Sabcomeline hydrochloride, CEB-2424, BRL-55473, SB-202026A, Memric, -Drug Synthesis Database

【结构式】

【药物名称】Sabcomeline hydrochloride, CEB-2424, BRL-55473, SB-202026A, Memric

【化学名称】(+)-2(Z)-(Methoxyimino)-2-[quinuclidin-3(R)-yl]acetonitrile hydrochloride

【CA登记号】159912-58-0, 151433-83-9 ((E)-isomer free base), 151433-82-8 ((Z)-isomer free base), 159912-53-5 (free base)

【分子式】C₁₀H₁₆ClN₃O

【分子量】229.71152

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Alzheimer's Dementia, Treatment of , Cognition Disorders, Treatment of, NEUROLOGIC DRUGS, Muscarinic M1 Agonists

合成路线1 合成路线2

合成路线1

Sabcomeline can be obtained by several related ways: 1) The reaction of N-methoxyquinuclidine-3-carboxamide (I) with triphenylphosphine in refluxing CCl4 or with PCl5 in nitromethane gives N-methoxyquinuclidin-3-ylcarboxyimidoyl chloride (II), which by reaction with NaCN in hot DMSO is converted into 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III). Finally, this compound is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP], or with 2,3:4,6-di-O-isopropylidene-2-oxo-L-gulonic acid [L-DIOG]. 2) The condensation of diethyl cyanomethylphosphonate (IV) with 3-quinuclidinone (V) by means of KOH in water gives 2-(quinuclidin-3-ylidene)acetonitrile (VI), which is hydrogenated with H2 over Pd/C in ethyl acetate to yield 2-(quinuclidin-3-yl)acetonitrile (VII). The nitrosation of (VII) with isoamyl nitrile and potassium tert-butoxide in THF affords 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), which is methylated with methyl p-toluenesulfonate and potassium tert-butoxide in DMSO to give 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (III), already obtained. 3) The condensation of 3-quinuclidinone (V) with cyanacetic acid (IX) by means of NaOH in water gives 2-(quinuclidin-3-ylidene)cyanacetic acid (X), which is hydrogenated with H2 over Pd/C in water to yield 2-(3-quinuclidinyl)cyanacetic acid (XI). Finally, this compound is nitrosated with NaNO2/HCl to afford 2-(hydroxyimino)-2-(3-quinuclidinyl)acetonitrile (VIII), already obtained.

参考文献中间体

【1】 Graul, A.; Prous, J.; Castañer, J.; Sabcomeline Hydrochloride. Drugs Fut 1998, 23, 1, 41.
【2】 Clark, M.S.G.; Bromidge, S.M.; Oriek,B.S.; Cassidy, F.; Eggleston, D.S.; Synthesis and properties of [R-(Z)]-(+)-alpha-(1-azabicyclo[2.2.2]oct-3-yl)-alpha-(methoxyimino) acetonitrile, a novel functionally selective muscarinic partial agonist. J Chem Soc Chem Commun 1994, 18, 18, 2189-90.
【3】 Cassidy, F.; Bromidge, S.M.; Clark, M.S.G.; Brown, F.; Riley, G.J.; Dabbs, S.; Loudon, J.M.; Hawkins, J.; Orlek, B.S.; A novel and selective class of azabicyclic muscarinic agonists incorporating an N-methoxy imidoyl halide or nitrile functionality. Bioorg Med Chem Lett 1992, 2, 8, 791-6.
【4】 Orlek, B.S.; Bromidge, S.M.; Dabbs, S. (SmithKline Beecham plc); Novel cpds. AU 9053159; EP 0392803; JP 1991007285; JP 1997188678; JP 1997188679; US 5278170 .

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)	16921	N-methoxy-3-quinuclidinecarboxamide		C₉H₁₆N₂O₂	详情	详情
(II)	16922	N-methoxy-3-quinuclidinecarboximidoyl chloride		C₉H₁₅ClN₂O	详情	详情
(III)	16923	N-methoxy-3-quinuclidinecarboximidoyl cyanide		C₁₀H₁₅N₃O	详情	详情
(IV)	10045	Diethyl cyanomethylphosphonate	2537-48-6	C₆H₁₂NO₃P	详情	详情
(V)	16925	3-quinuclidinone; 1-azabicyclo[2.2.2]octan-3-one	1193-65-3	C₇H₁₁NO	详情	详情
(VI)	16926	2-(1-azabicyclo[2.2.2]oct-3-ylidene)acetonitrile		C₉H₁₂N₂	详情	详情
(VII)	16927	2-(1-azabicyclo[2.2.2]oct-3-yl)acetonitrile		C₉H₁₄N₂	详情	详情
(VIII)	16928	N-hydroxy-3-quinuclidinecarboximidoyl cyanide		C₉H₁₃N₃O	详情	详情
(IX)	12591	Cyanoacetic Acid; 2-Cyanoacetic acid	372-09-8	C₃H₃NO₂	详情	详情
(X)	16930	2-(1-azabicyclo[2.2.2]oct-3-ylidene)-2-cyanoacetic acid		C₁₀H₁₂N₂O₂	详情	详情
(XI)	16931	2-(1-azabicyclo[2.2.2]oct-3-yl)-2-cyanoacetic acid		C₁₀H₁₄N₂O₂	详情	详情

合成路线2

A new synthesis of sabcomeline hydrochloride has been described: The hydrolysis of quinuclidine-3-carboxylic acid ethyl ester (I) with refluxing aqueous HCl gives the corresponding acid (II), which by reaction with thionyl chloride in refluxing dichloromethane yields the expected acyl chloride (III). The reaction of (III) with O-methylhydroxylamine in chloroform/pyridine affords N-methoxyquinuclidine-3-carboxamide (IV), which by reaction with triphenylphosphine/CCl4 in refluxing acetonirile is converted into the imidoyl chloride (V). The reaction of (V) with NaCN in hot DMSO gives 2-(methoxyimino)-2-(3-quinuclidinyl)acetonitrile (VI) as a mixture of the (E)- and (Z)-isomers that is resolved by column chromatography yielding the (Z)-isomer (VII). Finally, this compound (VII) is submitted to optical resolution with (R)-(-)-1,1'-binaphthyl-2,2'-diyl hydrogen phosphate [(R)-(-)-BNHP].

参考文献中间体

【1】 Bromidge, S.M.; Brown, F.; Cassidy, F.; et al.; Design of [R-(Z)]-(+)-alpha-(methoxyimino)-1-azabicyclo[2.2.2]octane-3-acetonitrile (SB 202026), a functionally selective azabicyclic muscarinic M1 agonist incorporating the N-methoxy imidoyl nitrile group as a novel ester bioisostere. J Med Chem 1997, 40, 26, 4265.

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)	20289	ethyl 3-quinuclidinecarboxylate; 3-carbethoxyquinuclidine; 1-azabicyclo[2.2.2]octane-3-ethylcarboxylate	6238-33-1	C₁₀H₁₇NO₂	详情	详情
(II)	20290	3-quinuclidinecarboxylic acid		C₈H₁₃NO₂	详情	详情
(III)	20291	3-quinuclidinecarbonyl chloride		C₈H₁₂ClNO	详情	详情
(IV)	16921	N-methoxy-3-quinuclidinecarboxamide		C₉H₁₆N₂O₂	详情	详情
(V)	16922	N-methoxy-3-quinuclidinecarboximidoyl chloride		C₉H₁₅ClN₂O	详情	详情
(VII)	16923	N-methoxy-3-quinuclidinecarboximidoyl cyanide		C₁₀H₁₅N₃O	详情	详情

Extended Information