(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid -Drug Synthesis Database

【结构式】

【分子编号】12882

【品名】(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid

【CA登记号】

【分子式】C₁₁H₁₆N₂O₄S

【分子量】272.32512

【元素组成】C 48.52% H 5.92% N 10.29% O 23.5% S 11.77%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(XIX)

The starting product (II) is obtained as follows: The condensation of N-(tert-butoxycarbonyl)-L-phenylalanine (XI) with magnesium diethylmalonate (XII) by means of N,N'-carbonyldiimidazole in THF - DMSO gives 4(S)-(tert-butoxycarbonylamino)-3-oxo-4-phenylpentanoic acid ethyl ester (XIII), which by an asymetric hydrogenation with H2 and (R)-2,2'-bis(diphenylphosphino)-1,1'-binaphthyl-Ruthenium complex in ethanol is converted into 4(S)-(tert-butoxycarbonylamino)-4(S)-hydroxy-5-phenylpentanoic acid ethyl ester (XIV). The hydrolysis of (XIV) with KOH in water - dioxane gives the corresponding free acid (XV), which is hydrogenated with H2 over Rh/Al2O3 in ethanol to yield N-(tert-butoxycarbonyl)cyclostatine (XVI).The condensation of (XVI) with 2-morpholinoethylamine (XVII) by means of triethylamine and diethylphosphoryl cyanide in THF affords the corresponding amide (XVIII), which is finally condensed with N-(tert-butoxycarbonyl)-3-(4-thiazolyl)-L-alanine (XIX) by means of a previous hydrolysis with HCl, followed by the condensation step with diethylphosphoryl cyanide in THF, to give the cyclostatine derivative (II).

参考文献中间体

合成目标

【1】 Nishi, T.; Nagahori, H.; Saito, F.; et al.; Syntheses and biological activities of renin inhibitors containing statine analogues. Chem Pharm Bull 1990, 38, 1, 103-9.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(II)	12865	tert-butyl (1S)-2-[((1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutyl)amino]-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate		C₂₈H₄₇N₅O₆S	详情	详情
(XI)	12874	(2R)-2-[(tert-Butoxycarbonyl)amino]-3-phenylpropionic acid; N-alpha-t-BOC-L-Phenylalanine	13734-34-4	C₁₄H₁₉NO₄	详情	详情
(XII)	12875	Bromo[2-ethoxy-1-(ethoxycarbonyl)-2-oxoethyl]magnesium		C₇H₁₁BrMgO₄	详情	详情
(XIII)	12876	ethyl (4S)-4-[(tert-butoxycarbonyl)amino]-3-oxo-5-phenylpentanoate		C₁₈H₂₅NO₅	详情	详情
(XIV)	12877	ethyl (3S,4S)-4-[(tert-butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoate		C₁₈H₂₇NO₅	详情	详情
(XV)	12878	(3S,4S)-4-[(tert-Butoxycarbonyl)amino]-3-hydroxy-5-phenylpentanoic acid	72155-46-5	C₁₆H₂₃NO₅	详情	详情
(XVI)	12879	(3S,4S)-4-[(tert-Butoxycarbonyl)amino]-5-cyclohexyl-3-hydroxypentanoic acid		C₁₆H₂₉NO₅	详情	详情
(XVII)	12880	4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide	2038-03-1	C₆H₁₄N₂O	详情	详情
(XVIII)	12881	tert-butyl (1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutylcarbamate		C₂₂H₄₁N₃O₅	详情	详情
(XIX)	12882	(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid		C₁₁H₁₆N₂O₄S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The condensation of N-tert-butoxycarbonyl-cyclostatin (I) with 2-morpholinoethylamine (II) by means of diethyl cyanophosphonate in THF gives the corresponding amide (III), which is deprotected with HCl in dioxane yielding cyclostatin 2-morpholinoethylamide (IV). The condensation of (IV) with N-tert-butoxycarbonyl-3-(4-thiazolyl)-L-alanine (V) by means of diethyl cyanophosphonate as before affords the protected dipeptide (VI), which is treated with HCl in dioxane to obtain the free dipeptide 3-(4-thiazolyl)-L-alanyl-cyclostatin 2-morpholinoethylamide (VII). Finally, this compound is condensed with 3-(morpholinocarbonyl)-2(R)-(4-thiazolyl)propionic acid (VIII) by means of diethyl cyanophosphonate as before.

参考文献中间体

合成目标

【1】 Kataoko, M.; Yabe, Y.; Iijima, Y.; Takahagi, H.; Koike, H.; Kokubu, T.; Hiwada, K.; Morisawa, Y. (Sankyo Co., Ltd.); New renin-inhibitory oligopeptides, their preparation and their use. EP 0274259; JP 1989063559; US 5378690 .
【2】 Prous, J.; Castaner, J.; ES-6864. Drugs Fut 1989, 14, 9, 852.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	42235	Diethyl phosphorocyanidate; Diethyl cyanophosphonate; Cyanophosphonic acid diethyl ester; Diethyl phosphoryl cyanide; DEPC	2942-58-7	C₅H₁₀NO₃P	详情	详情
(I)	21275	4-[(tert-butoxycarbonyl)amino]-5-cyclohexyl-3-hydroxypentanoic acid		C₁₆H₂₉NO₅	详情	详情
(II)	12880	4-(2-Aminoethyl)morpholine; 2-(4-Morpholinyl)ethylamine; 2-(4-Morpholinyl)-1-ethanamine; N-(2-Aminoethyl)morpholine; N-Morpholine ethanamide	2038-03-1	C₆H₁₄N₂O	详情	详情
(III)	21277	tert-butyl 1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutylcarbamate		C₂₂H₄₁N₃O₅	详情	详情
(IV)	21278	4-amino-5-cyclohexyl-3-hydroxy-N-[2-(4-morpholinyl)ethyl]pentanamide		C₁₇H₃₃N₃O₃	详情	详情
(V)	12882	(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid		C₁₁H₁₆N₂O₄S	详情	详情
(VI)	12865	tert-butyl (1S)-2-[((1S,2S)-1-(cyclohexylmethyl)-2-hydroxy-4-[[2-(4-morpholinyl)ethyl]amino]-4-oxobutyl)amino]-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate		C₂₈H₄₇N₅O₆S	详情	详情
(VII)	21281	4-[[(2S)-2-amino-3-(1,3-thiazol-4-yl)propanoyl]amino]-5-cyclohexyl-3-hydroxy-N-[2-(4-morpholinyl)ethyl]pentanamide		C₂₃H₃₉N₅O₄S	详情	详情
(VIII)	12864	(2R)-4-(4-Morpholinyl)-2-(1-naphthylmethyl)-4-oxobutyric acid		C₁₉H₂₁NO₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VII)

Alkylation of 4-cyano-4'-hydroxybiphenyl (I) with 1-bromo-3-chloropropane (II) yields the chloropropyl ether (III). This is then condensed with the mono-protected homopiperazine (IV) to furnish (V). Removal of the N-Boc group of (V) to afford amine (VI) is then accomplished by treatment with trifluoroacetic acid in CH2Cl2. Amine (VI) is subsequently coupled with N-Boc-D-thiazolylalanine (VII) in the presence of EDC/DMAP producing amide (VIII). (1,2)

参考文献中间体

合成目标

【1】 Curtis, M.P.; Dwight, W.; Fox, G.B.; Esbenshade, T.A.; Pan, J-B.; Bennani, Y.L.; Hancock, A.A.; Faghih, R.; A-320436: Potent human non-imidazole histamine H3 receptor antagonist. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 240.
【2】 Black, L.A.; Faghih, R.; Bennani, Y.L.; Liu, H.; Zhang, H.Q.; Dwight, W.J.; Gentles, R.G.; Phelan, K.M.; Vasudevan, A. (Abbott Laboratories Inc.); Cyclic and bicyclic diamino histamine-3 receptor antagonists. WO 0166534 .

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)	48735	4-Cyano-4'-hydroxybiphenyl; 4-Hydroxy-4'-cyanodiphenyl; 4'-Cyano-4-biphenylol; 4'-Hydroxy-4-biphenylcarbonitrile	19812-93-2	C₁₃H₉NO	详情	详情
(II)	10358	1-Bromo-3-chloropropane	109-70-6	C₃H₆BrCl	详情	详情
(III)	57817	4'-(3-chloropropoxy)[1,1'-biphenyl]-4-carbonitrile		C₁₆H₁₄ClNO	详情	详情
(IV)	54079	tert-Butyl 1-homopiperazine carboxylate	n/a	C₁₀H₂₀N₂O₂	详情	详情
(V)	64053	1,1-dimethylethyl 4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepane-1-carboxylate		C₂₆H₃₃N₃O₃	详情	详情
(VI)	64054	4'-{[3-(1,4-diazepan-1-yl)propyl]oxy}[1,1'-biphenyl]-4-carbonitrile		C₂₁H₂₅N₃O	详情	详情
(VII)	12882	(2S)-2-[(tert-Butoxycarbonyl)amino]-3-(1,3-thiazol-4-yl)propionic acid		C₁₁H₁₆N₂O₄S	详情	详情
(VIII)	64055	1,1-dimethylethyl 2-(4-{3-[(4'-cyano[1,1'-biphenyl]-4-yl)oxy]propyl}-1,4-diazepan-1-yl)-2-oxo-1-(1,3-thiazol-4-ylmethyl)ethylcarbamate		C₃₂H₃₉N₅O₄S	详情	详情

Extended Information