S-4048, -Drug Synthesis Database

【结构式】

【药物名称】S-4048

【化学名称】(1S,3R,4R,5R)-1-[(1R,2S)-2-(4-Chlorophenyl)cyclopropylmethoxy]-3,4-dihydroxy-5-[3-(1H-imidazo[4,5-b]pyridin-1-yl)-3-phenyl-2(Z)-propenoyloxy]cyclohexane-1-carboxylic acid

【CA登记号】173534-37-7

【分子式】C₃₂H₃₀ClN₃O₇

【分子量】604.0648

【开发单位】Aventis Pharma (Originator)

【药理作用】Antidiabetic Drugs, ENDOCRINE DRUGS, Glucose-6-phosphatase Inhibitors

合成路线1 合成路线2

合成路线1

Treatment of carboxylic acid (I) with refluxing cyclohexanone (II) and H2SO4 affords derivative (III), which is then condensed with propargyl bromide (IV) by means of NaH in DMF to yield propargyl ether (V). Treatment of (V) with Et3N in toluene followed by condensation with 4-cloro-iodobenzene (VI) by means of PdCl2, PPh3 and CuI provides propinyloxy derivative (VII), which is then converted into propenyloxy derivative (VIII) by hydrogenation over Pd/ BaSO4 in pyridine. Opening of the lactone ring of (VIII) by means of NaH in MeOH and THF affords methyl ester (IX), which is then condensed with benzoyl chloride (X) by means of DMAP and Et3N in CH2Cl2 to give benzoate (XI). Treatment of (XI) with Et2Zn and chloroiodomethane in dichloroethane (or alternatively in CH2Cl2 or THF) followed by recrystallization from isopropanol furnishes cyclopropane derivative (XII), which is then hydrolyzed by treatment with NaOH in dioxane to yield alcohol (XIII). Finally, (XIII) is condensed with intermediate (XIV) by means of NaH in DMF and then deprotected by treatment with HCl in dioxane to afford the target compound.

参考文献中间体

【1】 Hemmerle, H.; Schindler, P.; Herling, A. (Aventis SA); Derivs. of substd. cyclohexane, their process of preparation and their application for the treatment of diseases. EP 0587088; JP 1994211736; US 5463062 .
【2】 Hemmerle, H.; Schubert, G.; Burger, H.-J.; Herling, A.; Efendic, S. (Aventis SA); Cyclohexane derivs., processes for their preparation and their use as glucose-6-phosphatase inhibitors. CA 2149007; CA 4416433; EP 0682024; JP 1995330767; US 5739147 .

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)	44864	Quinic acid; 1,3,4,5-tetrahydroxycyclohexanecarboxylic acid		C₇H₁₂O₆	详情	详情
(II)	11059	Cyclohexanone	108-94-1	C₆H₁₀O	详情	详情
(III)	44855			C₁₃H₁₈O₅	详情	详情
(IV)	11176	3-Bromopropyne; 3-Bromo-1-propyne	106-96-7	C₃H₃Br	详情	详情
(V)	44856			C₁₆H₂₀O₅	详情	详情
(VI)	19395	1-chloro-4-iodobenzene	637-87-6	C₆H₄ClI	详情	详情
(VII)	44857			C₂₂H₂₃ClO₅	详情	详情
(VIII)	44858			C₂₂H₂₅ClO₅	详情	详情
(IX)	44859			C₂₃H₂₉ClO₆	详情	详情
(X)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XI)	44860			C₃₀H₃₃ClO₇	详情	详情
(XII)	44861			C₃₁H₃₅ClO₇	详情	详情
(XIII)	44862			C₂₃H₂₉ClO₆	详情	详情
(XIV)	44863			C₁₇H₁₂N₆O	详情	详情

合成路线2

Intermediate (XIV) can be obtained as follows: Bromination of methyl cinnamate (XV) with Br2 in CH2Cl2 provides 2,3-dibromo-3-phenylpropanoate (XVI), which is then converted into alpha-bromocinnamic ester (XVII) by reaction with Et3N in refluxing toluene. Treatment of (XVII) with imidazopyridine (XVIII) and NaH in DMF affords derivative (XIX), which is then hydrolyzed by treatment with NaOH in MeOH to furnish carboxylic acid (XX). Finally, (XX) reacts with carbonylditriazole in DMF to give the target intermediate (XIV).

参考文献中间体

【1】 Hemmerle, H.; Schubert, G.; Burger, H.-J.; Herling, A.; Efendic, S. (Aventis SA); Cyclohexane derivs., processes for their preparation and their use as glucose-6-phosphatase inhibitors. CA 2149007; CA 4416433; EP 0682024; JP 1995330767; US 5739147 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XIV)	44863			C₁₇H₁₂N₆O	详情	详情
(XV)	23888	methyl (E)-3-phenyl-2-propenoate	103-26-4	C₁₀H₁₀O₂	详情	详情
(XVI)	44865	methyl 2,3-dibromo-3-phenylpropanoate		C₁₀H₁₀Br₂O₂	详情	详情
(XVII)	44866	methyl (Z)-2-bromo-3-phenyl-2-propenoate		C₁₀H₉BrO₂	详情	详情
(XVIII)	44867	1H-imidazo[4,5-b]pyridine		C₆H₅N₃	详情	详情
(XIX)	44868	methyl (Z)-3-(1H-imidazo[4,5-b]pyridin-1-yl)-3-phenyl-2-propenoate		C₁₆H₁₃N₃O₂	详情	详情
(XX)	44869	(Z)-3-(1H-imidazo[4,5-b]pyridin-1-yl)-3-phenyl-2-propenoic acid		C₁₅H₁₁N₃O₂	详情	详情
(XXI)	44870	di(1H-1,2,4-triazol-1-yl)methanone		C₅H₄N₆O	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)