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【结 构 式】

【分子编号】36262

【品名】4-(4-morpholinyl)benzoic acid

【CA登记号】

【 分 子 式 】C11H13NO3

【 分 子 量 】207.22916

【元素组成】C 63.76% H 6.32% N 6.76% O 23.16%

与该中间体有关的原料药合成路线共 2 条

合成路线1

该中间体在本合成路线中的序号:(XII)

The alkylation of (R)-2-amino-8-methoxy-1,2,3,4-tetrahydronaphthalene (I) with benzyl bromide provided the corresponding dibenzyl amine (II). After conversion of (II) to the hydrochloride salt, methyl ether cleavage by means of BBr3 at low temperature gave rise to naphthol (III). Condensation of (III) with 2-bromoisobutyramide (IV) yielded the naphthyloxybutyramide (V), which was rearranged at 130 C in the presence of NaH to the N-naphthyl-2-hydroxybutyramide (VI). Acid hydrolysis of the amide function of (VI) gave diamine (VII). This was condensed with N-methyl iminodiacetic acid (VIII) using CDI in boiling THF to produce the piperazinedione (IX). After reduction of (IX) to the corresponding piperazine (X) with LiAlH4, the N-benzyl groups were cleaved by hydrogenolysis over Pd/C to afford the primary amine (XI). Finally, coupling of (XI) with 4-mo-pholinobenzoic (XII) acid using CDI provided the title amide.

1 Berg, S.; Florvall, L.; Ross, S.; Thorberg, S.-O. (AstraZeneca plc); Substd. 1,2,3,4-tetrahydronaphthalene derivs.. EP 0888319; JP 2000506883; US 6124283; WO 9734883 .
2 Thorberg, S.-O.; Ross, S.; Berg, S. (AstraZeneca plc); A combination of a selective 5-HT1A antagonist and a selective h5-HT1B antagonist or partial agonist. WO 9913876 .
3 Berg, S.; Ross, S.; Thorberg, S.-O. (AstraZeneca AB); A Combination of a 5-HT reuptake inhibitor and a H5-HT1B antagonist or partial agonist. AU 9193098; EP 1014985; WO 9913877 .
4 Berg, S.; Ross, S.; Thorberg, S.-O. (AstraZeneca AB); A combination of a monoamine oxidase inhibitor and a H5-HT1B antagonist or partial agonist. AU 9193198; EP 1014986; WO 9913878 .
中间体序号 中间体编号 品名 CAS号 分子式 供应商 用于合成
12912 1-(Bromomethyl)benzene; Alpha-bromotoluene 100-39-0 C7H7Br 详情 详情
(I) 36251 (2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C11H15NO 详情 详情
(II) 36252 N,N-dibenzyl-N-[(2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]amine; (2R)-N,N-dibenzyl-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C25H27NO 详情 详情
(III) 36253 (7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenol C24H25NO 详情 详情
(IV) 36254 2-bromo-2-methylpropanamide C4H8BrNO 详情 详情
(V) 36255 2-[[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]oxy]-2-methylpropanamide C28H32N2O2 详情 详情
(VI) 36256 N-[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]-2-hydroxy-2-methylpropanamide C28H32N2O2 详情 详情
(VII) 36257 (7R)-N(7),N(7)-dibenzyl-5,6,7,8-tetrahydro-1,7-naphthalenediamine; N-[(2R)-8-amino-1,2,3,4-tetrahydro-2-naphthalenyl]-N,N-dibenzylamine C24H26N2 详情 详情
(VIII) 36258 2-[(carboxymethyl)(methyl)amino]acetic acid 4408-64-4 C5H9NO4 详情 详情
(IX) 36259 1-[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]-4-methyl-2,6-piperazinedione C29H31N3O2 详情 详情
(X) 36260 (2R)-N,N-dibenzyl-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N,N-dibenzyl-N-[(2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenyl]amine C29H35N3 详情 详情
(XI) 36261 (2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenamine; (2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenylamine C15H23N3 详情 详情
(XII) 36262 4-(4-morpholinyl)benzoic acid C11H13NO3 详情 详情

合成路线2

该中间体在本合成路线中的序号:(XV)

Alkylation of (R)-8-methoxy-2-amino-1,2,3,4-tetrahydronaphthalene (I) with benzyl bromide provided the corresponding dibenzyl amine (II). The methyl ether of (II) was then cleaved to phenol (III) employing boron tribromide in cold CH2Cl2. Conversion of phenol (III) into amine (VII) was carried out by the sequence involving O-alkylation of (III) with 2-bromoisobutyramide (IV), followed by rearrangement of the resulting ester (V) to the N-substituted amide (VI) upon heating in the presence of NaH and DMPU, and acidic hydrolysis of the amide function of (VI). Acylation of amine (VII) with N-methyl iminodiacetic acid (VIII), via activation with CDI, furnished the cyclic imide (IX), which was further reduced to piperazine (X) using LiAlH4. Bromination of the aromatic amine (X) with Br2 in the presence of NaOAc and HOAc gave bromide (XI). Metalation of (XI) with t-BuLi, followed by addition of methyl chloroformate, produced the carboxylate ester (XII). Subsequent reduction of (XII) by means of LiAlH4 gave rise to the benzylic alcohol (XIII). Removal of the N-benzyl groups of (XIII) and simultaneous alcohol reduction to the methyl derivative (XIV) was achieved by using transfer hydrogenolysis in the presence of ammonium formate and Pd/C. Amine (XIV) was finally coupled with 4-morpholinobenzoic acid (XV) via activation with CDI.

1 Berg, S.; Ross, S.; Linderberg, M.; Thorberg, S.-O.; Ulff, B. (AstraZeneca plc); Substd. 1,2,3,4-tetrahydronaphthalene derivs.. EP 1000048; JP 2001510837; US 6313118; WO 9905134 .
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) 36251 (2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenylamine; (2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C11H15NO 详情 详情
(II) 36252 N,N-dibenzyl-N-[(2R)-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenyl]amine; (2R)-N,N-dibenzyl-8-methoxy-1,2,3,4-tetrahydro-2-naphthalenamine C25H27NO 详情 详情
(III) 36253 (7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenol C24H25NO 详情 详情
(IV) 36254 2-bromo-2-methylpropanamide C4H8BrNO 详情 详情
(V) 36255 2-[[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]oxy]-2-methylpropanamide C28H32N2O2 详情 详情
(VI) 36256 N-[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]-2-hydroxy-2-methylpropanamide C28H32N2O2 详情 详情
(VII) 36257 (7R)-N(7),N(7)-dibenzyl-5,6,7,8-tetrahydro-1,7-naphthalenediamine; N-[(2R)-8-amino-1,2,3,4-tetrahydro-2-naphthalenyl]-N,N-dibenzylamine C24H26N2 详情 详情
(VIII) 36258 2-[(carboxymethyl)(methyl)amino]acetic acid 4408-64-4 C5H9NO4 详情 详情
(IX) 36259 1-[(7R)-7-(dibenzylamino)-5,6,7,8-tetrahydro-1-naphthalenyl]-4-methyl-2,6-piperazinedione C29H31N3O2 详情 详情
(X) 36260 (2R)-N,N-dibenzyl-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N,N-dibenzyl-N-[(2R)-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenyl]amine C29H35N3 详情 详情
(XI) 52315 5-bromo-8-(4-methyl-1-piperazinyl)-N,N-bis(phenylmethyl)-1,2,3,4-tetrahydro-2-naphthalenamine; N-[5-bromo-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenyl]-N,N-bis(phenylmethyl)amine C29H34BrN3 详情 详情
(XII) 52316 methyl 6-[bis(phenylmethyl)amino]-4-(4-methyl-1-piperazinyl)-5,6,7,8-tetrahydro-1-naphthalenecarboxylate C31H37N3O2 详情 详情
(XIII) 52317 [6-[bis(phenylmethyl)amino]-4-(4-methyl-1-piperazinyl)-5,6,7,8-tetrahydro-1-naphthalenyl]methanol C30H37N3O 详情 详情
(XIV) 52318 5-methyl-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenylamine; 5-methyl-8-(4-methyl-1-piperazinyl)-1,2,3,4-tetrahydro-2-naphthalenamine C16H25N3 详情 详情
(XV) 36262 4-(4-morpholinyl)benzoic acid C11H13NO3 详情 详情
Extended Information