Phenol → HCID 9849074, compound

HRID 1246563Notes

Reaction equation

HRID 1246563 reaction equation
[C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[C:9]([CH3:12])([O-:11])[CH3:10].[K+].C1O[C@H]1CO[S:19]([C:22]1C=[C:26]([N+:28]([O-:30])=O)[CH:25]=[CH:24][CH:23]=1)(=O)=O.C([O-])=O.[NH4+].C(#N)C.[N+](C1C=CC=CC=1S(OCC1OC1)(=O)=O)([O-])=O.[Cl:55][C:56]1[CH:61]=[CH:60][C:59]([N:62]2[CH2:67][CH2:66][NH:65][CH2:64][CH2:63]2)=[CH:58][CH:57]=1>O.CN1C(=O)CCC1>[ClH:55].[Cl:55][C:56]1[CH:57]=[CH:58][C:59]([N:62]2[CH2:67][CH2:66][N:65]([CH2:10][C@@H:9]([OH:11])[CH2:12][O:7][C:1]3[CH:6]=[CH:5][CH:4]=[C:3]([C:26]4[C:25]5[S:19][CH:22]=[CH:23][C:24]=5[O:30][N:28]=4)[CH:2]=3)[CH2:64][CH2:63]2)=[CH:60][CH:61]=1

Participants

9

Reactant 6

HCID 996PhenolHCID 974781-(4-Chlorophenyl)piperazineHCID 146513Benzenesulfonic acid, 3-nitro-, (2R)-2-oxiranylmethyl esterHCID 13767637HCID 13767637, compoundHCID 23665647Potassium tert-butoxide2×HCID 86609821HCID 86609821, compound

Product 1

HCID 9849074HCID 9849074, compound

Reagents, catalysts & solvents 2

HCID 962WaterSolvent2×HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
23 °C

Procedure

Treat a stirred solution of the example 1 phenol (2.17 g, 0.010 mol) and N-methyl pyrrolidinone (30 mL) at 10° C. with solid potassium t-butoxide (1.12 g, 0.010 mol). Cool the reaction after 30 min. to 0–5° C. and treat with (2R)-(−)-glycidyl 3-nitrobenzenesulfonate (2.59 g, 0.010 mol, 99% ee, Aldrich Chemical Company). Monitor reaction progress by HPLC (Waters μ-Bondapak C-18 column, 0.1 N ammonium formate/acetonitrile (40:60); flow rate 1 mL/min., UV detection at 240 nm). After 2 hours, add 0.1 equivalent of both potassium t-butoxide and the glycidyl nitrobenzenesulfonate and stir for one hour. HPLC indicated >98% conversion to the intermediate epoxide. Add 1-(4-chlorophenyl)-piperazine (5.93 g, 0.030 mol) and water (3 mL) and heat to 70° C. HPLC analysis indicates >98% conversion of the epoxide to product after 5 hours. Cool to 23° C., pour into water (250 mL) and extract with ethyl acetate (150 mL, then 2×100 mL). Wash the combined extracts with 5% NaCl solution, concentrate in vacuo and purify the crude material by chromatography (silica gel, elute with ethyl acetate). Recrystallize the purified material from ethyl acetate:heptane (50:50) to give the free base of the title compound. Treat a slurry of the free base in methanol (25 mL) at 23° C. with 37% HCl (0.67 mL, 1.05 equiv.) to give the title compound (3.62 g, 76% yield) after drying (90° C., 6 hours), m.p. 163–165° C., chiral HPLC purity >98% ee; MS (Cl, methane) m/e 470 (MH+)

Workup

  1. temperatureCool
  2. customthe reaction after 30 min. to 0–5° C.
  3. customafter 5 hours
  4. extractionextract with ethyl acetate (150 mL
  5. washWash the combined extracts with 5% NaCl solution
  6. concentrationconcentrate in vacuo
  7. custompurify the crude material
  8. washby chromatography (silica gel, elute with ethyl acetate)
  9. customRecrystallize the purified material from ethyl acetate:heptane (50:50)

Sources & evidence

ORD record
ord-384e46e636c345309a280b9ce3c10f4e
Source dataset
uspto-grants-2006_10
Patent number
US07125903B1

Reaction notes

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