(2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone -Drug Synthesis Database

【结构式】

【分子编号】63012

【品名】(2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone

【CA登记号】

【分子式】C₁₉H₃₃BN₂O₃

【分子量】348.2937

【元素组成】C 65.52% H 9.55% B 3.1% N 8.04% O 13.78%

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：(XI)

Metalation of N-Boc-pyrrole (I) with the lithium amide of tetramethylpiperidine, followed by boronation with triethyl borate and acidic work-up leads to the pyrroleboronic acid (II). Subsequent catalytic hydrogenation over Pt/C provides the racemic pyrrolidineboronic acid (III). Alternatively, protection of pyrrolidine (IV) with Boc2O affords (V). After metalation of N-Boc-pyrrolidine (V) with s-butyllithium, treatment with triethyl borate gives rise to the boronic acid (III). Condensation of the racemic boronic acid (III) with (+)-pinanediol (VI) furnishes the corresponding mixture of diastereoisomeric pinanediol boronates, from which the desired isomer (VII) can be isolated by column chromatography. Further removal of the N-Boc protecting group under acidic conditions yields the pyrrolidineboronic ester (VIII). Coupling of pyrrolidine (VIII) with N-Boc-L-valine (IX) produces amide (X). The N-Boc group is then cleaved with HCl in Et2O to afford the deprotected amine (XI). Finally, removal of the pinanediol moiety by transesterification of the boronic ester (XI) with phenylboronic acid provides the desired boronic dipeptide

参考文献中间体

合成目标

【1】 Gibson, F.S.; Singh, A.K.; Soumeillant, M.C.; Manchand, P.S.; Humora, M.; Kronenthal, D.R.; A practical synthesis of L-valyl-pyrrolidine-(2R)-boronic acid: Efficient recycling of the costly chiral auxiliary (+)-pinanediol. Org Process Res Dev 2002, 6, 6, 814.
【2】 Coutts, S.J.; Kelly, T.A.; Snow, R.J.; Kennedy, C.A.; Barton, R.W.; Adams, J.; Krolikowski, D.A.; Freeman, D.M.; Campbell, S.J.; Ksiazek, J.F.; Bachovchin, W.W.; Structure-activity relationships of boronic acid inhibitors of dipeptidyl peptidase IV. 1. Variation of the P2 position of Xaa-boroPro dipeptides. J Med Chem 1996, 39, 10, 2087.
【3】 Wallner, B.P. (Point Therapeutics, Inc.); Cyclic boroproline cpds.. JP 2002517401; WO 9962914 .
【4】 Hoshi, H.; Okumura, J.; Naito, T.; Abe, Y.; Abukari, S. (Bristol-Myers Squibb Co.); Substituted vinyl cephalosporins. DE 3402642; US 4520022 .

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)	16432	tert-Butyl pyrrole-1-carboxylate; tert-Butyl-1H-pyrrole-1-carboxylate; tert-Butyl-1-pyrrolecarboxylate	5176-27-2	C₉H₁₃NO₂	详情	详情
(II)	63008	1-{[(1,1-dimethylethyl)oxy]carbonyl}-1H-pyrrol-2-ylboronic acid; 1-(tert-butoxycarbonyl)-1H-pyrrol-2-ylboronic acid		C₉H₁₄BNO₄	详情	详情
(III)	63002	1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid	149682-75-7	C₉H₁₈BNO₄	详情	详情
(IV)	11376	Pyrrolidine	123-75-1	C₄H₉N	详情	详情
(V)	16439	tert-butyl 1-pyrrolidinecarboxylate	86953-79-9	C₉H₁₇NO₂	详情	详情
(VI)	63005	(1S,2S,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]heptane-2,3-diol; (+)-Pinanediol	18680-27-8	C₁₀H₁₈O₂	详情	详情
(VII)	63006	tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate		C₁₉H₃₂BNO₄	详情	详情
(VIII)	63007	(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine	205116-75-2	C₁₄H₂₄BNO₂	详情	详情
(IX)	19733	(2S)-2-[(tert-butoxycarbonyl)amino]-3-methylbutyric acid		C₁₀H₁₉NO₄	详情	详情
(X)	63011	tert-butyl (1S)-2-methyl-1-({(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}carbonyl)propylcarbamate		C₂₄H₄₁BN₂O₅	详情	详情
(XI)	63012	(2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone		C₁₉H₃₃BN₂O₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

In a related synthetic procedure, N-trifluoroacetyl-L-valine (I) is activated as the corresponding acid chloride (II) by treatment with the Vilsmeier reagent in cold EtOAc. Coupling of (II) with the pyrrolidineboronic ester (III) yields amide (IV). The trifluoroacetyl protecting group is then removed by alkaline hydrolysis to produce (V). Finally, deprotection of the boronic acid moiety of (V) with concomitant recycling of the (+)-pinanediol chiral auxiliary is achieved by transesterification with N-Boc-2-pyrrolidineboronic acid (VI) in the presence of methanesulfonic acid to furnish the pinanediol boronate (VII) along with the title compound

参考文献中间体

合成目标

【1】 Gibson, F.S.; Singh, A.K.; Soumeillant, M.C.; Manchand, P.S.; Humora, M.; Kronenthal, D.R.; A practical synthesis of L-valyl-pyrrolidine-(2R)-boronic acid: Efficient recycling of the costly chiral auxiliary (+)-pinanediol. Org Process Res Dev 2002, 6, 6, 814.

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)	63014	(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoic acid; (2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoic acid		C₇H₁₀F₃NO₃	详情	详情
(II)	63015	(2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl chloride; (2S)-3-methyl-2-[(2,2,2-trifluoroacetyl)amino]butanoyl chloride		C₇H₉ClF₃NO₂	详情	详情
(III)	63007	(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidine	205116-75-2	C₁₄H₂₄BNO₂	详情	详情
(IV)	63016	2,2,2-trifluoro-N-[(1S)-2-methyl-1-({(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}carbonyl)propyl]acetamide; 2,2,2-trifluoro-N-[(1S)-2-methyl-1-({(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}carbonyl)propyl]acetamide		C₂₁H₃₂BF₃N₂O₄	详情	详情
(V)	63012	(2S)-2-amino-3-methyl-1-{(2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]pyrrolidinyl}-1-butanone		C₁₉H₃₃BN₂O₃	详情	详情
(VI)	63002	1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid	149682-75-7	C₉H₁₈BNO₄	详情	详情
(VII)	63006	tert-butyl (2R)-2-[(1S,2S,6R,8S)-2,9,9-trimethyl-3,5-dioxa-4-boratricyclo[6.1.1.0~2,6~]dec-4-yl]-1-pyrrolidinecarboxylate		C₁₉H₃₂BNO₄	详情	详情

Extended Information