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【结 构 式】 
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【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% |
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 |