Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate Chemical Properties

Melting point:

93-95 °C

Boiling point:

93-95 °C/5 mmHg (lit.)

alpha 

14 º (neat)

Density 

1.19 g/mL at 25 °C (lit.)

refractive index 

n20/D 1.452

Flash point:

>110°C

storage temp. 

Keep in dark place,Sealed in dry,Room Temperature

solubility 

Chloroform (Sparingly), DMSO (Slightly), Methanol (Slightly)

pka

13.23±0.20(Predicted)

form 

Oil

color 

Clear Colourless

Specific Gravity

1.190

optical activity

[α]23/D +14°, neat

InChIKey

ZAJNMXDBJKCCAT-RXMQYKEDSA-N

CAS DataBase Reference

90866-33-4(CAS DataBase Reference)

Safety Information

Hazard Codes 

Xi

Risk Statements 

41

Safety Statements 

26-36-36/39

RIDADR 

2810

WGK Germany 

3

HazardClass 

6.1

PackingGroup 

III

HS Code 

29181990

MSDS

• Language:English Provider:4-Chloro-3-hydroxybutyric acid ethyl ester
• Language:English Provider:ACROS
• Language:English Provider:SigmaAldrich
• Language:English Provider:ALFA

Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate Usage And Synthesis

Chemical Properties

Colorless to light yellow liqui

Uses

Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate is a chiral building block that can be used:

• To prepare allyl stannane, a precursor for the total synthesis of macrolide iriomoteolide-1b.
• As a starting material for the synthesis of a chiral g-αmino acid fragment, which in turn is used to prepare the immunosuppressive agent FR252921.

Synthesis

Example 1 (proportional): ethanol (340 mL) and ethyl 4-chloroacetoacetate (53 g) were added to a 600 mL stainless steel Parr reactor, the reactor stirrer was started, the speed was set to 600 rpm, and the reactor was pressurized with nitrogen to 7 bar. stirring was continued for 5 min. after 5 min, the reactor was slowly vented to ambient pressure, and the pressurizing/decompressing cycle was repeated a total of 5 times to ensure complete removal of dissolved oxygen. At the end of the last cycle, the temperature of the reactor was adjusted to 95°C. The (R)-[RuCl2(BINAP)] catalyst was accurately weighed (23 mg) into a catalyst transfer vessel and the vessel was purged with nitrogen for 5 min. The catalyst was rinsed from the transfer vessel into a 100 mL stainless steel injection cartridge attached to the Parr reactor using deoxidizing solvent. The injection cartridge was pressurized with hydrogen to 100 bar when the temperature of the Parr reactor was between 95°C and 100°C. Appropriate valves were then opened to transfer the catalyst mixture and hydrogen into the reactor. The reactor contents were stirred at 600 rpm for 30 minutes and then cooled to below 30°C. The reactor was then slowly vented to ambient pressure. The reactor contents were transferred to a 1 L rotary film evaporator flask and the mixture was evaporated to constant weight by applying vacuum and using a heated water bath. The residue was subjected to pot distillation under vacuum to afford ethyl (S)-(-)-4-chloro-3-hydroxybutyrate as a clear, colorless, oily liquid product in >98% yield, >98% purity and 94% enantiomeric excess. Example 2: 3.6 L of ethanol solvent was added to the feed tank. The solvent was deoxygenated by pumping the solvent through a nozzle while being pressurized with nitrogen to 7 bar and then depressurized at a controlled rate through a needle valve. The pressurization/decompression cycle was repeated three times and the entire process was automated using a PLC-based control system. In a similar manner, ethyl 4-chloroacetoacetate (3.6 L) was added to the second feed tank and deoxygenated using the same protocol as described above. Catalyst (R)-[RuCl2(BINAP)] (149 mg) was added to the transfer vessel and the vessel was purged with nitrogen before transferring the catalyst to the solvent feed tank. The concentration of the catalyst solution was 52.2 mg/kg. two feed systems were connected to the continuous hydrogenation reactor system via two high pressure pumps. The continuous hydrogenation reactor system was constructed of Hastalloy 276 and contained a number of in-line static mixers to allow residence times between 30 and 35 seconds. The static mixers also ensure good mixing of the process stream and rapid hydrogen uptake. The reactor system is equipped with circulation pumps and in-line valves, which are capable of operating as piston flow reactors (PFR, valves closed) or continuous loop tube reactors (CLR, valves open). The system is equipped with a gas/liquid separator and the liquid level in the separator is controlled using a differential pressure sensor, which in turn operates the outlet flow control valve. A PLC based control system was used to control the reactor system. The hydrogenation reactor was pressurized using hydrogen and the pressure was maintained at 90-100 bar by continuous addition of hydrogen at a rate of 2.7 g/h through a mass flow controller.The reaction liquid was pumped through a heat exchanger to maintain the process temperature between 102°C and 105°C. The reactor was operated as a piston flow reactor. The above system was operated as a piston flow reactor. The flow rate of ethyl 4-chloroacetoacetate was set to 2.6 mL/min and the flow rate of the catalyst solution was set to 8.9 mL/min. the process concentration for these processes was 30% w/w and the substrate to catalyst ratio was 20,000:1. In a series of successive runs, each varying between 4 and 8 hours, the reactor consistently converted >99% of ethyl 4-chloroacetoacetate to (S)-ethyl-4-chloro-3-hydroxybutyrate, which was isolated by evaporation to remove the solvent to give >98% chemical yield and 98-99% enantiomeric excess. Example 3: The reactor was set up as in Example 2, with the difference that it was operated as a continuous ring tube reactor. The flow rate of ethyl 4-chloroacetoacetate was set to 2.55 mL/min, the flow rate of the ethanol catalyst solution was set to 6.60 mL/min, and the catalyst concentration was 45.8 mg/kg. the process concentration for these processes was 37% w/w, and the substrate-to-catalyst ratio was 65,000:1. In a series of consecutive runs, varying between 4 and 8 hours each, the reactor consistently converted >99% of ethyl 4-chloroacetoacetate to (S)-ethyl-4-chloro-3-hydroxybutyrate, which was separated by evaporation to remove the solvent to give >98% chemical yield and 98-99% enantiomeric excess.

References

[1] Bioscience, Biotechnology and Biochemistry, 2005, vol. 69, # 3, p. 544 - 552
[2] Tetrahedron Asymmetry, 2007, vol. 18, # 16, p. 1883 - 1887
[3] Patent: WO2003/97569, 2003, A1. Location in patent: Page/Page column 10-13
[4] Organic Process Research and Development, 2002, vol. 6, # 4, p. 558 - 561
[5] Tetrahedron Asymmetry, 2005, vol. 16, # 4, p. 899 - 901

Ethyl (R)-(+)-4-chloro-3-hydroxybutyrate(90866-33-4)Related Product Information

• 4-Hydroxybenzoic acid
• Ethyl 3-hydroxybutyrate
• Ethyl acrylate
• Glycolic acid
• Ethyl acetate
• HYDROXYAPATITE TYPE I
• Ethyl isobutyrate
• Ethylparaben
• 2,3,4-Trihydroxybenzoic acid
• Epichlorohydrin
• Tris(trimethylsilyl)phosphate
• Ethyl butyrate
• 4-Cyanophenol
• Hydroxy silicone oil
• Ethanol
• (R)-4-CHLORO-3-HYDROXYBUTYRIC ACID METHYL ESTER
• Ethyl S-4-chloro-3-hydroxybutyrate
• Difluorochloromethane