3-Chlorobenzaldehyde -Drug Synthesis Database

【结构式】

【分子编号】13660

【品名】3-Chlorobenzaldehyde

【CA登记号】587-04-2

【分子式】C₇H₅ClO

【分子量】140.5688

【元素组成】C 59.81% H 3.59% Cl 25.22% O 11.38%

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：(V)

BRL 35135 may be obtained by the following synthetic procedures: Alkylation of 4-hydroxybenzaldehyde (I) with methyl chloroacetate in boiling acetone in the presence of potassium carbonate and a catalytic quantity of potassium iodide gives methyl 4-formylphenoxyacetate (II), which is condensed with nitroethane in glacial acetic acid in the presence of n-butylamine to give the nitrostyrene (III). Reduction of nitrostyrene (III) with steel wool and glacial acetic acid/methanol leads to methyl 4-(2-oxopropyl)phenoxyacetate (IV). Condensation of (IV) with alpha-(aminomethyl-3-chlorobenzenemethanol (VI) and hydrogenation of the resultant imine with platinum in methyl acetate leads to a mixture of diastereomers (VII). Pure BRL 35135 can be obtained from this mixture of diastereomers by fractional crystallization, and subsequent recrystallization, of the hydrobromide salt from methyl acetate-methanol. The ethanolamine (VI) is prepared by addition of trimethylsilyl cyanide to 3-chlorobenzaldehyde (V) in diethyl ether in the presence of a catalytic amount of zinc iodide and subsequent reduction of the trimethylsilylcyanohydrin with lithium aluminum hydride.

参考文献中间体

合成目标

【1】 Ainsworth, A.T.; Smith, D.G. (SmithKline Beecham plc); Ethanamine derivs., their preparation and use in pharmaceutical compsns. EP 0023385 .
【2】 Cantello, B.C.C.; Smith, S.A.; BRL 35135. Drugs Fut 1991, 16, 9, 797.

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)	13433	4-Hydroxybenzaldehyde; p-Hydroxybenzaldehyde	123-08-0	C₇H₆O₂	详情	详情
(II)	13657	methyl 2-(4-formylphenoxy)acetate		C₁₀H₁₀O₄	详情	详情
(III)	13658	methyl 2-[4-[(E)-2-nitro-1-propenyl]phenoxy]acetate		C₁₂H₁₃NO₅	详情	详情
(IV)	13659	methyl 2-[4-(2-oxopropyl)phenoxy]acetate		C₁₂H₁₄O₄	详情	详情
(V)	13660	3-Chlorobenzaldehyde	587-04-2	C₇H₅ClO	详情	详情
(VI)	13661	2-Amino-1-(3-chlorophenyl)-1-ethanol	121652-86-6	C₈H₁₀ClNO	详情	详情
(VII)	13662	methyl 2-[4-(2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl)phenoxy]acetate		C₂₀H₂₄ClNO₄	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 title dihydropyridine is prepared by condensation of benzoylacetone (I) with 3-chlorobenzaldehyde (II) in the presence of aqueous ammonia, following a variation of the Hantzsch reaction.

参考文献中间体

合成目标

【1】 Kawase, M.; et al.; 3,5-Dibenzoyl-1,4-dihydropyridines: Synthesis and MDR reversal in tumor cells. Bioorg Med Chem 2002, 10, 4, 1051.

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)	23829	1-phenyl-1,3-butanedione	93-91-4	C₁₀H₁₀O₂	详情	详情
(II)	13660	3-Chlorobenzaldehyde	587-04-2	C₇H₅ClO	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XII)

The optically pure diol intermediate (VIII) can be obtained by several procedures. Aldol condensation of 3-chlorobenzaldehyde (XII) with the lithium enolate of ethyl acetate gives the hydroxy ester (XIII), which is reduced to racemic 1-(3-chlorophenyl)-1,3-propanediol (XIV) by means of LiAlH4 in Et2O. Ketalization of diol (XIV) with (-)-menthone (XV) employing trimethylsilyl triflate and hexamethyldisilazane produces the spiro ketal (XVI) as a diastereomeric mixture, from which the target (S)-diol (VIII) is obtained by fractional crystallization, followed by acidic ketal hydrolysis (1-3). In a different strategy utilizing an enantioselective reduction, 3’-chloroacetophenone (XVII) is condensed with diethyl carbonate by means of t-BuOK in THF to yield the keto ester (XVIII), which is selectively reduced to the (S)-hydroxy ester (XIX) by catalytic hydrogenation over a chiral ruthenium catalyst. After saponification of ester (XIX), the chiral hydroxy acid obtained (XX) is reduced to (VIII) with borane in THF. Similarly, the (S)-hydroxy acid (XX) can be produced by condensation of 3-chlorobenzoyl chloride (XXI) with the lithium enolate of trimethylsilyl acetate, followed by acidic desilylation to yield the keto acid (XXII), which is then reduced to (XX) utilizing (–)-B-chlorodiisopinocamphenylborane (DIP-Cl) in cold CH2Cl2 (1-5). In a further method, 3-chlorocinnamic acid (XXIII) is esterified with H2SO4/EtOH, followed by reduction with DIBAL to provide the cinnamyl alcohol (XXIV), which undergoes Sharpless asymmetric epoxidation to (XXV) with t-butyl hydroperoxide in the presence of (+)-diethyl tartrate. Reductive cleavage of the chiral epoxide obtained (XXV) by means of Red-Al then furnishes the target 1(S)-(3-chlorophenyl)-1,3-propanediol (VIII) (1, 2). Scheme 2.

参考文献中间体

合成目标

【1】 Kopcho, J.J., Matelich, M.C., Reddy, K.R., Ugarkar, B.G. (Metabasis Therapeutics, Inc.). Process for preparation of cyclic prodrugs of PMEA and PMPA. JP 2005525422, US 2003225277, WO 2003095665.
【2】 Erion, M.D., Kopcho, J.J., Matelich, M.C., Reddy, K.R. (Metabasis Therapeutics, Inc.). Novel phosphonic acid based prodrugs of PMEA and its analogues. EP 1532157, US 2003229225, WO 2004037161.
【3】 Reddy, K.R., Matelich, M.C., Ugarkar, B.G. et al. HepDirect prodrugs of adefovir: Design, synthesis and optimization. 227th ACS Natl Meet (March 28-April 1, Anaheim) 2004, Abst MEDI- 27.
【4】 Martin, K. (Metabasis Therapeutics, Inc.). Lewis acid mediated synthesis of cyclic esters. CA 2565966, EP 1753762, US 2005282782, WO 2005123729.
【5】 Erion, M.D., Reddy, K.R., Boyer, S.H. et al. Design, synthesis, and characterization of a series of cytochrome P450 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phospho(on)ate-based drugs to the liver. J Am Chem Soc 2004, 126(16): 5154-63.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XII)	13660	3-Chlorobenzaldehyde	587-04-2	C₇H₅ClO	详情	详情
(XIII)	65236			C₁₁H₁₃ClO₃	详情	详情
(XIV)	65237	1(RS)-(3-chlorophenyl)-1,3-propanediol		C₉H₁₁ClO₂	详情	详情
(XV)	10208	L-Menthone; (2S,5R)-2-Isopropyl-5-methylcyclohexanone	14073-97-3	C₁₀H₁₈O	详情	详情
(XVI)	65238			C₁₉H₂₇ClO₂	详情	详情
(XVII)	15268	m-chloroacetophenone; 1-(3-chlorophenyl)-1-ethanone	99-02-5	C₈H₇ClO	详情	详情
(XVIII)	65239	ethyl 3-(3-chlorophenyl)-3-oxopropanoate		C₁₁H₁₁ClO₃	详情	详情
(XIX)	65240			C₁₁H₁₃ClO₃	详情	详情
(XX)	65241			C₉H₉ClO₃	详情	详情
(XXI)	16687	3-chlorobenzoyl chloride	618-46-2	C₇H₄Cl₂O	详情	详情
(XXII)	65242			C₉H₇ClO₃	详情	详情
(XXIII)	65243	3-Chlorocinnamic acid	14473-90-6	C₉H₇ClO₂	详情	详情
(XXIV)	65244			C₉H₉ClO	详情	详情
(XXV)	65245			C₉H₉ClO₂	详情	详情

Extended Information