JP2002104999A - Method for fluorination - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a method for fluorinating an organic compound having an alcoholic hydroxyl group excellent in cost, safety and selectivity. SOLUTION: This method for fluorinating is characterized by reacting an organic compound having a trialkylsiloxy group bound to a carbon atom with a compound represented by the general formula (1) (R1, R2, R3, and R4 are each identically or differently a substituted or unsubstituted saturated or unsaturated alkyl or a substituted or unsubstituted aryl group, provided that R1 and R2, or R3 and R4 may be bound to form a ring containing a nitrogen atom or the nitrogen atom and one or more other heterogeneous atoms, and R1 and R3 may be bound to form a ring containing a nitrogen atom or the nitrogen atom and one or more other heterogeneous atoms).

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for substituting a trialkylsiloxy group with a fluorine atom in an organic compound having a trialkylsiloxy group, and selectively converting an alcoholic hydroxyl group to a fluorine atom by applying this method. On how to do it.

[0002]

2. Description of the Related Art The fluorination of organic compounds is a relatively violent reaction, and even by using a mild fluorinating agent, many by-products are easily produced. In particular, in the method of substituting the alcoholic hydroxyl group of the organic compound having an alcoholic hydroxyl group with a fluorine atom, when the hydroxyl group inside the hydrocarbon chain is treated with a fluorinating agent, the reaction in which the intended hydroxyl group is substituted with a fluorine atom. At the same time, side reactions such as a reaction in which an unsaturated bond is generated by dehydration and a fluorination reaction accompanied by rearrangement tend to occur. Moreover, separation of these by-products from the target compound generally requires a complicated operation and is often not practical.

[0003] To solve this problem, Japanese Patent Publication No. 4-41
No. 129, the alcoholic hydroxyl group of an organic compound having an alcoholic hydroxyl group is converted to a trimethylsiloxy group, and then fluorinated with an aminosulfur fluoride-based fluorinating agent to replace the trimethylsiloxy group with a fluorine atom. A method of selectively converting an alcoholic hydroxyl group of an organic compound having an alcoholic hydroxyl group into a fluorine atom is disclosed.

In this method, an aminosulfur fluoride-based fluorinating agent represented by dimethylaminosulfurfluoride (DAST) is used as a fluorinating agent to be used, but the production of these fluorinating agents is expensive. It is very expensive due to the need for special raw materials and special production equipment, and also in terms of safety, there are reports that there was an explosion in the production and use of DAST,
[J. FluorineChem. , 42, 137 (1
989)] There are many problems in industrial use.

[0005] In addition, the selectivity of the reaction is also high.
According to Japanese Patent No. 1129, it is described that, for example, fluorination of 2-trimethylsiloxyoctane by DAST has a target 2-fluorooctane production rate of 84% and by-products such as octene of 16%. Although the value is improved as compared with the conventional method, the value is not yet satisfactory.

[0006]

SUMMARY OF THE INVENTION An object of the present invention is to provide a method for fluorinating an organic compound having an alcoholic hydroxyl group which is excellent in cost, safety and selectivity.

[0007]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve this problem, and as a result, the general formula (1)

[0008]

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(Wherein R ₁ , R ₂ , R ₃ and R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, and may be the same or different. . the R ₁ and R _2, R ₃ and R ₄ may form a ring including a bond to a nitrogen atom or a nitrogen atom and other hetero atom,. or by bonding R ₁ and R ₃ , A nitrogen atom, or a ring containing a nitrogen atom and another hetero atom may be used as a fluorinating agent to convert a trialkylsiloxy group bonded to a carbon atom into a conventional compound. It has been found that a fluorine atom can be directly substituted with a higher selectivity than the method, and that this fluorinating agent can be extremely safely and easily performed from its production to use in a fluorination reaction without requiring any special equipment. ,
The present invention has been achieved.

That is, the present invention is as follows. An organic compound having a trialkylsiloxy group bonded to a carbon atom is represented by the general formula (1)

[0011]

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(Wherein, R ₁ , R ₂ , R ₃ and R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, which may be the same or different. R ₁ and R ₂ , or R ₃ and R ₄ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom, or R ₁ and R ₃ may combine to form Which may form a nitrogen atom or a compound containing a nitrogen atom and another ring containing a hetero atom) to replace the trialkylsiloxy group with a fluorine atom. Method. The compound represented by the general formula (1) is represented by the general formula (2)

[0013]

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Wherein a is an integer of 2 or 3, R ₅ and R ₆ are a substituted or unsubstituted saturated or unsaturated lower alkyl group having 1 to ₆ carbon atoms, and may be the same or different. Fluorination method as described above. The compound represented by the general formula (2) is represented by the formula (3)

[0015]

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2,2-difluoro-1,3 represented by
-The fluorination method according to the above, which is dimethyl imidazolidine. Converting the alcoholic hydroxyl group of an organic compound having an alcoholic hydroxyl group into a trialkylsiloxy group;

[0017]

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(Wherein R ₁ , R ₂ , R ₃ and R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, and may be the same or different. . the R ₁ and R _2, R ₃ and R ₄ may form a ring including a bond to a nitrogen atom or a nitrogen atom and other hetero atom,. or by bonding R ₁ and R ₃ , A nitrogen atom or a ring containing a nitrogen atom and another hetero atom may be formed) to thereby replace the trialkylsiloxy group with a fluorine atom. A method of selectively converting an alcoholic hydroxyl group of an organic compound having an alcoholic hydroxyl group into a fluorine atom. The compound represented by the general formula (1) is represented by the general formula (2)

[0019]

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Wherein a is an integer of 2 or 3, R ₅ and R ₆ are a substituted or unsubstituted saturated or unsaturated lower alkyl group having 1 to ₆ carbon atoms, and may be the same or different. Fluorination method as described above. The compound represented by the general formula (2) is represented by the formula (3)

[0021]

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2,2-difluoro-1,3 represented by
-The fluorination method according to the above, which is dimethyl imidazolidine.

[0023]

DESCRIPTION OF THE PREFERRED EMBODIMENTS The present invention will be described below in detail.

The fluorinating agent according to the present invention has the general formula (1)

[0025]

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(Wherein R _{1 to} R ₄ are as defined above).

In the general formula (1), R _{1 to} R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, which may be the same or different. Examples of these are methyl, ethyl, n
-Propyl, isopropyl, n-butyl, butenyl, n-hexyl, n-heptyl, n-octyl, octenyl, 3,4-dimethylhexyl, phenyl, tolyl, 4-chlorophenyl And the like.

R ₁ and R 2, or R ₃ and R ₄ may combine to form a ring containing a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. Examples of such a ring include a pyrrolidine ring, a piperidine ring, a morpholine ring and the like.

Further, R ₁ and R ₃ are bonded to form a nitrogen atom,
Alternatively, a ring containing a nitrogen atom and another hetero atom may be formed. Examples of such rings include an imidazolidine ring,
Examples include a 1,3-diazacyclohexane ring, a 1,3-diazacycloheptane ring, a 1-oxa-3,5-diazacyclohexane ring, and the like.

Of these, the following general formula (2) is preferred.

[0031]

Embedded image (Wherein, a, R ₅ and R ₆ are as defined above).

In the general formula (2), R ₅ and R ₆ are a substituted or unsubstituted saturated or unsaturated lower alkyl group having 1 to ₆ carbon atoms, and the alkyl group may be linear or branched. Good. That is, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, butenyl group,
Examples thereof include an n-hexyl group, which may be the same or different. The ring structure is an imidazolidine ring (a = 2) or a 1,3-diazacyclohexane ring (a = 3).

Specific examples of the compounds represented by the general formulas (1) and (2) include the following compounds, but the present invention is not limited to these examples.

Bis-dimethylamino-difluoromethane, bis-diethylamino-difluoromethane, bis-
Di-n-propylamino-difluoromethane, bis-diisopropylamino-fluoromethane, bis-di-allylamino-difluoromethane, bis-di-n-butylamino-difluoromethane, bis-di-n-hexylamino-difluoromethane , Bis- (1-pyrrolidyl) -difluoromethane, bis- (1-piperidyl) -difluoromethane, 2,2-difluoro-1,3-dimethyl-imidazolidine, 2,2-difluoro-1,3-diethyl- Imidazolidine, 2,2-difluoro-1,3-di-
n-propyl-imidazolidin, 2,2-difluoro-
1,3-diisopropyl-imidazolidine, 2,2-difluoro-1,3-diallyl-imidazolidine, 2,2
-Difluoro-1,3-di-n-butyl-imidazolidine, bis- (N-methyl-N-phenyl) -difluoromethane, 2,2-difluoro-1,3-di-n-butyl-imidazolidine- 4,5-dione, 2,2-difluoro-1,3-dimethyl-1,3-diazacyclohexane, and the like.

Particularly preferred is 2,2-difluoro-1,3-dimethyl-imidazolidine represented by the general formula (3).

The compound represented by the general formula (1) according to the present invention can be produced by the following method. That is, the general formula (4)

[0037]

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(Wherein X ₁ and X ₂ represent a chlorine or bromine atom and may be the same or different; R ₁ , R ₂ ,
R ₃ and R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, and may be the same or different. R ₁ and R ₂ , or R ₃ and R ₄ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. Alternatively, R ₁ and R ₃ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. ) Can be safely and easily obtained by performing halogen exchange between the compound represented by formula (1) and an alkali metal salt of fluorine in a non-reactive solvent.

As alkali metal salts of fluorine, cesium fluoride, rubidium fluoride, potassium fluoride, sodium fluoride and the like can be used. Potassium fluoride for the fluorination reaction which is economically and reactionally advantageous The use of is preferred.

The compound represented by the general formula (4) is usually
Although a compound in which X ₁ and X ₂ are chlorine is used, even if either or both are bromine atoms, they can be used without any problem.

Specific examples include tetraalkyl chloroformamidium chloride, 2-chloro-1,3-dialkylamidinium bromide, and 2-bromo-1,3-dialkylamidinium bromide. .

The compound of the general formula (4) used as a raw material for producing the compound represented by the general formula (1) includes, for example, tetraalkylurea, tetraalkylthiourea,
It is produced by halogenating N, N'-dialkylimidazolidinone, N, N'-dialkylimidazolidinone or the like with a halogenating agent such as phosgene, thionyl chloride, thionyl bromide, phosphorus trichloride, phosphorus tribromide and the like. I can do it.

For example, the production of 1,3-dimethyl-2-chloroimidazolium chloride is described in JP-A-59-253.
No. 75, it can be easily manufactured. Alternatively, it can be produced by dropping a solution of oxalyl chloride in 1,3-dimethylimidazolidinone in a solvent such as carbon tetrachloride and reacting at room temperature to 60 ° C. for several hours to several tens of hours. it can.

In the production of the compound represented by the general formula (1) of the present invention, the amount of the alkali metal salt of fluorine used in the halogen exchange reaction is preferably based on tetraalkyl-haloformamidium = halide. 2 equivalents or more,
It is more preferably 2 to 5 equivalents. If it is less than 2 equivalents, the exchange reaction becomes insufficient and unexchanged chloride may remain. Also, the use of more than 5 equivalents does not significantly improve the reaction results.

The reaction solvent is not particularly limited as long as it does not react with the tetraalkyl-haloformamidium halide and the resulting compound. Preferably acetonitrile, dimethylformamide, 1,3-dimethyl-2-
Imidazolidinone, dichloromethane, ethylene dichloride and the like.

The amount of the reaction solvent is not particularly limited, but is preferably 1 to 100 times the weight of the reaction substrate from the viewpoint of reaction efficiency and operability.

The reaction temperature is not particularly limited, but is preferably -20 to 150 in view of the reaction rate and the stability of the product.
° C, more preferably in the range of 0 to 100 ° C.

The halogen exchange reaction in the method for producing the compound represented by the general formula (1) according to the present invention may be carried out in the presence of a phase transfer catalyst such as a quaternary alkyl ammonium salt or a quaternary alkyl phosphonium salt. It is possible.

The obtained compound represented by the general formula (1) can be used in the next fluorination reaction as it is in the halogen exchange reaction solution, or after the inorganic salt is removed by filtration and the reaction solvent is distilled off. Can be used for the next fluorination reaction, or can be used after being isolated by an operation such as distillation.

In the method of the present invention, the method of substituting an alcoholic hydroxyl group with a fluorine atom via a trialkylsiloxy group has higher selectivity and a higher selectivity than the method of directly substituting an alcoholic hydroxyl group with a fluorine atom. It has the feature that there are few side reactions other than the substitution reaction.

It is well known that a compound having an alcoholic hydroxyl group (hereinafter simply referred to as a hydroxyl group) is converted from a hydroxyl group to a trialkylsiloxy group in order to protect the hydroxyl group. In particular, in the synthesis of complex organic compounds such as pharmaceuticals, protecting a hydroxyl group by this method is widely performed. The conversion of a hydroxyl group to a trialkylsiloxy group can be easily performed using a trialkylsilyl chloride, a trialkylsilyldialkylamide, or another active compound having a trialkylsilyl group.

In the present invention, specific examples of the trialkylsiloxy group which can be substituted with a fluorine atom include a trimethylsiloxy group, a triethylsiloxy group, a dimethyl-t-butylsiloxy group and the like.

In the present invention, as the organic compound having an alcoholic hydroxyl group converted to a trialkylsiloxy group, a synthetic or natural organic compound having at least one alcoholic hydroxyl group can be used. For example, monohydric or polyhydric alcohols, sugar alcohols, amino sugars, sugars, prostaglandins, antibiotics having an alcoholic hydroxyl group (for example, anthracycline antibiotics and aminoglycoside antibiotics), sterols, and the like. . Particularly, a compound having at least one hydroxyl group bonded to a branched or linear unsaturated or saturated hydrocarbon chain having 3 or more carbon atoms is suitable.

Using the compound represented by the general formula (1),
When a reaction of substituting a trialkylsiloxy group with a fluorine atom of an organic compound having a trialkylsiloxy group is performed, the amount of the compound represented by the general formula (1) is preferably 1 to 1 to the trialkylsiloxy group. It suffices if it is equal to or more than the equivalent. If it is less than 1 equivalent, unreacted trialkylsiloxy groups may remain. Moreover, it is not preferable to use an excessive amount unnecessarily from the viewpoint of economy. Therefore, the amount of the compound represented by the general formula (1) is preferably about 1 to 5 equivalents to the trialkylsiloxy group. It is more preferably 1 to 1.5 equivalents.

Using the compound represented by the general formula (1),
When performing a reaction of replacing the trialkylsiloxy group of the organic compound having a trialkylsiloxy group with a fluorine atom, there is no particular problem without using a reaction solvent, but when used, a fluorinating agent and a raw material, and One that is inert to the product fluorine compound should be selected. For example, halogenated hydrocarbon, hydrocarbon, ether, acetonitrile, dimethylformamide, 1,3-dimethyl-2
-Imidazolidinone or the like is preferably used.

Using the compound represented by the general formula (1),
When a reaction of substituting a trialkylsiloxy group with a fluorine atom of an organic compound having a trialkylsiloxy group is performed, the reaction temperature is from -100 ° C to 100 ° C, particularly from -20 ° C to
About 80 ° C. is preferable.

Below -100 ° C., the reaction rate is small and not very practical. At a temperature higher than 80 ° C., the ratio of side reactions other than the intended fluorine substitution reaction tends to increase.

The product obtained by the method of the present invention can be easily removed or purified by a general method such as distillation, extraction, recrystallization and the like.

[0059]

EXAMPLES The present invention will be described in more detail with reference to the following Examples, but it should not be construed that the present invention is limited thereto. In the synthesis examples, the concentration of 2,2-difluoro-1,3-dimethylimidazolidine (DFI) in the acetonitrile solution was measured by high-performance liquid chromatography after derivatizing DFI by reacting it with aniline.

Fluorine ions (hereinafter abbreviated as F ⁻ )
Was measured by an absorption spectrophotometry method using an alizarin complexone reagent.

Synthesis Example 1 Synthesis of 2,2-difluoro-1,3-dimethyl-imidazolidine (DFI) Spray with 80.0 g (0.452 mol) of 1,3-dimethyl-2-chloro-imidazolium chloride 105.1 g of dry potassium fluoride (1.810 mo
l) and 320 ml of acetonitrile were charged into a 500 ml four-necked reaction flask and reacted at 80 ° C. for 17 hours under a nitrogen atmosphere. After cooling the reaction solution between 25 ° C., inorganic salts were separated from the reaction solution to obtain 414.2 g of a solution of 2,2-difluoro-1,3-dimethylimidazolidine (MW 136.15) in acetonitrile. 10. DFI concentration in solution
4 wt%, the yield was 77%. ¹ H-NMR (δ, ppm, CH ₃ CN): 2.51
_{(S, 6H, -CH 3 ×} 2), 3.04 (s, 4H, -
CH ₂ CH ₂ —), ¹³ C-NMR (δ, ppm, CH ₃ CN, −45 ° C.):
_{32.1 (s, -CH 3 × 2} ), 48.7 (s, -CH 2
− × 2), 130.0 (t, J = 230 Hz, −CF ₂₎
−) ¹³ C-NMR (δ, ppm, CH ₃ CN, 25 ° C.), 3
_{2.0 (s, -CH 3 × 2} ), 48.7 (s, -CH 2 -
× 2), 132.8 (broad, -CF ₂ -or = C
F-) Synthesis Example 2 Synthesis of 2-trimethylsiloxyoctane 6.53 g (50.14 mmol) of 2-octanol,
6.72 g (84.96 mmol) of anhydrous pyridine was dissolved in 20 ml of anhydrous methylene chloride, and 8.06 g (74.19 mmol) of chlorotrimethylsilane was added dropwise at 0 ° C. After stirring at room temperature for 4 hours, the mixture was diluted with anhydrous ether, poured into an ice-cooled saturated aqueous sodium hydrogen carbonate solution, and the organic phase was separated. The organic phase was washed with brine, dried over anhydrous magnesium sulfate, and then the solvent and pyridine were distilled off under reduced pressure to obtain 2-trimethylsiloxyoctane as a target compound in a yield of 90% and a purity of 96.6%. .

Example 1 Synthesis of 2-fluorooctane 1.50 g (7.16 mmol) of 2-trimethylsiloxyoctane obtained in Synthesis Example 2 was treated with 10 m of methylene chloride.
1 and isolated by distillation under ice-cooling.
20 g (8.81 mmol) were added. After 10 minutes, the ice bath was removed and the reaction was carried out at room temperature for another 3 hours. As a result of analyzing the obtained reaction mass by gas chromatography, the conversion of 2-trimethylsiloxyoctane as a raw material was 100%.
%, The desired 2-fluorooctane was produced in a yield of 91%, and octenes as by-products were produced in 9%.

Comparative Example 1 0.94 g of 2-octanol (7.22 mm
ol), except that the reaction was carried out in the same manner as in Example 1. As a result of analyzing the obtained reaction mass by gas chromatography, the conversion of 2-octanol as a raw material was 100%.
%, The product consisted of 82% of 2-fluorooctane and 18% of octenes.

Comparative Example 2 Diethylaminosulfur trifluoride (DAST) was used as a fluorinating agent, and the reaction temperature was 10
The reaction was carried out in the same manner as in Example 1 except that the reaction was carried out for 20 minutes at -20 ° C for 20 minutes. As a result of analyzing the obtained reaction mass by gas chromatography, the conversion of 2-trimethylsiloxyoctane as a raw material was 100%, the product was 2-fluorooctane 84%, and octenes were 16%.

[0065]

According to the present invention, an organic compound having a trialkylsiloxy group bonded to a carbon atom is represented by the general formula (1)
By reacting with a compound represented by the formula, a trialkylsiloxy group can be substituted with a fluorine atom. In this method, there are few side reactions other than the substitution reaction by the fluorine atom, and the reaction conditions are mild and safe. Further, the fluorinating agent to be used can be produced safely, easily and economically without using a highly dangerous chemical and without requiring special equipment. Therefore, it is useful as an industrial fluorine method which has solved the problems of the fluorination method.

 ────────────────────────────────────────────────── ─── Continuing on the front page (72) Inventor Hidetoshi Hayashi 30 Asamuta-cho, Omuta-shi, Fukuoka Mitsui Chemicals, Inc. F-term (reference) 4H006 AA02 AC30 BD60 BD60 BD70

Claims (6)

[Claims] 1. An organic compound having a trialkylsiloxy group bonded to a carbon atom is represented by the general formula (1): (Wherein, R ₁ , R ₂ , R ₃ , and R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, and may be the same or different. ₁
And R ₂ , and R ₃ and R ₄ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. Alternatively, R ₁ and R ₃ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. ), Wherein the trialkylsiloxy group is substituted with a fluorine atom by reacting the compound with the compound represented by the formula (1). 2. The compound represented by the general formula (1) is converted to a compound represented by the general formula (2): (In the formula, a is an integer of 2 or 3, R ₅ and R ₆ are a substituted or unsubstituted saturated or unsaturated lower alkyl group having 1 to ₆ carbon atoms, which may be the same or different.) The fluorination method according to claim 1, which is a compound represented by the formula: 3. The compound represented by the general formula (2) is a compound represented by the formula (3): The fluorination method according to claim 2, which is 2,2-difluoro-1,3-dimethylimidazolidine represented by the following formula: 4. The method according to claim 1, wherein the alcoholic hydroxyl group of the organic compound having an alcoholic hydroxyl group is converted into a trialkylsiloxy group. (Wherein, R ₁ , R ₂ , R ₃ , and R ₄ represent a substituted or unsubstituted saturated or unsaturated alkyl group or a substituted or unsubstituted aryl group, and may be the same or different. ₁
And R ₂ , and R ₃ and R ₄ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. Alternatively, R ₁ and R ₃ may combine to form a nitrogen atom or a ring containing a nitrogen atom and another hetero atom. A) reacting the compound represented by formula (1) with a fluorine atom to replace the trialkylsiloxy group with a fluorine atom, and selectively converting the alcoholic hydroxyl group of the organic compound having an alcoholic hydroxyl group into a fluorine atom. 5. The compound represented by the general formula (1) is converted to a compound represented by the general formula (2): (In the formula, a is an integer of 2 or 3, R ₅ and R ₆ are a substituted or unsubstituted saturated or unsaturated lower alkyl group having 1 to ₆ carbon atoms, which may be the same or different.) The fluorination method according to claim 4, which is a compound represented by the formula: 6. The compound represented by the general formula (2) is a compound represented by the formula (3): The fluorination method according to claim 5, which is 2,2-difluoro-1,3-dimethylimidazolidine represented by the following formula: