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 655557Notes

Reaction equation

HRID 655557 reaction equation
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]

Participants

12

Reactant 9

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

Product 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)-amideYield 38.2%

Reagents, catalysts & solvents 2

HCID 2724126TempoCatalystHCID 6344DichloromethaneSolvent2×

Procedure

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)+.

Workup

  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

Sources & evidence

ORD record
ord-9d258ee8964a4c64a1700e00d17e4688
Source dataset
uspto-grants-2011_12
Patent number
US08071586B2

Reaction notes

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