3-chlorobenzoyl chloride -Drug Synthesis Database

【结构式】

【分子编号】16687

【品名】3-chlorobenzoyl chloride

【CA登记号】618-46-2

【分子式】C₇H₄Cl₂O

【分子量】175.01356

【元素组成】C 48.04% H 2.3% Cl 40.51% O 9.14%

与该中间体有关的原料药合成路线共 2 条

合成路线1 合成路线2

合成路线1

该中间体在本合成路线中的序号：(I)

Liarozole fumarate is prepared as shown in Scheme 20970301a. Anisol is reacted with 3-chlorobenzoyl chloride (I) under Friedel-Craft conditions to give (3-chlorophenyl)(4-methoxyphenyl)methanone (II). Nitration of (II) is carried out in dichloromethane at 10 C to yield (III). The methoxy group in (III) is replaced by the amino group by means of NH3 in 2-propanol at 100 C under pressure, giving (IV). By reduction of the keto function of (IV) with sodium borohydride in 2-propanol, the corresponding alcohol (V) is obtained, which upon treatment with 1,1'-carbonyldiimidazole in refluxing dichloromethane yields the imidazolyl compound (VI). Hydrogenation of the nitro group in (VI), followed by cyclization of (VII) in a refluxing mixture of formic acid and 4N hydrochloric acid, gives the benzimidazole derivative (VIII). Finally, the treatment of (VIII) with fumaric acid in ethanol yields liarozole fumarate (IX).

参考文献中间体

合成目标

【1】 Huggins, C.; Hodges, C.V.; Studies on prostatic cancer. I. The effect of castration, of oestrogen and of androgen injection on serum phosphatases in metastatic carcinoma of the prostate. Cancer Res 1941, 1, 5, 293-7.
【2】 Raeymaekers, A.H.M.; Freyne, E.J.E.; Sanz, G.C. (Janssen Pharmaceutica NV); Novel (1H-imidazol-1-ylmethyl) substd. benzimidazole derivs. AU 8778385; EP 0260744; JP 1989085975; US 4859684 .
【3】 Mahler, C.; De Coster, R.; Freyne, E.; Bruynseels, J.; Denis, L.; De Porre, P.; Verhelst, J.; Liarozole Fumarate. Drugs Fut 1994, 19, 6, 552.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13297	Thiophene	110-02-1	C₄H₄S	详情	详情
	23767	Methoxybenzene; Methyl phenyl ether; Anisole	100-66-3	C₇H₈O	详情	详情
(I)	16687	3-chlorobenzoyl chloride	618-46-2	C₇H₄Cl₂O	详情	详情
(II)	16688	(3-chlorophenyl)(4-methoxyphenyl)methanone		C₁₄H₁₁ClO₂	详情	详情
(III)	16689	(3-Chlorophenyl)(4-methoxy-3-nitrophenyl)-methanone; (3-chlorophenyl)(4-methoxy-3-nitrophenyl)methanone	66938-41-8	C₁₄H₁₀ClNO₄	详情	详情
(IV)	16690	(4-amino-3-nitrophenyl)(3-chlorophenyl)methanone		C₁₃H₉ClN₂O₃	详情	详情
(V)	16691	(4-amino-3-nitrophenyl)(3-chlorophenyl)methanol		C₁₃H₁₁ClN₂O₃	详情	详情
(VI)	16692	4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-nitroaniline; 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-nitrophenylamine		C₁₆H₁₃ClN₄O₂	详情	详情
(VII)	16693	2-amino-4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]phenylamine; 4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1,2-benzenediamine		C₁₆H₁₅ClN₄	详情	详情
(VIII)	16694	5-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-1H-benzimidazole		C₁₇H₁₃ClN₄	详情	详情

合成路线2

该中间体在本合成路线中的序号：(XXI)

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