(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid -Drug Synthesis Database

【结构式】

【分子编号】29741

【品名】(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid

【CA登记号】7669-64-9

【分子式】C₂₂H₂₄N₂O₅

【分子量】396.44304

【元素组成】C 66.65% H 6.1% N 7.07% O 20.18%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(IV)

N2-tert-Butyloxycarbonyl-N5-benzyloxycarbonyl-L-arginine (I) is cyclized by treatment with isobutyloxycarbonyl chloride and N-methylmorpholine to the lactam (II). The tert-butyloxycarbonyl group is removed by hydrochloric acid to give the aminolactam (III), which is coupled with N-benzyloxycarbonyl-D-phenylalanyl-L-proline (IV) using, as in the first step, the mixed anhydride method. The resulting tripeptide lactam (V) is reduced with LiAlH4 to an aldehyde, present as the cyclic alpha-aminoalcohol (VI). Deblocking by hydrogenolysis gives RGH-2958. In solution the aldehyde group is either in the cyclic alpha-aminoalcohol form or is hydrated.

参考文献中间体

合成目标

【1】 Rabloczky, Gy.; Bagdy, D.; Bajusz, S.; RGH-2958. Drugs Fut 1985, 10, 10, 829.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	13423	1-[(Chlorocarbonyl)oxy]-2-methylpropane; Isobutyl chloroformate;isobutyl carbonochloridate	543-27-1	C₅H₉ClO₂	详情	详情
(B)	28928	4-methylmorpholine	109-02-4	C₅H₁₁NO	详情	详情
(I)	29740	N(5)-[[[(benzyloxy)carbonyl]amino](imino)methyl]-N(2)-(tert-butoxycarbonyl)ornithine	51219-18-2	C₁₉H₂₈N₄O₆	详情	详情
(II)	28933	tert-butyl 1-(amino[[(benzyloxy)carbonyl]imino]methyl)-2-oxo-3-piperidinylcarbamate		C₁₉H₂₆N₄O₅	详情	详情
(III)	28929	benzyl (E)-amino(3-amino-2-oxo-1-piperidinyl)methylidenecarbamate		C₁₄H₁₈N₄O₃	详情	详情
(IV)	29741	(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid	7669-64-9	C₂₂H₂₄N₂O₅	详情	详情
(V)	29742	benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-oxo-1-piperidinyl]methylidenecarbamate		C₃₆H₄₀N₆O₇	详情	详情
(VI)	29743	benzyl (E)-amino[3-([[(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)pyrrolidinyl]carbonyl]amino)-2-hydroxy-1-piperidinyl]methylidenecarbamate		C₃₆H₄₂N₆O₇	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

3-Methoxypropyl chloride (I) is converted to the corresponding Grignard reagent by means of Mg in THF, followed by reaction with trimethyl borate and quenching with aqueous sulfuric acid to produce 3-methoxypropylboronic acid (II). Subsequent treatment of boronic acid (II) with a toluene or heptane solution of pinacol gives the pinacol boronate (III). One-carbon insertion into (III) is accomplished by treatment with dichloromethane, LDA and zinc chloride to furnish the 1-chloro-4-methoxybutylboronate (IV). Substitution of the chloride (IV) with lithium hexamethyldisilazide in THF, followed by desilylation with HCl in cold n-heptane, leads to the aminoboronate (V), which is then coupled with N-benzyloxycarbonyl-D-phenylalanyl-L-proline (VI) via activation as the mixed anhydride with isobutyl chloroformate to afford the tripeptide analogue (VII). The diastereomeric mixture of pinacol boronates (VII) undergoes transesterification and epimerization with diethanolamine in boiling diethyl ether to provide the diethanolamine adduct (VIII). Subsequent acidic hydrolysis of adduct (VIII) gives the boronic acid flovagatran, which is finally isolated as the corresponding sodium salt by treatment with sodium hydroxide in acetonitrile/water (1-3). Scheme 1.

参考文献中间体

合成目标

【1】 Combe-Marzelle, S.M., Kennedy, A.J., Krimmer, D., Withington, R., Allen, G.D. (Trigen, Ltd.). Peptide boronic acid compounds useful in anticoagulation. US 2005282757.
【2】 Boucher, O.V.A. (Trigen, Ltd.). Peptide boronic acid inhibitors. US 2006084592.
【3】 Madge, D.J., Dolman, M., Combe-Marzelle, S.M. et al. (Trigen, Ltd.). Peptide boronic acids useful in making salts thereof. EP 1466916.

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)	65325	3-Methoxypropyl chloride; 1-Chloro-3-methoxypropane; 3-Chloro-1-methoxypropane; 3-Chloropropyl methyl ether	36215-07-3	C₄H₉ClO	详情	详情
(II)	65326	3-methoxypropylboronic acid		C₄H₁₁BO₃	详情	详情
(III)	65327			C₁₀H₂₁BO₃	详情	详情
(IV)	65328			C₁₀H₂₀BClO₃	详情	详情
(V)	65329			C₁₀H₂₂BNO₃	详情	详情
(VI)	29741	(2S)-1-((2R)-2-[[(benzyloxy)carbonyl]amino]-3-phenylpropanoyl)-2-pyrrolidinecarboxylic acid	7669-64-9	C₂₂H₂₄N₂O₅	详情	详情
(VII)	65330			C₃₃H₄₆BN₃O₇	详情	详情
(VIII)	65331			C₃₁H₄₃BN₄O₇	详情	详情

Extended Information