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【结 构 式】 
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【分子编号】25693 【品名】ethyl 3-piperidinecarboxylate 【CA登记号】5006-62-2 |
【 分 子 式 】C8H15NO2 【 分 子 量 】157.21264 【元素组成】C 61.12% H 9.62% N 8.91% O 20.35% |
合成路线1
该中间体在本合成路线中的序号：(II)The condensation of dibenzocycloheptylidene derivative (I) with radiolabelled piperidine-3-carboxylic acid ethyl ester (II) by means of K2CO3 in ethyl acetate gives the adduct (III), which is hydrolyzed with aqueous HCl to yield the carboxylic acid (IV). Finally, this compound is submitted to optical resolution by means of chiral chromatography to provide the chiral radiolabelled compound.
| 【1】 Valsborg, J.S.; Foged, C.; Radiolabelling of NNC 05-1869, a compound for treatment of diabetic neuropathy. J Label Compd Radiopharm 2002, 45, 4, 351. |
| 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) | 52139 | 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene | C18H17Br | 详情 | 详情 | |
| (II) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 58262 | ethyl 3-piperidinecarboxylate | C8H15NO2 | 详情 | 详情 | |
| (III) | 58263 | ethyl 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate | C26H31NO2 | 详情 | 详情 | |
| (III) | 58266 | ethyl 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate | C26H31NO2 | 详情 | 详情 | |
| (IV) | 58264 | 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid | C24H27NO2 | 详情 | 详情 | |
| (IV) | 58265 | 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid | C24H27NO2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II). Subsequent Dieckmann cyclization of (II) with t-BuOK, followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III). Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV), which was hydrogenated over Pd/C to provide (V). Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI). This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII). Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers, from which the exo compound (VIII) was isolated by column chromatography. The required butyl thioether was then obtained by reaction with sodium hydrosulfide and n-butyl bromide in DMF. Finally, resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.
| 【1】 Brown, T.J.; Bymaster, F.P.; Mitch, C.H.; et al.; Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome. J Med Chem 1997, 40, 4, 538. |
| 【2】 Sauerberg, P.; Olesen, P.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 25694 | ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate | C12H21NO4 | 详情 | 详情 | |
| (III) | 25695 | 1-azabicyclo[3.2.1]octan-6-one | C7H11NO | 详情 | 详情 | |
| (IV) | 25696 | ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate | C12H16N2O2 | 详情 | 详情 | |
| (V) | 25697 | ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate | C12H18N2O2 | 详情 | 详情 | |
| (VI) | 25698 | 2-(1-Azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt | C9H13N3O | 详情 | 详情 | |
| (VII) | 25699 | 6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane | C9H11Cl2N3S | 详情 | 详情 | |
| (VIII) | 25700 | (5R,6R)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane | C9H12ClN3S | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II). Subsequent Dieckmann cyclization of (II) with t-BuOK, followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III). Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV), which was hydrogenated over Pd/C to provide (V). Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI). This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII). Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers, from which the exo compound (VIII) was isolated by column chromatography. The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF. Finally, resolution with D-tartaric acid yielded the title (5R,6R) enantiomer.
| 【1】 Brown, T.J.; Bymaster, F.P.; Mitch, C.H.; et al.; Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome. J Med Chem 1997, 40, 4, 538. |
| 【2】 Sauerberg, P.; Olesen, P.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 25694 | ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate | C12H21NO4 | 详情 | 详情 | |
| (III) | 25695 | 1-azabicyclo[3.2.1]octan-6-one | C7H11NO | 详情 | 详情 | |
| (IV) | 25696 | ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate | C12H16N2O2 | 详情 | 详情 | |
| (V) | 25697 | ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate | C12H18N2O2 | 详情 | 详情 | |
| (VI) | 25698 | 2-(1-Azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt | C9H13N3O | 详情 | 详情 | |
| (VII) | 25699 | 6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane | C9H11Cl2N3S | 详情 | 详情 | |
| (VIII) | 25700 | (5R,6R)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane | C9H12ClN3S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(I)Alkylation of ethyl nipecotate (I) with ethyl bromoacetate gave diester (II). Subsequent Dieckmann cyclization of (II) with t-BuOK, followed by acid decarboxylation afforded azabicyclo[3.2.1]octane-6-one (III). Knoevenagel condensation of (III) with ethyl cyanoacetate afforded unsaturated cyano ester (IV), which was hydrogenated over Pd/C to provide (V). Nitrosation of (V) with isoamyl nitrite in the presence of NaOEt gave the hydroxymino nitrile (VI). This was treated with S2Cl2 in cold DMF to generate the thiadiazole (VII). Hydrogenolysis of the 6-chloro of (VII) provided a mixture of isomers, from which the exo compound (VIII) was isolated by column chromatography. The required propyl thioether was then obtained by reaction with sodium hydrosulfide and n-propyl bromide in DMF. Finally, resolution with L-tartaric acid yielded the title (5S,6S) enantiomer.
| 【1】 Brown, T.J.; Bymaster, F.P.; Mitch, C.H.; et al.; Muscarinic analgesics with potent and selective effects on the gastrointestinal tract: Potential application for the treatment of irritable bowel syndrome. J Med Chem 1997, 40, 4, 538. |
| 【2】 Sauerberg, P.; Olesen, P.H. (Novo Nordisk A/S); Heterocyclic cpds. and their preparation and use. EP 0544779; JP 1994500542; US 5260314; US 5418240; US 5527813; US 5578602; WO 9203433 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 25694 | ethyl 1-(2-ethoxy-2-oxoethyl)-3-piperidinecarboxylate | C12H21NO4 | 详情 | 详情 | |
| (III) | 25695 | 1-azabicyclo[3.2.1]octan-6-one | C7H11NO | 详情 | 详情 | |
| (IV) | 25696 | ethyl 2-(1-azabicyclo[3.2.1]oct-6-ylidene)-2-cyanoacetate | C12H16N2O2 | 详情 | 详情 | |
| (V) | 25697 | ethyl 2-(1-azabicyclo[3.2.1]oct-6-yl)-2-cyanoacetate | C12H18N2O2 | 详情 | 详情 | |
| (VI) | 25698 | 2-(1-Azabicyclo[3,2,1]oct-6-yl-2-(hydroxyimino)acetic acid sodium salt | C9H13N3O | 详情 | 详情 | |
| (VII) | 25699 | 6-chloro-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane | C9H11Cl2N3S | 详情 | 详情 | |
| (VIII) | 25700 | (5R,6R)-6-(4-chloro-1,2,5-thiadiazol-3-yl)-1-azabicyclo[3.2.1]octane | C9H12ClN3S | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 4-(bromomethyl)thiazole (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
| 【1】 Schleim, K.D.; Leung, K.; Cheng, K.; Patchent, A.A.; Morriello, G.; Smith, R.; Jacks, T.; Yang, L.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogues. Bioorg Med Chem Lett 1999, 9, 13, 1761. |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 26196 | 4-(bromomethyl)-1,3-thiazole | C4H4BrNS | 详情 | 详情 | |
| (IV) | 26197 | 1-(tert-butyl) 3-ethyl 3-(1,3-thiazol-4-ylmethyl)-1,3-piperidinedicarboxylate | C17H26N2O4S | 详情 | 详情 | |
| (V) | 26198 | ethyl 3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (VI) | 26190 | (2R)-2-(acetoxy)-2-phenylethanoic acid | C10H10O4 | 详情 | 详情 | |
| (VII) | 26199 | ethyl (3S)-1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C22H26N2O5S | 详情 | 详情 | |
| (VIII) | 26200 | ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26201 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C28H36N4O5S | 详情 | 详情 | |
| (XI) | 26202 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C23H28N4O3S | 详情 | 详情 | |
| (XII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIII) | 26203 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C32H43N5O6S | 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 synthesis of the precursor (XII) has been reported by two related procedures. Ethyl nipecotate (I) was protected as the N-Boc derivative (II) using di-tert-butyl dicarbonate. Benzylic bromination of 4-methylthiazole (III) with NBS and AIBN provided bromide (IV). Then, alkylation of protected nipecotate (II) with bromide (IV) in the presence of potassium hexamethyldisilazide gave the thiazolylmethyl derivative (V). Subsequent acid deprotection of the Boc group of (V) yielded racemic piperidine (VI). Resolution was achieved by coupling with (R)-O-acetylmandelic acid, followed by chromatographic separation of the diastereomeric amides (VII), and hydrolytic removal of the chiral auxiliary. The required (S)-nipecotate (VIII) was condensed with N-Boc-D-tryptophan (IX) to provide amide (X). Deprotection of the Boc group and further coupling of (X) with N-Boc-2-aminoisobutyric acid (XI) then furnished intermediate (XII).
| 【1】 Cheng, K.; Yang, L.; Morriello, G.; Smith, R.; Patchett, A.A.; Scheim, k.D.; Jacks, T.; Leung, K.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogue L-165,666. 217th ACS Natl Meet (March 21 1999, Anaheim) 1999, Abst MEDI 074. |
| 【2】 Morriello, G.J.; Patchett, A.A.; Yang, L.; Chen, M.H.; Nargund, R. (Merck & Co., Inc.); Piperidines, pyrrolidines and hexahydro-1H-azepines promote release of growth hormone. EP 0739204; US 5492916; US 5492920; US 5494919; WO 9513069 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 27718 | 4-methyl-1,3-thiazole | 693-95-8 | C4H5NS | 详情 | 详情 |
| (IV) | 26196 | 4-(bromomethyl)-1,3-thiazole | C4H4BrNS | 详情 | 详情 | |
| (V) | 27723 | 1-(tert-butyl) 3-ethyl 3-(1,3-thiazol-4-ylmethyl)-1,3-piperidinedicarboxylate | C17H26N2O4S | 详情 | 详情 | |
| (VI) | 27722 | ethyl 3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C10H19NO3 | 详情 | 详情 | |
| (VII) | 27724 | ethyl 1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C22H26N2O5S | 详情 | 详情 | |
| (VIII) | 26200 | ethyl (3S)-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C12H18N2O2S | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26201 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C28H36N4O5S | 详情 | 详情 | |
| (XI) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XII) | 26203 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(1,3-thiazol-4-ylmethyl)-3-piperidinecarboxylate | C32H43N5O6S | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)Protection of ethyl piperidine-3-carboxylate (I) with di tert-butyl dicarbonate gave carbamate (II), which was alkylated with 2-(chloromethyl)pyridine chloride (III) in the presence of potassium hexamethyldisilazide to afford racemic (IV). Acid deprotection of the Boc group of (IV) yielded amine (V). This was resolved by coupling with (R)-O-acetyl mandelic acid (VI), followed by chromatographic separation of the diastereoisomers. Then, acid hydrolysis of the desired isomer (VII) provided the (S)-piperidine (VIII). Subsequent coupling of (VIII) with N-Boc-D-tryptophan (IX) in the presence of EDC and HOBt gave amide (X). After Boc deprotection of (X), the resulting amine (XI) was coupled with N-Boc-2-aminoisobutyric acid (XII) to produce (XIII). Finally, acid removal of the Boc group of (XIII) furnished the title compound.
| 【1】 Schleim, K.D.; Leung, K.; Cheng, K.; Patchent, A.A.; Morriello, G.; Smith, R.; Jacks, T.; Yang, L.; Thiazole-derived potent, highly bioavailable short duration growth hormone secretagogues. Bioorg Med Chem Lett 1999, 9, 13, 1761. |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 26187 | 2-(Chloromethyl)pyridine | 4377-33-7 | C6H6ClN | 详情 | 详情 |
| (IV) | 26188 | 1-(tert-butyl) 3-ethyl 3-(2-pyridinylmethyl)-1,3-piperidinedicarboxylate | C19H28N2O4 | 详情 | 详情 | |
| (V) | 26189 | ethyl 3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (VI) | 26190 | (2R)-2-(acetoxy)-2-phenylethanoic acid | C10H10O4 | 详情 | 详情 | |
| (VII) | 26191 | ethyl (3S)-1-[(2R)-2-(acetoxy)-2-phenylethanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C24H28N2O5 | 详情 | 详情 | |
| (VIII) | 26192 | ethyl (3S)-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C14H20N2O2 | 详情 | 详情 | |
| (IX) | 16114 | N-alpha-t-BOC-L-tryptophan; (2S)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propionic acid | 13139-14-5 | C16H20N2O4 | 详情 | 详情 |
| (X) | 26193 | ethyl (3S)-1-[(2R)-2-[(tert-butoxycarbonyl)amino]-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C30H38N4O5 | 详情 | 详情 | |
| (XI) | 26194 | ethyl (3S)-1-[(2R)-2-amino-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C25H30N4O3 | 详情 | 详情 | |
| (XII) | 18471 | N-(tert-butoxycarbonyl)-2-methylalanine | 30992-29-1 | C9H17NO4 | 详情 | 详情 |
| (XIII) | 26195 | ethyl (3S)-1-[(2R)-2-([2-[(tert-butoxycarbonyl)amino]-2-methylpropanoyl]amino)-3-(1H-indol-3-yl)propanoyl]-3-(2-pyridinylmethyl)-3-piperidinecarboxylate | C34H45N5O6 | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)Ethyl nipecotate (I) was protected as the N-Boc derivative (II) and subsequently reduced to alcohol (III) by means of LiAlH4. Conversion of alcohol (III) into iodide (IV) was achieved by treatment with iodine and triphenylphosphine. The dianion of the chiral azetidinecarboxylic acid (V) was alkylated with iodide (IV) to furnish adduct (VI) as a diastereomeric mixture that was desilylated to (VII) using tetrabutylammonium fluoride. Benzyl ester (VIII) was then obtained by reaction of carboxylic acid (VII) with benzyl bromide and NaHCO3.
| 【1】 Treuner, U.; Kronenthal, D.R.; Xu, Z.; Seiler, S.; Slusarchyk, W.A.; Bisacchi, G.; Randazzo, M.E.; Sutton, J.C.; Shi, Z.; Zahler, R.; Schwinden, M.D. (Bristol-Myers Squibb Co.); Amidino and guanidino azetidinone tryptase inhibitors. WO 9967215 . |
| 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) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (II) | 26186 | 1-(tert-butyl) 3-ethyl 1,3-piperidinedicarboxylate | C13H23NO4 | 详情 | 详情 | |
| (III) | 51124 | tert-butyl 3-(hydroxymethyl)-1-piperidinecarboxylate | C11H21NO3 | 详情 | 详情 | |
| (IV) | 51120 | tert-butyl 3-(iodomethyl)-1-piperidinecarboxylate | C11H20INO2 | 详情 | 详情 | |
| (V) | 51121 | (2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C21H38N2O5Si | 详情 | 详情 | |
| (VI) | 49426 | (2S)-1-[tert-butyl(dimethyl)silyl]-4-oxo-2-azetidinecarboxylic acid | C10H19NO3Si | 详情 | 详情 | |
| (VII) | 51122 | (2S,3R)-3-[[1-(tert-butoxycarbonyl)-3-piperidinyl]methyl]-4-oxo-2-azetidinecarboxylic acid | C15H24N2O5 | 详情 | 详情 | |
| (VIII) | 51123 | tert-butyl 3-([(2S,3R)-2-[(benzyloxy)carbonyl]-4-oxoazetidinyl]methyl)-1-piperidinecarboxylate | C22H30N2O5 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(VI)Nucleophilic substitution of 4-fluoro-3-(trifluoromethyl)benzaldehyde (II) with 6-mercaptobenzodioxan (I) afforded the sulfanyl aldehyde (III). Knoevenagel condensation of aldehyde (III) with malonic acid furnished the cinnamic acid derivative (IV), which was subsequently converted to acid chloride (V) by treatment with oxalyl chloride. Acid chloride (V) was then coupled with ethyl nipecotate (VI), yielding amide (VII). The ethyl ester group of (VII) was finally hydrolyzed using NaOH in aqueous ethanol.
| 【1】 Pei, Z.; et al.; Discovery of potent antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 3. Maide (C-ring) structure-activity relationship and improvement of overall properties of arylthio cinnamides. J Med Chem 2001, 44, 18, 2913. |
| 【2】 Lynch, J.K.; Link, J.; Zhu, G.-D.; Boyd, S.A.; Winn, M.; Pei, Z.; Gunawardana, I.W.; Liu, G.; Xin, Z.; Jae, H.-S.; Freeman, J.C.; Von Geldern, T.; Staeger, M.A. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. US 6110922; WO 0039081 . |
| 【3】 Jae, H.-S.; Pei, Z.; Staeger, M.A.; Gunawardana, I.W.; Winn, M.; Freeman, J.C.; Liu, G.; Link, J.; Boyd, S.A.; Zhu, G.-D.; Von Geldern, T.W.; Xin, Z.; Lynch, J.K.; Wang, S. (Abbott Laboratories Inc.); Cell adhesion-inhibiting antiinflammatory and immune-suppressive cpds.. WO 0059880 . |
| 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) | 49976 | 2,3-dihydro-1,4-benzodioxin-6-ylhydrosulfide; 2,3-dihydro-1,4-benzodioxine-6-thiol | C8H8O2S | 详情 | 详情 | |
| (II) | 49977 | alpha,alpha,alpha,4-Tetrafluoro-m-tolualdehyde; 4-Fluoro-3-(trifluoromethyl)benzaldehyde | 67515-60-0 | C8H4F4O | 详情 | 详情 |
| (III) | 49978 | 4-(2,3-dihydro-1,4-benzodioxin-6-ylsulfanyl)-3-(trifluoromethyl)benzaldehyde | C16H11F3O3S | 详情 | 详情 | |
| (IV) | 49979 | (E)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylsulfanyl)-3-(trifluoromethyl)phenyl]-2-propenoic acid | C18H13F3O4S | 详情 | 详情 | |
| (V) | 49980 | (E)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylsulfanyl)-3-(trifluoromethyl)phenyl]-2-propenoyl chloride | C18H12ClF3O3S | 详情 | 详情 | |
| (VI) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (VII) | 49981 | ethyl 1-[(E)-3-[4-(2,3-dihydro-1,4-benzodioxin-6-ylsulfanyl)-3-(trifluoromethyl)phenyl]-2-propenoyl]-3-piperidinecarboxylate | C26H26F3NO5S | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XI)2,3-Dichloro-4-hydroxybenzaldehyde (I) was converted to the corresponding aryl triflate (II), which was subsequently condensed with 2-bromothiophenol (III), yielding the diaryl sulfide (IV). Wittig reaction of aldehyde (IV) with the ylide resulting from the phosphonium salt (V) afforded the unsaturated ester (VI). Cycloaddition between (VI) and the in situ-generated dimethylsulfoxonium methylide gave rise to the cyclopropane derivative (VII). After basic hydrolysis of the ethyl ester (VII), the resultant carboxylic acid (VIII) was coupled with 1-(3-aminopropyl)-2-pyrrolidinone (IX), providing amide (X). Displacement of the aryl bromide group of (X) with ethyl nipecotate (XI) in the presence of BINAP and Pd catalysts furnished the piperidine-substituted compound (XII). The ethyl ester group of (XII) was finally hydrolyzed to the target carboxylic acid under basic conditions.
| 【1】 Link, J.T.; et al.; Discovery and SAR of diarylsulfide cyclopropylamide LFA-1/ICAM-1 interaction antagonists. Bioorg Med Chem Lett 2001, 11, 8, 973. |
| 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) | 52028 | 2,3-dichloro-4-hydroxybenzaldehyde | C7H4Cl2O2 | 详情 | 详情 | |
| (II) | 52029 | 2,3-dichloro-4-formylphenyl trifluoromethanesulfonate | C8H3Cl2F3O4S | 详情 | 详情 | |
| (III) | 52030 | 2-Bromobenzenethiol; 2-Bromothiophenol;2-bromo-benzenethio;2-Bromo thiophenol | 6320-02-1 | C6H5BrS | 详情 | 详情 |
| (IV) | 52031 | 4-[(2-bromophenyl)sulfanyl]-2,3-dichlorobenzaldehyde | C13H7BrCl2OS | 详情 | 详情 | |
| (V) | 52032 | (2-ethoxy-2-oxoethyl)(triphenyl)phosphonium chloride | C22H22ClO2P | 详情 | 详情 | |
| (VI) | 52033 | ethyl (E)-3-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]-2-propenoate | C17H13BrCl2O2S | 详情 | 详情 | |
| (VII) | 52034 | ethyl (1S,2R)-2-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]cyclopropanecarboxylate | C18H15BrCl2O2S | 详情 | 详情 | |
| (VIII) | 52035 | (1S,2R)-2-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]cyclopropanecarboxylic acid | C16H11BrCl2O2S | 详情 | 详情 | |
| (IX) | 52036 | N-(3-Aminopropyl)-2-pyrrolidinone; N-(3'-Aminopropyl)-2-pyrrolidinone | 7663-77-6 | C7H14N2O | 详情 | 详情 |
| (X) | 52037 | (1S,2R)-2-[4-[(2-bromophenyl)sulfanyl]-2,3-dichlorophenyl]-N-[3-(2-oxo-1-pyrrolidinyl)propyl]cyclopropanecarboxamide | C23H23BrCl2N2O2S | 详情 | 详情 | |
| (XI) | 25693 | ethyl 3-piperidinecarboxylate | 5006-62-2 | C8H15NO2 | 详情 | 详情 |
| (XII) | 52038 | ethyl 1-[2-([2,3-dichloro-4-[(1R,2S)-2-([[3-(2-oxo-1-pyrrolidinyl)propyl]amino]carbonyl)cyclopropyl]phenyl]sulfanyl)phenyl]-3-piperidinecarboxylate | C31H37Cl2N3O4S | 详情 | 详情 |