2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile -Drug Synthesis Database

【结构式】

【分子编号】12861

【品名】2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile

【CA登记号】

【分子式】C₁₂H₁₁NO₂

【分子量】201.22488

【元素组成】C 71.63% H 5.51% N 6.96% O 15.9%

与该中间体有关的原料药合成路线共 3 条

合成路线1 合成路线2 合成路线3

合成路线1

该中间体在本合成路线中的序号：(V)

1) The cyclization of 4-cyanophenol (I) with 3-chloro-3-methylbutine (II) by means of benzyltrimethylammonium hydroxide in methanol-CH2Cl2 gives 6-cyano-2,2-dimethyl-2H-benzo[b]pyran (III), which is treated with N-bromosuccinimide in DMSO to afford 6-cyano-trans-3-bromo-3,4-dihydro-2,2-dimethyl 2H benzo[b]pyran-4-ol (IV). Epoxidation of (IV) by means of NaOH in dioxane-water yields 6-cyano-3-(4-dihydro-3,4-epoxy-2,2-dimethyl-2H-benzo[b]pyran (V), which is finally treated with 4-aminobutyric acid (VI) and NaHCO3 in refluxing ethanol. 2) By reaction of epoxide (V) with 2-pyrrolidone (X) by means of NaH in DMSO.

参考文献中间体

合成目标

【1】 Evans, J.M.; Buckingham, R.E.; Willcocks, K. (SmithKline Beecham plc); Benzopyrans. EP 0076075; JP 3014573; JP 5202034; US 4446113 .
【2】 Faruk, E.A. (SmithKline Beecham plc); Antihypertensive chromenes and chromans. EP 0093535; US 4510152 .
【3】 Castaner, J.; Mannhold, R.; BRL-34915. Drugs Fut 1986, 11, 3, 175.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	27394	Trimethylbenzylammonium Hydroxide; N,N,N-trimethyl(phenyl)methanaminium hydroxide; Triton B; Benzyltrimethylammonium hydroxide	100-85-6	C₁₀H₁₇NO	详情	详情
(I)	25109	4-hydroxybenzonitrile	767-00-0	C₇H₅NO	详情	详情
(II)	22416	3-chloro-3-methyl-1-butyne	1111-97-3	C₅H₇Cl	详情	详情
(III)	27395	2,2-dimethyl-2H-chromene-6-carbonitrile		C₁₂H₁₁NO	详情	详情
(IV)	27396	3-bromo-4-hydroxy-2,2-dimethyl-6-chromanecarbonitrile		C₁₂H₁₂BrNO₂	详情	详情
(V)	12861	2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile		C₁₂H₁₁NO₂	详情	详情
(VI)	13620	4-Amino-n-butyric acid; 4-Aminobutyric acid;Piperidinic acid;Piperidic acid	56-12-2	C₄H₉NO₂	详情	详情
(X)	27397	2-Pyrrolidinone	616-45-5	C₄H₇NO	详情	详情

合成路线2

该中间体在本合成路线中的序号：(V)

The reaction of epoxide (V) with ammonia in ethanol gives 4-amino-6-cyano-3,4-dihydro-2,2-dimethyl-trans-2H-benzo[b]pyran-3-ol (VII), which is condensed with 4-chlorobutyryl chloride (VIII) by means of NaOH in CHCl3 yielding 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(4-chlorobutyrylamino)-2H-benzo[blpyran 3-ol (IX). Finally, this compound is cyclized by means of NaH in THF.

参考文献中间体

合成目标

【1】 Faruk, E.A. (SmithKline Beecham plc); Antihypertensive chromenes and chromans. EP 0093535; US 4510152 .
【2】 Evans, J.M.; Buckingham, R.E.; Willcocks, K. (SmithKline Beecham plc); Benzopyrans. EP 0076075; JP 3014573; JP 5202034; US 4446113 .
【3】 Castaner, J.; Mannhold, R.; BRL-34915. Drugs Fut 1986, 11, 3, 175.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(A)	27394	Trimethylbenzylammonium Hydroxide; N,N,N-trimethyl(phenyl)methanaminium hydroxide; Triton B; Benzyltrimethylammonium hydroxide	100-85-6	C₁₀H₁₇NO	详情	详情
(I)	25109	4-hydroxybenzonitrile	767-00-0	C₇H₅NO	详情	详情
(II)	22416	3-chloro-3-methyl-1-butyne	1111-97-3	C₅H₇Cl	详情	详情
(III)	27395	2,2-dimethyl-2H-chromene-6-carbonitrile		C₁₂H₁₁NO	详情	详情
(IV)	27396	3-bromo-4-hydroxy-2,2-dimethyl-6-chromanecarbonitrile		C₁₂H₁₂BrNO₂	详情	详情
(V)	12861	2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile		C₁₂H₁₁NO₂	详情	详情
(VII)	27398	(3S,4R)-4-amino-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromene-6-carbonitrile		C₁₂H₁₄N₂O₂	详情	详情
(VIII)	11265	4-Chlorobutanoyl chloride; 4-Chlorobutyric acid chloride	4635-59-0	C₄H₆Cl₂O	详情	详情
(IX)	27399	4-chloro-N-[(3S,4R)-6-cyano-3-hydroxy-2,2-dimethyl-3,4-dihydro-2H-chromen-4-yl]butanamide		C₁₆H₁₉ClN₂O₃	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 cyclization of 3-acetyl-4-hydroxybenzonitrile (I) with acetone by means of pyrrolidine in toluene gives 2,2-dimethyl-4-oxo-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (II), which is reduced with NaBH4 yielding the corresponding alcohol (III). The dehydration of (III) with p-toluenesulfonic acid in refluxing toluene affords 2,2-dimethyl-2H-1-benzopyran-6-carbonitrile (IV), which is treated with m-chloroperbenzoic acid (MCPBA) to give the corresponding epoxide (V) . The condensation of (V) with pyridin-2(1H)-one (VI) by means of pyridine or benzyl trimethylammonium hydroxide (2) in refluxing ethanol yields trans-3-hydroxy-2,2-dimethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-3,4-dihydro-2H-1-benzopyran-6-carbonitrile (VII), which is finally dehydrated with NaOH in refluxing dioxane , or with NaH in refluxing THF. When the condensation of epoxide (V) with pyridone (VI) is carried out with NaH in DMSO mixtures of the intermediate (VII) and the final compound bimakalim are obtained; these compounds are easily separated.

参考文献中间体

合成目标

【1】 Robinson, C.; Robinson, K.A.; Castaner, J.; Bimakalim. Drugs Fut 1996, 21, 4, 351.
【2】 Hausler, G.; Gericke, R.; Wurziger, H.; Baumgarth, M.; Lues, I.; De Peyer, J.; Bergmann, R. (Merck Patent GmbH); Chroman derivs. AU 8782689; DE 3726261; EP 0273262; JP 1988170376 .
【3】 Garcia, G.; Di Malta, a.; Gautier, P. (Sanofi-Synthelabo ); 2,2-Dimethylchromene derivs., preparation process and pharmaceutical compsns. containing them. AU 8823660; EP 0312432; EP 0556872; FR 2621587; JP 1990000180 .
【4】 Hausler, G.; Gericke, R.; Wurziger, H.; Baumgarth, M.; Lues, I.; Bergmann, R.; De Peyer, J. (Merck Patent GmbH); Chroman derivs. AU 8936440; DE 3820506; EP 0346724; JP 1990040375; US 5387587 .
【5】 Bergmann, R.; Gericke, R.; Synthesis and antihypertensive activity of 4-(1,2-dihydro-2-oxo-1-pyridyl)-2H-1-benzopyrans and related compounds, new channel activators. J Med Chem 1990, 33, 2, 492-504.

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)	12857	3-Acetyl-4-hydroxybenzonitrile		C₉H₇NO₂	详情	详情
(II)	12858	2,2-Dimethyl-4-oxo-6-chromanecarbonitrile		C₁₂H₁₁NO₂	详情	详情
(III)	12859	4-Hydroxy-2,2-dimethyl-6-chromanecarbonitrile		C₁₂H₁₃NO₂	详情	详情
(IV)	12860	2,2-Dimethyl-2H-chromene-6-carbonitrile		C₁₂H₁₁NO	详情	详情
(V)	12861	2,2-Dimethyl-1a,7b-dihydro-2H-oxireno[2,3-c]chromene-6-carbonitrile		C₁₂H₁₁NO₂	详情	详情
(VI)	12862	2(1H)-Pyridinone	142-08-5	C₅H₅NO	详情	详情
(VII)	12863	(3S,4R)-3-Hydroxy-2,2-dimethyl-4-[2-oxo-1(2H)-pyridinyl]-3,4-dihydro-2H-chromene-6-carbonitrile		C₁₇H₁₆N₂O₃	详情	详情

Extended Information