【结 构 式】 |
【分子编号】65982 【品名】(3R)-(+)-1-Boc-3-aminopyrrolidine; (3R)-(+)-N-Boc-3-aminopyrrolidine; (3R)-(+)-N-tert-Butoxycarbonyl-3-aminopyrrolidine 【CA登记号】147081-49-0 |
【 分 子 式 】C9H18N2O2 【 分 子 量 】186.2542 【元素组成】C 58.04% H 9.74% N 15.04% O 17.18% |
合成路线1
该中间体在本合成路线中的序号:(IX)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 |