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Title:
PROCESS FOR THE PREPARATION OF GEMINAL DIFLUOROALKANES
Document Type and Number:
WIPO Patent Application WO/2005/014519
Kind Code:
A1
Abstract:
The invention relates to a process for the preparation of a substituted geminal difluoroalkane, wherein an oxime is converted to the gerninal difluoroalkane using a nitrite and a complex consisting of HF and an organic base, as well as its use as an intermediate in the manufacture of pharmaceutical products.

Inventors:
Schmand, Horst Ludwig-karl (Kramerstr. 3, Bad Nenndorf, 31542, DE)
Application Number:
PCT/EP2004/005756
Publication Date:
February 17, 2005
Filing Date:
May 27, 2004
Export Citation:
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Assignee:
HONEYWELL SPECIALTY CHEMICALS SEELZE GMBH (Wunstorfer Strasse 40, Seelze, 30926, DE)
Schmand, Horst Ludwig-karl (Kramerstr. 3, Bad Nenndorf, 31542, DE)
International Classes:
C07C51/09; C07C51/363; C07C61/15; C07C67/307; C07C69/75; C07C251/44; (IPC1-7): C07C67/307; C07C69/75; C07C51/363; C07C61/15; C07C251/44
Domestic Patent References:
WO2001090106A22001-11-29
Foreign References:
EP0905109A11999-03-31
US6262075B12001-07-17
US4792618A1988-12-20
Other References:
TORDEUX M ET AL: "Chlorination of oximes in hydrogen fluoride: formation of gem-dihalogenoalkanes", JOURNAL OF FLUORINE CHEMISTRY, ELSEVIER SEQUOIA. LAUSANNE, CH, vol. 70, no. 2, 1 February 1995 (1995-02-01), pages 207 - 214, XP004020758, ISSN: 0022-1139
S. ROZEN ET AL.: "Conversion of the carbonyl to CF2 using IF", JOURNAL OF ORGANIC CHEMISTRY, vol. 56, 1991, pages 4695 - 4700, XP002301843
C.G.OVERBERGER ET AL.: "Asymmetric polymers", JOURNAL OF POLYMER SCIENCE PARTA-1, vol. 10, 1972, pages 2265 - 2289, XP002301844
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002301845, Database accession no. 1963:469044
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; XP002301846, Database accession no. 1960:49887
DATABASE WPI Section Ch Week 200338, Derwent World Patents Index; Class B05, AN 2003-397449, XP002301847
Attorney, Agent or Firm:
Bublak, Wolfgang (Bardehle, Pagenberg Dost, Altenburg, Geissle, Galileiplatz 1 München, 81679, DE)
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Claims:
Claims
1. Process for the preparation of a geminal difluoroalkane of the general formula (I), wherein, independently from each other, R'and R"represent substituted alkyl, arylor aralkyl or may be combined by the formation of a cyclic sys tem, characterized in that an oxime of the general formula (II) whereas R'and R"are defined as aforesaid, is converted using a nitrite and a complex consisting of hydrogen fluoride and an organic base.
2. Process according to claim 1, characterized in that R'and R"represent Ci Cgalkyl or aryl or, in combination with the carbon atom they are bound to, C3 Csalkyl.
3. Process according to claim 2, characterized in that R'and R"form a cyclo hexane ring in combination with the carbon atom they are bound to.
4. Process according to claim 3, characterized in that the difluoroalkane of the general formula (I) is a difluorocyclohexanecarboxylic acid ester of the gen eral formula (I'), wherein R represents a hydrogen atom or ClC8aLkyl.
5. Process according to claim 4, characterized in that the difluoroalkane of the general formula (I') is 4,4difluorocyclohexanecarboxylic acid ethyl ester.
6. Process according to claim 4, characterized in that the difluoroalkane is 4,4 difluorocyclohexanecarboxylic acid.
7. Difluorocyclohexanecarboxylic acid ester of the general formula (I') ac cording to claim 4, wherein R represents a hydrogen atom or a ClC8alkyl residue.
8. Compound according to claim 7, namely 4,4difluorocyclohexanecarboxylic acid.
9. Compound according to the general formula (II') (II') wherein R represents a hydrogen atom or a ClCgalkyl residue.
10. Use of 4,4difluorocyclohexanecarboxylic acid as an intermediate in the manufacture of pharmaceutical products.
Description:
Process for the Preparation of Geminal Difluoroalkanes The present invention relates to a process for the preparation of geminal difluoro- alkanes, as well as to new compounds prepared by said process and their use as an intermediate of pharmaceutical products.

Owing to their advantageous biochemical properties geminal difluoroalkanes are of special significance, which is due to the fact that the CF2-group is isopolar and isometric in relation to the ether oxygen and a R-CHOH group. According to con- ventional manufacturing processes, a corresponding ketone is converted to a geminal difluoroalkane using fluorophosgene (J. Am. Chem. Soc. 84 (1962) 4275), sulfur tetrafluoride (Org. Reactions 21 (1974) 1), DAST (Et2NSF3, J. Org.

Chem. 40 (1975) 574) or trifluoroacetic acid anhydride or pyridine HF (JP-A-63- 054 332). Moreover, derivatized ketones such as hydrazones (J. Am. Chem. Soc.

109 (1987) 896), diazo compounds (J. Chem. Soc. , Perkin Trans. 1 (1978) 1224) and thioketals (J. Org. Chem. 51 (1986) 3508) can be converted to geminal difluo- roalkanes, respectively, using fluorine or halogen fluorides. In the present proc- esses mainly gaseous and highly aggressive reagents are used that were generated using F2 which involves a costly realisation of the conversion.

Recent literature has suggested to convert an unsubstituted oxime using a mixture of anhydrous hydrogen fluoride in ether in the presence of N204 (J. Fluorine Chem. 70 (1995) 207). However, the yield of this process is small. Concurrently, the conversion of an oxime using hydrogen fluoride in pyridine and nitrosyl tetra- fluoroborate (NOBF4) was published (Synlett (1994) 425). However, the reagent NOBF4 is costly and ill-suited for the use in the industry. Furthermore, according to the above manufacturing processes, only unsubstituted oximes can be con- verted to the corresponding geminal difluoroalkanes.

Thus, it is the object of the present invention to overcome the above disadvantages of the prior art and to provide a process for the preparation of geminal difluoroal- kanes which is specific, has sufficient yields, utilizes cost-effective reagents and which can also preferably be used for substituted difluoroalkanes.

This object can be achieved by reacting an oxime with a nitrite and a complex consisting of hydrogen fluoride and an organic base.

Thus, the invention relates to a process for the preparation of a geminal difluor- alkane having the general formula (I),

(I) wherein, independently from each other, R'and R"represent substituted alkyl-, aryl-or aralkyl or may be combined to form a cyclic system, characterized in that an oxime of the general formula (II)

(II) whereas R'and R"are defined as aforesaid, is converted using a nitrite and a complex comprising hydrogen fluoride and an organic base.

The oxime of the formula (II) is not particularly limited: in principle, any alkyl-, aryl-or aralkyl oxime can be used. If the oxime contains functional groups, these groups should be sufficiently stable with regard to acids and oxidants or be pro- tected from fluorination accordingly. The oximes can be manufactured from the respective ketones by use of conventional processes. Thereby, 4-cyclohexanoneoxime carboxylic acid (esters) are parent compounds for par- ticularly preferred difluoroalkanes according to the invention and novel, making them suitable for the use as intermediate compounds.

As the fluorination agent a combination of an hydrogen fluoride and an organic base may be used. Bases may be electron pair donors (Lewis bases) such as amines or ethers. In combination with an excess of hydrogen fluoride these or- ganic bases containing free electron pairs form remarkably stable complexes of the general formula BH+ (HF) XF-, generally known as onium poly (hydrogen fluo- ride). Examples thereof are: R2OH+ (HF) XF- (oxonium poly (hydrogen fluoride)), CsHsNH+ (HF) xF (pyridinium poly (hydrogen fluoride)), R3PH+ (HF) XF- (phosphonium poly (hydrogen fluoride)), R3NH+ (HF) XF- (ammonium poly (hydrogen fluoride) ) and (polyvinylpyridinium polyhydrogen fluoride).

As the nitrite inorganic or organic nitrites, or a combination thereof can be used, however, for practical reasons, the use of sodium nitrite and/or potassium nitrite is preferred. If organic nitrites are used, pentylnitrite and butylnitrite are suitable candidates.

Preferably, the nitrite is added as a solid to the reaction mixture consisting of an oxime and onium poly (hydrogen fluoride). The reaction is highly exotermic and is carried out preferably at a temperature of about 0 °C. After conversion, the reac- tion mixture is further processed with water, as usual.

The starting materials and the reagents can be added in any order.

In order to provide the hydrogen fluoride with the necessary reactivity, the pres- ence of an organic base is preferred. If nitrosyl tetrafluoroborate is used as a fluo- rination agent, this results in small yields, particularly for substituted oximes as shown in Comparative Example 1 below. Converting an oxime using only anhy- drous HF and nitrite results in a very small yield as shown in a Comparative Ex- ample 2 below.

The reaction scheme for the production of the preferred compound 4,4- difluorocyclohexane-carboxylic acid can be shown as follows. oximation ROOC 0) OH fluorination /---\ F/---\ F /\ saponification/\ ROOC 'F'F

The following examples illustrate the above discussion.

Example 1 Preparation of 4, 4-difluorocyclohexane-carboxylic acid ethyl ester (method A) In a nitrogen deactivated 250 ml PFA-flask comprising a magnetic stirrer, a ther- moindicator, an N2-inlet, a dosing pipe with a single-use syringe, a bubble gauge and an exhaust tube, 100 g pyridine/HF with wt. 70% HF were added and cooled down to 0 °C. While stirring for 20 minutes, 6 g sodium nitrite were added in small portions. After continued stirring for another 10 minutes at 0 °C 8.6 g 4- cyclohexanoneoxime-carboxylic acid ethyl ester were added via a dosing pipe with a single-use syringe over a period of 55 minutes. Thereby, the temperature was kept constant in a range between-2 and 1. 5 °C. Near completion of the dos- ing, gas was generated. The reaction mixture was then stirred for another 2 hours at 0 °C.

300 g ice were put in a 21 PE beaker, and the reaction mixture was poured in at constant stirring. The mixture was then extracted using 350 ml fluobenzene. Wa- ter was added to the combined organic phases, followed by neutralizing them with a saturated sodium hydrogen carbonate solution. After phase separation, the or-

ganic lower phase was washed with water, filtered and narrowed down. 5.77 g of the title compound were obtained (yield 64.7%), which was measured using gas chromatography.

Example 2 Preparation of 4, 4-difluorocyclohexane-carboxylic acid ethyl ester (method B) In a nitrogen deactivated 250 ml PFA-flask comprising a magnetic stirrer, a ther- moindicator, an N2-inlet, a dosing pipe with a single-use syringe, a bubble gauge and an exhaust tube, 100 g pyridine/HF with wt. 70% HF were added and cooled down to 0 °C. Then, 27.8 g 4-cyclohexanoneoxime-carboxylic acid ethyl ester were added via a dosing pipe with a single-use syringe over a period of 20 min- utes after continued stirring for another 30 minutes at 0 °C. 12.4 g sodium nitrite were added in small portions. Thereby, the temperature was kept constant in a range between-2 and 1. 5 °C. Near completion of the dosing gas was generated.

The reaction mixture was then stirred for another 2 hours at 0 °C.

300 g ice were put in a 21 PE beaker, and the reaction mixture was poured in at constant stirring. The mixture was then extracted using 350 ml fluobenzene. Wa- ter was added to the combined organic phases, followed by neutralizing them with a saturated sodium hydrogen carbonate solution. After phase separation, the or- ganic lower phase was washed with water, filtered and narrowed down. 18.2 g of the title compound were obtained (yield 63. 0%), which was measured using gas chromatography.

Example 3 Preparation of 4-cyclohexanoneoxime-carboxylic acid ethyl ester In a 500 ml three necked-flask comprising an stirrer, a cooler, a thermometer and a drip funnel, 200 ml water, 81.6 g sodium acetate and 52.2 g hydroxylamine hy-

drochloride were added and heated up to 60 °C. Then, 85.2 g 4-cyclohexanone- carboxylic acid ethyl ester were added to the mixture over a period of 1 hour. The emulsion was stirred for 1.5 hours and left to stand over night at room tempera- ture. This was followed by adding 50 ml tert-butyl methyl ether, by shaking, by separating the lower phase and by a repeated extraction of 50 ml tert-butyl methyl ether. Then, the combined organic phases were washed several times with water, filtered, dried and narrowed down under reduced pressure. 86.8 g 4-cyclohexanoneoxime-carboxylic acid ethyl ester were obtained (yield 93.6%).

Comparative Example 1 Preparation of 4, 4-difluorocyclohexane-carboxylic acid ethyl ester using NOBF4 In a 200 ml PFA-flask with N2-inlet, thermoindicator, dosing pipe with syringe, cooler, receiving flask, bubble gauge and exhaust tube, 100 g of pryidine/HF with 70 wt% HF were added and cooled down to 0 °C. Subsequently, 6.6 g nitrosyl tetrafluoroborate (white coarse crystals) were slowly added. 8.6 g of 4- cyclohexanone oxime carboxylic acid ethyl ester were drawn into a 10 ml syringe and added at-7 to-2 °C within 1 hour via the pipe. Then, the reaction mixture was heated up to room temperature and stirred for another 4 hours at room tempera- ture. After about 1 hour the temperature rose to 27 °C, gas was bubbling up and N20 could be observed in the bubble gauge. This was followed by cooling down with an ice bath. After the usual procedures, 3.4 g of the title compound (yield: 38. 5%) could be isolated.

Comparative Example 2 Preparation of 4, 4-difluorocyclohexane-carboxylic acid ethyl ester using HF without an organic base 70 g of HF were put into a 250 ml PFA-round bottom flask which was cooled in an ice/sodium chloride-freezing mixture. At a temperature of about-10 °C 18.5 g of 4-cyclohexanone oxime carboxylic acid ethyl ester were added to the HF, fol- lowed by portionwise adding 7 g NaN02 to the solution within 2 hours. In the meantime, the flask was closed with a bubble gauge which was removed during the addition of the nitrite. Only a minor gas generation could be observed. The reaction temperature was limited to a range between-5 °C and 2 °C. After dosing the nitrite, the reaction mixture was poured on ice, and after phase separation a sample was taken from the organic phase.

The GC-analysis showed 84 area% starting material, 7.6 area% of 4, 4- difluoro- cyclohexane-carboxylic acid ester and 5.6 area% of a monofluoro-compound. The assignment was performed using GC/MS.