JP5605008B2 - Method for producing optically active trans-4-fluoroproline high purity product - Google Patents

Description

  The present invention relates to a method for producing optically active trans-4-fluoroproline.

Optically active trans-4-fluoroproline is an important pharmaceutical intermediate (Non-Patent Document 1, Non-Patent Document 2). In the method for producing the compound, a dehydroxyfluorination reaction involving steric inversion of the optically active cis-4-hydroxyproline protector is frequently used, but a considerable amount other than the desired optically active trans-4-fluoroproline protector is used. An optically active 3,4-dehydroproline protector is by-produced (see Scheme 1; P ¹ represents a protecting group for a carboxyl group, and P ² represents a protecting group for a secondary amino group). It has been difficult to easily and efficiently remove by-products at this stage and remove by-product-derived impurities in the subsequent deprotection reaction step.

  Conventional removal methods include a method of removing a treated product by reacting a carbon-carbon double bond with a halogen-based oxidant (Patent Document 1), or N-benzyloxycarbonyl-trans-4-fluoro-L-proline. A method of recrystallization and purification by derivatization into a cyclohexylamine salt at the stage (Patent Document 2) is disclosed.

  In addition, the present applicant has filed a method for recrystallization purification by inducing a salt at the stage of N-tert-butoxycarbonyl-trans-4-fluoro-L-proline (Japanese Patent Application No. 2009-278791).

International Publication No. 2006/080401 Pamphlet US Pat. No. 4,214,076

Organic Process Research & Development (USA), 2008, Vol. 12, p. 183-191 Bioorganic & Medicinal Chemistry (Netherlands), 2006, Vol. 14, p. 6900-6916

  Optically active trans-4-fluoroproline is required to have a high purity as a pharmaceutical intermediate. Therefore, an object of the present invention is to provide a method for producing a highly pure product of optically active trans-4-fluoroproline.

  In Patent Document 1, the reaction between the carbon-carbon double bond and the halogen-based oxidant is not simple, and it is difficult to specify the structure of the processed product to be finally removed, and quality control is not always easy.

  In addition, Patent Document 2 and Japanese Patent Application No. 2009-278791 require induction into a salt, recrystallization purification, and release to a carboxyl group, and the operation is not very simple. Furthermore, it could not be said that the recrystallization purification removal efficiency was remarkably high.

Prior to the present invention, preliminary studies were conducted on the removal of the above-mentioned by-products or impurities derived therefrom (see FIG. 1). As a result, Patent Document 2 and Japanese Patent Application No. 2009-278791 were applied to any of the target compounds in Cases 1 to 7. It was not possible to find a method that greatly exceeded the removal efficiency of No. 2 (recrystallization purification and salt recrystallization purification employed general procedures in organic synthesis. Case 7 was performed after the hydrogenation reaction) .

  As described above, there has been a strong demand for a method that allows easy quality control in the production of optically active trans-4-fluoroproline and that can produce a high-purity product simply and efficiently.

As a result of intensive studies based on the above problems, the present inventors have found that the properties of optically active trans-4-fluoroproline and optically active proline are greatly different, and both compounds can be easily separated. That is, in the method for producing optically active trans-4-fluoroproline, only the target product is selectively recovered from the reaction product containing optically active trans-4-fluoroproline (target product) and optically active proline (impurity). The manufacturing method characterized by these was found. Preferably, the optically active trans-4-fluoroproline protector (main product) and the optically active 3,4-dehydroproline protector obtained in the dehydroxyfluorination reaction of the optically active cis-4-hydroxyproline protector The reaction product containing (by-product) is subjected to a hydrogenation reaction and a deprotection reaction of a protecting group for a carboxyl group and a protecting group for a secondary amino group, thereby producing an optically active trans-4-fluoroproline (objective). Product) and an optically active proline (impurity) -containing reaction-treated product, and found a method for producing optically active trans-4-fluoroproline that selectively recovers only the desired product (see Scheme 2). Further, the protecting group for the carboxyl group of the protected optically active cis-4-hydroxyproline as the raw material substrate is preferably a benzyl group, and the protecting group for the secondary amino group is preferably a benzyloxycarbonyl group. By combining these suitable protecting groups, the hydrogenation reaction of the carbon-carbon double bond of the optically active 3,4-dehydroproline protector and the reductive action of the protecting group of the carboxyl group and the protecting group of the secondary amino group are achieved. Deprotection reaction (debenzylation reaction and debenzyloxycarbonylation reaction) can be carried out simultaneously. This means that a reaction product containing an optically active trans-4-fluoroproline protector and an optically active 3,4-dehydroproline protector is converted into a reaction product containing optically active trans-4-fluoroproline and optically active proline. This means that the induction can be performed in one step, which is a preferred embodiment of the present invention.

  That is, the present invention includes [Invention 1] to [Invention 5], and provides a method for producing a highly pure product of optically active trans-4-fluoroproline.

[Invention 1]
Formula [A]

In the method for producing optically active trans-4-fluoroproline represented by formula (A), the optically active trans-4-fluoroproline (target product) represented by formula [A] and formula [B]

A method for selectively recovering only a target product from a reaction-treated product containing optically active proline (impurities) represented by

[In the formula, * represents an asymmetric carbon, and the absolute configuration at the 2-position of the formula [A] is an S (L) isomer or an R (D) isomer, and the relative configuration between the 2-position and the 4-position of the formula [A]. Take a transformer. The stereochemistry at the 2-position of formula [A] and formula [B] takes the same absolute configuration]
[Invention 2]
General formula [1]

Which is obtained in a dehydroxyfluorination reaction of a protected cis-4-hydroxy-L-proline represented by the general formula [2]

Protected trans-4-fluoro-L-proline (main product) represented by the general formula [3]

The reaction product containing the 3,4-dehydro-L-proline protector (by-product) represented by the following reaction is subjected to a hydrogenation reaction and a deprotection reaction of a protecting group for a carboxyl group and a protecting group for a secondary amino group. By doing the equation [4]

Trans-4-fluoro-L-proline (target product) represented by the formula [5]

A process for producing trans-4-fluoro-L-proline, wherein the reaction product containing L-proline (impurity) represented by formula (1) is induced to selectively recover only the target product.

[Wherein P ¹ represents an alkyl group, a substituted alkyl group, a benzyl group or a substituted benzyl group, and P ² represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group or a triphenylmethyl group. Represents. ]
[Invention 3]
Formula [6]

Which is obtained in the dehydroxyfluorination reaction of a protected cis-4-hydroxy-L-proline represented by the formula [7]

A trans-4-fluoro-L-proline protector (main product) represented by formula [8]

A reaction product containing a 3,4-dehydro-L-proline protector (by-product) represented by the following formula: hydrogenation reaction and reductive deprotection of a protecting group for a carboxyl group and a protecting group for a secondary amino group By carrying out the reaction simultaneously, the formula [4]

Trans-4-fluoro-L-proline (target product) represented by the formula [5]

A process for producing trans-4-fluoro-L-proline, wherein the reaction product containing L-proline (impurity) represented by formula (1) is induced to selectively recover only the target product.

[Wherein Bn represents a benzyl group and Cbz represents a benzyloxycarbonyl group]
[Invention 4]
General formula [9]

Which is obtained in the dehydroxyfluorination reaction of a protected cis-4-hydroxy-D-proline represented by the general formula [10]

Protected trans-4-fluoro-D-proline (main product) represented by the general formula [11]

The reaction product containing the 3,4-dehydro-D-proline protector (by-product) represented by the following formula is subjected to a hydrogenation reaction and a deprotection reaction of a protecting group for a carboxyl group and a protecting group for a secondary amino group. By doing the equation [12]

Trans-4-fluoro-D-proline (target product) represented by the formula [13]

A process for producing trans-4-fluoro-D-proline, wherein the reaction product containing D-proline (impurities) represented by the formula (1) is induced to selectively recover only the target product.

[Wherein P ¹ represents an alkyl group, a substituted alkyl group, a benzyl group or a substituted benzyl group, and P ² represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group or a triphenylmethyl group. Represents. ]
[Invention 5]
Formula [14]

Which is obtained in the dehydroxyfluorination reaction of a protected cis-4-hydroxy-D-proline represented by the formula [15]

A trans-4-fluoro-D-proline protector (main product) represented by the formula [16]

A reaction product containing a 3,4-dehydro-D-proline protector (by-product) represented by the following formula: hydrogenation reaction and reductive deprotection of a protecting group for a carboxyl group and a protecting group for a secondary amino group By carrying out the reaction simultaneously, the formula [12]

Trans-4-fluoro-D-proline (target product) represented by the formula [13]

A process for producing trans-4-fluoro-D-proline, wherein the reaction product containing D-proline (impurities) represented by the formula (1) is induced to selectively recover only the target product.

[Wherein Bn represents a benzyl group and Cbz represents a benzyloxycarbonyl group]

  The advantages of the present invention over the prior art will be described below.

  In the present invention, the induction of the optically active 3,4-dehydroproline protector (by-product) to the optically active proline (impurity) proceeds quantitatively under suitable reaction conditions, and the target optically active trans-4- Optically active proline that may remain in fluoroproline is much easier to perform quality control because of its abundant analytical methods and toxicity data. Further, as disclosed in Example 1, separation of optically active trans-4-fluoroproline and optically active proline can be handled by a remarkably simple operation such as hot stirring and washing, and the removal efficiency is remarkably improved. high. Furthermore, by combining a suitable protecting group for a carboxyl group and a secondary amino group, an optically active trans-4-fluoroproline high-purity product can be produced in a short process with a high yield.

  In the present invention, the carbon-carbon double bond of the optically active 3,4-dehydroproline protector, which is a by-product, is subjected to a reductive treatment. It is a good contrast in thought.

Further, in the present invention, impurities derived from the optically active cis-4-fluoroproline protector (4-position stereoisomer) in which the dehydroxyfluorination reaction in Scheme 2 proceeds with steric retention (see FIG. 2) are also removed. can do.

  Thus, the present invention is a method for producing optically active trans-4-fluoroproline high-purity products that solves the problems of the prior art.

  The method for producing the optically active trans-4-fluoroproline high-purity product of the present invention will be described in detail.

  The preferred production method of the present invention comprises three steps of “dehydroxyfluorination reaction”, “hydrogenation reaction & deprotection reaction” and “impurity removal”. Invention 1 corresponds to an impurity removal step.

  First, the dehydroxyfluorination reaction step will be described in detail.

In the dehydroxyfluorination reaction step, the optically active cis-4-hydroxyproline protector represented by the general formula [1] or the general formula [9] is reacted with a dehydroxyfluorinating agent to thereby react the general formula [2] or An optically active trans-4-fluoroproline protector represented by general formula [10] (main product) and an optically active 3,4-dehydroproline protector represented by general formula [3] or general formula [11] Product) is obtained. In this reaction, in addition to the by-product optically active 3,4-dehydroproline protector, a small amount of optically active 4,5-dehydroproline protector (see FIG. 3) may be produced as a by-product. It can be similarly induced and removed by certain optically active prolines.

P ¹ of the protected optically active cis-4-hydroxyproline represented by the general formula [1] or the general formula [9] represents an alkyl group, a substituted alkyl group, a benzyl group, or a substituted benzyl group. The alkyl group is a straight chain or branched chain type having 1 to 12 carbon atoms, or cyclic (when the number of carbon atoms is 3 or more). The substituted alkyl group has a substituent in any number and in any combination on any carbon atom of the alkyl group. Such substituents include fluorine atoms, chlorine atoms, bromine atoms, lower alkoxy groups such as methoxy groups, ethoxy groups, propoxy groups, and butoxy groups. In the present specification, “lower” represents a linear or branched chain or cyclic group having 1 to 6 carbon atoms (when the number of carbon atoms is 3 or more). The substituted benzyl group has substituents in any number and in any combination on any carbon atom of the phenyl group. Such substituents include fluorine atoms, trifluoromethyl groups, methyl groups, ethyl groups, propyl groups, lower alkyl groups such as butyl groups, lower alkoxy groups such as methoxy groups, ethoxy groups, propoxy groups, and butoxy groups. Specific examples of P ¹ include methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, n-pentyl group, n-hexyl group, Cyclohexyl group, 2-fluoroethyl group, 2,2-difluoroethyl group, 2,2,2-trifluoroethyl group, 2-chloroethyl group, 2,2-dichloroethyl group, 2,2,2-trichloroethyl group 2-methoxyethyl group, 3-methoxy-n-propyl group, 4-methoxy-n-butyl group, 2-ethoxyethyl group, 3-ethoxy-n-propyl group, 4-ethoxy-n-butyl group, benzyl Group, 2-fluorobenzyl group, 3-fluorobenzyl group, 4-fluorobenzyl group, 2-methylbenzyl group, 3-methylbenzyl group, 4-methylbenzyl group, 2- A methoxybenzyl group, 3-methoxybenzyl group, 4-methoxybenzyl group, etc. are mentioned. Among them, methyl group, ethyl group, n-propyl group, isopropyl group, n-butyl group, isobutyl group, sec-butyl group, tert-butyl group, benzyl group, 2-methylbenzyl group, 3-methylbenzyl group and 4 -A methylbenzyl group is preferred, and a benzyl group is particularly preferred.

P ² in the protected optically active cis-4-hydroxyproline represented by general formula [1] or general formula [9] is a tert-butoxycarbonyl group, benzyloxycarbonyl group, 9-fluorenylmethoxycarbonyl group or tri Represents a phenylmethyl group. Among them, a tert-butoxycarbonyl group and a benzyloxycarbonyl group are preferable, and a benzyloxycarbonyl group is particularly preferable.

  The optically active cis-4-hydroxyproline protector represented by the general formula [1] or the general formula [9] is disclosed in Patent Document 2, Fifth Edition Experimental Chemistry Course 16 Synthesis of Organic Compounds IV Carboxylic Acids / Amino Acids / Peptides (Japan) 2 amino acids and peptides published by Maruzen in 2005), Tetrahedron Letters (UK), 1998, Vol. 39, p. It can be similarly produced with reference to 1169-1172 and the like.

The dehydroxyfluorination agent, it is not particularly limited, _SO 2 _{F 2} / organic bases (wherein, _SO 2 _{F 2} is reacted with _SO 2 _{F 2} in the presence of. An organic base representing the sulfuryl fluoride Means RfSO ₂ F / organic base [wherein Rf represents CF ₃ (trifluoromethyl group) or n-C ₄ F ₉ (n-nonafluorobutyl group). . This means reacting with RfSO ₂ F in the presence of an organic base; JP 2005-336151 A; diethylaminosulfur trifluoride (DAST; A); bis (2-methoxyethyl) aminosulfur trifluoride (B ), Yarobenco reagent (CTT; C), Ishikawa reagent (PPDA; D), 2,2-difluoro-1,3-dimethylimidazolidine (E) and the like (see FIG. 4 for A to E). Among them, SO ₂ F ₂ / organic base, C, D and E are preferable, and SO ₂ F ₂ / organic base is particularly preferable. C and D are adducts of trifluorochloroethylene or hexafluoropropene and diethylamine, but other similar combinations (for example, fluoroolefins such as tetrafluoroethylene, dialkylamines having different carbon numbers such as dimethylamine) Since the adduct consisting of can be expected to have the same dehydroxyfluorination ability, it is treated as a dehydroxyfluorination agent in the present invention. All the above-mentioned dehydroxyfluorinating agents can be used in the presence of lower alcohol, hydrogen fluoride, or “a salt or complex comprising an organic base and hydrogen fluoride”. Treat as fluorinating agent. Among these, a preferable embodiment is one in which a suitable SO ₂ F ₂ / organic base is further subjected to a dehydroxyfluorination reaction in the presence of a “salt or complex comprising an organic base and hydrogen fluoride”.

The amount of SO ₂ F ₂ to be used in a suitable SO ₂ F ₂ / organic base is 0.000 per mol of the optically active cis-4-hydroxyproline protector represented by the general formula [1] or the general formula [9]. 7 mol or more may be used, 0.8 to 10 mol is preferable, and 0.9 to 5 mol is particularly preferable.

Suitable organic bases in SO ₂ F ₂ / organic base include triethylamine, diisopropylethylamine, tri-n-propylamine, tri-n-butylamine, pyridine, 2,6-lutidine, 2,4,6-collidine, 4-dimethyl Aminopyridine (DMAP), 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) and the like. It is done. Among them, triethylamine, diisopropylethylamine, tri n-propylamine, tri n-butylamine, pyridine, 2,6-lutidine and 2,4,6-collidine are preferable, and triethylamine, diisopropylethylamine, tri n-propylamine, tri n- Butylamine and pyridine are particularly preferred. These organic bases can be used alone or in combination.

The amount of organic base used in a suitable SO ₂ F ₂ / organic base is 0.7 mol relative to 1 mol of the optically active cis-4-hydroxyproline protector represented by general formula [1] or general formula [9]. The above may be used, preferably 0.8 to 20 moles, particularly preferably 0.9 to 10 moles.

As the organic base in the “salt or complex composed of an organic base and hydrogen fluoride”, the organic base in the above-mentioned preferable SO ₂ F ₂ / organic base can be preferably used.

  The molar ratio of the organic base and hydrogen fluoride in the “salt or complex comprising organic base and hydrogen fluoride” may be used in the range of 100: 1 to 1: 100, preferably 50: 1 to 1:50, 25 1 to 1:25 is particularly preferred. "Complex consisting of 1 mol of triethylamine and 3 mol of hydrogen fluoride" or "pyridine ~ 30% (-10 mol%) and hydrogen fluoride ~ 70% (~ 90) commercially available from Aldrich (Aldrich, 2009-2010 catalog). It is convenient to use a “complex consisting of (mol%)”.

The amount of the “salt or complex comprising an organic base and hydrogen fluoride” used is fluoride ion relative to 1 mol of the optically active cis-4-hydroxyproline protector represented by the general formula [1] or the general formula [9]. (F ⁻ ) may be 0.1 mol or more, preferably 0.3 to 30 mol, particularly preferably 0.5 to 20 mol.

The amount of RfSO ₂ F in RfSO ₂ F / organic bases, organic bases and amount of use is, the amount of _SO 2 _{F 2} as described in the preferred _SO 2 _{F 2} / organic bases, as well as organic bases and the amount of use It is.

  The amount of A to E etc. (including similar adducts) is 0.7 mol or more with respect to 1 mol of the optically active cis-4-hydroxyproline protector represented by the general formula [1] or the general formula [9]. May be used, preferably 0.8 to 10 mol, particularly preferably 0.9 to 5 mol.

  When the dehydroxyfluorinating agent is used in the presence of a lower alcohol or hydrogen fluoride, the amount used is 1 mol of the optically active cis-4-hydroxyproline protector represented by the general formula [1] or the general formula [9]. 0.01 mol or more may be used, preferably 0.02 to 30 mol, particularly preferably 0.03 to 20 mol.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane and n-heptane, aromatic hydrocarbons such as toluene and xylene, halogens such as methylene chloride and 1,2-dichloroethane, tetrahydrofuran, and tert-butylmethyl. Ethers such as ether, esters such as ethyl acetate and n-butyl acetate, amides such as N, N-dimethylformamide and 1,3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile and propionitrile And dimethyl sulfoxide. Among these, n-heptane, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, acetonitrile and dimethyl sulfoxide are preferable, and toluene, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide and acetonitrile are particularly preferable. These reaction solvents can be used alone or in combination.

  The reaction solvent may be used in an amount of 0.1 L or more per 1 mol of the optically active cis-4-hydroxyproline protector represented by the general formula [1] or [9], from 0.2 to 20 L. Is preferable, and 0.3 to 10 L is particularly preferable.

  The reaction temperature may be in the range of −60 to + 150 ° C., preferably −50 to + 125 ° C., particularly preferably −40 to + 100 ° C.

  The reaction time may be in the range of 24 hours or less, and varies depending on the raw material substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance. However, it is preferable that the end point is when the raw material substrate is almost lost.

  The post-treatment employs a general procedure in organic synthesis, whereby the optically active trans-4-fluoroproline protector (main product) represented by the general formula [2] or the general formula [10] and the general formula [ 3] or an optically active 3,4-dehydroproline protector (byproduct) represented by the general formula [11] can be obtained. As usual post-treatment operation, an aqueous solution of an inorganic base is added to the reaction-terminated solution, followed by extraction with an organic solvent. The crude product can be obtained by removing the organic solvent under reduced pressure. The crude product can be purified to a high purity by column chromatography or the like as necessary, but it is difficult to easily and efficiently remove the by-product.

  Next, the hydrogenation reaction & deprotection reaction step will be described in detail.

In the hydrogenation reaction & deprotection reaction step, the optically active trans-4-fluoroproline protector (main product) represented by general formula [2] or general formula [10] and general formula [3] or general formula [11] ] For the reaction product containing the optically active 3,4-dehydroproline protector (by-product) represented by formula (I), a hydrogenation reaction and a deprotection reaction of a protecting group for a carboxyl group and a protecting group for a secondary amino group By performing the reaction, an optically active trans-4-fluoroproline represented by formula [4] or formula [12] (target product) and an optically active proline (impurity) represented by formula [5] or formula [13] are contained. Guide to treatment. In this induction, deprotection of the protecting group for the carboxyl group (P ¹ ) and the protecting group for the secondary amino group (P ² ) under the hydrogenation reaction conditions of the carbon-carbon double bond of the protected optically active 3,4-dehydroproline. If the protection reaction can be carried out simultaneously, the reaction product containing the optically active trans-4-fluoroproline protector and the optically active 3,4-dehydroproline protector contains the optically active trans-4-fluoroproline and the optically active proline. Induction to the reaction product can be performed in one step. There is no restriction | limiting in the order which performs the hydrogenation reaction and the deprotection reaction of the protecting group of a carboxyl group, and the protecting group of a secondary amino group, It can carry out in arbitrary orders. Further, if suitable hydrogenation reaction conditions are employed, the reductive defluorination reaction (conversion to hydrogen atoms) of the 4-position fluorine atom hardly proceeds. Even if the reductive defluorination reaction proceeds slightly, it can be similarly induced and removed by the same impurity, optically active proline.

  The hydrogenation reaction will be specifically described.

The hydrogenation reaction is performed by reacting with hydrogen (H ₂ ) in the presence of a Group 10 transition metal catalyst. This reaction can be carried out with acids such as hydrogen fluoride, hydrogen chloride, hydrogen bromide, sulfuric acid, formic acid, acetic acid, trifluoroacetic acid or lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, lithium carbonate, sodium carbonate, potassium carbonate, water It may proceed smoothly by carrying out in the presence of a base such as lithium oxide, sodium hydroxide, potassium hydroxide, pyridine, triethylamine, diisopropylethylamine, cyclohexylamine. When the deprotection reaction is carried out prior to the hydrogenation reaction, the acid or base can be provided in the form of a salt of the raw material substrate. However, by employing suitable reaction conditions, it is not necessary to carry out in the presence of an acid or a base.

  Examples of Group 10 transition metal catalysts include nickel catalysts, palladium catalysts, and platinum catalysts. Among these, a palladium catalyst is preferable, and palladium sponge, palladium black, palladium charcoal, palladium alumina, palladium calcium carbonate, palladium barium sulfate, palladium hydroxide, palladium acetate, and palladium chloride are particularly preferable.

  The amount of Group 10 transition metal catalyst used is 0.000001 mol per mol of the optically active 3,4-dehydroproline protector represented by the general formula [3] or the general formula [11] contained in the reaction product. The above may be used, preferably from 0.00001 to 0.3 mol, particularly preferably from 0.00005 to 0.2 mol.

  The amount of hydrogen used may be 1 mol or more per 1 mol of the optically active 3,4-dehydroproline protector represented by the general formula [3] or the general formula [11] contained in the reaction product. It is preferable to carry out under an excessive hydrogen atmosphere (atmospheric pressure), and a large excess of pressure is particularly preferred. Further, when the deprotection reaction is also performed at the same time, it may be used in consideration of the amount of hydrogen used for the reaction.

  The hydrogen pressure when carried out under a large excess of pressure may be 10 MPa or less, preferably 0.01 to 5 MPa, particularly preferably 0.05 to 3 MPa.

  The amount used when the hydrogenation reaction is carried out in the presence of an acid or a base is the optically active trans-4-fluoroproline protector represented by the general formula [2] or the general formula [10] and the general formula [3] or The total amount of the reaction product including the optically active 3,4-dehydroproline protector represented by the general formula [11] may be 0.1 mol or more, preferably 0.2 to 30 mol, 3 to 20 mol is particularly preferred.

  Reaction solvents include ethers such as tetrahydrofuran and tert-butyl methyl ether, esters such as ethyl acetate and n-butyl acetate, amides such as N, N-dimethylformamide and 1,3-dimethyl-2-imidazolidinone. And alcohols such as dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, and n-butanol, and water. Of these, alcohols and water are preferable, and methanol, ethanol, isopropanol and water are particularly preferable. These reaction solvents can be used alone or in combination.

  The reaction solvent is used in an optically active trans-4-fluoroproline protector represented by general formula [2] or general formula [10] and optically active 3, represented by general formula [3] or general formula [11]. What is necessary is just to use 0.1L or more with respect to 1 mol of total reaction products containing a 4-dehydroproline protector, 0.2-30L is preferable, and 0.3-20L is especially preferable.

  The reaction time may be within 48 hours, and varies depending on the raw material substrate and reaction conditions. Therefore, the progress of the reaction is traced by analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, and nuclear magnetic resonance. However, it is preferable that the end point is when the raw material substrate is almost lost.

The post-treatment employs a general procedure in organic synthesis, whereby the optically active trans-4-fluoroproline represented by the general formula [4] or the general formula [12] and the general formula [5] or the general formula [13]. ] The reaction processed material containing the optically active proline shown by this can be obtained. As usual post-treatment operation, the reaction completion liquid is filtered through Celite, and if necessary, through a membrane filter. The residue is washed with methanol or water, and the filtrate is concentrated under reduced pressure. The crude product can be obtained as a solid by vacuum drying. In the present invention, separation is performed utilizing the difference in physical properties between optically active trans-4-fluoroproline and optically active proline, but the removal efficiency of impurities is maximized in the state of free amino acid (HN—CO ₂ H). Therefore, when the crude product is recovered as a salt with an acid or base, it is induced to a free amino acid by neutralization with a base or acid, desalting with an ion exchange resin, or the like, and subjected to an impurity removal step.

  When the deprotection reaction is performed prior to the hydrogenation reaction, the above-mentioned Group 10 transition metal catalyst, hydrogen, the acid or base used as necessary, and the reference target compound in the amount of the reaction solvent used are those after the deprotection reaction. Replace the name with the corresponding compound.

  The deprotection reaction will be specifically described.

  The deprotection reaction employs a general method in organic synthesis. Specifically, Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. , 5th edition, Laboratory Chemistry 16 Synthesis of Organic Compounds IV Carboxylic Acids / Amino Acids / Peptides (published by Maruzen in 2005 by the Chemical Society of Japan), Tetrahedron Letters (UK), 1998, Vol. 39, p. . 1169-1172 and the like can be used in the same manner. In these methods, only the desired deprotection reaction proceeds selectively, the stereochemistry of the 4-position fluorine atom of the main product is maintained throughout the reaction, and the by-product carbon-carbon double bond is almost isomerized. do not do.

  Finally, the impurity removal step will be described in detail.

* In the formula [A] and the formula [B] represents an asymmetric carbon.

The absolute configuration at the 2-position of the formula [A] takes an S (L) form or an R (D) form.

The relative arrangement of the 2nd and 4th positions in the formula [A] takes a transformer.

The stereochemistry at the 2-position of Formula [A] and Formula [B] takes the same absolute configuration.

  The impurity removal step includes an optically active trans-4-fluoroproline (target product) represented by Formula [4] or Formula [12] and an optically active proline (impurity) represented by Formula [5] or Formula [13]. Only the target product is selectively recovered from the reaction product. In this recovery, since the removal efficiency of impurities is remarkably high, a desired effect can be obtained only by washing the solid matter. Naturally, if recrystallization is performed, an effect that greatly exceeds the cleaning can be obtained. However, since a sufficient effect can be obtained even by a much simpler cleaning, it is a preferred embodiment of the present invention from the viewpoint of operability. This does not limit the practice of recrystallization, and a general recrystallization operation in organic synthesis can be employed as necessary. Specifically, 5th edition Experimental Chemistry Course 1 Basics I Experiments and Information Basics (published by Maruzen in 2003, Chemical Society of Japan), 5th Edition Experimental Chemistry Course 4 Basics IV Organic, Polymer and Biochemistry ( The same can be done with reference to the Chemical Society of Japan, published by Maruzen in 2003), the 5th edition of Experimental Chemistry Course, 5 Basic Technology for Chemical Experiments (edited by the Chemical Society of Japan, published in 2005 by Maruzen). Moreover, the following washing | cleaning solvent can be employ | adopted suitably for a recrystallization solvent.

  The washing solvent includes aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as toluene, ethylbenzene and xylene, halogens such as methylene chloride, chloroform and 1,2-dichloroethane, Ethers such as tetrahydrofuran, diisopropyl ether, tert-butyl methyl ether, ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, esters such as ethyl acetate, n-butyl acetate, tert-butyl acetate, N, N-dimethylformamide Amides such as N, N-dimethylacetamide and 1,3-dimethyl-2-imidazolidinone, nitriles such as acetonitrile, propionitrile and benzonitrile, dimethyl sulfoxide, methanol, ethanol, n-propanol, Propanol, n- butanol, n- pentanol, alcohol such as n- hexanol, water and the like. Among them, n-hexane, n-heptane, toluene, xylene, methylene chloride, 1,2-dichloroethane, tetrahydrofuran, tert-butyl methyl ether, acetone, methyl ethyl ketone, ethyl acetate, n-butyl acetate, N, N-dimethylformamide, 1,3-dimethyl-2-imidazolidinone, acetonitrile, propionitrile, dimethyl sulfoxide, methanol, ethanol, n-propanol, isopropanol, n-butanol, n-pentanol, n-hexanol and water are preferred, n- Hexane, n-heptane, toluene, xylene, tetrahydrofuran, tert-butyl methyl ether, acetone, methyl ethyl ketone, ethyl acetate, n-butyl acetate, acetonitrile, propionitrile, methanol, Ethanol, n- propanol, isopropanol, n- butanol and water is particularly preferred. These washing solvents can be used alone or in combination.

  The amount of the washing solvent used is a total of 1 mol of the reaction product containing the optically active trans-4-fluoroproline represented by the formula [4] or [12] and the optically active proline represented by the formula [5] or [13]. 0.05L or more may be used, preferably 0.1 to 30L, particularly preferably 0.15 to 20L.

  The cleaning can be performed while stirring to increase the efficiency of removing impurities. Therefore, stirring and cleaning is a preferred embodiment of the present invention.

  The washing temperature may be in the range of −40 to + 200 ° C., preferably −20 to + 175 ° C., particularly preferably 0 to + 150 ° C. Further, it is preferable that after the washing is completed, the temperature is gradually lowered to room temperature and ripened under ice cooling.

  The washing time may be within a range of 24 hours or less, and varies depending on the impurity content and washing conditions. Therefore, the solid impurities are contained by an analytical means such as gas chromatography, thin layer chromatography, liquid chromatography, or nuclear magnetic resonance. It is preferable that the situation is traced and the end point is a point at which impurities are almost removed.

  In the post-treatment, a high-purity product of optically active trans-4-fluoroproline represented by the formula [4] or the formula [12] can be obtained by adopting a general operation in organic synthesis. As a normal post-treatment operation, the washed product can be recovered by filtering the washed solid, washing with a poor solvent, and vacuum drying. In the present invention, the purity of the collected solid matter is improved, and impurities are concentrated in the filtrate. Moreover, it can refine | purify in still higher purity by repeating washing | cleaning operation.

  The optically active trans-4-fluoroproline represented by the formula [4] or formula [12] obtained in the present invention can be obtained from Protective Groups in Organic Synthesis, Third Edition, 1999, John Wiley & Sons, Inc. , 5th edition Experimental Chemistry Lecture 16 Synthesis of Organic Compounds IV Carboxylic Acids / Amino Acids / Peptides (published by Maruzen in 2005 by The Chemical Society of Japan) The amino group can be protected.

[Example]
Embodiments of the present invention will be specifically described by way of examples, but the present invention is not limited to these examples.

In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula

Protected cis-4-hydroxy-L-proline (liquid chromatography purity 85.8%) 35.5 g (85.7 mmol, 1.00 eq), toluene 200 mL (2.33 L / mol), diisopropyl 38.7 g (299 mmol, 3.49 eq) of ethylamine and 18.4 g (97.2 mmol, 1.13 eq) of diisopropylethylamine / hydrogen trifluoride were added, and 12.2 g (120 mmol, 1.40 eq) of sulfuryl fluoride was added from a cylinder. Blow and stir at 45 ° C. for 3 hours. The conversion rate was 99% from the liquid chromatography analysis of the reaction completion liquid. A potassium carbonate aqueous solution [prepared from 27.6 g (200 mmol, 2.33 eq) of potassium carbonate and 350 mL of water] was added to the reaction completion solution, extracted with 200 mL of ethyl acetate, the recovered aqueous layer was re-extracted with 150 mL of ethyl acetate, and recovered organic The layers were combined, washed with 100 mL of saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and vacuum dried to obtain the following formula.

Protected trans-4-fluoro-L-proline (main product) represented by the following formula

As a result, 34.4 g of a reaction product containing a protected 3,4-dehydro-L-proline (by-product) was obtained (theoretical yield: 30.6 g). The liquid chromatographic purity of the main product and by-products was 67.3% and 10.3% (86.7: 13.3), respectively. The ¹ H-NMR and ¹⁹ F-NMR of the main product are shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ], δ ppm; 2.11 (m, 1H), 2.62 (m, 1H), 3.68 (m, 1H ), 3.97 (m, 1H), 4.57 (m, 1H), 5.02 (d, 2H), 5.17 (m, 1H), 5.21 (m, 1H), 5.21 (M, 1H), 7.28 (Ar-H, 10H).

¹⁹ F-NMR [reference material: C ₆ F ₆ , heavy solvent: CDCl ₃ ], δ ppm: −15.31 (m, 40% of 1F), −15.96 (m, 60% of 1F).

The ¹ H-NMR of the by-product is shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CDCl ₃ ], δ ppm; 4.32 (m, 2H), 5.76 (m, 1H), 5.98 (m, 1H ) / Only characteristic areas are described.

To 15.0 g (37.4 mmol, 1.00 eq) of the reaction product containing the main product and by-products obtained above, 168 mL of methanol (4.49 L / mol) and 890 mg of 5% palladium on charcoal (containing water) 50%, 209 μmol, 0.00559 eq) was added, the hydrogen pressure was set to 500 kPa, and the mixture was stirred overnight at room temperature. From the ¹ H-NMR analysis of the reaction completed liquid, the conversion rate was 100%. The reaction-terminated liquid was filtered through Celite, and further filtered through a membrane filter. The residue was washed with methanol, and the filtrate was concentrated under reduced pressure and vacuum dried to obtain the following formula.

Trans-4-fluoro-L-proline (target product) represented by the following formula:

5.60 g of the reaction product containing L-proline (impurity) represented by the formula (theoretical yield: 4.98 g) was obtained. The liquid chromatographic purity of the target product and impurities was 85.2% and 9.77% (89.7: 10.3), respectively. Moreover, 1.57% of cis-4-fluoro-L-proline (4-position stereoisomer) was contained. ¹ H-NMR and ¹⁹ F-NMR of the target product are shown below.

¹ H-NMR [reference material; sodium 3-trimethylsilylpropionate-d ₄ , deuterated solvent; D ₂ O], δ ppm; 2.28 (m, 1H), 2.76 (m, 1H), 3.61 (M, 1H), 3.73 (m, 1H), 4.41 (m, 1H), 5.53 (m, 1H) / protons of carboxyl group and secondary amino group cannot be assigned.

¹⁹ F-NMR [reference material; C ₆ F ₆ , heavy solvent; (CD ₃ ) ₂ SO], δ ppm; -12.72 (m, 1F).

The ¹ H-NMR of the impurities is shown below.

¹ H-NMR [reference material; sodium 3-trimethylsilylpropionate-d ₄ , deuterated solvent; D ₂ O], δ ppm; 2.04 (m, 3H), 2.36 (m, 1H), 3.34 (M, 1H), 3.43 (m, 1H), 4.13 (m, 1H) / Proton of carboxyl group and secondary amino group cannot be assigned.

To 5.50 g (36.7 mmol) of the reaction product containing the target product and impurities obtained above, 27.5 mL (0.749 L / mol) of ethanol and 16.5 mL of water (0.450 L / mol) were added. In addition, the mixture was stirred at 60 ° C. for 30 minutes (a suspension state in which it was not completely dissolved), gradually cooled to room temperature, and aged for 1 hour under ice-cooling. The washed solid is filtered, washed with a small amount of ethanol, and vacuum dried to obtain the following formula:

3.45 g of trans-4-fluoro-L-proline (washed product) represented by the formula (theoretical yield: 4.89 g) was obtained. The total yield of the three steps from the dehydroxyfluorination reaction was 70.6%. The liquid chromatographic purity of the target product and impurities was 98.6% and 0.766% (99.2: 0.8), respectively. Further, cis-4-fluoro-L-proline (4-position stereoisomer) was not detected.

  Similar results could be obtained even when a protected cis-4-hydroxy-D-proline was used instead of the protected cis-4-hydroxy-L-proline as a raw material substrate.

In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula

Protected cis-4-hydroxy-L-proline (gas chromatography purity 94.4%) 22.0 g (74.4 mmol, 1.00 eq), toluene 110 mL (1.48 L / mol), diisopropyl 30.5 g (236 mmol, 3.17 eq) of ethylamine and 14.9 g (78.7 mmol, 1.06 eq) of diisopropylethylamine / hydrogen trifluoride were added and 9.64 g (94.5 mmol, 14.5 eq) of sulfuryl fluoride was added under ice cooling. .27 eq) was blown from a cylinder and stirred at 45 ° C. for 3 hours. The conversion was 100% by gas chromatography analysis of the reaction completed liquid. A potassium carbonate aqueous solution [prepared from 10.0 g (72.4 mmol, 0.973 eq) of potassium carbonate and 90.0 mL of water] was added to the reaction completion solution, extracted with 200 mL of ethyl acetate, and the recovered aqueous layer was re-extracted with 100 mL of ethyl acetate. The recovered organic layers were combined and washed with 100 mL (100 mmol, 1.34 eq) of 1N hydrochloric acid, washed with 100 mL of 10% brine, concentrated under reduced pressure, and dried under vacuum to obtain the following formula.

Protected trans-4-fluoro-L-proline (main product) represented by the following formula

As a result, 19.5 g of a reaction product containing a 3,4-dehydro-L-proline protector (byproduct) represented by the following formula (theoretical yield: 20.9 g) was obtained. The yield was 93.3%. The gas chromatographic purity of the main product and by-product was 84.6% and 13.2% (86.5: 13.5), respectively.

To a methanol solution [solvent use amount 80.0 mL (1.15 L / mol)] of the reaction product total amount 19.5 g (69.3 mmol, 1.00 eq) including the main product and by-products obtained above, Under ice cooling, 23.3 g of an aqueous sodium hydroxide solution [prepared from 3.30 g of sodium hydroxide (82.5 mmol, 1.19 eq) and 20.0 mL of water] was added, and the mixture was stirred at room temperature for 1 hour. The raw material substrate was not detected by thin layer chromatography analysis of the reaction completed solution. The reaction-terminated liquid was concentrated under reduced pressure, concentrated azeotropically under reduced pressure with 80.0 mL of toluene, 60.0 mL (120 mmol, 1.73 eq) of 2N hydrochloric acid was added to the residue, and the mixture was extracted with 100 mL of ethyl acetate. Re-extracted with 0.0 mL, and the collected organic layers were combined, washed with 30.0 mL of 10% brine, concentrated under reduced pressure, and vacuum dried to obtain the following formula.

Trans-4-fluoro -L- proline ^{P 2} protecting member and the following formula shown in

As a result, 19.5 g of a reaction product containing the by-product-derived impurity 1 represented by (18.5 g of theoretical yield) was obtained. Trans-4-fluoro -L- proline ^{P 2} protecting body and by-products derived from impurities -1 Gas chromatographic purity (by methylation esterified with trimethylsilyldiazomethane analysis), respectively 84.1%, 13.1% (86. 5: 13.5). ¹ H-NMR and ¹⁹ F-NMR of the trans-4-fluoro-L-proline P ² protected product are shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CD ₃ OD], δ ppm; 2.18 (m, 1H), 2.64 (m, 1H), 3.63 (m, 1H), 3.88 (m, 1H), 4.44 (m, 1H), 5.08 (d, 1H), 5.15 (d, 1H), 5.26 (m, 1H), 7. The proton of 35 (Ar—H, 5H) / carboxyl group cannot be assigned.

¹⁹ F-NMR [reference material; C ₆ F ₆ , deuterated solvent; CD ₃ OD], δ ppm; -13.71 (m, 40% of 1F), -14.20 (60% of m, 1F).

¹ H-NMR of byproduct-derived impurity-1 is shown below.

¹ H-NMR [reference material; (CH ₃ ) ₄ Si, deuterated solvent; CD ₃ OD], δ ppm; 4.27 (m, 2H), 5.84 (m, 1H), 6.04 (m, 1H) / Only characteristic areas are described.

(A 69.3 mmol, 1.00 eq) the reaction product the total amount 19.5g containing trans-4-fluoro -L- proline ^{P 2} protecting body and by-products derived from impurities -1 obtained above in methanol 150mL (2.16 L / mol) and 1.73 g of 5% palladium on charcoal (water content 50%, 406 μmol, 0.00586 eq) were added, the hydrogen pressure was set to 1.00 MPa, and the mixture was stirred at room temperature for 2 hours. The conversion rate was 100% from ¹⁹ F-NMR analysis of the reaction completed liquid. The reaction-terminated liquid was filtered through Celite, further filtered through a membrane filter, the residue was washed with 300 mL of water, the filtrate was concentrated under reduced pressure, azeotropically concentrated twice with 50.0 mL of toluene, and vacuum-dried. Following formula

Trans-4-fluoro-L-proline (target product) represented by the following formula:

9.10 g of a reaction product containing L-proline (impurity) represented by the formula (theoretical yield: 9.23 g) was obtained. The total yield of the two steps from the hydrolysis reaction was 98.6%. The liquid chromatographic purity of the target product and impurities were 84.1% and 7.69% (91.6: 8.4), respectively. Further, 1.12% of cis-4-fluoro-L-proline (4-position stereoisomer) was contained.

69.0 mL (0.921 L / mol) of toluene and 36.0 mL of methanol (0.526 L / mol) were added to 9.10 g (68.4 mmol) of the total amount of the reaction product containing the target product and impurities obtained above. The mixture was stirred at 70 ° C. for 3 hours (suspension state in which it was not completely dissolved), gradually cooled to room temperature, and aged for 1 hour under ice-cooling. The washed solid is filtered, washed with a small amount of toluene, and vacuum dried to obtain the following formula:

In this way, 7.34 g of trans-4-fluoro-L-proline represented by the formula (first washed product) was obtained. The recovery rate was 80.7%. The liquid chromatographic purity of the target product and impurities were 95.3% and 1.90% (98.0: 2.0), respectively. Moreover, 0.657% of cis-4-fluoro-L-proline (4-position stereoisomer) was contained.

  The total amount of the first washing product obtained above was 7.34 g (55.1 mmol), methanol 35.0 mL (0.635 L / mol), isopropanol 21.0 mL (0.381 L / mol) and water 21.0 mL (0 .381 L / mol) was added, and the mixture was stirred at 70 ° C. for 1 hour (a suspension state in which it was not completely dissolved), gradually cooled to room temperature, and aged for 30 minutes under ice cooling. The washed solid was filtered, washed with a small amount of isopropanol, and vacuum-dried to obtain 6.37 g of trans-4-fluoro-L-proline (second washed product) represented by the above formula. The recovery rate was 86.8%. The total yield of the four steps from the dehydroxyfluorination reaction was 64.4%. The liquid chromatographic purity of the target product and impurities was 98.8% and 0.779% (99.2: 0.8), respectively. Further, cis-4-fluoro-L-proline (4-position stereoisomer) was not detected.

  Similar results could be obtained even when a protected cis-4-hydroxy-D-proline was used instead of the protected cis-4-hydroxy-L-proline as a raw material substrate.

  The optically active trans-4-fluoroproline targeted in the present invention can be used as a pharmaceutical intermediate.

Claims (5)

Formula [A]

In the method for producing optically active trans-4-fluoroproline represented by formula (A), the optically active trans-4-fluoroproline (target product) represented by formula [A] and formula [B]

A method for selectively recovering only a target product from a reaction-treated product containing optically active proline (impurities) represented by
[In the formula, * represents an asymmetric carbon, and the absolute configuration at the 2-position of the formula [A] is an S (L) isomer or an R (D) isomer, and the relative configuration between the 2-position and the 4-position of the formula [A]. Take a transformer. The stereochemistry at the 2-position of formula [A] and formula [B] takes the same absolute configuration] General formula [1]

Which is obtained in a dehydroxyfluorination reaction of a protected cis-4-hydroxy-L-proline represented by the general formula [2]

Protected trans-4-fluoro-L-proline (main product) represented by the general formula [3]

The reaction product containing the 3,4-dehydro-L-proline protector (by-product) represented by the following reaction is subjected to a hydrogenation reaction and a deprotection reaction of a protecting group for a carboxyl group and a protecting group for a secondary amino group. By doing the equation [4]

Trans-4-fluoro-L-proline (target product) represented by the formula [5]

A process for producing trans-4-fluoro-L-proline, wherein the reaction product containing L-proline (impurity) represented by formula (1) is induced to selectively recover only the target product.
[Wherein P ¹ represents an alkyl group, a substituted alkyl group, a benzyl group or a substituted benzyl group, and P ² represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group or a triphenylmethyl group. Represents. ] Formula [6]

Which is obtained in the dehydroxyfluorination reaction of a protected cis-4-hydroxy-L-proline represented by the formula [7]

A trans-4-fluoro-L-proline protector (main product) represented by formula [8]

A reaction product containing a 3,4-dehydro-L-proline protector (by-product) represented by the following formula: hydrogenation reaction and reductive deprotection of a protecting group for a carboxyl group and a protecting group for a secondary amino group By carrying out the reaction simultaneously, the formula [4]

Trans-4-fluoro-L-proline (target product) represented by the formula [5]

A process for producing trans-4-fluoro-L-proline, wherein the reaction product containing L-proline (impurity) represented by formula (1) is induced to selectively recover only the target product.
[Wherein Bn represents a benzyl group and Cbz represents a benzyloxycarbonyl group] General formula [9]

Which is obtained in the dehydroxyfluorination reaction of a protected cis-4-hydroxy-D-proline represented by the general formula [10]

Protected trans-4-fluoro-D-proline (main product) represented by the general formula [11]

The reaction product containing the 3,4-dehydro-D-proline protector (by-product) represented by the following formula is subjected to a hydrogenation reaction and a deprotection reaction of a protecting group for a carboxyl group and a protecting group for a secondary amino group. By doing the equation [12]

Trans-4-fluoro-D-proline (target product) represented by the formula [13]

A process for producing trans-4-fluoro-D-proline, wherein the reaction product containing D-proline (impurities) represented by the formula (1) is induced to selectively recover only the target product.
[Wherein P ¹ represents an alkyl group, a substituted alkyl group, a benzyl group or a substituted benzyl group, and P ² represents a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a 9-fluorenylmethoxycarbonyl group or a triphenylmethyl group. Represents. ] Formula [14]

Which is obtained in the dehydroxyfluorination reaction of a protected cis-4-hydroxy-D-proline represented by the formula [15]

A trans-4-fluoro-D-proline protector (main product) represented by the formula [16]

A reaction product containing a 3,4-dehydro-D-proline protector (by-product) represented by the following formula: hydrogenation reaction and reductive deprotection of a protecting group for a carboxyl group and a protecting group for a secondary amino group By carrying out the reaction simultaneously, the formula [12]

Trans-4-fluoro-D-proline (target product) represented by the formula [13]

A process for producing trans-4-fluoro-D-proline, wherein the reaction product containing D-proline (impurities) represented by the formula (1) is induced to selectively recover only the target product.
[Wherein Bn represents a benzyl group and Cbz represents a benzyloxycarbonyl group]