Hydrochloric Acid → 91366-12-0

Temperature

0 °C

To a 22-L three-necked round-bottomed flask affixed with an overhead mechanical stirrer, thermocouple, nitrogen bubbler, and provision for external cooling was charged dry pyridine (3.0 L, K.F. <0.005%) and methyl (R)-3-hydroxybutyrate (1.14 assay Kg, 9.67 moles, K.F. <0.005 wt %). While maintaining the temperature at <-5° C., p-toluenesulfonyl chloride (2.35 Kg, 98% tech. grade, 12.4 mole) was added to the alcohol/pyridine mixture. (The charge of tosyl chloride should be at least 125 mole % of the alcohol charge and should be adjusted upward, mole for mole, to compensate for the total system water content.) The reaction mixture was stirred for 24 hours at 0° C. or until judged complete by HPLC. Workup commenced by cooling the batch to -16° C. and subsequently adding water (200 mL), dropwise, while maintaining the temperature at <2° C. (It is essential that all tosyl chloride be decomposed with the addition of water while the batch is still homogeneous. If too much water is added initially, the reaction becomes biphasic and the rate of hydrolysis slows dramatically. Tosyl chloride then co-crystallizes with the product.) The batch was then aged with vigorous agitation for 30 minutes at 0°-2° C. An additional 400 mL of water was then added in similar fashion. After 30 minutes, HPLC analysis (see below) showed no remaining tosyl chloride. The batch was then diluted with the slow addition of water (9 L) at 0°-5° C. Product crystallizes spontaneously. After a 2 hour age at 0°-5 ° C. the batch was filtered, the product cake slurry-washed with water at least five times to remove p-toluenesulfonic acid and pyridine, and sucked dry under nitrogen to constant weight. The yield of methyl (R)- 3-(p-toluenesulfonyloxy) butyrate was 2.57 Kg (98%), mp 46°-47.5° C. HPLC Conditions: [Sample preparation: A quantity of 0.1 mL of the above reaction mixture was shaken with 5 mL water, 5 mL ethyl acetate, and 0.1 mL concentrated hydrochloric acid to neutralize and remove the pyridine solvent. The mixture was then separated and the upper ethyl acetate layer diluted 1:10 with acetonitrile for injection. At 254 nm, an area ratio of 1:2 product tosylate:tosyl chloride signifies a complete reaction. Column: C-8 Altex Ultra sphere 5 micron (4.1 mm×25 cm); Eluant: 50:50 A:B isocratic @2.0 mL/min, A=H2O (0.1% H3PO4 v/v), B=CH3CN; Temp: 24° C.; Detector: UV@254 nm; RT tosylate (1) 3.5 min., RT tosyl chloride 5.5 min⟧ Analysis: 1H NMR (CDCl3) 7.79(d,2H,J=8.36 Hz), 7.34(d,2H,J=8.36 Hz), 4.97(m,1H), 3.59(s, 3H), 2.74(dd,1H,J=15.8,J=6.5 Hz), 2.52(dd,1H,J=15.8,J=6.8 Hz), 2.45(s,3H), 1.36(d,3H,J=6.3 Hz); 13C NMR (CDCl3) 169.7(s), 144.8(s), 133.9(s), 129.8(s), 127.7(s), 75.8(s), 51.8(s), 41.2(s), 21.6 (s), 20.9(s); [α]40525 =-16.3 (c=2,toluene); Anal. Calcd. for C12H16O5S: C,52.94; H,5.88; S,11.76. Found: C,52.98; H,5.93; S,11.76.

1. customTo a 22-L three-necked round-bottomed flask affixed with an overhead mechanical stirrer
2. temperaturethermocouple, nitrogen bubbler, and provision for external cooling
3. temperatureWhile maintaining the temperature at <-5° C.
4. additioncharge
5. temperatureby cooling the batch to -16° C.
6. customthe rate of hydrolysis
7. wait) The batch was then aged with vigorous agitation for 30 minutes at 0°-2° C
8. waitAfter 30 minutes
9. customProduct crystallizes spontaneously
10. filtrationAfter a 2 hour age at 0°-5 ° C. the batch was filtered
11. washthe product cake slurry-washed with water at least five times
12. customto remove p-toluenesulfonic acid and pyridine
13. customsucked dry under nitrogen to constant weight
14. customHPLC Conditions: [Sample preparation
15. customremove the pyridine solvent
16. customThe mixture was then separated
17. additionthe upper ethyl acetate layer diluted 1:10 with acetonitrile for injection
18. customa complete reaction
19. custom24° C.

ORD record

ord-8f678e2f01f04968a4e10468c0f3eaa8

Source dataset

uspto-grants-1990_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US04968814