Sodium Hydroxide → Cinacalcet Impurity 74

HRID 476314노트

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HRID 476314 반응식
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

참가 물질

7

반응물 3

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

생성물 1

HCID 46897288Cinacalcet Impurity 74

시약·촉매·용매 3

HCID 962Water용매2회HCID 1140Toluene용매HCID 15413tert-Butyl methyl ether용매3회

반응 조건

온도
60 °C

실험 절차

(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.

후처리

  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)

출처 및 근거

ORD 기록
ord-f957f93a588c47368119a2d9c61ee024
출처 데이터셋
uspto-grants-2014_01
특허 번호
US08637708B2

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