PROCESS FOR SYNTHESIZING CARBAPENEM SIDE CHAIN INTERMEDIATES

Abstract: A process for the synthesis of an N-(di-substituted phosphoryl)-trans-4-hydroxy-L-proline of formula (I) is disclosed, wherein R<1> and R<2> independently represent C1-18 alkyl, phenyl or phenyl-substituted C1-18 alkyl, or R<1> and R<2> are taken in combination to represent C2-4 alkylidene or phenyl. Trans-4-hydroxy-L-proline is reacted with a di-(substituted) phosphite of formula (III) in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula (I).

Description: TITLE OF THE INVENTION PROCESS FOR SYNTHESIZING CARBAPENEM SIDE CHAIN INTERMEDIATES BACKGROUND OF THE INVENTION The present invention relates to a process of synthesizing compounds that are useful in the manufacture of carbapenem side chains. These carbapenem antibiotic compounds are effective in the treatment of infections caused by susceptible bacterial organisms. In the past, the synthesis of appropriately substituted hydroxyprolines has been conducted in the presence of a mixture of carbon tetrachloride, an amine base, e. g., triethylamine, water and an inert organic cosolvent, e.g., ethanol. See, e.g., Synthesis. 1988: 444- 448. This process is somewhat undesirable in that it uses excess amounts of reagents and it uses and generates chlorinated hydrocarbons. The present invention utilizes stoichiometric amounts of more economical reagents and generates little undesirable side products. SUMMARY OF THE INVENTION A process for the synthesis of an N-(di-substituted phosphoryl)-trans-4-hydroxy-L-proline of the formula I : -Pc -o R 1 - 0 0. \ R 2 I wherein R! and R^ independently represent Cl-18 alkyl, phenyl or phenyl-Cl -18 alkyl, or Rl and R^ are taken in combination to represent C2-4 alkylidene or phenyl, is disclosed wherein trans-4-hydroxy-L-proline of the formula II: is reacted with a di-(substituted) phosphite of the formula III: H / ,1 „^^0 R '- O O. \ 2 III R in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula I. DETAILED DESCRIPTION OF THE INVENTION As used herein, C l - 1 alkyl refers to straight and branched alkyl groups, including C5-I8 alkyl groups which can be cyclic or bicyclic. Likewise, the values of R! and R^ include phenyl, phenyl- substituted Cl-18 alkyl and C2-4 alkylidene. Preferred values of Rl and R2 include methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl, 2-ethylhexyl, decyl, lauryl and octadecyl. The preferred value of Rl and R^ taken in combination is ethylene or phenyl. The most preferred value of Rl and R2 is isopropyl. The resulting compounds, III are useful in the synthesis of carbapenem antibiotics, such as the compounds that are described in U. S. Pat. No. 5,478,820 granted on December 26, 1995, and incorporated herein by reference. Generally, the reaction ingredients are combined slowly at a reduced temperature, e.g., about 0 to about 5°C. The pH can be maintained at about 9.0 by adding a suitable quantity of sodium hydroxide. In a preferred aspect of the invention, the pH of the reaction is maintained at about 9.0. Sodium hypochlorite can be used in concentrations ranging from about 5% to about 20 weight %. Upon completion of the reaction, the pH of the solution can be adjusted with acid, and the desired compound isolated. Typically a crystalline product can be obtained. In a preferred embodiment of the invention, the process is as described above wherein Rl and R^ independently or in combination represent members selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl, 2-ethylhexyl, decyl, lauryl, octadecyl and ethylene. In a preferred embodiment of the invention, the present process is as described above wherein R and R^ independently represent Cl-1 alkyl. In another preferred embodiment of the invention, the process is as described above wherein Rl and R^ independently represent phenyl-substituted C 1.1 alkyl. In another preferred embodiment of the invention, the process is as described above wherein Rl and R^ represent phenyl. In another preferred embodiment of the invention, the process is as described above wherein R 1 and R^ taken in combination represent C2-4 alkylidene or phenyl. In another preferred embodiment of the invention, the process is as described above wherein Rl and R^ taken in combination represent ethylene or phenyl. In a more preferred embodiment of the invention, the process described herein relates to the synthesis of N-(diisopropyl phosphoryl)-trans-4-hydroxy-L-proline of the formula la: which comprises reacting trans-4-hydroxy-L-proline of the formula II: with diisopropyl phosphite of the formula ffla: in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula la. The invention is further illustrated with the following non- limiting example. EXAMPLE 1 A mixture of water (12 L) and trans-hydroxy pro line (5 Kg) was cooled to 0-5°C. The pH of the solution was adjusted to 9.0 with NaOH (25%) and diisopropylphosphite (7.0 kg) was added. Sodium hypochlorite (12.5 wt % NaOCl) (20 L) was added while maintaining the pH at 9.0 by the addition of sodium hydroxide. After completion, the reaction was quenched with sodium bisulfite (750 g.) over 15 minutes. The pH of the solution was adjusted from neutrality to approximately 2 by the addition of cone. HC1 at 0- 5°C, and sodium chloride (6.0 Kg) was added. The aqueous solution was extracted with isopropyl acetate (50 L aliquots at 0-5°C). The target compound (8.5 Kg) was isolated via crystallization.

Claims: WHAT IS CLAIMED IS: 1. A process for the synthesis of an N-(di-substituted phosphoryl)-trans-4-hydroxy-L-proline of the formula I : -P 1 / I ■ O R π -σ O. \ R < wherein Rl and R^ independently represent Cl-18 alkyl, phenyl or phenyl-Cl-1 alkyl, or Rl and R2 are taken in combination to represent C2-4 alkylidene or phenyl, wherein trans-4-hydroxy-L-proline of the formula II: H is reacted with a di- (substituted) phosphite of the formula III: H in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula I. 2. A process in accordance with claim 1 wherein Rl and R2 independently represent Cl-18 alkyl. 3. A process in accordance with claim 1 wherein Rl and R2 independently represent phenyl-substituted Cl -18 alkyl. 4. A process in accordance with claim 1 wherein Rl and R2 each independently represent phenyl. 5. A process in accordance with claim 1 wherein Rl and R2 taken in combination represent C2-4 alkylidene or phenyl. 6. A process in accordance with claim 5 wherein Rl and R2 taken in combination represent ethylene. 7. A process in accordance with claim 1 wherein Rl and R2 independently or in combination represent members selected from the group consisting of: methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, phenyl, benzyl, 2-ethylhexyl, decyl, lauryl, octadecyl and ethylene. 8. A process for the synthesis of N-(diisopropyl phosphoryl)-trans-4-hydroxy-L-proline of the formula la: which comprises reacting trans-4-hydroxy-L-proline of the formula II: with diisopropyl phosphite of the formula Ilia: in the presence of sodium hypochlorite and sodium hydroxide to produce a compound of formula la. 9. A process in accordance with claim 1 wherein the pH of the reaction is maintained at about 9.0.

Inventors: BRANDS KAREL M J, BRANDS, KAREL, M., J.
Applicants: BRANDS KAREL M J, MERCK & CO INC, BRANDS, KAREL, M., J., MERCK & CO., INC.
Application year: 1997
Main classification: C07F9
IPC codes: C07F9