(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】17005

【品名】(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid

【CA登记号】

【分子式】C₁₃H₁₅NO₄

【分子量】249.26644

【元素组成】C 62.64% H 6.07% N 5.62% O 25.67%

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 title compound has been prepared by two related procedures. Treatment of N-carbobenzoxy-D-proline (I) with oxalyl chloride provided the corresponding acid chloride (II). This was condensed with 5-methoxyindolyl magnesium bromide, generated from 5-methoxyindole (III) and ethylmagnesium bromide, to afford the indolyl ketone (IV). Reduction of both keto and carbamate groups of (IV) by means of LiAlH4 in refluxing THF then furnished the target compound.

参考文献中间体

合成目标

【1】 Schmidt, A.W.; Macor, J.E.; Blake, J.; Ryan, K.; Fox, C.B.; Zorn, S.H.; Morrone, J.M.; Koe, B.K.; Johnson, C.; Schulz, D.W.; Lebel, L.A.; Synthesis and serotonergic pharmacology of the enantiomers of 3-[(N-methylpyrrolidin-2-yl)methyl]-5-methoxy-1H-indole: Discovery of stereogenic differentiation in the aminoethyl side chain of the neurotransmitter serotonin. J Med Chem 1992, 35, 23, 4503.

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)	17005	(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₅NO₄	详情	详情
(II)	17006	benzyl (2R)-2-(chlorocarbonyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₃H₁₄ClNO₃	详情	详情
(III)	25902	1H-Indol-5-yl methyl ether; 5-Methoxy-1H-indole; 5-Methoxyindole	1006-94-6	C₉H₉NO	详情	详情
(IV)	31540	benzyl (2R)-2-[(5-methoxy-1H-indol-3-yl)carbonyl]-1-pyrrolidinecarboxylate		C₂₂H₂₂N₂O₄	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 reaction of N-(benzyloxycarbonyl)-D-proline (I) with oxalyl chloride in dichloromethane/DMF gives the corresponding acyl chloride (II), which is condensed with 5-bromoindole (III) by means of ethylmagnesium bromide in ether yielding 3-(N-benzyloxycarbonyl-D-prolyl)-5-bromoindole (IV). The reduction of the carbonyl group of (IV) with LiAlH4 in THF affords 5-bromo-3-[1-methylpyrrolidin-2(R)-ylmethyl]indole (V), which is condensed with phenyl(vinyl)sulfone (VI) by means of tri-p-tolylphosphine, palladium acetate and triethylamine in refluxing acetonitrile giving the substituted (E)-vinyl sulfone (VII). Finally, this compound is hydrogenated with H2 over Pd/C in ethanol/HCl.

参考文献中间体

合成目标

【1】 Ngo, J.; Rabasseda, X.; Castañer, J.; Eletriptan. Drugs Fut 1997, 22, 3, 221.
【2】 Harding, V.D.; Macrae, R.J.; Ogilvie, R.J. (Pfizer Inc.); Salts of an anti-migraine indole deriv. EP 0776323; JP 1997512283; US 6110940; WO 9606842 .
【3】 Macor, J.E.; Wythes, M.J. (Pfizer Inc.); Indole derivs. EP 0592438; JP 1993507288; JP 1997003063; US 5545644; WO 9206973 .
【4】 Perkins, J.F. (Pfizer Inc.); Process for the preparation of 3-acyl-indoles. EP 1088817 .

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)	17005	(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₅NO₄	详情	详情
(II)	17006	benzyl (2R)-2-(chlorocarbonyl)tetrahydro-1H-pyrrole-1-carboxylate		C₁₃H₁₄ClNO₃	详情	详情
(III)	13309	5-Bromo-1H-indole; 5-Bromoindole	10075-50-0	C₈H₆BrN	详情	详情
(IV)	17008	benzyl (2R)-2-[(5-bromo-1H-indol-3-yl)carbonyl]tetrahydro-1H-pyrrole-1-carboxylate		C₂₁H₁₉BrN₂O₃	详情	详情
(V)	17009	5-bromo-3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indole		C₁₄H₁₇BrN₂	详情	详情
(VI)	17010	phenyl vinyl sulfone; dioxo(phenyl)vinyl-lambda(6)-sulfane; Benzene, (ethenylsulfonyl)-	5535-48-8	C₈H₈O₂S	详情	详情
(VII)	17011	(E)-2-(3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-1H-indol-5-yl)ethenyl phenyl sulfone; 3-[[(2R)-1-methyltetrahydro-1H-pyrrol-2-yl]methyl]-5-[(E)-2-(phenylsulfonyl)ethenyl]-1H-indole	180637-89-2	C₂₂H₂₄N₂O₂S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(VI)

The cyclocondensation of triphenylphosphite (I) with 4-(benzyloxycarbonyl-L-prolylamino)butyraldehyde (II) in hot acetic acid gives the pyrrolidinylphosphonate (III), which is deprotected by hydrogenation with H2 over Pd/C in methanol. The intermediates (I) and (II) have been obtained as follows: Phosphite (I): The acylation of 4-aminophenol (IV) with acetic acid and isobutyl chloroformate in DMF gives N-(4-hydroxyphenyl)acetamide (V), which is allowed to react with PCl3 and triethylamine in DMF yielding phosphite (I). 4-(Benzyloxycarbonyl-L-prolylamino)butyraldehyde (II): The condensation of N-(benzyloxycarbonyl)-L-proline (VI) with 4-aminobutyraldehyde diethylacetal (VII) by means of isobutyl chloroformate and triethylamine in chloroform gives 4-[N-(benzyloxycarbonyl)-L-prolylamino]butyraldehyde diethylacetal (VIII), which is hydrolyzed to the target aldehyde (II) with HCl in THF.

参考文献中间体

合成目标

【1】 De Meester, I.; Augustyns, K.; Haemers, A.; Zhang, X.; Vedernikova, I.; Belyaev, A.; Scharpé, S.; Lambeir, A.-M.; Structure-activity relationship of diaryl phosphonate esters as potent irreversible dipeptidyl peptidase IV inhibitors. J Med Chem 1999, 42, 6, 1041.

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)	26634	tris[4-(acetamido)phenyl] phosphite		C₂₄H₂₄N₃O₆P	详情	详情
(II)	26635	benzyl (2S)-2-[[(4-oxobutyl)amino]carbonyl]-1-pyrrolidinecarboxylate		C₁₇H₂₂N₂O₄	详情	详情
(III)	26636	benzyl (2S)-2-[(2-[bis[4-(acetamido)phenoxy]phosphoryl]-1-pyrrolidinyl)carbonyl]-1-pyrrolidinecarboxylate		C₃₃H₃₇N₄O₈P	详情	详情
(IV)	15715	4-Aminophenol	123-30-8	C₆H₇NO	详情	详情
(V)	21611	4'-Hydroxyacetanilide;4-Acetamidophenol;N-Acetyl-4-aminophenol;Paracetamol;Acetaminophen;p-Hydroxyacetanilide; Paracetamol; N-(4-hydroxyphenyl)acetamide	103-90-2	C₈H₉NO₂	详情	详情
(VI)	17005	(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₅NO₄	详情	详情
(VII)	23323	4,4-diethoxybutylamine; 4,4-diethoxy-1-butanamine	6346-09-4	C₈H₁₉NO₂	详情	详情
(VIII)	26637	benzyl (2S)-2-[[(4,4-diethoxybutyl)amino]carbonyl]-1-pyrrolidinecarboxylate		C₂₁H₃₂N₂O₅	详情	详情

合成路线4

该中间体在本合成路线中的序号：(I)

Esterification of N-benzyloxycarbonyl-D-proline (I) with MeOH in the presence of EDC, followed by deprotection of the resultant N-Cbz amino ester (II) with H2 and Pd(OH)2 leads to D-proline methyl ester (III). Subsequent coupling of (III) with N-benzyloxycarbonyl-O-t-butyl-L-4-trans-hydroxyproline (IV) yields the protected dipeptide (V). After removal of the N-benzyloxycarbonyl group of (V) by catalytic hydrogenolysis, the free amine (VI) is acylated by 3,3,3-triphenylpropionic acid (VII), producing amide (VIII). The methyl ester group of (VIII) is then hydrolyzed under alkaline conditions to furnish acid (IX).

参考文献中间体

合成目标

【1】 Sagara, Y.; Kimura, T.; Fujikawa, T.; Noguchi, K.; Ohtake, N.; Identification of novel muscarinic M3 selective antagonists with a conformationally restricted Hyp-Pro spacer. Bioorg Med Chem Lett 2003, 13, 1, 57.
【2】 Kimura, T.; Noguchi, K.; Otake, N.; Uchiyama, M.; Naya, A.; Sagara, Y.; Numazawa, T.; Fujikawa, T. (Banyu Pharmaceutical Co., Ltd.); Novel amide derivs.. EP 1213281; WO 0107406 .

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)	17005	(2R)-1-[(benzyloxy)carbonyl]tetrahydro-1H-pyrrole-2-carboxylic acid		C₁₃H₁₅NO₄	详情	详情
(II)	62798	1-benzyl 2-methyl (2R)-1,2-pyrrolidinedicarboxylate		C₁₄H₁₇NO₄	详情	详情
(III)	36811	methyl (2R)-2-pyrrolidinecarboxylate		C₆H₁₁NO₂	详情	详情
(IV)	62799	(2S,4R)-1-[(benzyloxy)carbonyl]-4-(tert-butoxy)-2-pyrrolidinecarboxylic acid		C₁₇H₂₃NO₅	详情	详情
(V)	62800	benzyl (2S,4R)-4-(tert-butoxy)-2-{[(2R)-2-(methoxycarbonyl)pyrrolidinyl]carbonyl}-1-pyrrolidinecarboxylate		C₂₃H₃₂N₂O₆	详情	详情
(VI)	62801	methyl (2R)-1-{[(2S,4R)-4-(tert-butoxy)pyrrolidinyl]carbonyl}-2-pyrrolidinecarboxylate		C₁₅H₂₆N₂O₄	详情	详情
(VII)	57640	3,3,3-Triphenylpropionic acid; Tritylacetic acid	900-91-4	C₂₁H₁₈O₂	详情	详情
(VIII)	62802	methyl (2R)-1-{[(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidinyl]carbonyl}-2-pyrrolidinecarboxylate		C₃₆H₄₂N₂O₅	详情	详情
(IX)	62803	(2R)-1-{[(2S,4R)-4-(tert-butoxy)-1-(3,3,3-triphenylpropanoyl)pyrrolidinyl]carbonyl}-2-pyrrolidinecarboxylic acid		C₃₅H₄₀N₂O₅	详情	详情

Extended Information