Thionyl Chloride → Cinacalcet Impurity 74

HRID 476313Notes

Reaction equation

HRID 476313 reaction equation
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.S(Cl)([Cl:31])=O>C1(C)C=CC=CC=1>[ClH:31].[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

Participants

4

Reactant 2

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

Product 1

HCID 46897288Cinacalcet Impurity 74

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
45 °C

Procedure

(R)-3-(1-(naphthalen-1-yl)ethylamino)-1-(3-(trifluoromethyl)phenyl)propan-1-ol hydrochloride (IX) (35.0 g, 85.393 mmol) is suspended in toluene (150 ml) at 20° C. and thionyl chloride (11.2 g, 94.141 mmol) is added slowly. The reaction mixture is stirred at 30°-40° C. for 4-5 hrs and then the solvent is distilled off under vacuum. The residual toluenic slurry is flushed with isopropanol, upon several distillation/refill cycles. The resulting isopropanol solution is refluxed for 1 hr, then cooled down to 45° C. and added with methyl tert-butyl ether (MTBE) (70 ml). The so-obtained suspension is stirred at 45° C. for 1 hr, then cooled down to 0° C. and aged 1 hr. 29.6 g of a 95.8:4.2 (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 hydro-chloride (XI) is obtained as a white powder after filtration, washing with a 3:1 vol/vol isopropanol/MTBE mixture (2×20 ml) end exsiccation at 55° C. under vacuum.

Workup

  1. distillationthe solvent is distilled off under vacuum
  2. customThe residual toluenic slurry is flushed with isopropanol, upon several distillation/refill cycles
  3. temperatureThe resulting isopropanol solution is refluxed for 1 hr
  4. additionadded with methyl tert-butyl ether (MTBE) (70 ml)
  5. stirringThe so-obtained suspension is stirred at 45° C. for 1 hr
  6. temperaturecooled down to 0° C. and aged 1 hr
  7. addition29.6 g of a 95.8:4.2 (HPLC % area) mixture of (R)-3-chloro-N-(1-(naphthalen-1-yl)ethyl)-3-(3-(trifluoromethyl)phenyl)propan-1-amine hydrochloride (X)

Sources & evidence

ORD record
ord-e54754a881fa4a2e863d4f6cda778370
Source dataset
uspto-grants-2014_01
Patent number
US08637708B2

Reaction notes

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