Hydrochloric Acid → HCID 86684901, compound

HRID 2402891Notes

Reaction equation

HRID 2402891 reaction equation
[F:1][C:2]([F:17])([F:16])[C:3]1([C:6]([N:8]2[CH2:13][C@@H:12]3[CH2:14][C@H:9]2[C:10](=[O:15])[O:11]3)=[O:7])[CH2:5][CH2:4]1.Cl.[NH2:19][C:20]1([C:23]#[N:24])[CH2:22][CH2:21]1.C(C(CCCC)C([O-])=O)C.[Na+].Cl.[Cl-].[Na+]>O.O1CCCC1>[C:23]([C:20]1([NH:19][C:10]([C@@H:9]2[CH2:14][C@H:12]([OH:11])[CH2:13][N:8]2[C:6]([C:3]2([C:2]([F:17])([F:16])[F:1])[CH2:5][CH2:4]2)=[O:7])=[O:15])[CH2:22][CH2:21]1)#[N:24]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 5234Sodium ChlorideHCID 145863631-Amino-1-cyclopropanecarbonitrile hydrochlorideHCID 23672331Sodium 2-ethylhexanoateHCID 86684899HCID 86684899, compound

Product 1

HCID 86684901HCID 86684901, compoundYield 87.2%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
53 °C

Procedure

(1S,4S)-5-(1-Trifluoromethyl-cyclopropanecarbonyl)-2-oxa-5-aza-bicyclo[2.2.1]heptan-3-one (220 g, 883 mmol), 1-amino-cyclopropanecarbonitrile hydrochloride (140 g, 1.18 mol) and sodium 2-ethylhexanoate (97%, 230 g, 1.34 mol) were dissolved in water (1.32 L). The mixture was stirred for 20 h at 53° C. After cooling to room temperature, tetrahydrofuran (880 mL) was added and the mixture was acidified by addition of concentrated hydrochloric acid (37% m/m, 47 mL), followed by the addition of sodium chloride (440 g). After extraction with ethyl acetate (1×1.4 L, 3×550 mL), the combined organic extracts were dried over sodium sulfate and concentrated in vacuo. At a volume of ca. 1.5 L, the product started to crystallize upon addition of seed crystals. The volume of the suspension was further reduced to ca. 500 mL and cooled to 2° C. (ice bath). After stirring for 60 min, the crystals were filtered off, washed with ethyl acetate/heptane 1:1 (v/v, 600 mL) and heptane (300 mL), and dried in vacuo to provide the title compound as off-white crystals (255.0 g, 87%). 1H NMR (CDCl3, 400 MHz): δ 1.18-1.29 (m, 4H), 1.30-1.42 (m, 2H), 1.50-1.59 (m, 2H), 2.17-2.26 (m, 1H), 2.29 (d, J=14.5 Hz, 1H), 3.73 and 3.96 (ABX, JAB=11.8 Hz, JAX=4.3 Hz, JBX=0 Hz, each 1H), 4.43-4.53 (m, 2H), 4.81 (br d, J=8.3 Hz, 1H), 7.73 (s, 1H).

Workup

  1. temperatureAfter cooling to room temperature
  2. extractionAfter extraction with ethyl acetate (1×1.4 L, 3×550 mL)
  3. dry with materialthe combined organic extracts were dried over sodium sulfate
  4. concentrationconcentrated in vacuo
  5. customto crystallize upon addition of seed crystals
  6. temperaturecooled to 2° C. (ice bath)
  7. stirringAfter stirring for 60 min
  8. filtrationthe crystals were filtered off
  9. washwashed with ethyl acetate/heptane 1:1 (v/v, 600 mL) and heptane (300 mL)
  10. customdried in vacuo

Sources & evidence

ORD record
ord-be88b1aa1bb742828c949ade6dd45618
Source dataset
uspto-grants-2014_08
Patent number
US08796471B2

Reaction notes

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