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【结 构 式】 
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【分子编号】11305 【品名】2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine 【CA登记号】504-29-0 |
【 分 子 式 】C5H6N2 【 分 子 量 】94.11612 【元素组成】C 63.81% H 6.43% N 29.76% |
合成路线1
该中间体在本合成路线中的序号：(II)Compound can be prepared in two different ways: 1) The cyclization of ethyl 2-[4-(chloroacetyl)phenyl]propionate (I) with 2-aminopyridine (II) in refluxing ethanol gives ethyl 2-[4-(imidazo[1,2-a]pyridin-2-yl)phenyl]propionate (III), which is then hydrolyzed with NaOH in refluxing ethanol water. 2) By cyclization of a mixture of pyridine (IV), hydroxylamine (V) and 2-[4-(chloroacetyl)phenyl]propionic acid (VI) by heating at 80-100 C.
| 【1】 Muro, T.; Ogawa K.; JP 7703954 . |
| 【2】 Nakanishi, M.; et al.; US 3978071 . |
| 【3】 Hillier, K.; Y-9213. Drugs Fut 1979, 4, 5, 373. |
| 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) | 39470 | ethyl 2-[4-(2-chloroacetyl)phenyl]propanoate | C13H15ClO3 | 详情 | 详情 | |
| (II) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (III) | 39471 | ethyl 2-(4-imidazo[1,2-a]pyridin-2-ylphenyl)propanoate | C18H18N2O2 | 详情 | 详情 | |
| (IV) | 29669 | Pyridine | 110-86-1 | C5H5N | 详情 | 详情 |
| (V) | 32201 | Hydroxylamine | 7803-49-8 | H3NO | 详情 | 详情 |
| (VI) | 39472 | 2-[4-(2-chloroacetyl)phenyl]propionic acid | C11H11ClO3 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(IX)The reaction of methyl 3-hydroxythiophene-2-carboxylate (I) with PCl5 in refluxing CCl4 gives 3-chlorothiophene-2-carboxylic acid (II), which by treatment with NaHSO3 and Cu in basic water at 143 C in a pressure vessel is converted into 3-sulfothiophene-2-carboxylic acid (III). The esterification of (III) with refluxing methanol affords methyl 3-sulfothiophene-2-carboxylate (IV), which by reaction with refluxing SOCl2 yields methyl-3-chlorosulfonylthiophene-2-carboxylate (V). The condensation of (V) with sarcosine ethyl ester (VI) in hot CHCl3 gives methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate (VII), which is cyclized by treatment with sodium methoxide in refluxing methanol affording 3-ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide (VIII). Finally, this compound is condensed with 2-aminopyridine (IX) in refluxing toluene.
| 【1】 Horomatka, O.; Binder, D.; Pfister, R.; Zeller, P. (F. Hoffmann-La Roche AG); Thienothaiazine derivatives. DE 2537070; FR 2303803; JP 51048694; NL 7510057 . |
| 【2】 Serradell, M.N.; Blancafort, P.; Castaner, J.; Tenoxicam. Drugs Fut 1982, 7, 7, 493. |
| 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) | 32134 | Methyl 3-hydroxy-2-thiophenecarboxylate | C6H6O3S | 详情 | 详情 | |
| (II) | 32135 | 3-Chloro-2-thiophenecarboxylic acid | 59337-89-2 | C5H3ClO2S | 详情 | 详情 |
| (III) | 32136 | 3-Sulfothiophene-2-carboxylic acid; 3-Sulfo-2-thiophenecarboxylic acid | C5H4O5S2 | 详情 | 详情 | |
| (IV) | 32137 | Methyl 3-sulfothiophene-2-carboxylate; 2-(Methoxycarbonyl)-3-thiophenesulfonic acid | C6H6O5S2 | 详情 | 详情 | |
| (V) | 17836 | Methyl 3-(chlorosulfonyl)-2-thiophenecarboxylate; Methyl-3-chlorosulfonylthiophene-2-carboxylate | C6H5ClO4S2 | 详情 | 详情 | |
| (VI) | 32138 | Sarcosine ethyl ester; Ethyl 2-(methylamino)acetate | 52605-49-9 | C5H11NO2 | 详情 | 详情 |
| (VII) | 32139 | Methyl-3-(N-ethoxycarbonyl-methyl-N-methylsulfamoyl)thiophene-2-carboxylate; Methyl 3-[[(2-ethoxy-2-oxoethyl)(methyl)amino]sulfonyl]-2-thiophenecarboxylate | C11H15NO6S2 | 详情 | 详情 | |
| (VIII) | 32140 | Ethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-thieno[2,3-e][1,2]thiazine-3-carboxylate; 3-Ethoxycarbonyl-4-hydroxy-2-methyl-2H-thieno-[2,3-e]-1,2-thiazine-1,1-dioxide | C10H11NO5S2 | 详情 | 详情 | |
| (IX) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(XI)This compound can be prepared by two similar ways: 1) The monoacylation of ethylene glycol (I) with chloroacetyl chloride (II) and triethylamine gives 2-hydroxyethyl chloroacetate (III), which is condensed with saccharine (IV) by means of NaOH in ethylene glycol yielding 2-hydroxyethyl 3-oxo-1,2-benzisothiazoline-2-acetate 1,1-dioxide (V). Isomerization of (V) by means of potassium tert-butoxide in DMSO affords2-hydroxyethyl 4-hydroxy-2H-1,2-benzothiazine-3-carboxylate 1,1-dioxide (VI), which is methylated with NaOH and methyl iodide in aqueous ethanol giving the corresponding N-methyl derivative (VII). Hydrolysis of (VII) with NaOH in ethanol - water yields the corresponding free acid (VIII), which is acylated with cinnamoyl chloride (IX) by means of triethylamine in dichloromethane to afford the biscinnamoyl derivative (X). Finally, this compound is treated with 2-aminopyridine (XI) in dichloromethane. 2) The preceding sequence can also be carried out with cyclohexanol (XII) instead of ethylene glycol (I), then producing compounds (XIII), (XIV), (XV) and (XVI), which by hydrolysis affords the free acid (VIII).
| 【1】 Bruzzese, T.; Dell'Acqua, E.; Ottonni, F.; Van den Heuvel, H.H. (SPA (Societa Prodotti Antibiotici)); Process for preparing benzothiazine compds. EP 0146102 . |
| 【2】 Prous, J.; Castaner, J.; CINNOXICAM. Drugs Fut 1990, 15, 2, 119. |
| 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) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (II) | 11296 | 2-Chloroacetyl chloride; Chloroacetic chloride | 79-04-9 | C2H2Cl2O | 详情 | 详情 |
| (III) | 11297 | 2-hydroxyethyl 2-chloroacetate | C4H7ClO3 | 详情 | 详情 | |
| (IV) | 11298 | 1H-1,2-Benzisothiazole-1,1,3(2H)-trione; Saccharin | 81-07-2 | C7H5NO3S | 详情 | 详情 |
| (V) | 11299 | 2-hydroxyethyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C11H11NO6S | 详情 | 详情 | |
| (VI) | 11300 | 2-hydroxyethyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO6S | 详情 | 详情 | |
| (VII) | 11301 | 2-hydroxyethyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C12H13NO6S | 详情 | 详情 | |
| (VIII) | 11302 | 4-Hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid | C10H9NO5S | 详情 | 详情 | |
| (IX) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (X) | 11304 | 2-Methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic (E)-2-phenyl-2-propenoic anhydride | C28H21NO7S | 详情 | 详情 | |
| (XI) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XII) | 11306 | Cyclohexanol | 108-93-0 | C6H12O | 详情 | 详情 |
| (XIII) | 11307 | cyclohexyl 2-chloroacetate | C8H13ClO2 | 详情 | 详情 | |
| (XIV) | 11308 | cyclohexyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C15H17NO5S | 详情 | 详情 | |
| (XV) | 11309 | cyclohexyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C15H17NO5S | 详情 | 详情 | |
| (XVI) | 11310 | cyclohexyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C16H19NO5S | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(IX)The condensation of sodium saccharin (I) with tert-butyl chloroacetate (II) in hot DMF gives the benzoisothiazolin-acetic ester (III), which is rearranged by means of potassium tert-butoxide in THF to yield 4-hydroxy-2H-1,2-benzothiazine-3-carboxylic acid tert-butyl ester 1,1-dioxide (IV). The methylation of (IV) with dimethyl sulfate and NaOH in water affords the 2-methyl derivative (V), which is acylated with cinnamoyl chloride (VI) and TEA in DMF to provide the 4-cinnamoyloxy derivative (VII). The cleavage of the tert-butyl group of (VII) by means of Tms-Cl, NaI and sodium thiosulfate gives the expected free acid (VIII), which is finally condensed with 2-aminopyridine (IX), previous activation with Cl2SO or ethyl chloroformate, and TEA in chloroform or dichloromethane to give rise to the target amide.
| 【1】 Montserrat Vidal, C.; Serra Masia, J. (Laboratorios Salvat SA); 4-Cinnamoyloxy-2-methyl-N-(2-pyridyl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, process for obtaining it and intermediates for its preparation. ES 2053395 . |
| 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) | 33704 | 1,1-Dioxide-1,2-benzisothiazol-3(2H)-one, sodium salt; 1,2-Benzisothiazol-3(2H)-one, 1,1-dioxide, sodium salt (1:1) | 38279-26-4 | C7H4NNaO3S | 详情 | 详情 |
| (II) | 40664 | tert-butyl 2-chloroacetate | 107-59-5 | C6H11ClO2 | 详情 | 详情 |
| (III) | 50875 | tert-butyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | C13H15NO5S | 详情 | 详情 | |
| (IV) | 50876 | tert-butyl 4-hydroxy-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C13H15NO5S | 详情 | 详情 | |
| (V) | 50877 | tert-butyl 4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C14H17NO5S | 详情 | 详情 | |
| (VI) | 11303 | (E)-3-Phenyl-2-propenoyl chloride; 3-Phenyl-2-propenoyl chloride | 102-92-1 | C9H7ClO | 详情 | 详情 |
| (VII) | 50878 | tert-butyl 2-methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylate | C23H23NO6S | 详情 | 详情 | |
| (VIII) | 50879 | 2-methyl-1,1-dioxo-4-[[(E)-3-phenyl-2-propenoyl]oxy]-1,2-dihydro-1lambda(6),2-benzothiazine-3-carboxylic acid | C19H15NO6S | 详情 | 详情 | |
| (IX) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(A)The isomerization of methyl 3-oxo-1,2-benzothiazolin-1,1-dioxide-2-acetate (I) by means of sodium methoxide in DMSO gives methyl 3,4-dihydro-4-oxo-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate (II), which is methylated with methyl iodide and NaOH in methanol giving methyl 3,4-dihydro-2-methyl-4-oxo-2H-1,2-benzothiazine-1,1-dioxide-3-carboxylate (III). Finally, this product is treated with 2-aminopyridine (A) in refluxing xylene.
| 【1】 Arrigoni-Martelli, E.; Castaner, J.; Piroxicam. Drugs Fut 1977, 2, 2, 124. |
| 【2】 Lombardino, J.G.; et al.; Potent anti-inflammatory N-heterocyclic 3-carboxamides of 4-hydroxy-2-methyl-2H-1,2-benzothiazine 1,1-dioxide. J Med Chem 1973, 16, 5, 493. |
| 【3】 Lombardino, J.G.; Wiseman, E.H.; Sudoxicam and related N.heterocyclic carboxamides of 4-hydroxy-2-methyl-2H-1,2-benzothiazine 1,1-dioxide, potent non steroidal anti-inflammatory agents. J Med Chem 1972, 15, 8, 848. |
| 【4】 Lombardino, J.G. (Pfizer Inc.); Benzothiazine dioxides. DE 1943265; FR 2016455; GB 1257180; US 3591584 . |
| 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) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (I) | 40062 | methyl 2-(1,1,3-trioxo-1,3-dihydro-2H-1,2-benzisothiazol-2-yl)acetate | 6639-62-9 | C10H9NO5S | 详情 | 详情 |
| (II) | 40063 | methyl 1,1,4-trioxo-1,2,3,4-tetrahydro-1lambda(6),2-benzothiazine-3-carboxylate | C10H9NO5S | 详情 | 详情 | |
| (III) | 40064 | methyl 2-methyl-1,1,4-trioxo-1,2,3,4-tetrahydro-1lambda(6),2-benzothiazine-3-carboxylate | C11H11NO5S | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(IX)The sulfonation of 2,5-dichlorothiophene (I) with ClSO3H -SOCl2 gives 2,5-dichlorothiophene-3-sulfonic acid chloride (II), which by reaction with methylamine in CHCl3 yields the corresponding methylamide (III). The carboxylation of (III) with butyllithium and CO2 in ether affords 5-chloro-3-(N-methylsulfamoyl)thiophene-2-carboxylic acid (IV), which is esterified with PCl5 and methanol to the methyl ester (V). The condensation of (V) with methyl iodoacetate (VI) by means of NaH in DMF gives 5-chloro-3-[N-(methoxycarbonylmethyl)-N-methylsulfamoyl]thiophene-2-carboxylic acid methyl ester (VII), which is cyclized with sodium methoxide in methanol yielding 6-chloro-4-hydroxy-2-methyl-2H-thieno[2,3-e]-1,2-thiazine-3-carboxylic acid methyl ester 1,1-dioxide (VIII). Finally, this compound is treated with 2-aminopyridine (IX) in refluxing xylene.
| 【1】 Pfister, R.; Zeller, P.; Binder, D.; Hromatka, O. (F. Hoffmann-La Roche AG); Thiazine derivs. DE 2838851 . |
| 【2】 Castaner, J.; Prous, J.; Lornoxicam. Drugs Fut 1992, 17, 8, 683. |
| 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) | 11339 | 2,5-Dichlorothiophene | 3172-52-9 | C4H2Cl2S | 详情 | 详情 |
| (II) | 11340 | 2,5-Dichloro-3-thiophenesulfonyl chloride; 2,5-Dichlorothiophene-3-sulphonyl chloride | 56946-83-9 | C4HCl3O2S2 | 详情 | 详情 |
| (III) | 11341 | 2,5-Dichloro-N-methyl-3-thiophenesulfonamide | C5H5Cl2NO2S2 | 详情 | 详情 | |
| (IV) | 11342 | 5-Chloro-3-[(methylamino)sulfonyl]-2-thiophenecarboxylic acid | C6H6ClNO4S2 | 详情 | 详情 | |
| (V) | 11343 | methyl 5-chloro-3-[(methylamino)sulfonyl]-2-thiophenecarboxylate | C7H8ClNO4S2 | 详情 | 详情 | |
| (VI) | 11344 | methyl 2-iodoacetate | C3H5IO2 | 详情 | 详情 | |
| (VII) | 11345 | methyl 5-chloro-3-[[(2-methoxy-2-oxoethyl)(methyl)amino]sulfonyl]-2-thiophenecarboxylate | C10H12ClNO6S2 | 详情 | 详情 | |
| (VIII) | 11346 | methyl 6-chloro-4-hydroxy-2-methyl-1,1-dioxo-1,2-dihydro-2H-thieno[2,3-e][1,2]thiazine-3-carboxylate | C9H8ClNO5S2 | 详情 | 详情 | |
| (IX) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
合成路线7
该中间体在本合成路线中的序号：(I)The intermediate 3-(2-chloroethyl)-2-methyl-6, 7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one (V) has been obtained as follows: The cyclization of 2-aminopyridine (I) with 3-acetyltetrahydrofuran-2-one (II) by means of polyphosphoric acid (PPA) at 160 C gives 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (III), which is hydrogenated with H2 over Pd/C in ethanol/water to yield the tetrahydro derivative (IV). Finally, the OH group of (IV) is treated with SOCl2 in dichloromethane to afford the target 2-chloroethyl intermediate (V).
| 【1】 Dalmases Barjoan, P.; Bosch Rovira, A.; Marquillas Olondriz, F.; Caldero Ges, J.M. (Vita-Invest, SA); Process for the preparation of 3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)piperidino]ethyl]-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidine-4-one. ES 2050069 . |
| 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) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (II) | 24709 | 3-acetyldihydro-2(3H)-furanone | 517-23-7 | C6H8O3 | 详情 | 详情 |
| (III) | 50866 | 3-(2-hydroxyethyl)-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one | C11H12N2O2 | 详情 | 详情 | |
| (IV) | 50867 | 3-(2-hydroxyethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | C11H16N2O2 | 详情 | 详情 | |
| (V) | 23044 | 3-(2-chloroethyl)-2-methyl-6,7,8,9-tetrahydro-4H-pyrido[1,2-a]pyrimidin-4-one | 63234-80-0 | C11H15ClN2O | 详情 | 详情 |
合成路线8
该中间体在本合成路线中的序号：(I)The cyclization of 2-aminopyridine (I) with ethyl 4-bromoacetoacetate (II) by means of NaHCO3 in hot dioxane gives the imidazopyridine (III), which is hydrolyzed at the ester function with KOH in ethanol yielding the free acid (IV) . Finally, the treatment of acid (IV) with phosphorous acid and PCl3 in chlorobenzene at 115 C, followed by hydrolysis in boiling 6N HCl yielded the target bisphosphonate.
| 【1】 Atsumi, T.; et al.; JP 7688965 . |
| 【2】 Takeuchi, M.; Sakamoto, S.; Kawamuki, K.; Kurihara, H.; Nakahara, H.; Isomura, Y.; Studies on novel bone resorption inhibitors. II. Synthesis and pharmacological activities of fused aza-heteroarylbisphosphonate derivatives. Chem Pharm Bull 1998, 46, 11, 1703. |
| 【3】 Isomura, Y.; Takeuchi, M.; Abe, T. (Yamanouchi Pharmaceutical Co., Ltd.); Heterocyclic biphosphonic acid derivs.. EP 0354806; US 4990503; US 5039669 . |
| 【4】 Casagrande, C.; et al.; Synthesis and pharmacological activity of imidazo-[1,2-a]pyridine-2-acetic and -2,3-dicarboxylic acid and related compounds. Farmaco 1968, 23, 12, 1141. |
| 【5】 Ishii, M.; Takaoka, K. (Yamanouchi Pharmaceutical Co., Ltd.); Novel preparation method of heterocyclic bis(phosphonic acid) derivs.. JP 1999269184 . |
| 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) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (II) | 36651 | Ethyl (bromoacetyl)acetate;ethyl 4-bromo-3-oxobutanoate | 13176-46-0 | C6H9BrO3 | 详情 | 详情 |
| (III) | 36652 | ethyl 2-imidazo[1,2-a]pyridin-3-ylacetate | C11H12N2O2 | 详情 | 详情 | |
| (IV) | 36653 | 2-imidazo[1,2-a]pyridin-3-ylacetic acid | C9H8N2O2 | 详情 | 详情 |
合成路线9
该中间体在本合成路线中的序号：(III)1,3-Cyclohexanedione (I) was brominated in cold water, and the resulting 2-bromo-1,3-cyclohexanedione (II) was condensed with 2-aminopyridine (III) in boiling EtOH to afford the dihydropyridobenzimidazolone (IV). Further bromination in concentrated HBr at 70 C gave bromoketone (V), which was finally condensed with thiourea (VI) in EtOH to yield the target tetracyclic compound.
| 【1】 Yoo, H.Y.; Chung, K.J.; Chai, J.P.; Chang, M.S.; Kim, S.G.; Choi, W.S.; Kim, Y.H.; Chun, J.K.; Chung, Y.K.; Kim, Y.H.; Paek, J.H.; Seo, K.H.; Kang, D.P. (Yung-Jin Pharmaceutical Co., Ltd.); Heterocycle-fused thiazole derivs.. EP 0843681; JP 1998508877; WO 9703076 . |
| 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) | 11244 | 1,3-Cyclohexanedione | 504-02-9 | C6H8O2 | 详情 | 详情 |
| (II) | 21027 | 2-bromo-1,3-cyclohexanedione | C6H7BrO2 | 详情 | 详情 | |
| (III) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (IV) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (IV) | 21029 | 7,8-dihydropyrido[1,2-a]benzimidazol-9(6H)-one | C11H10N2O | 详情 | 详情 | |
| (V) | 21030 | 8-bromo-7,8-dihydropyrido[1,2-a]benzimidazol-9(6H)-one | C11H9BrN2O | 详情 | 详情 |
合成路线10
该中间体在本合成路线中的序号：(XIII)N-Boc-L-isoleucine (XII) was coupled to 2-aminopyridine (XIII) via activation with carbonyldiimidazole to give the corresponding amide (XIV). Subsequent acidic cleavage of the Boc protecting group of (XIV) afforded the amino amide (XV), which was further coupled with the intermediate acid (XI), yielding the dipeptide derivative (XVI). The tetrahydropyranyl group of (XVI) was finally removed by hydrolysis with 80% acetic acid.
| 【1】 Chan, J.H.; Bubacz, D.G.; Andersen, M.W.; McDougald, D.L.; Stanford, J.B.; Andrews, R.C.; Gaul, M.D.; Rabinowitz, M.H.; Musso, D.L.; Cowan, D.J.; Wiethe, R.W. (GlaxoSmithKline plc); Reverse hydroxamate derivs. as metalloprotease inhibitors. EP 1019386; JP 2001513767; WO 9838179 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XI) | 52110 | (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutyl-4-methylpentanoic acid | C16H29NO5 | 详情 | 详情 | |
| (XII) | 30009 | (2S,3S)-2-[(tert-butoxycarbonyl)amino]-3-methylpentanoic acid | 13139-16-7 | C11H21NO4 | 详情 | 详情 |
| (XIII) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XIV) | 52111 | tert-butyl (1S,2S)-2-methyl-1-[(2-pyridinylamino)carbonyl]butylcarbamate | C16H25N3O3 | 详情 | 详情 | |
| (XV) | 52112 | (2S,3S)-2-amino-3-methyl-N-(2-pyridinyl)pentanamide | C11H17N3O | 详情 | 详情 | |
| (XVI) | 52113 | (2R,3S)-3-[formyl(tetrahydro-2H-pyran-2-yloxy)amino]-2-isobutyl-4-methyl-N-[(1S,2S)-2-methyl-1-[(2-pyridinylamino)carbonyl]butyl]pentanamide | C27H44N4O5 | 详情 | 详情 |
合成路线11
该中间体在本合成路线中的序号：(XV)Silylation of carboxylic acid (I) by means of tert-butyldimethylsilyl chloride and imidazole in DMF yields derivative (II), which then reacts with allyl glyoxylate (III) in toluene to afford (IV). Treatment of (IV) with SOCl2 and pyridine in THF provides chloro azetidinone (V), which is then converted into (VI) by means of PPh3 and pyridine or 2,6-lutidine in DMF. Ylide acid (VI) is treated with 2-pyridyl chlorothioformate (VII) and Et3N in CH2Cl2 to give derivative (VIII), which is then condensed with the Grignard reagent (XI) and desilylated by means of H2SO4 in MeOH to provide ketophosphorane (XII). Cyclization of (XII) via an internal Wittig reaction by treatment with refluxing p-xylene gives carbapenem (XIII), which is then converted into the corresponding iodide (XIV) via mesylation with MsCl by means of TEA in dichloromethane followed by Finkelstein reaction with NaI in acetone. Reaction of (XIV) with 2-aminopyridine (XV) in acetonitrile provides pyridinium salt (XVI), whose allyl protecting groups are removed by treatment with Pd(PPh3)4, PPh3 in CH2Cl2/EtOAc, followed by 2-ethylhexanoic acid and potassium 2-ethylhexanoate in EtOAc.
| 【1】 Guthikonda, R.N.; et al.; Structure-activity relationships in the 2-arylcarbapenem series: Synthesis of 1-methyl-2-arylcarbapenems. J Med Chem 1987, 30, 5, 871. |
| 【2】 Greenlee, M.L.; et al.; 2-Naphthylcarbapenems: Broad spectrum antibiotics with enhanced potency against MRSA. Bioorg Med Chem Lett 1999, 9, 19, 2893. |
| 【3】 DiNinno, F.P.; Greenlee, M.L. (Merck & Co., Inc.); 2-Naphthyl-carbapenem antibacterial agents. EP 0466254; JP 1992253980; US 5032587 . |
| 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) | 42552 | 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]acetic acid | C11H15NO6 | 详情 | 详情 | |
| (II) | 42553 | tert-butyl(dimethyl)silyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-4-oxoazetidinyl]acetate | C17H29NO6Si | 详情 | 详情 | |
| (III) | 30139 | allyl 2-oxoacetate | C5H6O3 | 详情 | 详情 | |
| (IV) | 42554 | allyl 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-(2-[[tert-butyl(dimethyl)silyl]oxy]-2-oxoethyl)-4-oxoazetidinyl]-2-hydroxyacetate | C22H35NO9Si | 详情 | 详情 | |
| (V) | 42555 | 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-1-[2-(allyloxy)-1-chloro-2-oxoethyl]-4-oxoazetidinyl]acetic acid | C16H20ClNO8 | 详情 | 详情 | |
| (VI) | 42556 | 2-[(2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-1-[2-(allyloxy)-2-oxo-1-(triphenylphosphoranylidene)ethyl]-4-oxoazetidinyl]acetic acid | C34H34NO8P | 详情 | 详情 | |
| (VII) | 42557 | 2-[(chlorocarbonyl)sulfanyl]pyridine | C6H4ClNOS | 详情 | 详情 | |
| (VIII) | 42558 | allyl 2-[(3S,4R)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-oxo-4-[2-oxo-2-(2-pyridinylsulfanyl)ethyl]azetidinyl]-2-(triphenylphosphoranylidene)acetate | C39H37N2O7PS | 详情 | 详情 | |
| (XI) | 42559 | bromo[6-([[tert-butyl(dimethyl)silyl]oxy]methyl)-2-naphthyl]magnesium | C17H23BrMgOSi | 详情 | 详情 | |
| (XII) | 42560 | allyl 2-((2R,3S)-3-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-2-[2-[6-(hydroxymethyl)-2-naphthyl]-2-oxoethyl]-4-oxoazetidinyl)-2-(triphenylphosphoranylidene)acetate | C45H42NO8P | 详情 | 详情 | |
| (XIII) | 42561 | allyl (5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[6-(hydroxymethyl)-2-naphthyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H27NO7 | 详情 | 详情 | |
| (XIV) | 42562 | allyl (5R,6S)-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-3-[6-(iodomethyl)-2-naphthyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate | C27H26INO6 | 详情 | 详情 | |
| (XV) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (XVI) | 42563 | 1-([6-[(5R,6S)-2-[(allyloxy)carbonyl]-6-((1R)-1-[[(allyloxy)carbonyl]oxy]ethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-en-3-yl]-2-naphthyl]methyl)-2-aminopyridinium iodide | C32H32IN3O6 | 详情 | 详情 |
合成路线12
该中间体在本合成路线中的序号：(VIII)Reduction of N-(benzyloxycarbonyl)-4-hydroxyproline (I) with boranedimethylsulfide complex in THF provided the corresponding diol, which was selectively protected at the primary hydroxyl group as the tert-butyldimethylsilyl ether (II). Swern oxidation of the remaining secondary alcohol of (II) afforded ketone (III). This was converted to alkene (IV) by Wittig olefination with methylene triphenylphosphorane. The 1,3-dipolar cycloaddition of (IV) with the nitrile oxide generated from chlorooxime (V) and Et3N furnished spirocycle (VI) as a diastereomeric mixture. Deprotection of the silyl ether of (VI) by treatment with tetrabutylammonium fluoride, followed by Swern oxidation of the resulting alcohol provided aldehyde (VII). Reductive amination of (VII) with 2-aminopyridine (VIII) gave amine (IX), which was protected as the tert-butyl carbamate (X) using Boc2O.
| 【1】 Jadhav, P.K.; Smallheer, J.M. (DuPont Pharmaceuticals Co.); Spirocycle integrin inhibitors. EP 0888344; US 5760029; WO 9733887 . |
| 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) | 36579 | (2S,4S)-1-[(benzyloxy)carbonyl]-4-hydroxy-2-pyrrolidinecarboxylic acid | 13504-85-3 | C13H15NO5 | 详情 | 详情 |
| (II) | 36580 | benzyl (2S,4S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-hydroxy-1-pyrrolidinecarboxylate | C19H31NO4Si | 详情 | 详情 | |
| (III) | 36581 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-oxo-1-pyrrolidinecarboxylate | C19H29NO4Si | 详情 | 详情 | |
| (IV) | 36582 | benzyl (2S)-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4-methylene-1-pyrrolidinecarboxylate | C20H31NO3Si | 详情 | 详情 | |
| (V) | 30424 | 2-ethoxy-N-hydroxy-2-oxoethanimidoyl chloride | 14337-43-0 | C4H6ClNO3 | 详情 | 详情 |
| (VI) | 36583 | 7-benzyl 3-ethyl 8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C24H36N2O6Si | 详情 | 详情 | |
| (VII) | 36584 | 7-benzyl 3-ethyl 8-formyl-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C18H20N2O6 | 详情 | 详情 | |
| (VIII) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (IX) | 36585 | 7-benzyl 3-ethyl 8-[(2-pyridinylamino)methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C23H26N4O5 | 详情 | 详情 | |
| (X) | 36586 | 7-benzyl 3-ethyl 8-[[(tert-butoxycarbonyl)(2-pyridinyl)amino]methyl]-1-oxa-2,7-diazaspiro[4.4]non-2-ene-3,7-dicarboxylate | C28H34N4O7 | 详情 | 详情 |
合成路线13
该中间体在本合成路线中的序号：(VI)The Friedel-Crafts condensation of 2-[4-(methylsulfanyl)phenyl]acetyl chloride (I) with toluene (II) gives 1-(3-methylphenyl)-2-[4-(methylsulfanyl)phenyl]ethanone (III), which is oxidized with MCPBA to yield the corresponding sulfonyl compound (IV). The bromination of (IV) with Br2 affords the bromoethanone (V), which is finally cyclized with pyridine-2-amine (VI) to provide the target imidazopyridine compound.
| 【1】 Farrerons, C.; et al.; Diarylimidazo[1,2-a]pyridine derivatives as a new class of selective COX-2 inhibitors. 11th RSC-SCI Med Chem Symp (Sept 9 2001, Cambridge) 2001, Abst P2. |
| 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) | 25755 | 2-[4-(methylsulfanyl)phenyl]acetyl chloride | C9H9ClOS | 详情 | 详情 | |
| (II) | 12890 | Toluene | 108-88-3 | C7H8 | 详情 | 详情 |
| (III) | 55386 | 1-(3-methylphenyl)-2-[4-(methylsulfanyl)phenyl]-1-ethanone | C16H16OS | 详情 | 详情 | |
| (IV) | 55387 | 1-(3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone | C16H16O3S | 详情 | 详情 | |
| (V) | 55388 | 2-bromo-1-(3-methylphenyl)-2-[4-(methylsulfonyl)phenyl]-1-ethanone | C16H15BrO3S | 详情 | 详情 | |
| (VI) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
合成路线14
该中间体在本合成路线中的序号：(IV)The cyclization of 3,4-diaminobenzoic acid (I) with 4-nitrobenzaldehyde (II) in nitrobenzene at 160 C gives 2-(4-nitrophenyl)-1H-benzimidazole-5-carboxylic acid (III), which is condensed with 2-aminopyridine (IV) by means of CDI in DMF to yield the corresponding amide (V). The reduction of the nitro group of (V) with H2 over Pd/C in methanol affords 2-(4-aminophenyl)-N-(2-pyridinyl)-1H-benzimidazole-5-carboxamide (VI). Finally, this compound is condensed with adamantane-1-carboxylic acid (VII) to provide the target diamide.
| 【1】 Sircar, J.C.; Richards, M.L.; Major, M.W. (Avanir Pharmaceuticals); Benzimidazole cpds. for modulating IgE and inhibiting cellular proliferation. EP 1368028; WO 0272090 . |
| 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) | 62528 | C7H8N2O2 | 详情 | 详情 | ||
| (II) | 18184 | 4-Nitrobenzaldehyde | 555-16-8 | C7H5NO3 | 详情 | 详情 |
| (III) | 64591 | 2-(4-nitrophenyl)-1H-benzimidazole-5-carboxylic acid | C14H9N3O4 | 详情 | 详情 | |
| (IV) | 11305 | 2-Pyridinamine; 2-Pyridinylamine; 2-Aminopyridine | 504-29-0 | C5H6N2 | 详情 | 详情 |
| (V) | 64592 | 2-(4-nitrophenyl)-N-(2-pyridinyl)-1H-benzimidazole-5-carboxamide | C19H13N5O3 | 详情 | 详情 | |
| (VI) | 64593 | 2-(4-aminophenyl)-N-(2-pyridinyl)-1H-benzimidazole-5-carboxamide | C19H15N5O | 详情 | 详情 | |
| (VII) | 64594 | tricyclo[3.3.1.1~3,7~]decane-1-carbonyl chloride | C11H15ClO | 详情 | 详情 |