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【结 构 式】 
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【分子编号】18178 【品名】4,4-piperidinediol 【CA登记号】73390-11-1 |
【 分 子 式 】C5H11NO2 【 分 子 量 】117.14788 【元素组成】C 51.26% H 9.46% N 11.96% O 27.31% |
合成路线1
该中间体在本合成路线中的序号：(IX)Acid-catalyzed condensation of 4-piperidone hydrate hydrochloride (IX) with indole (IV) produced the tetrahydropyridyl indole (X). This was alkylated with 1-(2-chloroethyl)imidazolinone (XII), (prepared by chlorination of the corresponding hydroxyethyl imidazolinone (XI)) to afford the N-substituted tetrahydropyridine (XIII). The target piperidine derivative was then obtained by catalytic hydrogenation of tetrahydropyridine (XIII).
| 【1】 Perregaard, J.K. (H. Lundbeck A/S); Heterocyclic cpds.. AU 8655901; EP 0200322; ES 8707499; JP 1986236764; US 4710500 . |
| 【2】 Perregaard, J.K.; Costall, B. (H. Lundbeck A/S); Piperidyl-substd. indoles. EP 0533824; JP 1993509080; US 5439922; WO 9200070 . |
| 【3】 Bech Sommer, M. (H. Lundbeck A/S); Method of manufacturing sertindole. WO 9851685 . |
| 【4】 Bogeso, K.P.; Hyttel, J.; Sanchez, C.; Arnt, J.; Perregaard, J.; Noncataleptogenic, centrally acting dopamine D-2 and serotonin 5-HT2 antagonists within a series of 3-substituted 1-(4-fluorophenyl)-1H-indoles. J Med Chem 1992, 35, 6, 1092. |
| 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) | 59582 | 5-chloro-1-(4-fluorophenyl)-1H-indole | C14H9ClFN | 详情 | 详情 | |
| (IX) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (X) | 59587 | 5-chloro-1-(4-fluorophenyl)-3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole | C19H16ClFN2 | 详情 | 详情 | |
| (XI) | 59588 | 1-(2-hydroxyethyl)-2-imidazolidinone | 3699-54-5 | C5H10N2O2 | 详情 | 详情 |
| (XII) | 21329 | 1-(2-chloroethyl)-2-imidazolidinone | 2387-20-4 | C5H9ClN2O | 详情 | 详情 |
| (XIII) | 59589 | 1-{2-[4-[5-chloro-1-(4-fluorophenyl)-1H-indol-3-yl]-3,6-dihydro-1(2H)-pyridinyl]ethyl}-2-imidazolidinone | 106516-54-5 | C24H24ClFN4O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Treatment of a benzenic solution of 4-piperidone hydrate (I) with anhydrous AlCl3 provided 4,4-diphenylpiperidine (II). Then, conjugate addition of acrylonitrile (III) in the presence of triethylamine in ethanol gave the cyanoethylpiperidine (IV), which was reduced with borane in THF to afford the intermediate primary amine (V). Dihydropyridine (IX) was prepared by Hantzsch synthesis by condensation of 3-aminocrotonamide (VI), 4-nitrobenzaldehyde (VII) and cyanoethyl acetoacetate (VIII) in refluxing ethanol. Cyanoethyl ester was then cleaved with dilute KOH at 0 C to give acid (X), which was finally coupled with amine (V) by treatment with DEC to yield the target amide.
| 【1】 Cox, E.D.; et al.; Identification of a dihydropyridine as a potent alpha1a adrenoceptor-selective antagonist that inhibits phenylephrine-induced contraction of the human prostate. J Med Chem 1998, 41, 14, 2643. |
| 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) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (II) | 13154 | 4,4-Diphenylpiperidine | C17H19N | 详情 | 详情 | |
| (III) | 10847 | Acrylonitrile | 107-13-1 | C3H3N | 详情 | 详情 |
| (IV) | 18181 | 3-(4,4-diphenyl-1-piperidinyl)propanenitrile | C20H22N2 | 详情 | 详情 | |
| (V) | 18182 | 3-(4,4-diphenyl-1-piperidinyl)-1-propanamine; 3-(4,4-diphenyl-1-piperidinyl)propylamine | C20H26N2 | 详情 | 详情 | |
| (VI) | 18183 | (E)-3-amino-2-butenamide | C4H8N2O | 详情 | 详情 | |
| (VII) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (VIII) | 13993 | 2-cyanoethyl 3-oxobutanoate | C7H9NO3 | 详情 | 详情 | |
| (IX) | 18186 | 2-cyanoethyl 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylate | C18H18N4O5 | 详情 | 详情 | |
| (X) | 18187 | 5-(aminocarbonyl)-2,6-dimethyl-4-(4-nitrophenyl)-1,4-dihydro-3-pyridinecarboxylic acid | C15H15N3O5 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Synthesis of intermediate (XIV): Protection of 4-piperidone (I) with (Boc)2O in presence of DMAP and Et3N yields (II), which is converted into hydantoin (III) by means of NaCN in presence of (NH4)2CO3. Hydantoin (III) is then fully protected to provide (IV) by treatment with (Boc)2O and DMAP in THF. Alternatively (IV) can be obtained by treatment of 4-piperidone (I) with KCN in presence of (NH4)2CO3 to yield hydantoin (V), which is then protected with (Boc)2O and DMAP in DME. Hydrolysis of (IV) with NaOH affords aminoacid (VI) whose free amine is protected to provide carboxylic acid (VII). Treatment of (VII) with isobutyl chloroformate (IBCF) in DME in presence of NMM, followed by aqueous ammonia, yields amide (VIII), which is converted to (IX) by hydrogenation with H2 over Pd/C. Reductive amination of (IX) with aldehyde (X) affords amino amide (XI), which is treated with triethyl orthoformate to provide spirocycle (XII). Reduction of (XII) with NaBH4 in EtOH gives (XIII), which is alkylated with ethyl bromoacetate (A) followed by hydrolysis with NaOH to yield intermediate (XIV).
| 【1】 Wysong, C.L.; et al.; 4-Aminopiperidine-4-carboxamylic acid: A cyclic alpha,alpha-disubstituted amino acid for preparation of water-soluble highly helical peptides. J Org Chem 1996, 61, 22, 7650-51. |
| 【2】 Amblard, M.; Subra, G.; Bedos, P.; et al.; A rational approach to the design and synthesis of a new bradykinin B1 receptor antagonist. J Med Chem 2000, 43, 12, 2387. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (A) | 16640 | Ethyl 2-bromoacetate; Ethyl bromoacetate | 105-36-2 | C4H7BrO2 | 详情 | 详情 |
| (I) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (II) | 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 |
| (III) | 41678 | tert-butyl 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-8-carboxylate | C12H19N3O4 | 详情 | 详情 | |
| (IV) | 41679 | tri(tert-butyl) 2,4-dioxo-1,3,8-triazaspiro[4.5]decane-1,3,8-tricarboxylate | C22H35N3O8 | 详情 | 详情 | |
| (V) | 41680 | 1,3,8-triazaspiro[4.5]decane-2,4-dione | 13625-39-3 | C7H11N3O2 | 详情 | 详情 |
| (VI) | 41681 | 4-amino-1-(tert-butoxycarbonyl)-4-piperidinecarboxylic acid | 183673-71-4 | C11H20N2O4 | 详情 | 详情 |
| (VII) | 41682 | 1-(tert-butoxycarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-4-piperidinecarboxylic acid | C26H30N2O6 | 详情 | 详情 | |
| (VIII) | 41683 | tert-butyl 4-(aminocarbonyl)-4-[[(9H-fluoren-9-ylmethoxy)carbonyl]amino]-1-piperidinecarboxylate | C26H31N3O5 | 详情 | 详情 | |
| (IX) | 41684 | tert-butyl 4-amino-4-(aminocarbonyl)-1-piperidinecarboxylate | C11H21N3O3 | 详情 | 详情 | |
| (X) | 18456 | 2-phenylacetaldehyde | 122-78-1 | C8H8O | 详情 | 详情 |
| (XI) | 41685 | tert-butyl 4-(aminocarbonyl)-4-(phenethylamino)-1-piperidinecarboxylate | C19H29N3O3 | 详情 | 详情 | |
| (XII) | 41686 | tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-2-ene-8-carboxylate | C20H27N3O3 | 详情 | 详情 | |
| (XIII) | 41687 | tert-butyl 4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate | C20H29N3O3 | 详情 | 详情 | |
| (XIV) | 41688 | 2-[8-(tert-butoxycarbonyl)-4-oxo-1-phenethyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid | C22H31N3O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IV)The indole intermediate (V) has been obtained as follows: The reaction of 4-fluoro-2-nitrotoluene (I) with dimethylformamide dimethylacetal afforded enamine (II). Reductive cyclization of (II) by hydrogenation over Pd/C produced 6-fluoroindole (III). Subsequent condensation of indole (III) with piperidone monohydrate (IV) in the presence of KOH furnished the intermediate indolyl tetrahydropyridine (V).
| 【1】 Fairhurst, J. (Eli Lilly and Company); Substd. 4-(6-fluoro-(1H)-indol-3-yl)-1,2,3,6-tetrahydropyridine for the treatment of CNS-disorders. EP 0854146; WO 9831686 . |
| 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) | 48011 | 4-fluoro-1-methyl-2-nitrobenzene | 446-10-6 | C7H6FNO2 | 详情 | 详情 |
| (II) | 48012 | N-[(E)-2-(4-fluoro-2-nitrophenyl)ethenyl]-N,N-dimethylamine; (E)-2-(4-fluoro-2-nitrophenyl)-N,N-dimethyl-1-ethenamine | C10H11FN2O2 | 详情 | 详情 | |
| (III) | 48013 | 6-Fluoroindole; 6-Fluoro-1H-indole | 399-51-9 | C8H6FN | 详情 | 详情 |
| (IV) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (V) | 18014 | tert-butyl 4-[2-[2-([[(2S)-2-[[(2-bromo-4-methylphenyl)sulfonyl]amino]-3-(tert-butoxy)-3-oxopropyl]amino]carbonyl)-4-oxo-7,8-dihydro-4H-pyrazolo[1,5-a][1,4]diazepin-5(6H)-yl]ethyl]-1-piperidinecarboxylate | C34H49BrN6O8S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(IV)Nitrosation of tetrahydrobenzothiazepine (I) with NaNO2 and HOAc, followed by LiAlH4 reduction of the resulting N-nitroso derivative (II), furnished hydrazine (III). Subsequent Fischer indole cyclization of hydrazine (III) with piperidone hydrate (IV) under acidic conditions afforded the tetracyclic system (V). The pyrrole ring double bond of (V) was then reduced employing NaBH3CN and CF3COOH to provide the racemic cis-tetracycle (VI). Resolution of (VI) was carried out by preparative chiral HPLC of the corresponding N-Boc derivative. The desired N-Boc enantiomer (VII) was then deprotected by acidic treatment to give the chiral secondary amine (VIII). This was finally alkylated with 4-chloro-4'-fluorobutyrophenone (IX) to yield the title compound.
| 【1】 Boyle, K.E.; Robichaud, A.J.; Lee, T.; et al.; Novel, highly potent and selective serotonin 5-HT2A/dopamine D2 receptor antagonists as potential antipsychotics. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 98. |
| 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) | 22617 | 2,3,4,5-tetrahydro-1,5-benzothiazepine | C9H11NS | 详情 | 详情 | |
| (II) | 48145 | 5-nitroso-2,3,4,5-tetrahydro-1,5-benzothiazepine | C9H10N2OS | 详情 | 详情 | |
| (III) | 48146 | 3,4-dihydro-1,5-benzothiazepin-5(2H)-amine; 3,4-dihydro-1,5-benzothiazepin-5(2H)-ylamine | C9H12N2S | 详情 | 详情 | |
| (IV) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (V) | 48147 | 6,7,9,10,11,12-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H16N2S | 详情 | 详情 | |
| (VI) | 48148 | 6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H18N2S | 详情 | 详情 | |
| (VII) | 48149 | tert-butyl (8aS,12aR)-6,7,9,10,12,12a-hexahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole-11(8aH)-carboxylate | C19H26N2O2S | 详情 | 详情 | |
| (VIII) | 48150 | (8aS,12aR)-6,7,8a,9,10,11,12,12a-octahydro-5H-pyrido[4,3-b][1,4]thiazepino[2,3,4-hi]indole | C14H18N2S | 详情 | 详情 | |
| (IX) | 48151 | 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone | C10H11ClFNO | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IV)Nitrosation of dihydrobenzoxazine (I) with NaNO2 and HOAc, followed by LiAlH4 reduction of the resulting N-nitroso derivative (II), furnished hydrazine (III). Subsequent Fischer indole cyclization of hydrazine (III) with piperidone hydrate (IV) under acidic conditions afforded the tetracyclic system (V). The pyrrole ring double bond of (V) was then reduced employing NaBH3CN and CF3COOH to provide the racemic cis-tetracycle (VI). Resolution of (VI) was carried out by preparative chiral HPLC of the corresponding N-Boc derivative. The desired N-Boc enantiomer (VII) was then deprotected by acidic treatment to give the chiral secondary amine (VIII). This was finally alkylated with 2'-amino-4-chloro-4'-fluorobutyrophenone (IX) to yield the title compound.
| 【1】 Boyle, K.E.; Robichaud, A.J.; Lee, T.; et al.; Novel, highly potent and selective serotonin 5-HT2A/dopamine D2 receptor antagonists as potential antipsychotics. 221st ACS Natl Meet (April 1 2001, San Diego) 2001, Abst MEDI 98. |
| 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) | 48152 | 3,4-dihydro-2H-1,4-benzoxazine | C8H9NO | 详情 | 详情 | |
| (II) | 48153 | 4-nitroso-3,4-dihydro-2H-1,4-benzoxazine | C8H8N2O2 | 详情 | 详情 | |
| (III) | 48154 | 2,3-dihydro-4H-1,4-benzoxazin-4-amine; 2,3-dihydro-4H-1,4-benzoxazin-4-ylamine | C8H10N2O | 详情 | 详情 | |
| (IV) | 18178 | 4,4-piperidinediol | 73390-11-1 | C5H11NO2 | 详情 | 详情 |
| (V) | 48155 | 1,2,7,8,9,10-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole | C13H14N2O | 详情 | 详情 | |
| (VI) | 48156 | 1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole | C13H16N2O | 详情 | 详情 | |
| (VII) | 48157 | tert-butyl (6bR,10aS)-1,2,6b,9,10,10a-hexahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole-8(7H)-carboxylate | C18H24N2O3 | 详情 | 详情 | |
| (VIII) | 48158 | (6bR,10aS)-1,2,6b,7,8,9,10,10a-octahydro[1,4]oxazino[2,3,4-hi]pyrido[4,3-b]indole | C13H16N2O | 详情 | 详情 | |
| (IX) | 48151 | 1-(2-amino-4-fluorophenyl)-4-chloro-1-butanone | C10H11ClFNO | 详情 | 详情 |