Soblidotin, Auristatin PE, NSC-654663, TZT-1027, -Drug Synthesis Database

【结构式】

【药物名称】Soblidotin, Auristatin PE, NSC-654663, TZT-1027

【化学名称】3(S)-[1-[4(S)-[N-(N,N-Dimethyl-L-valyl-L-valyl)-N-methylamino]-3(R)-methoxy-5(S)-methylheptanoyl]pyrrolidin-2(S)-yl]-3(R)-methoxy-2(R)-methyl-N-(2-phenylethyl)propionamide
　　　　　　N,N-dimethyl-L-valyl-N-[2(R)-methoxy-4-[2(S)-[1(R)-methoxy-2(R)-methyl-3-oxo-3-(2-phenylethylamino)propyl]-1-pyrrolidinyl]-1(S)-[1(S)-methylpropyl]-4-oxobutyl]-N-methyl-L-valinamide

【CA登记号】149606-27-9

【分子式】C₃₉H₆₇N₅O₆

【分子量】701.99874

【开发单位】Teikoku Hormone (Originator), Daiichi Pharmaceutical (Licensee)

【药理作用】Lung Cancer Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Solid Tumors Therapy, Antimitotic Drugs, Microtubule-Stabilizing Agents

合成路线1 合成路线2 合成路线3

合成路线1

1) The reaction of tert-butoxycarbonyl-L-prolinal (I) with benzyl propionate (II) by means of lithium diisopropylamide (LDA) in THF gives a mixture of isomers that is separated by flash chromatography, yielding the (2R,3R)-isomer (III). The methylation of (III) with diazomethane and boron trifluoride ethearate or NaH and methyl iodide affords the methoxy derivative (IV), which is deprotected with HCl in dioxane, giving (V). The condensation of (V) with tripeptide (VI) by means of diethyl phosphorocyanidate (DEPC) in DMF yields the tetrapeptide benzyl ester (VII), which is finally debenzylated by hydrogenolysis over Pd/C in tert-butanol and amidated with 2-phenylethylamine (VIII) and DEPC and triethylamine in DMF.

参考文献中间体

【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706.
【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404.
【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(I)	16724	tert-Butyl (2S)-2-formyltetrahydro-1H-pyrrole-1-carboxylate; tert-Butoxycarbonyl-L-prolinal	69610-41-9	C₁₀H₁₇NO₃	详情	详情
(II)	23501	benzyl propionate	122-63-4	C₁₀H₁₂O₂	详情	详情
(III)	23502	tert-butyl (2S)-2-[(1R,2R)-3-(benzyloxy)-1-hydroxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate		C₂₀H₂₉NO₅	详情	详情
(IV)	23503	tert-butyl (2S)-2-[(1R,2R)-3-(benzyloxy)-1-methoxy-2-methyl-3-oxopropyl]-1-pyrrolidinecarboxylate		C₂₁H₃₁NO₅	详情	详情
(V)	23504	benzyl (2R,3R)-3-methoxy-2-methyl-3-[(2S)pyrrolidinyl]propanoate		C₁₆H₂₃NO₃	详情	详情
(VI)	23505	(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid		C₂₂H₄₃N₃O₅	详情	详情
(VII)	23506	benzyl (2R,3R)-3-((2S)-1-[(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoyl]pyrrolidinyl)-3-methoxy-2-methylpropanoate		C₃₈H₆₄N₄O₇	详情	详情
(VIII)	18333	Phenethylamine; 2-Phenyl-1-ethanamine	64-04-0	C₈H₁₁N	详情	详情

合成路线2

Intermediate (VI) has been obtained as follows: The condensation of benzyloxycarbonyl-L-isoleucine (IX) with malonic acid monomethyl ester potassium salt (X) by means of carbonyldiimidazole (CDI) and MgCl2 in THF gives the ketoester (XI), which is reduced to the hydroxyester (XII) with NaBH4 in methanol. The methylation of (XII) with methyl iodide and silver oxide in DMF affords the N-methyl methoxyester (XIII). The hydrolysis of (XIII) with NaOH in dioxane/water followed by reesterification with isobutylene gives the tert-butyl ester (XIV), which is deprotected by hydrogenation over Pd/C, yielding the amino acid (XV). The condensation of (XV) with benzyloxycarbonyl-L-valine (XVI) by means of DCC in dichloromethane gives the protected dipeptide (XVII), which is debenzylated as usual, yielding (XVIII). The condensation of (XVIII) with N,N-dimethyl-L-valine (XIX) affords the tripeptide ter-butyl ester (XX). Finally, (XX) is hydrolyzed by treatment with trifluoroacetic acid to the free acid intermediate (VI).

参考文献中间体

【1】 Tsukagoshi, S.; Sakakibara, K.; Gondo, M.; Natsume, T.; Mikami, T.; Kobayashi, M.; Miyazaki, K.; Synthesis and antitumor activity of novel dolastat. Chem Pharm Bull 1995, 43, 10, 1706.
【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404.
【3】 Sakakibara, K.; Gondo, M.; Miyazaki, K. (Teikoku Hormone Manufacturing Co., Ltd.); Novel tetrapeptide derivs.. EP 0598129; JP 1993503479; US 5654399; WO 9303054 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(VI)	23505	(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid		C₂₂H₄₃N₃O₅	详情	详情
(IX)	23508	(2S,3S)-2-[[(benzyloxy)carbonyl]amino]-3-methylpentanoic acid	3160-59-6	C₁₄H₁₉NO₄	详情	详情
(X)	23509	3-methoxy-3-oxopropanoate		C₄H₅O₄	详情	详情
(XI)	23510	methyl (4S,5S)-4-[[(benzyloxy)carbonyl]amino]-5-methyl-3-oxoheptanoate		C₁₇H₂₃NO₅	详情	详情
(XII)	23511	methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl]amino]-3-hydroxy-5-methylheptanoate		C₁₇H₂₅NO₅	详情	详情
(XIII)	23512	methyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate		C₁₉H₂₉NO₅	详情	详情
(XIV)	23513	tert-butyl (3R,4S,5S)-4-[[(benzyloxy)carbonyl](methyl)amino]-3-methoxy-5-methylheptanoate		C₂₂H₃₅NO₅	详情	详情
(XV)	23514	tert-butyl (3R,4S,5S)-3-methoxy-5-methyl-4-(methylamino)heptanoate		C₁₄H₂₉NO₃	详情	详情
(XVI)	18092	(2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutyric acid		C₁₃H₁₇NO₄	详情	详情
(XVII)	23516	tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(benzyloxy)carbonyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate		C₂₇H₄₄N₂O₆	详情	详情
(XVIII)	23517	tert-butyl (3R,4S,5S)-4-[[(2S)-2-amino-3-methylbutanoyl](methyl)amino]-3-methoxy-5-methylheptanoate		C₁₉H₃₈N₂O₄	详情	详情
(XIX)	23518	(2S)-2-(dimethylamino)-3-methylbutyric acid		C₇H₁₅NO₂	详情	详情
(XX)	23519	tert-butyl (3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoate		C₂₆H₅₁N₃O₅	详情	详情

合成路线3

2) The reaction of 3(R)-[1-(tert-butoxycarbonyl)-2(S)-pyrrolidinyl]-3-methoxy-2(R)-methylpropionic acid (XXI) with 2-phenylethylamine (VIII) by means of DEPC in dichloromethane gives the amide (XXII), which is deprotected with trifluoroacetic acid to yield the amide (XXIII). Finally, this compound is condensed with the previously described intermediate (VI) by means of DEPC in dichloromethane.

参考文献中间体

【1】 Hamel, E.; Williams, M.D.; Srirangam, J.K.; Chapuis, J.-C.; Durkin, K.P.M.; Barkoczy, J.; Schmidt, J.M.; Bai, R.; Boyd, M.R.; Pettit, G.R.; Antineoplastic agents 337. Synthesis of dolastatin. Anti-Cancer Drug Des 1995, 10, 7, 529.
【2】 Castañer, J.; Leeson, P.; Hoshi, A.; TZT-1027. Drugs Fut 1999, 24, 4, 404.
【3】 Petit, G.R.; Barkoczy, J. (Arizona State University); The elucidation and synthesis of antineoplastic te. EP 0600745; JP 1995002894 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	65169	(2R,3R)-3-methoxy-2-methyl-N-phenethyl-3-[(2S)pyrrolidinyl]propanamide		C₁₇H₂₆N₂O₂	详情	详情
(VI)	23505	(3R,4S,5S)-4-[((2S)-2-[[(2S)-2-(dimethylamino)-3-methylbutanoyl]amino]-3-methylbutanoyl)(methyl)amino]-3-methoxy-5-methylheptanoic acid		C₂₂H₄₃N₃O₅	详情	详情
(VIII)	18333	Phenethylamine; 2-Phenyl-1-ethanamine	64-04-0	C₈H₁₁N	详情	详情
(XXI)	23520	(2R,3R)-3-[(2S)-1-(tert-butoxycarbonyl)pyrrolidinyl]-3-methoxy-2-methylpropionic acid		C₁₄H₂₅NO₅	详情	详情
(XXII)	23521	tert-butyl (2S)-2-[(1R,2R)-1-methoxy-2-methyl-3-oxo-3-(phenethylamino)propyl]-1-pyrrolidinecarboxylate		C₂₂H₃₄N₂O₄	详情	详情

Extended Information