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 655557ノート

反応式

HRID 655557 の反応式
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]

参加物

12

反応物 9

HCID 176Acetic AcidHCID 222AmmoniaHCID 8471TriethylamineHCID 253877Potassium BromideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 23665760Sodium HypochloriteHCID 44541812(4S)-6-Azaspiro[2.5]octan-4-ol hydrochloride2 回HCID 67080598(S)-4-(3-Hydroxy-propyl)-2-methyl-3-oxo-piperazine-1-carboxylic acid (3,4-dichloro-phenyl)-amide2 回

生成物 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)-amide収率 38.2%

試薬・触媒・溶媒 2

HCID 2724126Tempo触媒HCID 6344Dichloromethane溶媒2 回

実験手順

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)+.

後処理

  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

出典と根拠

ORDレコード
ord-9d258ee8964a4c64a1700e00d17e4688
出典データセット
uspto-grants-2011_12
特許番号
US08071586B2

反応ノート

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