ethyl 3-bromopropanoate -Drug Synthesis Database

【结构式】

【分子编号】29132

【品名】ethyl 3-bromopropanoate

【CA登记号】539-74-2

【分子式】C₅H₉BrO₂

【分子量】181.02926

【元素组成】C 33.17% H 5.01% Br 44.14% O 17.68%

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：(B)

The alkylation of ethyl benzoylacetate (A) with beta-ethoxyethyl bromide (B) using potassium carbonate in dimethyl formamide at 80 C gives the beta-3-keto ester (I). Condensation of (I) with guanidine hydrochloride (C) using sodium methoxide in tert-butanol at 80 C gives the pyrimidine (II). Protection of the amino group is achieved by tormylation at room temperature with the mixed anhydride (III) from formic and acetic acids. Chlorination with an excess of phosphorus oxychloride at 100 C gives a mixture of (V) and (VIII). The mixture of chloropyrimidines (V, VIII) is stirred at room temperature with excess hydrazi-ne hydrate to give the aminohydrazinopyrimidine (VI). This is heated with ethyl orthoformate in triglyme at 135 C to give the bicyclic compound (VII). This triglyme solution is then heated to 20 C to effect a Dimroth type rearrangement to give SC-33643.

参考文献中间体

合成目标

【1】 Rorig, K.L.; Heilman, R.D.; SC-33643. Drugs Fut 1985, 10, 4, 298.

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)	10004	Ethyl 3-oxo-3-phenylpropanoate; Benzoylacetic acid, ethyl ester	94-02-0	C₁₁H₁₂O₃	详情	详情
(D)	21304	Triethyl orthoformate; 1-(Diethoxymethoxy)ethane; Diethoxymethyl ethyl ether	122-51-0	C₇H₁₆O₃	详情	详情
(B)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(I)	29133	diethyl 2-benzoylpentanedioate		C₁₆H₂₀O₅	详情	详情
(II)	29134	2-amino-5-(2-ethoxyethyl)-6-phenyl-4-pyrimidinol		C₁₄H₁₇N₃O₂	详情	详情
(III)	29135	Acetyl formyl mixed anhydride		C₃H₄O₃	详情	详情
(IV)	29136	5-(2-ethoxyethyl)-4-hydroxy-6-phenyl-2-pyrimidinylformamide		C₁₅H₁₇N₃O₃	详情	详情
(V)	29137	4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylformamide		C₁₅H₁₆ClN₃O₂	详情	详情
(VI)	29138	5-(2-ethoxyethyl)-4-hydrazino-6-phenyl-2-pyrimidinamine		C₁₄H₁₉N₅O	详情	详情
(VII)	29139	8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[4,3-c]pyrimidin-5-amine		C₁₅H₁₇N₅O	详情	详情
(VIII)	29140	4-chloro-5-(2-ethoxyethyl)-6-phenyl-2-pyrimidinylamine		C₁₄H₁₆ClN₃O	详情	详情
(C)	14790	Guanidine	113-00-8	CH₅N₃	详情	详情

合成路线2

该中间体在本合成路线中的序号：(IV)

Alkylation of 3,4-dichlorophenylacetonitrile (I) with 2-(tetrahydropyranyloxy)ethyl bromide (II) in the presence of NaH in THF afforded nitrile (III). This was further alkylated with ethyl 3-bromopropionate (IV) using LDA to produce the cyano ester adduct (V). Catalytic hydrogenation of the cyano group of (V) in the presence of Raney-nickel, with concomitant intramolecular cyclization of the intermediate amino ester, gave rise to the piperidinone (VI). This was further reduced to piperidine (VII) using LiAlH4 in THF. After acidic deprotection of the tetrahydropyranyl group of (VII), the racemic amine was resolved by means of tartaric acid to furnish the desired enantiomer (VIII). Acylation of piperidine (VIII) with 3-isopropoxyphenylacetic acid (IX) employing BOP as the coupling reagent yielded amide (X). Conversion of (X) to the mesylate (XI) was carried out by treatment with methanesulfonyl chloride and Et3N. Then, N-alkylation of 4-phenylquinuclidine (XII) with mesylate (XI) produced the corresponding ammonium salt, which was finally subjected to anion exchange of the mesylate for a chloride group by treatment with HCl.

参考文献中间体

合成目标

【1】 Emonds-Alt, X.; Gueule, P.; Proietto, V.; Van Broeck, D. (Sanofi-Synthelabo); Quaternary basic amides as tachykinines antagonists. EP 0591040; FR 2696178; JP 1998175976; US 5583134; US 5712288 .

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)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(II)	26934	2-bromoethyl tetrahydro-2H-pyran-2-yl ether		C₇H₁₃BrO₂	详情	详情
(III)	26936	2-(3,4-dichlorophenyl)-4-(tetrahydro-2H-pyran-2-yloxy)butanenitrile		C₁₅H₁₇Cl₂NO₂	详情	详情
(IV)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(V)	59767	ethyl 4-cyano-4-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanoate		C₂₀H₂₅Cl₂NO₄	详情	详情
(VI)	59768	5-(3,4-dichlorophenyl)-5-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]-2-piperidinone		C₁₈H₂₃Cl₂NO₃	详情	详情
(VII)	59769	2-[3-(3,4-dichlorophenyl)-3-piperidinyl]ethyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[2-(tetrahydro-2H-pyran-2-yloxy)ethyl]piperidine		C₁₈H₂₅Cl₂NO₂	详情	详情
(VIII)	59770	2-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-ethanol		C₁₃H₁₇Cl₂NO	详情	详情
(IX)	59771	2-(3-isopropoxyphenyl)acetic acid		C₁₁H₁₄O₃	详情	详情
(X)	59772	1-[(3S)-3-(3,4-dichlorophenyl)-3-(2-hydroxyethyl)piperidinyl]-2-(3-isopropoxyphenyl)-1-ethanone		C₂₄H₂₉Cl₂NO₃	详情	详情
(XI)	59773	2-{(3S)-3-(3,4-dichlorophenyl)-1-[2-(3-isopropoxyphenyl)acetyl]piperidinyl}ethyl methanesulfonate		C₂₅H₃₁Cl₂NO₅S	详情	详情
(XII)	59774	4-phenyl-1-azabicyclo[2.2.2]octane		C₁₃H₁₇N	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXVIII)

In a further procedure, nitrile (XXIII) was alkylated with ethyl 3-bromopropionate (XXVIII) to give cyano ester (XXIX). Catalytic hydrogenation of the cyano group of (XXIX) gave rise to the piperidinone (XXX), which was further reduced to piperidine (XXXI) with LiAlH4 in THF. Acid deprotection of the tetrahydropyranyl group of (XXXI), followed by resolution with (+)-camphorsulfonic acid, furnished the desired (S)-piperidinoalcohol camphorsulfonate salt (XXXII). Treatment of piperidine (XXXII) with benzoyl chloride in the presence of DIEA yielded benzamide (XXXIII). Conversion of the primary alcohol of (XXXIII) into the desired alkyl iodide (XXXV) was achieved via formation of the mesylate ester (XXXIV), followed by displacement of the mesylate group with KI in refluxing acetone.

参考文献中间体

合成目标

【1】 Chen, H.G.; et al.; A practical and scalable synthesis of SR 142801, a tachykinin NK3 antagonist. Bioorg Med Chem Lett 1997, 7, 5, 555.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIII)	59274	2-(3,4-dichlorophenyl)-5-(tetrahydro-2H-pyran-2-yloxy)pentanenitrile		C₁₆H₁₉Cl₂NO₂	详情	详情
(XXVIII)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(XXIX)	59279	ethyl 4-cyano-4-(3,4-dichlorophenyl)-7-(tetrahydro-2H-pyran-2-yloxy)heptanoate		C₂₁H₂₇Cl₂NO₄	详情	详情
(XXX)	59280	5-(3,4-dichlorophenyl)-5-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]-2-piperidinone		C₁₉H₂₅Cl₂NO₃	详情	详情
(XXXI)	59281	3-[3-(3,4-dichlorophenyl)-3-piperidinyl]propyl tetrahydro-2H-pyran-2-yl ether; 3-(3,4-dichlorophenyl)-3-[3-(tetrahydro-2H-pyran-2-yloxy)propyl]piperidine		C₁₉H₂₇Cl₂NO₂	详情	详情
(XXXII)	59282			C₂₄H₃₅Cl₂NO₅S	详情	详情
(XXXIII)	29467	[(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone		C₂₁H₂₃Cl₂NO₂	详情	详情
(XXXIV)	29468	3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate		C₂₂H₂₅Cl₂NO₄S	详情	详情
(XXXV)	29469	[(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone		C₂₁H₂₂Cl₂INO	详情	详情

合成路线4

该中间体在本合成路线中的序号：(V)

The protection of 3-bromo-1-propanol (I) with dihydropyran (DHP) and p-toluenesulfonic acid gives the tetrahydropyranyl ether (II), which is condensed with 3,4-dichlorophenylacetonitrile (III) by means of NaH in THF yielding the pentanenitrile (IV). The condensation of (IV) with ethyl 3-bromopropionate (V) by means of potassium hexamethyldisylazide (KHMDS) in THF affords the heptanoate (VI), which is reductocyclized with H2 over RaNi in ethanol/aq. NH4OH affording the piperidone (VII). The reduction of (VII) by means of LiAlH4 in THF gives the piperidine (VIII), which is deprotected with HCl in ethyl ether yielding the racemic propanol (IX). The optical resolution of (IX) by means of (+)-camphorsulfonic acid in isopropanol affords the desired enantiomer (X), which is acylated with benzoyl chloride (XI) and DIEA in dichloromethane providing the benzoylpiperidine (XII). The reaction of (XII) with methanesulfonyl chloride and triethylamine gives the mesylate (XIII), which is treated with KI in refluxing acetone to yield the 3-iodopropyl derivative (XIV). Finally, (XIV) is condensed with 4-hydroxy-4-phenylpiperidine (XV) by means of KHCO3 in hot acetonitrile. The intermediate 4-hydroxy-4-phenylpiperidine (XV) has been obtained as follows: The reaction of 1-benzyl-4-piperidone (XVI) with phenyllithium in THF gives 1-benzyl-4-hydroxy-4-phenylpiperidine (XVII), which is then debenzy-lated by hydrogenation with H2.

参考文献中间体

合成目标

【1】 Kuo, B.-S.; Lee, H.T.; Roth, B.D.; Chung, F.-Z.; Atherton, J.; Chen, M.H.; Syntheses and biological activities of chiral piperidines-tachykinin NK3 antagonists. Acta Pharm Sin 1999, 20, 3, 283.
【2】 Chen, M.H.G.; Lee, H.T.; Chung, F.-Z. (Pfizer Inc.); 3-Alkyl-3-phenyl-piperidines. WO 9811090 .

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)	12573	3-Bromo-1-propanol; 3-Bromopropanol	627-18-9	C₃H₇BrO	详情	详情
(II)	29460	2-(4-bromobutoxy)tetrahydro-2H-pyran; 4-bromobutyl tetrahydro-2H-pyran-2-yl ether		C₉H₁₇BrO₂	详情	详情
(III)	26935	2-(3,4-dichlorophenyl)acetonitrile	3218-49-3	C₈H₅Cl₂N	详情	详情
(IV)	29461	2-(3,4-dichlorophenyl)-6-(tetrahydro-2H-pyran-2-yloxy)hexanenitrile		C₁₇H₂₁Cl₂NO₂	详情	详情
(V)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(VI)	29462	ethyl 4-cyano-4-(3,4-dichlorophenyl)-8-(tetrahydro-2H-pyran-2-yloxy)octanoate		C₂₂H₂₉Cl₂NO₄	详情	详情
(VII)	29463	5-(3,4-dichlorophenyl)-5-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]-2-piperidinone		C₂₀H₂₇Cl₂NO₃	详情	详情
(VIII)	29464	3-(3,4-dichlorophenyl)-3-[4-(tetrahydro-2H-pyran-2-yloxy)butyl]piperidine; 4-[3-(3,4-dichlorophenyl)-3-piperidinyl]butyl tetrahydro-2H-pyran-2-yl ether		C₂₀H₂₉Cl₂NO₂	详情	详情
(IX)	29465	3-[3-(3,4-dichlorophenyl)-3-piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(X)	29466	3-[(3S)-3-(3,4-dichlorophenyl)piperidinyl]-1-propanol		C₁₄H₁₉Cl₂NO	详情	详情
(XI)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(XII)	29467	[(3S)-3-(3,4-dichlorophenyl)-3-(3-hydroxypropyl)piperidinyl](phenyl)methanone		C₂₁H₂₃Cl₂NO₂	详情	详情
(XIII)	29468	3-[(3S)-1-benzoyl-3-(3,4-dichlorophenyl)piperidinyl]propyl methanesulfonate		C₂₂H₂₅Cl₂NO₄S	详情	详情
(XIV)	29469	[(3S)-3-(3,4-dichlorophenyl)-3-(3-iodopropyl)piperidinyl](phenyl)methanone		C₂₁H₂₂Cl₂INO	详情	详情
(XV)	28021	4-phenyl-4-piperidinol; 4-Hydroxy-4-phenylpiperidine; 4-(4-Phenyl)-4-hydroxypiperidine	40807-61-2	C₁₁H₁₅NO	详情	详情
(XVI)	15720	1-benzyltetrahydro-4(1H)-pyridinone; 1-Benzyl-4-piperidone; N-Benzyl-4-piperidone; 1-(benzyl)-4-piperidinone; 1-benzylpiperidin-4-one; 1-(benzyl)piperidin-4-one	3612-20-2	C₁₂H₁₅NO	详情	详情
(XVII)	24014	Phenyllithium	591-51-5	C₆H₅Li	详情	详情
(XVIII)	29470	1-benzyl-4-phenyl-4-piperidinol		C₁₈H₂₁NO	详情	详情

合成路线5

该中间体在本合成路线中的序号：(XXVII)

In a related synthesis of (XXV) starting from the mono-protected diamine (XXVI), alkylation with ethyl 3-bromopropionate (XXVII) leads to amino ester (XXVIII), which is further protected as the di-Boc derivative (XXIX). Reduction of ester (XXIX) employing LiAlH4 furnishes alcohol (XXIV), which is further oxidized to aldehyde (XXV) under Swern conditions.

参考文献中间体

合成目标

【1】 Nantermet, P.G.; Barrow, J.C.; Newton, C.L.; Pellicore, J.M.; Young, M.; Lewis, S.D.; Lucas, B.J.; Krueger, J.A.; McMasters, D.R.; Youwei, Y.; Kuo, L.C.; Vacca, J.P.; Selnick, H.G.; Design and synthesis of potent and selective macrocyclic thrombin inhibitors. 225th ACS Natl Meet (March 23 2003, New Orleans) 2003, Abst MEDI 168.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XXIV)	64216	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-hydroxypropyl)carbamate		C₂₂H₃₆N₂O₅	详情	详情
(XXV)	64217	tert-butyl 2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl(3-oxopropyl)carbamate		C₂₂H₃₄N₂O₅	详情	详情
(XXVI)	64218	tert-butyl 2-(2-aminoethyl)benzylcarbamate		C₁₄H₂₂N₂O₂	详情	详情
(XXVII)	29132	ethyl 3-bromopropanoate	539-74-2	C₅H₉BrO₂	详情	详情
(XXVIII)	64219	ethyl 3-[(2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl)amino]propanoate		C₁₉H₃₀N₂O₄	详情	详情
(XXIX)	64220	ethyl 3-[(tert-butoxycarbonyl)(2-{[(tert-butoxycarbonyl)amino]methyl}phenethyl)amino]propanoate		C₂₄H₃₈N₂O₆	详情	详情

Extended Information