Dizocilpine, MK-801(maleate), L-640689, Neurogard(maleate), -Drug Synthesis Database

【结构式】

【药物名称】Dizocilpine, MK-801(maleate), L-640689, Neurogard(maleate)

【化学名称】(+)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine

【CA登记号】77086-21-6, 77086-22-7 ((Z)-2-butenedioate (1:1))

【分子式】C₁₆H₁₅N

【分子量】221.30465

【开发单位】Merck Sharp & Dohme (Originator)

【药理作用】Antiepileptic Drugs, Cerebrovascular Diseases, Treatment of, Cognition Disorders, Treatment of, Neurodegenerative Diseases, Treatment of, NEUROLOGIC DRUGS, Prion Diseases, Treatment of, Stroke, Treatment of, NMDA Antagonists

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 [11C]-labeled MK-801 has been reported: The reaction of 10,11-dihydro-5H-dibenzo[a,d]cycloheptene (I) with N,N-dimethyl-N'-tert-butylformamidine in refluxing toluene gives the formamidine (II), which is alkylated with butyllithium and [11C]-labeled methyl iodide in ether-cyclohexane to yield the 5-methyl derivative (III). Finally, this compound is hydrolyzed with KOH in ethylene glycol.

参考文献中间体

【1】 Kiesewetter, D.O.; Rice, K.C.; Finn, R.D.; Monn, J.A.; Synthesis of C-11-labeled (+/-)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]c yclohepten-5,10-imine [(+/-)-[C-11]MK801]. Appl Radiat Isot - Int J Radiat Appl Instrum Part A 1990, 41, 2, 139.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
	63418	N'-(tert-butyl)-N,N-dimethyliminoformamide	C₇H₁₆N₂	详情	详情
(I)	12082	16-Azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaene	C₁₅H₁₃N	详情	详情
(II)	12083	N-[(E)-16-Azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-16-ylmethylidene]-N-(tert-butyl)amine; N-[(E)-16-Azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-16-ylmethylidene]-2-methyl-2-propanamine	C₂₀H₂₂N₂	详情	详情
(III)	12084	N-(tert-Butyl)-N-[(E)-(1-methyl-16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-16-yl)methylidene]amine; 2-Methyl-N-[(E)-(1-methyl-16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-16-yl)methylidene]-2-propanamine	C₂₁H₂₄N₂	详情	详情
(III)	45108	N-(tert-butyl)-N-[(E)-(1-methyl-16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-16-yl)methylidene]amine; 2-methyl-N-[(E)-(1-methyl-16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-16-yl)methylidene]-2-propanamine	C₂₁H₂₄N₂	详情	详情

合成路线2

The reaction of 10-bromo-5H-dibenzo[a,d]cyclohepten-5-one (I) with N-methylpiperazine (A) by means of potassium tert-butoxide in refluxing tert-butanol gives 10-(N-methylpiperazin-1-yl)-5H-dibenzo[a,d]cyclohepten-5-one (II), which by treatment first with methyllithium in ether and then with refluxing ethanolic HCl is converted into 5-methylene-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-10-one (III). The reaction of (III) with hydroxylamine in refluxing methanol yields 5-methylene-10-hydroxyimino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (IV), which is reduced with sodium cyanoborohydride in methanol to afford 5-methylene-10-hydroxamino-10,11-dihydro-5H-dibenzo[a,d]cycloheptene (V). The internal reaction of (V) in refluxing xylene gives 5-(hydroxymethyl)-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (V), which is reduced with Zn in hot acetic acid.

参考文献中间体

【1】 Evans, B.E.; Engelhardt, E.L.; Remy, D.C.; Britcher, S.F.; Andderson, P.S.; Colton, C.D.; Christy, M.E.; Transannular reaction of dibenzo[a,d]cycloalkenes. 1. Synthesis of dibenzo[a,d]cycloocten-6,12-imines and dibenzo[a,d]cyclohepten-5,10-imines. J Org Chem 1979, 44, 18, 3117-27.
【2】 Thorpe, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; MK-801. Drugs Fut 1983, 8, 2, 120.

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)	10061	1-Methylpiperazine; 1-Methyl piperazine; N-Methylpiperazine	109-01-3	C₅H₁₂N₂	详情	详情
(I)	35924	10-bromo-5H-dibenzo[a,d]cyclohepten-5-one		C₁₅H₉BrO	详情	详情
(II)	35925	10-(4-methyl-1-piperazinyl)-5H-dibenzo[a,d]cyclohepten-5-one		C₂₀H₂₀N₂O	详情	详情
(III)	35926	5-methylene-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one		C₁₆H₁₂O	详情	详情
(IV)	35927	5-methylene-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one oxime		C₁₆H₁₃NO	详情	详情
(V)	35928	10-(hydroxyamino)-5-methylene-5H-dibenzo[a,d]cycloheptene; N-(5-methylene-5H-dibenzo[a,d]cyclohepten-10-yl)hydroxylamine		C₁₆H₁₃NO	详情	详情
(VI)	35929	16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaen-1-ylmethanol		C₁₆H₁₅NO	详情	详情

合成路线3

Intermediate (III) can be obtained as follows: The reaction of (I) with piperidine (B) by means of potassium tertbutoxide in refluxing tert-butanol gives 10-(1-piperidyl)-5H-dibenzo[a,d]cyclohepten-5-one (XII), which by reaction with methyllithium in ether is converted into 5-hydroxy-5-methyl-10-(1-piperidyl)-5H-dibenzo[a,d]cycloheptene (XIII). Finally, the dehydration of (XIII) in refluxing ethanolic HCl yields (III), already obtained.

参考文献中间体

【1】 Anderson, P.S.; Christy, M.E.; Evans, B.E.; ES 473492 .
【2】 Thorpe, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; MK-801. Drugs Fut 1983, 8, 2, 120.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(B)	10158	Piperidine	110-89-4	C₅H₁₁N	详情	详情
(I)	35924	10-bromo-5H-dibenzo[a,d]cyclohepten-5-one		C₁₅H₉BrO	详情	详情
(III)	35926	5-methylene-5,11-dihydro-10H-dibenzo[a,d]cyclohepten-10-one		C₁₆H₁₂O	详情	详情
(XII)	35930	10-(1-piperidinyl)-5H-dibenzo[a,d]cyclohepten-5-one		C₂₀H₁₉NO	详情	详情
(XIII)	35931	5-methyl-10-(1-piperidinyl)-5H-dibenzo[a,d]cyclohepten-5-ol		C₂₁H₂₃NO	详情	详情

合成路线4

The reaction of 5H-dibenzo[a,d]cyclohepten-5-one (VII) with NH3 and TiCl4 in toluene gives 5H-dibenzo[a,d]cycloheptene-5-imine (VIII), which is tosylated with p-toluenesulfonyl chloride in pyridine to yield 5-(p-toluenesulfonimino)-5H-dibenzo[a,d]cycloheptene (IX). The methylation of (IX) with methyllithium in dry THF affords 5-methyl-5-(p-toluenesulfonimido)-5H-dibenzo[a,d]cycloheptene (X), which is internally cyclized by means of KOH in diglyme at 170 C giving 5-methyl-N-(p-toluenesulfonyl)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5,10-imine (XI). Finally, this compound is hydrolyzed with aqueous HCl in refluxing AcOH.

参考文献中间体

【1】 Shepard, K.L.; Brenner, D.G.; EP 0019866 .
【2】 Thorpe, P.J.; Castaner, J.; Serradell, M.N.; Blancafort, P.; MK-801. Drugs Fut 1983, 8, 2, 120.

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(VII)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(VIII)	35932	5H-dibenzo[a,d]cyclohepten-5-imine		C₁₅H₁₁N	详情	详情
(IX)	35933	N-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-4-methylbenzenesulfonamide		C₂₂H₁₇NO₂S	详情	详情
(X)	35934	4-methyl-N-(5-methyl-5H-dibenzo[a,d]cyclohepten-5-yl)benzenesulfonamide		C₂₃H₂₁NO₂S	详情	详情
(XI)	35935	1-methyl-16-[(4-methylphenyl)sulfonyl]-16-azatetracyclo[7.6.1.0(2,7).0(10,15)]hexadeca-2,4,6,10,12,14-hexaene		C₂₃H₂₁NO₂S	详情	详情

Extended Information