Adinazolam, U-41123, Deracyn, -Drug Synthesis Database

【结构式】

【药物名称】Adinazolam, U-41123, Deracyn

【化学名称】8-Chloro-N,N-dimethyl-6-phenyl-4H-[1,2-4]triazolo[4,3-a][1,4]benzodiazepine-1-methanamine
　　　　　　8-Chloro-1-[(dimethylamino)methyl]-6-phenyl-4H-s-triazolo[4,3-a][1,4]benzodiazepine

【CA登记号】37115-32-5, 57938-82-6 (mesylate)

【分子式】C₁₉H₁₈ClN₅

【分子量】351.84181

【开发单位】Pfizer (Originator)

【药理作用】Antidepressants, Anxiolytics, Mood Disorders, Treatment of, PSYCHOPHARMACOLOGIC DRUGS, Benzodiazepines

合成路线1 合成路线2 合成路线3 合成路线4

合成路线1

A new synthesis of adinazolam has been described: The condensation of phthaloyl-glycyl chloride (I) with 2-amino-5-chlorobenzophenone (II) in refluxing toluene gives 4-chloro-2-(phthaloylglycylamido)benzophenone (III), which is cyclized by means of hydrazine in refluxing ethanol yielding 7-chloro-5-phenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one (IV). The reaction of (IV) with P2S5 in hot pyridine affords the corresponding thione (V), which is finally cyclized with N,N-dimethylglycine hydrazide by means of triethylamine in refluxing butanol. The starting products (I) and (II) are obtained as follows: The reaction of N-(ethoxycarbonyl)phthalimide (VI) with glycine by means of Na2CO3 in water gives the N-phthaloylglycine (VII), which is then treated with refluxing SOCl2 to give (I). The protection of 2-amino-4-chlorobenzoic acid (VIII) with tosyl chloride gives the corresponding N-tosyl derivative (IX), which by reaction with refluxing SOCl2 is converted into the acyl chloride (X). Finally, this compound is submitted to a Friedel-Craft's condensation with benzene and AlCl3 to afford (II).

参考文献中间体

【1】 Johnson, T.D.; Hsi, R.S.P.; Carbon-14 labeled 1,4-benzodiazepines. 3. J Label Compd Radiopharm 1976, 12, 4, 613-619.
【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87.
【3】 Stelzer, L.S.; Hsi, R.S.P.; Synthesis of adinazolam mesylate-multiply labeled with carbon-13 and deuterium. J Label Compd Radiopharm 1989, 26, 3, 287.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
	13364	Benzene	71-43-2	C₆H₆	详情	详情
	40924	2-(dimethylamino)acetohydrazide	539-64-0	C₄H₁₁N₃O	详情	详情
(I)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(II)	10279	(2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone	719-59-5	C₁₃H₁₀ClNO	详情	详情
(III)	10280	N-(2-Benzoyl-4-chlorophenyl)-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetamide		C₂₃H₁₅ClN₂O₄	详情	详情
(IV)	10281	7-Chloro-5-phenyl-1,3-dihydro-2H-1,4-benzodiazepin-2-one; 1,4-benzdiazepin-2-one-5-phenyl-7-chloro	1088-11-5	C₁₅H₁₁ClN₂O	详情	详情
(V)	10282	7-Chloro-5-phenyl-3H-1,4-benzodiazepin-2-ylhydrosulfide; 7-Chloro-5-phenyl-3H-1,4-benzodiazepine-2-thiol		C₁₅H₁₁ClN₂S	详情	详情
(VI)	10283	ethyl 1,3-dioxo-1,3-dihydro-2H-isoindole-2-carboxylate; N-Carbethoxyphthalimide	22509-74-6	C₁₁H₉NO₄	详情	详情
(VII)	10284	N-Phthaloylglycine; 2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetic acid	4702-13-0	C₁₀H₇NO₄	详情	详情
(VIII)	10285	2-Amino-5-chlorobenzoic acid	635-21-2	C₇H₆ClNO₂	详情	详情
(IX)	10286	5-Chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoic acid		C₁₄H₁₂ClNO₄S	详情	详情
(X)	10287	5-Chloro-2-[[(4-methylphenyl)sulfonyl]amino]benzoyl chloride		C₁₄H₁₁Cl₂NO₃S	详情	详情

合成路线2

The reaction of 2-amino-5-chlorobenzophenone (I) with formic acid gives 2-formylamino-5-chlorobenzophenone (II), which by cyclization with hydrazine in ethanol is converted into 3-amino-6-chloro-4-hydroxy-4-phenyl-3,4-dihydroquinazoline (III). The reaction of (III) with formic acid in acetic anhydride - acetic acid yields 5-chloro-2-(4H-1,2,4-triazol-4-yl)benzophenone (IV), which by reaction with formaldehyde in refluxing xylene affords 5-chloro-2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]benzophenone (V). The reaction of (V) with phthalimide (VI), triethylphosphine and diethyl azodicarboxylate in THF gives 5-chloro-2-[3,5-bis(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (VII), which is cyclized with hydrazine in hot ethanol to 8-chloro-1-(aminomethyl)-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (VIII). Finally, this compound is methylated with formaldehyde and sodium cyanoborohydride in acetonitrile - acetic acid.

参考文献中间体

【1】 Gall, M.; Hester, J.B.; US 3947466 .
【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87.

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)	10279	(2-Amino-5-chlorophenyl)(phenyl)methanone; 2-Amino-5-chlorobenzophenone	719-59-5	C₁₃H₁₀ClNO	详情	详情
(II)	35936	2-benzoyl-4-chlorophenylformamide		C₁₄H₁₀ClNO₂	详情	详情
(III)	35937	3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol		C₁₄H₁₂ClN₃O	详情	详情
(IV)	35938	[5-chloro-2-(4H-1,2,4-triazol-4-yl)phenyl](phenyl)methanone		C₁₅H₁₀ClN₃O	详情	详情
(V)	35939	[2-[3,5-bis(hydroxymethyl)-4H-1,2,4-triazol-4-yl]-5-chlorophenyl](phenyl)methanone		C₁₇H₁₄ClN₃O₃	详情	详情
(VI)	12376	Phthalimide; 1H-Isoindole-1,3(2H)-dione; Isoindole-1,3-dione;Phthalic dicarboximide;Phenylimide;Isoindole-1,3-dione	85-41-6	C₈H₅NO₂	详情	详情
(VII)	35940	2-([4-(2-benzoyl-4-chlorophenyl)-5-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-4H-1,2,4-triazol-3-yl]methyl)-1H-isoindole-1,3(2H)-dione		C₃₃H₂₀ClN₅O₅	详情	详情
(VIII)	35941	(8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methylamine; (8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-1-yl)methanamine		C₁₇H₁₄ClN₅	详情	详情

合成路线3

By reaction of 8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine (IX) with N,N-dimethylmethyleneammonium chloride (X) in hot DMF.

参考文献中间体

【1】 Gall, M.; US 4001262 .
【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(IX)	35942	8-chloro-6-phenyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepine	29975-16-4	C₁₆H₁₁ClN₄	详情	详情
(X)	35943	N-methyl-N-methylenemethanaminium chloride		C₃H₈ClN	详情	详情

合成路线4

The reaction of (III) with (XI) by means of pyridine in THF gives 1,3-dioxo-2-isoindolineacetic acid [[N-(2-benzoyl-4-chlorophenyl)-1,3-dioxo-2-isoindolineacetamido]methylene]hydrazide (XVI), which by cyclization by means of trifluoroacetic acid in refluxing toluene yields 5-chloro-2-[3-(phtalimidomethyl)-4H-1,2,4-triazol-4-yl-benzophenone (XVII). The reaction of (XVII) with N,N,N',N'-tetramethyldiaminomethane (A) by means of acetyl chloride in DMF affords 5-chloro-2-[3-[(dimethylamino)methyl-5-(phthalimidomethyl)-4H-1,2,4-triazol-4-yl]benzophenone (XVIII), which is finally cyclized by means of hydrazine in hot ethanol.

参考文献中间体

【1】 Gall, M.; Hester, J.B.; US 3957761 .
【2】 Castaner, J.; Pento, J.T.; Blancafort, P.; Serradell, M.N.; Adinazolam. Drugs Fut 1983, 8, 2, 87.

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)	14349	N,N,N,N-tetramethylmethanediamine; tetramethylmethylenediamine;bis(dimethylamino)methane; N-[(dimethylamino)methyl]-N,N-dimethylamine	51-80-9	C₅H₁₄N₂	详情	详情
(III)	35937	3-amino-6-chloro-4-phenyl-3,4-dihydro-4-quinazolinol		C₁₄H₁₂ClN₃O	详情	详情
(XI)	10278	2-(1,3-Dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl chloride	6780-38-7	C₁₀H₆ClNO₃	详情	详情
(XVI)	35944	N-(2-benzoyl-4-chlorophenyl)-N,N'-bis[2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)acetyl]hydrazonoformamide		C₃₄H₂₂ClN₅O₇	详情	详情
(XVII)	35945	2-[[4-(2-benzoyl-4-chlorophenyl)-4H-1,2,4-triazol-3-yl]methyl]-1H-isoindole-1,3(2H)-dione		C₂₄H₁₅ClN₄O₃	详情	详情
(XVIII)	35946	2-([4-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)methyl]-4H-1,2,4-triazol-3-yl]methyl)-1H-isoindole-1,3(2H)-dione		C₂₇H₂₂ClN₅O₃	详情	详情

Extended Information