Mexiprostil, MDL-646, DL-646, -Drug Synthesis Database

【结构式】

【药物名称】Mexiprostil, MDL-646, DL-646

【化学名称】[8alpha,11alpha,15R,16R]-11,15-Dihydroxy-16-methyl-16-methoxy-9-oxoprost-13-en-1-oic acid methyl ester
　　　　　　16-Methyl-16-methoxyprostaglandin E1 methyl ester

【CA登记号】83656-28-4, 88980-20-5 ((E)-isomer)

【分子式】C₂₃H₄₀O₆

【分子量】412.57165

【开发单位】Lepetit (Originator)

【药理作用】Antiulcer Drugs, Gastric Antisecretory Drugs, GASTROINTESTINAL DRUGS

合成路线1 合成路线2 合成路线3

合成路线1

The reaction of 3(R)-(tert-butyldimethylsilyloxy)-4(R)-methoxy-4(R)-methyl-1-(tributylstannyl)-1(E)-octene (II) with butyllithium, cuprous iodide and tributylphosphine gives an intermediate copper derivative which is condensed first with 4(R)-(tert-butyldimethylsilyloxy)-2-cyclopentenone (I) and then with methyl 6-formylhexanoate (III) to give the 7-hydroxy PGE1 derivative (IV). The dehydration of (IV) with mesyl chloride yields the unsaturated PGE compound (V), which is reduced with tributystannyl hydride and finally deprotected with acetic acid in THF. The starting products (I) and (II) are obtained as follows: 1) The oxidation of cyclopentadiene (VI) gives 2-cyclopentene-1,4-diol (VII), which is acetylated to the diacetate (VIII). Selective hydrolysis of (VIII) yields (1S, 4R)-4-hydroxy-2-cyclopentenyl acetate (IX), which is protected with tert-butyldimethylsilyl chloride to the protected acetate (X). Partial hydrolysis of (X) affords the semiprotected alcohol (XI), which is finally oxidized to the cyclopentenone (I).

参考文献中间体

【1】 Kolb, M.; Van Hijfte, L.; Ireland, R.E.; A highly convergent synthesis of mexiprostil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester. Tetrahedron Lett 1988, 29, 51, 6769.

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)	13805	(4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one		C₁₁H₂₀O₂Si	详情	详情
(II)	21528	(1R,2R,3E)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether		C₂₈H₆₀O₂SiSn	详情	详情
(III)	21529	methyl 7-oxoheptanoate	35376-00-2	C₈H₁₄O₃	详情	详情
(IV)	21530	methyl 7-[(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentyl]-7-hydroxyheptanoate		C₃₅H₆₈O₇Si₂	详情	详情
(V)	21531	methyl 7-[(2R,3R)-3-[[tert-butyl(dimethyl)silyl]oxy]-2-((E,3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyl-1-octenyl)-5-oxocyclopentylidene]heptanoate		C₃₅H₆₆O₆Si₂	详情	详情
(VI)	11183	1,3-Cyclopentadiene		C₅H₆	详情	详情
(VII)	21533	4-cyclopentene-1,3-diol		C₅H₈O₂	详情	详情
(VIII)	21534	4-(acetoxy)-2-cyclopenten-1-yl acetate		C₉H₁₂O₄	详情	详情
(IX)	21535	(1R,4R)-4-hydroxy-2-cyclopenten-1-yl acetate		C₇H₁₀O₃	详情	详情
(X)	21536	(1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-yl acetate		C₁₃H₂₄O₃Si	详情	详情
(XI)	21537	(1R,4R)-4-[[tert-butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-ol		C₁₁H₂₂O₂Si	详情	详情

合成路线2

2) The epoxidation of nerol (XII) with tert-butyl peroxide and titanium isopropoxide gives the epoxide (XIII), which is benzylated with benzyl bromide to the protected epoxide (XIV). A stereo- and regioselective cleavage of the epoxide (XIV) with methanol yields the methoxy hydroxy derivative (XV), which is ozonolyzed in methanol dichloromethane to the aldehyde (XVI). The Wittig condensation of (XVI) with triphenylmethylphosphonium bromide and potassium tert-butoxide affords the methylene alcohol (XVII), which is protected with tert-butyldimethylsilyl chloride as before to give silyl derivative (XVIII). The hydrogenation of (XVIII) with H2 over Pd in ethyl acetate yields the saturated alcohol (XIX), which is oxidized with oxalyl chloride in DMSO to the aldehyde (XX).The reaction of (XX) with tetrabromomethane and triphenylphosphine affords the dibromovinyl compound (XXI), which by reaction with butyllithium in THF is converted into the acetylene (XXII). Finally, this compound is treated with tributylstannyl hydride and azobisisobutyronitrile to give the stannyl derivative (II).

参考文献中间体

【1】 Kolb, M.; Van Hijfte, L.; Ireland, R.E.; A highly convergent synthesis of mexiprostil: 16(R) 16-methoxy 16-methyl PGE1 methyl ester. Tetrahedron Lett 1988, 29, 51, 6769.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	30484	Methyl(triphenyl)phosphonium bromide	1779-49-3	C₁₉H₁₈BrP	详情	详情
(A)	12912	1-(Bromomethyl)benzene; Alpha-bromotoluene	100-39-0	C₇H₇Br	详情	详情
(II)	21528	(1R,2R,3E)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-4-(tributylstannyl)-3-butenyl methyl ether		C₂₈H₆₀O₂SiSn	详情	详情
(XII)	21538	(2Z)-3,7-dimethyl-2,6-octadien-1-ol	106-25-2	C₁₀H₁₈O	详情	详情
(XIII)	21539	[(2R,3S)-3-methyl-3-(4-methyl-3-pentenyl)oxiranyl]methanol		C₁₀H₁₈O₂	详情	详情
(XIV)	21540	(2S,3R)-3-[(benzyloxy)methyl]-2-methyl-2-(4-methyl-3-pentenyl)oxirane		C₁₇H₂₄O₂	详情	详情
(XV)	21541	(2R,3R)-1-(benzyloxy)-3-methoxy-3,7-dimethyl-6-octen-2-ol		C₁₈H₂₈O₃	详情	详情
(XVI)	21542	(4R,5R)-6-(benzyloxy)-5-hydroxy-4-methoxy-4-methylhexanal		C₁₅H₂₂O₄	详情	详情
(XVII)	21543	(2R,3R)-1-(benzyloxy)-3-methoxy-3-methyl-6-hepten-2-ol		C₁₆H₂₄O₃	详情	详情
(XVIII)	21544	([(1R,2R)-1-[(benzyloxy)methyl]-2-methoxy-2-methyl-5-hexenyl]oxy)(tert-butyl)dimethylsilane		C₂₂H₃₈O₃Si	详情	详情
(XIX)	21545	(2R,3R)-2-[[tert-butyl(dimethyl)silyl]oxy]-3-methoxy-3-methyl-1-heptanol		C₁₅H₃₄O₃Si	详情	详情
(XX)	21546	(3R,4R)-3-[[tert-butyl(dimethyl)silyl]oxy]-4-methoxy-4-methyloctanal		C₁₆H₃₄O₃Si	详情	详情
(XXI)	21547	tert-butyl(dimethyl)silyl (1R)-3,3-dibromo-1-[(1R)-1-methoxy-1-methylpentyl]-2-propenyl ether		C₁₆H₃₂Br₂O₂Si	详情	详情
(XXII)	21548	(1R,2R)-1-butyl-2-[[tert-butyl(dimethyl)silyl]oxy]-1-methyl-3-butynyl methyl ether		C₁₆H₃₂O₂Si	详情	详情

合成路线3

The Wittig condensation of methyl 7-(5alpha-acetoxy-2beta-formyl-3alpha-hydroxycyclopent-1-yl)heptanoate (I) with dimethyl 3-mothoxy-3-methyl-2-oxoheptyl phosphonate (II) by means of NaH in dimethoxy ethane gives methyl 9alpha-acetoxy-11alpha-hydroxy-16-methoxy-16-methyl-15-oxoprosta-13-en-1-oate (III), which is treated with dihydropyran and p-toluenesulfonic acid to yield the 11alpha-tetrahydropyranyloxy derivative (IV). The reduction of (IV) with NaBH4 in methanol affords methyl 9alpha-acetoxy-15-hydroxy-16-methoxy-16-methyl-11alpha-(tetrahydropyranyloxy)prosta-13-en-1-oate (IV), which is protected again with dihydropyran as before to give the 11,15-bis(tetrahydropyranyloxy) derivative (VI). The hydrolysis of the acetoxy group of (VI) with K2CO3 in methanol affords methyl 9alpha-hydroxy-16-methoxy-16-methyl-11alpha,15-bis(tetrahydropyranyloxy)prosta-13-en-1-oate (VII), which is oxidized with Collins' reagent (CrO3-pyridine) in methylene chloride yielding methyl 16-methoxy-16-methyl-9-oxo-11alpha,15-bis(tetrahydropyranyloxy)prosta-13-en-1-oate (VIII). Finally, this compound is deprotected by a treatment with acetic acid in THF - water.

参考文献中间体

【1】 Guzzi, U.; Ciabatti, R.; DE 3012306 .
【2】 Castaner, J.; Blancafort, P.; Serradell, M.N.; DL-646. Drugs Fut 1983, 8, 12, 1018.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	36184	methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-2-formyl-3-hydroxycyclopentyl]heptanoate	C₁₆H₂₆O₆	详情	详情
(II)	36185	dimethyl 3-methoxy-3-methyl-2-oxoheptylphosphonate	C₁₁H₂₃O₅P	详情	详情
(III)	36186	methyl 7-[(1R,2R,3R,5S)-5-(acetoxy)-3-hydroxy-2-[(E)-4-methoxy-4-methyl-3-oxo-1-octenyl]cyclopentyl]heptanoate	C₂₅H₄₂O₇	详情	详情
(IV)	36187	methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E)-4-methoxy-4-methyl-3-oxo-1-octenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate	C₃₁H₅₂O₈	详情	详情
(V)	36188	methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3R)-3-hydroxy-4-methoxy-4-methyl-1-octenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate	C₃₁H₅₄O₈	详情	详情
(VI)	36189	methyl 7-[(1R,2S,3R,5S)-5-(acetoxy)-2-[(E,3S)-4-methoxy-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate	C₃₇H₆₄O₉	详情	详情
(VII)	36190	methyl 7-[(1R,2S,3R,5S)-5-hydroxy-2-[(E,3S)-4-methoxy-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate	C₃₅H₆₂O₈	详情	详情
(VIII)	36191	methyl 7-[(1R,2S,3R)-2-[(E,3S)-4-methoxy-4-methyl-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]-1-octenyl]-5-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)methyl]cyclopentyl]heptanoate	C₃₅H₆₀O₈	详情	详情

Extended Information