JP2008013519A - Production method for optically active 2-fluoroalcohol derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a production method suitable for producing an optically active 2-fluoroalcohol derivative on a large scale, which is an important intermediate of medicine and optical materials. <P>SOLUTION: The optically active 2-fluoroalcohol derivative is produced by reacting an optically active α-hydroxycarboxylic ester derivative with sulfuryl fluoride in the presence of an organic base or in the presence of an organic base and "a salt or complex comprising an organic base and hydrogen fluoride" and then reacting the resultant optically active α-fluorocarboxylic ester derivative with a hydride reducing agent. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a method for producing an optically active 2-fluoroalcohol derivative which is an important intermediate between pharmaceuticals and optical materials.

  The optically active 2-fluoroalcohol derivative is a compound useful as an intermediate material for pharmaceuticals and optical materials.

  In order to produce an optically active 2-fluoroalcohol derivative, an optically active α-fluorocarboxylic acid ester derivative is synthesized (first step), and thereafter the ester site of the compound is reduced to a hydroxyl group (second step). Process) is considered a useful method. When such a method is employed, the key reaction is the first step. That is, in order to efficiently produce the optically active 2-fluoroalcohol derivative targeted by the present invention, it depends on whether the optically active α-fluorocarboxylic acid ester derivative can be synthesized with good yield and optical purity. ing.

  Here, the following methods are known as conventional production methods of optically active α-fluorocarboxylic acid ester derivatives and techniques related to the present invention.

  1) A method of deaminofluorination of an optically active α-amino acid derivative in a hydrogen fluoride / pyridine complex (Non-patent Document 1).

  2) A method in which a racemic α-fluorocarboxylic acid ester derivative is optically resolved by asymmetric hydrolysis with an enzyme (Non-patent Document 2).

3) A method in which an optically active α-hydroxycarboxylic acid ester derivative is dehydroxyfluorinated by various techniques. 3) The production method of 3-1) DAST [(C ₂ H ₅ ) ₂ NSF ₃ ] (Non-patent Document 3), 3-2) Method using fluoroalkylamine reagent (Non-patent Document 4), 3-3) There are methods (Non-Patent Document 5 and Non-Patent Document 8) in which a hydroxyl group is converted to a sulfonate group and substituted with a fluorine anion (F ⁻ ).

4) A substrate having a hydroxyl group is converted to perfluorobutanesulfonyl fluoride (C ₄ F ₉ SO) in the presence of a special organic base such as DBU (1,8-diazabicyclo [5.4.0] undec-7-ene). A method of dehydroxyfluorination with perfluoroalkanesulfonyl fluoride (RfSO ₂ F; Rf represents a perfluoroalkyl group) such as ₂ F) (Patent Documents 1 and 2).

5) Presence of an organic base such as triethylamine [(C ₂ H ₅ ) ₃ N] and a fluorinating agent such as triethylamine / hydrogen trifluoride complex [(C ₂ H ₅ ) ₃ N · 3HF] as a substrate having a hydroxyl group A method of dehydroxyfluorination with perfluorobutanesulfonyl fluoride below (Non-patent Documents 6 and 7).
6) Trifluoromethanesulfonyl fluoride (CF) in a hydroxy derivative in the presence of an organic base or in the presence of an organic base and a salt or complex comprising an organic base and hydrogen fluoride (such as triethylamine / hydrogen trifluoride complex). ₃ SO ₂ F) and a method for producing a fluoro derivative by reacting with (SO ₂ F) (Patent Documents 3 to 6).
US Pat. No. 5,760,255 US Pat. No. 6,248,889 International Publication No. 2004/089968 Pamphlet (Japanese Patent Laid-Open No. 2004-323518) Japanese Patent Laying-Open No. 2005-083163 JP 2005-336151 A JP 2005008534 A Tetrahedron Letters (UK), 1993, 34, No. 2, p. 293-296 Organic Synthesis (USA), 1990, Vol. 69, p. 10-18 Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry (1972-1999) (UK), 1980, No. 9, p. 2029-2032 The Chemical Society of Japan (Japan), 1983, No. 9, p. 1363-1368 Tetrahedron; Asymmetry (UK), 1994, Vol. 5, No. 6, p. 981-986 Organic Letters (USA), 2004, Vol. 6, No. 9, p. 1465-1468 227th ACS Spring National Meeting Abstracts, March 28-April 1, 2004, ORGN 198, D.C. Zarkowski et al. (Merck) Tetrahedron Letters (UK), 1996, 37, No. 1, p. 17-20

  An object of the present invention is to provide a production method suitable for large-scale production of an optically active 2-fluoroalcohol derivative that is an important intermediate between pharmaceuticals and optical materials.

In the production methods of Non-Patent Document 1 and Non-Patent Document 4, the α-fluorocarboxylic acid ester derivative having high optical purity could not be obtained. In the production method of Non-Patent Document 2, the yield did not exceed 50% because of the optical resolution of the racemate. In the production method of Non-Patent Document 3, it is necessary to use DAST which is very expensive and dangerous to handle in large quantities. In the production method of Non-Patent Document 5, it was necessary to separately perform the step of converting a hydroxyl group into a sulfonate group and the step of substituting with a fluorine anion (F ⁻ ). In addition, the optical purity was significantly decreased through the two steps, and the optical purity of the optically active α-hydroxycarboxylic acid ester derivative used as the substrate was changed to the optical purity of the optically active α-fluorocarboxylic acid ester derivative as the target product. There was a problem that it was not reflected.

In the method of Non-Patent Document 8, it is necessary to pass through an imidazole sulfate in order to convert a hydroxy derivative into a fluorosulfate, and there is a problem that a substitution step with a fluorine anion (F ⁻ ) has to be performed separately. (See Scheme 1).

In Patent Document 1, Patent Document 2, Non-Patent Document 6, and Non-Patent Document 7, a dehydroxyfluorination reaction using perfluoroalkanesulfonyl fluoride as a substrate having a hydroxyl group is widely disclosed. It has the merit that the step of converting to a sulfonic acid ester group (perfluoroalkanesulfonic acid ester group) and the step of substitution with a fluorine anion (F ⁻ ) can be carried out continuously in one reactor. However, it uses perfluoroalkanesulfonyl fluorides with 4 or more carbon atoms, which have been pointed out as long-term persistence and toxicity to the environment and have limited industrial use [for example, to the environment of perfluorooctane sulfonic acid derivatives For long-term persistence and toxicity, see Pharmacia Vol. 40 No. 2 2004]. Furthermore, in the production methods of Patent Document 1 and Patent Document 2, it is necessary to use a special organic base such as DBU that is expensive for industrial use. In addition, in the production methods of Non-Patent Document 6 and Non-Patent Document 7, triethylamine is used. -It was necessary to add a fluorinating agent such as a hydrogen trifluoride complex in addition to perfluorobutanesulfonyl fluoride.

  On the other hand, since the methods of Patent Documents 3 to 6 use trifluoromethanesulfonyl fluoride having 1 carbon, it is an excellent method that can avoid long-term environmental persistence and toxicity problems, but trifluoromethanesulfonyl fluoride. The industrial production of is limited compared to perfluorobutanesulfonyl fluoride and perfluorooctanesulfonyl fluoride, and it was not always easy to obtain a large amount.

  In any of the documents disclosing the dehydroxyfluorination reaction using the above-mentioned perfluoroalkanesulfonyl fluoride, a production method suitable for large-scale production of an optically active α-fluorocarboxylic acid ester derivative having high optical purity Was not specified.

  Thus, a method capable of industrially producing an optically active 2-fluoroalcohol derivative has been strongly desired.

From the above viewpoint, the present inventors have intensively studied to find a method for producing an optically active 2-fluoroalcohol derivative that can be easily carried out on a large scale. As a result, sulfuryl fluoride (SO ₂ F ₂ ) widely used as a fumigant is represented by the general formula [1].

The present inventors have obtained the knowledge that the optically active α-hydroxycarboxylic acid ester derivative represented by the formula (1) is extremely suitable for dehydroxyfluorination, and have solved the problem. That is, the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1], which is an object of the present invention, is added in the presence of an organic base or an organic base and a “salt composed of an organic base and hydrogen fluoride or It has been found that by reacting with sulfuryl fluoride in the presence of “complex”, the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] can be produced with good yield and optical purity. An example of using sulfuryl fluoride as a dehydroxyfluorination agent has not yet been reported.

  In this dehydroxyfluorination reaction, fluorosulfonylation and fluorine substitution can be carried out continuously in one reactor without isolating the fluorosulfuric acid ester that is a reaction intermediate. The characteristic of this reaction is that, as shown in Scheme 2, a hydroxy derivative can be converted into a fluorosulfate by using sulfuryl fluoride, and “organic” produced as a by-product in the reaction system in this fluorosulfonylation step. A salt or complex comprising a base and hydrogen fluoride can be effectively used as a fluorine source for fluorine substitution. Further, as shown in Scheme 3, fluorosulfonylation can also be carried out in the presence of “a salt or complex composed of an organic base and hydrogen fluoride”. Compared with the method shown in Scheme 2, optically active α-fluorocarboxylic acid is used. It has also been found that acid ester derivatives can be obtained with higher yield and selectivity.

  In the present invention, sulfuryl fluoride used as a dehydroxyfluorination agent has two reactive sites with a hydroxyl group. When an optically active α-hydroxycarboxylic acid ester derivative is used as a hydroxy derivative, It was found that the substitution of fluorine proceeded satisfactorily through the target fluorosulfuric acid ester with almost no substituted sulfuric acid ester (see Scheme 4). It was clarified that such a problem cannot occur in perfluoroalkanesulfonyl fluoride, and that sulfuryl fluoride can be suitably used as a dehydroxyfluorination agent.

  Furthermore, when the optically active substance resulting from the chirality of the carbon atom to which the hydroxyl group is covalently bonded as in the present invention is used as the α-hydroxycarboxylic acid ester derivative, the present inventors have reacted with sulfuryl fluoride. It was found that the stereochemistry of the α-fluorocarboxylic acid ester derivative obtained in 1 was reversed. In this dehydroxyfluorination reaction, it is considered that fluorosulfonylation proceeds by steric retention and subsequent fluorine substitution proceeds by steric inversion. Such a dehydroxyfluorination reaction involving inversion of stereochemistry has already been disclosed in the method using perfluoroalkanesulfonyl fluoride of Patent Document 2, but the elimination ability of the fluorosulfate group is perfluoroalkanesulfone. Since it is much inferior to the acid group [Synthesis (Germany), 1982, No. 2, p. 85-126], in a dehydroxyfluorination reaction using a chain substrate in which stereochemistry is difficult to control, in particular, a sulfuryl fluoride of an optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] It is unclear whether or not it proceeds at a high asymmetric transcription rate. In contrast, the present inventors have shown that in the general formula [1], the dehydroxyfluorination reaction using the sulfuryl fluoride of the present invention proceeds well under very mild reaction conditions and is used as a raw material substrate. It was found that the optical purity of the optically active α-hydroxycarboxylic acid ester derivative shown was reflected, and an optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] having an extremely high optical purity was obtained.

  The present inventors react the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] thus obtained with a hydride reducing agent, thereby producing an optical compound represented by the general formula [7]. The present inventors have found that an active 2-fluoroalcohol derivative can be produced in a high yield and without impairing optical purity, thereby completing the present invention.

That is, the present invention provides a method for producing an optically active 2-fluoroalcohol derivative based on [Invention 1] to [Invention 4].
[Invention 1]
A method for producing an optically active 2-fluoroalcohol derivative represented by the general formula [7], comprising the following two steps.
First step: General formula [1]

Is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base to give a general formula [2]

A step of obtaining an optically active α-fluorocarboxylic acid ester derivative represented by the formula:
Second Step: By reacting the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] obtained in the first step with a hydride reducing agent, the general formula [7]

The process of obtaining the optically active 2-fluoro alcohol derivative shown by these.
[In General Formula [1], General Formula [2], and General Formula [7], R represents a linear or branched alkyl group having 1 to 12 carbon atoms, and an aromatic group is formed on any carbon atom of the alkyl group. Aromatic hydrocarbon group, unsaturated hydrocarbon group, straight or branched alkoxy group having 1 to 6 carbon atoms, aryloxy group, halogen atom (fluorine, chlorine, bromine, iodine), protected carboxyl group, amino group Or a protective group of a hydroxyl group can be substituted by one or any combination. R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms. Arbitrary carbon atoms of the alkyl group of R and R ¹ may form a covalent bond. * Represents an asymmetric carbon. ]
[Invention 2]
In the invention 1, the optically active 2-fluoroalcohol derivative represented by the general formula [7], wherein the reaction in the first step is carried out in the presence of “a salt or complex comprising an organic base and hydrogen fluoride” How to manufacture.
[Invention 3]
The optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is represented by the general formula [3].

Formula [8] according to Invention 1 or Invention 2, wherein the organic base is triethylamine [(C ₂ H ₅ ) ₃ N].

A method for producing an optically active 2-fluoroalcohol derivative represented by the formula:
[In General Formula [3] and Formula [8], R ² represents a methyl group, an ethyl group or an isopropyl group, and * represents an asymmetric carbon. ]
[Invention 4]
The optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is represented by the formula [5].

Wherein the organic base is triethylamine [(C ₂ H ₅ ) ₃ N]. The formula [9] according to the invention 1 or 2, wherein the organic base is triethylamine [(C ₂ H ₅ ) ₃ N].

A method for producing an optically active 2-fluoroalcohol derivative represented by the formula:

  In the dehydroxyfluorination reaction of the present invention, it is not necessary to use perfluoroalkanesulfonyl fluoride, which is a problem in waste treatment, long-term persistence and toxicity to the environment, and sulfuryl fluoride widely used as a fumigant is used. Can be used.

Further, in the present invention, fluorosulfuric acid is quantitatively by-produced as a salt of an organic base, but the acid can be easily treated as final waste to fluorite (CaF ₂ ) on an industrial scale. Very suitable for fluorination reaction.

  Furthermore, the perfluoroalkyl moiety of the perfluoroalkanesulfonyl fluoride is not finally incorporated into the target product, and if it has sufficient sulfonylation ability and elimination ability, the fluorine content should be lower. This is industrially advantageous, and sulfuryl fluoride is remarkably superior from such a viewpoint.

  Further, it is not necessary to use an expensive and special organic base such as DBU, and an inexpensive and industrially widely used organic base such as triethylamine can be used.

  Further, unlike the method of Non-Patent Document 8, there is no need to go through an imidazole sulfate, and it is also excellent in that a hydroxy derivative can be directly converted into a fluorosulfate by using sulfuryl fluoride.

  Moreover, the effect of the new invention was discovered by using a sulfuryl fluoride. In a dehydroxyfluorination reaction using perfluoroalkanesulfonyl fluoride, a salt of perfluoroalkanesulfonic acid and an organic base is quantitatively contained in the reaction end solution, and the salt, particularly having 4 or more carbon atoms. Since salts derived from perfluoroalkanesulfonic acid have extremely high solubility in organic solvents, post-treatment operations commonly employed in organic synthesis, such as washing the organic layer with water or an aqueous alkaline solution, are performed. However, it was found that the salt could not be removed effectively, and there was a problem that the purification operation was burdened. Further, a salt composed of perfluoroalkanesulfonic acid and an organic base may act as an acid catalyst. In order to produce a compound having an acid labile functional group, it is necessary to remove the salt efficiently. On the other hand, the salt of fluorosulfuric acid and organic base produced as a by-product in the present invention is extremely water-soluble, and can be completely removed by washing the organic layer with water or an aqueous alkali solution. It has been found that it is extremely suitable for industrial fluorination reactions.

  The production method of the present invention is highly selective for efficiently producing an optically active 2-fluoroalcohol derivative on a large scale because both of the first step and the second step are highly selective and hardly produce impurities that are difficult to separate. This is a useful method.

  Hereafter, the manufacturing method of the optically active 2-fluoro alcohol derivative of this invention is demonstrated in detail.

  In this production method, the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is added in the presence of an organic base or the presence of an organic base and a “salt or complex comprising an organic base and hydrogen fluoride”. Below, it reacts with sulfuryl fluoride, and the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] obtained is reacted with a hydride reducing agent (Scheme 5).

  First, dehydroxyfluorination in the first step will be described. In the first step, dehydroxyfluorination is carried out by reacting the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] in the presence of an organic base or an organic base and a salt comprising an organic base and hydrogen fluoride. Or by reacting with sulfuryl fluoride in the presence of "complex".

  In the first step, fluorosulfonylation and fluorine substitution can be carried out continuously in one reactor without isolating the fluorosulfuric acid ester which is a reaction intermediate. Fluorosulfonylation preserves the stereochemistry of the hydroxyl group, and subsequent fluorine substitution reverses the stereochemistry. Therefore, from the α-position R-form of the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1], the α-position S-form of the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] Similarly, the α-position R-form is obtained from the α-position S-form.

  R of the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is methyl group, ethyl group, propyl group, butyl group, amyl group, hexyl group, heptyl group, octyl group, nonyl group, decyl. Group, an undecyl group, and a lauryl group, and an alkyl group having 3 or more carbon atoms can be linear or branched. In addition, on any carbon atom of the alkyl group, an aromatic hydrocarbon group such as a phenyl group or a naphthyl group, an unsaturated hydrocarbon group such as a vinyl group, a linear or branched alkoxy group having 1 to 6 carbon atoms, a phenoxy Aryloxy group such as a group, halogen atom (fluorine, chlorine, bromine, iodine), protector of carboxyl group, protector of amino group or protector of hydroxyl group shall be substituted by one or any combination ("Substituted alkyl group"). Examples of protecting groups for carboxyl group, amino group and hydroxyl group include Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. Can be used. Specifically, examples of the carboxyl-protecting group include an ester group. Examples of the amino-protecting group include a benzyl group, an acyl group (acetyl group, chloroacetyl group, Benzoyl group, 4-methylbenzoyl group, etc.), phthaloyl group and the like, and as protecting groups for hydroxyl group, benzyl group, 2-tetrahydropyranyl group, acyl group (acetyl group, chloroacetyl group, benzoyl group, 4- Methylbenzoyl group, etc.), silyl groups (trialkylsilyl group, alkylarylsilyl group, etc.) and the like, and in particular, 2,2-dimethyl-1,3-dioxolane is used as a protective group for 1,2-dihydroxyl group. Examples of the protective group to be formed include.

Examples of R ¹ of the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] include a methyl group, an ethyl group, a propyl group, a butyl group, an amyl group, a hexyl group, a heptyl group, and an octyl group. An alkyl group having 3 or more carbon atoms can be linear or branched. Furthermore, R of the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] and an arbitrary carbon atom of the alkyl group or substituted alkyl group of R ¹ form a covalent bond to take a lactone ring. You can also.

  As the stereochemistry of the asymmetric carbon of the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1], the R configuration or the S configuration can be adopted, and the enantiomeric excess (% ee) is particularly limited. However, 90% ee or more may be used, and usually 95% ee or more is preferable, and 97% ee or more is more preferable.

  The optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is described in Synthetic Communications (USA), 1991, Vol. 21, No. 21, p. With reference to 2165-2170, it can be similarly produced from various optically active α-amino acids that are commercially available. In addition, (S) -lactic acid ethyl ester used in the examples was a commercially available product.

  The reaction in the first step is carried out by reacting any of the above-mentioned optically active α-hydroxycarboxylic acid ester derivatives in the presence of an organic base or in the presence of an organic base and a “salt or complex comprising an organic base and hydrogen fluoride”. In addition, in consideration of a predetermined reaction solvent, temperature, pressure, reaction time, and the like, which will be described later, it can be achieved by contacting with sulfuryl fluoride and thoroughly mixing.

The amount of sulfuryl fluoride (SO ₂ F _2), is not particularly limited, if the formula using the least 1 mol of the optically active α- hydroxy carboxylic acid ester derivative 1 mol represented by [1] It is usually preferably 1 to 10 moles, more preferably 1 to 5 moles.

  Examples of the organic base include trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6-collidine, 3,4,5-collidine, 3,5 6-collidine and the like can be mentioned. Among them, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6 -Colidine and 3,5,6-collidine are preferred, especially triethylamine, diisopropylethylamine, pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine.

  Although there is no restriction | limiting in particular as the usage-amount of an organic base, What is necessary is just to use 1 mol or more with respect to 1 mol of optically active alpha-hydroxy carboxylic acid ester derivatives shown by General formula [1], Usually, 1-20. Mole is preferable, and 1 to 10 mol is more preferable.

  Next, the “salt or complex comprising an organic base and hydrogen fluoride” that can be used in the first step will be described in detail.

  Examples of the organic base of the “salt or complex comprising an organic base and hydrogen fluoride” include trimethylamine, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,5- Lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,3,4-collidine, 2,4,5-collidine, 2,5,6-collidine, 2,4,6- Collidine, 3,4,5-collidine, 3,5,6-collidine and the like can be mentioned. Among them, triethylamine, diisopropylethylamine, tri-n-propylamine, pyridine, 2,3-lutidine, 2,4-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6 -Colidine and 3,5,6-collidine are preferred, especially triethylamine, diisopropylethylamine, pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine.

  The molar ratio of the organic base and hydrogen fluoride in the “salt or complex comprising an organic base and hydrogen fluoride” is in the range of 100: 1 to 1: 100, and usually in the range of 50: 1 to 1:50. The range of 25: 1 to 1:25 is particularly preferable. Furthermore, “complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride” commercially available from Aldrich (2003-2004 general catalog), and “pyridine 30% (-10 mol%) and hydrogen fluoride˜70 It is very convenient to use “complex consisting of% (˜90 mol%)”.

The amount of the “salt or complex comprising an organic base and hydrogen fluoride” is not particularly limited, but fluorine anion (1 mol per 1 mol of the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] F ⁻ ) may be used in an amount of 0.3 mol or more, usually 0.5 to 50 mol, and particularly preferably 0.7 to 25 mol.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane, cyclohexane, and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene, and halogens such as methylene chloride, chloroform, and 1,2-dichloroethane. Hydrocarbons, diethyl ether, tetrahydrofuran, ethers such as tert-butyl methyl ether, esters such as ethyl acetate and n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone Amides such as acetonitrile, nitriles such as acetonitrile and propionitrile, dimethyl sulfoxide and the like. Among them, n-heptane, toluene, mesitylene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile, propionitrile and dimethyl sulfoxide are preferable, and particularly toluene, mesitylene, methylene chloride. Tetrahydrofuran, N, N-dimethylformamide and acetonitrile are more preferred. These reaction solvents can be used alone or in combination.

  Although there is no restriction | limiting in particular as the usage-amount of a reaction solvent, 0.1 L (liter) or more should just be used with respect to 1 mol of optically active alpha-hydroxycarboxylic acid ester derivatives shown by General formula [1], and it is normal. Is preferably 0.1 to 20 L, more preferably 0.1 to 10 L.

  The temperature condition is not particularly limited, but may be performed in the range of −100 to + 100 ° C., and is usually preferably −80 to + 80 ° C., more preferably −60 to + 60 ° C. In the case where the reaction is carried out at a temperature not lower than the boiling point of sulfuryl fluoride (−49.7 ° C.), a pressure resistant reactor can be used.

  The pressure condition is not particularly limited, but may be in the range of atmospheric pressure to 2 MPa. Usually, atmospheric pressure to 1.5 MPa is preferable, and atmospheric pressure to 1 MPa is more preferable. Therefore, it is preferable to perform the reaction using a pressure resistant reaction vessel made of a material such as stainless steel (SUS) or glass (glass lining).

  The reaction time is not particularly limited, but may be in the range of 0.1 to 72 hours, and varies depending on the substrate and reaction conditions. Therefore, the reaction proceeds by an analytical means such as gas chromatography, liquid chromatography, or NMR. It is preferable that the end point is the time when the raw material is almost disappeared by tracking the situation.

  There is no particular limitation on the post-treatment, but usually the reaction-terminated solution is poured into water or an aqueous solution of an alkali metal inorganic base (eg, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate), and an organic solvent ( For example, a crude product can be obtained by extraction with toluene, mesitylene, methylene chloride, ethyl acetate or the like. Since the salt of fluorosulfuric acid and organic base by-produced from sulfuryl fluoride, or the alkali metal salt of fluorosulfuric acid, has a very high distribution to water, these salts can be efficiently removed by simple operations such as washing with water. The desired optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] can be obtained with high chemical purity. Moreover, it can refine | purify to higher chemical purity by activated carbon treatment, distillation, recrystallization, etc. as needed.

  Among the reactions in the first step, the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is represented by the general formula [3].

Is particularly preferable when the organic base is triethylamine [(C ₂ H ₅ ) ₃ N]. In this case, as a result of the dehydroxyfluorination reaction, the general formula [4]

Is an optically active α-fluorocarboxylic acid ester derivative.
[In General Formula [3] and General Formula [4], R ² represents a methyl group, an ethyl group or an isopropyl group, and * represents an asymmetric carbon. ]
Among them, the optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is represented by the formula [5].

In the case of the optically active α-hydroxycarboxylic acid ester derivative represented by the formula [6], it is produced as a result of the dehydroxyfluorination reaction.

Is an optically active α-fluorocarboxylic acid ester derivative.

  Next, the hydride reduction in the second step will be described. The hydride reduction in the second step is performed by reacting the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] obtained by dehydroxyfluorination in the first step with a hydride reducing agent. 7] to obtain an optically active 2-fluoroalcohol derivative represented by [7].

  In this hydride reduction, the stereochemistry of the carbon atom substituted with the fluorine atom is retained, and the 2-position R-form of the optically active 2-fluoroalcohol derivative is obtained from the α-position R-form of the optically active α-fluorocarboxylic acid ester derivative, Similarly, a 2-position S-form is obtained from the α-position S-form. This hydride reduction can be carried out in the same manner with reference to known methods, for example, Japanese Patent No. 2879456.

Examples of the hydride reducing agent include (i-Bu) ₂ AlH, LiAlH ₄ and NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ , aluminum hydride series, diborane, BH ₃ · tetrahydrofuran, BH ₃ · S (CH ₃ ) _2. And boron hydride systems such as BH ₃ .N (CH ₃ ) ₃ , NaBH ₄ , and LiBH ₄ (i-Bu represents an isobutyl group). Among them, (i-Bu) ₂ AlH, LiAlH ₄ , NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ , diborane, BH ₃ · tetrahydrofuran, NaBH ₄ and LiBH ₄ are preferable, and (i-Bu) ₂ AlH, LiAlH are particularly preferable. ₄ and NaAlH ₂ (OCH ₂ CH ₂ OCH ₃ ) ₂ are more preferred. These hydride reducing agents can also be used in the presence of various inorganic salts.

  Although there is no restriction | limiting in particular as the usage-amount of a hydride reducing agent, 0.5 mol or more should just be used with respect to 1 mol of optically active alpha-fluorocarboxylic acid ester derivatives shown by General formula [2], Usually, 0.5-5 mol is preferable, and 0.5-3 mol is more preferable especially.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane, cyclohexane, and n-heptane, aromatic hydrocarbons such as benzene, toluene, xylene, and mesitylene, and halogens such as methylene chloride, chloroform, and 1,2-dichloroethane. Hydrocarbons, ethers such as diethyl ether, tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, alcohols such as methanol, ethanol, n-propanol, i-propanol, and the like. Among them, n-heptane, toluene, mesitylene, methylene chloride, diethyl ether, tetrahydrofuran, tert-butyl methyl ether, 1,4-dioxane, methanol, ethanol and i-propanol are preferable, and particularly toluene, mesitylene, tetrahydrofuran, tert-butyl. More preferred are methyl ether, methanol and ethanol. These reaction solvents can be used alone or in combination.

  Although there is no restriction | limiting in particular as the usage-amount of a reaction solvent, 0.1 L (liter) or more should just be used with respect to 1 mol of optically active (alpha) -fluoro carboxylic acid ester derivatives shown by General formula [2], Usually Is preferably 0.1 to 20 L, more preferably 0.1 to 10 L.

  As temperature conditions, it is -100 to +100 degreeC, Usually, -80 to +80 degreeC is preferable, and -60 to +60 degreeC is especially more preferable.

  The reaction time is 0.1 to 24 hours, but since it varies depending on the substrate and reaction conditions, the progress of the reaction is traced by analytical means such as gas chromatography, liquid chromatography, NMR, etc., and most of the raw materials disappeared. The time point is preferably the end point.

  There are no particular restrictions on the post-treatment, but usually water, sodium sulfate / hydrate, methanol or ethanol, etc. are added to the reaction finished solution to decompose excess hydride reducing agent, inorganic matter is filtered, and the filtrate is filtered. The crude product can be obtained by fractional distillation. By performing precision distillation as necessary, the optically active 2-fluoroalcohol derivative represented by the general formula [7], which is the target product, can be obtained with high chemical purity.

Hereinafter, the embodiments of the present invention will be specifically described by way of examples. However, the present invention is not limited to these examples.
[Example 1]
(First step)
In the pressure resistant reaction vessel 500L made of stainless steel (SUS), the following formula

19.2 kg (163 mol, 1.00 eq, optical purity 97.5% ee), mesitylene 125 kg (145 L) and triethylamine 17.0 kg (168 mol, 1.03 eq) were added. The internal temperature was cooled to 5 ° C., and 20.0 kg (196 mol, 1.20 eq) of sulfuryl fluoride was blown from the cylinder. The internal temperature was returned to room temperature and stirred for 4 hours. The conversion rate of the reaction was measured by gas chromatography and found to be 98% or more. The reaction-terminated liquid was poured into an aqueous solution of potassium carbonate and sodium chloride [prepared from potassium carbonate 15.8 kg (114 mol, 0.70 eq), sodium chloride 15.8 kg and water 126 kg] (PFA treatment tank 1000 L), and the organic layer was washed. The collected organic layer was washed with an aqueous solution of hydrochloric acid and sodium chloride [adjusted from 17.8 kg (171 mol, 1.05 eq) of 35% hydrochloric acid, 17.8 kg of sodium chloride and 148 kg of water], and further an aqueous solution of calcium chloride and sodium chloride [calcium chloride 5. Washed with 6 kg (50 mol, 0.31 eq), 5.6 kg of salt and 45 kg of water]

A mesitylene solution (fluorine ion concentration <1 ppm) of a crude product of the optically active α-fluorocarboxylic acid ester derivative represented by When the selectivity of the crude product was measured by gas chromatography, it was 99.0% or more (excluding optically active α-hydroxycarboxylic acid ester derivatives and mesitylene). The crude product mesitylene solution was subjected to fractional distillation (boiling point 60-86 ° C./21000 Pa) to recover 11.0 kg of the main distillation, 3.9 kg of the final distillation, and the residue (mesitylene solution). As a result of quantifying each fraction by ¹ H or ¹⁹ F-NMR spectrum (internal standard method), the main distillation contained 10.9 kg, the rear distillation contained 3.6 kg, and the kettle residue contained 0.3 kg. The total yield was 74%. Instrument data of the main product of the obtained optically active α-fluorocarboxylic acid ester derivative is shown below.
¹ H-NMR (reference material: Me ₄ Si, heavy solvent: CDCl ₃ ), δ ppm: 1.32 (t, 7.2 Hz, 3H), 1.58 (dd, 23.6 Hz, 6.9 Hz, 3H) ), 4.26 (q, 7.2 Hz, 2H), 5.00 (dq, 49.0 Hz, 6.9 Hz, 1H).
¹⁹ F-NMR (reference material: C ₆ F ₆ , heavy solvent: CDCl ₃ ), δ ppm: -21.88 (dq, 48.9 Hz, 24.4 Hz, 1F).
(Second step)
To a tetrahydrofuran solution containing 450 g (121 mmol, 0.59 eq) of lithium aluminum hydride (amount of tetrahydrofuran used: 150 ml) (500 ml glass four-necked flask), the following formula

A tetrahydrofuran solution (amount of tetrahydrofuran used: 50 ml) containing 26.7 g of the optically active α-fluorocarboxylic acid ester derivative represented by the formula (the above-mentioned residual fraction, 205 mmol, 1.00 eq) is cooled with ice and the internal temperature is 10 ° C. or lower. The mixture was gradually added while being controlled, and stirred at room temperature overnight. The conversion rate of the reaction was measured by gas chromatography and found to be 100%. To the reaction-terminated solution, a tetrahydrofuran solution containing 17.3 g (960 mmol, 4.68 eq) of water (tetrahydrofuran use amount 50 ml) was gradually added while controlling the internal temperature at 10 ° C. or lower under ice cooling, and the hydrogenation used in excess. Lithium aluminum was roughly decomposed and further stirred at 60 ° C. for 1 hour. After the temperature was lowered to room temperature, the inorganic substance was filtered with a centrifuge, and the inorganic substance was washed twice with 50 ml of tetrahydrofuran.

As a result, 250 g of a crude product of the optically active 2-fluoroalcohol derivative represented by the formula [ ¹⁹ F-NMR spectrum (internal standard method) quantitative value 152 mmol, moisture 3.2%] was obtained. When the selectivity of the crude product was measured by gas chromatography, it was 99.0% or more (excluding tetrahydrofuran and mesitylene). The resulting tetrahydrofuran solution of the crude product was subjected to fractional distillation (boiling point to 100 ° C./normal pressure) to recover 6.8 g of the first fraction, 6.1 g of the main fraction and the residue of the kettle. As a result of quantifying each fraction by ¹⁹ F-NMR spectrum (internal standard method), it contained 3.2 g in the first distillation, 6.1 g in the main distillation, and 1.2 g in the remainder. The total yield was 58%. The optical purity of the main distillate was 97.4% ee (R-form) as determined by gas chromatography after derivatizing to Mosher acid ester. The water content of the main distillation was 0.1% or less. Instrument data of the obtained optically active 2-fluoroalcohol derivative is shown below.
¹ H-NMR (reference material: Me ₄ Si, heavy solvent: CDCl ₃ ), δ ppm: 1.33 (dd, 23.6 Hz, 6.4 Hz, 3H), 2.00 (br, 1H), 3. 50-3.85 (m × 2, 2H), 4.76 (dm, 49.6 Hz, 1H).
¹⁹ F-NMR (reference substance: C ₆ F ₆ , heavy solvent: CDCl ₃ ), δ ppm: -21.40 (d / sextet, 48.9 Hz, 24.4 Hz, 1F).

Claims (4)

A method for producing an optically active 2-fluoroalcohol derivative represented by the general formula [7], comprising the following two steps.
First step: General formula [1]

Is reacted with sulfuryl fluoride (SO ₂ F ₂ ) in the presence of an organic base to give a general formula [2]

A step of obtaining an optically active α-fluorocarboxylic acid ester derivative represented by the formula:
Second Step: By reacting the optically active α-fluorocarboxylic acid ester derivative represented by the general formula [2] obtained in the first step with a hydride reducing agent, the general formula [7]

The process of obtaining the optically active 2-fluoro alcohol derivative shown by these.
[In General Formula [1], General Formula [2], and General Formula [7], R represents a linear or branched alkyl group having 1 to 12 carbon atoms, and an aromatic group is formed on any carbon atom of the alkyl group. Aromatic hydrocarbon group, unsaturated hydrocarbon group, straight or branched alkoxy group having 1 to 6 carbon atoms, aryloxy group, halogen atom (fluorine, chlorine, bromine, iodine), protected carboxyl group, amino group Or a protective group of a hydroxyl group can be substituted by one or any combination. R ¹ represents a linear or branched alkyl group having 1 to 8 carbon atoms. Arbitrary carbon atoms of the alkyl group of R and R ¹ may form a covalent bond. * Represents an asymmetric carbon. ] The optically active 2-fluoroalcohol derivative represented by the general formula [7] according to claim 1, wherein the reaction in the first step is performed in the presence of "a salt or complex composed of an organic base and hydrogen fluoride". How to manufacture. The optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is represented by the general formula [3].

The formula [8] according to claim 1 or ₂ , wherein the organic base is triethylamine [(C ₂ H ₅ ) ₃ N].

A method for producing an optically active 2-fluoroalcohol derivative represented by the formula:
[In General Formula [3] and Formula [8], R ² represents a methyl group, an ethyl group or an isopropyl group, and * represents an asymmetric carbon. ] The optically active α-hydroxycarboxylic acid ester derivative represented by the general formula [1] is represented by the formula [5].

The formula [9] according to claim 1 or ₂ , wherein the organic base is triethylamine [(C ₂ H ₅ ) ₃ N].

A method for producing an optically active 2-fluoroalcohol derivative represented by the formula: