1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride; -Drug Synthesis Database

【结构式】

【分子编号】45871

【品名】1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride;

【CA登记号】10147-36-1

【分子式】C₃H₇ClO₂S

【分子量】142.60608

【元素组成】C 25.27% H 4.95% Cl 24.86% O 22.44% S 22.49%

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：(VIII)

N-protection of the NH group of (I) with Boc2O and NaOH in Et2O yields derivative (II), which is then condensed with compound (III) by means of NaH in DMF to provide (IV). N-deprotection of (IV) by treatment with TFA in CH2Cl2 followed by reductocondensation with N-Boc-4-piperidone (V) in CH2Cl2 in the presence of Na(OAc)3BH affords compound (VI), which is oxidized with NaBO3.4H2O to provide (VII). Boc removal of (VII) by treatment with TFA in CH2Cl2, followed by reaction of the resulting secondary amine with sulfonyl chloride (VIII) in CH2Cl2 in the presence of Et3N, affords propylsulfonamide derivative (IX). Finally, treatment of (IX) with ethyleneglycol (X) in toluene in the presence of HC(OEt)3 and p-TsOH furnishes the target compound.

参考文献中间体

合成目标

【1】 Boyle, C.D.; Chackalamannil, S.; Chen, L.-Y.; et al.; Benzylidine ketal derivatives as M2 muscarinic receptor antagonists. Bioorg Med Chem Lett 2000, 10, 24, 2727.
【2】 Chackalamannil, S.; Chen, L.-Y.; Boyle, C.D.; et al.; Benzylidene ketal derivatives as M2 muscarinic receptor antagonists. 220th ACS Natl Meet (Aug 20 2000, Washington DC) 2000, Abst MEDI 114.

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)	21497	(4-Fluorophenyl)(4-piperidinyl)methanone; 4-(4-Fluorobenzoyl)piperidine; 4-(p-Fluorobenzoyl)piperidine	56346-57-7	C₁₂H₁₄FNO	详情	详情
(II)	45867	tert-butyl 4-(4-fluorobenzoyl)-1-piperidinecarboxylate		C₁₇H₂₂FNO₃	详情	详情
(III)	28620	1,3-benzodioxole-5-thiol		C₇H₆O₂S	详情	详情
(IV)	45868	tert-butyl 4-[4-(1,3-benzodioxol-5-ylsulfanyl)benzoyl]-1-piperidinecarboxylate		C₂₄H₂₇NO₅S	详情	详情
(V)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(VI)	45869			C₂₉H₃₆N₂O₅S	详情	详情
(VII)	45870			C₂₉H₃₆N₂O₇S	详情	详情
(VIII)	45871	1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride;	10147-36-1	C₃H₇ClO₂S	详情	详情
(IX)	45872			C₂₇H₃₄N₂O₇S₂	详情	详情
(X)	11295	Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol	107-21-1	C₂H₆O₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

In one strategy, 2,4-difluoroaniline (I) is lithiated with BuLi in the presence of 1,2-bis(chlorodimethylsilyl)ethane in THF at –78 °C, and subsequently acylated with benzyl chloroformate, yielding benzyl 3-amino-2,6-difluorobenzoate (II). N-Sulfonylation of aniline (II) with propane-1-sulfonyl chloride (III) using pyridine in CH2Cl2 gives the corresponding sulfonamide (IV), which is then debenzylated with H2 over Pd(OH)2/C in MeOH to provide the benzoic acid derivative (V). After chlorination of acid (V) with SOCl2 in refluxing toluene, the resulting acid chloride (VI) is subjected to Friedel–Crafts reaction with 5-bromopyrrolo[2,3-b]pyridine (VII) in the presence of AlCl3 in CH2Cl2 to afford ketone (VIII). Finally, the aryl bromide (VIII) is submitted to a Suzuki coupling with 4-chlorophenylboronic acid (IX) in the presence of Pd(PPh3)4 and K2CO3 in acetonitrile .
In an alternative strategy, 2,4-difluoroaniline (I) is coupled with propane-1-sulfonyl chloride (III) by means of Et3N in THF to give N-(2,4-difluorophenyl)propane-1-sulfonamide (X), which, after lithiation with LDA in THF, is formylated by reaction with DMF, yielding 2,6-difluoro-3-(propylsulfonamido)benzaldehyde (XI). Condensation of aldehyde (XI) with 5-(4-chlorophenyl)pyrrolo[2,3-b]pyridine (XII) (obtained by Suzuki coupling of 5-bromopyrrolo[2,3-b]pyridine (VII) with boronic acid (IX) in the presence of Pd(PPh3)4 and K2CO3 in acetonitrile/H2O) using KOH in MeOH provides a mixture of the diarylcarbinol (XIII) and its corresponding methyl ether, which is further enriched in the desired alcohol (XIII) by demethylation with HBr in AcOH. Alcohol (XIII) is finally oxidized using DDQ in dioxane .

参考文献中间体

合成目标

【1】 Ibrahim, P.N., Artis, D.R., Bremer, R. et al. (Plexxicon, Inc.). Pyrrolo[2,3-b]pyridine derivatives as protein kinase inhibitors. JP 20008546797, WO 2007002325.
【2】 Ibrahim, P.N., Artis, D.R., Bremer, R. et al. (Plexxicon, Inc.). Pyrrolo[2,3-b]pyridine derivatives as protein kinase inhibitors. EP 1893612, WO 200700233.

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)	19462	2,4-difluoroaniline; 2,4-difluorophenylamine；2,4-Difluoro-benzenamine;1-Amino-2,4-difluorobenzene	367-25-9	C₆H₅F₂N	详情	详情
(II)	68766	1-(3-amino-2,6-difluorophenyl)-2-phenylethanone		C₁₄H₁₁F₂NO	详情	详情
(III)	45871	1-propanesulfonyl chloride；Propanesulfonylchloride；n-Propylsulphonyl chloride；Propylsulfonyl chloride;n-Propanesulfonyl chloride;	10147-36-1	C₃H₇ClO₂S	详情	详情
(IV)	68767	N-(2,4-difluoro-3-(2-phenylacetyl)phenyl)propane-1-sulfonamide		C₁₇H₁₇F₂NO₃S	详情	详情
(V)	68768	2,6-difluoro-3-(propylsulfonamido)benzoic acid		C₁₀H₁₁F₂NO₄S	详情	详情
(VI)	68769	2,6-difluoro-3-(propylsulfonamido)benzoyl chloride		C₁₀H₁₀ClF₂NO₃S	详情	详情
(VII)	68771	5-bromopyrrolo[2,3-b]pyridine;5-Bromo-1H-pyrrolo[2,3-b]pyridine	183208-35-7	C₇H₅BrN₂	详情	详情
(VIII)	68770	N-(3-(5-bromo-1H-pyrrolo[2,3-b]pyridine-3-carbonyl)-2,4-difluorophenyl)propane-1-sulfonamide		C₁₇H₁₄BrF₂N₃O₃S	详情	详情
(IX)	17575	4-chlorophenylboronic acid	1679-18-1	C₆H₆BClO₂	详情	详情
(X)	68772	N-(2,4-difluorophenyl)propane-1-sulfonamide		C₉H₁₁F₂NO₂S	详情	详情
(XI)	68773	2,6-difluoro-3-(propylsulfonamido)benzaldehyde;N-(2,4-difluoro-3-formylphenyl)propane-1-sulfonamide	918523-58-7	C₁₀H₁₁F₂NO₃S	详情	详情
(XII)	68774	5-(4-chlorophenyl)pyrrolo[2,3-b]pyridine		C₁₃H₉ClN₂	详情	详情
(XIII)	68775	N-(3-((5-(4-chlorophenyl)-1H-pyrrolo[2,3-b]pyridin-3-yl)(hydroxy)methyl)-2,4-difluorophenyl)propane-1-sulfonamide		C₂₃H₂₀ClF₂N₃O₃S	详情	详情

Extended Information