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【结 构 式】 
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【分子编号】15168 【品名】methyl 2-chloro-2-fluorocyclopropanecarboxylate 【CA登记号】 |
【 分 子 式 】C5H6ClFO2 【 分 子 量 】152.5525432 【元素组成】C 39.37% H 3.96% Cl 23.24% F 12.45% O 20.98% |
合成路线1
该中间体在本合成路线中的序号：(XXX)The chiral intermediate (1R,2S)-N-(tert-butoxycarbonyl)-2-fluorocyclopropylamine (III) can also be obtained as follows: 4) The cyclopropanation of 1-chloro-1-fluoroethylene (XXVIII) with diazoacetic esters (XXIX) catalyzed by rhodium catalysts, especially dirhodium (II) tetrakistriphenylacetate, gives preferentially the corresponding 2t-chloro-2c-fluorocyclopropane-1r-carboxylic esters (XXX), which are easily dechlorinated to the cis-racemic-2-fluorocyclopropanecarboxylic acid (XII), already obtained as intermediate in the synthesis shown in Scheme 2.
| 【1】 Castaner, J.; Graul, A.; Prous, J.; DU-6859. Drugs Fut 1994, 19, 9, 827. |
| 【2】 Kohda, H.; Takahashi, H.; Ishida, Y.; et al.; Practical synthesis of DU-6859a: Novel synthesis of cis-2-fluorocyclopropanecarboxylic acid, the key intermediate of 1-substituent. 33rd Intersci Conf Antimicrob Agents Chemother (Oct 17-20, New Orleans) 1993, Abst 975. |
合成路线2
该中间体在本合成路线中的序号：(XIV)1) Synthesis of intermediate (V): The reduction of 2,4,6-triisopropylbenzoyl chloride (I) with LiAlH4 in ethyl ether gives 2,4,6-triisopropylbenzyl alcohol (II) (1-4), which by reaction with SOCl2 in toluene is converted into 2,4,6-triisopropylbenzyl chloride (III). The reaction of (III) with NaCN or KCN in DMSO affords 2,4,6-triisopropylphenylacetonitrile (IV), which is hydrolyzed with aqueous H2SO4 or KOH in diethylene glycol/water, yielding the phenylacetic acid (V). 2) Synthesis of intermediate (III): The intermediate benzyl chloride (III) can also be obtained by direct chloromethylation of 1,3,5-triisopropylbenzene (XI) with paraformaldehyde/HCl in acetic acid. 3) Synthesis of intermediate (V): Phenylacetic acid (V) can also be obtained by condensation of 1,3,5-triisopropylbenzene (XI) with glyoxylic acid (XIV) by means of H2SO4 in refluxing acetic acid, yielding a mixture of acetoxyacetic acid (XV) and hydroxyacetic acid (XVI). This mixture is finally reduced with HI in acetic acid to the phenylacetic acid (V). 4) Synthesis of intermediate (IV): The acetonitrile (IV) can also be obtained by reaction of benzyl bromide (XII) with KCN in DMSO. 5) Synthesis of intermediate (XIII): Avasimibe can also be obtained by reaction of benzyl alcohol (II) with PBr3 in ether to give the benzyl bromide (XII), which is treated with Mg in THF to yield the corresponding Grignard reagent (XIII).
| 【1】 Sliskovic, D.R.; CI-1011: An atypical ACAT inhibitor with antiatherosclerotic activity. Int Symp Med Chem 1996, Abst SR-06.2. |
| 【2】 Lee, H.T.; Sliskovic, D.R.; Picard, J.A.; et al.; Inhibitors of acyl-CoA:cholesterol O-acyl transferase (ACAT) as hypocholesterolemic agents. CI-1011: An acyl sulfamate with unique cholesterol-lowering activity in animals fed noncholesterol-supplemented diets. J Med Chem 1996, 39, 26, 5031. |
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【3】
Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Avasimibe |
| 【4】 Lee, H.T.; Picad, J.A.; Sliskovic, D.R.; Wierenga, W. (Pfizer Inc.); N-Acyl sulfamic acid esters (or thioesters), N-acyl sulfonamides, and N-sulfonyl carbamic acid esters (or thioesters) as hypercholesterolemic agents. EP 0698010; JP 1996510256; US 5491172; WO 9426702 . |
| 【5】 Dozeman, G.J.; et al.; Chemical development of a pilot scale process for the ACAT inhibitor 2,6-diisopropylphenyl [(2,4,6-triisopropylphenyl)acetyl]sulfamate. Org Process Res Dev 1997, 1, 2, 137-48. |
| 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) | 20236 | 2,4,6-triisopropylbenzoyl chloride | 57199-00-5 | C16H23ClO | 详情 | 详情 |
| (II) | 20237 | (2,4,6-triisopropylphenyl)methanol | C16H26O | 详情 | 详情 | |
| (III) | 20238 | 2-(chloromethyl)-1,3,5-triisopropylbenzene | C16H25Cl | 详情 | 详情 | |
| (IV) | 20239 | 2-(2,4,6-triisopropylphenyl)acetonitrile | C17H25N | 详情 | 详情 | |
| (V) | 20240 | 2-(2,4,6-triisopropylphenyl)acetic acid | C17H26O2 | 详情 | 详情 | |
| (XI) | 14888 | 1,3,5-triisopropylbenzene | 717-74-8 | C15H24 | 详情 | 详情 |
| (XII) | 20242 | 2-(bromomethyl)-1,3,5-triisopropylbenzene | C16H25Br | 详情 | 详情 | |
| (XIII) | 20243 | bromo(2,4,6-triisopropylbenzyl)magnesium | C16H25BrMg | 详情 | 详情 | |
| (XIV) | 15168 | methyl 2-chloro-2-fluorocyclopropanecarboxylate | C5H6ClFO2 | 详情 | 详情 | |
| (XV) | 20245 | 2-(acetoxy)-2-(2,4,6-triisopropylphenyl)acetic acid | C19H28O4 | 详情 | 详情 | |
| (XVI) | 20246 | 2-hydroxy-2-(2,4,6-triisopropylphenyl)acetic acid | C17H26O3 | 详情 | 详情 |