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【结 构 式】 
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【分子编号】25433 【品名】1,1-dimethoxyacetone 【CA登记号】6342-56-9 |
【 分 子 式 】C5H10O3 【 分 子 量 】118.1326 【元素组成】C 50.84% H 8.53% O 40.63% |
合成路线1
该中间体在本合成路线中的序号：(II)The cyclization of 2-hydroxyacetophenone (I) with pyruvic aldehyde dimethylacetal (II) by means of pyridine in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-3,4-dihydro-2H-1-benzopyran-4-one (III), which is nitrated with ammonium nitrate and TFA yielding the 6-nitro derivative (IV). The reduction of (IV) with NaBH4 in methanol affords the benzopyranol (V), which is treated with MsCl and DIEA to provide the mesylate (VI). The reaction of (VI) with DBU in refluxing toluene gives 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-1-benzopyran (VII), which is treated with NBS in DMSO to yield the bromohydrin (VIII). Epoxidation of (VIII) with NaOH in dioxane/water affords the epoxide (IX), which is treated with 2-pyrrolidinone (X) and potassium tert-butoxide in tert-butanol to furnish 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-3,4-dihydro-2H-1-benzpyran-4-yl]pyrrolidin-2-one (XI). The trans-acetalization of (XI) with ethylene glycol (XII) and TsOH in refluxing toluene gives the 1,3-dioxolanyl derivative (XIII), which is finally dehydrated to the target compound with NaOH in refluxing dioxane.
| 【1】 Yoo, S.-E.; Yi, K.Y.; Jeong, N.C.; Suh, J.H.; Kim, S.-J.; Shin, H.-S.; Lee, B.H.; Jung, K.S. (Korea Research Institute of Chemical Technology); Spiro-benzopyran derivs. and useful for treating asthma and hypertension. EP 0514935; US 5300511; US 5493029 . |
| 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) | 29654 | 2-hydroxyacetophenone; 1-(2-hydroxyphenyl)-1-ethanone | 118-93-4 | C8H8O2 | 详情 | 详情 |
| (II) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (III) | 38906 | 2-(dimethoxymethyl)-2-methyl-2,3-dihydro-4H-chromen-4-one | C13H16O4 | 详情 | 详情 | |
| (IV) | 38907 | 2-(dimethoxymethyl)-2-methyl-6-nitro-2,3-dihydro-4H-chromen-4-one | C13H15NO6 | 详情 | 详情 | |
| (V) | 38908 | 2-(dimethoxymethyl)-2-methyl-6-nitro-4-chromanol | C13H17NO6 | 详情 | 详情 | |
| (VI) | 38909 | 2-(dimethoxymethyl)-2-methyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-nitrochromane; methoxy(2-methyl-4-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-nitro-3,4-dihydro-2H-chromen-2-yl)methyl methyl ether | C16H23NO6S | 详情 | 详情 | |
| (VII) | 38910 | methoxy(2-methyl-6-nitro-2H-chromen-2-yl)methyl methyl ether; 2-(dimethoxymethyl)-2-methyl-6-nitro-2H-chromene | C13H15NO5 | 详情 | 详情 | |
| (VIII) | 38911 | 3-bromo-2-(dimethoxymethyl)-2-methyl-6-nitro-4-chromanol | C13H16BrNO6 | 详情 | 详情 | |
| (IX) | 38912 | methoxy(2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromen-2-yl)methyl methyl ether; 2-(dimethoxymethyl)-2-methyl-6-nitro-1a,7b-dihydro-2H-oxireno[2,3-c]chromene | C13H15NO6 | 详情 | 详情 | |
| (X) | 27397 | 2-Pyrrolidinone | 616-45-5 | C4H7NO | 详情 | 详情 |
| (XI) | 38913 | 1-[2-(dimethoxymethyl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]-2-pyrrolidinone | C17H22N2O7 | 详情 | 详情 | |
| (XII) | 11295 | Polyethylene glycol;1,2-Ethanediol;Monoethylene glycol; Ethylene glycol | 107-21-1 | C2H6O2 | 详情 | 详情 |
| (XIII) | 38914 | 1-[2-(1,3-dioxolan-2-yl)-3-hydroxy-2-methyl-6-nitro-3,4-dihydro-2H-chromen-4-yl]-2-pyrrolidinone | C17H20N2O7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(V)Condensation of pyruvic aldehyde dimethyl acetal (V) with dimethylformamide dimethyl acetal produced enamino ketone (VI). Cyclization of (VI) with thiourea (VII), followed by methylation with iodomethane furnished the (methylsulfanyl)pyrimidine (VIII). Acid hydrolysis of the dimethyl acetal gave rise to aldehyde (IX). Cyclohexanedione monoketal (X) was converted to oxime (XI) and then hydrogenated to give amine (XII). This was condensed with aldehyde (IX) yielding imine (XIII). Reaction of imine (XIII) with sulfonyl isocyanide (IV) gave rise to imidazole (XIV). The methylsulfanyl group of (XIV) was then oxidized to sulfone (XV) employing oxone®. Further displacement of the methylsulfonyl group of (XV) with NaOMe produced the methoxy pyrimidine (XVI). After ketal (XVI) hydrolysis, reduction of the resulting ketone (XVII) with NaBH4 furnished the title alcohol.
| 【1】 Adams, J.L.; Garigipati, R.S.; Sorenson, M.E. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0889726; JP 2000503304; WO 9725048 . |
| 【2】 Adams, J.L.; Garigipati, R.S. (SmithKline Beecham plc); Novel cycloalkyl substd. imidazoles. EP 0883402; WO 9725047 . |
| 【3】 Boehm, J.C.; Garigipati, R.S.; Adams, J.L. (SmithKline Beecham Corp.); Novel cycloalkyl substd. imidazoles. EP 1019396; WO 9901452 . |
| 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) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 | |
| (V) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (VI) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (VII) | 10180 | Thiourea | 62-56-6 | CH4N2S | 详情 | 详情 |
| (VIII) | 41422 | methoxy[2-(methylsulfanyl)-4-pyrimidinyl]methyl methyl ether; 4-(dimethoxymethyl)-2-(methylsulfanyl)pyrimidine | C8H12N2O2S | 详情 | 详情 | |
| (IX) | 41423 | 2-(methylsulfanyl)-4-pyrimidinecarbaldehyde | C6H6N2OS | 详情 | 详情 | |
| (X) | 11377 | 1,4-Dioxaspiro[4.5]decan-8-one | 4746-97-8 | C8H12O3 | 详情 | 详情 |
| (XI) | 41424 | 1,4-dioxaspiro[4.5]decan-8-one oxime | C8H13NO3 | 详情 | 详情 | |
| (XII) | 41425 | 1,4-dioxaspiro[4.5]dec-8-ylamine; 1,4-dioxaspiro[4.5]decan-8-amine | C8H15NO2 | 详情 | 详情 | |
| (XIII) | 41426 | N-(1,4-dioxaspiro[4.5]dec-8-yl)-N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]amine; N-[(Z)-[2-(methylsulfanyl)-4-pyrimidinyl]methylidene]-1,4-dioxaspiro[4.5]decan-8-amine | C14H19N3O2S | 详情 | 详情 | |
| (XIV) | 41427 | 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfanyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfide | C22H23FN4O2S | 详情 | 详情 | |
| (XV) | 41428 | 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-(methylsulfonyl)pyrimidine; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl sulfone | C22H23FN4O4S | 详情 | 详情 | |
| (XVI) | 41429 | 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-pyrimidinyl methyl ether; 4-[1-(1,4-dioxaspiro[4.5]dec-8-yl)-4-(4-fluorophenyl)-1H-imidazol-5-yl]-2-methoxypyrimidine | C22H23FN4O3 | 详情 | 详情 | |
| (XVII) | 41430 | 4-[4-(4-fluorophenyl)-5-(2-methoxy-4-pyrimidinyl)-1H-imidazol-1-yl]cyclohexanone | C20H19FN4O2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimethyl acetal (II) afforded ketoenamine (III), which was condensed with N-methyl guanidine (IV) to give pyrimidine (V). Acid hydrolysis of the acetal function of (V) yielded pyrimidine carboxaldehyde (VI), which was converted to the imine (VIII) by treatment with 1-Boc-4-aminopiperidine (VII). Isonitrile (XII) was prepared by condensation of 4-fluorobenzaldehyde (IX) with formamide and p-thiocresol (X), followed by dehydration of the resulting formamide (XI) by means of POCl3 and Et3N. Reaction of isonitrile (XII) with imine (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) produced imidazole (XIII). Finally, acid deprotection of the Boc group of (XIII) provided the title compound.
| 【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 . |
| 【2】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 【3】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 . |
| 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) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (II) | 11984 | N-(Dimethoxymethyl)-N,N-dimethylamine;dimethylformamide dimethylacetal;1,1-dimethoxy-N,N-dimethylmethanamine； Dimethoxy-N,N-dimethylmethanamine; N,N-Dimethylformamide dimethyl acetal | 4637-24-5 | C5H13NO2 | 详情 | 详情 |
| (III) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (IV) | 28411 | N-Methylguanidine | 598-12-9 | C2H7N3 | 详情 | 详情 |
| (V) | 28412 | 4-(dimethoxymethyl)-N-methyl-2-pyrimidinamine | C8H13N3O2 | 详情 | 详情 | |
| (VI) | 28413 | 2-(methylamino)-4-pyrimidinecarbaldehyde | C6H7N3O | 详情 | 详情 | |
| (VII) | 28414 | 4-Amino-1-N-Boc-piperidine; tert-butyl 4-amino-1-piperidinecarboxylate; N-Boc-4-aminopiperidine | 87120-72-7 | C10H20N2O2 | 详情 | 详情 |
| (VIII) | 28415 | tert-butyl 4-([(Z)-[2-(methylamino)-4-pyrimidinyl]methylidene]amino)-1-piperidinecarboxylate | C16H25N5O2 | 详情 | 详情 | |
| (IX) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (X) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (XI) | 25438 | (4-fluorophenyl)[(4-methylphenyl)sulfanyl]methylformamide | C15H14FNOS | 详情 | 详情 | |
| (XII) | 28416 | 4-Fluoro-alpha-(4-methylphenylsulfanyl)benzyl isocyanide | C15H12FNS | 详情 | 详情 | |
| (XIII) | 28417 | tert-butyl 4-[4-(4-fluorophenyl)-5-[2-(methylamino)-4-pyrimidinyl]-1H-imidazol-1-yl]-1-piperidinecarboxylate | C24H29FN6O2 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(VI)In the original procedure, pyruvic aldehyde dimethyl acetal (VI) was condensed with N,N-dimethylformamide dimethyl acetal to give enaminoketone (VII). Subsequent reaction of (VII) with guanidine (VIII) provided 2-aminopyrimidine-4-carboxaldehyde dimethyl acetal (IX), which was hydrolyzed to the corresponding aldehyde (X) with 3 N HCl at 48 C. This was condensed with 4-amino-2,2,6,6-tetramethylpiperidine (XI) to produce imine (XII). Finally, reaction between imine (XII) and tosyl isonitrile (V) in the presence of K2CO3 generated the target imidazole.
| 【1】 Adams, J.L.; Gallagher, T.F.; Garigipati, R.S.; Boehm, J.C.; Sisko, J.; Peng, Z.-Q.; Lee, J.C.-L. (SmithKline Beecham plc); Certain 1,4,5-tri-substd. imidazole cpds. useful as cytokine. EP 0809499; JP 1998512555; US 5593992; WO 9621452 . |
| 【2】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 . |
| 【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (V) | 25595 | 4-Fluoro-alpha-(4-methylphenylsulfonyl)benzyl isocyanide | C15H12FNO2S | 详情 | 详情 | |
| (VI) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (VII) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (VIII) | 14790 | Guanidine | 113-00-8 | CH5N3 | 详情 | 详情 |
| (IX) | 25435 | 4-(dimethoxymethyl)-2-pyrimidinylamine | C7H11N3O2 | 详情 | 详情 | |
| (X) | 25436 | 2-amino-4-pyrimidinecarbaldehyde | C5H5N3O | 详情 | 详情 | |
| (XI) | 25596 | 2,2,6,6-tetramethyl-4-piperidinamine | 36768-62-4 | C9H20N2 | 详情 | 详情 |
| (XII) | 25597 | 4-[[(2,2,6,6-tetramethyl-4-piperidinyl)imino]methyl]-2-pyrimidinamine | C14H23N5 | 详情 | 详情 |
合成路线5
该中间体在本合成路线中的序号：(I)Condensation of pyruvic aldehyde dimethyl acetal (I) with dimethylformamide dimehylacetal provided ketoenamine (II). This was cyclized with guanidine to afford aminopyrimidine (III). Then, hydrolysis of the dimethyl acetal of (III) with 3 M HCl yielded aldehyde (IV). 4-Fluorobenzaldehyde (V) was condensed with thiocresol (VI) and formamide in refluxing toluene to give 4-fluorophenyl-tolylthiomethyl formamide (VII), which was dehydrated to isocyanide (VIII) with POCl3 and Et3N at -30 C. Finally, imine (X), (obtained from pyrimidine aldehyde (IV) and 4-(3-aminopropyl)morpholine (IX)), was condensed with isocyanide (VIII) in the presence of 1,5,7-triazabicyclo[4.4.0]dec-5-ene to furnish the title imidazole.
| 【1】 Adams, J.L.; Boehm, J.C.; Kassis, S.; Gorycki, P.D.; Webb, E.F.; Hall, R.; Sorenson, M.; Lee, J.C.; Ayrton, A.; Griswold, D.E.; Gallagher, T.F.; Pyrimidinylimidazole inhibitors of CSBP/p38 kinase demonstrating decreased inhibition of hepatic cytochrome P450 enzymes. Bioorg Med Chem Lett 1998, 8, 22, 3111. |
| 【2】 Adams, J.L.; Sheldrake, P.W.; Gallagher, T.F.; Garigipati, R.S.; Bender, P.E.; Boehm, J.C. (SmithKline Beecham plc); Tri-substd. imidazoles having multiple therapeutic properties. EP 0708768; WO 9502591 . |
| 【3】 Garigipati, R.S.; Adams, J.L.; Boehm, J.C. (SmithKline Beecham Corp.); Pyridyl imidazole cpds. and compsns.. US 5670527 . |
| 【4】 Adams, J.L.; Boehm, J.C.; Imidazole cpds., use and process of making. US 5593991 . |
| 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) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (II) | 25434 | (E)-4-(dimethylamino)-1,1-dimethoxy-3-buten-2-one | C8H15NO3 | 详情 | 详情 | |
| (III) | 25435 | 4-(dimethoxymethyl)-2-pyrimidinylamine | C7H11N3O2 | 详情 | 详情 | |
| (IV) | 25436 | 2-amino-4-pyrimidinecarbaldehyde | C5H5N3O | 详情 | 详情 | |
| (V) | 12337 | 4-fluorobenzaldehyde | 459-57-4 | C7H5FO | 详情 | 详情 |
| (VI) | 25437 | 4-methylphenylhydrosulfide | 106-45-6 | C7H8S | 详情 | 详情 |
| (VII) | 25438 | (4-fluorophenyl)[(4-methylphenyl)sulfanyl]methylformamide | C15H14FNOS | 详情 | 详情 | |
| (VIII) | 25439 | 4-Fluoro-alpha-(4-methylphenylsulfanyl)benzyl isocyanide | C15H12FNS | 详情 | 详情 | |
| (IX) | 25440 | 3-(4-morpholinyl)-1-propanamine | 123-00-2 | C7H16N2O | 详情 | 详情 |
| (X) | 25441 | 4-([[3-(4-morpholinyl)propyl]imino]methyl)-2-pyrimidinamine | C12H19N5O | 详情 | 详情 |
合成路线6
该中间体在本合成路线中的序号：(XXIII)Pyrrolidinone (X) was alkylated with ethyl bromoacetate to afford ester (XVII), which was further hydrolyzed to acid (XVIII). Its coupling with amino ester (XIX) in the presence of EDC and HOBt furnished amide (XX). The N-Boc group of (XX) was then cleaved with HCl in EtOAc to provide amine (XXI) Aldehyde (XXVI) was obtained by condensation of 2-aminopyridine-3-carboxaldehyde (XXII) with pyruvaldehyde dimethyl acetal (XXIII), followed by partial hydrogenation of the resulting naphthyridine (XXIV) and acid hydrolysis of the dimethyl acetal group. Finally, reductive condensation of amine (XXI) with aldehyde (XXVI) in the presence of sodium triacetoxyborohydride yielded the title compound.
| 【2】 Duggan, M.E.; Hartman, G.D.; Hoffman, W.F.; Meissner, R.S.; Perkins, J.J.; Askew, B.C.; Coleman, P.J.; Hutchinson, J.H.; Naylor-Olsen, A.M. (Merck & Co., Inc.); Integrin antagonists. EP 0934305; US 5981546; WO 9808840 . |
| 【1】 Nakanishi, T.; Otsuka, T.; Hashimoto, S.; Okamoto, M.; Muramatsu, Y.; Hino, M.; Hatanaka, H.; WF14865A and B, new cathepsins B and L inhibitors produed by Aphanoascus fulvescens. I. Taxomy, production, purification and biological properties. J Antibiot 2000, 53, 5, 449. |
| 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) | 45015 | tert-butyl (3S,5R)-5-methyl-2-oxopyrrolidinylcarbamate | C10H18N2O3 | 详情 | 详情 | |
| (XVII) | 45022 | ethyl 2-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methyl-2-oxopyrrolidinyl]acetate | C14H24N2O5 | 详情 | 详情 | |
| (XVIII) | 45023 | 2-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methyl-2-oxopyrrolidinyl]acetic acid | C12H20N2O5 | 详情 | 详情 | |
| (XIX) | 16297 | ethyl (3S)-3-amino-4-pentynoate | C7H11NO2 | 详情 | 详情 | |
| (XX) | 45024 | ethyl (3S)-3-[(2-[(3S,5R)-3-[(tert-butoxycarbonyl)amino]-5-methyl-2-oxopyrrolidinyl]acetyl)amino]-4-pentynoate | C19H29N3O6 | 详情 | 详情 | |
| (XXI) | 45025 | ethyl (3S)-3-([2-[(3S,5R)-3-amino-5-methyl-2-oxopyrrolidinyl]acetyl]amino)-4-pentynoate | C14H21N3O4 | 详情 | 详情 | |
| (XXII) | 45026 | C6H6N2O | 详情 | 详情 | ||
| (XXIII) | 25433 | 1,1-dimethoxyacetone | 6342-56-9 | C5H10O3 | 详情 | 详情 |
| (XXIV) | 45027 | methoxy([1,8]naphthyridin-2-yl)methyl methyl ether; 2-(dimethoxymethyl)[1,8]naphthyridine | C11H12N2O2 | 详情 | 详情 | |
| (XXV) | 45028 | methoxy(5,6,7,8-tetrahydro[1,8]naphthyridin-2-yl)methyl methyl ether; 7-(dimethoxymethyl)-1,2,3,4-tetrahydro[1,8]naphthyridine | C11H16N2O2 | 详情 | 详情 | |
| (XXVI) | 45029 | 5,6,7,8-tetrahydro[1,8]naphthyridine-2-carbaldehyde | C9H10N2O | 详情 | 详情 |