BCH-2763, -Drug Synthesis Database

【结构式】

【药物名称】BCH-2763

【化学名称】5-[5-[5-(D-Phenylalanyl-L-propyl-L-arginyl)pentanamido]pentanamido]pentanoyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-prolyl-L-isoleucyl-L-prolyl-L-leucine
　　　　　　D-Phenylalanyl-L-propyl-7(S)-amino-10-guanidino-6-oxodecanoyl-5-aminopentanoyl-5-aminopentanoyl-L-aspartyl-L-phenylalanyl-L-glutamyl-L-prolyl-L-isoleucyl-L-prolyl-L-leucine

【CA登记号】183968-56-1

【分子式】C₇₅H₁₁₃N₁₅O₁₈

【分子量】1512.82656

【开发单位】National Research Council of Canada (Originator), Shire BioChem (Codevelopment)

【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3 合成路线4

合成路线1

Nalpha-Boc-Ngamma-tosyl-L-arginine (I) was converted to the N,O-dimethyl hydroxamate (II) by treatment with dimethylhydroxylamine and BOP. Condensation of (II) with the Grignard reagent (IV), prepared from 6-bromo-1-hexene (III), produced ketone (V). Then, oxidative cleavage of the terminal alkene of (V) by means of NaIO4 and RuCl3 yielded carboxylic acid (VI).

参考文献中间体

【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13361	(Methoxyamino)methane; N,O-Dimethylhydroxylamine	1117-97-1	C₂H₇NO	详情	详情
(I)	19064	(2S)-2-[(tert-butoxycarbonyl)amino]-5-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]pentanoic acid		C₁₈H₂₈N₄O₆S	详情	详情
(II)	37329	tert-butyl (1S)-4-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]-1-[[methoxy(methyl)amino]carbonyl]butylcarbamate		C₂₀H₃₃N₅O₆S	详情	详情
(III)	37330	6-bromo-1-hexene	2695-47-8	C₆H₁₁Br	详情	详情
(IV)	37331	bromo(5-hexenyl)magnesium		C₆H₁₁BrMg	详情	详情
(V)	37332	tert-butyl (1S)-1-[3-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]propyl]-2-oxo-7-octenylcarbamate		C₂₄H₃₈N₄O₅S	详情	详情
(VI)	37333	(7S)-7-[(tert-butoxycarbonyl)amino]-10-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]-6-oxodecanoic acid		C₂₃H₃₆N₄O₇S	详情	详情

合成路线2

Solid-phase peptide synthesis started with N-Boc-L-leucine linked to a PAM resin (VII). Deprotection of the Boc group was effected by treatment with trifluoroacetic acid in CH2Cl2 to give leucine-resin (VIII). Sequential couplings with the respective protected amino acids were mediated by DCC and HOBt, and trifluoroacetic acid in CH2Cl2 was used for deprotection of the Boc groups. The following protected amino acids were sequentially coupled: N-Boc-L-proline (IX), N-Boc-L-isoleucine (XI), N-Boc-L-proline (IX), N-Boc-L-glutamic acid omega-benzyl ester (XIV), N-Boc-L-phenylalanine (XVI) and N-Boc-L-aspartic acid omega-cyclohexyl ester (XVIII) to afford the peptide resins (X), (XII), (XIII), (XV), (XVII) and (XIX), respectively.

参考文献中间体

【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	23663	(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine		C₁₁H₂₁NO₄	详情	详情
(VIII)	26057	L-Leucine	61-90-5	C₆H₁₃NO₂	详情	详情
(IX)	16374	(1R,4S)-7-[(2,2-dimethylpropanoyl)oxy]-7-azabicyclo[2.2.1]heptan-2-one		C₁₁H₁₇NO₃	详情	详情
(IX)	16734	(2S)-1-(tert-butoxycarbonyl)tetrahydro-1H-pyrrole-2-carboxylic acid; N-alpha-t-BOC-L-proline; (2S)-1-(tert-butoxycarbonyl)-2-pyrrolidinecarboxylic acid		C₁₀H₁₇NO₄	详情	详情
(X)	37334	(2S)-4-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoic acid	52899-07-7	C₁₁H₂₀N₂O₃	详情	详情
(XI)	30009	(2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid	13139-16-7	C₁₁H₂₁NO₄	详情	详情
(XII)	37335	(2S)-2-[([(2S)-1-[(2S,3S)-2-amino-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid		C₁₇H₃₁N₃O₄	详情	详情
(XIII)	37336	(2S)-4-methyl-2-([[(2S)-1-((2S,3S)-3-methyl-2-[[(2S)pyrrolidinylcarbonyl]amino]pentanoyl)pyrrolidinyl]carbonyl]amino)pentanoic acid		C₂₂H₃₈N₄O₅	详情	详情
(XIV)	25141	(2S)-5-(benzyloxy)-2-[(tert-butoxycarbonyl)amino]-5-oxopentanoic acid	13574-13-5	C₁₇H₂₃NO₆	详情	详情
(XV)	37337	(2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-amino-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid		C₃₄H₅₁N₅O₈	详情	详情
(XVI)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XVII)	37338	(2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[[(2S)-2-amino-3-phenylpropanoyl]amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid		C₄₃H₆₀N₆O₉	详情	详情
(XVIII)	37339	(2S)-2-[(tert-butoxycarbonyl)amino]-4-(cyclohexyloxy)-4-oxobutyric acid	73821-95-1	C₁₅H₂₅NO₆	详情	详情
(XIX)	37340	(2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-amino-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid		C₅₃H₇₅N₇O₁₂	详情	详情

合成路线3

Then, two sequential couplings with N-Boc-5-aminopentanoic acid (XX), followed by deprotections with trifluoroacetic acid in the presence of ethyl methyl sulfide, provided peptide resins (XXI) and (XXII).

参考文献中间体

【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XIX)	37340	(2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-amino-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid	C₅₃H₇₅N₇O₁₂	详情	详情
(XX)	37341	5-[(tert-butoxycarbonyl)amino]pentanoic acid	C₁₀H₁₉NO₄	详情	详情
(XXI)	37342	(2S)-2-[[((2S)-1-[(2S,3S)-2-[([(2S)-1-[(2S)-2-[((2S)-2-[[(2S)-2-[(5-aminopentanoyl)amino]-4-(cyclohexyloxy)-4-oxobutanoyl]amino]-3-phenylpropanoyl)amino]-5-(benzyloxy)-5-oxopentanoyl]pyrrolidinyl]carbonyl)amino]-3-methylpentanoyl]pyrrolidinyl)carbonyl]amino]-4-methylpentanoic acid	C₅₈H₈₄N₈O₁₃	详情	详情
(XXII)	37343	(2S)-2-([[(2S)-1-((2S,3S)-2-[[((2S)-1-[(2S,5S,8S)-20-amino-5-benzyl-2-[3-(benzyloxy)-3-oxopropyl]-8-[2-(cyclohexyloxy)-2-oxoethyl]-4,7,10,16-tetraoxo-3,6,9,15-tetraazaicos-1-anoyl]pyrrolidinyl)carbonyl]amino]-3-methylpentanoyl)pyrrolidinyl]carbonyl]amino)-4-methylpentanoic acid	C₆₃H₉₃N₉O₁₄	详情	详情

合成路线4

Amino acid (VI) was then coupled to the peptide sequence to provide, after trifluoroacetic acid deprotection, resin (XXIII). The terminal D-Phe and L-Pro residues were incorporated as the preformed dipeptide (XXIV). Finally, cleavage of all protecting groups by means of HF in the presence of dimethyl sulfide and anisole furnished the title compound.

参考文献中间体

【1】 DiMaio, J. (National Research Council of Canada); Thrombin inhibitors based on the amino acid sequence of hirudin. JP 1999502203; WO 9629347 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(VI)	37333	(7S)-7-[(tert-butoxycarbonyl)amino]-10-[(imino[[(4-methylphenyl)sulfonyl]amino]methyl)amino]-6-oxodecanoic acid	C₂₃H₃₆N₄O₇S	详情	详情
(XXII)	37343	(2S)-2-([[(2S)-1-((2S,3S)-2-[[((2S)-1-[(2S,5S,8S)-20-amino-5-benzyl-2-[3-(benzyloxy)-3-oxopropyl]-8-[2-(cyclohexyloxy)-2-oxoethyl]-4,7,10,16-tetraoxo-3,6,9,15-tetraazaicos-1-anoyl]pyrrolidinyl)carbonyl]amino]-3-methylpentanoyl)pyrrolidinyl]carbonyl]amino)-4-methylpentanoic acid	C₆₃H₉₃N₉O₁₄	详情	详情
(XXIII)	37344	(2S)-2-[([(2S)-1-[(2S,3S)-2-([[(2S)-1-((2S,5S,8S,28S)-28-amino-5-benzyl-2-[3-(benzyloxy)-3-oxopropyl]-8-[2-(cyclohexyloxy)-2-oxoethyl]-33-imino-33-[[(4-methylphenyl)sulfonyl]amino]-4,7,10,16,22,27-hexaoxo-3,6,9,15,21,32-hexaazatritriacont-1-anoyl)pyrrolidinyl]carbonyl]amino)-3-methylpentanoyl]pyrrolidinyl]carbonyl)amino]-4-methylpentanoic acid	C₈₁H₁₁₉N₁₃O₁₈S	详情	详情
(XXIV)	28932	(2S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoyl]-2-pyrrolidinecarboxylic acid	C₁₉H₂₆N₂O₅	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)