1-aminocyclopentanecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】33149

【品名】1-aminocyclopentanecarboxylic acid

【CA登记号】52-52-8

【分子式】C₆H₁₁NO₂

【分子量】129.15888

【元素组成】C 55.8% H 8.58% N 10.84% O 24.77%

与该中间体有关的原料药合成路线共 4 条

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

该中间体在本合成路线中的序号：(I)

The N-protection of 1-aminocyclopentane-1-carboxylic acid (I) with Boc2O and NaOH in dioxane gives the carbamate (II), which is condensed with 4-O-methyl-L-tyrosine ethyl ester (III) by means of DCC and HOBt yielding the protected dipeptide (IV). The reaction of (IV) with HCl in dichloromethane affords the free dipeptide (V), which is finally condensed with 2(S)-(acetylsulfanyl)-3-methylbutyric acid (VI) by means of DCC, N-hydroxy-7-azabenzotriazole (HOAt) and triethylamine in dichloromethane.

参考文献中间体

合成目标

【1】 Fink, C.A.; et al.; Mercaptoacyl dipeptides as orally active dual inhibitors of angiotensin-converting enzyme and neutral endopeptidase. J Med Chem 1996, 39, 16, 3158.
【2】 Johnson, E.P.; et al.; Efficient large scale preparation of neutral endopeptidase/angiotensin-converting enzyme dual inhibitor CGS30440. Org Process Res Dev 1998, 2, 4, 238.

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)	33149	1-aminocyclopentanecarboxylic acid	52-52-8	C₆H₁₁NO₂	详情	详情
(II)	30890	1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid		C₁₁H₁₉NO₄	详情	详情
(III)	33150	ethyl (2S)-2-amino-3-(4-methoxyphenyl)propanoate		C₁₂H₁₇NO₃	详情	详情
(IV)	33151	ethyl (2S)-2-[([1-[(tert-butoxycarbonyl)amino]cyclopentyl]carbonyl)amino]-3-(4-methoxyphenyl)propanoate		C₂₃H₃₄N₂O₆	详情	详情
(V)	33152	ethyl (2S)-2-[[(1-aminocyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₁₈H₂₆N₂O₄	详情	详情
(VI)	33153	(2S)-2-(acetylsulfanyl)-3-methylbutyric acid		C₇H₁₂O₃S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

The N-protection of 1-aminocyclopentane-1-carboxylic acid (I) with PhCH2-OCOCl and NaOH in tert-butyl methyl ether gives the carbamate (VII), which is condensed with L-tyrosine ethyl ester (VIII) by means isobutyl chloroformate and triethylamine in THF yielding the protected dipeptide (IX). The methylation of (IX) with dimethyl sulfate and K2CO3 in ethyl acetate affords the protected 4-O-methyl dipeptide (X). The deprotection of (X) with HCO2H and Pd/C in ethyl acetate affords the previously reported free dipeptide (V), which is condensed with 2(R)-bromo-3-methylbutyryl chloride (XI) by means of NMM in toluene giving the acylated dipeptide (XII). Finally, this compound is treated with thioacetic acid and K2CO3 in ethyl acetate. The intermediate 2(R)-bromo-3-methylbutyryl chloride (XI) has been obtained by reaction of D-valine (XIII) with NaNO2 and HBr giving the 2(R)-bromo-3-methylbutyric acid (XIV), which is then treated with SOCl2 and DMF to afford the target intermediate (XI).

参考文献中间体

合成目标

【1】 Johnson, E.P.; et al.; Efficient large scale preparation of neutral endopeptidase/angiotensin-converting enzyme dual inhibitor CGS30440. Org Process Res Dev 1998, 2, 4, 238.

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)	33149	1-aminocyclopentanecarboxylic acid	52-52-8	C₆H₁₁NO₂	详情	详情
(V)	33152	ethyl (2S)-2-[[(1-aminocyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₁₈H₂₆N₂O₄	详情	详情
(VII)	33154	1-[[(benzyloxy)carbonyl]amino]cyclopentanecarboxylic acid		C₁₄H₁₇NO₄	详情	详情
(VIII)	33155	ethyl (2S)-2-amino-3-(4-hydroxyphenyl)propanoate	949-67-7	C₁₁H₁₅NO₃	详情	详情
(IX)	33156	ethyl (2S)-2-[[(1-[[(benzyloxy)carbonyl]amino]cyclopentyl)carbonyl]amino]-3-(4-hydroxyphenyl)propanoate		C₂₅H₃₀N₂O₆	详情	详情
(X)	33157	ethyl (2S)-2-[[(1-[[(benzyloxy)carbonyl]amino]cyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₂₆H₃₂N₂O₆	详情	详情
(XI)	33159	(2R)-2-bromo-3-methylbutanoyl chloride		C₅H₈BrClO	详情	详情
(XII)	33160	ethyl (2S)-2-[[(1-[[(2R)-2-bromo-3-methylbutanoyl]amino]cyclopentyl)carbonyl]amino]-3-(4-methoxyphenyl)propanoate		C₂₃H₃₃BrN₂O₅	详情	详情
(XIII)	21056	(R)-(-)-Valine; D-Valine; (R)-alpha-Aminoisovaleric acid	640-68-6	C₅H₁₁NO₂	详情	详情
(XIV)	33158	(2R)-2-bromo-3-methylbutyric acid	565-74-2	C₅H₉BrO₂	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

Cycloleucine (I) is esterified with HCl/MeOH, and the resultant amino ester (II) is further protected as the tert-butyl carbamate (III) employing Boc2O and Et3N in CH2Cl2. Then, hydrolysis of the methyl ester group of (III) with LiOH furnishes N-Boc-cycloleucine (IV). N-Boc-L-Biphenylalanine (V) is simultaneously deprotected and esterified with HCl/MeOH to yield amino ester (VI). Coupling between N-Boc-cycloleucine (IV) and L-biphenylalanine methyl ester (VI) in the presence of EDC/HOAt gives rise to the protected dipeptide (VII). Subsequent removal of the N-Boc group of (VII) under acidic conditions yields the dipeptide methyl ester (VIII).

参考文献中间体

合成目标

【1】 Fink, C.A.; De Lombaert, S.; Hoyer, D.W.; Jeng, A.Y.; Firoozina, F. (Novartis AG; Novartis Pharma GmbH); Certain thiol inhibitors of endothelin-converting enzyme. WO 9955726 .

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)	33149	1-aminocyclopentanecarboxylic acid	52-52-8	C₆H₁₁NO₂	详情	详情
(II)	10444	methyl 1-aminocyclopentanecarboxylate		C₇H₁₃NO₂	详情	详情
(III)	62819	methyl 1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylate		C₁₂H₂₁NO₄	详情	详情
(IV)	30890	1-[(tert-butoxycarbonyl)amino]cyclopentanecarboxylic acid		C₁₁H₁₉NO₄	详情	详情
(V)	62820	(2S)-3-[1,1'-biphenyl]-4-yl-2-[(tert-butoxycarbonyl)amino]propanoic acid		C₂₀H₂₃NO₄	详情	详情
(VI)	62821	methyl (2S)-2-amino-3-[1,1'-biphenyl]-4-ylpropanoate		C₁₆H₁₇NO₂	详情	详情
(VII)	62822	methyl (2S)-3-[1,1'-biphenyl]-4-yl-2-[({1-[(tert-butoxycarbonyl)amino]cyclopentyl}carbonyl)amino]propanoate		C₂₇H₃₄N₂O₅	详情	详情
(VIII)	62823	methyl (2S)-2-{[(1-aminocyclopentyl)carbonyl]amino}-3-[1,1'-biphenyl]-4-ylpropanoate		C₂₂H₂₆N₂O₃	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VII)

Ibodutant is synthesized (1) starting from commercially available methyl tetrahydro-2H-pyran-4-carboxylate (I), which is hydrolyzed to the corresponding carboxylic acid by treatment with sodium hydroxide (1 M) and immediately transformed to the acyl chloride (II) with oxalyl chloride and catalytic DMF in dichloromethane. Reaction of (II) with isonipecotamide (III) in DMF/dichloromethane in the presence of triethylamine gives the diamide (IV), which is successfully reduced to the corresponding diamine (V) using lithium aluminum hydride in refluxing THF. Coupling of (V) with tert-butyloxycarbonyl-(R )-phenylalanine N-hydroxysuccinimide ester (Boc-D-Phe-OSu) in THF and Boc deprotection with HCl/dioxane gives (VI). Further coupling of (VI) with the N-Boc derivative of aminocyclopentanecarboxylic acid (VII) in the presence of EDC.HCl and HOBT, and deprotection of the Boc group with HCl/dioxane, provides 1-aminocyclopentanecarboxylic acid [2-phenyl-1-(R)-[[1-(tetrahydropyran-4-ylmethyl)piperidin-4-ylmethyl]carbamoyl]ethyl]amide (VIII). The free amine compound (VIII) is in turn coupled with 6-methylbenzo[b]thiophene-2-carbonyl chloride (IX), obtained from the corresponding carboxylic acid by reaction with oxalyl chloride under the usual conditions, finally giving ibodutant. Scheme 1.

参考文献中间体

合成目标

【1】 Fedi, V., Altamura, M., Catalioto, R.M. et al. Discovery of a series of potent and selective linear tachykinin NK2 receptor antagonists. J Med Chem 2007, 50(20): 4793-807.

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)	65548	Methyl tetrahydropyran-4-carboxylate; Tetrahydropyran-4-carboxylic acid methyl ester; THPE	110238-91-0	C₇H₁₂O₃	详情	详情
(II)	50860	tetrahydro-2H-pyran-4-carbonyl chloride	40191-32-0	C₆H₉ClO₂	详情	详情
(III)	11762	4-Piperidinecarboxamide; Isonipecotamide	39546-32-2	C₆H₁₂N₂O	详情	详情
(IV)	65549			C₁₂H₂₀N₂O₃	详情	详情
(V)	65550			C₁₂H₂₄N₂O	详情	详情
(VI)	65551			C₂₁H₃₃N₃O₂	详情	详情
(VII)	33149	1-aminocyclopentanecarboxylic acid	52-52-8	C₆H₁₁NO₂	详情	详情
(VIII)	65552			C₂₇H₄₂N₄O₃	详情	详情
(IX)	65553	6-Methyl-1-Benzothiophene-2-Carbonyl Chloride; 6-Methyl-Benzo[B]Thiophene-2-Carbonyl Chloride		C₁₀H₇ClOS	详情	详情

Extended Information