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【结 构 式】

【分子编号】68802

【品名】N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide

【CA登记号】

【 分 子 式 】C5H11NO3S

【 分 子 量 】165.213

【元素组成】C 36.35% H 6.71% N 8.48% O 29.05% S 19.41%

与该中间体有关的原料药合成路线共 1 条

合成路线1

该中间体在本合成路线中的序号:(XV)

Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .

1 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350.
2 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355.
3 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637.
4 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889.
5 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519.
6 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979.
7 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640.
8 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127.
9 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976.
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) 18619 (2-aminophenyl)methanol; 2-Amino-benzenemethanol;2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 5344-90-1 C7H9NO 详情 详情
(II) 36334 [2-(isopropylamino)phenyl]methanol;2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol C10H15NO 详情 详情
(III) 36335 2-(isopropylamino)benzaldehyde C10H13NO 详情 详情
(IV) 14738 Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione;Malonic acid cyclic isopropylidene ester 2033-24-1 C6H8O4 详情 详情
(V) 36333 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid C13H13NO3 详情 详情
(VI) 68799 (1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate C12H22N2O2 详情 详情
(VII) 68803 (1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate C25H33N3O4 详情 详情
(VIII) 68804 N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate C20H25N3O2.C2HF3O2 详情 详情
(IX) 68807 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate C9H18ClNO3 详情 详情
(X) 13917 (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin 67843-74-7 C3H5ClO 详情 详情
(XI) 68808 (S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol C11H16ClNO 详情 详情
(XII) 68805 tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate C29H42N4O5 详情 详情
(XIII) 68806 N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate C24H34N4O3.C2HF3O2 详情 详情
(XIV) 13467 Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride 124-63-0 CH3ClO2S 详情 详情
(XV) 68802 N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide C5H11NO3S 详情 详情
(XVI) 67859 N-methylmethanesulfonamide 1184-85-6 C2H7NO2S 详情 详情
(XVII) 13917 (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin 67843-74-7 C3H5ClO 详情 详情
(XVIII) 12132 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether 696-59-3 C6H12O3 详情 详情
(XIX) 15530 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid;3-oxoglutaric acid 542-05-2 C5H6O5 详情 详情
(XX) 68801 (1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one C14H17NO 详情 详情
(XXI) 68800 N-Boc-8-azabicyclo[3.2.1]octan-3-one C12H19NO3 详情 详情
Extended Information