2-Thienylhydrosulfide; 2-Thiophenethiol -Drug Synthesis Database

【结构式】

【分子编号】16019

【品名】2-Thienylhydrosulfide; 2-Thiophenethiol

【CA登记号】7774-74-5

【分子式】C₄H₄S₂

【分子量】116.20776

【元素组成】C 41.34% H 3.47% S 55.19%

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：(II)

The synthesis of pipethiadene (VII) is carried out by four steps from phthalide (I) and 2-thio-phenethiol (II). A solution of the sodium salt of (II) in ethanol, prepared by dissolving (II) in ethanolic sodium ethoxide, is refluxed with (I) to give 2-(2-thienylthiomethyl)benzoic acid (III). A modified procedure for preparing (III) consists of using the crude products of reactions of 2-thienylmagnesium bromide or 2-thienylmagnesium iodide sulfur instead of the Na salt of (II).The acid (III) is then cyclized either with polyphosphoric acid in the presence of boiling toluene, with phosphorus pentoxide in boiling toluene or with phosphoric ethyl ester in toluene at 100 C. The ketone (IV) is then treated with 1-methyl-4-piperidylmagnesium chloride (A) in tetrahydrofuran and the resulting amino alcohol (V) is dehydrated with boiling dilute sulfuric acid to give the desired (VII). More recently it has been established that the expected formation of (V) is accompanied by a 1,6-addition with the subsequent air-oxidation producing the byproduct (VI). This compound melts precisely at the same temperature as compound (V), and it is necessary to separate it on the basis of its good solubility in ethanol, in which (V) is almost insoluble in the cold. Neutralization of the base (VII) with (+)-tartaric acid in ethanol affords pipethiadene (+)-tartrate.

参考文献中间体

合成目标

【1】 Protiva, M.; Rajsner, M.; US 3519649 .
【2】 Rajsner, M.; Vejdelek, Z.J.; Protiva, M.; Seidlova,V.; Adlerova, E.; Some new types of 6,11-dihydrodibenzo[b,e]thiepin derivatives and their analogues. Coll Czech Chem Commun 1964, 29, 2161.
【3】 Metys, J.; Rajsner, M.; Svatek, E.; Protiva, M.; Geometric isomerism of 4-(3-dimethylaminopropylidene)-9H-thieno[2,3-b]benzo[e]thiepin. Coll Czech Chem Commun 1974, 39, 1366.
【4】 Metys, J.; Protiva, M.; Svatek, E.; Rajsner, M.; 4,9-Dihyfrothieno[2,3-b]benzo[3]thiepin derivatives. Coll Czech Chem Commun 1967, 32, 2854.
【5】 Rajsner, M.; Protiva, M.; Metys, J.; Holubek, J.; Ryska, M.; Polívka, Z.; Svátek, E.; Antiaminic agents derived from thieno[2,3-c][2]benzothiepin: 4-(1-methyl-4-piperidylidene)-4,9-dihydroyhieno[2,3-c][2]benzothiepin and some related compounds. Coll Czech Chem Commun 1983, 48, 623.
【6】 Protiva, M.; Pipethiadene tartrate. Drugs Fut 1983, 8, 4, 334.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	36058	chloro[(1-methyl-4-piperidinyl)methyl]magnesium		C₇H₁₄ClMgN	详情	详情
(I)	12576	2-Benzofuran-1(3H)-one; Phthalide; Benzo[b]furan-1(3H)-one; 1(3H)-Isobenzofuranoneisobenzofuran-1-one	87-41-2	C₈H₆O₂	详情	详情
(II)	16019	2-Thienylhydrosulfide; 2-Thiophenethiol	7774-74-5	C₄H₄S₂	详情	详情
(III)	36056	2-[(2-thienylsulfanyl)methyl]benzoic acid		C₁₂H₁₀O₂S₂	详情	详情
(IV)	36057	thieno[2,3-c][2]benzothiepin-4(9H)-one		C₁₂H₈OS₂	详情	详情
(V)	36059	4-(1-methyl-4-piperidinyl)-4,9-dihydrothieno[2,3-c][2]benzothiepin-4-ol		C₁₈H₂₁NOS₂	详情	详情
(VI)	36060	7-(1-methyl-4-piperidinyl)thieno[2,3-c][2]benzothiepin-4(9H)-one		C₁₈H₁₉NOS₂	详情	详情
(VII)	36061	1-methyl-4-thieno[2,3-c][2]benzothiepin-4(9H)-ylidenepiperidine		C₁₈H₁₉NS₂	详情	详情
(VIII)	28379	(2R,3R)-2,3-dihydroxybutanedioic acid; L-Tartaric acid; (2R,3R)-2,3-dihydroxysuccinic acid	87-69-4	C₄H₆O₆	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

The treatment of D-leucine (I) with NaNO2, H2SO4 and NaBr gives 2(R)-bromo-5-methylpentanoic acid (II), which is esterified with isobutene and H2SO4 to the corresponding tert-butyl ester (III). The condensation of (III) with dibenzyl malonate (IV) by means of potassium tert-butoxide in DMF yields the malonyl derivative (V), which is treated with trifluoroacetic acid to hydrolyze the tert-butyl ester, and without isolation is condensed with L-phenylalanine methyl amide (VI) by means of hydroxybenzotriazole (HOBT) and dicyclohexylcarbodiimide (DCC), affording 4-benzyloxy-3-(benzyloxycarbonyl)-2(R)-isobutylsuccinyl-L-phenylalanine methylamide (VII). The elimination of the benzyl groups of (VII) by hydrogenolysis over Pd/C in ethanol gives the dicarboxylic acid (VIII), which by partial decarboxylation and reaction with aqueous formaldehyde and piperidine yields 4-hydroxy-2(R)-isobutyl-3-methylenesuccinyl-L-phenylalanine methylamide (IX). The addition of thiophene-2-thiol (X) to the double bond of (IX) affords 4-hydroxy-2(R)-isobutyl-3(S)-(2-thienylsulfanylmethyl)succinyl-L-phenylalanine methylamide (XI), which is finally treated with hydroxylamine and hydroxybenzotriazole in dichloromethane/DMF.

参考文献中间体

合成目标

【1】 Ngo, J.; Graul, A.; Castaner, J.; Batimastat. Drugs Fut 1996, 21, 12, 1215.
【2】 Campion, C.; Davidson, A.H.; Dickens, J.P.; Crimmin, M.J. (British Biotech plc); Hydroxamic acid based collagenase inhibitors. US 5240958; US 5310763; WO 9005719 .
【3】 Beckett, R.P.; Crimmin, M.J.; Galloway, W.A.; Matrix metalloproteinase inhibitors in the treatment of rheumatoid arthritis and cancer. 205th ACS Natl Meet (March 28-April 2, Denver) 1993, Abst MEDI 147.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	15926	2-methyl-1-propene; isobutylene	115-11-7	C₄H₈	详情	详情
(I)	16010	D-leucine	328-38-1	C₆H₁₃NO₂	详情	详情
(II)	16011	(2R)-2-bromo-4-methylpentanoic acid		C₆H₁₁BrO₂	详情	详情
(III)	16012	tert-butyl (2R)-2-bromo-4-methylpentanoate		C₁₀H₁₉BrO₂	详情	详情
(IV)	16013	dibenzyl malonate	15014-25-2	C₁₇H₁₆O₄	详情	详情
(V)	16014	1,1-dibenzyl 2-(tert-butyl) (2R)-4-methyl-1,1,2-pentanetricarboxylate		C₂₇H₃₄O₆	详情	详情
(VI)	16015	(2S)-2-amino-N-methyl-3-phenylpropanamide		C₁₀H₁₄N₂O	详情	详情
(VII)	16016	dibenzyl 2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonate		C₃₃H₃₈N₂O₆	详情	详情
(VIII)	16017	2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]malonic acid		C₁₉H₂₆N₂O₆	详情	详情
(IX)	16018	2-[(1R)-1-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-3-methylbutyl]acrylic acid		C₁₉H₂₆N₂O₄	详情	详情
(X)	16019	2-Thienylhydrosulfide; 2-Thiophenethiol	7774-74-5	C₄H₄S₂	详情	详情
(XI)	16020	(2S,3R)-3-([[(1S)-1-benzyl-2-(methylamino)-2-oxoethyl]amino]carbonyl)-5-methyl-2-[(2-thienylsulfanyl)methyl]hexanoic acid		C₂₃H₃₀N₂O₄S₂	详情	详情

Extended Information