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【结 构 式】 
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【分子编号】63002 【品名】1-{[(1,1-dimethylethyl)oxy]carbonyl}-2-pyrrolidinylboronic acid; 1-(tert-butoxycarbonyl)-2-pyrrolidinylboronic acid 【CA登记号】149682-75-7 |
【 分 子 式 】C9H18BNO4 【 分 子 量 】215.05726 【元素组成】C 50.27% H 8.44% B 5.03% N 6.51% O 29.76% |
合成路线1
该中间体在本合成路线中的序号：(III)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
该中间体在本合成路线中的序号：(VI)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 |
合成路线3
该中间体在本合成路线中的序号：(III)Protection of pyrrolidine (I) with Boc2O in MTBE provides the corresponding N-Boc derivative (II) , which after metalation with sec-BuLi in THF and quenching with B(OMe)3 gives N-Boc-boroproline (III) . Condensation of racemic boronic acid (III) with (+)-pinanediol (IV) in isopropyl acetate or MTBE affords the boronate ester (V) as a diastereomeric mixture. After deprotection by removing the Boc group with HCl in i-PrOH or Et2O , the 2(R)-boroproline pinanediol ester hydrochloride (VI) diastereomer is separated by recrystallization from i-PrOH (1-3). Acylation of compound (VI) with 2-chloroacetyl chloride (VII) in the presence of NMM in CH2Cl2 provides the 2-chloroacetamide (VIII), which is then condensed with 3(R)-amino-1-Boc-pyrrolidine (IX) by means of K2CO3 in THF to give the glycinamide derivative (X). Finally, simultaneous hydrolysis of the N-Boc and boronate ester groups in compound (X) using phenylboronic acid in H2O/hexane provides dutogliptin free base (XI) .
Alternatively, coupling of the 2(R)-boroproline derivative (VI) with either the diprotected N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) via activation as the corresponding mixed anhydride with isobutyl chloroformate and NMM in 2-MeTHF , or by means of EDC, HOBt and NMM in CH2Cl2 , or also with the dicyclohexylamine salt (XIII) in the presence of EDC, HOBt and NMM , affords amide (XIV), which is deprotected by catalytic hydrogenolysis over Pd/C in MeOH to give diamine (XV). Finally, diamine (XV) undergoes boronate ester cleavage by means of phenylboronic acid in the presence of L-tartaric acid in H2O/MTBE to afford dutogliptin tartrate .
| 【1】 Wu, Z.P., Campbell, D.A., Cherrington, J.M. (Phenomix Corp.). Solid citrate and tartrate salts of DPP-IV inhibitors. EP 2061474, JP 2010502610, WO 2008027273. |
| 【2】 Campbell, D.A., Winn, D. (Phenomix Corp.). Heterocyclic boronic acid compounds. CA 2545311, EP 1689757, EP 1743676, EP 1997533, JP 2007512254, JP 2009007377, US 2007060547, WO 2005047297. |
| 【3】 Campbell, D.A., Winn, D.T., Betancort, J.M. (Phenomix Corp.). Pyrrolidine compounds and methods for selective inhibition of dipeptidyl peptidase-IV. US 2006264400, US 7317109. |
| 【4】 Campbell, D.A., Winn, D.T. (Phenomix Corp.). Methods of preparing heterocyclic boronic acids and derivatives thereof. EP 1919485, JP 2009503077, US 2008300413, WO2007016356. |
| 【5】 Wu, Z.-P. (Phenomix Corp.). A crystalline synthetic intermediate for preparation of a DPP-IV inhibitor and method of purification thereof. EP 2175727, WO 2009009751. |
| 【6】 Campbell, D.A., Leitao, E.P.T., Wu, Z.-P., Wang, P. (Phenomix Corp.). Methods and intermediates for synthesis of selective DPP-IV inhibitors. EP 2173709, WO 2008109681. |
| 【7】 Wang, P. (Phenomix Corp.). A crystalline synthetic intermediate for pyrrolidin-3-yl-glycylaminoalkylboronates. WO 2009094462. |
| 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) | 11376 | Pyrrolidine | 123-75-1 | C4H9N | 详情 | 详情 |
| (II) | 16439 | tert-butyl 1-pyrrolidinecarboxylate | 86953-79-9 | C9H17NO2 | 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) | 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 |
| (V) | 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 | |
| (VI) | 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 |
| (VII) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (VIII) | 65981 | C16H25BClNO3 | 详情 | 详情 | ||
| (IX) | 65982 | (3R)-(+)-1-Boc-3-aminopyrrolidine; (3R)-(+)-N-Boc-3-aminopyrrolidine; (3R)-(+)-N-tert-Butoxycarbonyl-3-aminopyrrolidine | 147081-49-0 | C9H18N2O2 | 详情 | 详情 |
| (X) | 65983 | C25H42BN3O5 | 详情 | 详情 | ||
| (XI) | 65984 | [(2R)-1-[[(3R)-3-Pyrrolidinylamino]acetyl]-2-pyrrolidinyl]-boronic acid; Dutogliptin | 852329-66-9 | C10H20BN3O3 | 详情 | 详情 |
| (XII) | 65985 | C21H24N2O6 | 详情 | 详情 | ||
| (XIII) | 65986 | C21H24N2O6.C12H23N | 详情 | 详情 | ||
| (XIV) | 65987 | C35H44BN3O7 | 详情 | 详情 | ||
| (XV) | 65988 | C20H34BN3O3 | 详情 | 详情 |