ethyl 5-bromopentanoate -Drug Synthesis Database

【结构式】

【分子编号】37151

【品名】ethyl 5-bromopentanoate

【CA登记号】14660-52-7

【分子式】C₇H₁₃BrO₂

【分子量】209.08302

【元素组成】C 40.21% H 6.27% Br 38.22% O 15.3%

与该中间体有关的原料药合成路线共 10 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6 合成路线7 合成路线8 合成路线9 合成路线10

合成路线1

该中间体在本合成路线中的序号：(II)

The reaction of 2-hydroxy-6-methoxybenzaldehyde (I) with ethyl 5-bromopentanoate (II) by means of K2CO3 and NaI in refluxing ethanol gives ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate (III), which is hydrolyzed with NaOH in ethanol - water yielding 5-(2-formyl-3-methoxyphenoxy)pentanoic acid (IV). Finally, this compound is demethylated by treatment with BCl3 in CH2Cl2.

参考文献中间体

合成目标

【1】 Kneen, G (Glaxo Wellcome plc); Substd. phenol ethers, their preparation, intermediates therefor, pharmaceutical compsns. containing them and the preparation thereof. EP 0022229 .
【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; BW-12C. Drugs Fut 1982, 7, 9, 613.

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)	37150	2-Hydroxy-6-methoxybenzaldehyde	700-44-7	C₈H₈O₃	详情	详情
(II)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(III)	37152	ethyl 5-(2-formyl-3-methoxyphenoxy)pentanoate		C₁₅H₂₀O₅	详情	详情
(IV)	37153	5-(2-formyl-3-methoxyphenoxy)pentanoic acid		C₁₃H₁₆O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(II)

The reaction of 2-hydroxy-6-benzyloxybenzaldehyde (V) with ethyl 5-bromopentanoate (II) by means of K2CO3 and NaI in refluxing ethanol gives ethyl 5-(2-formyl-3-benzyloxyphenoxy)pentanoate (VI), which is hydrolyzed with KOH in ethanol yielding 5-(2-formyl-3-benzyloxyphenoxy)pentanoic acid (VII) Finally, this compound is debenzylated by hydrogenation with H2 over Pd/c in ethanol.

参考文献中间体

合成目标

【1】 Kneen, G (Glaxo Wellcome plc); Substd. phenol ethers, their preparation, intermediates therefor, pharmaceutical compsns. containing them and the preparation thereof. EP 0022229 .
【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; BW-12C. Drugs Fut 1982, 7, 9, 613.

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)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(V)	37157	2-(benzyloxy)-6-hydroxybenzaldehyde		C₁₄H₁₂O₃	详情	详情
(VI)	37158	ethyl 5-[3-(benzyloxy)-2-formylphenoxy]pentanoate		C₂₁H₂₄O₅	详情	详情
(VII)	37159	5-[3-(benzyloxy)-2-formylphenoxy]pentanoic acid		C₁₉H₂₀O₅	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 reaction of methyl 2,4-dihydroxy-3-formylbenzoate (VIII) with ethyl 5-bromopentanoate (II) by means of NaH in DMF gives ethyl 5-(2-formyl-3-hydroxy-4-methoxycarbonylphenoxy)pentanoate (IX), which is hydrolyzed with NaOH in water yielding 5-(2-formyl-3-hydroxy-4-carboxyphenoxy)pentanoic acid (X). Finally, this compound is decarboxylated by treatment with acidic alumina in refluxing dioxane-H2O or with copper in quinoline at 210 C.

参考文献中间体

合成目标

【1】 Kneen, G (Glaxo Wellcome plc); Substd. phenol ethers, their preparation, intermediates therefor, pharmaceutical compsns. containing them and the preparation thereof. EP 0022229 .
【2】 Hillier, K.; Castaner, J.; Serradell, M.N.; Blancafort, P.; BW-12C. Drugs Fut 1982, 7, 9, 613.

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)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(VIII)	37154	methyl 3-formyl-2,4-dihydroxybenzoate		C₉H₈O₅	详情	详情
(IX)	37155	methyl 4-[(5-ethoxy-5-oxopentyl)oxy]-3-formyl-2-hydroxybenzoate		C₁₆H₂₀O₇	详情	详情
(X)	37156	4-(4-carboxybutoxy)-3-formyl-2-hydroxybenzoic acid		C₁₃H₁₄O₇	详情	详情

合成路线4

该中间体在本合成路线中的序号：(VI)

4-Formylbenzonitrile (IV) was converted to the aryl tetrazole (V) upon treatment with trimethylsilyl azide and dibutyltin oxide. Regioselective alkylation of tetrazole (V) with ethyl 5-bromovalerate (VI) afforded the (2-tetrazolyl)pentanoate (VII).

参考文献中间体

合成目标

【1】 Maw, G.N. (Pfizer Inc.); Anti-inflammatory piperazinyl-benzyl-tetrazole derivs. and intermediates thereof. EP 0983251; JP 2000513024; WO 9852929 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IV)	17552	4-formylbenzonitrile; 4-Cyanobenzaldehyde	105-07-7	C₈H₅NO	详情	详情
(V)	48159	4-(1H-1,2,3,4-tetraazol-5-yl)benzaldehyde		C₈H₆N₄O	详情	详情
(VI)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(VII)	48160	ethyl 5-[5-(4-formylphenyl)-2H-1,2,3,4-tetraazol-2-yl]pentanoate		C₁₅H₁₈N₄O₃	详情	详情

合成路线5

该中间体在本合成路线中的序号：(VI)

A related procedure for the synthesis of the precursor ethyl ester (XI) was also reported. The condensation between 4-formylbenzonitrile (IV), piperazine (III) and benzotriazole furnished the benzotriazolyl adduct (XII). Subsequent reaction of (XII) with the Grignard reagent (XIII) yielded the (diarylmethyl)piperazine (XIV). The cyano group of (XIV) was then converted to the tetrazole (XV) by treatment with trimethylsilyl azide and dibutyltin oxide. Alkylation of tetrazole (XV) with ethyl 5-bromovalerate (VI) gave rise to a mixture of 1-triazolyl (XVII) and 2-triazolylpentanoate (XVI). After desilylation of this mixture with tetraethylammonium fluoride, the desired 2-triazolyl derivative (XI) was isolated by column chromatography.

参考文献中间体

合成目标

【1】 Maw, G.N. (Pfizer Inc.); Anti-inflammatory piperazinyl-benzyl-tetrazole derivs. and intermediates thereof. EP 0983251; JP 2000513024; WO 9852929 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(III)	20690	(2R,5S)-1-allyl-2,5-dimethylpiperazine		C₉H₁₈N₂	详情	详情
(IV)	17552	4-formylbenzonitrile; 4-Cyanobenzaldehyde	105-07-7	C₈H₅NO	详情	详情
(VI)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(XI)	48163	ethyl 5-(5-[4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-hydroxyphenyl)methyl]phenyl]-2H-1,2,3,4-tetraazol-2-yl)pentanoate		C₃₀H₄₀N₆O₃	详情	详情
(XII)	48164	4-[[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](1H-1,2,3-benzotriazol-1-yl)methyl]benzonitrile		C₂₃H₂₆N₆	详情	详情
(XIII)	20706	bromo(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)magnesium		C₁₂H₁₉BrMgOSi	详情	详情
(XIV)	48165	4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]benzonitrile		C₂₉H₄₁N₃OSi	详情	详情
(XV)	48166	(2R,5S)-1-allyl-4-[(R)-(3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)[4-(1H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]-2,5-dimethylpiperazine; 3-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl][4-(1H-1,2,3,4-tetraazol-5-yl)phenyl]methyl]phenyl tert-butyl(dimethyl)silyl ether		C₂₉H₄₂N₆OSi	详情	详情
(XVI)	48168	ethyl 5-(5-[4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]phenyl]-1H-1,2,3,4-tetraazol-1-yl)pentanoate		C₃₆H₅₄N₆O₃Si	详情	详情
(XVII)	48167	ethyl 5-(5-[4-[(R)-[(2S,5R)-4-allyl-2,5-dimethylpiperazinyl](3-[[tert-butyl(dimethyl)silyl]oxy]phenyl)methyl]phenyl]-2H-1,2,3,4-tetraazol-2-yl)pentanoate		C₃₆H₅₄N₆O₃Si	详情	详情

合成路线6

该中间体在本合成路线中的序号：(II)

Alkylation of ethyl 4-chloroindole-2-carboxylate (I) with ethyl 5-bromovalerate (II) in the presence of NaH in DMF afforded diester (III). Regioselective hydrolysis of the aliphatic ester group employing sulfuric acid and acetic acid at 75 C produced the mono-carboxylic acid (IV). The intramolecular cyclization of acid (IV) by means of phosphoric acid and phosphorus pentoxide furnished the tricyclic system (V). The ethyl ester group of (V) was then treated with guanidine (VI) to yield the target acyl guanidine derivative, which was finally converted to the title methanesulfonate salt.

参考文献中间体

合成目标

【1】 Kitano, M.; Ohashi, N. (Sumitomo Pharmaceuticals Co., Ltd.); Substd. guanidine derivs., process for production thereof, and pharmaceutical uses thereof. EP 0787728; JP 1998237073; US 5834454; US 5977100; US 6271251 .

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)	47754	ethyl 4-chloro-1H-indole-2-carboxylate		C₁₁H₁₀ClNO₂	详情	详情
(II)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(III)	47755	ethyl 4-chloro-1-(5-ethoxy-5-oxopentyl)-1H-indole-2-carboxylate		C₁₈H₂₂ClNO₄	详情	详情
(IV)	47756	5-[4-chloro-2-(ethoxycarbonyl)-1H-indol-1-yl]pentanoic acid		C₁₆H₁₈ClNO₄	详情	详情
(V)	47757	ethyl 11-chloro-8-oxo-5,6,7,8-tetrahydro-4H-azocino[3,2,1-hi]indole-2-carboxylate		C₁₆H₁₆ClNO₃	详情	详情
(VI)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情

合成路线7

该中间体在本合成路线中的序号：(V)

2-Methoxyphenethylamine (I) is condensed with methyl 4-formylbenzoate (II) to form imine (III), which is further reduced to amine (IV) with NaBH4 in MeOH. Alkylation of amine (IV) by ethyl 5-bromovalerate (V) affords the amino diester (VI). Methyl ether cleavage in (VI) by means of BBr3 gives rise to the phenol compound (VII), which is alkylated with 4-(chloromethyl)stilbene (VIII) to yield ether (IX). Catalytic hydrogenation of stilbene (IX) yields the phenethylbenzyl derivative (X). Finally, alkaline hydrolysis of the methyl ester groups of (X) leads to the title dicarboxylic acid.

参考文献中间体

合成目标

【1】 Perzborn, E.; Stasch, J.-P.; Heil, M.; Naab, P.; Dembowsky, K.; Alonso-Alija, C.; Stahl, E.; Pernerstorfer, J.; Flubacher, D.; Wunder, F. (Bayer AG); Novel derivs. of dicarboxylic acid having pharmaceutical properties. DE 19943635; EP 1216225; WO 0119780 .

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)	57674	1-Amino-2-(2-methoxyphenyl)ethane; 2-(2-Aminoethyl)anisole; 2-(2-Methoxyphenyl)ethylamine; 2-Methoxyphenethylamine	2045-79-6	C₉H₁₃NO	详情	详情
(II)	10170	methyl 4-formylbenzoate	1571-08-0	C₉H₈O₃	详情	详情
(III)	57675	methyl 4-{[(2-methoxyphenethyl)imino]methyl}benzoate		C₁₈H₁₉NO₃	详情	详情
(IV)	57676	methyl 4-{[(2-methoxyphenethyl)amino]methyl}benzoate		C₁₈H₂₁NO₃	详情	详情
(V)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(VI)	57677	methyl 4-{[(5-ethoxy-5-oxopentyl)(2-methoxyphenethyl)amino]methyl}benzoate		C₂₅H₃₃NO₅	详情	详情
(VII)	57678	methyl 4-{[(2-hydroxyphenethyl)(5-methoxy-5-oxopentyl)amino]methyl}benzoate		C₂₃H₂₉NO₅	详情	详情
(VIII)	57679	4-Chloromethylstilbene		C₁₅H₁₃Cl	详情	详情
(IX)	57680	methyl 4-({(5-methoxy-5-oxopentyl)[2-({4-[(E)-2-phenylethenyl]benzyl}oxy)phenethyl]amino}methyl)benzoate		C₃₈H₄₁NO₅	详情	详情
(X)	57681	methyl 4-[((5-methoxy-5-oxopentyl){2-[(4-phenethylbenzyl)oxy]phenethyl}amino)methyl]benzoate		C₃₈H₄₃NO₅	详情	详情

合成路线8

该中间体在本合成路线中的序号：(XIV)

Protection of 4-methoxyphenol (I) with methyl chloroformate in the presence of pyridine affords the carbonate ester (II), which is condensed with dichloromethyl methyl ether and TiCl4 to yield alpha-chloro ether (III). Acidic hydrolysis of (III) with HCl furnishes aldehyde (IV), which is converted into the sodium phenoxide (V) by methanolysis of the carbonate ester (IV). Subsequent alkylation of (V) with p-methoxybenzyl bromide (VI) produces the p-methoxybenzyl ether (VII), which is condensed with 3-morpholinopropionitrile (VIII) employing a catalytic amount of NaOMe to give the morpholino acrylonitrile (IX). After conversion of (IX) to the 3-anilino acrylonitrile (X) upon heating with aniline hydrochloride, condensation with guanidine (XI) produces the diaminopyrimidine (XII). The p-methoxybenzyl group of (XII) is then cleaved by treatment with p-toluenesulfonic acid in MeOH, producing phenol (XIII). The sodium salt generated from phenol (XIII) and NaOEt is then alkylated with ethyl 5-bromopentanoate (XIV) to furnish ether (XV). Finally, alkaline hydrolysis of the ethyl ester group of (XV) leads to the title compound.

参考文献中间体

合成目标

【1】 Rosowsky, A.; Queener, S.F.; Forsch, R.A.; Inhibition of Pneumocystis carinii, Toxoplasma gondii, and Mycobacterium avium dihydrofolate reductases by 2,4-diamino-5-[2-methoxy-5-(omega-carboxyalkyloxy)benzyl]pyrimidines: Marked improvement in potency relative to trimethoprim and species selectivity. J Med Chem 2002, 45, 1, 233.

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)	32744	4-methoxyphenol	150-76-5	C₇H₈O₂	详情	详情
(II)	59058	4-methoxyphenyl methyl carbonate		C₉H₁₀O₄	详情	详情
(III)	59059	3-[chloro(methoxy)methyl]-4-methoxyphenyl methyl carbonate		C₁₁H₁₃ClO₅	详情	详情
(IV)	59060	3-formyl-4-methoxyphenyl methyl carbonate		C₁₀H₁₀O₅	详情	详情
(V)	59061	sodium 3-formyl-4-methoxybenzenolate		C₈H₇NaO₃	详情	详情
(VI)	27490	1-(bromomethyl)-4-methoxybenzene		C₈H₉BrO	详情	详情
(VII)	59062	2-methoxy-5-[(4-methoxybenzyl)oxy]benzaldehyde		C₁₆H₁₆O₄	详情	详情
(VIII)	31933	3-Morpholinopropionitrile; 3-(4-Morpholinyl)propanenitrile	4542-47-6	C₇H₁₂N₂O	详情	详情
(IX)	59063	(Z)-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-3-(4-morpholinyl)-2-propenenitrile		C₂₃H₂₆N₂O₄	详情	详情
(X)	59064	(Z)-3-anilino-2-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2-propenenitrile		C₂₅H₂₄N₂O₃	详情	详情
(XI)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情
(XII)	59065	2-amino-5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-4-pyrimidinylamine; 5-{2-methoxy-5-[(4-methoxybenzyl)oxy]benzyl}-2,4-pyrimidinediamine		C₂₀H₂₂N₄O₃	详情	详情
(XIII)	59066	3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenol		C₁₂H₁₄N₄O₂	详情	详情
(XIV)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(XV)	59067	ethyl 5-{3-[(2,4-diamino-5-pyrimidinyl)methyl]-4-methoxyphenoxy}pentanoate		C₁₉H₂₆N₄O₄	详情	详情

合成路线9

该中间体在本合成路线中的序号：(III)

Ketone (I) was converted to the corresponding oxime (II) by treatment with hydroxylamine hydrochloride and pyridine. Subsequent alkylation of the oxime (II) with ethyl 5-bromovalerate (III) in the presence of NaH provided (IV). After desilylation of (IV) by means of tetrabutylammonium fluoride, the liberated alcohol (V) was converted to mesylate (VI). The title compound was then obtained by condensation of mesylate (VI) with the pyridothienotriazolodiazepine derivative (VII).

参考文献中间体

合成目标

【1】 Sano, T.; Seki, T.; Fujita, M.; Inada, H. (Nikken Chemicals Co., Ltd.); Triazolo-1,4-diazepine cpds. and medicinal compsn. containing the same. EP 0995752; JP 1999071378; US 6433167; WO 9858930 .

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)	56588	[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone		C₂₉H₂₉NO₂Si	详情	详情
(II)	56589	[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone oxime		C₂₉H₃₀N₂O₂Si	详情	详情
(III)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(IV)	56590	ethyl 5-({[(E)-[3-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₃₆H₄₂N₂O₄Si	详情	详情
(V)	56591	ethyl 5-({[(E)-[3-(hydroxymethyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₂₀H₂₄N₂O₄	详情	详情
(VI)	56592	ethyl 5-({[(E)-(3-{[(methylsulfonyl)oxy]methyl}phenyl)(3-pyridinyl)methylidene]amino}oxy)pentanoate		C₂₁H₂₆N₂O₆S	详情	详情
(VII)	14057	6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine		C₁₉H₁₈ClN₅S	详情	详情

合成路线10

该中间体在本合成路线中的序号：(III)

Treatment of 4-(t-butyldiphenylsilyloxymethyl)phenyl-(3-pyridyl)ketone (I) with hydroxylamine hydrochloride in pyridine affords oxime (II) as a mixture of geometric isomers. Then, alkylation of oxime (II) with ethyl 5-bromovalerate (III) in the presence of NaH provides ester (IV). After desilylation of (IV) with tetrabutylammonium fluoride, the deprotected primary alcohol (V) is oxidized by KMnO4 to furnish carboxylic acid (VI). Finally, DCC-mediated coupling of acid (VI) with the known tetracyclic precursor (VII) gives rise to the corresponding amide.

参考文献中间体

合成目标

【1】 Sano, T.; Seki, T.; Fujita, M.; Inada, H. (Nikken Chemicals Co., Ltd.); Triazolo-1,4-diazepine cpds. and medicinal compsn. containing the same. EP 0995752; JP 1999071378; US 6433167; WO 9858930 .

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)	54466	[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone		C₂₉H₂₉NO₂Si	详情	详情
(II)	61007	[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methanone oxime		C₂₉H₃₀N₂O₂Si	详情	详情
(III)	37151	ethyl 5-bromopentanoate	14660-52-7	C₇H₁₃BrO₂	详情	详情
(IV)	61008	ethyl 5-({[(E)-[4-({[tert-butyl(diphenyl)silyl]oxy}methyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₃₆H₄₂N₂O₄Si	详情	详情
(V)	61009	ethyl 5-({[(E)-[4-(hydroxymethyl)phenyl](3-pyridinyl)methylidene]amino}oxy)pentanoate		C₂₀H₂₄N₂O₄	详情	详情
(VI)	61010	4-[{[(5-ethoxy-5-oxopentyl)oxy]imino}(3-pyridinyl)methyl]benzoic acid		C₂₀H₂₂N₂O₅	详情	详情
(VII)	14057	6-(2-Chlorophenyl)-1,4-dimethyl-7,8,9,10-tetrahydro-4H-pyrido[4',3':4,5]thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepine		C₁₉H₁₈ClN₅S	详情	详情

Extended Information