S-31922, -Drug Synthesis Database

【结构式】

【药物名称】S-31922

【化学名称】5-Amino-1(R)-[1-[N-(2-phenylethyl)carbamoyl]cyclopentylcarboxamido]pentylboronic acid

【CA登记号】196209-59-3 (monoHCl)

【分子式】C₂₀H₃₂BN₃O₄

【分子量】389.30674

【开发单位】Servier (Originator)

【药理作用】Anticoagulants, Coagulation Disorders Therapy, HEMATOLOGIC DRUGS, Thrombin Inhibitors

合成路线1 合成路线2

合成路线1

Coupling of 4-bromo-1-butene (I) with catecholborane (II) afforded the bromobutyl boronate (III). Subsequent exchange of (III) with alpha-pinanediol (IV) produced (V), which was regioselectively chlorinated to give (VI). Displacement of the chlorine atom of (VI) with lithium hexamethyldisilazide, followed by acid treatment furnished intermediate (VII).

参考文献中间体

【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	34273	N,N-bis(trimethylsilyl)amine; trimethyl-N-(trimethylsilyl)silanamine	999-97-3	C₆H₁₉NSi₂	详情	详情
(I)	11720	4-Bromo-1-butene	5162-44-7	C₄H₇Br	详情	详情
(II)	32533	1,3,2-benzodioxaborole	274-07-7	C₆H₅BO₂	详情	详情
(III)	32534	2-(4-bromobutyl)-1,3,2-benzodioxaborole		C₁₀H₁₂BBrO₂	详情	详情
(IV)	32535	(1R,2S,3R,5R)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol		C₁₀H₁₈O₂	详情	详情
(V)	32536	(1R,2S,6R,8R)-4-(5-bromopentyl)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₅H₂₆BBrO₂	详情	详情
(VI)	32537	(1R,2S,6R,8R)-4-[(1R)-5-bromo-1-chloropentyl]-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]decane		C₁₅H₂₅BBrClO₂	详情	详情
(VII)	32538	(1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-pentanamine; (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentylamine		C₁₅H₂₇BBrNO₂	详情	详情

合成路线2

Condensation of cyclopentanecarboxylic acid (VIII) with ethyl chloroformate in the presence of LDA afforded 1,1-cyclopentanedicarboxylic acid monoethyl ester (IX), which was coupled with phenethylamine (X) by means of TBTU to produce amide (XI). Ester hydrolysis of (XI) with NaOH gave carboxylic acid (XII), which was activated as the mixed anhydride (XIII) with isobutyl chloroformate, and then coupled to the chiral aminoboronate (VII), yielding diamide (XIV). Displacement of the bromine of (XIV) with NaN3, followed by hydrogenation of the resulting azide (XV) gave rise to amine (XVI). The chiral auxiliary of (XVI) was finally removed by treatment with phenylboronic acid.

参考文献中间体

【1】 Verbeuren, T.; Rupin, A.; De Nanteuil, G.; Gloanec, P.; New dicarbonyl cycloalkyl based thrombin inhibitors with improved activity and selectivity compared to (D)-Phe-Pro-boroArg derivatives . 218th ACS Natl Meet (Aug 22 1999, New Orleans) 1999, Abst MEDI 201.
【2】 Gloanec, P.; Portevin, B.; Lila, C.; Rupin, A.; de Nanteuil, G.; Simonet, S.; Verbeuren, T. (ADIR et Cie.); Cpds. derived from boronic acid. EP 0792883; FR 2745288; US 5814622 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	11229	1-[(Chlorocarbonyl)oxy]ethane;ethyl carbonochloridate; Carbonchloridic acid ethyl ester;Ethyl chloroformate;Ethyl chlorocarbonate	541-41-3	C₃H₅ClO₂	详情	详情
(VII)	32538	(1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]-1-pentanamine; (1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentylamine		C₁₅H₂₇BBrNO₂	详情	详情
(VIII)	20734	cyclopentanecarboxylic acid	3400-45-1	C₆H₁₀O₂	详情	详情
(IX)	32539	1-(ethoxycarbonyl)cyclopentanecarboxylic acid		C₉H₁₄O₄	详情	详情
(X)	18333	Phenethylamine; 2-Phenyl-1-ethanamine	64-04-0	C₈H₁₁N	详情	详情
(XI)	32540	ethyl 1-[(phenethylamino)carbonyl]cyclopentanecarboxylate		C₁₇H₂₃NO₃	详情	详情
(XII)	32541	1-[(phenethylamino)carbonyl]cyclopentanecarboxylic acid		C₁₅H₁₉NO₃	详情	详情
(XIII)	32542	1-[N-(2-Phenylethyl)carbamoyl]cyclopentylcarbonyl isobutoxycarbonyl anhydride		C₂₀H₂₇NO₅	详情	详情
(XIV)	32543	N(1)-[(1R)-5-bromo-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide		C₃₀H₄₄BBrN₂O₄	详情	详情
(XV)	32544	N(1)-[(1R)-5-azido-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide		C₃₀H₄₄BN₅O₄	详情	详情
(XVI)	32545	N(1)-[(1R)-5-amino-1-[(1R,2S,6R,8R)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0(2,6)]dec-4-yl]pentyl]-N(1)-phenethyl-1,1-cyclopentanedicarboxamide		C₃₀H₄₆BN₃O₄	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)