2-Methoxybenzoic acid; o-Methoxybenzoic Acid -Drug Synthesis Database

【结构式】

【分子编号】13926

【品名】2-Methoxybenzoic acid; o-Methoxybenzoic Acid

【CA登记号】579-75-9

【分子式】C₈H₈O₃

【分子量】152.14972

【元素组成】C 63.15% H 5.3% O 31.55%

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：(IX)

This compound is obtained by condensation of 2(S)-(aminomethyl)-1-ethylpyrrolidine (I) with 5-(aminosulfonyl)-2-methoxybenzoyl chloride (II) by means of K2CO3 in acetone. The starting compounds (I) and (II) are obtained as follows: a) The acylation of 2(S)-(hydroxymethyl)pyrrolidine (III) with acetic anhydride in refluxing methanol gives 1-acetyl-2(S)-(hydroxymethyl)pyrrolidine (IV), which by reaction with SOCl2 in CHCl3 is converted into 1-acetyl-2(S)-(chloromethyl)pyrrolidine (V). The reaction of (V) with sodium azide in hot DMF affords the corresponding azide (VI), which is reduced with LiAlH4 in refluxing THF to yield the desired product (I). b) The methylation of 2-hydroxybenzaldehyde (VII) with dimethyl sulfate and K2SO3 in refluxing acetone gives 2-methoxybenzaldehyde (VIII), which is oxidized with KMnO4 in hot aqueous NaOH affording 2-methoxybenzoic acid (IX). The sulfonation of (IX) with hot chlorosulfonic acid yields 5-(chlorosulfonyl)-2-methoxybenzoic acid (X), which is finally treated with 28% aqueous NaOH to give the desired product (II).

参考文献中间体

合成目标

【1】 Al-Koutayni-Rifai, M.; Jamet, G.; Kerr, R.R.; Jung, L.; Koffel, J.C.; Synthesis of D3-sulpiride and its (R) and (S) isomers. J Label Compd Radiopharm 1989, 27, 7, 811.

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)	21345	(2S)-1-Ethyl-2-(aminomethyl)pyrrolidine; [(2S)-1-Ethylpyrrolidinyl]methanamine		C₇H₁₆N₂	详情	详情
(II)	21346	5-(aminosulfonyl)-2-methoxybenzoyl chloride		C₈H₈ClNO₄S	详情	详情
(III)	21347	(2S)pyrrolidinylmethanol	23356-96-9	C₅H₁₁NO	详情	详情
(IV)	21348	1-[(2S)-2-(hydroxymethyl)pyrrolidinyl]-1-ethanone		C₇H₁₃NO₂	详情	详情
(V)	21349	1-[(2S)-2-(chloromethyl)pyrrolidinyl]-1-ethanone		C₇H₁₂ClNO	详情	详情
(VI)	21350	1-[(2S)-2-(azidomethyl)pyrrolidinyl]-1-ethanone		C₇H₁₂N₄O	详情	详情
(VII)	21351	2-Hydroxybenzaldehyde;Salicylic aldehyde；2-Formylphenol;salicylaldehyde	90-02-8	C₇H₆O₂	详情	详情
(VIII)	12568	2-Methoxybenzaldehyde; o-Methoxybenzaldehyde	135-02-4	C₈H₈O₂	详情	详情
(IX)	13926	2-Methoxybenzoic acid; o-Methoxybenzoic Acid	579-75-9	C₈H₈O₃	详情	详情
(X)	21354	5-(chlorosulfonyl)-2-methoxybenzoic acid		C₈H₇ClO₅S	详情	详情
(XI)	21355	5-(aminosulfonyl)-2-methoxybenzoic acid; 2-methoxy-5-sulfamoylbenzoic acid	22117-85-7	C₈H₉NO₅S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(VI)

The synthesis of the biphenyl tail involves first the conversion of 2-methoxybenzoic acid (VI) into oxazoline (VII), followed by displacement of the methoxy group by 4-tolylmagnesium bromide to yield biphenyloxazoline (VIII). Oxazoline (VIII) may be converted into biphenylnitrile (IX) by reaction with phosphorous oxychloride in pyridine. Reaction of biphenylnitrile (VIII) with tri-n-butyltin azide in refluxing xylenes, followed by destannylation and protection with a triphenylmethyl group, yields triphenylmethyl-protected biphenyltetrazole (X). Benzylic bromination yields the completed tail (XI)

参考文献中间体

合成目标

【1】 Duncia, J.V.; Carini, D.J.; Chiu, A.T.; Pierce, M.E.; Price, W.A.; Smith, R.D.; Wells, G.J.; Wong, P.C.; Wexler, R.R.; Johnson, A.L.; Timmermans, P.B.M.W.M.; DuP 753. Drugs Fut 1991, 16, 4, 305.
【2】 Carini, D.J.; Duncia, J.V.; Aldrich, P.E.; Chiu, A.T.; Johnson, A.L.; Pierce, M.E.; Santella, J.B.; Wells, G.J.; Wexler, R.R.; Wong, P.C.; Timmermans, P.B.M.W.M.; Nonpeptide angiotensin II receptor antagonists: The discovery of a series of N-(biphenylmethyl)imidazoles as potent, orally-active antihypertensives. J Med Chem 1991, 34, 8, 2225-47.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VI)	13926	2-Methoxybenzoic acid; o-Methoxybenzoic Acid	579-75-9	C₈H₈O₃	详情	详情
(VII)	13927	2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether	57598-33-1	C₁₂H₁₅NO₂	详情	详情
(VIII)	13928	4,4-Dimethyl-2-(4'-methyl-2-biphenyllyl)2-oxazoline; 4,4-Dimethyl-2-(4'-methyl[1,1'-biphenyl]-2-yl)-4,5-dihydro-1,3-oxazole	84392-32-5	C₁₈H₁₉NO	详情	详情
(IX)	13929	2-Cyano-4'-methylbiphenyl; 4'-Methyl[1,1'-biphenyl]-2-carbonitrile	114772-53-1	C₁₄H₁₁N	详情	详情
(X)	13930	5-(4'-Methyl[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole		C₃₃H₂₆N₄	详情	详情
(XI)	13931	5-(4'-Bromo[1,1'-biphenyl]-2-yl)-1-trityl-1H-1,2,3,4-tetraazole		C₃₂H₂₃BrN₄	详情	详情

合成路线3

该中间体在本合成路线中的序号：(I)

2-Methoxybenzoic acid (I) was protected as the oxazoline (II). Further coupling with tolylmagnesium bromide, followed by acid hydrolysis of the oxazoline provided the intermediate biphenyl carboxylic acid (III).

参考文献中间体

合成目标

【1】 Hosogai, N.; Tanaka, H.; Tomita, M.; Ohkawa, T.; Hemmi, K.; Setoi, H.; Zenkoh, O.; Synthesis and characterization of orally active nonpeptide vasopressin V2 receptor antagonists. Chem Pharm Bull 1999, 47, 4, 501.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	35657	bromo(4-methylphenyl)magnesium	4294-57-9	C₇H₇BrMg	详情	详情
(I)	13926	2-Methoxybenzoic acid; o-Methoxybenzoic Acid	579-75-9	C₈H₈O₃	详情	详情
(II)	13927	2-(2-Methoxyphenyl)-4,4-dimethyl-2-oxazoline; 2-(2-Methoxyphenyl)-4,4-dimethyl-4,5-dihydro-1,3-oxazole; 2-(4,4-Dimethyl-4,5-dihydro-1,3-oxazol-2-yl)phenyl methyl ether	57598-33-1	C₁₂H₁₅NO₂	详情	详情
(III)	16915	4'-methyl[1,1'-biphenyl]-2-carboxylic acid	7148-03-0	C₁₄H₁₂O₂	详情	详情

合成路线4

该中间体在本合成路线中的序号：(XIV)

The reaction of the chiral epoxide (I) with 4-methoxybenzaldehyde (II) by means of NaAl(OMe)3H in THF gives the 1,3-dioxane (III), which is opened by reduction with DIBAL in dichloromethane to yield the chiral benzyl ether (IV). The oxidation of the primary alcohol of (IV) with DMP in dichloromethane affords the corresponding aldehyde (V), which is condensed with the boronate (VI) and S,S-diisopropyl tartrate in toluene to provide the unsaturated alcohol (VII).The protection of (VII) with Tbdps-Cl and imidazole yields the fully protected triol (VIII), which is oxidized at the terminal double bond with 9-BBN in THF to give the primary alcohol (IX). The oxidation of (IX) with DMP in dichloromethane affords the aldehyde (X), which is condensed with methylenetriphenylphosphorane (XI) in THF to provide the terminal olefin (XII). Elimination of the Pmb protecting group of (XII) with DDQ in dichloromethane gives the alcohol (XIII), which is esterified with 2-allyl-6-methoxybenzoic acid (XIV)(obtained by allylation of 2-methoxybenzoic acid (XV) with allyl bromide (XVI), BuLi and MgBr2) by means of DEAD and PPh3 yielding the ester (XVII). The cyclization of (XVII) by means of a metathesis reaction catalyzed by a ruthenium catalyst in refluxing dichloromethane affords the bicyclic lactone (XVIII), which is treated with BBr3 in dichloromethane to provide the dihydroxylated lactone (XIX).

参考文献中间体

合成目标

【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.

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)	47480	[(2R,3R)-3-[3-(benzyloxy)propyl]oxiranyl]methanol		C₁₃H₁₈O₃	详情	详情
(II)	27251	4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde	123-11-5	C₈H₈O₂	详情	详情
(III)	47481	(4R)-4-[3-(benzyloxy)propyl]-2-(4-methoxyphenyl)-1,3-dioxane; benzyl 3-[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propyl ether		C₂₁H₂₆O₄	详情	详情
(IV)	47482	(3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]-1-hexanol		C₂₁H₂₈O₄	详情	详情
(V)	47483	(3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]hexanal		C₂₁H₂₆O₄	详情	详情
(VI)	47484	dimethyl (E)-2-butenylboronate		C₆H₁₃BO₂	详情	详情
(VII)	47485	(3S,4R,6R)-9-(benzyloxy)-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonen-4-ol		C₂₅H₃₄O₄	详情	详情
(VIII)	47486	[((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-3-butenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-8-nonenyl ether		C₄₁H₅₂O₄Si	详情	详情
(IX)	47487	(3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonanol		C₄₁H₅₄O₅Si	详情	详情
(X)	47488	(3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methylnonanal		C₄₁H₅₂O₅Si	详情	详情
(XI)	27301	methylene(triphenyl)phosphorane		C₁₉H₁₇P	详情	详情
(XII)	47489	[((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-4-pentenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-9-decenyl ether		C₄₂H₅₄O₄Si	详情	详情
(XIII)	47490	(4R,6R,7S)-1-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-7-methyl-9-decen-4-ol		C₃₄H₄₆O₃Si	详情	详情
(XIV)	13926	2-Methoxybenzoic acid; o-Methoxybenzoic Acid	579-75-9	C₈H₈O₃	详情	详情
(XV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XVI)	47491	2-allyl-6-methoxybenzoic acid		C₁₁H₁₂O₃	详情	详情
(XVII)	47492	(1S,3R,4S)-1-[3-(benzyloxy)propyl]-3-[[tert-butyl(diphenyl)silyl]oxy]-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate		C₄₅H₅₆O₅Si	详情	详情
(XVIII)	47493	(3S,5R,6S)-3-[3-(benzyloxy)propyl]-5-[[tert-butyl(diphenyl)silyl]oxy]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one		C₄₃H₅₂O₅Si	详情	详情
(XIX)	47494	(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one		C₃₅H₄₄O₅Si	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XIV)

参考文献中间体

合成目标

【1】 Labrecque, D.; et al.; Enantioselective total synthesis of salicylihalamides A and B. Tetrahedron Lett 2001, 42, 14, 2645.

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)	47480	[(2R,3R)-3-[3-(benzyloxy)propyl]oxiranyl]methanol		C₁₃H₁₈O₃	详情	详情
(II)	27251	4-methoxybenzaldehyde; Anisicaldehyde; p-anisaldehyde	123-11-5	C₈H₈O₂	详情	详情
(III)	47481	(4R)-4-[3-(benzyloxy)propyl]-2-(4-methoxyphenyl)-1,3-dioxane; benzyl 3-[(4R)-2-(4-methoxyphenyl)-1,3-dioxan-4-yl]propyl ether		C₂₁H₂₆O₄	详情	详情
(IV)	47482	(3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]-1-hexanol		C₂₁H₂₈O₄	详情	详情
(V)	47483	(3R)-6-(benzyloxy)-3-[(4-methoxybenzyl)oxy]hexanal		C₂₁H₂₆O₄	详情	详情
(VI)	47484	dimethyl (E)-2-butenylboronate		C₆H₁₃BO₂	详情	详情
(VII)	47485	(3S,4R,6R)-9-(benzyloxy)-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonen-4-ol		C₂₅H₃₄O₄	详情	详情
(VIII)	47486	[((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-3-butenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-8-nonenyl ether		C₄₁H₅₂O₄Si	详情	详情
(IX)	47487	(3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methyl-1-nonanol		C₄₁H₅₄O₅Si	详情	详情
(X)	47488	(3S,4R,6R)-9-(benzyloxy)-4-[[tert-butyl(diphenyl)silyl]oxy]-6-[(4-methoxybenzyl)oxy]-3-methylnonanal		C₄₁H₅₂O₅Si	详情	详情
(XI)	27301	methylene(triphenyl)phosphorane		C₁₉H₁₇P	详情	详情
(XII)	47489	[((1R,2S)-1-[(2R)-5-(benzyloxy)-2-[(4-methoxybenzyl)oxy]pentyl]-2-methyl-4-pentenyl)oxy](tert-butyl)diphenylsilane; benzyl (4R,6R,7S)-6-[[tert-butyl(diphenyl)silyl]oxy]-4-[(4-methoxybenzyl)oxy]-7-methyl-9-decenyl ether		C₄₂H₅₄O₄Si	详情	详情
(XIII)	47490	(4R,6R,7S)-1-(benzyloxy)-6-[[tert-butyl(diphenyl)silyl]oxy]-7-methyl-9-decen-4-ol		C₃₄H₄₆O₃Si	详情	详情
(XIV)	13926	2-Methoxybenzoic acid; o-Methoxybenzoic Acid	579-75-9	C₈H₈O₃	详情	详情
(XV)	11463	3-Bromo-1-propene; 3-Bromopropene；allyl bromide	106-95-6	C₃H₅Br	详情	详情
(XVI)	47491	2-allyl-6-methoxybenzoic acid		C₁₁H₁₂O₃	详情	详情
(XVII)	47492	(1S,3R,4S)-1-[3-(benzyloxy)propyl]-3-[[tert-butyl(diphenyl)silyl]oxy]-4-methyl-6-heptenyl 2-allyl-6-methoxybenzoate		C₄₅H₅₆O₅Si	详情	详情
(XVIII)	47493	(3S,5R,6S)-3-[3-(benzyloxy)propyl]-5-[[tert-butyl(diphenyl)silyl]oxy]-14-methoxy-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one		C₄₃H₅₂O₅Si	详情	详情
(XIX)	47494	(3S,5R,6S)-5-[[tert-butyl(diphenyl)silyl]oxy]-14-hydroxy-3-(3-hydroxypropyl)-6-methyl-3,4,5,6,7,10-hexahydro-1H-2-benzoxacyclododecin-1-one		C₃₅H₄₄O₅Si	详情	详情

Extended Information