5-bromo-2-chlorobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】25545

【品名】5-bromo-2-chlorobenzoic acid

【CA登记号】21739-92-4

【分子式】C₇H₄BrClO₂

【分子量】235.46426

【元素组成】C 35.71% H 1.71% Br 33.93% Cl 15.06% O 13.59%

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：(XV)

An further synthetic route to the intermediate ketoester (XI) is depicted in Scheme 23794901c. Pyrazole aldehyde (XIV) was condensed with 5-bromo-2-chlorobenzoic acid (XV) in the presence of two equivalents of n--BuLi to afford carbinol (XVI). Subsequent reaction of (XVI) with (trimethylsilyl) diazomethane provided methyl ester (XVII). Then, oxidation of (XVII) with activated MnO2 in boiling 1,2-dichloroethane led to the required ketone (XI).

参考文献中间体

合成目标

【1】 Numata, H.; Okamoto, Y.; Shinoda, M.; Kobayashi, N.; Miyazawa, S.; Kawahara, T.; Shirota, H.; Nagakura, N.; Horizoe, T.; Abe, S.; Kobayashi, S.; Yamanaka, T. (Eisai Co., Ltd.); Pyrazole derivs. exhibiting anti-inflammatory and analgesic effects. JP 1998509140; WO 9614302 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(XI)	25541	methyl 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl]carbonyl]-2-chlorobenzoate		C₂₆H₂₁ClN₂O₅	详情	详情
(XIV)	25544	1,5-bis(4-methoxyphenyl)-1H-pyrazole-3-carbaldehyde		C₁₈H₁₆N₂O₃	详情	详情
(XV)	25545	5-bromo-2-chlorobenzoic acid	21739-92-4	C₇H₄BrClO₂	详情	详情
(XVI)	25546	5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl](hydroxy)methyl]-2-chlorobenzoic acid		C₂₅H₂₁ClN₂O₅	详情	详情
(XVII)	25547	methyl 5-[[1,5-bis(4-methoxyphenyl)-1H-pyrazol-3-yl](hydroxy)methyl]-2-chlorobenzoate		C₂₆H₂₃ClN₂O₅	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Dapagliflozin can be synthesized as follows: 2-Chloro-5-bromobenzoic acid (I) is chlorinated with oxalyl chloride and catalytic DMF in CH2Cl2 to afford the benzoyl chloride derivative (II), which is subjected to Friedel-Crafts reaction with ethoxybenzene (III) in the presence of AlCl3 in CH2Cl2 to give the benzophenone derivative (IV). Subsequent decarbonylation of ketone (IV) employing triethylsilane and boron trifluoride etherate in acetonitrile yields 5-bromo-2-chloro-4’-ethoxydiphenylmethane (V). The lithiated derivative of bisarylmethane (V) (generated by treatment with BuLi in THF/toluene at –78 ºC) is coupled with the persilylated lactone (VII) (obtained from D-gluconolactone [VI] by treatment with trimethylsilyl chloride and NMM in THF) to yield the corresponding lactol adduct, which is deprotected in situ with methanesulfonic acid in MeOH to afford the desilylated ketal (VIII) (1-3). Polyol (VIII) is peracetylated with acetic anhydride and DIEA in THF resulting in the tetraacetate (IX). The glucosidic methoxy group of (IX) is then reductively removed using triethylsilane and boron trifluoride etherate in water/acetonitrile to give the glucoside (X) (1, 2), which is finally deacetylated by treatment with LiOH in aqueous MeOH (1-3).
Alternatively, intermediate (X) can be prepared by reduction of the glucosidic methoxy group of (VIII) with trethylsilane and boron trifluoride etherate in CH2Cl2/acetonitrite, and subsequent peracetylation with Ac2O, DMAP in CH2Cl2/pyridine (3).

参考文献中间体

合成目标

【1】 Ellsworth, B., Meng, W., Sher, P.M., Washburn, W.N., Wu, G. (Bristol-Myers Squibb Co.). C-Aryl glucoside SGLT2 inhibitors and method. EP 1506211, JP 2005531588, US 2002137903, US 6515117, WO 2003099836.
【2】 Crispino, G., Denzel, T.W., Deshpande, P.P. et al. (Bristol-Myers Squibb Co.). Methods of producing C-aryl glucoside SGLT2 inhibitors. CA 2512389, EP 1581543, JP 2006516257, US 2004138439, WO 2004063209.
【3】 Meng, W., Ellsworth, B.A., Nirschl, A.A. et al. Discovery of dapagliflozin: A potent, selective renal sodium-dependent glucose cotransporter 2 (SGLT2) inhibitor for the treatment of type 2 diabetes. J Med Chem 2008, 51(5): 1145-9.

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)	25545	5-bromo-2-chlorobenzoic acid	21739-92-4	C₇H₄BrClO₂	详情	详情
(II)	65743	5-Bromo-2-chlorobenzoyl chloride	21900-52-7	C₇H₃BrCl₂O	详情	详情
(III)	65744	Phenetole; Ethoxybenzene; Ethyl phenyl ether	103-73-1	C₈H₁₀O	详情	详情
(IV)	65745	(5-Bromo-2-chlorophenyl)(4-ethoxyphenyl)methanone	461432-22-4	C₁₅H₁₂BrClO₂	详情	详情
(V)	65746	4-(5-Bromo-2-chlorobenzyl)phenyl ethyl ether	461432-23-5	C₁₅H₁₄BrClO	详情	详情
(VI)	65747	D-Gluconolactone；GLUCONIC ACID DELTA-LACTONE；D-(+)-GLUCONO-1,5-LACTONE;DELTA-LACTONE;GLUCONIC ANHYDRIDE;GLUCONIC-D-LACTONE	4253-68-3	C₆H₁₀O₆	详情	详情
(VII)	65748	2,3,4,6-Tetrakis-O-trimethylsilyl-D-gluconolactone; D-2,3,4,6-Tetrakis-O-(trimethylsilyl)-gluconic acid delta-lactone; (3R,4S,5R,6R)-3,4,5-Tris[(trimethylsilyl)oxy]-6-[[(trimethylsilyl)oxy]methyl]tetrahydropyran-2-one	32384-65-9	C₁₈H₄₂O₆Si₄	详情	详情
(VIII)	65749	Methyl 1-C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-alpha-D-glucopyranoside	714269-57-5	C₂₂H₂₇ClO₇	详情	详情
(IX)	65750			C₃₀H₃₉ClO₁₁	详情	详情
(X)	65751			C₂₉H₃₇ClO₁₀	详情	详情

Extended Information