3-nitro-4-chlorobenzoic acid; 4-chloro-3-nitrobenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】14485

【品名】3-nitro-4-chlorobenzoic acid; 4-chloro-3-nitrobenzoic acid

【CA登记号】96-99-1

【分子式】C₇H₄ClNO₄

【分子量】201.5658

【元素组成】C 41.71% H 2% Cl 17.59% N 6.95% O 31.75%

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：(I)

The reaction of 4-chloro-3-nitrobenzoic acid (I) with thionyl chloride gives the acid chloride (II) which, by reaction with 4-methylpiperidine, affords the amide (III). Amination of (III) with methanolic ammonia followed by reduction of the nitro group gives the diamine compound (IV), which reacts with 1,3-bis(methoxycarbonyl)-S-methylisothiourea affording CDRI-87-144.

参考文献中间体

合成目标

【1】 Beard, C.C. (Syntex (USA), Inc.); 5(6)-Benzene ring substd. benzimidazole-2-carbamate derivs. having anthelmintic activity. US 4086235 .
【2】 Arya, V.P.; CDRI-87-144. Drugs Fut 1991, 16, 5, 420.

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)	14485	3-nitro-4-chlorobenzoic acid; 4-chloro-3-nitrobenzoic acid	96-99-1	C₇H₄ClNO₄	详情	详情
(II)	14486	4-Chloro-3-nitrobenzoylchloride; 4-chloro-3-nitrobenzoyl chloride	38818-50-7	C₇H₃Cl₂NO₃	详情	详情
(III)	14487	(4-chloro-3-nitrophenyl)(4-methylpiperidino)methanone		C₁₃H₁₅ClN₂O₃	详情	详情
(IV)	14488	(3,4-diaminophenyl)(4-methylpiperidino)methanone		C₁₃H₁₉N₃O	详情	详情

合成路线2

该中间体在本合成路线中的序号：(I)

Displacement of the chloride group of 4-chloro-3-nitrobenzoic acid (I) with sodium disulfide, followed by reduction of the disulfide and nitro groups with Sn/HCl yields 3-amino-4-mercaptobenzoic acid (II), which is further esterified to (III) with methanolic HCl. Condensation of (III) with 2,3-dichloropyrazine (IV) produces the pyrazinobenzothiazine compound (V). The ester group of (V) is then reduced to alcohol (VI) employing LiAlH4. Subsequent treatment of alcohol (VI) with methanesulfonyl chloride and pyridine leads to the benzyl chloride (VII).

参考文献中间体

合成目标

【1】 Kaneko, T.; et al.; Inhibitors of adhesion molecules expression: The synthesis and pharmacological properties of 10H-pyrazino[2,3-b][1,4]benzothiazine derivatives. Chem Pharm Bull 2002, 50, 7, 922.
【2】 Kaneko, T.; Clark, R.; Ohi, N.; Ozaki, F.; Kawahara, T.; Kamada, A.; Okano, K.; Yokohama, H.; Muramoto, K.; Arai, T.; Ohkuro, M.; Takenaka, O.; Sonoda, J. (Eisai Co., Ltd.); Benzopiperidine derivs.. EP 0934941; WO 9806720 .

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)	14485	3-nitro-4-chlorobenzoic acid; 4-chloro-3-nitrobenzoic acid	96-99-1	C₇H₄ClNO₄	详情	详情
(II)	58451	3-amino-4-sulfanylbenzoic acid		C₇H₇NO₂S	详情	详情
(III)	58452	methyl 3-amino-4-sulfanylbenzoate		C₈H₉NO₂S	详情	详情
(IV)	32326	2,3-dichloropyrazine	4858-85-9	C₄H₂Cl₂N₂	详情	详情
(V)	58453	methyl 10H-pyrazino[2,3-b][1,4]benzothiazine-8-carboxylate		C₁₂H₉N₃O₂S	详情	详情
(VI)	58454	10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethanol		C₁₁H₉N₃OS	详情	详情
(VII)	58455	8-(chloromethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine		C₁₁H₈ClN₃S	详情	详情

合成路线3

该中间体在本合成路线中的序号：(XXVIII)

The preparation of segment C (I) can be accomplished as follows. One-pot treatment of 4-chloro-3-nitrobenzoic acid (XXVIII) with Na2S and Ac2O/AcOH gives 2-methylbenzothiazole-5-carboxylic acid (XXIX), which is subsequently reduced with LiAlH4 in boiling THF followed by reoxidation of the obtained alcohol (XXX) with DMSO and SO3-pyridine complex to give the aldehyde (XXXI) (2). In an alternative procedure, aldehyde (XXXI) is produced by coupling of 5-chloro-2-methylbenzothiazole (XXXII) with acrylic acid in the presence of Pd2(dba)3 and NiBr2 followed by oxidative cleavage of the resulting arylacrylic acid (XXXIII) with OsO4 and NaIO4 (1). Aldol condensation of aldehyde (XXXI) with the chiral N-acetyloxazolidinone (XXXIV) by means of BuLi and ZnCl2 produces adduct (XXXV) as the major diastereoisomer. After protection of the free hydroxyl group of (XXXV) as the corresponding tert-butyldimethylsilyl ether (XXXVI), the chiral auxiliary group is removed by treatment with titanium ethoxide in boiling EtOH. The resulting ethyl ester (XXXVII) is then reduced to alcohol (XXXVIII) employing DIBAL in cold toluene/CH2Cl2. Subsequent reaction of alcohol (XXXVIII) with I2 and PPh3 provides the alkyl iodide (XXXIX), which is then displaced with triphenylphosphine in hot toluene, producing the target phosphonium salt (I) (1, 2). Scheme 4.

参考文献中间体

合成目标

【1】 Klar, U., Schwede, W., Lichtner, R., Buchmann, B., Hoffmann, J., Skuballa, W. (Schering AG). 6-Alkenyl, 6-alkinyl- and 6-epoxy-epothilone derivatives, process for their production, and their use in pharmaceutical preparations. DE 19921086, EP 1173441, JP 2002543203, JP 2007224038, WO 2000066589.
【2】 Klar, U., Buchmann, B., Schwede, W., Skuballa, W., Hoffmann, J., Lichtner, R.B. Total synthesis and antitumor activity of ZK-EPO: The first fully synthetic epothilone in clinical development. Angew Chem Int Ed Engl 2006, 45(47): 7942-8.

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)	65644			C₃₅H₄₁INOPSSi	详情	详情
(XXVIII)	14485	3-nitro-4-chlorobenzoic acid; 4-chloro-3-nitrobenzoic acid	96-99-1	C₇H₄ClNO₄	详情	详情
(XXIX)	65667	2-Methyl-1,3-Benzothiazole-5-Carboxylic Acid	24851-69-2	C₉H₇NO₂S	详情	详情
(XXX)	65668	(2-Methyl-1,3-benzothiazol-5-yl)methanol	32770-97-1	C₉H₉NOS	详情	详情
(XXXI)	65669	2-Methyl-1,3-Benzothiazole-5-Carbaldehyde	20061-46-5	C₉H₇NOS	详情	详情
(XXXII)	65670	5-chloro-2-methyl-1,3-benzothiazole		C₈H₆ClNS	详情	详情
(XXXIII)	65671			C₁₁H₉NO₂S	详情	详情
(XXXIV)	65672			C₁₂H₁₃NO₃	详情	详情
(XXXV)	65673			C₂₁H₂₀N₂O₄S	详情	详情
(XXXVI)	65674			C₂₇H₃₄N₂O₄SSi	详情	详情
(XXXVII)	65675			C₁₉H₂₉NO₃SSi	详情	详情
(XXXVIII)	65676			C₁₇H₂₇NO₂SSi	详情	详情
(XXXIX)	65677			C₁₇H₂₆INOSSi	详情	详情

Extended Information