Avasimibe, CI-1011, -Drug Synthesis Database

【结构式】

【药物名称】Avasimibe, CI-1011

【化学名称】N-[2-(2,4,6-Triisopropylphenyl)acetyl]sulfamic acid 2,6-diisopropylphenyl ester

【CA登记号】166518-60-1, 166518-61-2 (sodium salt)

【分子式】C₂₉H₄₃NO₄S

【分子量】501.73436

【开发单位】Pfizer (Originator)

【药理作用】Atherosclerosis Therapy, CARDIOVASCULAR DRUGS, Lipoprotein Disorders, Treatment of , METABOLIC DRUGS, Treatment of Disorders of the Coronary Arteries and Atherosclerosis, ACAT Inhibitors

合成路线1 合成路线2

合成路线1

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).

参考文献中间体

【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.
【3】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Avasimibe . Drugs Fut 1999, 24, 1, 9.
【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

合成路线2

1) The reaction of (V) with SOCl2 or (COCl)2 in DMF affords the expected acyl chloride (VI), which is finally condensed with 2,6-diisopropylphenyl sulfamate (VII) by means of triethylamine in hot toluene to obtain Avasimibe. 2) The sulfamate (VII) can be obtained by condensation of 2,6-diisopropylphenol (VIII) with chlorosulfonyl isocyanate (IX) in refluxing toluene to give the isocyanate (X), which is hydrolyzed with water to the sulfamate (VII). compound is condensed with the previously described isocyanate (X) in refluxing THF to obtain Avasimibe. 3) Avasimibe can also be obtained by condensation of isocyanate (X) with Grignard reagent (XIII).

参考文献中间体

【1】 Sorbera, L.A.; Rabasseda, X.; Castañer, J.; Avasimibe . Drugs Fut 1999, 24, 1, 9.
【2】 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 .

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)	20240	2-(2,4,6-triisopropylphenyl)acetic acid		C₁₇H₂₆O₂	详情	详情
(VI)	20247	2-(2,4,6-triisopropylphenyl)acetyl chloride		C₁₇H₂₅ClO	详情	详情
(VII)	20248	2,6-diisopropylphenylsulfamate		C₁₂H₁₉NO₃S	详情	详情
(VIII)	20249	2,6-Diisopropylphenol	2078-54-8	C₁₂H₁₈O	详情	详情
(IX)	14101	Chlorosulfonyl isocyanate	1189-71-5	CClNO₃S	详情	详情
(X)	20251	2-[(isocyanatosulfonyl)oxy]-1,3-diisopropylbenzene		C₁₃H₁₇NO₄S	详情	详情
(XIII)	20243	bromo(2,4,6-triisopropylbenzyl)magnesium		C₁₆H₂₅BrMg	详情	详情

Extended Information