-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】N-[2-[4-[2(R)-[2(R)-(3-Chlorophenyl)-2-hydroxyethylamino]propylamino]phenyl]acetyl]-4-methylbenzenesulfonamide

【CA登记号】

【分子式】C₂₆H₃₀ClN₃O₄S

【分子量】516.0637

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antidiabetic Drugs, Antiobesity Drugs, ENDOCRINE DRUGS, METABOLIC DRUGS, Treatment of Nutritional Disorders, Type 2 Diabetes Mellitus, Agents for, beta3-Adrenoceptor Agonists

合成路线1 合成路线2

合成路线1

Esterification of (R)-3-chloromandelic acid (I) with MeOH and H2SO4 to yield ether (II), followed by hydroxyl group silylation using t-butyldimethylsilyl chloride and imidazole furnished (III). Reduction of the ester function of (III) by means of DIBAL produced aldehyde (IV), which was subjected to reductive amination with D-alanine methyl ester (V) to produce amino ester (VI). After protection of the amino group of (VI) as the N-Boc derivative (VII), further DIBAL reduction of the ester group afforded aldehyde (VIII).

参考文献中间体

【1】 Uehling, D.E.; Donaldson, K.H.; Deaton, D.N.; Hyman, C.E.; Sugg, E.E.; Barret, D.G.; Hughes, R.G.; Reitter, B.; Adkison, K.K.; Lancaster, M.E.; Lee, F.; Hart, R.; Paulik, M.A.; Sherman, B.W.; True, T.; Cowan, C.; Synthesis and evaluation of potent and selective beta3 adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres. J Med Chem 2002, 45, 3, 567.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	59930	(2R)-2-(3-chlorophenyl)-2-hydroxyethanoic acid	C₈H₇ClO₃	详情	详情
(II)	59931	methyl (2R)-2-(3-chlorophenyl)-2-hydroxyethanoate	C₉H₉ClO₃	详情	详情
(III)	59932	methyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethanoate	C₁₅H₂₃ClO₃Si	详情	详情
(IV)	59933	(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethanal	C₁₄H₂₁ClO₂Si	详情	详情
(V)	20694	methyl (2S)-2-aminopropanoate	C₄H₉NO₂	详情	详情
(VI)	59934	methyl (2R)-2-{[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]amino}propanoate	C₁₈H₃₀ClNO₃Si	详情	详情
(VII)	59935	methyl (2R)-2-{(tert-butoxycarbonyl)[(2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl]amino}propanoate	C₂₃H₃₈ClNO₅Si	详情	详情
(VIII)	59936	tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl[(1R)-1-methyl-2-oxoethyl]carbamate	C₂₂H₃₆ClNO₄Si	详情	详情

合成路线2

Coupling of p-nitrophenylacetic acid (IX) with p-toluenesulfonamide (X) using CDI provided the N-acyl sulfonamide (XI). The nitro group of (XI) was then reduced by catalytic hydrogenation to furnish aniline (XII). Reductive condensation of aniline (XII) with aldehyde (VIII) in the presence of NaBH(OAc)3 gave rise to amine (XIII). Finally, simultaneous removal of the O-silyl and N-Boc protecting groups of (XIII) was accomplished by treatment with 4 N aqueous HCl.

参考文献中间体

【1】 Uehling, D.E.; Donaldson, K.H.; Deaton, D.N.; Hyman, C.E.; Sugg, E.E.; Barret, D.G.; Hughes, R.G.; Reitter, B.; Adkison, K.K.; Lancaster, M.E.; Lee, F.; Hart, R.; Paulik, M.A.; Sherman, B.W.; True, T.; Cowan, C.; Synthesis and evaluation of potent and selective beta3 adrenergic receptor agonists containing acylsulfonamide, sulfonylsulfonamide, and sulfonylurea carboxylic acid isosteres. J Med Chem 2002, 45, 3, 567.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VIII)	59936	tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl[(1R)-1-methyl-2-oxoethyl]carbamate		C₂₂H₃₆ClNO₄Si	详情	详情
(IX)	59937	4-methylbenzenesulfonamide	70-55-3	C₇H₉NO₂S	详情	详情
(X)	30305	2-(4-nitrophenyl)acetic acid	104-03-0	C₈H₇NO₄	详情	详情
(XI)	59938	4-methyl-N-[2-(4-nitrophenyl)acetyl]benzenesulfonamide		C₁₅H₁₄N₂O₅S	详情	详情
(XII)	59939	N-[2-(4-aminophenyl)acetyl]-4-methylbenzenesulfonamide		C₁₅H₁₆N₂O₃S	详情	详情
(XIII)	59940	tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl{(1R)-1-methyl-2-[4-(2-{[(4-methylphenyl)sulfonyl]amino}-2-oxoethyl)anilino]ethyl}carbamate		C₃₇H₅₂ClN₃O₆SSi	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)