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【结 构 式】

【分子编号】68639

【品名】6-amino-2-chloro-3-methylpyridine;2-Amino-6-chloro-5-methylpyridine;6-chloro-5-methyl-2-Pyridinamine

【CA登记号】442129-37-5

【 分 子 式 】C6H7ClN2

【 分 子 量 】142.58776

【元素组成】C 50.54% H 4.95% Cl 24.86% N 19.65%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XIII)

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 .

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:(XIII)

The intermediate 6-amino-2-chloro-3-methylpyridine (XIII) is prepared by protection of 2-amino-5-methylpyridine (XVIII) with pivaloyl chloride in the presence of Et3N in CH2Cl2 to give the N-pyridyl pivalamide (XIX), which is converted to the corresponding N-oxide (XX) by treatment with H2O2 in AcOH at 80 °C. Rearrangement of the N-oxide (XX) by means of POCl3 and Et3N in refluxing CH2Cl2 leads to the chloropyridine (XXI), which is finally hydrolyzed with aqueous HCl at 80 °C .

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.
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
(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
(XVIII) 12752 5-Methyl-2-pyridinylamine; 2-Amino-5-methylpyridine; 5-Methyl-2-pyridinamine; 6-Amino-beta-picoline; 6-Amino-3-picoline 1603-41-4 C6H8N2 详情 详情
(XIX) 68643 N-(5-methylpyridin-2-yl)pivalamide   C11H16N2O 详情 详情
(XX) 68644 5-methyl-2-pivalamidopyridine 1-oxide   C11H16N2O2 详情 详情
(XXI) 68645 N-(6-chloro-5-methylpyridin-2-yl)pivalamide   C11H15ClN2O 详情 详情
Extended Information