5-bromo-3-thiophenecarbaldehyde -Drug Synthesis Database

【结构式】

【分子编号】31660

【品名】5-bromo-3-thiophenecarbaldehyde

【CA登记号】

【分子式】C₅H₃BrOS

【分子量】191.04822

【元素组成】C 31.43% H 1.58% Br 41.82% O 8.37% S 16.78%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(I)

The reduction of 5-bromothiophene-3-carbaldehyde (I) with NaBH4 in THF gives the corresponding carbinol (II), which is treated with Zn(CN)2 and palladium tetrakis(triphenylphosphine) in DMF to yield 4-(hydroxymethyl)thiophene-2-carbonitrile (III). The reaction of (III) with tetrabromomethane and triphenylphosphine affords the corresponding bromomethyl derivative (IV), which is condensed with 3(S)-(tert-butoxycarbonylamino)pyrrolidin-2-one (V) by means of NaH in THF/DMF to give the expected addition product (VI). The deprotection of the amino group of (VI) with HCl in ethyl acetate yields the primary amine (VII), which is acylated with 7-methoxynaphthalene-2-sulfonyl chloride (VIII) and triethylamine in dichloromethane providing the sulfonamide (IX). The methylation of (IX) with methyl iodide and K2CO3 in DMF affords the N-methylsulfonamide (X), which is finally treated first with HCl in ethanol, and then with NH3 in methanol to convert the cyano group of (X) into the amidino group of the target compound.

参考文献中间体

合成目标

【1】 Ewing, W.R.; Manetta, V.E.; Becker, M.R.; et al.; Design and structure-activity relationships of potent and selective inhibitors of blood coagulation factor Xa. J Med Chem 1999, 42, 18, 3557.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	31660	5-bromo-3-thiophenecarbaldehyde	C₅H₃BrOS	详情	详情
(II)	31661	(5-bromo-3-thienyl)methanol	C₅H₅BrOS	详情	详情
(III)	31662	4-(hydroxymethyl)-2-thiophenecarbonitrile	C₆H₅NOS	详情	详情
(IV)	31663	4-(bromomethyl)-2-thiophenecarbonitrile	C₆H₄BrNS	详情	详情
(V)	29492	tert-butyl (3S)-2-oxopyrrolidinylcarbamate	C₉H₁₆N₂O₃	详情	详情
(VI)	31664	tert-butyl (3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinylcarbamate	C₁₅H₁₉N₃O₃S	详情	详情
(VII)	31665	4-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-2-thiophenecarbonitrile	C₁₀H₁₁N₃OS	详情	详情
(VIII)	31666	7-methoxy-2-naphthalenesulfonyl chloride	C₁₁H₉ClO₃S	详情	详情
(IX)	31667	N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-2-naphthalenesulfonamide	C₂₁H₁₉N₃O₄S₂	详情	详情
(X)	31668	N-[(3S)-1-[(5-cyano-3-thienyl)methyl]-2-oxopyrrolidinyl]-7-methoxy-N-methyl-2-naphthalenesulfonamide	C₂₂H₂₁N₃O₄S₂	详情	详情

合成路线2

该中间体在本合成路线中的序号：(X)

In an alternative procedure, the bithiophene aldehyde (II) was reduced to alcohol (VII) with NaBH4, and this was protected with dihydropyran to give (VIII). Lithiation and subsequent treatment of (VIII) with tributyltin chloride afforded the stannyl compound (IX). This was then coupled with 2-bromo-4-thiophene-carboxaldehyde (X) in the presence of Pd(PPh3)4 and an additional amount of PPh3 to provide the terthiophene (XI). The reduction of the aldehyde group of (XI) with NaBH4, and then acid hydrolysis of the tetrahydropyranyl protecting group furnished diol (XII). Finally, the oxidation of (XII) by means of DDQ gave rise to a 1:3 mixture of the desired hydroxy aldehyde and its regioisomer (XIII).

参考文献中间体

合成目标

【1】 Xu, W.-C.; Chang, C.-j.; Zhou, Q.; Ashendel, C.L.; Chang, C.t.; Novel protein kinase C inhibitors: Synthesis and PKC inhibition of beta-substituted polythiophene derivatives. Bioorg Med Chem Lett 1999, 9, 15, 2279.
【2】 Chang, C.-T.; Chang, C.-J.; Lee, C.-T.; Lin, F.-L.; Tsai, J.-D.; Ashendel, C.L.; Chan, T.C.K.; Geahlen, R.L.; Waters, D.J. (Industrial Technology & Research Institute; Purdue Research Foundation); Polythiophene anti-tumor agents. EP 1007035; WO 9823269 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(II)	43131	2,2'-Bithienyl-5-carboxaldehyde 2,2'-Bithienyl-5-carboxaldehyde 2,2'-Bithienyl-5-carboxaldehyde	3779-27-9	C₉H₆OS₂	详情	详情
(VII)	43136	2,2'-Bithien-5-ylmethanol	3515-30-8	C₉H₈OS₂	详情	详情
(VIII)	43137			C₁₄H₁₆O₂S₂	详情	详情
(IX)	43138			C₂₆H₄₂O₂S₂Sn	详情	详情
(X)	31660	5-bromo-3-thiophenecarbaldehyde		C₅H₃BrOS	详情	详情
(XI)	43139			C₁₉H₁₈O₃S₃	详情	详情
(XII)	43140			C₁₄H₁₂O₂S₃	详情	详情
(XIII)	43141			C₁₄H₁₀O₂S₃	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XI)

Thienylacrylic acid (XII), prepared from thiophene aldehyde (XI), was activated as the mixed anhydride with ethyl chloroformate and then treated with NaN3 to yield acyl azide (XIII). Cyclization of (XIII) in the presence of Bu3P in boiling diphenyl ether generated the thienopyridine system (XIV). Chlorination of (XIV) with POCl3 afforded the chloro derivative (XV). After lithium-bromine exchange with n-butyllithium, the resulting organolithium derivative (XVI) was treated with SO2 and further oxidized to sulfonyl chloride (XVII) with SO2Cl2. Coupling of (XVII) with aminopyrrolidinone (X) yielded sulfonamide (XVIII). Conversion of the nitrile of (XVIII) to the corresponding imidate (XIX), followed by reaction with ammonia produced benzamidine (XX). Finally, hydrogenolytic dechlorination of (XX) over Pd/C provided the title compound.

参考文献中间体

合成目标

【1】 Ewing, W.R.; Davis, R.S.; Becker, M.R.; et al.; Synthesis, SAR and in vivo activity of novel thienopyridine sulfonamide pyrrolidinones as factor Xa inhibitors. Bioorg Med Chem Lett 1999, 9, 18, 2753.
【2】 Ewing, W.R.; Becker, M.R.; Choi-Sledeski, Y.M.; Pauls, H.W.; McGarry, D.G.; Davis, R.S.; Spada, A.P. (Aventis Pharma SA); Substd. sulfonic acid N-[(aminoiminomethyl)phenylalkyl]-azaheterocyclamide cpds.. EP 0894088; JP 2000505815; US 5731315; WO 9824784 .

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(X)	31677	3-[[(3S)-3-amino-2-oxopyrrolidinyl]methyl]-4-hydroxybenzonitrile	C₁₂H₁₃N₃O₂	详情	详情
(XI)	31660	5-bromo-3-thiophenecarbaldehyde	C₅H₃BrOS	详情	详情
(XII)	38299	(E)-3-(5-bromo-3-thienyl)-2-propenoic acid	C₇H₅BrO₂S	详情	详情
(XIII)	38300	(E)-3-(5-bromo-3-thienyl)-2-propenoyl azide	C₇H₄BrN₃OS	详情	详情
(XIV)	38301	2-bromothieno[2,3-c]pyridin-7(6H)-one	C₇H₄BrNOS	详情	详情
(XV)	38302	2-bromo-7-chlorothieno[2,3-c]pyridine	C₇H₃BrClNS	详情	详情
(XVI)	38303	(7-chlorothieno[2,3-c]pyridin-2-yl)lithium	C₇H₃ClLiNS	详情	详情
(XVII)	38304	7-chlorothieno[2,3-c]pyridine-2-sulfonyl chloride	C₇H₃Cl₂NO₂S₂	详情	详情
(XVIII)	38305	7-chloro-N-[(3S)-1-(5-cyano-2-hydroxybenzyl)-2-oxopyrrolidinyl]thieno[2,3-c]pyridine-2-sulfonamide	C₁₉H₁₅ClN₄O₄S₂	详情	详情
(XIX)	38306	ethyl 3-[((3S)-3-[[(7-chlorothieno[2,3-c]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidoate	C₂₁H₂₁ClN₄O₅S₂	详情	详情
(XX)	38307	3-[((3S)-3-[[(7-chlorothieno[2,3-c]pyridin-2-yl)sulfonyl]amino]-2-oxopyrrolidinyl)methyl]-4-hydroxybenzenecarboximidamide	C₁₉H₁₈ClN₅O₄S₂	详情	详情

Extended Information