ReN-1869, NNC-05-1869, -Drug Synthesis Database

【结构式】

【药物名称】ReN-1869, NNC-05-1869

【化学名称】1-[3-(10,11-Dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]piperidine-3(R)-carboxylic acid

【CA登记号】170149-99-2, 170149-76-5 (HCl)

【分子式】C₂₄H₂₇NO₂

【分子量】361.48829

【开发单位】Novo Nordisk (Originator), ReNeuron (Licensee)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Neuropathic Pain, Treatment of, Non-Opioid Analgesics, Histamine H1 Antagonists

合成路线1 合成路线2 合成路线3

合成路线1

Addition of cyclopropylmagnesium bromide (II) to dibenzocycloheptanone (I) afforded the carbinol adduct (III), which was further rearranged to the bromopropylidene derivative (IV) upon treatment with bromotrimethylsilane. Alkylation of ethyl (R)-nipecotate (V) with bromide (IV) gave the tertiary amine (VI). The ethyl ester group of (VI) was finally hydrolyzed under basic conditions to furnish the corresponding carboxylic acid.

参考文献中间体

【1】 Andersen, K.E.; Olsen, U.B.; Petersen, H.; Grønvald, F.C.; Sonnewald, U.; Jørgensen, T.K.; Andersen, H.S. (Novo Nordisk A/S); Novel heterocyclic cpds.. US 5595989; US 5668129; US 5688788; US 5693649; US 5712292; US 5721254; US 5795888; US 6043239; WO 9518793 .
【2】 Olsen, U.B. (Novo Nordisk A/S); Novel method. JP 1999507947; WO 9722338 .

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)	40123	10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one; Dibenzosuberone	1210-35-1	C₁₅H₁₂O	详情	详情
(II)	12450	Bromo(cyclopropyl)magnesium;cyclopropylmagnesium bromide;cyclopropylmagnesiumbromide	23719-80-4	C₃H₅BrMg	详情	详情
(III)	52138	5-cyclopropyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol		C₁₈H₁₈O	详情	详情
(IV)	52139	5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene		C₁₈H₁₇Br	详情	详情
(V)	35224	ethyl (3S)-3-piperidinecarboxylate		C₈H₁₅NO₂	详情	详情
(VI)	52140	ethyl (3R)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate		C₂₆H₃₁NO₂	详情	详情

合成路线2

The condensation of dibenzocycloheptylidene derivative (I) with radiolabelled piperidine-3-carboxylic acid ethyl ester (II) by means of K2CO3 in ethyl acetate gives the adduct (III), which is hydrolyzed with aqueous HCl to yield the carboxylic acid (IV). Finally, this compound is submitted to optical resolution by means of chiral chromatography to provide the chiral radiolabelled compound.

参考文献中间体

【1】 Valsborg, J.S.; Foged, C.; Radiolabelling of NNC 05-1869, a compound for treatment of diabetic neuropathy. J Label Compd Radiopharm 2002, 45, 4, 351.

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)	52139	5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene		C₁₈H₁₇Br	详情	详情
(II)	25693	ethyl 3-piperidinecarboxylate	5006-62-2	C₈H₁₅NO₂	详情	详情
(II)	58262	ethyl 3-piperidinecarboxylate		C₈H₁₅NO₂	详情	详情
(III)	58263	ethyl 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate		C₂₆H₃₁NO₂	详情	详情
(III)	58266	ethyl 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylate		C₂₆H₃₁NO₂	详情	详情
(IV)	58264	1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid		C₂₄H₂₇NO₂	详情	详情
(IV)	58265	1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid		C₂₄H₂₇NO₂	详情	详情

合成路线3

The reduction of 1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-1,2,5,6-tetrahydropyridine-3-carboxylic acid (I) with tritium over PdO in methanol gives the racemic ditritiated compound (II), which is then submitted to optical resolution by chiral chromatography to afford the chiral radiolabelled compound.

参考文献中间体

【1】 Valsborg, J.S.; Foged, C.; Radiolabelling of NNC 05-1869, a compound for treatment of diabetic neuropathy. J Label Compd Radiopharm 2002, 45, 4, 351.

中间体序号	中间体编号	品名	分子式	供应商	用于合成
(I)	58267	1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-1,2,5,6-tetrahydro-3-pyridinecarboxylic acid	C₂₄H₂₅NO₂	详情	详情
(II)	58264	1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid	C₂₄H₂₇NO₂	详情	详情
(II)	58268	1-[3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ylidene)propyl]-3-piperidinecarboxylic acid	C₂₄H₂₇NO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)