Hydrochloric Acid → 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt

HRID 130366노트

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HRID 130366 반응식
[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])/[C:12](=[CH:15]\[C:16]3[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=3)/[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1.NCC(O)=O.[CH2:31]1N2CN3CN(C2)[CH2:33][N:32]1C3.Cl>CN1CCCC1=O.C1(C)C=CC=CC=1>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[C@@:12]3([C@H:15]([C:16]4[CH:17]=[CH:18][C:19]([C:20]#[N:21])=[CH:22][CH:23]=4)[CH2:33][NH:32][CH2:31]3)[N:11]([CH3:24])[C:10]2=[O:25])[CH:5]=[C:6]([Cl:8])[CH:7]=1

참가 물질

7

반응물 4

HCID 313Hydrochloric Acid2회HCID 750GlycineHCID 4101HexamethylenetetramineHCID 10270593(E)-4-((1-(3,5-Dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile

생성물 1

HCID 692187994-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloric acid salt수율 179.4%

시약·촉매·용매 2

HCID 1140Toluene용매HCID 13387N-methyl-2-pyrrolidone용매

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온도
140 °C

실험 절차

A mixture of (E)-4-((1-(3,5-dichlorophenyl)-3-methyl-2,5-dioxoimidazolidin-4-ylidene)methyl)benzonitrile (1.00 kg, 2.69 mol), glycine (0.50 kg, 6.72 mol) and hexamethylenetetramine (0.28 kg, 2.02 mol) in 1-methyl-2-pyrrolidinone (5.00 L) and toluene (2.50 L) was heated at 140° C. for 7-8 hours. The completeness of the reaction was followed by HPLC. Upon reaction completion, the mixture was cooled to 40-50° C. and filtered. The filtered solid was washed with toluene (0.67 L). To the filtrate was added HCl (1M, 13.33 L, 13.33 mol). The resulting biphasic mixture was heated to 50-60° C. and was stirred for 10-15 minutes. The aqueous phase was separated and the organic phase was washed with HCl (1M, 1.67 L, 1.67 mol) at 60-80° C. The aqueous phases were combined and were stirred at 80° C. for 2 hours. The solution was cooled slowly in 3-4 hours to 20-25° C. with gentle stirring and seeding. Crystallization occurred and the resulting suspension was put aside at 20-25° C. for at least 16 hours with occasional stirring, cooled to 0-5° C. in 2 hours, stirred gently at 0-5° C. for 2 hours and then filtered. The filter cake was washed with ice water (2×2.50 L) and dried at maximum 40° C. to a constant weight. 4-[(5S*,9R*)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile hydrochloride salt (1.09 kg, 90%) was obtained as beige crystalline solid. mp=183-185° C. 1H NMR (DMSO-d6): 7.87(2H, d, J=8.1 Hz), 7.61 (1H, m), 7.40 (2H, d, J=8.1 Hz), 6.68 (2H, m), 4.17 (1H, m), 3.85 (2H, m), 3.76 (2H, m), 3.43 (3H, s), 3.24(2H, s). 13C NMR (DMSO-d6): 14 Carbons (170.84, 152.92, 137.35, 133.94, 132.87, 132.35, 128.01, 124.50, 118.12, 111.30, 71.42, 46.57, 45.11, 25.51). Anal. Calcd for C20H17Cl3N4O2+1.3 H2O: C, 50.51; H, 3.91; N, 11.79; Cl, 22.39. Found: C, 50.56; H, 3.86; N, 11.58; Cl, 21.98; KF, 5.12.

후처리

  1. customUpon reaction completion
  2. temperaturethe mixture was cooled to 40-50° C.
  3. filtrationfiltered
  4. washThe filtered solid was washed with toluene (0.67 L)
  5. temperatureThe resulting biphasic mixture was heated to 50-60° C.
  6. customThe aqueous phase was separated
  7. stirringwere stirred at 80° C. for 2 hours
  8. temperatureThe solution was cooled slowly in 3-4 hours to 20-25° C.
  9. stirringwith gentle stirring
  10. customCrystallization
  11. waitthe resulting suspension was put aside at 20-25° C. for at least 16 hours with occasional stirring
  12. temperaturecooled to 0-5° C. in 2 hours
  13. stirringstirred gently at 0-5° C. for 2 hours
  14. filtrationfiltered
  15. washThe filter cake was washed with ice water (2×2.50 L)
  16. customdried at maximum 40° C. to a constant weight

출처 및 근거

ORD 기록
ord-dd3e84068deb4c5fa038cd4a502af0f1
출처 데이터셋
uspto-grants-2008_06
특허 번호
US07381737B2

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