Cyclobenzaprine hydrochloride, Flexiban, Flexeril, -Drug Synthesis Database

【结构式】

【药物名称】Cyclobenzaprine hydrochloride, Flexiban, Flexeril

【化学名称】3-(5H-Dibenzo[a,d]cyclohepten-5-ylidene)-N,N-dimethylpropan-1-amine hydrochloride

【CA登记号】303-53-7(free base)

【分子式】C₂₀H₂₂ClN

【分子量】311.85804

【开发单位】Merck & Co. (Originator), Vela Pharmaceuticals (Not Determined), Alza (Licensee)

【药理作用】Antispastic Drugs and Drugs for Muscle Spasms, Anxiolytics, Fibromyalgia, Treatment of, Generalized Anxiety Disorder (GAD), Treatment of, Muscle Spasms, Drugs for, NEUROLOGIC DRUGS, Neurologic Drugs (Miscellaneous), PSYCHOPHARMACOLOGIC DRUGS, Sensation Disorders, Treatment of, Sleep Disorders, Treatment of, Smooth Muscle Relaxants

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

The starting product dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) is prepared by condensation of phthalic anhydride (X) with phenylacetic acid (XI) by means of sodium acetate at 240 C that gives benzalphthalide (XII). This compound is reduced with red phosphorus in refluxing aqueous HI yielding 2-(2-phenylethyl)benzoic acid (XIII), which is then cyclized with polyphosphoric acid at 175 C afforing dibenzo[a,d]cyclohepta-1,4-diene-5-one (XIV). The ketone (XIV) is brominated with NBS in CCl4 to the bromo ketone (XV) and finally dehydrobrominated with triethylamine.

参考文献中间体

【1】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【2】 Vilani, F.J. (Schering Corp.); 5-(3'-Dimethylamino-2'-methylpropyl)dibenzocycloheptenes. US 3409640 .

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)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(X)	11900	2-Benzofuran-1,3-dione;1,2-Benzenedicarboxylic Anhydride;1,2-BENZENE DICARBOXYLIC ACID ANHYDRIDE;1,2-BENZENEDICARBONIC ACID, ANHYDRIDE;1,3-DIOXOPHTHALAN;1,3-ISOBENZOFURANDIONE;o-phthalic anhydride; Phthalic anhydride	85-44-9	C₈H₄O₃	详情	详情
(XI)	16148	Benzeneacetic acid; 2-Phenylacetic acid; Phenyl Acetic Acid	103-82-2	C₈H₈O₂	详情	详情
(XII)	40121	3-[(Z)-benzylidene]-2-benzofuran-1-one; Benzalphthalide; 3-[(Z)-benzylene]-1-isobenzofuranone; Benzylidenephthalide; 3-[(Z)-benzylene]-1(3H)-isobenzofuranone; 3-(Z)-Benzylidenephthalide	575-61-1	C₁₅H₁₀O₂	详情	详情
(XIII)	40122	2-phenethylbenzoic acid	4890-85-1	C₁₅H₁₄O₂	详情	详情
(XIV)	40123	10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberone	1210-35-1	C₁₅H₁₂O	详情	详情
(XV)	40124	10-bromo-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one		C₁₅H₁₁BrO	详情	详情

合成路线2

The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with allyl magnesium bromide (A) in ethyl ether gives 5-hydroxy-5-allyldibenzo[a,d]cyclohepta-1,4,6-triene (II), which is dehydrated with acetic anhydride and acetyl chloride at 90 C yielding 5-propenylidenedibenzo[a,d]cyclohepta-1,4,6-triene (III). Finally, this compound is treated with phenylmagnesium bromide and dimethylamine (B) at 80 C.

参考文献中间体

【1】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【2】 Schmitt, G. (F. Hoffmann-La Roche AG); A process for the manufacture of tricyclic amines. BE 0636000; CH 385191; DE 1468006; FR 1366413; GB 990105 .

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)	10386	Allyl(bromo)magnesium	1730-25-2	C₃H₅BrMg	详情	详情
(B)	19443	N-methylmethanamine; N,N-dimethylamine	124-40-3	C₂H₇N	详情	详情
(I)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(II)	40125	5-allyl-5H-dibenzo[a,d]cyclohepten-5-ol		C₁₈H₁₆O	详情	详情
(III)	40126	5-(2-propenylidene)-5H-dibenzo[a,d]cycloheptene		C₁₈H₁₄	详情	详情

合成路线3

The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with dimethylaminopropyl magnesium (C) chloride in ethyl ether gives 5-hydroxy-5-(3-dimethylaminopropyl)dibenzo[a,d]cyclohepta-1,4,6-triene (IV), which is then treated with HCl in refluxing acetic acid. Alternatively, it can also be obtained by methylation of 5-(3-methylaminopropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (IX) with formic acid and formaldehyde at 100 C.

参考文献中间体

【1】 Protiva, M.; Vera, S.; CZ 136585 .
【2】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【3】 Vilani, F.J. (Schering Corp.); 5-(3'-Dimethylamino-2'-methylpropyl)dibenzocycloheptenes. US 3409640 .

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)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(IV)	40127	5-[3-(dimethylamino)propyl]-5H-dibenzo[a,d]cyclohepten-5-ol	18029-54-4	C₂₀H₂₃NO	详情	详情
(IX)	40128	N-[3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-N-methylamine; 3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-N-methyl-1-propanamine		C₁₉H₁₉N	详情	详情
(C)	37604	bromo[3-(dimethylamino)propyl]magnesium	120615-47-6	C₅H₁₂BrMgN	详情	详情

合成路线4

The Grignard reaction of dibenzo[a,d]cyclohepta-1,4,6-triene-5-one (I) with cyclopropyl magnesium bromide (D) in THF gives 5-hydroxy-5-cyclopropyldibenzo[a,d]cyclohepta-1,4,6-triene (V), which is then treated with HBr in acetic acid to yield 5-(3-bromopropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (VI). Finally, (VI) is treated with dimethylamine (B) in benzene at 95 C. The hydroxycompound (V), obtained as before, is treated with HClO4 in dioxane to yield 5-(3-hydroxypropylidene)dibenzo[a,d]cyclohepta-1,4,6-triene (VII), which is then treated with p-toluenesulfonyl chloride in pyridine to afford the tosyl derivate (VIII). Finally, (VIII) is treated with dimethylamine (B) in benzene at 100 C.

参考文献中间体

【1】 Roberts, P.J.; Castañer, J.; Cyclobenzaprine. Drugs Fut 1977, 2, 5, 299.
【2】 Hoffsommer, R.D. Jr.; et al.; Nouveaux derives de dibenzocycloheptenes et leur preparation. BE 0631012 .
【3】 Wendler, N.L.; Dibenzocycloheptenes. BE 0633316 .

中间体序号	中间体编号	品名	CAS号	分子式	供应商	用于合成
(D)	12450	Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide	23719-80-4	C₃H₅BrMg	详情	详情
(B)	19443	N-methylmethanamine; N,N-dimethylamine	124-40-3	C₂H₇N	详情	详情
(I)	29151	5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberenone	2222-33-5	C₁₅H₁₀O	详情	详情
(V)	40129	5-cyclopropyl-5H-dibenzo[a,d]cyclohepten-5-ol		C₁₈H₁₆O	详情	详情
(VI)	40130	5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene		C₁₈H₁₅Br	详情	详情
(VII)	40131	3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-propanol		C₁₈H₁₆O	详情	详情
(VIII)	40132	3-(5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl 4-methylbenzenesulfonate		C₂₅H₂₂O₃S	详情	详情

Extended Information