【结 构 式】 |
【药物名称】ValboroPro, PT-100 【化学名称】L-Valyl-L-boroproline 【CA登记号】174276-10-9, 149663-30-9 (HCl), 251976-07-5 (monomethanesulfonate salt) 【 分 子 式 】C9H19BN2O3 【 分 子 量 】214.07438 |
【开发单位】Point Therapeutics (Originator) 【药理作用】HEMATOLOGIC DRUGS, Hematopoiesis Disorders Therapy, Hematopoietic Agents, IMMUNOMODULATING AGENTS, Immunostimulants, Leukemia Therapy, Lung Cancer Therapy, Lymphocytic Leukemia Therapy, Lymphoma Therapy, Melanoma Therapy, Non-Hodgkin's Lymphoma Therapy, Non-Small Cell Lung Cancer Therapy, Oncolytic Drugs, Dipeptidyl-Peptidase IV Inhibitors |
合成路线1
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
【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
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
【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 |