HK1107331B - Stereoselective method for preparing a chiral fluorinated molecule - Google Patents

Description

Stereoselective preparation of chiral fluorinated molecules

Technical Field

The present invention relates to a process for the preparation of chiral fluorinated molecules, in particular fluorinated molecules having a fluorine atom carried by an asymmetric carbon of (R) or (S) configuration located in the alpha position of an ester or ketone group. The invention more particularly relates to the preparation of methyl (R) -2-fluoropropionate (R2F).

Background

These compounds are industrially valuable products and can be used, in particular, as intermediates for the synthesis of plant protection agents or pesticides.

Patent US3100225 describes a process for producing fluorine-containing organic compounds by thermal decomposition of the corresponding fluorosulfite compounds in the presence of tertiary amines. This document does not teach a stereoselective process.

Patent DE4131242 describes a stereoselective way of synthesizing R2F, which involves the following two steps:

-sulfomethylation step:

-exchange step by KF:

this way of obtaining R2F is very efficient from a chemical point of view, but has the great disadvantage of generating large amounts of waste liquid, requiring very high reprocessing costs.

Disclosure of Invention

The inventors of the present invention have thus determined their own aim to develop a new process for stereoselectively obtaining these fluorinated molecules, which allows to obtain satisfactory yields from less expensive reagents and without generating large amounts of waste liquid.

The inventors of the present invention have succeeded in developing a process which achieves the above-mentioned objects and which makes it possible to prepare optically active products having a defined configuration, in particular products having an optical purity of 95% or more.

The object of the present invention is therefore a process for the stereoselective preparation of chiral fluorinated molecules, in which process:

(i) adding C into a reactor^*Molecules of OSOF units (hereinafter fluorosulfite compounds);

(2i) thermally decomposing the molecule in the presence of a nucleophilic catalyst;

(3i) recoveringThe resulting fluorinated molecule comprising the starting C^*C in inverted configuration for OSOF cell^*-an F unit.

"nucleophilic" refers to a catalyst having an atom capable of donating an electron pair. Suitable are compounds containing a tertiary nitrogen atom, a source of fluoride anions, and mixtures or complexes thereof.

The catalyst may be a tertiary amine, for example, the catalyst may be selected from: triethylamine, diisopropylethylamine, tri-N-propylamine, tri-N-butylamine, methyldibutylamine, methyldicyclohexylamine, ethyldiisopropylamine, N, N-diethylcyclohexylamine, pyridine, 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, N-N-butylpiperidine, 1, 2-dimethylpiperidine, N-methylpyrrolidine, 1, 2-dimethylpyrrolidine, dimethylaniline, picoline, and mixtures thereof.

It is also possible to use amides or formamides containing tertiary nitrogen atoms, such as dimethylformamide, dimethylacetamide.

Urea derivatives, such as ureas substituted with alkyl groups, such as tetramethylurea, may also be used.

As the fluoride anion source, basic fluorides such as KF, quaternary ammonium fluorides such as tetrabutylammonium fluoride, phosphonium fluorides such as tetrabutylphosphonium fluoride, and mixtures thereof can be cited.

It is also possible to use complexes of the HF/tertiary amine type, such as pyridine/(HF)_nOr Et₃N/(HF)_nWherein n is 1 to 10.

In a preferred embodiment, the catalyst is pyridine.

Specifically, the following reaction (I) → (II) is carried out:

(R) or (S) (S) or (R)

Wherein, in the above formula:

-R¹，R²and R⁴Each represents a hydrogen atom, or an alkyl, alkenyl, alkynyl group, which groups may be linear or branched, aryl, cycloalkyl, alkylcycloalkyl,

-CO₂R⁵，-(CH₂)_n-CO₂R⁵，-COR⁵，-SOR⁵，-SO₂R⁵wherein n is an integer, preferably 1 to 12,

R⁵hydrogen or alkyl, alkenyl, alkynyl, which groups may be linear or branched, cycloalkyl, alkylcycloalkyl, aryl, in particular substituted aryl,

R¹it is also possible to form aromatic or non-aromatic heterocycles containing one or more heteroatoms, selected from oxygen, sulphur or nitrogen, in place of one or more carbon atoms;

-R¹，R²and R⁴Are all different.

The following reaction (Ia) → (IIa) was carried out:

or the following reaction (Ib) → (IIb) is carried out:

according to a preferred embodiment, the invention is directed to a process for the preparation of fluorinated molecules having a fluorine atom carried by an asymmetric carbon of a given configuration located in the alpha position of a ketone or ester group, in which process:

(i) introducing C bearing fluorosulfite groups of formula (III) into a reactor^*The compound containing a fluorosulfite group of the given configuration

(R or S)

(2i) Thermally decomposing the fluorosulfite compound in the presence of a nucleophilic catalyst, preferably a catalyst containing a tertiary nitrogen atom,

(3i) recovering the resulting fluorinated molecule having an inverted configuration of formula (IV):

(S or R)

Wherein:

-R¹represents alkyl, alkenyl, alkynyl, these radicals being linear or branched, aryl, cycloalkyl, alkylcycloalkyl,

-CO₂R⁵，-(CH₂)_n-CO₂R⁵，-COR⁵，-SOR⁵，-SO₂R⁵，

n is an integer, preferably 1 to 12,

R⁵hydrogen or alkyl, alkenyl, alkynyl, which groups may be linear or branched, cycloalkyl, alkylcycloalkyl, aryl, in particular substituted aryl;

R¹it is also possible to form aromatic or nonaromatic heterocycles which containOne or more heteroatoms substituted with one or more carbon atoms, the heteroatoms selected from oxygen, sulfur or nitrogen;

-R²represents hydrogen or corresponds to the above for R¹A group of the given definition;

-R¹and R²Is different;

-R³represents hydrogen or R⁶OR-OR⁶Group, wherein R⁶Selected from the group consisting of⁵The given definitions;

R⁶and R¹May be the same or different.

In the present invention, the alkyl group, alkenyl group and alkynyl group may contain 1 to 12 carbon atoms, preferably 1 to 6 carbon atoms. Aryl, cycloalkyl, alkylcycloalkyl may contain from 3 to 8 carbon atoms, preferably from 5 to 6 carbon atoms. The heterocyclic ring may contain 3 to 8 atoms, preferably 5 to 6 atoms, in the ring.

R²May particularly represent hydrogen.

R³May particularly represent-OR⁶。

R¹May particularly represent C₁-C₁₂Alkyl, preferably C₁-C₆Alkyl groups, such as methyl.

R⁶May particularly represent C₁-C₁₂Alkyl, preferably C₁-C₆Alkyl groups, such as methyl.

According to a particular variant of the invention, the process is applied to compounds of formula III of the lactate type, in which R¹Is methyl, R²Is hydrogen and R³is-Oalkyl.

According to a particular form of the invention, R¹Is methyl, R²Is hydrogen, and R³is-OMe and the configuration of the fluorinated molecule is the (R) configuration.

It is particularly preferred that the material (massse) of the fluorosulfite compound (I), preferably the compound of the formula (III), used is essentially or completely free of HF and HCl.

Under the conditions of the present invention, the decomposition of the fluorosulfite compound is effected in a manner such that the configuration on the asymmetric carbon is reversed (stereoselective reaction).

The decomposition can be carried out by gradually increasing the temperature of the mixture or by operating at a fixed temperature.

Thus, the catalyst may be introduced into the fluorosulfite compound (I), preferably of the formula (III), and the temperature may then be increased to a value sufficient to initiate the decomposition, for example to a value of from 60 to 180 ℃, preferably 100 to 150 ℃. The catalyst is thus added to the fluorosulfite compound at a temperature below that which leads to the removal of SO₂The decomposition temperature of (a). The fluorosulfite compound can thus be used, for example, at ambient temperature (approximately 20-25 ℃). During this reaction, a solvent may be used, the fluorosulfite compound and the catalyst are added to the solvent, and the temperature is then increased (the definition of the solvent is given below).

In the fixed-temperature process, the fluorosulfite (I) to be decomposed, preferably of the formula (III), is gradually added to a reaction binder (seed particle) which is brought to and maintained at a temperature suitable for the decomposition, for example from 60 to 180 ℃ and preferably 100 ℃ to 150 ℃, and a catalyst is present in this binder or is added together with the fluorosulfite or after the fluorosulfite. The binder may comprise a solvent, or may be formed from a portion of the fluorosulfite compound, preferably of formula (III), or from reactants that produce fluorosulfite in a previous step. This embodiment makes it possible to carry out this step continuously by adjusting the input of the fluorosulfite compound to be decomposed and the withdrawal of the reactants.

As the solvent that can be used in these two embodiments, there can be mentioned:

aliphatic hydrocarbons, in particular paraffins, such as, in particular, pentane, hexane, heptane, octaneAlkanes, isooctanes, nonanes, decanes, undecanes, tetradecanes, petroleum ethers and cyclohexanes; aromatic hydrocarbons, such as, inter alia, benzene, toluene, xylene, ethylbenzene, diethylbenzene, trimethylbenzene, cumene, pseudocumene, petroleum fractions consisting of mixtures of alkylbenzenes, in particularA fraction of the type;

aliphatic or aromatic halogenated hydrocarbons, and mention may be made of: difluorobenzene, trifluorotoluene, fluorobenzene, monochlorobenzene, 1, 2-dichlorobenzene, 1, 3-dichlorobenzene, 1, 4-dichlorobenzene, or mixtures thereof;

aliphatic, cycloaliphatic or aromatic ether oxides, in particular methyl tert-butyl ether, dipentyloxy, diisopentyloxy, ethylene glycol dimethyl ether (or 1, 2-dimethoxyethane), diethylene glycol dimethyl ether (or 1, 5-dimethoxy-3-oxapentane) or cyclic ethers, for example dioxane, tetrahydrofuran;

aliphatic or aromatic nitriles, such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile, benzonitrile, benzylcyanide;

-N-methylpyrrolidone.

In a continuous process, the embodiment wherein the fluorosulfite compound is supplied to the medium maintained at the desired temperature is the preferred form.

The amount of catalyst used is advantageously from 0.1 to 10 mol%, preferably from 0.1 to 2 mol%, based on the fluorosulfite compound. Preferably, the operation is carried out at a pressure of from 50 mbar to 10 bar, more preferably from 1 to 10 bar.

When decomposition is complete (which is typically carried out for tens of minutes to hours, e.g. 1 to 5 hours). The medium may be cooled. One or more washing steps can then be carried out with water and the washed crude product is then purified, for example by vacuum distillation, to obtain the pure product.

The fluorosulfite compound (III) can be obtained by: reacting HF with a corresponding chlorosulfite compound of formula (V) (defined as referring to a compound comprising a chlorosulfite group) comprising an OSOCl group in place of the OSOF group in formula (III):

wherein R is¹，R²And R³Have the same meaning as given for formula (III) and formula (IV).

The reaction is carried out in a liquid HF medium.

According to this embodiment, in general from 1 to 10 equivalents, preferably from 1 to 5 equivalents, of HF are used, based on the chlorosulfite compound. HF is preferably added to the chlorosulfite compound. It is also preferred to operate under an inert atmosphere, preferably a nitrogen atmosphere. The absolute pressure is advantageously sufficient to keep the HF liquid under temperature conditions. The pressure may be, for example, atmospheric to 10 bar. It is therefore advantageous to operate at a temperature of from-30 to +50 ℃ and preferably from-10 to +20 ℃.

After the addition of liquid HF, the medium is advantageously stirred at the desired temperature for a time sufficient for the reaction to be complete, which, depending on the reaction temperature, may generally be from 1 to 10 hours.

In view of the subsequent decomposition step, it is preferable to remove residual HF and HCl formed. This can be achieved, for example, by operating under a nitrogen (or other inert gas) purge during the reaction. The HF and HCl are preferably removed at the end of the reaction, for example by purging with an inert gas (e.g. nitrogen), preferably in combination with the following operations: the medium is heated for several hours at a temperature (e.g., 20 to 80 c, e.g., about 50 c) that promotes removal of dissolved HF and HCl. HF and HCl can also be removed under reduced pressure.

The use of a solvent (as described above) in this step is not excluded, it being understood that it is preferred to work without a solvent.

Can be prepared by reacting SOCl₂With a corresponding hydroxylated precursor (VI) comprising an OH group replacing the OSOCl group of the chlorosulfite compound to obtain a chlorosulfite compound:

wherein R is¹，R²And R³Have the same meaning as given for formula (III) and formula (IV). SOCl used₂The amount of (A) is advantageously from 1 to 10 equivalents, preferably from 1 to 2 equivalents, of SOCl, based on the hydroxylated precursor₂. The temperature is advantageously from-30 to +50 ℃, preferably from-10 to +20 ℃ in practice, the precursor is preferably added gradually to the SOCl₂On a base (generally for a period of 1-10 hours). It is also preferred to operate under a nitrogen purge. During the addition of the precursor, the base of thionyl chloride is preferably stirred, and then the stirring is advantageously maintained for the time of completion (generally 1 to 10 hours).

The use of a solvent (as described above) in this step is not excluded, it being understood that it is preferred to work without a solvent.

These methods for preparing fluorosulfite on the one hand and chlorosulfite on the other hand can be used in order to obtain the totality of the fluorosulfite compounds of the formula (I) from chlorosulfite or from a hydroxylated precursor corresponding to the desired compound of the formula (I).

According to a particular embodiment, the following reaction sequence is carried out, which enables the production of methyl (R) -2-fluoropropionate.

The reaction sequence may be carried out in the same reactor or in different reactors.

Various routes for obtaining fluorosulfite compounds, in particular fluorosulfite of formula (III), can be contemplated. Among these routes, a route comprising the following steps can be mentioned:

(i) a compound of formula (VI) as defined above together with a compound of formula (VII) SOX₂Reaction, in which X represents identical or different halogen atoms, preferably chosen from Cl, Br and F, so as to obtain a halosulfite compound of formula (VIII) having the same configuration:

(2i) when one or more X is not F, compound (VIII) is reacted with HF to obtain the fluorosulfite compound of formula (III).

When X in formula (VII) is Cl, the sequential steps of hydroxylation precursor → chlorosulfite compound → fluorosulfite compound can be confirmed, as described in detail above.

When X in formula (VII) is F, the fluorosulfite compound is obtained in one step from the hydroxylated precursor (VI).

When SOFCl is used, the fluorosulfite compound can be obtained substantially and directly.

By using SOX₂(wherein X represents a halogen atom other than F or Cl) to obtain the fluorosulfite compound (III), it should be noted that₂Then the same operating conditions in the route with HF.

Detailed Description

The invention will now be illustrated in more detail by the description of embodiments as non-limiting examples.

The first step is as follows: preparation of chlorosulfite compound

Chlorosulfite

Esters of sulfurous acid

At a temperature of 20 ℃ 100 g of SOCl were placed in the bottom of the reactor₂(2 equivalents). 43.8g of methyl (S) lactate were added over 1 hour with stirring and under nitrogen purge. The liberated HCl is trapped in an aqueous sodium hydroxide solution.

After 6 hours from the end of this addition, the mixture had a residual content determined by NMR (residual SOCl not analyzed)₂) The following molar composition:

residual methyl lactate: 0.1% (CR 99.9%)

-chlorosulfite: 89.5% (yield 80.9%)

-esters of sulfurous acid: 10.5 percent

The second step is that: obtaining fluorosulfite compounds

The third step: decomposition of fluorosulfite compounds

Steps 2 and 3 are carried out successively starting from the solution of the chlorosulfite compound obtained in step 1.

Fluorination was carried out at 10 ℃ for 6 hours using 1.5 equivalents of HF relative to the chlorosulfite compound introduced. After stripping (striping) at 50 ℃ and under a nitrogen purge for 15 hours, pyridine was introduced in an amount of 1.5 mol% relative to the initial chlorosulfite. The reactor temperature was then brought to 140 ℃ and maintained at this temperature for 3 hours. During the decomposition, the pressure in the reactor was adjusted at 2 bar. The medium is subsequently cooled, dichloromethane is added and then washed twice with water. Quantitative analysis and chiral analysis were performed by gas chromatography.

Under these conditions, the yield of methyl fluoropropionate was 47% based on the chlorosulfite compound used.

The chemical purity of the (R) enantiomer was 96.3%.

It is to be understood that the invention defined by the appended claims is not to be limited by particular embodiments set forth in the foregoing description, but includes various modifications thereof without departing from the scope and spirit of the invention.

Claims (39)

1. A method for stereoselectively producing a fluorinated molecule having a fluorine atom carried by an asymmetric carbon atom of configuration (R) or (S) located in position α to an ester or ketone or aldehyde group, said method comprising:

(i) introducing C bearing fluorosulfite groups of formula (III) into a reactor^*A single enantiomer of the fluorosulfite compound having the given configuration

(2i) Thermally decomposing the fluorosulfite compound in the presence of a nucleophilic catalyst, and

(3i) recovering the resulting compound of formula (IV) at C^*A single enantiomer fluorinated molecule having an inverted configuration:

wherein:

C^*represents a chiral carbon;

R¹represents a linear or branched alkyl radical having 1 to 12 carbon atoms, a cycloalkyl or alkylcycloalkyl radical having 3 to 8 carbon atoms, a CO₂R⁵，-(CH₂)_n-CO₂R⁵，-COR⁵，-SOR⁵or-SO₂R⁵；

n is an integer from 1 to 12;

R⁵is hydrogen or a linear or branched alkyl group having 1 to 12 carbon atoms, a cycloalkyl group having 3 to 8 carbon atoms or an alkylcycloalkyl group;

R²represents hydrogen or above for R¹A group of the given definition;

R¹and R²Is different; and is

R³Represents hydrogen or R⁶OR-OR⁶Group, wherein R⁶Selected from the group consisting of⁵Given definition, wherein R⁶And R¹Are the same or different from each other and,

-when the single enantiomer of the fluorosulfite compound in step (i) has the R configuration, the single-enantiomer fluorinated molecule in step (3i) has the S configuration,

-when the single enantiomer of the fluorosulfite compound in step (i) has the S configuration, the single-enantiomer fluorinated molecule in step (3i) has the R configuration,

wherein the catalyst is introduced into the fluorosulfite compound and the temperature is then raised to 100-150 ℃ or

Wherein the fluorosulfite compound is gradually added to a solvent which is heated to a temperature of 100-150 ℃, the catalyst being present in the solvent or being added together with or after the fluorosulfite compound.

2. The method of claim 1, wherein R³represents-OR⁶。

3. The method of claim 1, wherein R⁶Represents C₁-C₁₂An alkyl group.

4. The method of claim 3, wherein R⁶Represents C₁-C₆An alkyl group.

5. The method of claim 3, wherein R⁶Represents a methyl group.

6. The method of claim 1, wherein R¹Is methyl, R²Is hydrogen and R³is-O-an alkyl group having 1 to 12 carbon atoms.

7. The method of claim 1, wherein R³is-OMe.

8. The method of claim 1, wherein R²Is hydrogen.

9. The method of claim 1, wherein R¹Represents C₁-C₁₂An alkyl group.

10. The method of claim 9, wherein R¹Represents a methyl group.

11. The process of claim 1 wherein the catalyst is a tertiary nitrogen atom containing compound, a source of fluoride anions, and mixtures or complexes thereof.

12. The process of claim 11 wherein the catalyst is selected from the group consisting of: triethylamine, diisopropylethylamine, tri-N-propylamine, tri-N-butylamine, methyldibutylamine, methyldicyclohexylamine, N, N-diethylcyclohexylamine, pyridine, 4-dimethylaminopyridine, N-methylpiperidine, N-ethylpiperidine, N-N-butylpiperidine, 1, 2-dimethylpiperidine, N-methylpyrrolidine, 1, 2-dimethylpyrrolidine, dimethylaniline, picoline, and mixtures thereof.

13. The process of claim 11 wherein the catalyst is selected from the group consisting of tertiary nitrogen atom containing amides, basic fluorides, ammonium fluorides.

14. The process of claim 11 wherein the catalyst is pyridine.

15. The method of claim 1 wherein the feed of fluorosulfite compound is substantially or completely free of HF and HCl.

16. The method of claim 13, wherein the amide is a formamide.

17. The process of claim 13 wherein the catalyst is selected from the group consisting of urea derivatives containing tertiary nitrogen atoms.

18. The process according to claim 1, wherein the amount of catalyst used is from 0.1 to 10 mol%, based on the fluorosulfite compound.

19. The process according to claim 18, wherein the amount of catalyst used is from 0.1 to 2 mol%, based on the fluorosulfite compound.

20. The process of claim 1, wherein the operation is carried out at a pressure of from 50 mbar to 10 bar.

21. The process of claim 20, wherein the operation is carried out at a pressure of from 1 to 10 bar.

22. The method of claim 1, wherein the fluorosulfite compound is obtained by reacting HF with a corresponding chlorosulfite compound containing an OSOCl group in place of the OSOF group.

23. The process according to claim 22, wherein from 1 to 10 equivalents of HF, based on the chlorosulfite compound, are used.

24. The process according to claim 23, wherein from 1 to 5 equivalents of HF, based on the chlorosulfite compound, are used.

25. The method of claim 22, wherein HF is added to the chlorosulfite compound.

26. The method of claim 22, wherein the operation is conducted under an inert atmosphere.

27. The process of claim 22, wherein the operation is carried out at a temperature of-30 to +50 ℃.

28. The process of claim 27, wherein the operation is carried out at a temperature of-10 to +20 ℃.

29. The method of claim 22, wherein HF and HCl are removed at the end of the reaction of HF with the chlorosulfite compound.

30. The process of claim 22 wherein the improvement is made by contacting SOCl₂With a corresponding hydroxylated precursor comprising an OH group instead of an OSOCl group to obtain a chlorosulfite compound.

31. The process of claim 30, wherein 1 to 10 equivalents of SOCl based on the hydroxylated precursor₂SOCl of₂The amount is manipulated.

32. The process of claim 31, wherein 1 to 2 equivalents of SOCl based on the hydroxylated precursor₂SOCl of₂The amount is manipulated.

33. The process of claim 30, wherein the operation is carried out at a temperature of-30 to +50 ℃.

34. The process of claim 33, wherein the operation is carried out at a temperature of-10 to +20 ℃.

35. The method of claim 30, wherein the precursor is added gradually to the SOCl₂In the base material.

36. The process of claim 30, wherein the operation is conducted under a nitrogen purge.

37. The method of claim 30, comprising:

a) reacting (S) -methyl 2-hydroxypropionateReacting with thionyl chloride to obtain (S) -1- (methoxycarbonyl) ethyl chlorosulfite

b) (S) -1- (methoxycarbonyl) ethyl fluorosulfite is obtained by reacting (S) -1- (methoxycarbonyl) ethyl chlorosulfite with hydrogen fluorideAnd is

c) Reacting (S) -1- (methoxycarbonyl) ethylfluorosulfite with catalytic amount of pyridine under heating to obtain (R) -methyl 2-fluoropropionate

38. The method of claim 37, wherein the reaction sequence is performed in the same reactor or in different reactors.

39. The process of claim 11 wherein the catalyst is selected from the group consisting of fluorination。