NNC-63-0532, -Drug Synthesis Database

【结构式】

【药物名称】NNC-63-0532

【化学名称】2-[8-(1-Naphthylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid methyl ester

【CA登记号】250685-44-0

【分子式】C₂₇H₂₉N₃O₃

【分子量】443.55048

【开发单位】Novo Nordisk (Originator)

【药理作用】ANALGESIC AND ANESTHETIC DRUGS, Analgesic Drugs, Opioid Analgesics, ORL1 (OP4) Agonists

合成路线1 合成路线2

合成路线1

Solid phase synthesis: Attachment of 8-Fmoc-3-carboxymethyl-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one (I) to Wang resin by means of 2,6-dichlorobenzoyl chloride (A) in DMF in the presence of pyridine, followed by treatment with benzoyl chloride (B) in dichloromethane in the presence of pyridine, provides resin-anchored derivative (II). Treatment of resin (II) with piperidine in DMF allows Fmoc removal to yield deprotected piperidine derivative (III), which is then converted into the target compound by alkylation with 1-(bromomethyl)naphthalene (IV) by heating in DMSO in the presence of DIEA, followed by cleavage of the molecule from the resin by heating with NaOMe in THF/MeOH. Alternatively, the conversion of (III) into the desired compound can be achieved by reductive amination between resin (III) and aldehyde (V) by means of NaBH3CN in THF in the presence of HOAc to afford anchored derivative (VI), followed by cleavage from the resin by heating with NaOMe in THF/MeOH.

参考文献中间体

【1】 Watson, B.; Thomsen, C.; Hohlweg, R. (Novo Nordisk A/S); Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes. EP 1080091; WO 9959997 .

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)	10463	Benzoyl chloride	98-88-4	C₇H₅ClO	详情	详情
(A)	25087	2,6-dichlorobenzoyl chloride	4659-45-4	C₇H₃Cl₃O	详情	详情
(I),(II)	47322	2-[8-[(9H-fluoren-9-ylmethoxy)carbonyl]-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid		C₃₀H₂₉N₃O₅	详情	详情
(III)	47323	2-(4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl)acetic acid		C₁₅H₁₉N₃O₃	详情	详情
(IV)	47324	1-(bromomethyl)naphthalene	3163-27-7	C₁₁H₉Br	详情	详情
(V)	12314	1-Naphthaldehyde	66-77-3	C₁₁H₈O	详情	详情
(VI)	47325	2-[8-(1-naphthylmethyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]dec-3-yl]acetic acid		C₂₆H₂₇N₃O₃	详情	详情

合成路线2

Solution synthesis: In this case the target product is obtained by alkylation of 1-phenyl-1,3,8-triaza-spiro[4.5]decan-4-one (VII) with 1-(chloromethyl)naphthalene (VIII) by means of K2CO3 and NaI in refluxing 2-butanone, followed by acylation with methyl bromoacetate (X) in DMF by means of NaH.

参考文献中间体

【1】 Watson, B.; Thomsen, C.; Hohlweg, R. (Novo Nordisk A/S); Novel 1,3,8-triazaspiro[4.5]decanones with high affinity for opioid receptor subtypes. EP 1080091; WO 9959997 .

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)	18116	1-Phenyl-1,3,8-triazaspiro[4.5]decan-4-one	1021-25-6	C₁₃H₁₇N₃O	详情	详情
(VIII)	27408	1-(Chloromethyl)naphthalene	86-52-2	C₁₁H₉Cl	详情	详情
(IX)	47326	8-(1-naphthylmethyl)-1-phenyl-1,3,8-triazaspiro[4.5]decan-4-one		C₂₄H₂₅N₃O	详情	详情
(X)	12309	methyl 2-bromoacetate; methyl bromoacetate	96-32-2	C₃H₅BrO₂	详情	详情

Extended Information

Drug NewChemical Entity Original Patent(1)