PROCESS FOR PREPARING EPIHALOHYDRIN ENANTIOMERS

Abstract: Processes for preparing (S) or (R) epihalohydrin and an (S) substituted glycerol intermediate are disclosed.

Description: PROCESS FOR PREPARING EPIHALOHYDRIN ENANTIOMERS AND INTERMEDIATES Background of the Invention he present invention is concerned with processes for preparing epihalohydrin enantiomers and intermediates. Zpibormohydrin enantiomers have been prepared by a resolution process - and an epichlorohydrin enantiomer has been prepared from 1-brcmo-3- chlorpropan-2-ol. enantiomer derived from the epibromohydrin [Chemische Berichte 48, 1862-184, (1915)J. An improved method for preparing the epihalohydrin enantiomers from sulfonyloxyhaloalcohol has been discovered - and an improved process for preparing an intermediate useful in the synthesis has also been discovered. Summary of the invention: Process for (a) preparing (S) or (Rj epihalohydrin from an (S) or (R) sulfonyloxyhaloalcohol and (b) preparing (S) glycerol-l, 2-acetonide from isopropylidine-D-mannitOl. Description of the Preferred Embodiments: An embodiment of the present invention is a process for preparing an enantiomer of epihalohydrin which comprises treating an enantiomer of an alcohol having the formula EMI1.1 wherein Z is phenyl, monosubstitued phenyl, CF3 or C1-C6 alkyl and X is Cl or Br with an alkali metal glycolate and recovering said epihalohydrin by distillation. The reaction is illustrated by the following EMI2.1 The product as recovered in good yield by direct vacuum distillation at room temperature from the reaction mixture. Z may be phenyl, monosubstituted phenyl or C1-C6 alkyl. The monosubstituted phenyl group is exemplified by Cl-C3-alkylphenyl e.g. p-propylphenyl, o-methylphenyl, and m-ethylphenyl, p-N02-phenyl, p-OCH3-phenyl, 2-chlorophenyl and the like. The C1-C6 alkyl group includes CH3, C(CH3)3, isopropyl, n-hexyl and the like. The p methyiphenyl and CH3 groups are preferred. The alkali metal glycolate includes K or Na ethylene glycolate, with Naethylene glycolate being preferred. When a more conventional low boiling solvent/ strong base, e.g. methanol/NaOCH3 is used in place of the glycolate in reaction the product yield obtained on direct vacuum distillation at room temperature is low. Another embodiment of the present invention is a process for preparing (S)-glycerol-l, 2-acetonide of the formula EMI2.2 which comprises a (a) treating 1,2:5,6-di-0- isopro- pylidine-D-mannitol having the formula EMI3.1 with lead tetraacetate in a suitable solvent and (b) reducing the reaction product from (a) with alkalimetal borohydride and (c) treating the reaction mixture from (b) with an ammonium halide. Suitable solvents include aprotic compounds such as tetrahydrofuron (THF), ethylacetate, dimethylformamide (DMF) and the like. THF and ethylacetate are preferred solvents. Ammonium halides include NE4Br and NH4C1. NH4C1 is preferred. The reaction of (B) with Pb(OAc)4 in step (a) may be carried out at any convenient temperature. Temperatures below about 10-C are preferred. The preferred molar nature of leadtetraacetate to (B) is about 1:1. The reduction of the step (b) is also carried out at a convenient temperature. Preferred temperatures are below about 10-C. The NaBH4 reducing agent is generally added to the reaction mixture in solution e.g. in aqueous NaOH. The amount of NaBH4 may be varied. It is preferred that about 2 moles of NaBH4 per mole of (B) reactant be used. The reaction of step (b) is allowed to proceed for a period sufficient for the reaction to be complete, e.g. for about 30 minutes at about O0C and for about 90 minutes at room temperature. At the appropriate time, NH4C1 is added to solution until the PH reaches about 8. After the reaction solvent is removed under reduced pressure, the produce (A) is recovered using conventional procedures. When sodium periodate synthesis 423 (1977); Biochemistry 3, 976 (1964)) is used in place of Pb(OAc)4 the product obtained is generally racemic. When H2/Raney nickel 1J. Biol. hem. 128, 463 (1939)) is used in place of the NaBH4, yields obtained are variable depending on the quality of the Raney nickel. The formula (A) glycerol is especially useful as an intermediate in the preparation of (S) and (R) epihalohydrins. The following flow sheet illustrates this utility: EMI5.1 Reactions related to 1 and 2 are disclosed in J.A.C.S. 64, 1291 (1942). Reaction 3 is related to that described in Tetrahedron Letters, 4361 (1969). Reaction sequence 5 and 6 has been carried out with racemic reactants [Bull. Chem. Soc. Japan 39, 413 (1966)). The¯preparation illustrated by the flow sheet shows that either the (S) or (R) enantiomer of an epihalohydrin, especially epichlorohydrin, can be prepared directly from a common starting material [compound (A) or product (B)] without requiring costly and inefficient resolution procedures. This constitutes another aspect of the present invention. Epihalohydrins have wide utility in organic synthesis. The enantiomers of epihalohydrin may be especially useful to prepare intermediates which in turn can be used to prepare specific isomers which have pharmaceutical utility. One such preparation is illustrated by the following reaction equations: REACTION SEQUENCE A EMI7.1 STEP 2 EMI7.2 The product (C) is a commercial ss-adrenergic blocking agent. Other preparations utilizing the Step 1, sequence A type reaction are illustrated by the following reaction equation: REACTION 3 EMI8.1 X X in this equation is H, CHO, CN or OCH3. Where a stronger base, such as NaH in DMFJ is used in the above reactions, the intermediate (C or C1) is obtained as a mixture of (S) and (R) isomer. Another aspect of the present invention relates to the novel sulfonyl intermediates of the type obtained in Step (5) in the above flow sheet. These compounds are represented by the formula EMI8.2 where L may be an alkyl group such a. CH3, C4H9, CF3 and the like, or a phenyl group such as phenyl, p-chlorophenyl, p-tolyl, p-nitrophenyl and the like. The formula (E) compounds are useful as intermediates in reactions related to Reactions A and B as illustrated by the following equation: REACTION C EMI9.1 ; aryl includes groups such as phenyl, EMI9.2 where X is a substituent such as chloro, CHO, CN, C1-C4 alkoxy and the like, pyridyl, cyanopyridyl 4-morpholino-1,2,5-thiadiazolyl and the like. When an enantiomer i.e. (R) or S isomer, of the (E) compound is used in the reaction, the type of base and the L group have an effect on the isomer configuration of the final product. Illustrating this effect are the following two equations: REACTION D EMI10.1 mixture of (R)and(S) isomers about 80%(S) isomer REACTION E EMI10.2 100% (S) isomer Thus, where L is CF3 and a strong base is used, the (S) isomer of the formula (E) compounds yields the (S) isomer of the formula (G) compound. Therefore, by utilizing an enantiomer of 3-trifloxy-1,2-epoxy propane and a suitable base in the (C) reaction the isomeric configuration of the trifloxy enantiomer is maintained in the product. If an enantiomer of mesyloxy mesyloxyepoxypropane is used, a mixture of enantiomers is obtained. The following example describes the prepara tion of (S)-3-trifloxy-1,2-epoxypropane. All temperatures are in C. EXAMPLE A To pyridine (10.3 g, 0.13 m) in CH2C12 (300 ml) cooled to -230 in a dry ice/CC14 bath was added trifluoromethanesulfonic anhydride (36.7 g, 0.13 m) in CH2C12 (100 ml) dropwise over 1/2 hour. While still cooling this mixture at -230, (R)-glycidol (8.6 g, 0.116 m) in CH2C12 (100 ml) was added dropwise over 1/2 hour. After stirring for 5 minutes with cooling and 15 minutes without, an equal volume of hexane was added and the solids were filtered. Concentration of the solution at 300/25 tor-. left a residue which was distilled to give (S)-3-trifloxy-1,2-epoxy- propane (40%); b.p. 35-39 /0.2 mm; [&alpha;]D24=14.7 (c= 3.90, CHCl3); 1H NMR (CDC13) 4.8 (1H, d of d, J=11, J=3), 4.4 (1H, d of d, J=11, J=3), 3.3 (1H, m), 2.9 (1H, t, J=4.5), 2.7 (1H, J=4.5, J=2). The following examples illustrate the processes of the present invention. All temperatures are in C. EXAMPLE 1 (S) -Glycerol-l, 2-acetonide To an ice-cooled solution of 1,2:5,6- di-O-isopropylidine-D-mannitol (80.0 g., 0.3 ml) in TEF (400 m) was added portionwise with stirring dry b(OAc)4 (134 g, 0.3 m), while maintaining the temperature below IOOC. The solution was stirred for 30 minutes with ice cooling and an additional 30 minutes without. After filtering through Super-Cel and cooling in an ice bath, a solution of NaBH4 (22.9 g, 0.62 m) in 4% aqueous NaOH (400 ml)was added dropwise with vigorous stirring while maintaining the temperature below 10 C. After stirring in an ice bath for 30 minutes and at room temperature for 90 minutes, solid ammonium chloride was added to the solution until it buffered at about pH 8. The THF was removed under reduced pressure, and the resulting aqueous solution was saturated with Nazi. After extracting into ethyl acetate, the organic layer was washed with 5% aqueous NaOH saturated with NaCl, dried (Na2S04), and concentrated. Distilla- tion afforded pure (S)-glycerol-1,2-acetonide (58.4 g, 73%); bp 80-90 C/20mm; 1H NMR (CDCl3) 1.45 (6E, r), 3.5-4.5 (6H, m); 125= 11.3 (c=5.174, CH3OH). EXAMPLE 2 (a) (R)-3-Tosyloxy-1,2-propanediol To an ice-cooled solution of (S)-glycrol- 1,2-acetonide (72.0 g, 0.55 m) in pyridine (300 ml) was added portionwise with stirring p-toluensul- fonyl chloride (104.0 g, 0.55 m). After standing in a refrigerator for 16 hours, the reaction mixture was diluted with ether (300 ml), washed with 1NHCl until the aqueous wash was acidic, and then washed with saturated aqueous NaHCO3. The ether layer was dried (Na2604) and concentrated to give (R)-3-toxyloxypropanediol acetonide (141.0 g, 91%), which was used without further purification. The acetonide from above in acetone (100 ml) and 1NHCl (300 ml) was heated on a steam bath for 30 minutes. The resulting solution was concentrated to dryness, and the residue was dissolved in CH2Cl2. After drying (Na2SO4) and concentration, the resulting oil solidified upon standing. Residual solvents were removed at 25 C. and 0.5 mm over 18 hours to give (R)-3-tosyloxy-1,2-propanediol, (121.0 g, 100%); mp 54-59 C. (lit=61-63 C.); 1H NMR (CDCl3) 2.4 (3H, a), 3.3-4.3 (7 H, m), 7.35 and 7.9 (4H, 2d, J = 8). (b) (R)-Glycidol To an ice-cooled solution of (R)-3-tosyioxy- 1,2-propanediol (120.5 g, 0.49 m) in methanol (200 ml) and ether (100 ml) was added sodium pellets (10.7 g, 0.45 m) in three portions over approximately 1 hour. Stirring was continued with ice cooling for 1 hour. The reaction mixture was concentrated at 30*C., and the residue was taken up in ether. After filtration, the solvent was removed at 30C./25 am, and the residue was treated with chloroform and reconcentrated to remove the last traces of methanol. An additional chloroform treat agent as above gave (R)-glycidol (33.5 g, 93%), which was used without purification in subsequent steps. (c) (S)-3-Mesyloxy-1,2-epoxypropane To an ice-cooled solution of (R)-glycidol (5.0 g, 0.068 m) and triethylamine t8.1 g, 0.080 m) in toluene (100 ml) was added, over 15 minutes, methanesulfonyl chloride (8.0 g, 0.070 m) in toluene (25 ml). Stirring was continued with cooling for 1 hour. The Solution was filtered and concentrated to give an 80-85% yield of the crude (S)-3-mesyloxy- 1,2-epoxypropane; this material could be used without further purification. Distillation gave 7 (61%); bp 92-95 C./0.1 mm; [&alpha;]D22 = 23.7 (c=5.16, CH30E); 1H NMR (CDC13) 4.5 (1H, d of d, J = 12, J s 3), 4.1 (1H, d of d, J a 12, J a 6), 3.3 (1H, m), 3.1 (3H, s), 2.8 (2H,m). (d) (R) -Epichlorohydrin Concentrated HCl (20 ml) was added to (S)-3-mesyloxy-1,2-epoxypropane (5.0 g, 0.033 m) over 15-20 minutes. After stirring for an additional 30 minutes, the water was removed through the addition and subsequent evaporation of ethanol. Pinally, residual ethanol was removed at room temperature and 0.1 mm to give (R)-3-mesyloxy-2tydroxy-l-chloropropane, (5.4 g, 85%); H NMR (CDCl3) 4.35 (2H, d), 4.1 (1H, m), 3,65 (2H, d), 3.1 (3H, s), 2.9 (1H, broad s); [&alpha;]D22= 7.1 (c = 5.78, CH3OH). To (R)-3-mesyloxy-2-hydroxy-1-chloropropane (5.4 g, 0.029 m) in dry ethylene glycol (20 ml) After stirring for 15 minutes1 (R)-epichlorohydrin (2.2 g, 86%) was distilled from the reaction mixture at room temperature and 0.2 mm and trapped in dry ice/acetone; 1H NMR (COCl3) & 3.6 (2R, d), 3.2 (1H, m), 2.B (2H, m); [&alpha;]D22=33.0 (c= 4.22, CH30H). A small sample was further purified by preparative GC on an HP 5710 A instrument using a 6' 5% OV-17 column with an oven temperature of 60 C. to give (R)-epichlorohydrin; [&alpha;]D23= (c = 1.50, CH3OH). EXAMPLE 3 (S)-Epichlorohydrin To triphenylphosphine (13.2 g, 0.05 m) in CCl4 (20 ml) and DMF (50 ml), (R)-3-tosyloxy1,2-propanediol (12.3 g, 0.05 m) in DMF (50 ml) was added all at once. After the addition was complete, the temperature increased to 50 C. over 15 minutes. The mixture was then allowed to stir for 3 hours. The residual solvents were removed (500C., 2 mm) and the residue was taken up in H2O, dried (Na2SO4), and concentrated. Residual solvents were removed at 25 C. and 0.2 mm over 18 hours. To this residue, composed of triphenylphosphine oxide and (S) -3-tosyloxy-2-hydroxy-l- chloropropane, in dry ethylene glycol (50 ml) was added a solution of sodium ethylene glycolate [from sodium pellets (1.25 g, 0.054 m)] in dry ethylene glycol (50 al). After stirring for 15 minutes, (S)-epichlorohydrin was distilled from the reaction mixture at room temperature and 0.2 mm and trapped in dry ice/acetone. The 1M NMR indicated that traces of CH2Cl2 and H2O were present; [&alpha;]D20= 28.1 (c = 2.47, CH3OH). A small sample was purified by preparative GC to yield pure (S)-epichlorohydrin [&alpha;]D23=33.0 (c = 2.47, CH3OH). Analogous epibromohydrins are obtained when the corresponding bromo reactants replace the chloro reactants in Examples 2 and 3. Claims to the invention follow.

Claims: WHAT IS CLAIMED IS: 1. A process for preparing an enantiomer of epihalohydrin which comprises treating an enantiomer of an alcohol of the formula: EMI17.1 wherein Z is phenyl, monosubstituted phenyl or C1-C6 alkyl and X is C1 or Br, with alkali metal glycolate and removing said epihalohydrin by distillation. 2. The process of claim 1 wherein Z is p-tolyl or methyl and the glycolate is sodium ethylene glycolate. 3. The process of claim 2 wherein said epihalohydrin and said alcohol are both the (S)isomer and Z is p-tolyl. 4. The process of claim 2 wherein said epihalohydrin and said alcohol are both the (R)isomer and Zis methyl. 5. The process of claim 3 wherein said epihalohydrin is epichlorohydrin. 6. The process of claim 4 wherein said epihalohydrin is epichlorohydrin. 7. A process for preparing (S)-glycerol1,2-acetonide which comprises: a) treating 1,2:5,6-di-O-isopropylidine D-mannitol with lead tetraacetate in a suitable solvent, b) reducing the reaction product from a) with an alkyli metal borohydride and c) treating the reaction mixture containing the reduced product with an ammonium halide to obtain said (S)-glycerol derivative. 8. The process of claim 7 wherein (i) said solvent is tetrahydrofuran, (ii) said solvent is tetrahydrofuran and said ammonium halide is NH4Cl, or (iii) said solvent is tetrahydrofuran, said ammonium halide is NH 4 C1 and sufficient halide is added to lower the solution pH to about 8. 9. A process for preparing an enantiomer of a compound of the formula EMI18.1 wherein said aryl group is phenyl; monosubstituted phenyl wherein the substituent is C1, CHO, CN, C1 C4 alkoxy; pyridyl, cyanopyridyl; or 4-morpholino1,2,5-thiadiazolyl, which comprises the reaction of the corresponding enantiomer of a compound of the formula EMI18.2 and an arylhydroxy compound of the formula Aryl-OH in the presence of a strong base. 10. An enantiomer of a compound of the formula EMI19.1 wherein (i)Lis CH3 or CF3, (ii) L is CH3, or (iii) L is CF3 and said compound is the S-isomer.

Inventors: BALDWIN, JOHN JAMES, MCCLURE, DAVID EARL
Applicants: MERCK & CO. INC.
Application year: 1979
Main classification: C07D301
IPC codes: C07D303, C07D317, C07D301