|
【结 构 式】 
|
【分子编号】34808 【品名】1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine 【CA登记号】50541-93-0 |
【 分 子 式 】C12H18N2 【 分 子 量 】190.2884 【元素组成】C 75.74% H 9.53% N 14.72% |
合成路线1
该中间体在本合成路线中的序号：(II)4-Amino-1-benzylpiperidine (II) was acylated with 5-methyl-2-nitrobenzoyl chloride (I) to afford the ortho-nitrobenzamide (III), which was reduced to the amino derivative (IV) by catalytic hydrogenation in the presence of Pd/C. Treatment of (IV) with ethyl chloroformate produced the bis-carbamate (V) with concomitant cleavage of the N-benzyl group. This was cyclized to the dioxoquinazoline (VI) upon treatment with KOH in refluxing EtOH. After N-methylation employing iodomethane and NaH in DMF, hydrolysis of the carbamate group with concentrated HBr yielded the piperidinylquinazoline (VIII). This was then condensed with 2,4-dichloro-6,7-diethoxyquinazoline (IX) to furnish adduct (X). Finally, displacement of the remaining chlorine of (X) with morpholine (XI) in hot NMP gave rise to the title compound.
| 【1】 Kase, H.; Fujiwara, S.; Okamura, Y.; Karasawa, A.; Nonaka, H.; Yao, K.; Takai, H.; Synthesis and evaluation of adenosine transporter inhibitors. 16th Int Symp Med Chem (Sept 18 2000, Bologna) 2000, Abst PC-19. |
| 【2】 Fujiwara, S.; Okamura, Y.; Takai, H.; Nonaka, H.; Moriyama, T. (Kyowa Hakko Kogyo Co., Ltd.); Quinazoline deriv.. EP 0726267; JP 1997165385; US 5948784; WO 9606841 . |
| 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) | 44744 | 5-methyl-2-nitrobenzoyl chloride | C8H6ClNO3 | 详情 | 详情 | |
| (II) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (III) | 44746 | N-(1-benzyl-4-piperidinyl)-5-methyl-2-nitrobenzamide | C20H23N3O3 | 详情 | 详情 | |
| (IV) | 44747 | 2-amino-N-(1-benzyl-4-piperidinyl)-5-methylbenzamide | C20H25N3O | 详情 | 详情 | |
| (V) | 44748 | ethyl 4-([2-[(ethoxycarbonyl)amino]-5-methylbenzoyl]amino)-1-piperidinecarboxylate | C19H27N3O5 | 详情 | 详情 | |
| (VI) | 44749 | ethyl 4-[6-methyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinecarboxylate | C17H21N3O4 | 详情 | 详情 | |
| (VII) | 44750 | ethyl 4-[1,6-dimethyl-2,4-dioxo-1,4-dihydro-3(2H)-quinazolinyl]-1-piperidinecarboxylate | C18H23N3O4 | 详情 | 详情 | |
| (VIII) | 44751 | 1,6-dimethyl-3-(4-piperidinyl)-2,4(1H,3H)-quinazolinedione | C15H19N3O2 | 详情 | 详情 | |
| (IX) | 44752 | 2,4-dichloro-6,7-diethoxyquinazoline; 2,4-dichloro-6-ethoxy-7-quinazolinyl ethyl ether | C12H12Cl2N2O2 | 详情 | 详情 | |
| (X) | 44753 | 3-[1-(2-chloro-6,7-diethoxy-4-quinazolinyl)-4-piperidinyl]-1,6-dimethyl-2,4(1H,3H)-quinazolinedione | C27H30ClN5O4 | 详情 | 详情 | |
| (XI) | 10388 | Morpholine | 110-91-8 | C4H9NO | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)A new synthetic route has been reported. 4-Amino-1-benzylpiperidine (I) was protected as the t-butyl carbamate (II) using Boc2O, and the N-benzyl group was subsequently removed by transfer hydrogenolysis, yielding 4-(t-butoxycarbonylamino)piperidine (III). Butyl chloroacetate (V), prepared by treatment of chloroacetyl chloride (IV) with n-butanol, was then condensed with piperidine (III) to afford (VI). After acidic cleavage of the Boc protecting group of (VI), the resultant amino piperidine (VII) was acylated with the mixed anhydride (VIII) to provide the target amide.
| 【1】 Sakaguchi, J.; et al.; An improved synthesis of butyl 4-[(4-amino-5-chloro-2-methoxybenzoyl)amino]-1-piperidineacetate (AU-224). Chem Pharm Bull 2001, 49, 6, 788. |
| 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) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 56563 | tert-butyl 1-benzyl-4-piperidinylcarbamate | C17H26N2O2 | 详情 | 详情 | |
| (III) | 41601 | tert-butyl 4-piperidinylcarbamate; 4-tert-Boc-aminopiperidine | 73874-95-0 | C10H20N2O2 | 详情 | 详情 |
| (IV) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (V) | 14595 | n-Butyl Chloroacetate; butyl 2-chloroacetate | 590-02-3 | C6H11ClO2 | 详情 | 详情 |
| (VI) | 51930 | butyl 2-[4-[(tert-butoxycarbonyl)amino]-1-piperidinyl]acetate | C16H30N2O4 | 详情 | 详情 | |
| (VII) | 51931 | butyl 2-(4-amino-1-piperidinyl)acetate | C11H22N2O2 | 详情 | 详情 | |
| (VIII) | 29299 | 4-Amino-5-chloro-2-methoxybenzoic acid methoxycarbonyl anhydride | C10H10ClNO5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Condensation of 4-amino-1-benzylpiperidine (I) with benzoyl isocyanate gave the benzoyl urea (II), which was subsequently hydrolyzed to urea (III) with NaOH in aqueous methanol. Then, condensation of (III) with 2-hydroxypropiophenone (IV) in the presence of trifluoroacetic acid afforded a mixture of minor amounts of the required imidazolone (V) along with the major undesired regioisomer (VI).
| 【1】 Carling, R.W.; Moyes, C.R.; Moore, K.W.; et al.; 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: A selective high-affinity antagonist for the human dopamine D(4) receptor with excellent selectivity over ion channels. J Med Chem 1999, 42, 14, 2706. |
| 【2】 Carling, W.R.; Moore, K.W. (Merck Sharp & Dohme Ltd.); Imidazolone and oxazolone derivs. as dopamine antagonists. EP 0719264; JP 1997504272; US 5698573; WO 9507904 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40601 | benzoyl isocyanate | 4461-33-0 | C8H5NO2 | 详情 | 详情 | |
| (I) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 34809 | N-benzoyl-N'-(1-benzyl-4-piperidinyl)urea | C20H23N3O2 | 详情 | 详情 | |
| (III) | 34810 | N-(1-benzyl-4-piperidinyl)urea | C13H19N3O | 详情 | 详情 | |
| (IV) | 34811 | 2-hydroxy-1-phenyl-1-propanone | C9H10O2 | 详情 | 详情 | |
| (V) | 34812 | 1-(1-benzyl-4-piperidinyl)-5-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one | C22H25N3O | 详情 | 详情 | |
| (VI) | 34813 | 1-(1-benzyl-4-piperidinyl)-4-methyl-5-phenyl-1,3-dihydro-2H-imidazol-2-one | C22H25N3O | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Aminopiperidine (I) was alkylated with 2-bromopropiophenone (VII), and the resulting unstable aminoketone (VIII) was treated with benzoyl isocyanate to produce the benzoyl urea (IX). Cyclization of (IX), followed by benzoyl group cleavage upon treatment with methanolic NaOMe gave the hydroxy imidazolinone (X). This was dehydrated to the imidazolone (V) by means of trifluoroacetic acid. The intermediate (V) was debenzylated to (XII) by reaction with 1-chloroethyl chloroformate, followed by treatment of the resulting (1-chloroethyl) carbamate (XI) with boiling MeOH. The debenzylated piperidine (XII) was finally alkylated with alpha-bromo-m-tolunitrile (XIII) to give the target m-cyanobenzyl derivative.
| 【1】 Carling, R.W.; Moyes, C.R.; Moore, K.W.; et al.; 1-(3-Cyanobenzylpiperidin-4-yl)-5-methyl-4-phenyl-1, 3-dihydroimidazol-2-one: A selective high-affinity antagonist for the human dopamine D(4) receptor with excellent selectivity over ion channels. J Med Chem 1999, 42, 14, 2706. |
| 【2】 Carling, W.R.; Moore, K.W. (Merck Sharp & Dohme Ltd.); Imidazolone and oxazolone derivs. as dopamine antagonists. EP 0719264; JP 1997504272; US 5698573; WO 9507904 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 22014 | 1-chloro-1-[(chlorocarbonyl)oxy]ethane | 50893-53-3 | C3H4Cl2O2 | 详情 | 详情 | |
| 40601 | benzoyl isocyanate | 4461-33-0 | C8H5NO2 | 详情 | 详情 | |
| (I) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (V) | 34812 | 1-(1-benzyl-4-piperidinyl)-5-methyl-4-phenyl-1,3-dihydro-2H-imidazol-2-one | C22H25N3O | 详情 | 详情 | |
| (VII) | 34814 | 2-bromo-1-phenyl-1-propanone | 2114-00-3 | C9H9BrO | 详情 | 详情 |
| (VIII) | 34815 | 2-[(1-benzyl-4-piperidinyl)amino]-1-phenyl-1-propanone | C21H26N2O | 详情 | 详情 | |
| (IX) | 34816 | N'-benzoyl-N-(1-benzyl-4-piperidinyl)-N-(1-methyl-2-oxo-2-phenylethyl)urea | C29H31N3O3 | 详情 | 详情 | |
| (X) | 34817 | 1-(1-benzyl-4-piperidinyl)-4-hydroxy-5-methyl-4-phenyl-2-imidazolidinone | C22H27N3O2 | 详情 | 详情 | |
| (XI) | 34818 | 1-chloroethyl 4-(5-methyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)-1-piperidinecarboxylate | C18H22ClN3O3 | 详情 | 详情 | |
| (XII) | 34819 | 5-methyl-4-phenyl-1-(4-piperidinyl)-1,3-dihydro-2H-imidazol-2-one | C15H19N3O | 详情 | 详情 | |
| (XIII) | 13244 | alpha-Bromo-m-tolunitrile; 3-(Bromomethyl)benzonitrile | 28188-41-2 | C8H6BrN | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Palladium-catalyzed coupling of 4-amino-1-benzylpiperidine (I) with tert-butyl 4-bromobenzoate (II) afforded the anilinopiperidine derivative (III). Removal of the benzyl protecting group of (III) to give (IV) was achieved by transfer hydrogenolysis in the presence of ammonium formate and Pd/C. Piperidine (IV) was then coupled with 4-amino-2-chloro-6,7-dimethoxyquinazoline (V) in hot isoamyl alcohol yielding piperidino quinazoline (VI). The title carboxylic acid was finally obtained by acidic deprotection of tert-butyl ester of (VI).
| 【1】 Casper, M.D.; Kung, P.-P.; Cook, K.L.; et al.; Structure-activity relationships of novel 2-substituted quinazoline antibacterial agents. J Med Chem 1999, 42, 22, 4705. |
| 【2】 Guinosso, C.J.; Cook, P.D.; Kung, P.-P. (Isis Pharmaceuticals, Inc.); Antibacterial quinazoline cpds.. US 6156758 . |
| 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) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 14286 | tert-butyl 4-bromobenzoate | C11H13BrO2 | 详情 | 详情 | |
| (III) | 40527 | tert-butyl 4-[(1-benzyl-4-piperidinyl)amino]benzoate | C23H30N2O2 | 详情 | 详情 | |
| (IV) | 40528 | tert-butyl 4-(4-piperidinylamino)benzoate | C16H24N2O2 | 详情 | 详情 | |
| (V) | 10443 | 2-Chloro-6,7-dimethoxy-4-quinazolinamine; 4-Amino-2-chloro-6,7-dimethoxyquinazoline; 2-Chloro-6,7-dimethoxy-4-quinazolinylamine | 23680-84-4 | C10H10ClN3O2 | 详情 | 详情 |
| (VI) | 40529 | tert-butyl 4-[[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidinyl]amino]benzoate | C26H33N5O4 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)The condensation of 4-amino-1-benzylpiperidine (I) with 2,5-dimethoxytetrahydrofuran-3-carbaldehyde (II) under modified Paal-Knorr conditions produced the pyrrole derivative (III). Construction of the target oxazole ring was then achieved by cyclocondensation reaction of aldehyde (III) with tosylmethyl isocyanide in the presence of NaOMe.
| 【1】 Hubner, H.; Gmeiner, P.; Haubmann, C.; Piperidinylpyrroles: Design, synthesis and binding properties of novel and selective dopamine D4 receptor ligands. Bioorg Med Chem Lett 1999, 9, 21, 3143. |
| 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) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 26664 | 2,5-dimethoxytetrahydro-3-furancarbaldehyde | C7H12O4 | 详情 | 详情 | |
| (III) | 41973 | 1-(1-benzyl-4-piperidinyl)-1H-pyrrole-3-carbaldehyde | C17H20N2O | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(II)The reductive amination of 2-nitrobenzaldehyde (I) with 4-amino-1-benzylpiperidine (II) in the presence of NaBH4 gave amine (III). Subsequent hydrogenation of the nitro group of (III) over Rh/C afforded (IV), which was converted to oxoquinazoline (V) upon treatment with carbonyl diimidazole in hot DMF. Hydrogenolysis of the benzyl protecting group of (V) yielded intermediate (VI).
| 【1】 Eberlein, W.; Wienen, W.; Doods, H.; Rudolf, K.; Entzeroth, M.; Pieper, H.; Engel, W.; Hallermayer, G. (Dr. Karl Thomae GmbH); Modified aminoacids, pharmaceuticals containing these cpds. and methods for their production. JP 2000505100; WO 9811128 . |
| 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) | 11370 | 2-Nitrobenzaldehyde | 552-89-6 | C7H5NO3 | 详情 | 详情 |
| (II) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (III) | 39269 | 1-benzyl-N-(2-nitrobenzyl)-4-piperidinamine; N-(1-benzyl-4-piperidinyl)-N-(2-nitrobenzyl)amine | C19H23N3O2 | 详情 | 详情 | |
| (IV) | 39270 | N-(2-aminobenzyl)-N-(1-benzyl-4-piperidinyl)amine; N-(2-aminobenzyl)-1-benzyl-4-piperidinamine | C19H25N3 | 详情 | 详情 | |
| (V) | 39271 | 3-(1-benzyl-4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone | C20H23N3O | 详情 | 详情 | |
| (VI) | 39272 | 3-(4-piperidinyl)-3,4-dihydro-2(1H)-quinazolinone | C13H17N3O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(XVI)Acylation of 4-amino-1-benzylpiperidine (XVI) with 5-chlorovaleryl chloride (XVII) yielded chloro amide (XVIII). This was cyclized to the piperidino piperidinone (XIX) by treatment with NaH in THF. Subsequent hydrogenolysis of the N-benzyl group of (XIX) furnished piperidine (XX). Finally, reductive alkylation of piperidine (XX) with aldehyde (XV) in the presence of sodium triacetoxyborohydride gave rise to the title compound.
| 【1】 Carruthers, N.I.; Alaimo, C.A.; Shih, N.-Y.; Lavey, B.J.; Ting, P.C.; Reichard, G.A. (Schering Corp.); Substd. oximes as neurokinin antagonists. EP 1032561; WO 9926924 . |
| 【2】 Carruthers, N.I.; Reichard, G.A.; Shih, N.-Y.; Lavey, B.J.; Alaimo, C.A.; Ting, P.C. (Schering Corp.); Substd. oximes as neurokinin antagonists. US 6063926 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XV) | 44276 | 3,5-dichloro-N-[(3R)-3-(3,4-dichlorophenyl)-2-(methoxyimino)-5-oxopentyl]-N-methylbenzamide | C20H18Cl4N2O3 | 详情 | 详情 | |
| (XVI) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (XVII) | 44277 | 5-chloropentanoyl chloride | 1575-61-7 | C5H8Cl2O | 详情 | 详情 |
| (XVIII) | 44278 | N-(1-benzyl-4-piperidinyl)-5-chloropentanamide | C17H25ClN2O | 详情 | 详情 | |
| (XIX) | 44279 | C17H24N2O | 详情 | 详情 | ||
| (XX) | 44280 | N-(4-Piperidine)-2-piperidinone | C10H18N2O | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(XIII)Regioselective coupling of the 2-arylpiperazine (IV) with 3,5-dimethylbenzoic acid (IX) at the less hindered N atom by means of EDC and HOBt afforded the 4-benzoyl piperazine (X). This was subsequently acylated with bromoacetyl bromide (XI) to yield the bromo amide (XII). Bromide displacement in (XII) with 4-amino-1-benzylpiperidine (XIII) then gave the title compound.
| 【1】 Shue, H.-J.; Shih, N.-Y.; Blythin, D.J.; Chen, X.; Tom, W.C.; Piwinski, J.J.; McCormick, K.D. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0823906; US 5719156; WO 9634864 . |
| 【2】 Piwinski, J.J.; McCormick, K.D.; Shue, H.-J.; Chen, X.; Shih, N.-Y.; Blythin, D.J. (Schering Corp.); Piperazino derivs. as neurokinin antagonists. EP 0850236; JP 2000344766; US 5795894; US 5892039; WO 9708166 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47946 | 2-(3,4-dichlorophenyl)piperazine | C10H12Cl2N2 | 详情 | 详情 | |
| (IX) | 26775 | 3,5-dimethylbenzoic acid | 499-06-9 | C9H10O2 | 详情 | 详情 |
| (X) | 47950 | [3-(3,4-dichlorophenyl)-1-piperazinyl](3,5-dimethylphenyl)methanone | C19H20Cl2N2O | 详情 | 详情 | |
| (XI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIII)In a related method, the 2-arylpiperazine (IV) was first protected as the 4-tert-butyl carbamate (XIV) upon treatment with di-tert-butyl dicarbonate in MeOH at -78 C. Subsequent acylation of (XIV) with bromoacetyl bromide (XI) produced the bromo amide (XV), which was then condensed with the aminopiperidine (XIII), yielding the glycinamide derivative (XVI). Acidic cleavage of the Boc group of (XVI) afforded the 1-acyl piperazine (XVII). This was finally coupled with 3,5-dimethylbenzoic acid using EDC and HOBt.
| 【1】 Anthes, J.C.; McPhail, A.T.; Blythin, D.J.; Shue, H.-J.; Chen, X.; Piwinski, J.J.; shih, N.-Y.; Discovery of Sch 62373 and analogs, of novel series of 2-phenylpiperazines exhibiting potent dual NK1/NK2 antagonist activity. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 244. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (IV) | 47946 | 2-(3,4-dichlorophenyl)piperazine | C10H12Cl2N2 | 详情 | 详情 | |
| (IX) | 26775 | 3,5-dimethylbenzoic acid | 499-06-9 | C9H10O2 | 详情 | 详情 |
| (XI) | 14005 | 2-Bromoacetyl bromide; Bromoacetyl bromide | 598-21-0 | C2H2Br2O | 详情 | 详情 |
| (XIII) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (XIV) | 47952 | tert-butyl 3-(3,4-dichlorophenyl)-1-piperazinecarboxylate | C15H20Cl2N2O2 | 详情 | 详情 | |
| (XV) | 47953 | tert-butyl 4-(2-bromoacetyl)-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate | C17H21BrCl2N2O3 | 详情 | 详情 | |
| (XVI) | 47954 | tert-butyl 4-[2-[(1-benzyl-4-piperidinyl)amino]acetyl]-3-(3,4-dichlorophenyl)-1-piperazinecarboxylate | C29H38Cl2N4O3 | 详情 | 详情 | |
| (XVII) | 47955 | 2-[(1-benzyl-4-piperidinyl)amino]-1-[2-(3,4-dichlorophenyl)-1-piperazinyl]-1-ethanone | C24H30Cl2N4O | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(VIII)4-Amino-1-benzylpiperidine (VIII) is condensed with dimethylsulfamoyl chloride to give the sulfamide (IX). Subsequent benzyl group hydrogenolysis in (IX) over Pd/C provides the piperidine (X). Finally, alkylation of piperidine (X) with chloride (VII) yields the title compound.
| 【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 |
|---|---|---|---|---|---|---|
| (VII) | 58455 | 8-(chloromethyl)-10H-pyrazino[2,3-b][1,4]benzothiazine | C11H8ClN3S | 详情 | 详情 | |
| (VIII) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (IX) | 58456 | N'-(1-benzyl-4-piperidinyl)-N,N-dimethylsulfamide | C14H23N3O2S | 详情 | 详情 | |
| (X) | 58457 | N,N-dimethyl-N'-(4-piperidinyl)sulfamide | C7H17N3O2S | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(I)Acylation of 4-amino-1-benzylpiperidine (I) with acetyl chloride provides the amide (II). Subsequent debenzylation of (II) by transfer hydrogenation with ammonium formate in the presence of Pd/C yields the piperidine (III), which is finally acylated with 4-fluorobenzenesulfonyl chloride (IV) to give the corresponding sulfonamide.
| 【1】 Manetti, D.; Martini, E.; Ghelardini, C.; Dei, S.; Galeotti, N.; Guandalini, L.; Romanelli, M.N.; Scapecchi, S.; Teodori, E.; Bartolini, A.; Gualtieri, F.; 4-Aminopiperidine derivatives as a new class of potent cognition enhancing drugs. Bioorg Med Chem Lett 2003, 13, 14, 2303. |
| 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) | 34808 | 1-Benzyl-4-piperidinylamine; 1-Benzyl-4-piperidinamine; 4-Amino-1-benzylpiperidine | 50541-93-0 | C12H18N2 | 详情 | 详情 |
| (II) | 64809 | N-[1-(phenylmethyl)-4-piperidinyl]acetamide | C14H20N2O | 详情 | 详情 | |
| (III) | 64810 | N-(4-piperidinyl)acetamide | C7H14N2O | 详情 | 详情 | |
| (IV) | 12292 | 4-Fluorobenzenesulfonyl chloride | 349-88-2 | C6H4ClFO2S | 详情 | 详情 |