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【结 构 式】 
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【分子编号】18619 【品名】(2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol 【CA登记号】5344-90-1 |
【 分 子 式 】C7H9NO 【 分 子 量 】123.1546 【元素组成】C 68.27% H 7.37% N 11.37% O 12.99% |
合成路线1
该中间体在本合成路线中的序号：(X)Treatment of alpha-chlorophenylacetyl chloride (VIII) with methylamine provided the corresponding chloro amide (IX), which was subsequently condensed with 2-aminobenzyl alcohol (X) to afford amino alcohol (XI). Cyclization of (XI) in the presence of AlCl3 led to the dibenzoazepine (XII). This was converted to the tetracyclic compound (XIV) by reaction with dibromoethane (XIII) in the presence of Na2CO3. Reduction of the amide carbonyl group of (XIV) by means of LiAlH4 furnished the title compound. In a related strategy, amide (XII) was initially reduced to diamine (VI) by using LiAlH4. Subsequent condensation of (VI) with dibromoethane (XIII) led to the target tetracyclic derivative
| 【1】 Haider, A.; Bollinger, H.; Fischer, A. (Sochinaz SA); Process for the preparation of a tetracyclic compound and application of this process for the preparation of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin. FR 2647114 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VI) | 62397 | 6,11-dihydro-5H-dibenzo[b,e]azepin-6-yl-N-methylmethanamine; N-(6,11-dihydro-5H-dibenzo[b,e]azepin-6-ylmethyl)-N-methylamine | C16H18N2 | 详情 | 详情 | |
| (VIII) | 62399 | 2-chloro-2-phenylacetyl chloride | C8H6Cl2O | 详情 | 详情 | |
| (IX) | 62400 | 2-chloro-N-methyl-2-phenylacetamide | C9H10ClNO | 详情 | 详情 | |
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XI) | 62401 | 2-[2-(hydroxymethyl)anilino]-N-methyl-2-phenylacetamide | C16H18N2O2 | 详情 | 详情 | |
| (XII) | 62402 | N-methyl-6,11-dihydro-5H-dibenzo[b,e]azepine-6-carboxamide | C16H16N2O | 详情 | 详情 | |
| (XIII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XIV) | 62403 | 2-methyl-3,4,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepin-1(2H)-one | C18H18N2O | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(X)In a different method, reaction of styrene oxide (XV) with methylamine provided amino alcohol (XVI), which was further condensed with ethylene oxide (XVII) to afford amino diol (XVIII). Alternatively, diol (XVIII) was prepared by a more direct procedure by condensation of epoxide (XV) with 2-(methylamino)ethanol (XIX). Chlorination of (XVIII) employing SOCl2 yielded the dichloro derivative (XX), which was subsequently condensed with 2-aminobenzyl alcohol (X) leading to piperazine (XXI). Cyclization of (XXI) to the title compound was accomplished by treatment with hot polyphosphoric acid. Optionally, alcohol (XXI) was converted to chloride (XXII), which was then cyclized in the presence of AlCl3. In a related method, alcohol (XXI) was esterified with AcOH, and the resultant acetate ester (XXIII) was then cyclized in the presence of polyphosphoric acid
| 【1】 Olivié, J.; Synthesis for the preparation of tetracyclic cpds.. US 4217452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XV) | 23017 | 2-phenyloxirane | 96-09-3 | C8H8O | 详情 | 详情 |
| (XVI) | 62404 | 2-(methylamino)-1-phenyl-1-ethanol | C9H13NO | 详情 | 详情 | |
| (XVII) | 10393 | Oxirane; Ethylene oxide | 75-21-8 | C2H4O | 详情 | 详情 |
| (XVIII) | 62405 | 2-[(2-hydroxyethyl)(methyl)amino]-1-phenyl-1-ethanol | C11H17NO2 | 详情 | 详情 | |
| (XIX) | 13324 | 2-Methylaminoethanol; 2-(Methylamino)-1-ethanol | 109-83-1 | C3H9NO | 详情 | 详情 |
| (XX) | 62406 | 2-chloro-N-(2-chloroethyl)-N-methyl-2-phenyl-1-ethanamine; N-(2-chloroethyl)-N-(2-chloro-2-phenylethyl)-N-methylamine | C11H15Cl2N | 详情 | 详情 | |
| (XXI) | 62407 | [2-(4-methyl-2-phenyl-1-piperazinyl)phenyl]methanol | C18H22N2O | 详情 | 详情 | |
| (XXII) | 62408 | 1-[2-(chloromethyl)phenyl]-4-methyl-2-phenylpiperazine | C18H21ClN2 | 详情 | 详情 | |
| (XXIII) | 62409 | 2-(4-methyl-2-phenyl-1-piperazinyl)benzyl acetate | C20H24N2O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(X)The key intermediate (XXI) was also prepared by several related procedures. Chlorination of aminoalcohol (XVI) gave chloro amine (XXIV), which was condensed with 2-aminobenzyl alcohol (X) to afford diamine (XXV). Then, alkylation of diamine (XXV) with dibromoethane (XIII) in hot pyridine gave rise to the target piperazine (XXI). Alternatively, diamine (XXV) was condensed with ethyl chloroacetate or with diethyl oxalate to produce the mono- or dioxopiperazines (XXVII) and (XXVI), respectively, which were then reduced to (XXI) by means of LiAlH4. Cyclization of alcohol (XXI) to the title compound was achieved by treatment with concentrated sulfuric acid
| 【1】 Olivié, J.; Synthesis for the preparation of tetracyclic cpds.. US 4217452 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16601 | ethyl chloroacetate; ethyl 2-chloroacetate | 105-39-5 | C4H7ClO2 | 详情 | 详情 | |
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XIII) | 10252 | 1,2-Dibromoethane; Ethylene dibromide | 106-93-4 | C2H4Br2 | 详情 | 详情 |
| (XVI) | 62404 | 2-(methylamino)-1-phenyl-1-ethanol | C9H13NO | 详情 | 详情 | |
| (XXI) | 62407 | [2-(4-methyl-2-phenyl-1-piperazinyl)phenyl]methanol | C18H22N2O | 详情 | 详情 | |
| (XXIV) | 62410 | C10H16ClN | 详情 | 详情 | ||
| (XXV) | 62411 | (2-{[2-(methylamino)-1-phenylethyl]amino}phenyl)methanol | C16H20N2O | 详情 | 详情 | |
| (XXVI) | 62413 | 4-[2-(hydroxymethyl)phenyl]-1-methyl-5-phenyl-2,3-piperazinedione | C18H18N2O3 | 详情 | 详情 | |
| (XXVII) | 62412 | 1-[2-(hydroxymethyl)phenyl]-4-methyl-6-phenyl-2-piperazinone | C18H20N2O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(X)In a further procedure, styrene oxide (XV) was condensed with 2-(benzylamino)ethanol (XXVIII) to give amino diol (XXIX). After chlorination of (XXIX) using SOCl2 and DMAP, dichloro derivative (XXX) was condensed with 2-aminobenzyl alcohol (X) yielding piperazine (XXXI). Cyclization of (XXXI) in hot sulfuric acid afforded the tetracyclic compound (XXXII). The N-benzyl group of (XXXII) was then removed by treatment with butyl chloroformate producing carbamate (XXXIII), which was further hydrolyzed and decarboxylated to (XXXIV) under basic conditions. Finally, methylation of the secondary amine (XXXIV) was performed by reductive alkylation with formaldehyde either in the presence of formic acid under Leuckart-Wallach conditions or by catalytic hydrogenation
| 【1】 Grafe, I.; Ahrens, K.-H.; Morsdorf, J.P.; Kisielowski-Ruppert, L. (Heumann Pharma GmbH); Process for the preparation of 1,2,3,4,10,14b-hexahydro-2-methyldibenzo[c,f]pyrazino[1,2-a]azepin and their salts. DE 4305659; EP 0612745 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (XV) | 23017 | 2-phenyloxirane | 96-09-3 | C8H8O | 详情 | 详情 |
| (XXVIII) | 25630 | 2-(benzylamino)-1-ethanol | 104-63-2 | C9H13NO | 详情 | 详情 |
| (XXIX) | 62414 | 2-[benzyl(2-hydroxyethyl)amino]-1-phenyl-1-ethanol | C17H21NO2 | 详情 | 详情 | |
| (XXX) | 62415 | N-benzyl-2-chloro-N-(2-chloroethyl)-2-phenyl-1-ethanamine; N-benzyl-N-(2-chloroethyl)-N-(2-chloro-2-phenylethyl)amine | C17H19Cl2N | 详情 | 详情 | |
| (XXXI) | 62416 | [2-(4-benzyl-2-phenyl-1-piperazinyl)phenyl]methanol | C24H26N2O | 详情 | 详情 | |
| (XXXII) | 62417 | 2-benzyl-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine | C24H24N2 | 详情 | 详情 | |
| (XXXIII) | 62418 | butyl 3,4,10,14b-tetrahydrodibenzo[c,f]pyrazino[1,2-a]azepine-2(1H)-carboxylate | C22H26N2O2 | 详情 | 详情 | |
| (XXXIV) | 62419 | 1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine | C17H18N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)1) 2-Aminobenzyl alcohol (I) was condensed with N-tert-butoxycarbonyl-4-piperidone (II) in toluene with azeotropical removal of water, and the resulting imine (III) was reduced with sodium cyanoborohydride to yield the secondary amine (IV). Further treatment of (IV) with triphosgene in the presence of N,N-diisopropyl ethylamine (DIEA) produced the benzoxazinone (V), which was then deprotected with HCl in EtOAc to give piperidine (VI).
| 【1】 Development of orally active oxytocin antagonists: Studies on 1-(1-[4-[1-(2-methyl-1-oxidopyridin-3-ylmethyl)piperidin-4-yloxy]-2-methoxybenzoyl]piperidin-4-yl)-1, 4-dihydrobenz[d][1,3]oxazin-2-one (L-372,662) and related pyridines. J Med Chem 1998, 41, 12, 2146. |
| 【2】 Bock, M.G.; Evans, B.E.; Hobbs, D.W.; Williams, P.D.; Anderson, P.S.; Freidinger, R.M.; Pettibone, D.J. (Merck & Co., Inc.); Benzoxazinone and benzopyrimidinone piperidinyl tocolytic oxytocin receptor antagonists. EP 0714299; JP 1997500134; US 5665719; WO 9502405 . |
| 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) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 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) | 19417 | tert-butyl 4-[[2-(hydroxymethyl)phenyl]imino]-1-piperidinecarboxylate | C17H24N2O3 | 详情 | 详情 | |
| (IV) | 18621 | tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate | C17H26N2O3 | 详情 | 详情 | |
| (V) | 18622 | tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (VI) | 19420 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C13H16N2O2 | 详情 | 详情 | |
| (VII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VIII) | 16623 | methyl 2,4-dihydroxybenzoate | 2150-47-2 | C8H8O4 | 详情 | 详情 |
| (IX) | 19423 | tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C18H25NO6 | 详情 | 详情 | |
| (X) | 18627 | tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C19H27NO6 | 详情 | 详情 | |
| (XI) | 18628 | 4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid | C18H25NO6 | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(I)Condensation of 2-(hydroxymethyl)aniline (I) with N-Boc-4-piperidone (II), followed by reduction with NaBH3CN provided anilinopiperidine (III). Cyclization of aminoalcohol (III) with triphosgene gave benzoxazinone (IV), which was deprotected by acidic treatment to yield piperidinylbenzoxazinone (V). Methyl 2,4-dihydroxybenzoate (VI) was selectively alkylated on the 4-position by coupling with N-Boc-4-piperidinol (VII) under Mitsunobu conditions to give ether (VIII). Then, the remaining 2-OH group was methylated with MeI and NaH to give (IX), which was saponified to provide the benzoic acid derivative (X). Coupling of amine (V) and acid (X) using EDC and HOBt produced amide (XI). Then, removal of the tert-butoxycarbonyl group by acid treatment, followed by acetylation of the resulting piperidine (XII) with Ac2O, furnished the target compound.
| 【1】 Williams, P.D.; et al.; 1-[1-[4-[(N-Acetyl-4-piperidinyl)oxy]-2-methoxybenzoyl]piperidin-4-yl]-4H-3,1-benzoxazin-2(1H)-one (L-371, 257): A new, orally bioavailable, non-peptide oxytocin antagonist. J Med Chem 1995, 38, 23, 4634. |
| 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) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 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) | 18621 | tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate | C17H26N2O3 | 详情 | 详情 | |
| (IV) | 18622 | tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (V) | 18623 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride | C13H17ClN2O2 | 详情 | 详情 | |
| (VI) | 16623 | methyl 2,4-dihydroxybenzoate | 2150-47-2 | C8H8O4 | 详情 | 详情 |
| (VII) | 18625 | tert-butyl 4-hydroxy-1-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VIII) | 19423 | tert-butyl 4-[3-hydroxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C18H25NO6 | 详情 | 详情 | |
| (IX) | 18627 | tert-butyl 4-[3-methoxy-4-(methoxycarbonyl)phenoxy]-1-piperidinecarboxylate | C19H27NO6 | 详情 | 详情 | |
| (X) | 18628 | 4-[[1-(tert-butoxycarbonyl)-4-piperidinyl]oxy]-2-methoxybenzoic acid | C18H25NO6 | 详情 | 详情 | |
| (XI) | 18629 | tert-butyl 4-[3-methoxy-4-([4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinyl]carbonyl)phenoxy]-1-piperidinecarboxylate | C31H39N3O7 | 详情 | 详情 | |
| (XII) | 18630 | 1-[1-[2-methoxy-4-(4-piperidinyloxy)benzoyl]-4-piperidinyl]-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride | C26H32ClN3O5 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(V)Reductive ring closure of diethyl 2-nitrobenzylidenemalonate (I) afforded quinolone (II). Subsequent N-alkylation of (II) with isopropyl iodide gave (III). Carboxylic acid (IV) was then obtained by basic hydrolysis of the ethyl ester (III). In a related procedure, reductive alkylation of 2-aminobenzyl alcohol (V) with acetone in the presence of NaBH4 gave the N-isopropyl derivative (VI). Oxidation of (VI) using activated MnO2 in toluene yielded aldehyde (VII). Further Knoevenagel condensation of (VII) with diethyl malonate in the presence of piperidine and AcOH produced the previously described quinolone ester (III). Alternatively, condensation of (VII) with malonic acid directly produced the previously described quinolonecarboxylic acid (IV). Acid chloride (VIII) was then prepared by treatment of (IV) with thionyl chloride in hot toluene.
| 【1】 Yokomori, S.; Muramatsu, M.; Suzuki, M.; Ito, C.; Asanuma, H.; Isobe, Y.; Ohuchi, Y.; Kaneko, T.; Synthesis and evaluation of novel 2-oxo-1,2-dihydro-3-quinolinecarboxamide derivatives as potent and selective serotonin 5-HT4 receptor agonists. Chem Pharm Bull 2001, 49, 1, 29. |
| 【2】 Ohuchi, Y.; Suzuki, M.; Asanuma, H.; Yokomori, S.; Hatayama, K. (Taisho Pharmaceutical Co., Ltd.); Quinolinecarboxylic acid deriv.. EP 0710662; JP 1996034784; US 5753673; WO 9531455 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 16829 | Diethyl malonate | 105-53-3 | C7H12O4 | 详情 | 详情 | |
| (I) | 36330 | diethyl 2-(2-nitrobenzylidene)malonate | C14H15NO6 | 详情 | 详情 | |
| (II) | 36331 | ethyl 2-oxo-1,2-dihydro-3-quinolinecarboxylate | C12H11NO3 | 详情 | 详情 | |
| (III) | 36332 | ethyl 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylate | C15H17NO3 | 详情 | 详情 | |
| (IV) | 36333 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid | C13H13NO3 | 详情 | 详情 | |
| (V) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (VI) | 36334 | [2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol | C10H15NO | 详情 | 详情 | |
| (VII) | 36335 | 2-(isopropylamino)benzaldehyde | C10H13NO | 详情 | 详情 | |
| (VIII) | 36336 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarbonyl chloride | C13H12ClNO2 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(III)4-Piperidinone hydrochloride (I) was protected as the tert-butyl carbamate (II) using Boc2O and diisopropyl ethylamine. Condensation of (II) with 2-aminobenzyl alcohol (III) in boiling toluene, followed by reduction with sodium cyanoborohydride gave secondary amine (IV). Subsequent cyclization of (IV) in the presence of triphosgene and diisopropyl ethylamine produced the benzoxazinone (V), from which the Boc group was removed with HCl in EtOAc to yield intermediate (VI).
| 【1】 Freidinger, R.M.; Stauffer, K.; Perlow, D.S.; Sparks, M.A.; Williams, P.D.; Bell, I.M. (Merck & Co., Inc.); Tocolytic oxytocin receptor antagonists. GB 2326410; US 6090805 . |
| 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) | 27115 | 4-piperidinone | 40064-34-4 | C5H9NO | 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) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (IV) | 18621 | tert-butyl 4-[2-(hydroxymethyl)anilino]-1-piperidinecarboxylate | C17H26N2O3 | 详情 | 详情 | |
| (V) | 18622 | tert-butyl 4-[2-oxo-2H-3,1-benzoxazin-1(4H)-yl]-1-piperidinecarboxylate | C18H24N2O4 | 详情 | 详情 | |
| (VI) | 19420 | 1-(4-piperidinyl)-1,4-dihydro-2H-3,1-benzoxazin-2-one | C13H16N2O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(I)Reaction of 2-aminobenzyl alcohol (I) with acetone in aqueous AcOH affords 2,2-dimethyl-1,4-dihydro-2H-3,1-benzoxazine, which is reduced with LiAlH4 in THF, producing 2-(isopropylamino)benzyl alcohol (II). After oxidation of alcohol (II) to the corresponding benzaldehyde (III) by means of MnO2 in toluene at 117 °C, Knoevenagel condensation with Meldrum’s acid (IV) in the presence of AcOH and ethylenediamine in MeOH gives 1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxylic acid (V) . Chlorination of acid (V) with SOCl2 in toluene at 95 °C and subsequent coupling of the resulting acid chloride with N-Boc-endo-3-aminotropane (VI) in the presence of NaOH in toluene/water affords the corresponding amide (VII). Deprotection of the N-Boc-tropane derivative (VII) by means of TFA in CH2Cl2 furnishes the corresponding amine TFA salt (VIII) (1-9), which is then N-alkylated with 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol (IX) [prepared by condensation of (S)-epichlorohydrin (X) with Nmethylbenzylamine in hexane and subsequent hydrogenolysis of the obtained benzylamine derivative (XI) in the presence of Pd(OH)2/C and Boc2O in EtOAc] in the presence of DIEA in MeOH at 80 °C to give the N-Boc-methylamine derivative (XII). Deprotection of this compound by means of TFA in CH2Cl2 and N-sulfonylation of the obtained free amine (XIII) with methanesulfonyl chloride (XIV) in the presence of DBU in CH2Cl2 then affords velusetrag. Alternatively, reaction of amine (VIII) with N-[(S)-glycidyl]-N-methylmethanesulfonamide (XV) [prepared by alkylation of N-methylmethanesulfonamide (XVI) with (S)-epichlorohydrin (XVII) using aqueous NaOH] in the presence of NaOH in MeOH yields velusetrag . N-Boc-endo-3-aminotropane (VI) is prepared by hydrolysis of 2,5-dimethoxytetrahydrofuran (XVIII) with aqueous HCl, followed by Mannich reaction of the resulting succinaldehyde with BnNH2 and 1,3-acetonedicarboxylic acid (XIX) in the presence of HCl in H2O to give N-benzyl-8-azabicyclo[3.2.1]octan-3-one (XX). Treatment of this compound with H2 over Pd(OH)2/C and Boc2O in EtOAc yields N-Boc-8-azabicyclo[3.2.1]octan-3-one (XXI), which is then converted to the desired amine (VI) by reductive amination with HCOONH4 in the presence of Pd/C in MeOH/H2O .
Velusetrag can be converted to its salts, including hydrochloride, citrate,adipate, phosphate, sulfate, tartrate, malate, hydrobromide and mesylate, by treatment with the respective acids .
| 【1】 Marquess, D., Fatheree, P.R., Turner, D.S., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. EP 1735304, JP 2007535546, JP 2008174569, US 2005228014, US 2007281970, US 7375114, US 7728006, WO 2005100350. |
| 【2】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2007270457, US 7592355. |
| 【3】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4, receptor agonists. US 2008176895, US 7763637. |
| 【4】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. US 2008255187, US 7534889. |
| 【5】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolinone-carboxamide compounds as 5-HT4 receptor agonists. US 2010285519. |
| 【6】 Marquess, D., Fatheree, P.R., Turner, S.D., Long, D.D., Choi, S.-K., Goldblum, A.A., Genov, D. (Theravance, Inc.). Quinolone-carboxamide compounds as 5-HT4 receptor agonists. US 2010311979. |
| 【7】 Choi, S.-K., Fatheree, P., Goldblum, A.A., Jiang, L., Long, D.D., Marquess, D., Turner, S.D. (Theravance, Inc.). 5-HT4 receptor agonist compounds. EP 1807422, JP 2008518965, US 2006100236, US 7399862, WO 2006052640. |
| 【8】 Fatheree, P.R., Turner, S.D., Goldblum, A., Chao, R., Genov, D. (Theravance, Inc.). Crystalline form of a quinolinone-carboxamide compound. EP 1874766, JP 2008535848, US 2006229332, US 7728004, WO 2006108127. |
| 【9】 Genov, D., Lee, J., Liu, J. (Theravance, Inc.). Process for preparing intermediates to 5-HT4 receptor agonist compounds. EP 1984362, JP 2009526852, US 2007191355, WO 2007097976. |
| 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) | 18619 | (2-aminophenyl)methanol; 2-Amino-benzenemethanol；2-Hydroxymethyl aniline;2-aminobenzyl alcohol;o-Aminobenzyl 2-aminobenzylalcohol;alcohol; 2-aminobenzenemethanol; 2-aminobenzyl alcohol | 5344-90-1 | C7H9NO | 详情 | 详情 |
| (II) | 36334 | [2-(isopropylamino)phenyl]methanol；2-(isopropylamino)benzyl alcohol;(2-(isopropylamino)phenyl)methanol | C10H15NO | 详情 | 详情 | |
| (III) | 36335 | 2-(isopropylamino)benzaldehyde | C10H13NO | 详情 | 详情 | |
| (IV) | 14738 | Meldrum's acid; 2,2-dimethyl-1,3-dioxane-4,6-dione；Malonic acid cyclic isopropylidene ester | 2033-24-1 | C6H8O4 | 详情 | 详情 |
| (V) | 36333 | 1-isopropyl-2-oxo-1,2-dihydro-3-quinolinecarboxylic acid | C13H13NO3 | 详情 | 详情 | |
| (VI) | 68799 | (1R,3r,5R)-tert-butyl 3-amino-8-azabicyclo[3.2.1]octane-8-carboxylate | C12H22N2O2 | 详情 | 详情 | |
| (VII) | 68803 | (1R,3R)-tert-butyl 3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octane-8-carboxylate | C25H33N3O4 | 详情 | 详情 | |
| (VIII) | 68804 | N-((1R,3R)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate | C20H25N3O2.C2HF3O2 | 详情 | 详情 | |
| (IX) | 68807 | 1-chloro-3-(N-Boc-N-methylamino)propan-2(S)-ol;(S)-tert-butyl (3-chloro-2-hydroxypropyl)(methyl)carbamate | C9H18ClNO3 | 详情 | 详情 | |
| (X) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XI) | 68808 | (S)-1-(benzyl(methyl)amino)-3-chloropropan-2-ol | C11H16ClNO | 详情 | 详情 | |
| (XII) | 68805 | tert-butyl ((S)-2-hydroxy-3-((1R,3R,5S)-3-(1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamido)-8-azabicyclo[3.2.1]octan-8-yl)propyl)(methyl)carbamate | C29H42N4O5 | 详情 | 详情 | |
| (XIII) | 68806 | N-((1R,3R,5S)-8-((R)-2-hydroxy-3-(methylamino)propyl)-8-azabicyclo[3.2.1]octan-3-yl)-1-isopropyl-2-oxo-1,2-dihydroquinoline-3-carboxamide 2,2,2-trifluoroacetate | C24H34N4O3.C2HF3O2 | 详情 | 详情 | |
| (XIV) | 13467 | Methanesulfonyl chloride;Mesyl chloride;Methylsulfonyl chloride;Methanesulfonic acid chloride;Methanesulfonyl chloride;Methanesulphonyl chloride | 124-63-0 | CH3ClO2S | 详情 | 详情 |
| (XV) | 68802 | N-[(S)-glycidyl]-N-methylmethanesulfonamide;(S)-N-methyl-N-(oxiran-2-ylmethyl)methanesulfonamide | C5H11NO3S | 详情 | 详情 | |
| (XVI) | 67859 | N-methylmethanesulfonamide | 1184-85-6 | C2H7NO2S | 详情 | 详情 |
| (XVII) | 13917 | (S)-Epichlorohydrin; (2S)-2-(Chloromethyl)oxirane;(S)-(+)-epichlorohydrin | 67843-74-7 | C3H5ClO | 详情 | 详情 |
| (XVIII) | 12132 | 2,5-Dimethoxytetrahydrofuran; 5-Methoxytetrahydro-2-furanyl methyl ether | 696-59-3 | C6H12O3 | 详情 | 详情 |
| (XIX) | 15530 | 1,3-Acetonedicarboxylic Acid; 3-Oxopentanedioic acid；3-oxoglutaric acid | 542-05-2 | C5H6O5 | 详情 | 详情 |
| (XX) | 68801 | (1R,5R)-8-benzyl-8-azabicyclo[3.2.1]octan-3-one;N-benzyl-8-azabicyclo[3.2.1]octan-3-one | C14H17NO | 详情 | 详情 | |
| (XXI) | 68800 | N-Boc-8-azabicyclo[3.2.1]octan-3-one | C12H19NO3 | 详情 | 详情 |