Cromakalim, M&B-44809, BRL-38227((-)-enantiomer), BRL-38266((+)-enantiomer), BRL-34915, -Drug Synthesis Database

【结构式】

【药物名称】Cromakalim, M&B-44809, BRL-38227((-)-enantiomer), BRL-38266((+)-enantiomer), BRL-34915

【化学名称】(±)-trans-6-Cyano-2,2-dimethyl-4-(2-oxo-1-pyrrolidinyl)-3,4-dihydro-2H-benzo[b]pyran-3-ol

【CA登记号】94470-67-4, 86776-67-2 (undefined stereoch.)

【分子式】C₁₆H₁₈N₂O₃

【分子量】286.33346

【开发单位】GlaxoSmithKline (Originator)

【药理作用】Antiallergy/Antiasthmatic Drugs, Antiulcer Drugs, Asthma Therapy, Bronchodilators, CARDIOVASCULAR DRUGS, GASTROINTESTINAL DRUGS, Hypertension, Treatment of, Irritable Bowel Syndrome, Agents for, RENAL-UROLOGIC DRUGS, RESPIRATORY DRUGS, Urinary Incontinence Therapy, Vasodilators, K(ATP) Channel Activators

合成路线1 合成路线2

合成路线1

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

【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

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

【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

Extended Information