2-amino-3-methylbenzoic acid -Drug Synthesis Database

【结构式】

【分子编号】48130

【品名】2-amino-3-methylbenzoic acid

【CA登记号】4389-45-1

【分子式】C₈H₉NO₂

【分子量】151.165

【元素组成】C 63.56% H 6% N 9.27% O 21.17%

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：(VIII)

Treatment of piperidine (I) with 9-BBN in refluxing THF followed by reaction with bromo derivative (II) by means of K2CO3, PdCl2(dppf) and Ph3As in DMF/H2O provides chlorophenylsulfonyl derivative (III), whose Boc group is removed by means of TFA in CH2Cl2/H2O to afford secondary amine (IV). Reductive amination between amine (IV) and piperidone (V) by means of NaB(OAc)3H in CH2Cl2 in the presence of HOAc furnishes compound (VI), which is then deprotected by means of TFA in CH2Cl2/H2O to yield bipiperidinyl derivative (VII). Finally, coupling of (VII) with 2-amino-3-methyl benzoic acid (VIII) by means of HOBt, DIEA and EDCI in DMF provides the target product. Alternatively, the synthesis of intermediate (VII) can be performed as follows: Protection of the piperidine moiety of (IX) by means of trifluoroacetic anhydride in CH2Cl2 followed by treatment with methanesulfonic acid and dibromodimethylhydantoin (DBDMH) affords bromo derivative (X), whose trifluoroacetate moiety is then removed by reaction with K2CO3 in MeOH/H2O to give piperidine derivative (XI). Reductive amination between (XI) and piperidone (V) by means of NaB(OAc)3H in CH2Cl2 in the presence of HOAc furnishes compound (XII), which is condensed with 3-chlorbenzenesulfonyl fluoride (XIII) by means of BuLi in THF and finally treated with TFA in CH2Cl2/H2O for Boc removal to provide the intermediate chlorophenylsulfonyl derivative (VII).

参考文献中间体

合成目标

【1】 Miller, M.W.; Clader, J.W.; McCombie, S.W.; Vice, S.F.; Kozlowski, J.A. (Schering Corp.); Muscarinic antagonists. WO 0121590 .

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)	48124	tert-butyl 4-methylene-1-piperidinecarboxylate		C₁₁H₁₉NO₂	详情	详情
(II)	48125	(4-bromophenyl)(3-chlorophenyl)dioxo-lambda(6)-sulfane; 4-bromophenyl 3-chlorophenyl sulfone		C₁₂H₈BrClO₂S	详情	详情
(III)	48126	tert-butyl 4-[4-[(3-chlorophenyl)sulfonyl]benzyl]-1-piperidinecarboxylate		C₂₃H₂₈ClNO₄S	详情	详情
(IV)	48127	3-chlorophenyl 4-(4-piperidinylmethyl)phenyl sulfone; 4-[4-[(3-chlorophenyl)sulfonyl]benzyl]piperidine		C₁₈H₂₀ClNO₂S	详情	详情
(V)	18620	tert-butyl 4-oxo-1-piperidinecarboxylate;BOC-Piperidone;N-(tert-Butoxycarbonyl)-4-piperidone; N-Boc-4-piperidone	79099-07-3	C₁₀H₁₇NO₃	详情	详情
(VI)	48128			C₂₈H₃₇ClN₂O₄S	详情	详情
(VII)	48129			C₂₃H₂₉ClN₂O₂S	详情	详情
(VIII)	48130	2-amino-3-methylbenzoic acid	4389-45-1	C₈H₉NO₂	详情	详情
(IX)	26225	4-benzylpiperidine	31252-42-3	C₁₂H₁₇N	详情	详情
(X)	48131	1-[4-(4-bromobenzyl)-1-piperidinyl]-2,2,2-trifluoro-1-ethanone		C₁₄H₁₅BrF₃NO	详情	详情
(XI)	48132	4-(4-bromobenzyl)piperidine		C₁₂H₁₆BrN	详情	详情
(XII)	48133			C₂₂H₃₃BrN₂O₂	详情	详情
(XIII)	48134	3-chlorobenzenesulfonyl fluoride		C₆H₄ClFO₂S	详情	详情

合成路线2

该中间体在本合成路线中的序号：(III)

The intermediate 6-methyldiphenylamine-2,2'-dicarboxylic acid (V) has been synthesized in two similar ways. 1. By Jourdan-Ullman copper-catalyzed condensation of 6-methylbenzoic acid (I) with 2-aminobenzoic acid (II); and 2. By the same type of condensation, but using 2-amino-3-methylbenzoic acid (III) and 2-chlorobenzoic acid (IV). The cyclization of the intermediate dicarboxylic acid (V) under acidic conditions gives 5-methyl-9-oxo-9,10-dihydroacridine-4-carboxylic acid (VI), which is treated with hot SOCl2 and DMF to yield 9-choloro-5-methylacridine-4-carbonyl chloride (VII). The reaction of (VII) with N,N-dimethylethylenediamine (VIII) in dichloromethane affords the corresponding amide (IX), which is finally treated first with phenol at 100 C and then with a stream of dry ammonia at 110-20 C to obtain the target 9-aminoacridine derivative.

参考文献中间体

合成目标

【1】 Rewcastle, G.W.; et al.; Potential antitumor agents. 46. Structure-activity relationships for acridine monosubstituted derivatives of the antitumor agent N-[2-(dimethylamino)ethyl]-9-aminoacridine-4-carboxamide. J Med Chem 1986, 29, 4, 472.

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)	51949	2-Chloro-3-methylbenzoic acid	15068-35-6	C₈H₇ClO₂	详情	详情
(II)	11661	2-Aminobenzoic acid;Anthranilic acid; o-Aminobenzoic acid	118-92-3	C₇H₇NO₂	详情	详情
(III)	48130	2-amino-3-methylbenzoic acid	4389-45-1	C₈H₉NO₂	详情	详情
(IV)	10203	o-Chlorobenzoic acid; 2-Chlorobenzoic acid	118-91-2	C₇H₅ClO₂	详情	详情
(V)	51950	2-(2-carboxyanilino)-3-methylbenzoic acid		C₁₅H₁₃NO₄	详情	详情
(VI)	30493	5-methyl-9-oxo-9,10-dihydro-4-acridinecarboxylic acid		C₁₅H₁₁NO₃	详情	详情
(VII)	30494	9-chloro-5-methyl-4-acridinecarbonyl chloride		C₁₅H₉Cl₂NO	详情	详情
(VIII)	14481	(6S,8S,9R,10S,11S,13S,14S,16R,17R)-6,9-difluoro-11,17-dihydroxy-10,13,16-trimethyl-3-oxo-6,7,8,9,10,11,12,13,14,15,16,17-dodecahydro-3H-cyclopenta[a]phenanthrene-17-carbothioic S-acid		C₂₁H₂₆F₂O₄S	详情	详情
(IX)	51951	9-chloro-N-[2-(dimethylamino)ethyl]-5-methyl-4-acridinecarboxamide		C₁₉H₂₀ClN₃O	详情	详情

Extended Information