-Drug Synthesis Database

【结构式】

【药物名称】

【化学名称】11alpha,15alpha-Dihydroxy-16-(3-methoxymethylphenyl)-9-oxo-17,18,19,20-tetranor-5-thia-13(E)-prostenoic acid methyl ester

【CA登记号】256382-08-8

【分子式】C₂₄H₃₄O₆S

【分子量】450.59898

【开发单位】Ono (Originator)

【药理作用】IMMUNOMODULATING AGENTS, Immunomodulators, Prostanoid EP4 Agonists

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

Bromine displacement in 3-bromobenzyl bromide (I) with sodium methoxide gives the methyl ether (II). Subsequent addition of the Grignard reagent prepared from aryl bromide (II) to (S)-O-trityl glycidol (III) in the presence of CuI affords alcohol (IV). Deprotection of the O-trityl group of (IV) under acidic conditions yields diol (V), which is selectively acetylated at the primary hydroxyl group with acetyl chloride and s-collidine in cold CH2Cl2. The resultant secondary alcohol (VI) is then protected as the tetrahydropyranyl ether (VII) upon treatment with dihydropyran and pyridinium p-toluenesulfonate. After basic hydrolysis of the acetate ester (VII), the liberated primary alcohol (VIII) is oxidized to aldehyde (IX) under Swern conditions. Condensation of aldehyde (IX) with carbon tetrabromide in the presence of triphenylphosphine produces the dibromovinyl adduct (X). Debromination of (X) by means of butyllithium in cold THF furnishes the terminal acetylene (XI).

参考文献中间体

【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743.
【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 .

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)	20466	1-bromo-3-(bromomethyl)benzene	823-78-9	C₇H₆Br₂	详情	详情
(II)	56397	3-bromobenzyl methyl ether; 1-bromo-3-(methoxymethyl)benzene		C₈H₉BrO	详情	详情
(III)	41006	(2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane		C₂₂H₂₀O₂	详情	详情
(IV)	56395	(2R,4R,6S,7R,10R,13S,14R,15S,16S,18S)-13-(acetyloxy)-18-({(2R,3S)-3-[(tert-butoxycarbonyl)amino]-3-(3-fluoro-2-pyridinyl)-2-[(triisopropylsilyl)oxy]propanoyl}oxy)-4-[(dimethylamino)methyl]-16-hydroxy-7,19,20,20-tetramethyl-3,5,11-trioxapentacyclo[14.3.1.0~2,6~.0~7,14~.0~10,13~]icosa-1(19),8-dien-15-yl benzoate		C₅₅H₇₈FN₃O₁₃Si	详情	详情
(V)	56399	(2S)-3-[3-(methoxymethyl)phenyl]-1,2-propanediol		C₁₁H₁₆O₃	详情	详情
(VI)	56400	(2S)-2-hydroxy-3-[3-(methoxymethyl)phenyl]propyl acetate		C₁₃H₁₈O₄	详情	详情
(VII)	56401	(2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propyl acetate		C₁₈H₂₆O₅	详情	详情
(VIII)	56402	(2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol		C₁₆H₂₄O₄	详情	详情
(IX)	56403	(2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propanal		C₁₆H₂₂O₄	详情	详情
(X)	56404	(1S)-3,3-dibromo-1-[3-(methoxymethyl)benzyl]-2-propenyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-3,3-dibromo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)tetrahydro-2H-pyran		C₁₇H₂₂Br₂O₃	详情	详情
(XI)	56405	(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran		C₁₇H₂₂O₃	详情	详情

合成路线2

After acidic cleavage of the tetrahydropyranyl group of (XI), the resultant alcohol (XII) is reprotected as the silyl ether (XIII). Hydroiodination of acetylene (XIII) is effected by treatment with iodine and zirconocene chloride hydride, yielding vinyl iodide (XIV). The organolithium derivative generated from iodide (XIV) undergoes conjugate addition to cyclopentenone (XV), producing the intermediate lithium enolate (XVI) which, upon quenching with aldehyde (XVII), leads to the substituted cyclopentanone adduct (XVIII). Dehydration of aldol (XVIII) to dienone (XIX) is performed by treatment with mesyl chloride and DMAP. The conjugated double bond of (XIX) is selectively reduced to (XX) by means of tributyltin hydride and t-butyl hydroperoxide. Finally, desilylation of (XX) with HF in pyridine affords the title prostaglandin derivative.

参考文献中间体

【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 3: 16-Phenyl-5-thiaPGE1 and 9-beta-halo derivatives with improved stability. Bioorg Med Chem 2002, 10, 6, 1743.
【2】 Ohuchida, S.; Maruyama, T. (Ono Pharmaceutical Co., Ltd.); 5-Thia-omega-substd. phenyl-prostaglandin E derivs., process for producing the same and drugs containing the same as the active ingredient. EP 1097922; JP 2001089444; US 6462081; WO 0003980 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(XI)	56405	(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl tetrahydro-2H-pyran-2-yl ether; 2-({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)tetrahydro-2H-pyran	C₁₇H₂₂O₃	详情	详情
(XII)	56406	(2S)-1-[3-(methoxymethyl)phenyl]-3-butyn-2-ol	C₁₂H₁₄O₂	详情	详情
(XIII)	56407	tert-butyl(dimethyl)silyl (1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl ether; tert-butyl({(1S)-1-[3-(methoxymethyl)benzyl]-2-propynyl}oxy)dimethylsilane	C₁₈H₂₈O₂Si	详情	详情
(XIV)	56408	tert-butyl(dimethyl)silyl (1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl ether; tert-butyl({(1S,2E)-3-iodo-1-[3-(methoxymethyl)benzyl]-2-propenyl}oxy)dimethylsilane	C₁₈H₂₉IO₂Si	详情	详情
(XV)	13805	(4R)-4-[[tert-Butyl(dimethyl)silyl]oxy]-2-cyclopenten-1-one	C₁₁H₂₀O₂Si	详情	详情
(XVI)	56409	lithium (4R)-4-{[tert-butyl(dimethyl)silyl]oxy}-3-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-1-cyclopenten-1-olate	C₂₉H₄₉LiO₄Si₂	详情	详情
(XVII)	56410	methyl 4-[(2-oxoethyl)sulfanyl]butanoate	C₇H₁₂O₃S	详情	详情
(XVIII)	56411	methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)-2-hydroxyethyl]sulfanyl}butanoate	C₃₆H₆₂O₇SSi₂	详情	详情
(XIX)	56412	methyl 4-{[2-((2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentylidene)ethyl]sulfanyl}butanoate	C₃₆H₆₀O₆SSi₂	详情	详情
(XX)	56413	methyl 4-{[2-((1R,2R,3R)-3-{[tert-butyl(dimethyl)silyl]oxy}-2-{(E,3S)-3-{[tert-butyl(dimethyl)silyl]oxy}-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-oxocyclopentyl)ethyl]sulfanyl}butanoate	C₃₆H₆₂O₆SSi₂	详情	详情

合成路线3

Oxidation of the lactone alcohol (I) using DMSO in the presence of SO3-pyridine complex gives aldehyde (II). Horner-Emmons condensation of aldehyde (II) with phosphonate (III) affords enone (IV). Stereoselective reduction of (IV) with LiAlH4 in the presence of (S)-BINOL provides the (S)-alcohol (V), which is further protected with dihydropyran in the presence of p-toluenesulfonic acid to yield the bis-tetrahydropyranyl ether (VI). Lactone ring opening in (VI) under reductive conditions leads to diol (VII). Selective mesylation of the primary alcohol of (VII), followed by protection of the secondary hydroxyl with chlorotrimethylsilane produces the intermediate mesylate (VIII), which is then displaced with potassium thioacetate to yield the thioacetate ester (IX).

参考文献中间体

【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	56988	(3aR,4S,5R,6aS)-4-(hydroxymethyl)-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one	C₁₃H₂₀O₅	详情	详情
(II)	56989	(3aR,4R,5R,6aS)-2-oxo-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-4-carbaldehyde	C₁₃H₁₈O₅	详情	详情
(III)	56990	dimethyl 3-[3-(methoxymethyl)phenyl]-2-oxopropylphosphonate	C₁₃H₁₉O₅P	详情	详情
(IV)	56991	(3aR,4R,5R,6aS)-4-{(E)-4-[3-(methoxymethyl)phenyl]-3-oxo-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one	C₂₄H₃₀O₆	详情	详情
(V)	56992	(3aR,4R,5R,6aS)-4-{(E,3S)-3-hydroxy-4-[3-(methoxymethyl)phenyl]-1-butenyl}-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one	C₂₄H₃₂O₆	详情	详情
(VI)	56993	(3aR,4R,5R,6aS)-4-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-(tetrahydro-2H-pyran-2-yloxy)hexahydro-2H-cyclopenta[b]furan-2-one	C₂₉H₄₀O₇	详情	详情
(VII)	56994	(1S,2R,3R,4R)-2-(2-hydroxyethyl)-3-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-4-(tetrahydro-2H-pyran-2-yloxy)cyclopentanol	C₂₉H₄₄O₇	详情	详情
(VIII)	56995	2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl methanesulfonate	C₃₃H₅₄O₉SSi	详情	详情
(IX)	56996	S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate	C₃₄H₅₄O₇SSi	详情	详情

合成路线4

Methanolysis of the thioacetate and silyl ether groups of (IX), with concomitant S-alkylation by methyl 4-iodobutyrate (X) lead to thioether (XI). The deprotected alcohol function of (XI) is then oxidized to ketone (XII) under modified Swern conditions. Finally, acidic hydrolysis of the tetrahydropyranyl ether groups of (XII) provide the title diol.

参考文献中间体

【1】 Maruyama, T.; et al.; Design and synthesis of a selective EP4-receptor agonist. Part 4: Practical synthesis and biological evaluation of a novel highly selective EP4-receptor agonist. Bioorg Med Chem 2002, 10, 7, 2103.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	56996	S-(2-{(1R,2R,3R,5S)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-5-[(trimethylsilyl)oxy]cyclopentyl}ethyl) ethanethioate		C₃₄H₅₄O₇SSi	详情	详情
(X)	13816	Methyl 4-iodobutyrate; Methyl 4-iodobutanoate	14273-85-9	C₅H₉IO₂	详情	详情
(XI)	56997	methyl 4-({2-[(1R,2R,3R,5S)-5-hydroxy-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate		C₃₄H₅₂O₈S	详情	详情
(XII)	56998	methyl 4-({2-[(1R,2R,3R)-2-[(E,3S)-4-[3-(methoxymethyl)phenyl]-3-(tetrahydro-2H-pyran-2-yloxy)-1-butenyl]-5-oxo-3-(tetrahydro-2H-pyran-2-yloxy)cyclopentyl]ethyl}sulfanyl)butanoate		C₃₄H₅₀O₈S	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(2)