MXPA99001612A - Process for preparing intermediates to florfenicol - Google Patents
Process for preparing intermediates to florfenicolInfo
- Publication number
- MXPA99001612A MXPA99001612A MXPA/A/1999/001612A MX9901612A MXPA99001612A MX PA99001612 A MXPA99001612 A MX PA99001612A MX 9901612 A MX9901612 A MX 9901612A MX PA99001612 A MXPA99001612 A MX PA99001612A
- Authority
- MX
- Mexico
- Prior art keywords
- compound
- formula
- alkyl
- florfenicol
- benzyl
- Prior art date
Links
- 238000004519 manufacturing process Methods 0.000 title claims abstract description 10
- AYIRNRDRBQJXIF-NXEZZACHSA-N (-)-Florfenicol Chemical compound CS(=O)(=O)C1=CC=C([C@@H](O)[C@@H](CF)NC(=O)C(Cl)Cl)C=C1 AYIRNRDRBQJXIF-NXEZZACHSA-N 0.000 title abstract description 8
- 229960003760 florfenicol Drugs 0.000 title abstract description 8
- 239000000543 intermediate Substances 0.000 title abstract description 6
- 150000001875 compounds Chemical class 0.000 claims abstract description 26
- 238000006243 chemical reaction Methods 0.000 claims description 16
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 10
- 125000004051 hexyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 7
- 239000003638 reducing agent Substances 0.000 claims description 6
- 125000003118 aryl group Chemical group 0.000 claims description 5
- 238000000034 method Methods 0.000 claims description 5
- 125000001188 haloalkyl group Chemical group 0.000 claims description 4
- 125000003106 haloaryl group Chemical group 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- HHUJLKPGQMFFMS-UHFFFAOYSA-N potassium;boron(1-) Chemical compound [B-].[K+] HHUJLKPGQMFFMS-UHFFFAOYSA-N 0.000 claims description 3
- 125000001316 cycloalkyl alkyl group Chemical group 0.000 claims description 2
- 125000000753 cycloalkyl group Chemical group 0.000 claims description 2
- 125000000160 oxazolidinyl group Chemical group 0.000 claims description 2
- 125000002653 sulfanylmethyl group Chemical group [H]SC([H])([H])[*] 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 abstract description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 22
- 125000000217 alkyl group Chemical group 0.000 description 6
- 239000002904 solvent Substances 0.000 description 6
- 239000003586 protic polar solvent Substances 0.000 description 5
- JFDZBHWFFUWGJE-UHFFFAOYSA-N Benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000005755 formation reaction Methods 0.000 description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Chemical compound OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 4
- LYCAIKOWRPUZTN-UHFFFAOYSA-N glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 4
- 229910052736 halogen Inorganic materials 0.000 description 4
- 150000002367 halogens Chemical class 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000203 mixture Substances 0.000 description 4
- -1 oxazoline compound Chemical class 0.000 description 4
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- IMSODMZESSGVBE-UHFFFAOYSA-N 2-oxazoline Chemical compound C1CN=CO1 IMSODMZESSGVBE-UHFFFAOYSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- 239000006184 cosolvent Substances 0.000 description 3
- 238000004821 distillation Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- 235000011187 glycerol Nutrition 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- 238000005406 washing Methods 0.000 description 3
- MVPPADPHJFYWMZ-UHFFFAOYSA-N Chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- STZZWJCGRKXEFF-UHFFFAOYSA-N Dichloroacetonitrile Chemical compound ClC(Cl)C#N STZZWJCGRKXEFF-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- ADABDSJWQOSQMO-NSHDSACASA-N ethyl (2S)-3-hydroxy-2-(4-methylsulfonylanilino)propanoate Chemical compound CCOC(=O)[C@H](CO)NC1=CC=C(S(C)(=O)=O)C=C1 ADABDSJWQOSQMO-NSHDSACASA-N 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- YXFVVABEGXRONW-UHFFFAOYSA-N toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 2
- CRBMMULOALMFHH-UHFFFAOYSA-N 2,4-dichloro-4,5-dihydro-1,3-oxazole Chemical compound ClC1COC(Cl)=N1 CRBMMULOALMFHH-UHFFFAOYSA-N 0.000 description 1
- FRSCTGCNUCVOAC-UHFFFAOYSA-N 2-(dichloromethyl)-4,5-dihydro-1,3-oxazole Chemical compound ClC(Cl)C1=NCCO1 FRSCTGCNUCVOAC-UHFFFAOYSA-N 0.000 description 1
- HNFSPSWQNZVCTB-UHFFFAOYSA-N 2-methyl-2-propan-2-yloxypropane Chemical compound CC(C)OC(C)(C)C HNFSPSWQNZVCTB-UHFFFAOYSA-N 0.000 description 1
- ZXTHWIZHGLNEPG-UHFFFAOYSA-N 2-phenyl-4,5-dihydro-1,3-oxazole Chemical compound O1CCN=C1C1=CC=CC=C1 ZXTHWIZHGLNEPG-UHFFFAOYSA-N 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N Di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 229940052303 Ethers for general anesthesia Drugs 0.000 description 1
- BZLVMXJERCGZMT-UHFFFAOYSA-N MeOtBu Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 1
- UIIMBOGNXHQVGW-UHFFFAOYSA-M NaHCO3 Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 1
- 241000577218 Phenes Species 0.000 description 1
- 240000001203 Potentilla anserina Species 0.000 description 1
- 235000016594 Potentilla anserina Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- DLFVBJFMPXGRIB-UHFFFAOYSA-N acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 238000007792 addition Methods 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003849 aromatic solvent Substances 0.000 description 1
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 description 1
- WKBOTKDWSSQWDR-UHFFFAOYSA-N bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 description 1
- 125000004432 carbon atoms Chemical group C* 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 230000000875 corresponding Effects 0.000 description 1
- 229960004132 diethyl ether Drugs 0.000 description 1
- 201000009910 diseases by infectious agent Diseases 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- YCKRFDGAMUMZLT-UHFFFAOYSA-N fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 1
- 125000004216 fluoromethyl group Chemical group [H]C([H])(F)* 0.000 description 1
- 235000019253 formic acid Nutrition 0.000 description 1
- 150000005171 halobenzenes Chemical class 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atoms Chemical group [H]* 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000004170 methylsulfonyl group Chemical group [H]C([H])([H])S(*)(=O)=O 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- WYNCHZVNFNFDNH-UHFFFAOYSA-N oxazolidine Chemical compound C1COCN1 WYNCHZVNFNFDNH-UHFFFAOYSA-N 0.000 description 1
- 230000001376 precipitating Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 125000002914 sec-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 150000003457 sulfones Chemical class 0.000 description 1
- 235000011149 sulphuric acid Nutrition 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 150000003738 xylenes Chemical class 0.000 description 1
Abstract
A process for preparing a compound of formula (I) wherein R and R''are as described herein. Compounds of formula (I) are useful as intermediates in the preparation of florfenicol.
Description
PROCESS FOR PREPARING FLORFENICOL INTERMEDIARIES FIELD OF THE INVENTION The present invention relates to florfenicol intermediates and a new process for their preparation.
BACKGROUND OF THE INVENTION Florfenicol, also known as [R- (R, S) j -2,2-dichloro-N- [1- (fluoromethyl) -2-hydroxy-2- [4- (methylsulfonyl) phenyl] ] ethyl] acetamide, is a broad-spectrum antibacterial agent in the treatment of gram positive, gram negative and ricketsia infections as described in the US Patent
United States 4,361,557 corresponding to Argentine Patents 230,260, 230 427 and 230,428. Patents 230,427 and 230,428 are divisional of Patent 230,260, which is incorporated herein by reference. The present invention relates to florfenicol intermediates and a new process for preparing them. The intermediates described in the present application can be used to prepare florfenicol as can be seen, for example in US Pat. No. 4,876,352, which is incorporated herein by reference. SUMMARY In one embodiment, the present invention is directed to a process for preparing a compound of formula I:
where R is H, N02, CH3S, CH3S02, or C4 to C6 alkyl; and R "is aryl, halo aryl, benzyl, substituted benzyl, Ct to C6 alkyl, C3 to C7 cycloalkyl, and haloalkyl, and the configuration of the oxazolidine ring is 4R trans: comprising: a) contacting a compound of formula II:
where R is as described above, and R 'is H, C-, C6 alkyl, C3 to C7 cycloalkyl, benzyl, substituted benzyl or aryl; with a reducing agent such as potassium borohydride, in a suitable reaction vessel, to obtain a compound of formula III:
where R is as described above, and b) then a compound of formula III, with a compound of formula IV, reacts in the same reaction vessel:
R "- c = N IV where R" is as described above to obtain the compound of formula I. The present invention has the advantage of being an economical and efficient process for preparing florfenicol, its analogues and oxazolidine intermediates thereof. DETAILED DESCRIPTION OF THE EMBODIMENTS When used in the present application and the appended claims, the terms listed below, unless otherwise indicated, are defined as follows: The term "protic solvent" means solvent with hydrogen bond, as defined in James B. Hendrickson, Cram, Donald J., and Hammond, George S., Organic Chemistry, Me Graw Hill Book Company, New York, New York, (1970), 1279 pp. The solvent may preferably, but not necessarily, be capable of precipitating oxazoline (I) from a solution. Such solvents include, but are not limited to, water, C to C 0 alkanoic acids, such as formic acid, acetic acid and the like, C-, to C 10 alcohols such as methanol and ethanol and mixtures thereof, C 2 -alcohols to C10 such as ethylene glycol and C, to C10 trialcohoies such as glycerin. Alternatively, the protic solvent may be added with any suitable co-solvent in order to effect the precipitation of the oxazoline compound (I). Such cosolvents may include other protic solvents which are miscible with the protic solvent such as C4 to C10 alkanes aromatic solvents such as benzene, toluene, xylenes, halobenzenes such as chlorobenzene, and ethers such as diethylether, tert-butyl ether, tert-butyl methyl ether , isopropyl ether and tetrahydrofuran, or mixtures of any of the foregoing solvents or cosolvents. The term "alkyl" means straight or branched alkyl such as methyl, ethyl, propyl, or sec-butyl. Alternatively, the number of carbons in alkyl can be specified. For example, alkyl C-, a C6 means an alkyl as described above containing from 1 to 6 carbon atoms. "Haloalkyl" means an alkyl as described above where one or more hydrogens are replaced by halogen. The term "aryl" means phenyl, or phene substituted by C, C6 alkyl or halogen. Benzyl substituted means benzyl substituted by C-, C6-, or halo alkyl. The term "halogen" means fluorine, chlorine, bromine, or iodine. The term "halo aryl" means phenyl substituted by halogen.
In the present application,
which is an aminodiol sulfone, is referred to as ADS. The process for preparing the compounds of the invention can be prepared as follows: wherein R, R 'and R "are as described herein With reference to the formula of the above scheme, a compound of formula I can be prepared as follows. compound of formula II
n
where R and R 'are as described above is treated with a reducing agent such as NaBH 4, Ca (BH 4) 2, LiBH 4 or more preferably KBH 4 in a protic solvent such as ethanol, ethylene glycol, or more preferably methanol, at room temperature in the range of about 0 ° C to about 30 ° C more preferably room temperature for a period of about 2 to about 8 hours, more preferably about 4 hours to obtain a compound of formula III: CHOOH m
where R is as described above. If, for example, in the reaction described above, methanol is used as a solvent in the reduction, it can be recovered by distillation for reuse in the subsequent reactions. Removing the methanol can also improve the production of the compound of formula 1. In the same reaction vessel, the compound of formula III is contacted with a compound of formula IV, R "- C = N IV where R" is as described above, in the amount of about 1.1 to about 2.5 equivalents, preferably about 1.7 equivalents compared to the compound of formula III.
Compounds of formula IV can be, for example, benzonitrile or dichloroacetonitrile. the reaction is run at a temperature between 25 ° C and 115 ° C depending on the nitrile and the solvent used. The reaction is run for about 6 hours to about 30 hours, preferably 18 hours. The reaction mixture is then cooled, for example, by addition of cold water and worked by conventional means such as filtration and washing to reach the compound of formula I. Preferably this step of the reaction is run at a pH in the range of about 6 to approximately 7.
An advantage of the following process is that it eliminates the need to isolate ADS, since both reaction steps are run in the same vessel. The formation of dichloromethyl oxazoline is preferred and the formation of phenyl oxazollna is more preferred. The serine ethyl ester compound, as shown below, is preferred as the starting material of formula II.
COOCHoCK.
The following examples illustrate the present invention in a manner that can be practiced but, as such should not be understood as limiting the scope of the invention. EXAMPLE 1
KBH4 (1 g) is placed in approximately 40 ml of methanol. D-threo p-methylsulfonyl phenyl serine ethyl ester (5 g) is added with stirring. The reduction of the ADS is complete in a few hours and can be monitored by HPLC.
When the reaction is complete, 20 ml of glycerin is added to destroy any excess reducing agent and methanol is removed by distillation. After the methanol has been removed, the resulting mixture is heated to 105 ° C and benzonitrile (3.1 ml) is added while continuing to heat for about 18 hours. The formation of the desired oxazoline can be monitored by HPLC. The reaction is then cooled to room temperature and worked up by adding cold water, filtering the resulting solids, washing the solids with methanol then drying under vacuum, yields about 4.7 g (81%) of material which is identical to an authentic sample of phenyl oxazoline. EXAMPLE 2
KBH4 (1 g) is placed in approximately 40 ml of methanol. D-threo p-methylsulfonyl phenyl serine ethyl ester (5 g) is added with stirring. The reduction of the ADS is complete in a few hours and can be monitored by HPLC. When the reaction is complete, 20 ml of glycerin is added to destroy any excess reducing agent and methanol is removed by distillation. After the methanol has been removed, the resulting mixture is acidified to pH of about 6 to 7 with H2SO4 and dichloroacetonitrile (2.4 g) is added. The reaction is stirred at 50 ° C for 18 hours. The formation of the desired oxazoline can be monitored by HPLC. The reaction is then cooled to room temperature and worked up by adding cold water, filtering the resulting solids, washing the solids with isopropanol and 2% NaHCO 3 then drying under vacuum. The production is about 3.8 g (65%) of material that is identical to a real sample of dichloro oxazoline. THE STARTING MATERIALS The starting materials of formula (II) and (IV) are known to those with knowledge of the art.
Claims (4)
1. A process for preparing a compound of formula (I):
I where R is H, N02, CH3S, CH3S02, or C4 to C6 alkyl; and R "is aryl, halo aryl, benzyl, substituted benzyl, C, a C6 alkyl, C3 to C7 cycloalkyl, and haloalkyl, and the configuration of the oxazolidine ring is 4R trans: comprising: a) contacting a compound of formula II: where R is as described above, and R 'is H, C-, C6 alkyl, C3 to C7 cycloalkyl, benzyl, substituted benzyl or aryl; with a reducing agent such as potassium borohydride, in a suitable reaction vessel, to obtain a compound of formula III: wherein R is as described above, and b) then a compound of formula III is reacted in the same reaction vessel, with a compound of formula IV:
R -_- C = N IV to obtain a compound of formula I. 2. A process according to claim 1 wherein the reducing agent is potassium borohydride. 3. A process according to claim 1 wherein the compound of formula I that is formed is:
4. A process according to claim 1 wherein the compound of formula I that is formed is: 10
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08699271 | 1996-08-19 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA99001612A true MXPA99001612A (en) | 1999-06-01 |
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