Sodium Hydroxide → Piboserod

HRID 1871037ノート

反応式

HRID 1871037 の反応式
C[Al](C)C.[CH2:5]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH2:16])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8].[O:17]1[C:22]2=[C:23]([C:30](OC)=[O:31])[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:21]2[CH2:20][CH2:19][CH2:18]1.[OH-].[Na+]>C1(C)C=CC=CC=1.O>[CH2:5]([N:9]1[CH2:14][CH2:13][CH:12]([CH2:15][NH:16][C:30]([C:23]2[C:24]3[CH:25]=[CH:26][CH:27]=[CH:28][C:29]=3[N:21]3[CH2:20][CH2:19][CH2:18][O:17][C:22]=23)=[O:31])[CH2:11][CH2:10]1)[CH2:6][CH2:7][CH3:8]

参加物

7

反応物 4

HCID 14798Sodium Hydroxide2 回HCID 104421334-Aminomethyl-1-N-butylpiperidineHCID 11746477methyl 3,4-dihydro-2H-[1,3]oxazino[3,2-a]indole-10-carboxylateHCID 16682925Trimethylaluminum

生成物 1

HCID 177336Piboserod収率 93%

試薬・触媒・溶媒 2

HCID 962Water溶媒HCID 1140Toluene溶媒2 回

反応条件

温度
10 °C

実験手順

Method A Toluene (85L) was azeotropically dried in an argon purged reactor, cooled to 10° C. and a solution of trimethylaluminum in toluene (18.57 kg, 16.7% w/w, 43 mole) added. To this at 20 to 24° C. was added a solution of 1-n-butyl-4-piperidinylmethylamine (7.39 kg, 99.4% pure, 42.7 mole) in toluene (22 L) over 43 minutes. Methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (9.65 kg, 98.9% pure, 41.3 mole) was added in one portion and the reaction heated to reflux at 112° C. for 4 hours 10 minutes after which time the reaction was judged to be complete by HPLC analysis. 10% Sodium hydroxide solution (52.2 L), prepared from 32% ww sodium hydroxide (24 L) and water (80 L), was added cautiously over 16 minutes at about 60 to 70° C. The resulting mixture was heated to 70 to 80° C. and the aqueous layer separated. The toluene layer was washed with 10% sodium hydroxide (52.2 L) followed twice by water (29 L each wash). The toluene layer was cooled and diluted with hexane fraction (133 L) to crystallise the product. After cooling to about 2° C. overnight the product was collected by filtration, washed on the filter with hexane (21 L) and dried in vacuo at 40° C. overnight to give SB-207266 batch 207266-HP8 (12.26 kg, 94.5% pure, 75.9%).

後処理

  1. dry with materialMethod A Toluene (85L) was azeotropically dried in an argon purged reactor
  2. temperaturethe reaction heated
  3. temperatureto reflux at 112° C. for 4 hours 10 minutes after which time the reaction
  4. additionwas added cautiously over 16 minutes at about 60 to 70° C
  5. temperatureThe resulting mixture was heated to 70 to 80° C.
  6. customthe aqueous layer separated
  7. washThe toluene layer was washed with 10% sodium hydroxide (52.2 L)
  8. temperatureThe toluene layer was cooled
  9. additiondiluted with hexane fraction (133 L)
  10. customto crystallise the product
  11. temperatureAfter cooling to about 2° C. overnight the product
  12. filtrationwas collected by filtration
  13. washwashed on the
  14. filtrationfilter with hexane (21 L)
  15. customdried in vacuo at 40° C. overnight

出典と根拠

ORDレコード
ord-32999ef9afa94edc84024876f0971f10
出典データセット
uspto-grants-2000_08
特許番号
US06100397

反応ノート

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