(2S)-3-[3-(methoxymethyl)phenyl]-1,2-propanediol -Drug Synthesis Database

【结构式】

【分子编号】56399

【品名】(2S)-3-[3-(methoxymethyl)phenyl]-1,2-propanediol

【CA登记号】

【分子式】C₁₁H₁₆O₃

【分子量】196.24624

【元素组成】C 67.32% H 8.22% O 24.46%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(VI)

Treatment of 3-bromobenzyl bromide (I) with sodium methoxide gives 1-bromo-3-(methoxymethyl)benzene (II). After conversion of aryl bromide (II) into the corresponding Grignard reagent (III), addition to epoxide (IV) in the presence of CuI affords the chiral alcohol (V). Removal of the O-trityl protecting group of (V) under acidic conditions provides diol (VI), which is selectively acylated at the primary hydroxyl group by means of acetyl chloride and 2,4,6-collidine to produce the mono-acetate (VII). After protection of the secondary hydroxyl group of (VII) as the tetrahydropyranyl ether (VIII), alkaline hydrolysis of the acetate ester group leads to the primary alcohol (IX). Subsequent Swern oxidation of alcohol (IX) provides aldehyde (X). Condensation of aldehyde (X) with tetrabromomethane in the presence of triphenylphosphine furnishes the gem-dibromoolefin (XI). This is then converted to the terminal alkyne (XII) by treatment with butyllithium in cold THF.

参考文献中间体

合成目标

【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 .
【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.

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)	57226	bromo[3-(methoxymethyl)phenyl]magnesium		C₈H₉BrMgO	详情	详情
(IV)	41006	(2S)-oxiranylmethyl trityl ether; (2S)-2-[(trityloxy)methyl]oxirane		C₂₂H₂₀O₂	详情	详情
(V)	56398	(2S)-1-[3-(methoxymethyl)phenyl]-3-(trityloxy)-2-propanol		C₃₀H₃₀O₃	详情	详情
(VI)	56399	(2S)-3-[3-(methoxymethyl)phenyl]-1,2-propanediol		C₁₁H₁₆O₃	详情	详情
(VII)	56400	(2S)-2-hydroxy-3-[3-(methoxymethyl)phenyl]propyl acetate		C₁₃H₁₈O₄	详情	详情
(VIII)	56401	(2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propyl acetate		C₁₈H₂₆O₅	详情	详情
(IX)	56402	(2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)-1-propanol		C₁₆H₂₄O₄	详情	详情
(X)	56403	(2S)-3-[3-(methoxymethyl)phenyl]-2-(tetrahydro-2H-pyran-2-yloxy)propanal		C₁₆H₂₂O₄	详情	详情
(XI)	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
(XII)	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

该中间体在本合成路线中的序号：(V)

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

合成目标

【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

Extended Information