Sodium Hydroxide → Cinacalcet Impurity 74

HRID 476314ノート

反応式

HRID 476314 の反応式
Cl.[C:2]1([CH:12]([NH:14][CH2:15][CH2:16][C@H:17]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)O)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].S(Cl)([Cl:33])=O>CC(OC)(C)C.O.C1(C)C=CC=CC=1>[ClH:33].[C:2]1([C@H:12]([NH:14][CH2:15]/[CH:16]=[CH:17]/[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:26])([F:27])[F:28])[CH:20]=2)[CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][CH:3]=1

参加物

7

反応物 3

HCID 14798Sodium HydroxideHCID 24386Thionyl ChlorideHCID 67052600(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride

生成物 1

HCID 46897288Cinacalcet Impurity 74

試薬・触媒・溶媒 3

HCID 962Water溶媒2 回HCID 1140Toluene溶媒HCID 15413tert-Butyl methyl ether溶媒3 回

反応条件

温度
60 °C

実験手順

(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IX) (50.0 g, 121.990 mmol) is suspended in MTBE (200 ml) and water (80 ml) at room temperature. Sodium hydroxide (30% w/w aqueous solution) is added drop-wise (17.1 g, 128.250 mmol) in order to control the exothermic reaction and the mixture is stirred until the starting solid dissolves completely. The organic layer is then separated and washed repeatedly with water up to neutral pH. Thus MTBE is flushed with toluene and thionyl chloride (16.7 g, 140.372 mmol) is added slowly to the resulting toluenic solution, while maintaining 10°-20° C. The reaction mixture is heated up to 60° C. and maintained for 4 hrs, or until positive IPC (via HPLC). At reaction completion MTBE is charged (170 ml) and the mixture is heated up to 80°-85° C. and trace water is removed azeotropically. The mixture is cooled down to 60° C., MTBE is restored, then cooled down to 10° C. and aged two hours. 46.1 g of a 96.2:3.8 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X) and (R,E)-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)prop-2-en-1-amine hydrochloride (XI) is obtained as a white powder after filtration, washing with a 1:1 vol/vol toluene/MTBE mixture (3×40 ml) end exsiccation at 55° C. under vacuum.

後処理

  1. customat room temperature
  2. customthe exothermic reaction
  3. dissolutiondissolves completely
  4. customThe organic layer is then separated
  5. washwashed repeatedly with water up to neutral pH
  6. additionis added slowly to the resulting toluenic solution
  7. temperaturewhile maintaining 10°-20° C
  8. temperaturemaintained for 4 hrs
  9. additionis charged (170 ml)
  10. temperaturethe mixture is heated up to 80°-85° C.
  11. customis removed azeotropically
  12. temperatureThe mixture is cooled down to 60° C.
  13. temperaturecooled down to 10° C. and aged two hours
  14. addition46.1 g of a 96.2:3.8 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X)

出典と根拠

ORDレコード
ord-f957f93a588c47368119a2d9c61ee024
出典データセット
uspto-grants-2014_01
特許番号
US08637708B2

反応ノート

読み込み中…