methyl formate -Drug Synthesis Database

【结构式】

【分子编号】45474

【品名】methyl formate

【CA登记号】107-31-3

【分子式】C₂H₄O₂

【分子量】60.05256

【元素组成】C 40% H 6.71% O 53.28%

与该中间体有关的原料药合成路线共 5 条

合成路线1 合成路线2 合成路线3 合成路线4 合成路线5

合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of 2-cyclopropylacetonitrile (I) with ethyl formate (II) by means of t-BuOK in THF gives the hydroxymethylene derivative (III), which is cyclized with 1-(2-fluorobenzyl)pyrazolo[3,4-b]pyridine-3-carboxamidine (IV)(see scheme no. 28591301a, intermediate (IX)) by heating at 105 C to afford the target aminopyrimidine derivative.

参考文献中间体

合成目标

【1】 Feurer, A.; et al.; 3-(2-Pyrimidinyl)pyrazolo[3,4-b]pyridines: A novel class of orally active NO-independent stimulators of soluble guanylate cyclase. 222nd ACS Natl Meet (Aug 26 2001, Chicago) 2001, Abst MEDI 205.

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)	16824	2-cyclopropylacetonitrile; Cyclopropylacetonitrile	6542-60-5	C₅H₇N	详情	详情
(II)	45474	methyl formate	107-31-3	C₂H₄O₂	详情	详情
(III)	63160	(Z)-2-cyclopropyl-3-hydroxy-2-propenenitrile		C₆H₇NO	详情	详情
(IV)	50477	1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridine-3-carboximidamide	256376-68-8	C₁₄H₁₂FN₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

Treatment of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and diisopropyl amine (DIPA) in THF provides carboxaldehyde (III), which is converted into ester (VI) by first condensation with 4-chlorophenol (IV) by means of tBuOK in THF followed by cyclization with methyl thioglycolate (V) and Cs2CO3. Methyl ester (VI) reacts with methanolic ammonia to yield carboxamide (VII), which is then treated with trifluoroacetic anhydride (TFAA) in pyridine to furnish carbonitrile (VIII). Finally, (VIII) is converted into the desired compound by reaction with hydroxylamine hydrochloride (NH2OH·HCl) and TEA in EtOH.

参考文献中间体

合成目标

【1】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 .

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)	35535	3,5-dichloropyridine	2457-47-8	C₅H₃Cl₂N	详情	详情
(II)	45474	methyl formate	107-31-3	C₂H₄O₂	详情	详情
(III)	35536	3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde	136590-83-5	C₆H₃Cl₂NO	详情	详情
(IV)	35543	4-chlorophenol	106-48-9	C₆H₅ClO	详情	详情
(V)	18838	methyl 2-sulfanylacetate	2365-48-2	C₃H₆O₂S	详情	详情
(VI)	35542	methyl 4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxylate		C₁₅H₁₀ClNO₃S	详情	详情
(VII)	45475	4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carboxamide		C₁₄H₉ClN₂O₂S	详情	详情
(VIII)	45476	4-(4-chlorophenoxy)thieno[2,3-c]pyridine-2-carbonitrile		C₁₄H₇ClN₂OS	详情	详情

合成路线3

该中间体在本合成路线中的序号：(II)

The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is hydrolyzed with LiOH in THF/water to provide the corresponding carboxylic acid (VIII). Finally, this compound is condensed with methylamine (IX) by means of EDC and HOBt in DMF to give the target amide. Alternatively, the target amide can also be obtained by direct reaction of methyl ester (VII) with methylamine (IX) in hot methanol in a sealed tube.

参考文献中间体

合成目标

【1】 Zhu, G.-D.; et al.; Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)theino[2,3-c]pyridines with fine-tuning at C-2 carbamides. J Med Chem 2001, 44, 21, 3469.
【2】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 .

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)	35535	3,5-dichloropyridine	2457-47-8	C₅H₃Cl₂N	详情	详情
(II)	45474	methyl formate	107-31-3	C₂H₄O₂	详情	详情
(III)	35536	3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde	136590-83-5	C₆H₃Cl₂NO	详情	详情
(IV)	25313	4-bromophenol	106-41-2	C₆H₅BrO	详情	详情
(V)	52015	3-(4-bromophenoxy)-5-chloroisonicotinaldehyde		C₁₂H₇BrClNO₂	详情	详情
(VI)	18838	methyl 2-sulfanylacetate	2365-48-2	C₃H₆O₂S	详情	详情
(VII)	52016	methyl 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylate		C₁₅H₁₀BrNO₃S	详情	详情
(VIII)	52017	4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid		C₁₄H₈BrNO₃S	详情	详情
(IX)	11021	Methanamine; Methylamine	74-89-5	CH₅N	详情	详情

合成路线4

该中间体在本合成路线中的序号：(II)

参考文献中间体

合成目标

【1】 Zhu, G.-D.; et al.; Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)theino[2,3-c]pyridines with fine-tuning at C-2 carbamides. J Med Chem 2001, 44, 21, 3469.
【2】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 .

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)	35535	3,5-dichloropyridine	2457-47-8	C₅H₃Cl₂N	详情	详情
(II)	45474	methyl formate	107-31-3	C₂H₄O₂	详情	详情
(III)	35536	3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde	136590-83-5	C₆H₃Cl₂NO	详情	详情
(IV)	25313	4-bromophenol	106-41-2	C₆H₅BrO	详情	详情
(V)	52015	3-(4-bromophenoxy)-5-chloroisonicotinaldehyde		C₁₂H₇BrClNO₂	详情	详情
(VI)	18838	methyl 2-sulfanylacetate	2365-48-2	C₃H₆O₂S	详情	详情
(VII)	52016	methyl 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylate		C₁₅H₁₀BrNO₃S	详情	详情

合成路线5

该中间体在本合成路线中的序号：(II)

The formylation of 3,5-dichloropyridine (I) with methyl formate (II), BuLi and DIEA in THF gives 3,5-dichloropyridine-4-carbaldehyde (III), which is treated with 4-bromophenol (IV) and potassium tert-butoxide in hot THF to yield the adduct (V). This compound, without isolation is cyclized with methyl 2-mercaptoacetate (VI) by means of Cs2CO3 to afford 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid methyl ester (VII), which is hydrolyzed with LiOH in THF/water to provide the corresponding carboxylic acid (VIII). Finally, this compound is condensed with ethanolamine (IX) by means of EDC and HOBt in DMF to give the target ethanolamide. Alternatively, the target amide can also be obtained by direct reaction of methyl ester (VII) with ethanolamine (IX) in refluxing methanol.

参考文献中间体

合成目标

【1】 Zhu, G.-D.; et al.; Selective inhibition of ICAM-1 and E-selectin expression in human endothelial cells. 2. Aryl modifications of 4-(aryloxy)theino[2,3-c]pyridines with fine-tuning at C-2 carbamides. J Med Chem 2001, 44, 21, 3469.
【2】 Lartey, K.; Gunawardana, I.W.; Stout, D.M.; Bhatia, P.; Patel, M.V.; Staeger, M.A.; Boyd, S.A.; Mort, N.A.; Zhu, G.-D.; McCarty, C.M.; Stewart, A.O.; Arendsen, D.L.; Condroski, K.R.; Freeman, J.C. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory cpds.. WO 9962908 .

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)	35535	3,5-dichloropyridine	2457-47-8	C₅H₃Cl₂N	详情	详情
(II)	45474	methyl formate	107-31-3	C₂H₄O₂	详情	详情
(III)	35536	3,5-dichloroisonicotinaldehyde; 3,5-Dichloropyridine-4-carbaldehyde	136590-83-5	C₆H₃Cl₂NO	详情	详情
(IV)	25313	4-bromophenol	106-41-2	C₆H₅BrO	详情	详情
(V)	52015	3-(4-bromophenoxy)-5-chloroisonicotinaldehyde		C₁₂H₇BrClNO₂	详情	详情
(VI)	18838	methyl 2-sulfanylacetate	2365-48-2	C₃H₆O₂S	详情	详情
(VII)	52016	methyl 4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylate		C₁₅H₁₀BrNO₃S	详情	详情
(VIII)	52017	4-(4-bromophenoxy)thieno[2,3-c]pyridine-2-carboxylic acid		C₁₄H₈BrNO₃S	详情	详情
(IX)	13324	2-Methylaminoethanol; 2-(Methylamino)-1-ethanol	109-83-1	C₃H₉NO	详情	详情

Extended Information