Hydrochloric Acid → HCID 59378889, compound

HRID 1643908Notes

Reaction equation

HRID 1643908 reaction equation
Cl.[F:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][NH2:21])[CH2:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=1.[NH2:22][C:23](N)=[O:24].Cl.O>CN1C(=O)CCC1>[F:2][C:3]1[CH:4]=[C:5]([S:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[C@H:16]([CH2:20][NH:21][C:23]([NH2:22])=[O:24])[CH2:15][CH2:14][CH2:13]3)[CH:6]=[CH:7][CH:8]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 962WaterHCID 1176UreaHCID 66755473HCID 66755473, compound

Product 1

HCID 59378889HCID 59378889, compoundYield 80.5%

Reagents, catalysts & solvents 1

HCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
100 °C

Procedure

(R)-6-(3-fluorophenylsulfanyl)-1,2,3,4-tetrahydronaphthalen-1-methylamine hydrochloride salt (4.6 kg) and urea (3.4 kg) were suspended in fresh NMP (9.5 kg). Concentrated aqueous 37% HCl (0.15 kg) was added and the reaction mixture was heated to 100° C. for three hours. On completion of reaction (confirmed by HPLC), the reaction mixture was cooled to 60° C. and water (45 kg) was added. The resulting slurry was stirred vigorously while cooling down to 20° C., and the mixture was allowed to sit for 24 hours. The resulting solid was filtered and washed with water. The wet filter cake was taken into toluene (23.6-kg) and heated to 80° C., then washed with water (twice with 13.5 L) and the reaction mixture was cooled to 40° C. [(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea crystallized on addition of n-heptane (7.8 kg). The product was filtered and dried under reduced pressure at 50° C. to afford 3.78-kg of [(R)-6-(3-fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea: MP=115.1-116.0° C.; MS (M+1)=288; H1 NMR (300 MHz): δ ppm (DMSO): 1.59-1.84 (3H, m), 2.59-2.78 (2H, m), 2.86 (1H, m), 3.10 (1H, ddd, J=6.03, 9.04 Hz), 3.28 (1H, ddd, J=5.65, 6.03), 3.34 (1H, s), 5.46 (2H, s, NH), 6.11 (1H, t, J=6.03 Hz) 6.96-7.09 (3H, m), 7.17-7.23 (2H, m), 7.26-7.31 (1H, m), 7.32-7.41 (1H, m): [α]D=25.5° (MeOH). Chiral Assay (Area Norm): Column: Chiralpak AS-H (150×4.6 mm), mobile phase 80/20 hexane/ethanol(isocratic), flow rate 0.7 ml/min, 25° C., uv @230 nm.: (R)-isomer 99.03/(S)-isomer 0.97.

Workup

  1. customOn completion of reaction (confirmed by HPLC)
  2. temperaturethe reaction mixture was cooled to 60° C.
  3. temperaturewhile cooling down to 20° C.
  4. filtrationThe resulting solid was filtered
  5. washwashed with water
  6. temperatureheated to 80° C.
  7. washwashed with water (twice with 13.5 L) and the reaction mixture
  8. temperaturewas cooled to 40° C. [(R)-6-(3-Fluoro-phenylsulfanyl)-1,2,3,4-tetrahydro-naphthalen-1-ylmethyl]-urea
  9. customcrystallized on addition of n-heptane (7.8 kg)
  10. filtrationThe product was filtered
  11. customdried under reduced pressure at 50° C.

Sources & evidence

ORD record
ord-cf73d2a7e2274b0fae3127a91f520939
Source dataset
uspto-grants-2012_02
Patent number
US08119842B2

Reaction notes

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