tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate -Drug Synthesis Database

【结构式】

【分子编号】68642

【品名】tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate

【CA登记号】　

【分子式】C₁₇H₂₀N₂O₂

【分子量】284.35808

【元素组成】C 71.81% H 7.09% N 9.85% O 11.25%

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：(XVI)

Methoxycarbonylation of 5-bromo-2,2-difluoro-1,3-benzodioxole (I) under CO atmosphere in the presence of Pd(PPh3)4 and Et3N in MeOH/acetonitrile at 75 °C produces the benzodioxole carboxylate (II), which is reduced to primary alcohol (III) using LiAlH4 in THF . Similarly, alcohol (III) can be obtained by reduction of 2,2-difluoro-1,3-benzodioxole-5-carboxylic acid (IV) with Red-Al in toluene . Chlorination of alcohol (III) with SOCl2, optionally in the presence of DMAP, in CH2Cl2 or MTBE affords 5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole (V), which upon cyanation with NaCN in DMSO produces nitrile (VI) . In an alternative procedure, coupling of bromo benzodioxole (I) with ethyl cyanoacetate (VII) by means of Pd(dba)2, t-Bu3P and Na3PO4 in toluene/H2O at 70 °C yields the 2-cyanoacetate derivative (VIII), which undergoes decarboethoxylation to compound (VI) by means of HCl in DMSO/H2O at 75 °C . Dialkylation of nitrile (VI) with 1-bromo-2-chloroethane (IX) in the presence of either NaOH and BnNEt3Cl or KOH and Oct4NBr at 70 °C yields 1-(2,2-difluoro-1,3-benzodioxol-5-yl)cyclopropanecarbonitrile (X). After hydrolysis of nitrile (X) with NaOH in boiling H2O or EtOH, the resulting carboxylic acid (XI) is chlorinated with SOCl2 in the presence of DMF toluene at 60 °C to provide the acid chloride (XII) . Condensation of the cyclopropanecarbonyl chloride (XII) with 6-amino-2-chloro-3-methylpyridine (XIII) in pyridine at 110 °C affords the N-pyridyl amide (XIV), which finally undergoes Suzuki coupling with pinacol 3-carboxyphenylboronate (XV) by means of Pd(dppf)Cl2 and K2CO3 in hot DMF/H2O to furnish lumacaftor .
Alternatively, condensation of acid chloride (XII) with the biaryl amine (XVI) in the presence of Et3N and DMAP in toluene generates the tert-butyl ester (XVII), which is finally hydrolized by treatment with HCl in acetonitrile/water , followed by dissolving the obtained amino acid hydrochloride salt in aqueous NaOH or H2O, or by direct hydrolysis of ester (XVII) with HCOOH at 60-80 °C .

参考文献中间体

合成目标

【1】 Hadida Rua, S., Hamilton, M., Miller, M., Grootenhuis, P.D.J., Bear, B., McCarthy, J., Zhou, J. (Vertex Pharmaceuticals, Inc.). Heterocyclic modulators of ATP-binding cassette transporters. EP 1945632, EP 2395002, EP 2404919, JP 2009514962, US 2008113985, US 7741321, US 7973038, US 2011172229, US 2011312958, US 2012232059, WO 2007056341.
【2】 Siesel, D. (Vertex Pharmaceuticals, Inc.). Processes for producing cycloalkylcarboxamido-pyridine benzoic acids. CN 101910134, EP 2231606, JP 2011506332, KR 201010132, US 2009176989, US 8124781, US 2012190856, WO 2009076142.
【3】 Pilewski, J.M., Frizzell, R.A. Role of CFTR in airway disease. Physiol Rev 1999, 79(1, Suppl.): S215-55.

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)	57609	5-Bromo-2,2-difluoro-1,3-benzodioxole；4-Bromo-1,2-[(difluoromethylene)dioxy]benzene	33070-32-5	C₇H₃BrF₂O₂	详情	详情
(II)	68629	methyl 2,2-difluorobenzo[d][1,3]dioxole-5-carboxylate	773873-95-3	C₉H₆F₂O₄	详情	详情
(III)	68630	(2,2-difluorobenzo[d][1,3]dioxol-5-yl)methanol		C₈H₆F₂O₃	详情	详情
(IV)	68631	2,2-difluorobenzo[d][1,3]dioxole-5-carboxylic acid;2,2-difluoro-1,3-benzodioxole-5-carboxylic acid		C₈H₄F₂O₄	详情	详情
(V)	68632	5-(chloromethyl)-2,2-difluorobenzo[d][1,3]dioxole;5-(chloromethyl)-2,2-difluoro-1,3-benzodioxole		C₈H₅ClF₂O₂	详情	详情
(VI)	68633	2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetonitrile		C₉H₅F₂NO₂	详情	详情
(VII)	11877	Cyanoacetic acid ethyl ester; Ethyl 2-cyanoacetate; Ethyl cyanoacetate; Ethyl isocyanacetate	105-56-6	C₅H₇NO₂	详情	详情
(VIII)	68634	ethyl 2-cyano-2-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)acetate		C₁₂H₉F₂NO₄	详情	详情
(IX)	24271	1-bromo-2-chloroethane	107-04-0	C₂H₄BrCl	详情	详情
(X)	68635	1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonitrile		C₁₁H₇F₂NO₂	详情	详情
(XI)	68636	1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxylic acid		C₁₁H₈F₂O₄	详情	详情
(XII)	68637	1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride		C₁₁H₇ClF₂O₃	详情	详情
(XIII)	68639	6-amino-2-chloro-3-methylpyridine;2-Amino-6-chloro-5-methylpyridine;6-chloro-5-methyl-2-Pyridinamine	442129-37-5	C₆H₇ClN₂	详情	详情
(XIV)	68638	N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide		C₁₇H₁₃ClF₂N₂O₃	详情	详情
(XV)	68641	3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoic acid;3-Carboxyphenylboronic acid pinacol ester	269409-73-6	C₁₃H₁₇BO₄	详情	详情
(XVI)	68642	tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate		C₁₇H₂₀N₂O₂	详情	详情
(XVII)	68640	tert-butyl 3-(6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-3-methylpyridin-2-yl)benzoate		C₂₈H₂₆F₂N₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XVI)

Intermediate (XVI) is prepared by Suzuki coupling of 2-bromo-3-methylpyridine (XXII) with 3-(tert-butoxycarbonyl)phenylboronic acid (XXIII) in the presence of PdCl2(dppf) and K2CO3 in toluene at 65 °C to give tert-butyl 3-(3-methylpyridin-2-yl)benzoate (XXIV), which upon oxidation of the pyridine ring using urea-hydrogen peroxide and phthalic anhydride in EtOAc/H2O furnishes the pyridine-N-oxide (XXV). Finally, compound (XXV) is submited to rearrangement with Ms2O in the presence of pyridine in acetonitrile at 70 °C followed by quenching with ethanolamine .

参考文献中间体

合成目标

【1】 Siesel, D. (Vertex Pharmaceuticals, Inc.). Processes for producing cycloalkylcarboxamido-pyridine benzoic acids. CN 101910134, EP 2231606, JP 2011506332, KR 201010132, US 2009176989, US 8124781, US 2012190856, WO 2009076142.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XVI)	68642	tert-butyl 3-(6-amino-3-methylpyridin-2-yl)benzoate		C₁₇H₂₀N₂O₂	详情	详情
(XXII)	57602	2-Bromo-3-methylpyridine; 2-Bromo-3-picoline	3430-17-9	C₆H₆BrN	详情	详情
(XXIII)	68646	3-(tert-butoxycarbonyl)phenylboronic acid;3-tert-Butoxycarbonylphenylboronic acid	220210-56-0	C₁₁H₁₅BO₄	详情	详情
(XXIV)	68648	tert-butyl 3-(3-methylpyridin-2-yl)benzoate		C₁₇H₁₉NO₂	详情	详情
(XXV)	68647	2-(3-(tert-butoxycarbonyl)phenyl)-3-methylpyridine 1-oxide		C₁₇H₁₉NO₃	详情	详情

Extended Information