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【结 构 式】 
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【分子编号】40673 【品名】ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester 【CA登记号】667-27-6 |
【 分 子 式 】C4H5BrF2O2 【 分 子 量 】202.9833064 【元素组成】C 23.67% H 2.48% Br 39.36% F 18.72% O 15.76% |
合成路线1
该中间体在本合成路线中的序号：Aldehyde (I), derived from vitamin D2, was submitted to a Reformatsky reaction with ethyl bromodifluoroacetate and activated Zn to produce a mixture of diastereomeric b-hydroxyesters (II). After chromatographic separation, the required (23S)-isomer was condensed with MeMgBr to give tertiary alcohol (III). Finally, desilylation of (III) with tetra n-butylammonium fluoride in THF provided the title compound.
| 【1】 Iwasaki, H.; Miyamoto, Y.; Hosotani, R.; Nakano, Y.; Konno, K.; Takayama, H.; Synthesis and biological evaluation of (23R)- and (23S)-24,24-difluoro-1alpha,23,25-trihydroxyvitamin D3. Chem Pharm Bull 1998, 46, 12, 1932. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40673 | ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester | 667-27-6 | C4H5BrF2O2 | 详情 | 详情 | |
| (I) | 25263 | (3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal | C35H62O3Si2 | 详情 | 详情 | |
| (II) | 25264 | ethyl (5R)-5-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-2,2-difluoro-3-hydroxyhexanoate | C39H68F2O5Si2 | 详情 | 详情 | |
| (III) | 25321 | (4R,6R)-6-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-3,3-difluoro-2-methyl-2,4-heptanediol | C39H70F2O4Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：Aldehyde (I), derived from vitamin D2, was submitted to a Reformatsky reaction with ethyl bromodifluoroacetate and activated Zn to produce a mixture of diastereomeric b-hydroxyesters (II). After chromatographic separation, the required (23S)-isomer was condensed with MeMgBr to give tertiary alcohol (III). Finally, desilylation of (III) with tetra n-butylammonium fluoride in THF provided the title compound.
| 【1】 Iwasaki, H.; Miyamoto, Y.; Hosotani, R.; Nakano, Y.; Konno, K.; Takayama, H.; Synthesis and biological evaluation of (23R)- and (23S)-24,24-difluoro-1alpha,23,25-trihydroxyvitamin D3. Chem Pharm Bull 1998, 46, 12, 1932. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 40673 | ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester | 667-27-6 | C4H5BrF2O2 | 详情 | 详情 | |
| (I) | 25263 | (3R)-3-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]butanal | C35H62O3Si2 | 详情 | 详情 | |
| (II) | 25264 | ethyl (5R)-5-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-2,2-difluoro-3-hydroxyhexanoate | C39H68F2O5Si2 | 详情 | 详情 | |
| (III) | 25265 | (4S,6R)-6-[(1R,3aR,7aR)-4-[(E)-2-((3S,5R)-3,5-bis[[tert-butyl(dimethyl)silyl]oxy]-2-methylenecyclohexylidene)ethylidene]-7a-methyloctahydro-1H-inden-1-yl]-3,3-difluoro-2-methyl-2,4-heptanediol | C39H70F2O4Si2 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(V)The intermediate 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) has been obtained as follows. The esterification of N-(benzyloxycarbonyl)-DL-phenylalanine (I) with methyl iodide and KHCO3 in DMF gives the corresponding methyl ester (II), which is reduced with LiCl and NaBH4 in THF to yield protected DL-phenylalaninol (III). The oxidation of (III) by means of 2,2,6,6-tetramethylpiperdine-1-oxyl free radical (TEMPO), NaBr and NaClO in ethyl acetate/toluene affords protected DL-phenylalaninal (IV), which is condensed with ethyl 2-bromo-2,2-difluoroacetate (V) by means of Zn in THF to provide the 2,2-difluoropentanoic ester (VI). The reaction of ester (VI) with benzylamine (VII) in THF gives the corresponding amide (VIII), which is finally deprotected by means of H2 over Pd/C in methanol/dioxane to yield the target 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide (IX) intermediate.
| 【1】 Kobayashi, F.; Naito, K.; Yoshikawa, T.; Kuwahara, S.; Imada, T.; Komorita, N. (Mitsubishi Pharma Corp.); IgE antibody production inhibitors and autoimmune diseases inhibitors. EP 1062949; US 6528514; WO 9945928 . |
| 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) | 58077 | N-[(benzyloxy)carbonyl]phenylalanine | C17H17NO4 | 详情 | 详情 | |
| (II) | 57836 | methyl 2-{[(benzyloxy)carbonyl]amino}-3-phenylpropanoate | C18H19NO4 | 详情 | 详情 | |
| (III) | 58078 | benzyl 1-benzyl-2-hydroxyethylcarbamate | C17H19NO3 | 详情 | 详情 | |
| (IV) | 48629 | benzyl 1-benzyl-2-oxoethylcarbamate; N-(benzyloxycarbonyl)-L-phenylalaninal | 59830-60-3 | C17H17NO3 | 详情 | 详情 |
| (V) | 40673 | ethyl 2-bromo-2,2-difluoroacetate; Ethylbromodifluoroacetate; 2-bromo-2,2-difluoroacetic acid ethyl ester; bromodifluoroacetic acid ethyl ester | 667-27-6 | C4H5BrF2O2 | 详情 | 详情 |
| (VI) | 57837 | ethyl 4-{[(benzyloxy)carbonyl]amino}-2,2-difluoro-5-phenylpentanoate | C21H23F2NO4 | 详情 | 详情 | |
| (VII) | 15147 | Benzylamine; Phenylmethanamine | 100-46-9 | C7H9N | 详情 | 详情 |
| (VIII) | 57838 | benzyl 1-benzyl-4-(benzylamino)-3,3-difluoro-4-oxobutylcarbamate | C26H26F2N2O3 | 详情 | 详情 | |
| (IX) | 57839 | 4-amino-N-benzyl-2,2-difluoro-5-phenylpentanamide | C18H20F2N2O | 详情 | 详情 |