Dutogliptin tartrate； PHX-1149, -Drug Synthesis Database

【结构式】

【药物名称】Dutogliptin tartrate； PHX-1149

【化学名称】Boronic acid, [(2R)-1-[[(3R)-3-pyrrolidinylamino]acetyl]-2-pyrrolidinyl]-, (2R,3R)-2,3-dihydroxybutanedioate (1:1)

【CA登记号】890402-81-0；852329-66-9 (free base)

【分子式】C₁₀H₂₀BN₃O₃.C₄H₆O₆

【分子量】391.182

【开发单位】Phenomix Corp. (US); licensed to Chiesi Farmaceutici (IT) for Europe and other regions.

【药理作用】Dipeptidyl Peptidase 4 Inhibitor; Treatment of Diabetes

合成路线1 合成路线2

合成路线1

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 .

参考文献中间体

【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

合成路线2

The precursors N-(benzyloxycarbonyl)-N-[1-(benzyloxycarbonyl)-3(R)-pyrrolidinyl]glycine (XII) and its dicyclohexylamine salt (XIII) are prepared as follows. Alkylation of 3(R)-amino-1-(benzyloxycarbonyl)pyrrolidine or its hydrochloride (XVI) with methyl 2-bromoacetate (XVII) by means of K2CO3 in MTBE/H2O yields the amino ester (XVIII), which, without isolation, is further protected with benzyloxycarbonyl chloride to provide the diprotected compound (XIX). Hydrolysis of the methyl ester (XIX) with NaOH in refluxing MTBE/H2O followed by in situ treatment of the obtained sodium salt with HCl leads to the carboxylic acid (XII) , which by treatment with dicyclohexylamine in THF provides the corresponding dicyclohexylammonium salt (XIII) .

参考文献中间体

【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.
【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.
【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
(XII)	63162	2-[(E)-2-phenyldiazenyl]malononitrile	6017-21-6	C₉H₆N₄	详情	详情
(XIII)	63163	2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4,6-pyrimidinediamine; 6-amino-2-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-5-[(E)-2-phenyldiazenyl]-4-pyrimidinylamine	428854-23-3	C₂₃H₁₈FN₉	详情	详情
(XVI)	65989	(3R)-1-Cbz-3-Aminopyrrolidine hydrochloride	870621-17-3	C₁₂H₁₆N₂O₂.HCl	详情	详情
(XVII)	12309	methyl 2-bromoacetate; methyl bromoacetate	96-32-2	C₃H₅BrO₂	详情	详情
(XVIII)	65990			C₁₅H₂₀N₂O₄	详情	详情
(XIX)	65991			C₂₃H₂₆N₂O₆	详情	详情

Extended Information