Acetic Acid → (S)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide

HRID 655557노트

반응식

HRID 655557 반응식
C(=O)([O-])O.[Na+].[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25]O)[C:19](=[O:27])[C@@H:18]2[CH3:28])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13].[Br-].[K+].Cl[O-].[Na+].Cl.[CH2:35]1[C:37]2([CH2:42][CH2:41][NH:40][CH2:39][C@H:38]2[OH:43])[CH2:36]1.C(N(CC)CC)C.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].N>ClCCl.CC1(C)N([O])C(C)(C)CCC1>[Cl:6][C:7]1[CH:8]=[C:9]([NH:14][C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][N:40]3[CH2:41][CH2:42][C:37]4([CH2:35][CH2:36]4)[C@H:38]([OH:43])[CH2:39]3)[C:19](=[O:27])[C@@H:18]2[CH3:28])=[O:16])[CH:10]=[CH:11][C:12]=1[Cl:13]

참가 물질

12

반응물 9

HCID 176Acetic AcidHCID 222AmmoniaHCID 8471TriethylamineHCID 253877Potassium BromideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 23665760Sodium HypochloriteHCID 44541812(4S)-6-Azaspiro[2.5]octan-4-ol hydrochloride2회HCID 67080598(S)-4-(3-Hydroxy-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide2회

생성물 1

HCID 44612134(S)-4-[3-((S)-4-Hydroxy-6-aza-spiro[2.5]oct-6-yl)-propyl]-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide수율 38.2%

시약·촉매·용매 2

HCID 2724126Tempo촉매HCID 6344Dichloromethane용매2회

실험 절차

Saturated aq. sodium hydrogencarbonate solution (0.13 ml) was added to a solution of (S)-4-(3-hydroxy-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (intermediate 21; 95 mg, 0.26 mmol), potassium bromide (3 mg, 0.03 mmol), and 2,2,6,6-tetramethylpiperidin-1-oxyl (0.4 mg, 0.003 mmol) in dichloromethane (5 ml). Sodium hypochlorite solution (10% in water, 0.16 ml, 0.26 mmol) was added portionwise at 0° C., and the course of the oxidation was monitored by thin layer chromatography. After all starting material had reacted, the reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution, and the aqueous layer was extracted twice with dichloromethane. The organic phases were pooled, dried (MgSO4), filtered, and evaporated, thus affoding (S)-2-methyl-3-oxo-4-(3-oxo-propyl)-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide (75 mg). This was dissolved in dichloromethane (2 ml) and added over 20 min to a suspension of (S)-6-aza-spiro[2.5]octan-4-ol hydrochloride (intermediate 2; 39 mg, 0.24 mmol) triethylamine (25 mg, 0.25 mmol), acetic acid (29 mg, 0.48 mmol) and sodium triacetoxyborohydride (58 mg, 0.26 mmol) in dichloromethane (2 ml). After 16 h the reaction mixture was treated with 25% aq. ammonia solution (70 μL, 0.48 mmol) and evaporated. Chromatography (SiO2; dichloro-methane/methanol/25% aq. ammonia solution 90:10:0.25) produced the title compound (43 mg, 35%). White solid, MS (ISP)=469.3 (M+H)+.

후처리

  1. customAfter all starting material had reacted
  2. washthe reaction mixture was washed with sat. aq. sodium hydrogencarbonate solution
  3. extractionthe aqueous layer was extracted twice with dichloromethane
  4. dry with materialdried (MgSO4)
  5. filtrationfiltered
  6. customevaporated
  7. dissolutionThis was dissolved in dichloromethane (2 ml)
  8. customevaporated

출처 및 근거

ORD 기록
ord-9d258ee8964a4c64a1700e00d17e4688
출처 데이터셋
uspto-grants-2011_12
특허 번호
US08071586B2

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