Sodium Carbonate → N-Boc-sitagliptin

HRID 84154

反応式

HRID 84154 の反応式
Cl.[F:2][C:3]([F:14])([F:13])[C:4]1[N:8]2[CH2:9][CH2:10][NH:11][CH2:12][C:7]2=[N:6][N:5]=1.C(N(C(C)C)CC)(C)C.ON1C2C=CC=CC=2N=N1.CCN=C=NCCCN(C)C.Cl.[C:46]([O:50][C:51]([NH:53][C@H:54]([CH2:59][C:60]1[CH:65]=[C:64]([F:66])[C:63]([F:67])=[CH:62][C:61]=1[F:68])[CH2:55][C:56](O)=[O:57])=[O:52])([CH3:49])([CH3:48])[CH3:47].C([O-])([O-])=O.[Na+].[Na+]>CN(C)C=O>[C:46]([O:50][C:51]([NH:53][C@H:54]([CH2:59][C:60]1[CH:65]=[C:64]([F:66])[C:63]([F:67])=[CH:62][C:61]=1[F:68])[CH2:55][C:56]([N:11]1[CH2:10][CH2:9][N:8]2[C:4]([C:3]([F:13])([F:2])[F:14])=[N:5][N:6]=[C:7]2[CH2:12]1)=[O:57])=[O:52])([CH3:49])([CH3:47])[CH3:48]

参加物

8

反応物 6

HCID 10340Sodium CarbonateHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 7146288(R)-3-(tert-butoxycarbonylamino)-4-(2,4,5-trifluorophenyl)butanoic acidHCID 119613713-(Trifluoromethyl)-5,6,7,8-tetrahydro-[1,2,4]triazolo[4,3-a]pyrazine hydrochloride

生成物 1

HCID 46836576N-Boc-sitagliptin

試薬・触媒・溶媒 1

HCID 6228Dimethylformamide溶媒2 回

反応条件

温度
27.5 °C

実験手順

To a solution of 3-trifluoromethyl-5,6,7,8-tetrahydro[1,2,4]triazolo[4,3-a]pyrazine hydrochloride (11) (1.0 eq, 28.0 gm), diisopropylethylamine (2.0 eq, 31.0 gm), 1-hydroxybenzotriazole (1.2 eq, 22.0 gm), and EDC-HCl (1.2 eq, 28.0 gm) in N,N-dimethylformamide (4.0 vol, 160.0 ml), a solution of (3R)-3-[N-(tert-butoxycarbonyl)amino]-4-(2,4,5-trifluorophenyl)butanoic acid (07) (40.0 gm, 0.12 mol) in N,N-dimethylformamide (4.0 vol, 160.0 ml) was charged at 0-5° C. within 1 hour. The clear pale yellow solution was further stirred for 12 hours at 25-30° C. After stirring for 12 hours, the N,N-dimethylformamide was distilled out completely at 55-65° C. under reduced pressure to give a brown coloured residue. The brown coloured residue was further basified with 10% Na2CO3 solution (1.0 vol, 40.0 ml) and the product was extracted in ethyl acetate (3×10.0 vol, 3×400.0 ml). The combined ethyl acetate layers were washed with water, charcoalized and filtered, and the ethyl acetate was distilled out completely to give a white coloured product. The product was triturated with hexane (10.0 vol, 400.0 ml) and filtered at 25-30° C. The crude Boc-protected sitagliptin free base (12) was further purified by crystallising it from a mixture of isopropanol (20.0 vol) and water (2.0 vol).

後処理

  1. stirringAfter stirring for 12 hours
  2. distillationthe N,N-dimethylformamide was distilled out completely at 55-65° C. under reduced pressure
  3. customto give a brown coloured residue
  4. extractionthe product was extracted in ethyl acetate (3×10.0 vol, 3×400.0 ml)
  5. washThe combined ethyl acetate layers were washed with water
  6. filtrationfiltered
  7. distillationthe ethyl acetate was distilled out completely
  8. customto give a white coloured product
  9. customThe product was triturated with hexane (10.0 vol, 400.0 ml)
  10. filtrationfiltered at 25-30° C
  11. customThe crude Boc-protected sitagliptin free base (12) was further purified
  12. customby crystallising it
  13. additionfrom a mixture of isopropanol (20.0 vol) and water (2.0 vol)

出典と根拠

ORDレコード
ord-33ff946fa2834da2aed15067aea23af5
出典データセット
uspto-grants-2014_09
特許番号
US08846916B2

関連ノート

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