inhibition efficacy, target selectivity, solubility, safety profiles, or bioavailability.

Synthetic Scheme 1

The l-phenyl/benzyl-3-bromo-pyrrolidinones/piperidinones V may be reacted with (4-oxy-phenyl)cyclic amines VI in the presence of base to produce protected products VII, which may be subjected to cleavage conditions appropriate for the protecting group (PGi) to generate final products I, which may be separated into individual enantiomers/diastereomers I*, as shown in synthetic scheme 2.

Synthetic Scheme 2

I I*

Compounds la may be prepared by condensing l-phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with substituted 4(4-oxyphenyl)piperidines Vllla-c to generate protected intermediates IX, which may be subjected to cleavage conditions appropriate for the protecting group (PGi) to generate final products la, which may be separated into individual enantiomers/diastereomers la*, as shown in synthetic scheme 3.

Synthetic Scheme 3

The 4(4-oxyphenyl)piperidines Vllla-c may be synthesized in turn by a sequence starting with a protected tetrahydropiperidine X, which can be hydroxylated via hydroboration/oxidation to give the protected hydroxypiperidine XI, which may be either directly transformed into the protected fluoropiperidine XII by treatment with DAST or oxidized into the protected 3-oxopiperidine XIII, which may be further transformed into protected 3,3-difluoropiperidines XIV via treatment with DAST. XI, XII, and XIV may be transformed into Villa, Vlllb, and VIIIc, respectively, by employing cleaving conditions appropriate for the protecting group (PG₂), as shown in synthetic scheme 3 a.

S nthetic scheme 3 a

Chiral

Cleavage Individual enantiomers/

G₂P-N diastereomers

separation

conditions

OH
Villa*

Villa

Chiral

Cleavage Individual enantiomers/

G₂P-N diastereomers

%_\J> PQ separation

PG₁ conditions

R F

F Vlllb*

Vlllb

XII

Chiral

Individual enantiomers/

G₂P- diastereomers separation

Vlllc*

For tetrahydropyridines X which are not commercially available may be synthesized by coupling protected bromophenols XV with protected unsaturated

piperidineboronic acids XVI, as shown in synthetic scheme 4a.

Synthetic scheme 4a:

For tetrahydropyridines X which are not commercially available may be synthesized by adding the anion generated from protected bromophenols XV to a protected 4-piperidinone XVII to yield 4-phenyl-4-piperidinol XVIII, which may be dehydrated under acid conditions to yield the desired X, as shown in synthetic scheme 4b.

Synthetic scheme 4b:

l-Phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V may be condensed with isolated individual enantiomers VIIIa-c*, which results in diastereomers 1- phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones IX*, which may be deprotected and separated to give final products la*, as shown in scheme 5.

Alternatively, the backbone scaffold may be synthesized by condensing 1- phenyl/benzyl-3-bromo-pyrroli-dinones/piperidinones V with hydroxypiperidines Villa to yield the protected 3-fluoropiperidines IXa, which may themselves be converted to the protected 3-fluoropiperidines IXb or oxidized to the ketones XIX, which may be converted to the 3,3-difluoropiperidines Ixc, as shown in scheme 6. The final compounds can then be isolated after the deprotection of IXa-c.

Scheme 6

Example 46, P-1 Example 46, P-2

(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one.

Example 46, P-3 Example 46, P-4

Step A. (±)-rel-(3S,4S)- 1 -benzyl-4-(4-methoxyphenyl)piperidin-3-ol.

To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200 mL) at 0 °C under a nitrogen atmosphere was added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture was stirred for 30 minutes. Then 1-benzyl- 4-(4-methoxyphenyl)-l,2,3,6-tetrahydropyridine (10 g, 36 mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was then quenched by the dropwise addition of 100 mL of water. Next were added

sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30%> hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL). The organic layer was dried over Na₂S0₄, filtered, and evaporated under reduced pressure to give (±)-rel-(3S,4S)- 1 -benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69%> yield) which was used without further purification. LCMS (Method K) RT 1.99 min; m/z 298.0 (M+H⁺).

Step B. (±)-re -(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol.

To a solution of (±)-re/-(35′,45)-l-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in methanol (150 mL) was added 10 % Pd/C (4.8 g) and the reaction mixture was stirred overnight under a hydrogen atmosphere. The catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (±)-re/-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield) which was used without further purification. 1H NMR (400 MHz, DMSO-de) δ ppm 7.10 – 7.15 (m, 2 H) 6.80 – 6.86 (m, 2 H) 4.30 (d, J=5.27 Hz, 1 H) 3.37 – 3.43 (m, 1 H) 3.04 (dd, J=11.58, 4.36 Hz, 1 H) 2.86 (d, J=12.17 Hz, 1 H) 2.43 (td, J=12.09, 2.67 Hz, 1 H) 2.22 – 2.35 (m, 2 H) 1.57 – 1.63 (m, 1 H) 1.43 – 1.54 (m, 1 H).

To a solution of (±)-re/-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5 g, 21.7 mmol) in DCM (150 mL) at -10°C under nitrogen was added a 1 M solution of boron tribromide in DCM (109 mL, 109 mmol). The reaction mixture was allowed to warm to rt, stired for 2 h, and then rechilled to 0 °C and quenched by the addition of a saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was washed with 250 mL of DCM and then to it was added 200 mL 10% aqueous NaOH, followed by 9.5 g (43.5 mmol) of di-t-butyl dicarbonate and the resulting mixture was stirred for an additional 2 h. The mixture was then extracted with 200 mL ethyl acetate and the organic layer was separated, dried over Na₂S0₄,filtered, and evaporated under reduced pressure to (±)-re/-(35′,45)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate (6.5 g, 12 mmol, 56 % yield) which was used without further purification. LCMS (Method K) RT 2.33 min, m/z 282 (M+H⁺ -2 t-butyl), 370; 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.27 (d, J=8.66 Hz, 2 H) 7.08 (d, J=8.66 Hz, 2 H) 4.85 (d, J=5.65 Hz, 1 H) 4.13 (d, J=8.41 Hz, 1 H) 3.97 (d, J=10.48 Hz, 1 H) 3.45 (tt, J=10.27, 5.19 Hz, 1 H) 1.67 (d, J=3.39 Hz, 1 H) 1.50 – 1.59 (m, 1 H) 1.49 (s, 11 H).

Step D. (±)-re/-(35′,45)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate.

To a solution of (±)-re/-(35′,45)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate (6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassium carbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h. The organic solvent was removed under reduced pressure and the residue was partitioned between IN HC1 (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was dried over Na₂S0₄ and evaporated under reduced pressure to give (±)-re/-(35′,45)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (5 g, 15 mmol, 92 % yield) which was used without further purification. LCMS (method F) RT 1.85 min, m/z 238 (M+H⁺ – 1-butyl), 279 (M+H⁺ – t-butyl+CH₃CN), 1H NMR (400 MHz, DMSO-d₆) δ ppm 7.01 (d, J=8.53 Hz, 2 H) 6.66 (d, J=8.53 Hz, 2 H) 4.70 (d, J=5.02 Hz, 1 H) 4.09 (br. s., 1 H) 3.94 (d, J=11.55 Hz, 1 H) 3.35 – 3.41 (m, 1 H) 2.66 – 2.77 (m, 1 H) 2.29 – 2.39 (m, 1 H) 1.63 (dd, J=13.30, 3.26 Hz, 1 H) 1.44 – 1.52 (m, 1 H) 1.42 (s, 9 H).

Step E. (3S,4S)-tert-Butyl 3 -hydroxy-4-(4-hydroxyphenyl)piperidine-l -carboxylate and (3R, -tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate.

E-1 E-2

(±)-rel-(3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine- 1 -carboxylate (5 g, 17 mmol, from step D) was subjected to chiral SFC separation (method C-5) to yield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0 % yield) and E-2 (2.4 g, 8.18 mmol, 48.0 % yield). Data for E-1 : chiral HPLC (method A5 ) retention time 3.42 min. Data for E-2: chiral HPLC (method A5) retention time 4.2 min.

Step F. (3R,4R)-tert-Butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-l-carboxylate.

A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydous Na₂S0₄, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-l -carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z = 310 (M+H⁺ – t-butyl -water), 328 (M+H⁺ -t-butyl).

Step G. (3i?,4i?)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride.

A mixture of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCI in dioxane was stirred at rt for 2h. The reaction was then evaporated to dryness to yield 550 mg of (3i?,4i?)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which was used without further purification. LCMS (method J) RT 0.70 min, m/z 284 (M+H⁺).

Step H. 3-((3i?,4i?)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-l -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one .

A mixture of 3-bromo-l-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3i?,4i?)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60 °C for lh, 80 °C for 1 h, 100 °C for 1 h and 120 °C for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3 ?,4i?)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H⁺).

Step I. 3-((3R, 4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one .

A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0 °C was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3i?,4i?)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H⁺).

Step J. 3-((3i?,4i?)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)-l -(4-methylbenzyl)pyrrolidin-2-one .

A mixture of 3-((Ji?,4i?)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen, followed by the addition of 172 mg of 10% Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi hydrogen pressure. The reaction was then transferred to a 100 mL autoclave and stirred at 7 kg/cm² hydrogen pressure for 4 days. The catalyst was removed by filtration through Celite and the solvent was evaporated off. The crude product was subjected to HPLC purification (method B) to yield 77.3 mg 3-((Ji?,4i?)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H⁺).

Step K. (5)-3-((3i?,4i?)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl>

methylbenzyl)pyrrolidin-2-one and (i?)-3-((3i?,4i?)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.

The diastereomeric mixture from step J was separated by SFC method C-7 to yield homochiral Examples 46 P-l (29.3 mg) and P-2 (32.8 mg). Data for P-l (S)-3-((3R, 4R)-3 -fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H⁺), 405.2 (M+Na⁺); HPLC (method B) RT 8.24 min (98.8% AP); HPLC (method C) RT 6.52 min (99.1% AP); Chiral HPLC (method C-6) RT 4.1 min; 1H NMR (400 MHz, methanol-d₄) δ ppm 1.76 – 1.86 (m, 2 H) 2.07 (d, J=8.53 Hz, 1 H) 2.13 – 2.21 (m, 1 H) 2.34 (s, 3 H) 2.43 (s, 0 H) 2.55 – 2.60 (m, 1 H) 2.65 – 2.70 (m, 1 H) 2.75 (br. s., 1 H) 3.20 – 3.30 (m, 2 H) 3.38 – 3.45 (m, 1 H) 3.70 (t, J=8.78 Hz, 1 H) 4.44 (t, J=79.81 Hz, 3 H) 4.63 – 4.71 (m, 1 H) 6.70 – 6.80 (m, 2 H) 7.07 – 7.15 (m, 2 H) 7.07 – 7.12 (m, 1 H) 7.13 – 7.22 (m, 4 H); ¹⁹F NMR δ ppm -184.171. Data for P-2: (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H⁺), 405.2 (M+Na⁺); HPLC (method B) RT 8.29 min (99.7% AP); HPLC (method C) RT 6.52 min (99.8% AP); Chiral HPLC (method C-6) RT 6.92 min; 1H NMR (400 MHz, methanol-d₄) δ ppm 1.80 – 1.90 (m, 2 H) 2.07 (d, J=8.03 Hz, 1 H) 2.19 (s, 1 H) 2.34 (s, 3 H) 2.41 – 2.48 (m, 1 H) 2.66 (d, J=4.52 Hz, 2 H) 2.95 – 3.03 (m, 1 H) 3.10 – 3.18 (m, 1 H) 3.20 – 3.30 (m, 2 H) 3.68 – 3.78 (m, 1 H) 4.38 (s, 1 H) 4.51 (d, J=14.56 Hz, 2 H) 6.70 – 6.80 (m, 2 H) 7.05 – 7.13 (m, 2 H) 7.13 – 7.22 (m, 4 H); ¹⁹F NMR δ ppm -184.311.

(3S,4S)-tert-Butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-carboxylate.

To a solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-l-carboxylate (400 mg, 1.36 mmol, the first eluting enantiomer E-l from step E) in DCM (5 mL) cooled to 0 °C was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. The mixture was allowed to warm up to rt and was stirred for 2h. The reaction was slowly quenched with 50 mL of a 10%> aqueous sodium bicarbonate solution and extracted four times with 50 mL of DCM. The combined organic layerss were washed with 75 mL of brine, dried, and concentrated under vacuum to yield 390 mg of {3S,4S)-tert-bvXy\ 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-

carboxylate which was used without further purification. LCMS (Method Q) RT 0.92 min, m z 240.1(M+H⁺).

Step M. 4-((3S’,4S)-3-Fluoropi ridin-4-yl)phenol hydrochloride.

A mixture of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-l-carboxylate (390 mg, 1.3 mmol) and 4M HC1 in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL) was stirred at rt for 2 hr. It was then concentrated to dryness, washed with 10 mL of 5% DCM/diethyl ether mixture and the solid was isolated by filtration. Yield: 260 mg of 4-((J£4S)-3-fluoropiperidin-4-yl)phenol hydrochloride; LCMS

(method Q) RT 0.46 min, mz 196.1(M+H⁺) 1H NMR (400 MHz, DMSO-d₆) δ = 9.57 (br. s., 4 H), 8.92 – 8.68 (m, 1 H), 7.14 (d, J= 8.5 Hz, 1 H), 7.06 (d, J= 8.5 Hz, 2 H), 6.82 – 6.73 (m, 2 H), 5.07 – 4.85 (m, 1 H), 3.77 – 3.36 (m, 9 H), 3.32 – 3.22 (m, 2 H), 3.13 – 2.85 (m, 5 H), 2.06 – 1.88 (m, H).

Step N. 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.

A mixture of 3-bromo-l-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75 mmol) in DMF (3 mL) was heated to 120 °C in a microwave reactor for 1.5 h. The mixture was allowed to cool and was then mixed with 60 mL water and extracted 5 times with 40 mL of DCM. The combined organic extracts were washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 265 mg of 3-((3 4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z 383.4 (M+H⁺).

Step O. (5)-3-((3_lS,45)-3-Fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one and (i?)-3-((35^,,45)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one.

A portion of the diasteromer mixture from step N (130 mg) was subjected to chiral purification via SFC (method C-7) to give homochiral Examples 46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for P-3 (S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin- 1 -yl)- 1 -(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT = 2.10 min, m/z 383.2 (M+H⁺); HPLC (Method C) RT 6.54 min, (Method D) RT 8.20 min; chiral HPLC (method C-6) RT 3.42 min;1H NMR (400 MHz, methanol-d₄) δ ppm 1.76 – 1.86 (m, 2 H) 2.06 (d, J=8.53 Hz, 1 H) 2.10 – 2.21 (m, 1 H) 2.34 (s, 3 H) 2.40 – 2.48 (m, 1 H) 2.53 – 2.60 (m, 1 H) 2.61 – 2.70 (m, 2 H) 2.95 -3.01 (m, 1 H) 3.01 (s, 2 H) 3.10 – 3.16 (m, 1 H) 3.18 – 3.28 (m, 2 H) 3.72 (s, 1 H) 4.35 – 4.41 (m, 1 H) 4.46 – 4.70 (m, 2 H) 6.72 – 6.80 (m, 2 H) 7.05 – 7.23 (m, 6 H). Data for P-4 (R)-3-((3S,4S)-3-fiuoro-4-(4-hydroxyphenyl)piperidin-l-yl)-l-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT 2.11 min, m/z 383.2 (M+H⁺);; HPLC (Method C) RT 6.50 min, (Method D) RT 8.21 min; chiral HPLC (method C-6) RT 6.31 min; 1H NMR (400 MHz, methanol-d₄) δ ppm 1.81 (dd, J=7.28, 2.76 Hz, 2 H) 2.06 (d, J=9.04 Hz, 2 H) 2.33 (s, 3 H) 2.43 (s, 1 H) 2.55 (br s, 1 H) 2.66 (d, J=40.16 Hz, 2 H) 2.75 – 2.80 (m, 1 H) 2.96 – 3.10 (m, 2 H) 3.20 – 3.28 (m, 2 H) 3.41 (d, J=5.52 Hz, 1 H) 3.66 – 3.75 (m, 1 H) 4.31 – 4.41 (m, 1 H) 4.46 – 4.71 (m, 2 H) 6.76 (d, J=8.53 Hz, 2 H) 7.05 – 7.23 (m, 6 H).

PATENT

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Example 46 (Peak-1, Peak-2, Peak-3, Peak-4)

(S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

(S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

Step A. (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol

(MOL) (CDX)

To a suspension of sodium tetrahydroborate (2.7 g, 72 mmol) in THF (200 mL) at 0° C. under a nitrogen atmosphere was added dropwise boron trifluoride etherate (8.8 mL, 70 mmol) and the resulting mixture was stirred for 30 minutes. Then 1-benzyl-4-(4-methoxyphenyl)-1,2,3,6-tetrahydropyridine (10 g, 36 mmol, from S. Halazy et al WO 97/28140 (8/7/97)) dissolved in 100 mL of tetrahydrofuran was added. The mixture was allowed to warm to rt and stirred for 2 h. The reaction was then quenched by the dropwise addition of 100 mL of water. Next were added sequentially 100 mL of ethanol, 100 mL of a 10% aqueous sodium hydroxide solution, and 30% hydrogen peroxide (18 mL, 180 mmol) and the mixture was stirred at reflux temperature overnight. The reaction mixture was then allowed to cool, diluted with saturated aqueous ammonium chloride (200 mL), and extracted with ethyl acetate (500 mL). The organic layer was dried over Na₂SO₄, filtered, and evaporated under reduced pressure to give (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (8.5 g, 24.6 mmol, 69% yield) which was used without further purification. LCMS (Method K) RT 1.99 min; m/z 298.0 (M+H⁺).

Step B. (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol

To a solution of (±)-rel-(3S,4S)-1-benzyl-4-(4-methoxyphenyl)piperidin-3-ol (9 g, 30 mmol) in methanol (150 mL) was added 10% Pd/C (4.8 g) and the reaction mixture was stirred overnight under a hydrogen atmosphere. The catalyst was then removed by filtration through Celite and the solvent was evaporated under reduced pressure to give (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (5.1 g, 24.6 mmol, 81% yield) which was used without further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.10-7.15 (m, 2H) 6.80-6.86 (m, 2H) 4.30 (d, J=5.27 Hz, 1H) 3.37-3.43 (m, 1H) 3.04 (dd, J=11.58, 4.36 Hz, 1H) 2.86 (d, J=12.17 Hz, 1H) 2.43 (td, J=12.09, 2.67 Hz, 1H) 2.22-2.35 (m, 2H) 1.57-1.63 (m, 1H) 1.43-1.54 (m, 1H).

Step C. (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate

(

To a solution of (±)-rel-(3S,4S)-4-(4-methoxyphenyl)piperidin-3-ol (4.5 g, 21.7 mmol) in DCM (150 mL) at −10° C. under nitrogen was added a 1 M solution of boron tribromide in DCM (109 mL, 109 mmol). The reaction mixture was allowed to warm to rt, stirred for 2 h, and then rechilled to 0° C. and quenched by the addition of a saturated aqueous sodium bicarbonate solution (300 mL). The aqueous layer was washed with 250 mL of DCM and then to it was added 200 mL 10% aqueous NaOH, followed by 9.5 g (43.5 mmol) of di-t-butyl dicarbonate and the resulting mixture was stirred for an additional 2 h. The mixture was then extracted with 200 mL ethyl acetate and the organic layer was separated, dried over Na₂SO₄, filtered, and evaporated under reduced pressure to (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (6.5 g, 12 mmol, 56% yield) which was used without further purification. LCMS (Method K) RT 2.33 min, m/z 282 (M+H⁺-2 t-butyl), 370; ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.27 (d, J=8.66 Hz, 2H) 7.08 (d, J=8.66 Hz, 2H) 4.85 (d, J=5.65 Hz, 1H) 4.13 (d, J=8.41 Hz, 1H) 3.97 (d, J=10.48 Hz, 1H) 3.45 (tt, J=10.27, 5.19 Hz, 1H) 1.67 (d, J=3.39 Hz, 1H) 1.50-1.59 (m, 1H) 1.49 (s, 11H).

Step D. (±)-rel-(3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate

To a solution of (±)-rel-(3S,4S)-tert-butyl 4-(4-(tert-butoxycarbonyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (6.5 g, 16.5 mmol) in 100 mL of methanol was added 11.42 g of potassium carbonate (83 mmol) and the reaction mixture was stirred at rt for 5 h. The organic solvent was removed under reduced pressure and the residue was partitioned between 1N HCl (300 mL) and ethyl acetate (300 mL). The layers were separated and the organic layer was dried over Na₂SO₄and evaporated under reduced pressure to give (±)-rel-(3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 15 mmol, 92% yield) which was used without further purification. LCMS (method F) RT 1.85 min, m/z 238 (M+H⁺-t-butyl), 279 (M+H⁺-t-butyl+CH₃CN), ¹H NMR (400 MHz, DMSO-d₆) δ ppm 7.01 (d, J=8.53 Hz, 2H) 6.66 (d, J=8.53 Hz, 2H) 4.70 (d, J=5.02 Hz, 1H) 4.09 (br. s., 1H) 3.94 (d, J=11.55 Hz, 1H) 3.35-3.41 (m, 1H) 2.66-2.77 (m, 1H) 2.29-2.39 (m, 1H) 1.63 (dd, J=13.30, 3.26 Hz, 1H) 1.44-1.52 (m, 1H) 1.42 (s, 9H).

Step E. (3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate and (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate

(±)-rel-(3S,4S)-tert-Butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (5 g, 17 mmol, from step D) was subjected to chiral SFC separation (method C-5) to yield enantiomers E-1 (1.9 g, 6.48 mmol, 38.0% yield) and E-2 (2.4 g, 8.18 mmol, 48.0% yield). Data for E-1: chiral HPLC (method A5) retention time 3.42 min. Data for E-2: chiral HPLC (method A5) retention time 4.2 min.

Step F. (3R,4R)-tert-Butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate

A mixture of (3R,4R)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (620 mg, 2.1 mmol, E-2 from step E), potassium carbonate (584 mg, 4.2 mmol), and benzyl bromide (0.25 mL, 2.1 mmol) in DMF (5 mL) was stirred at rt for 16 h. The solvent was removed by evaporation and the residue was treated with 50 mL of water. The aqueous mixture was then extracted 4 times with 50 mL of chloroform. The combined organic phases were dried over anhydrous Na₂SO₄, filtered, and evaporated to yield 750 mg of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate which was used without further purification. LCMS (method F) RT 2.28 min, m/z=310 (M+H⁺-t-butyl -water), 328 (M+H⁺-t-butyl).

Step G. (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride

A mixture of (3R,4R)-tert-butyl 4-(4-(benzyloxy)phenyl)-3-hydroxypiperidine-1-carboxylate (750 mg, 2 mmol), dioxane (4 mL) and 4.9 mL of 4 M HCl in dioxane was stirred at rt for 2 h. The reaction was then evaporated to dryness to yield 550 mg of (3R,4R)-4-(4-(Benzyloxy)phenyl)piperidin-3-ol hydrochloride which was used without further purification. LCMS (method J) RT 0.70 min, m/z 284 (M+H⁺).

Step H. 3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (Intermediate 2, 220 mg, 0.82 mmol), (3R,4R)-4-(4-(benzyloxy)phenyl)piperidin-3-ol hydrochloride (262 mg, 0.82 mmol, from step G) and triethylamine (11 mL, 8.2 mmol) was stirred at 60° C. for 1 h, 80° C. for 1 h, 100° C. for 1 h and 120° C. for 1 h. The reaction mixture was then allowed to cool, diluted with 40 mL of water and extracted four times with 50 mL of chloroform. The combined organic layers were washed with 60 mL brine, dried over anhydrous sodium sulfate, filtered, and evaporated to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one which was used without further purification. LCMS (method J) (main component of a mixture) RT 2.23 min, m/z 471 (M+H⁺).

Step I. 3-((3R,4R)-4-(4-(Benzyloxy)phenyl)-3-fluoropiperidin-1l-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A solution of 3-(-4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) in DCM (5 mL) cooled to 0° C. was treated dropwise with DAST (0.32 mL, 2.4 mmol) over 3 min. The reaction mixture was then allowed to warm to rt and was stirred for 2 h. The reaction was then quenched with 50 mL of 10% aqueous sodium bicarbonate solution and extracted 4 times with 40 mL of DCM. The combined organic layers were washed with 50 mL of brine, dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum to yield 382 mg of 3-((3R,4R)-4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of two diastereomers and rearrangement products which was used without further purification. LCMS (method J) (main component of a mixture) RT 0.9 min, m/z 473 (M+H⁺).

Step J. 3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 3-((3R,4R)-(4-(4-(benzyloxy)phenyl)-3-fluoropiperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (382 mg, 0.81 mmol) and methanol (4 mL) was flushed with nitrogen, followed by the addition of 172 mg of 10% Pd/C. Then the mixture was stirred at rt overnight under 25-99 psi hydrogen pressure. The reaction was then transferred to a 100 mL autoclave and stirred at 7 kg/cm²hydrogen pressure for 4 days. The catalyst was removed by filtration through Celite and the solvent was evaporated off. The crude product was subjected to HPLC purification (method B) to yield 77.3 mg 3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)-piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one (diastereomeric pair) LCMS (method Q) RT 1.15 min, m/z 383.0 (M+H⁺).

Step K. (S)-3-((3R,4R)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

The diastereomeric mixture from step J was separated by SFC method C-7 to yield homochiral Examples 46 P-1 (29.3 mg) and P-2 (32.8 mg). Data for P-1 (S)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H⁺), 405.2 (M+Na⁺); HPLC (method B) RT 8.24 min (98.8% AP); HPLC (method C) RT 6.52 min (99.1% AP); Chiral HPLC (method C-6) RT 4.1 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.76-1.86 (m, 2H) 2.07 (d, J=8.53 Hz, 1H) 2.13-2.21 (m, 1H) 2.34 (s, 3H) 2.43 (s, 0H) 2.55-2.60 (m, 1H) 2.65-2.70 (m, 1H) 2.75 (br. s., 1H) 3.20-3.30 (m, 2H) 3.38-3.45 (m, 1H) 3.70 (t, J=8.78 Hz, 1H) 4.44 (t, J=79.81 Hz, 3H) 4.63-4.71 (m, 1H) 6.70-6.80 (m, 2H) 7.07-7.15 (m, 2H) 7.07-7.12 (m, 1H) 7.13-7.22 (m, 4H); ¹⁹F NMR δ ppm −184.171. Data for P-2: (R)-3-((3R,4R)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (method F) RT 2.10 min, m/z 383.2 (M+H⁺), 405.2 (M+Na⁺); HPLC (method B) RT 8.29 min (99.7% AP); HPLC (method C) RT 6.52 min (99.8% AP); Chiral HPLC (method C-6) RT 6.92 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.80-1.90 (m, 2H) 2.07 (d, J=8.03 Hz, 1H) 2.19 (s, 1H) 2.34 (s, 3H) 2.41-2.48 (m, 1H) 2.66 (d, J=4.52 Hz, 2H) 2.95-3.03 (m, 1H) 3.10-3.18 (m, 1H) 3.20-3.30 (m, 2H) 3.68-3.78 (m, 1H) 4.38 (s, 1H) 4.51 (d, J=14.56 Hz, 2H) 6.70-6.80 (m, 2H) 7.05-7.13 (m, 2H) 7.13-7.22 (m, 4H); ¹⁹F NMR δ ppm −184.311.

Step L. (3S,4S)-tert-Butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate

To a solution of (3S,4S)-tert-butyl 3-hydroxy-4-(4-hydroxyphenyl)piperidine-1-carboxylate (400 mg, 1.36 mmol, the first eluting enantiomer E-1 from step E) in DCM (5 mL) cooled to 0° C. was added dropwise DAST (0.54 mL, 4.1 mmol) over 10 min. The mixture was allowed to warm up to rt and was stirred for 2 h. The reaction was slowly quenched with 50 mL of a 10% aqueous sodium bicarbonate solution and extracted four times with 50 mL of DCM. The combined organic layers were washed with 75 mL of brine, dried, and concentrated under vacuum to yield 390 mg of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate which was used without further purification. LCMS (Method Q) RT 0.92 min, m/z 240.1 (M+H⁺).

Step M. 4-((3S,4S)-3-Fluoropiperidin-4-yl)phenol hydrochloride

A mixture of (3S,4S)-tert-butyl 3-fluoro-4-(4-hydroxyphenyl)piperidine-1-carboxylate (390 mg, 1.3 mmol) and 4M HCl in dioxane (3.3 mL, 13.2 mmol) in dioxane (4 mL) was stirred at rt for 2 hr. It was then concentrated to dryness, washed with 10 mL of 5% DCM/diethyl ether mixture and the solid was isolated by filtration. Yield: 260 mg of 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride; LCMS (method Q) RT 0.46 min, mz 196.1 (M+H⁺)¹H NMR (400 MHz, DMSO-d₆) δ=9.57 (br. s., 4H), 8.92-8.68 (m, 1H), 7.14 (d, J=8.5 Hz, 1H), 7.06 (d, J=8.5 Hz, 2H), 6.82-6.73 (m, 2H), 5.07-4.85 (m, 1H), 3.77-3.36 (m, 9H), 3.32-3.22 (m, 2H), 3.13-2.85 (m, 5H), 2.06-1.88 (m, H).

Step N. 3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A mixture of 3-bromo-1-(4-methylbenzyl)pyrrolidin-2-one (200 mg, 0.75 mmol), triethylamine (0.52 mL, 3.7 mmol) and 4-((3S,4S)-3-fluoropiperidin-4-yl)phenol hydrochloride (173 mg, 0.75 mmol) in DMF (3 mL) was heated to 120° C. in a microwave reactor for 1.5 h. The mixture was allowed to cool and was then mixed with 60 mL water and extracted 5 times with 40 mL of DCM. The combined organic extracts were washed with 80 mL of brine, dried over anhydrous sodium sulfate, filtered, and evaporated to give 265 mg of 3-((3S,4S)-3-fluoro-4-(4-hydroxy-phenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one as a mixture of 2 diastereoisomers. LCMS (method P) RT 0.92 min m/z 383.4 (M+H⁺).

Step O. (S)-3-((3S,4S)-3-Fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one and (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one

A portion of the diastereomer mixture from step N (130 mg) was subjected to chiral purification via SFC (method C-7) to give homochiral Examples 46 P-3 (37.7 mg) and P-4 (60.7 mg). Data for P-3 (S)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT=2.10 min, m/z 383.2 (M+H⁺); HPLC (Method C) RT 6.54 min, (Method D) RT 8.20 min; chiral HPLC (method C-6) RT 3.42 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.76-1.86 (m, 2H) 2.06 (d, J=8.53 Hz, 1H) 2.10-2.21 (m, 1H) 2.34 (s, 3H) 2.40-2.48 (m, 1H) 2.53-2.60 (m, 1H) 2.61-2.70 (m, 2H) 2.95-3.01 (m, 1H) 3.01 (s, 2H) 3.10-3.16 (m, 1H) 3.18-3.28 (m, 2H) 3.72 (s, 1H) 4.35-4.41 (m, 1H) 4.46-4.70 (m, 2H) 6.72-6.80 (m, 2H) 7.05-7.23 (m, 6H). Data for P-4 (R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrrolidin-2-one: LCMS (Method F) RT 2.11 min, m/z 383.2 (M+H⁺); HPLC (Method C) RT 6.50 min, (Method D) RT 8.21 min; chiral HPLC (method C-6) RT 6.31 min; ¹H NMR (400 MHz, methanol-d₄) δ ppm 1.81 (dd, J=7.28, 2.76 Hz, 2H) 2.06 (d, J=9.04 Hz, 2H) 2.33 (s, 3H) 2.43 (s, 1H) 2.55 (br s, 1H) 2.66 (d, J=40.16 Hz, 2H) 2.75-2.80 (m, 1H) 2.96-3.10 (m, 2H) 3.20-3.28 (m, 2H) 3.41 (d, J=5.52 Hz, 1H) 3.66-3.75 (m, 1H) 4.31-4.41 (m, 1H) 4.46-4.71 (m, 2H) 6.76 (d, J=8.53 Hz, 2H) 7.05-7.23 (m, 6H).

ADDITIONAL INFORMATION

Intravenous administration of BMS-986169 or BMS-986163 dose-dependently increased GluN2B receptor occupancy and inhibited in vivo [3H](+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]MK-801) binding, confirming target engagement and effective cleavage of the prodrug. BMS-986169 reduced immobility in the mouse forced swim test, an effect similar to intravenous ketamine treatment. Decreased novelty suppressed feeding latency, and increased ex vivo hippocampal long-term potentiation was also seen 24 hours after acute BMS-986163 or BMS-986169 administration. BMS-986169 did not produce ketamine-like hyperlocomotion or abnormal behaviors in mice or cynomolgus monkeys but did produce a transient working memory impairment in monkeys that was closely related to plasma exposure. Finally, BMS-986163 produced robust changes in the quantitative electroencephalogram power band distribution, a translational measure that can be used to assess pharmacodynamic activity in healthy humans. Due to the poor aqueous solubility of BMS-986169, BMS-986163 was selected as the lead GluN2B NAM candidate for further evaluation as a novel intravenous agent for TRD.

ADDITIONAL INFORMATION

REFERENCES

1: Bristow LJ, Gulia J, Weed MR, Srikumar BN, Li YW, Graef JD, Naidu PS, Sanmathi
C, Aher J, Bastia T, Paschapur M, Kalidindi N, Kumar KV, Molski T, Pieschl R,
Fernandes A, Brown JM, Sivarao DV, Newberry K, Bookbinder M, Polino J, Keavy D,
Newton A, Shields E, Simmermacher J, Kempson J, Li J, Zhang H, Mathur A, Kallem
RR, Sinha M, Ramarao M, Vikramadithyan RK, Thangathirupathy S, Warrier J, Islam
I, Bronson JJ, Olson RE, Macor JE, Albright CF, King D, Thompson LA, Marcin LR,
Sinz M. Preclinical Characterization of
(R)-3-((3S,4S)-3-fluoro-4-(4-hydroxyphenyl)piperidin-1-yl)-1-(4-methylbenzyl)pyrr
olidin-2-one (BMS-986169), a Novel, Intravenous, Glutamate N-Methyl-d-Aspartate
2B Receptor Negative Allosteric Modulator with Potential in Major Depressive
Disorder. J Pharmacol Exp Ther. 2017 Dec;363(3):377-393. doi:
10.1124/jpet.117.242784. Epub 2017 Sep 27. PubMed PMID: 28954811.

2. BMS-986163, a Negative Allosteric Modulator of GluN2B with Potential Utility in Major Depressive Disorder
Lawrence R. Marcin, Jayakumar Warrier, Srinivasan Thangathirupathy, Jianliang Shi, George N. Karageorge, Bradley C. Pearce, Alicia Ng, Hyunsoo Park, James Kempson, Jianqing Li, Huiping Zhang, Arvind Mathur, Aliphedi B. Reddy, G. Nagaraju, Gopikishan Tonukunuru, Grandhi V. R. K. M. Gupta, Manjunatha Kamble, Raju Mannoori, Srinivas Cheruku, Srinivas Jogi, Jyoti Gulia, Tanmaya Bastia, Charulatha Sanmathi, Jayant Aher, Rajareddy Kallem, Bettadapura N. Srikumar, Kumar Kuchibhotla Vijaya, Pattipati S. Naidu, Mahesh Paschapur, Narasimharaju Kalidindi, Reeba Vikramadithyan, Manjunath Ramarao, Rex Denton, Thaddeus Molski, Eric Shields, Murali Subramanian, Xiaoliang Zhuo, Michelle Nophsker, Jean Simmermacher, Michael Sinz, Charlie Albright, Linda J. Bristow, Imadul Islam, Joanne J. Bronson, Richard E. Olson, Dalton King, Lorin A. Thompson, and John E. Macor
Publication Date (Web): April 13, 2018 (Letter)
DOI: 10.1021/acsmedchemlett.8b00080

Patent ID	Patent Title	Submitted Date	Granted Date
US9221796	Selective NR2B antagonists	2015-01-05	2015-12-29

//////////////////BMS-986169, BMS-986169, BMS 986169, BMS986169

O=C1N(CC2=CC=C(C)C=C2)CC[C@H]1N3C[C@@H](F)[C@H](C4=CC=C(O)C=C4)CC3

New ICH Guidelines: ICH Q13 on Conti Manufacturing and ICH Q14 on AQbD

June 29, 2018 1:07 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

New ICH Guidelines:

*ICH Q13* on Continuous Manufacturing &
🎛🎚

*ICH Q14* on ATP – QbD (Analytical target profile and quality by design)
⚗⏱

New ICH Guidelines: ICH Q13 on Conti Manufacturing and ICH Q14 on AQbD

In a press release from 22 June the International Council for Harmonisation (ICH) has announced that they will prepare new topics for the future. The Assembly agreed to begin working on two new topics for ICH harmonisation:

Analytical Procedure Development and Revision of Q2(R1) Analytical Validation (Q2(R2)/Q14)
and
Continuous Manufacturing (Q13)

The long anticipated revision of ICH Q2(R1) “Guideline on Validation of Analytical Procedures: Text and Methodology” has been approved and the work plan is scheduled to commence in Q3 2018. It is intended that the new guidelines will be consistent with ICH Q8(R2), Q9, Q10, Q11 and Q12 .

The AQbD approach is very important to collect information in order…

View original post 154 more words

Rebamipide, ребамипид , ريباميبيد ,瑞巴派特 ,

June 28, 2018 10:27 am / Leave a comment

ChemSpider 2D Image | Rebamipide | C19H15ClN2O4

Rebamipide

Molecular FormulaC₁₉H₁₅ClN₂O₄
Average mass370.786 Da
Monoisotopic mass370.072021 Da

OPC-12759
OPC-12759E
OPC-759

(±)-a-(p-Chlorobenzamido)-1,2-dihydro-2-oxo-4-quinolinepropionic acid

2-(4-Chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid

4-Quinolinepropanoic acid, α-[(4-chlorobenzoyl)amino]-1,2-dihydro-2-oxo- [ACD/Index Name]

4-quinolinepropanoic acid, α-[(4-chlorobenzoyl)amino]-2-hydroxy-

6454

CAS 90098-04-7 [RN]

a-[(4-Chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid

LR583V32ZR

UNII:LR583V32ZR

ребамипид [Russian] [INN]

ريباميبيد [Arabic] [INN]

瑞巴派特 [Chinese] [INN]

(±)-2-(4-CHLOROBENZOYLAMINO)-3-(2(1H)-QUINOLINON-4-YL)-PROPIONIC ACID

obtain the white powder from dimethylformamide-water with its hemihydrate m.p. being 288-290°C (decomposition).
(-)-Configuration: from dimethylformamide to give colorless needles, mp 305~306 °C (decomposition). [α] D20-116.7 ° (C = 1.0, dimethylformamide).
(+)-Configuration: from dimethylformamide to give colorless needles, mp 305~306 °C (decomposition). [α] D20 + 116.9 ° (C = 1.0, dimethylformamide).

Rebamipide is a quinolone derivative that was launched in 1990 by Otsuka in Japan for the oral treatment of Helicobacter pylori-induced gastric inflammation after eradication therapy and peptic ulcer

Title: Rebamipide

CAS Registry Number: 90098-04-7

CAS Name: a-[(4-Chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid

Additional Names: (±)-a-(p-chlorobenzamido)-1,2-dihydro-2-oxo-4-quinolinepropionic acid; 2-(4-chlorobenzoylamino)-3-[2(1H)-quinolinon-4-yl]propionic acid; proamipide

Manufacturers’ Codes: OPC-12759

Trademarks: Mucosta (Otsuka)

Molecular Formula: C19H15ClN2O4

Molecular Weight: 370.79

Percent Composition: C 61.55%, H 4.08%, Cl 9.56%, N 7.56%, O 17.26%

Literature References: Gastric cytoprotectant. Prepn: M. Uchida et al., DE 3324034; eidem, US 4578381; (1984, 1986 both to Otsuka). Synthesis and pharmacology: M. Uchida et al., Chem. Pharm. Bull. 33, 3775 (1985); of enantiomers: eidem, ibid. 35, 853 (1987). Antiulcer activity in rats: K. Yamasaki et al., Eur. J. Pharmacol. 142, 23 (1987); K. Yamasaki et al., Jpn. J. Pharmacol. 49,441 (1989). HPLC determn in plasma and urine: Y. Shioya, T. Shimizu, J. Chromatogr. 434, 283 (1988).

Properties: White powder from DMF-water, mp 288-290° (dec) as hemihydrate.

Melting point: mp 288-290° (dec) as hemihydrate

Derivative Type: (-)-Form

Properties: Colorless needles from DMF, mp 305-306° (dec). [a]D20 -116.7° (c = 1.0 in DMF).

Melting point: mp 305-306° (dec)

Optical Rotation: [a]D20 -116.7° (c = 1.0 in DMF)

Derivative Type: (+)-Form

Properties: Colorless needles from DMF, mp 305-306° (dec). [a]D20 +116.9° (c = 1.0 in DMF).

Melting point: mp 305-306° (dec)

Optical Rotation: [a]D20 +116.9° (c = 1.0 in DMF)

Therap-Cat: Antiulcerative.

Keywords: Antiulcerative; Cytoprotectant (Gastric).

Rebamipide has been investigated for the treatment of Stomach Ulcer, Keratoconjunctivitis Sicca, and Gastric Adenoma and Early Gastric Cancer.

Rebamipide is a quinolinone derivative that stimulates endogenous PGE2 generation in gastric mucosa, enhancing gastric mucosal defense in a COX-2-dependent manner.
Rebamipide has been shown to inhibit the production of reactive oxygen species and to decrease cytokine release induced by H. pylori infection.
A daily oral dose of 100 mg/kg was found to be protective against the development of pyloric channel ulcers in Mongolian gerbils infected with H. pylori.
In addition to the stomach, rebamipide can also enhance secretion of mucin covering the conjunctiva and cornea, which is important for tear film adhesion.
Rebamipide, a gastroprotective drug, was developed in Japan and was proven to be superior to cetraxate, the former most prescribed drug of the same category, in 1989 in the treatment for gastric ulcers. The initially discovered basic mechanisms of action of rebamipide included its action as a prostaglandin inducer and oxygen free-radical scavenger. In the last 5 years, several basic and clinical studies have been performed for functional dyspepsia, chronic gastritis, NSAID-induced gastrointestinal injuries, gastric ulcer following eradication therapy for Helicobacter pylori, gastric ulcer after endoscopic surgery and ulcerative colitis. In addition, several molecules have been identified as therapeutic targets of rebamipide to explain its pleiotropic pharmacological actions.

Rebamipide, an amino acid derivative of 2-(1H)-quinolinone, is used for mucosal protection, healing of gastroduodenal ulcers, and treatment of gastritis. It works by enhancing mucosal defense, scavenging free radicals, and temporarily activating genes encoding cyclooxygenase-2.

Rebamipide is used in a number of Asian countries including Japan (marketed as Mucosta), South Korea, China^[1] and India (where it is marketed under the trade name Rebagen). It is also approved in Russia under the brand name Rebagit.^[2] It is not approved by the Food and Drug Administration for use in the United States.

Studies have shown that rebamipide can fight the damaging effects of NSAIDs on the GIT mucosa, and more recently, the small intestine.^{[citation needed]} It has also been studied for the treatment of Behçet’s disease.^[3] It was shown to successfully treat pouchitis in a single-N study after first-line therapies for the condition were unsuccessful.^[4] Some studies have shown effectiveness in presbyacusis(age-related hearing loss).^{[citation needed]}

It has also been shown to alleviate signs and symptoms of dry eyes in a randomised controlled trial although this is not yet widely available clinically.^[5]

SYN

Rebamipide (CAS NO.: 111911-87-6), with its systematic name of 4-Quinolinepropanic acid, alpha-((4-chlorobenzoyl)amino)-1,2-dihydro-2-oxo-, (+-)-, could be produced through many synthetic methods.

Following is one of the reaction routes:

Synthesis of Rebamipide

4-(Bromomethyl)quinolin-2(1H)-one (I) could react with hot phosphorus oxychloride to produce a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), and then the mixture without separation is ondensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) in the presence of butyllithium in hexane, affording (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl produces 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to afford 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). At last, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K₂CO₃in acetone, affording (R)-OPC-12759.

Figure 2 The synthetic route of Rebamipide.

DE 3324034; US 4578381 ABOVE

The condensation of 4-(bromomethyl)quinolin-2(1H)-one (I) with diethyl acetamidomalonate (II) by means of sodium ethoxide in refluxing ethanol gives ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4yl)propionate (III), which is submitted to a decarboxylative hydrolysis with refluxing 20% HCl yielding 3-(2-oxo-1,2-dihydroquinolin-4yl)alanine (IV). Finaily this compound is acylated with 4-chlorobenzoyl chloride by means of K2CO3 in acetone water.

SYN

Chem Pharm Bull 1991,39(11),2906 ABOVE

The synthesis of (R)- and (S)-isomers of OPC-12759 has been described: These optical isomers can be obtained in three different ways: 1) The reaction of 4-(bromomethyl)quinolin-2(1H)-one (I) with hot phosphorus oxychloride gives a mixture of 4-(bromomethyl)-2-chloroquinoline (II) and 2-chloro-4-(chloromethyl)quinoline (III), which, without separation, is condensed with 2(S)-isopropyl-3,6-dimethoxy-2,5-dihydropyrazine (IVs) by means of butyllithium in hexane, yielding (-)-2-chloro-4-[6(S)-isopropyl-2,5-dimethoxy-3,6-dihydropyrazin-3(R)-yl methyl]quinoline (Vr). The hydrolysis of (Vr) with HCl affords 3-(2-chloroquinolin-4-yl)-(R)-alanine methyl ester (VIr), which is treated with HCl and propylene oxide to give 3-(2-oxo-2,3-dihydroquinolin-4-yl)-(R)-alanine (VIIr). Finally, this compound is acylated with 4-chlorobenzoyl chloride (VIII) by means of K2CO3 in acetone, affording (R)-OPC-12759.

SYN

3) The methylation of 3-(2-oxo-1,2-dihydroquinolin-4-yl)-(R,S)-alanine (IX) with SOCl2 and methanol yields the corresponding methyl ester (X), which is submitted to optical resolution with D-(-)-mandelic acid, affording adducts (XII) and (XIII). The hydrolytic treatment of (XII) and (XIII) with HCl and propylene oxide finally yields isomers (VIIr) and (VIIs), already obtained. Racemic OPC-12759 can also be resolved into its optical isomers by treatment with brucine and fractionated crystallization.

Rebamipide

- Synonyms:Proamipide
- ATC:A02BX
Use:ulcer therapeutic
Chemical name:α-[(4-chlorobenzoyl)amino]-1,2-dihydro-2-oxo-4-quinolinepropanoic acid
Formula:C₁₉H₁₅ClN₂O₄

MW:370.79 g/mol
CAS-RN:90098-04-7
LD₅₀:572 mg/kg (M, i.v.);
700 mg/kg (R, i.v.);
>2 g/kg (dog, p.o.)

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
39098-85-6	C₄H₅ClO₂	acetoacetyl chloride	Butanoyl chloride, 3-oxo-
62-53-3	C₆H₇N	aniline	Benzenamine
4876-10-2	C₁₀H₈BrNO	4-(bromomethyl)-2(1H)-quinolinone	2(1H)-Quinolinone, 4-(bromomethyl)-
128-08-5	C₄H₄BrNO₂	N-bromosuccinimide	2,5-Pyrrolidinedione, 1-bromo-
122-01-0	C₇H₄Cl₂O	4-chlorobenzoyl chloride	Benzoyl chloride, 4-chloro-
1068-90-2	C₉H₁₅NO₅	diethyl acetamidomalonate	Propanedioic acid, (acetylamino)-, diethyl ester
4900-38-3	C₁₉H₂₂N₂O₆	ethyl 2-acetamido-2-(ethoxycarbonyl)-3-(2-oxo-1,2-dihydroquinolin-4-yl)propionate	Propanedioic acid, (acetylamino)[(1,2-dihydro-2-oxo-4-quinolinyl)methyl]-, diethyl ester
5162-90-3	C₁₂H₁₂N₂O₃	3-(2-oxo-1,2-dihydroquinolin-4-yl)alanine	4-Quinolinepropanoic acid, α-amino-1,2-dihydro-2-oxo-
102-01-2	C₁₀H₁₁NO₂	3-oxo-N-phenylbutanamide	Butanamide, 3-oxo-N-phenyl-

Trade Names

Country	Trade Name	Vendor	Annotation
J	Mucosta	Otsuka

Formulations

tabl. 100 mg

References

- Uchida, M. et al.: Chem. Pharm. Bull. (CPBTAL) 33, 3775 (1985).
- DOS 3 324 034 (Otsuka; appl. 7.4.1983; J-prior. 7.5.1982).
- GB 2 123 825 (Otsuka; appl. 7.5.1983; J-prior. 7.5.1982).

oral and parenteral formulations:
- JP 60 019 767 (Otsuka; appl. 7.11.1983).

PAPER

Magic Bullet! Rebamipide, a Superior Anti-ulcer and Ophthalmic Drug and Its Large-Scale Synthesis in a Single Organic Solvent via Process Intensification Using Krapcho Decarboxylation

https://pubs.acs.org/doi/10.1021/acs.oprd.7b00382#

Prashanth Kumar Babu, Mohan Reddy Bodireddy, Reshma Choudlu Puttaraju, Dnyaneshwar Vagare, Raghu Nimmakayala, Naresh Surineni, Madhusudana Rao Gajula *, and Pramod Kumar *

Chemical Research Division, API R&D Centre, Micro Labs Ltd., Plot No.43-45, KIADB Industrial Area, fourth phase, Bommasandra-Jigani Link Road, Bommasandra, Bangalore 560 105, Karnataka, India

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.7b00382

Publication Date (Web): May 31, 2018

*E-mail: pramodkumar@microlabs.in., *E-mail: gmadhusudanrao@yahoo.com.

Rebamipide (1) is a superior drug compared to existing drugs for use in healing of peptic ulcers, gastrointestinal bleeding, and dyspepsia. It is also useful as an ophthalmic drug for the treatment of dry eye syndrome. Process intensification for its synthesis was achieved by (i) averting uncontrollable frothing using Krapcho decarboxylation instead of conventional acid hydrolysis, where uncontrollable frothing became chaotic, (ii) minimizing organic waste generation by using a single organic solvent, and (iii) avoiding anti-foaming agents (n-octanol, acetophenone) and acetic acid. With these trifling modifications, the overall yield of active pharmaceutical ingredient (API) was ≥83% with excellent purity (≥99.89%), and the process meets the metrics of “green” chemistry with an E-factor = 11.5. The developed hassle-free commercial process is viable for multi-kilogram synthesis of Rebamipide (1) as the key step, Krapcho decarboxylation is safe to run at 130–140 °C in DMSO, and it was proved to be effective by differential scanning calorimetry thermal screening studies. The characterization data of intermediates, process-related impurities, and API are reported. The carryover and process-related impurities were controlled efficiently. The present work can enhance the scope and worldwide adoptability of Rebamipide (1), which is currently limited to Asian countries.

https://pubs.acs.org/doi/suppl/10.1021/acs.oprd.7b00382/suppl_file/op7b00382_si_001.pdf

Articles

Arakawa T, Watanabe T, Fukuda T, Yamasaki K, Kobayashi K (1995). “Rebamipide, novel prostaglandin-inducer accelerates healing and reduces relapse of acetic acid-induced rat gastric ulcer. Comparison with cimetidine”. Dig Dis Sci. 40 (11): 2469–72. doi:10.1007/BF02063257. PMID 7587834.
Arakawa T, Kobayashi K, Yoshikawa T, Tarnawski A (1998). “Rebamipide: overview of its mechanisms of action and efficacy in mucosal protection and ulcer healing”. Dig Dis Sci. 43 (9 Suppl): 5S–13S. PMID 9753220.
Tarnawski AS, Chai J, Pai R, Chiou SK (2004). “Rebamipide activates genes encoding angiogenic growth factors and Cox2 and stimulates angiogenesis: a key to its ulcer healing action?”. Dig Dis Sci. 49 (2): 202–9. doi:10.1023/B:DDAS.0000017439.60943.5c. PMID 15104358.
Takumida M, Anniko M (2009). “Radical scavengers for elderly patients with age-related hearing loss”. Acta Otolaryngol. 129 (1): 36–44. doi:10.1080/00016480802008215. PMID 18607930.

References

Jump up^ drugs.com
Jump up^ “Russian State Register of Medicines. Registration Sertificate: Rebagit (rebamipide) Film-Coated Tablets” (in Russian). Retrieved 10 June 2017.
Jump up^ Matsuda T, Ohno S, Hirohata S, Miyanaga Y, Ujihara H, Inaba G, Nakamura S, Tanaka S, Kogure M, Mizushima Y (2003). “Efficacy of rebamipide as adjunctive therapy in the treatment of recurrent oral aphthous ulcers in patients with Behcet’s disease: a randomised, double-blind, placebo-controlled study”. Drugs R D. 4 (1): 19–28. doi:10.2165/00126839-200304010-00002. PMID 12568631.
Jump up^ http://www.wjgnet.com/1007-9327/12/656.pdf Archived October 20, 2013, at the Wayback Machine.
Jump up^ Kinoshita, S.; K. Oshiden; S. Awamura; H. Suzuki; N. Nakamichi (2013). “A randomized, multicenter phase 3 study comparing 2% rebamipide (OPC-12759) with 0.1% sodium hyaluronate in the treatment of dry eye”. Ophthalmology. 120 (6): 1158–65. doi:10.1016/j.ophtha.2012.12.022. PMID 23490326.

Rebamipide
Clinical data

Trade names	Mucosta (JP), Rebagen (KR,CN, IN), Rebagit (RU)
AHFS/Drugs.com	International Drug Names
Routes of administration	Oral (tablets)
ATC code	A02BX14 (WHO)
Identifiers
IUPAC name [show]
CAS Number	90098-04-7
PubChem CID	5042
IUPHAR/BPS	871
DrugBank	DB11656
ChemSpider	4866
UNII	LR583V32ZR
KEGG	D01121
ChEMBL	CHEMBL1697771
Chemical and physical data
Formula	C₁₉H₁₅ClN₂O₄
Molar mass	370.786 g/mol
3D model (JSmol)	Interactive image

/////////Rebamipide, UNII:LR583V32ZR, ребамипид , ريباميبيد ,瑞巴派特 , OPC-12759 , OPC-12759E , OPC-759 , OPC 12759 , OPC 12759E , OPC 759 , OTSUKA, JAPAN 1990

OC(=O)C(CC1=CC(O)=NC2=CC=CC=C12)NC(=O)C1=CC=C(Cl)C=C1

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Process Research for (+)-Ambrisentan, an Endothelin-A Receptor Antagonist

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Scale-up Synthesis of Tesirine

Design and Synthesis of Tesirine, a Clinical Antibody–Drug Conjugate Pyrrolobenzodiazepine Dimer Payload

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BMS-978587

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Mercaptamine bitartrate

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1. Preparation of Cysteamine Bitartrate.

2. Purification of Cysteamine Bitartrate.

3. Preparation of Crystalline Form L1 of Cysteamine Bitartrate.

4. Preparation of Crystalline Form L2 of Cysteamine Bitartrate.

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Acamprosate calcium

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Acamprosate is not metabolized by the human body.[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.[13]

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Acamprosate calcium

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free acid

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synthesis of 3-aminopropane-1-sulfonic acid:

Acamprosate is not metabolized by the human body.^[13] Acamprosate’s absolute bioavailability from oral administration is approximately 11%.^[13] Following administration and absorption of acamprosate, it is excreted unchanged (i.e., as acamprosate) via the kidneys.^[13]