JP2005336151A - Method for producing 4-fluoroproline derivative - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially producing a 4-fluoroproline derivative which is an important intermediate for a pharmaceutical. <P>SOLUTION: This method for producing the 4-fluoroproline derivative comprises making a protected 4-hydroxyproline compound react with trifluoromethanesulfonyl fluoride in the presence of an organic base, wherein an organic base which is industrially produced at a low cost and generally used, such as triethylamine, is used as the organic base. The method is characterized so that trifluoromethanesulfonylation of the protected 4-hydroxyproline compound is well progressed by using the trifluoromethanesulfonyl fluoride and subsequent fluorine substitution reaction is well progressed only by of a hydrofluoric acid salt or complex of the organic base, such as the trimethylamine, which is by-produced in an equivalent amount in a reaction system of the trifluoromethanesulfonylation. <P>COPYRIGHT: (C)2006,JPO&NCIPI

Description

  The present invention relates to a method for producing a 4-fluoroproline derivative, which is an important intermediate of medicine.

  Conventional production methods of 4-fluoroproline derivatives targeted in the present invention can be broadly classified into the following two, and representative documents are cited respectively.

1) A method of dehydroxyfluorinating a 4-hydroxyproline protected body with DAST [(C ₂ H ₅ ) ₂ NSF ₃ ] (Non-patent Document 1), and 2) a 4-hydroxyproline protected body with trifluoromethanesulfonic anhydride A method of converting the product [(CF ₃ SO ₂ ) ₂ O] into a trifluoromethanesulfonic acid ester and reacting with tetraethylammonium fluoride [(C ₂ H ₅ ) ₄ N ¹⁸ F] (Non-patent Document 2) is disclosed. Has been.

In addition, as a related technical field, 3) a substrate having a hydroxyl group is converted into perfluorobutanesulfonyl 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 fluoride (C ₄ F ₉ SO ₂ F) (Patent Document 1 and Patent Document 2); 4) 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] are used as a substrate having a hydroxyl group. In the presence, methods for dehydroxyfluorination with perfluorobutanesulfonyl fluoride (Non-patent Documents 3 and 4) are disclosed.
US Pat. No. 5,760,255 US Pat. No. 6,248,889 Tetrahedron Letters (UK), 1998, Vol. 39, No. 10, p. 1169-1172 Journal of Labeled Compounds and Radiopharmaceuticals (USA), 1983, Vol. 20, No. 4, p. 453-461 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)

  An object of the present invention is to provide an industrial production method of a 4-fluoroproline derivative, which is an important intermediate of medicine.

  In the manufacturing method of Non-Patent Document 1, 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 2, it is necessary to use expensive trifluoromethanesulfonic anhydride and tetraethylammonium fluoride which is difficult to obtain industrially for industrial use.

  In the related technical fields, Patent Document 1, Patent Document 2, Non-Patent Document 3, and Non-Patent Document 4 widely disclose dehydroxyfluorination reactions of substrates having a hydroxyl group, but they are not suitable for industrial use. Perfluoroalkanesulfonyl fluoride having a long carbon chain is used, and in addition, in the production methods of Patent Document 1 and Patent Document 2, it is necessary to use a special organic base such as DBU which is expensive in industrial use. In addition, in the production methods of Non-Patent Document 3 and Non-Patent Document 4, it was necessary to add a fluorinating agent such as triethylamine / hydrogen trifluoride complex in addition to perfluorobutanesulfonyl fluoride.

In the production methods of Patent Document 1, Patent Document 2, Non-Patent Document 3, and Non-Patent Document 4, perfluoroalkanesulfonyl fluoride is perfluoroalkanesulfonylated on a substrate, followed by substitution with a fluorine anion (F ⁻ ). In the reaction, since it is eliminated as a perfluoroalkanesulfonate anion (RfSO ₃ ⁻ ; Rf represents a perfluoroalkyl group), it has sufficient sulfonylation ability and elimination ability from the viewpoint of fluorine atom economy. as long as, but shorter carbon chain is more advantageous in industrial use [perfluorooctane sulfonyl fluoride _{(C 8 F 17 SO 2 F} ) < perfluorobutane sulfonyl fluoride <trifluoromethanesulfonyl fluoride _{(CF 3 SO 2 F)]} , trifluoromethanesulfonyl Dehydroxyfluorination reaction using Ruorido are not specifically disclosed. Further, from the viewpoint of elimination ability as a perfluoroalkanesulfonate anion, the longer the carbon chain, the higher the elimination ability [Synthesis (Germany), 1982, No. 2, p. 85-126], on the other hand, perfluoroalkanesulfonic acid is eliminated from the perfluoroalkanesulfonic acid ester and an unsaturated compound is formed as a by-product. It is not always preferable to use one having a higher elimination ability, that is, one having a longer carbon chain, and the selection of the optimal perfluoroalkanesulfonyl fluoride is very dependent on the specificity of the reaction substrate, The optimal perfluoroalkanesulfonyl fluoride in the dehydroxyfluorination reaction of the 4-hydroxyproline protector targeted in the present invention has not been disclosed.

  In addition, perfluoroalkanesulfonic acid derivatives having a long carbon chain, particularly those having 4 or more carbon atoms, have been pointed out to have long-term persistence and toxicity in the environment and are restricted in industrial use [for example, perfluorooctane For the long-term persistence and toxicity of sulfonic acid derivatives in the environment, see Pharmacia Vol. 40 No. 2 2004].

  Thus, a method that can industrially produce a 4-fluoroproline derivative has been strongly desired.

  Prior to the present application, the present applicant obtained by reacting a 4-hydroxyproline protector with trifluoromethanesulfonyl fluoride in the presence of an organic base and a “salt or complex comprising an organic base and hydrogen fluoride”. -A method for producing a fluoroproline derivative was filed (Japanese Patent Application No. 2004-184099).

  As a result of intensive studies to solve the above problems, the inventors of the present invention obtained a 4-hydroxyproline protector in the presence of trifluoromethanesulfonyl fluoride in the presence of an industrially inexpensive and widely used organic base such as triethylamine. It was clarified that 4-fluoroproline derivatives can be produced by reaction.

  The feature of this production method is that trifluoromethanesulfonylation of the protected 4-hydroxyproline proceeds well by using trifluoromethanesulfonyl fluoride, and the subsequent fluorine substitution reaction is equivalent in the reaction system in trifluoromethanesulfonylation. It is to proceed well only with a hydrogen fluoride salt or complex of an organic base such as triethylamine as a by-product. A reaction substrate in which the dehydroxyfluorination reaction proceeds favorably under such reaction conditions has not yet been disclosed in known literature, but is due to the substrate specificity of the 4-hydroxyproline protector.

  Further, in the production method of Non-Patent Document 3, 2-hydroxy-1, 3, 5 having structural characteristics (secondary hydroxyl group on a hetero five-membered ring) similar to the 4-hydroxyproline protector targeted in the present invention. It is disclosed that it cannot be applied to the dehydroxyfluorination reaction of -tri-O-benzoyl-α-D-ribofuranose. Further, in the description of Non-Patent Document 3, a point to be particularly noted is that the dehydroxyfluorination agent comprising trifluoromethanesulfonic anhydride-triethylamine / hydrogen trifluoride complex-triethylamine is gaseous ( Trifluoromethanesulfonyl fluoride having a boiling point of -21 ° C. is formed, and the hydroxyl group of the substrate cannot be efficiently converted to trifluoromethanesulfonyl, and is combined with perfluorobutanesulfonyl fluoride having a high boiling point (64 ° C.) (perfluorobutane). Sulfonyl fluoride-triethylamine / hydrogen trifluoride complex-triethylamine) is disclosed as being suitable. This description clearly shows that trifluoromethanesulfonyl fluoride having a low boiling point is not suitable as perfluoroalkanesulfonyl fluoride as a dehydroxyfluorination agent, and trifluoromethanesulfonyl fluoride can be suitably used in the present invention. Contrast with.

  The present inventors have found that the above-described reaction proceeds particularly favorably under specific conditions. In particular, by using an organic base (such as triethylamine) in a minimal excess with respect to the 4-hydroxyproline protector (1.0 to 1.5 mol with respect to 1.0 mol of 4-hydroxyproline protector), the desired product It was found that the selectivity of the is particularly improved.

  Furthermore, by washing the reaction mixture after completion of the reaction with water or an aqueous solution of an inorganic base, a salt or alkali metal salt composed of trifluoromethanesulfonic acid and organic base by-produced from the raw material trifluoromethanesulfonyl fluoride is efficiently produced. The inventors have also found that they can be removed well and completed the present invention.

  That is, the present invention relates to the general formula [1]

［式中、Ｒは二級アミノ基の保護基を表し、Ｒ¹はカルボキシル基の保護基を表し、＊は不斉炭素を表す］で示される４−ヒドロキシプロリン保護体を有機塩基の存在下にトリフルオロメタンスルホニルフルオリド（ＣＦ₃ＳＯ₂Ｆ）と反応させることにより、一般式［２］

[In the formula, R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon.] Is reacted with trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) to give a general formula [2]

［式中、Ｒは二級アミノ基の保護基を表し、Ｒ¹はカルボキシル基の保護基を表し、＊は不斉炭素を表す］で示される４−フルオロプロリン誘導体を製造する方法を提供する。

[Wherein, R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon], and provides a method for producing a 4-fluoroproline derivative represented by .

  The present invention also provides a general formula [1].

［式中、Ｒは二級アミノ基の保護基を表し、Ｒ¹はカルボキシル基の保護基を表し、＊は不斉炭素を表す］で示される４−ヒドロキシプロリン保護体をトリエチルアミン［（Ｃ₂Ｈ₅）₃Ｎ］の存在下にトリフルオロメタンスルホニルフルオリド（ＣＦ₃ＳＯ₂Ｆ）と反応させることにより、一般式［２］

[Wherein, R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon.] A protected 4-hydroxyproline represented by triethylamine [(C ₂ H ₅ ) ₃ N] is reacted with trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) in the presence of general formula [2]

［式中、Ｒは二級アミノ基の保護基を表し、Ｒ¹はカルボキシル基の保護基を表し、＊は不斉炭素を表す］で示される４−フルオロプロリン誘導体を製造する方法を提供する。

[Wherein, R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon], and provides a method for producing a 4-fluoroproline derivative represented by .

  Further, the present invention provides the formula [3]

［式中、Ｂｏｃはｔｅｒｔ−ブトキシカルボニル基を表す］で示される４−ヒドロキシプロリン保護体をトリエチルアミン［（Ｃ₂Ｈ₅）₃Ｎ］の存在下にトリフルオロメタンスルホニルフルオリド（ＣＦ₃ＳＯ₂Ｆ）と反応させることにより、式［４］

[Wherein Boc represents a tert-butoxycarbonyl group] A protected 4-hydroxyproline represented by trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) in the presence of triethylamine [(C ₂ H ₅ ) ₃ N] ) To give the formula [4]

［式中、Ｂｏｃはｔｅｒｔ−ブトキシカルボニル基を表す］で示される４−フルオロプロリン誘導体を製造する方法を提供する。

[Wherein Boc represents a tert-butoxycarbonyl group] is provided.

Further, the present invention provides any one of the above methods, wherein only trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is used as a fluorinating agent and no other fluorinating agent is used in combination. A method as described above is provided.

  In addition, in any of the above methods, the present invention uses 1.0 to 1.5 mol of an organic base or triethylamine with respect to 1.0 mol of the 4-hydroxyproline protector. A method as described above is provided.

  Further, the present invention provides any one of the above methods, wherein the 4-fluoroproline derivative is synthesized by any of the above methods, and then the obtained reaction mixture is washed with water or an aqueous solution of an inorganic base. A method as described above is provided.

  The production method of the present invention is the most industrially inexpensive means of producing 4-fluoroproline derivatives disclosed in publicly known literatures. The advantages of the manufacturing method of the present invention over the prior art will be described below.

  For Non-Patent Document 1, it is not necessary to use a very expensive reagent such as DAST that is dangerous to handle in large quantities.

For Non-Patent Document 2, it is not necessary to use an expensive reagent such as trifluoromethanesulfonic anhydride and an industrially difficult reagent such as tetraethylammonium fluoride. Trifluoromethanesulfonic anhydride has two trifluoromethanesulfonyl groups (CF ₃ SO ₂ groups), but only one can be used for trifluoromethanesulfonylation, and the rest is trifluoromethanesulfonate anion (CF ₃ SO 2). ₃ ^- serves as a leaving group in the form of a), if mentioned in terms of functional groups economics of trifluoromethanesulfonyl group, use of trifluoromethanesulfonic acid anhydride was not efficient. Furthermore, the industrial production flow of a series of trifluoromethanesulfonylating agents is shown in Scheme 1, in which trifluoromethanesulfonyl fluoride is located upstream, and compared to trifluoromethanesulfonic anhydride and trifluoromethanesulfonyl chloride, Can be advantageously used.

特許文献１、特許文献２、非特許文献３および非特許文献４に対しては、ＤＢＵ等の様な工業的な使用において高価で特殊な有機塩基を使用する必要がなく、また環境への長期残留性や毒性が問題となっている炭素鎖が長いパーフルオロアルカンスルホニルフルオリドを使用する必要がない。さらにフッ素の原子経済性が最も高いトリフルオロメタンスルホニルフルオリドが使用できる。

For Patent Document 1, Patent Document 2, Non-Patent Document 3, and Non-Patent Document 4, it is not necessary to use an expensive and special organic base in industrial use such as DBU, and long-term environmental It is not necessary to use perfluoroalkanesulfonyl fluoride having a long carbon chain, which is a problem of persistence and toxicity. Furthermore, trifluoromethanesulfonyl fluoride, which has the highest atomic economy of fluorine, can be used.

  Furthermore, for Non-Patent Document 3 and Non-Patent Document 4, it is not necessary to add a fluorinating agent such as triethylamine / hydrogen trifluoride complex to the system. In the method of the present invention, the fluorine substitution reaction proceeds satisfactorily only with a hydrogen fluoride salt or complex of an organic base such as triethylamine by-produced in the reaction system in the trifluoromethanesulfonylation.

Moreover, the effect of the new invention was discovered by using trifluoromethanesulfonyl fluoride. In the dehydroxyfluorination reaction using perfluoroalkanesulfonyl fluoride, a salt composed of perfluoroalkanesulfonic acid and an organic base is generated as a by-product in the reaction end solution, but the carbon chain is long, especially the number of carbon atoms. Since a salt composed of 4 or more perfluoroalkanesulfonic acids and an organic base has a relatively high partition to the organic solvent, the target product and the organic layer containing the salt are washed with water, and further, an alkali metal inorganic base (for example, hydrogen carbonate) It cannot be efficiently removed by a general desalting operation such as washing with an aqueous solution of sodium, potassium hydrogen carbonate, sodium carbonate or potassium carbonate). In fact, potassium perfluorobutanesulfonate (C ₄ F ₉ SO ₃ K) organic solvents - even in distribution to water, potassium trifluoromethanesulfonate (CF ₃ SO ₃ K It was found to be present in the organic solvent at a significantly higher distribution ratio compared to (Reference Example 1, Reference Example 2). Therefore, in the dehydroxyfluorination reaction using perfluoroalkanesulfonyl fluoride having 4 or more carbon atoms, a large amount of salt or alkali metal salt composed of perfluoroalkanesulfonic acid and organic base is brought into the crude product, and the desired product is produced. In order to obtain a product with high chemical purity, a heavy purification method was required. In particular, if the target product is an oily substance and has a high boiling point, distillation purification cannot be adopted, and complicated purification operations such as column chromatography are required. Even if the target product can be purified by distillation, these salts are not dissolved. In order to recover the target product remaining in a large amount as a residue and with a high yield, it is necessary to carry out a distillation operation for a long time at a high temperature condition, and the target product is thermally unstable. In some cases, it could not be a suitable purification method.

  Furthermore, a salt composed of a perfluoroalkanesulfonic acid having 4 or more carbon atoms and an organic base may act as an acid catalyst, and a compound having an acid-labile functional group is purified by distillation over a long period of time under high temperature conditions. It was also not preferable. In fact, in the distillation purification of the crude product of 4-fluoroproline derivative in which the protecting group of secondary amino group is tert-butoxycarbonyl (Boc) group, a large amount of salt composed of perfluorobutanesulfonic acid and organic base is contained. As a result, de-Boc formation was considerably observed (Comparative Example 2). As described above, the problems in the industrial dehydroxyfluorination reaction using perfluoroalkanesulfonyl fluoride having a long carbon chain have been clarified.

  Since salts or alkali metal salts composed of trifluoromethanesulfonic acid and an organic base by-produced from trifluoromethanesulfonyl fluoride used in the present invention have a significantly high distribution with respect to water, these salts can be efficiently removed by washing with water. The target product can be easily obtained with high chemical purity by adopting a purification method that does not require load. Therefore, by using trifluoromethanesulfonyl fluoride, the purification load can be significantly reduced and the dehydroxyfluorination reaction can be carried out industrially.

  In addition, in the dehydroxyfluorination reaction of the 4-hydroxyproline protector targeted in the present invention, the use of trifluoromethanesulfonyl fluoride is higher than the perfluorobutanesulfonyl fluoride in the chemical purity of the crude product. By using trifluoromethanesulfonyl fluoride, side reactions such as elimination of perfluoroalkanesulfonic acid from perfluoroalkanesulfonic acid ester and generation of unsaturated compounds are significantly controlled. (Example 1 vs. Comparative Example 1, Example 2 vs. Comparative Example 2)

  The dehydroxyfluorination reaction having the characteristics disclosed in the present invention is not disclosed in Patent Document 1, Patent Document 2, Non-Patent Document 3, and Non-Patent Document 4 in the related technical fields, and It was also not disclosed that the 4-hydroxyproline protector can be suitably applied to the dehydroxyfluorination reaction.

  Since the production method of the present invention is highly selective and hardly produces impurities that are difficult to separate, it is an extremely useful method for industrial production of 4-fluoroproline derivatives.

  Hereinafter, the production method of the 4-fluoroproline derivative of the present invention will be described in detail.

  This production method comprises reacting a 4-hydroxyproline protector represented by the general formula [1] with trifluoromethanesulfonyl fluoride in the presence of an organic base. First, trifluoromethanesulfonylation of the protected 4-hydroxyproline proceeds, followed by a fluorine substitution reaction with a hydrogen fluoride salt or complex of an organic base by-produced in the reaction system, and the desired product 4-fluoro Proline derivative is given. In trifluoromethanesulfonylation, the stereochemistry at the 4-position is retained, and in the subsequent fluorine substitution reaction, the stereochemistry at the 4-position is reversed. Therefore, the 4S / 2R form of the 4-fluoroproline derivative is obtained from the 4R / 2R form of the 4-hydroxyproline protected form, and similarly, the 4R / 2R form is obtained from the 4S / 2R form, and the 4S / 2R form is obtained from the 4S / 2S form. As for 2S body, 4R / 2S body is obtained from 4S / 2S body.

  In this production method, it is an important feature that the subsequent fluorine substitution reaction proceeds satisfactorily only with a hydrogen fluoride salt or a complex of an organic base such as triethylamine as a by-product in the reaction system in trifluoromethanesulfonylation. For this reason, this production method is preferably carried out without using a fluorinating agent (such as triethylamine / hydrogen trifluoride complex) in addition to trifluoromethanesulfonyl fluoride.

  The protecting group R for the secondary amino group of the protected 4-hydroxyproline represented by the general formula [1] includes benzyloxycarbonyl (Z) group, tert-butoxycarbonyl (Boc) group, 9-fluorenylmethoxycarbonyl (Fmoc) group, 3-nitro-2-pyridinesulfenyl (Npys) group, p-methoxybenzyloxycarbonyl [Z (OMe)] group and the like. Among these, a benzyloxycarbonyl (Z) group and a tert-butoxycarbonyl (Boc) group are preferable, and a tert-butoxycarbonyl (Boc) group is more preferable.

As the protective group R ¹ for the carboxyl group of the 4-hydroxyproline protected body represented by the general formula [1], a methyl (Me) group, an ethyl (Et) group, a tert-butyl (t-Bu) group, trichloroethyl ( Tce) group, phenacyl (Pac) group, benzyl (Bzl) group, 4-nitrobenzyl [Bzl (4-NO ₂ )] group, 4-methoxybenzyl [Bzl (4-OMe)] group and the like. Among them, a methyl (Me) group, an ethyl (Et) group, and a benzyl (Bzl) group are preferable, and a methyl (Me) group and an ethyl (Et) group are particularly preferable.

The 4-hydroxyproline protector represented by the general formula [1] is a commercially available optical material with reference to the 4th edition Experimental Chemistry Course 22 Organic Synthesis IV Acids, Amino Acids and Peptides (Maruzen, 1992, p.193-309). It can be produced from active 4-hydroxyproline. Also a combination of protecting groups R ¹ protecting group R and the carboxyl group of the secondary amino groups while others are commercially available, can use these. The equation [3] indicated by 4-hydroxyproline protected form (secondary protecting group R is tert- butoxycarbonyl group of the amino group, the protecting group R ¹ is a methyl group of a carboxyl group), according non-patent document 1 above From the hydrochloride of optically active 4-hydroxyproline methyl ester.

  As the stereochemistry of the asymmetric carbon of the protected 4-hydroxyproline represented by the general formula [1], the 2-position and the 4-position can each independently adopt the R configuration or the S configuration. There are 4R / 2R, 4S / 2R, 4R / 2S, or 4S / 2S, and the enantiomeric excess (% ee) or diastereomeric excess (% de) of each stereoisomer is particularly limited. However, 90% ee or 90% de or more may be used, respectively. Usually, 95% ee or 95% de or more is preferable, and 97% ee or 97% de or more is particularly preferable.

  Although there is no restriction | limiting in particular as the usage-amount of a trifluoromethanesulfonyl fluoride, in order to obtain a favorable yield, 1 mol or more should be carried out with respect to 1 mol of 4-hydroxyproline protectors shown by General formula [1]. What is necessary is just to use, and 1-10 mol is preferable normally, and 1-5 mol is more preferable especially. As described above, in the present invention, it is important that the subsequent fluorine substitution reaction proceeds well only with a hydrogen fluoride salt or a complex of an organic base such as triethylamine by-produced in an equal amount in the reaction system in trifluoromethanesulfonylation. In order to take advantage of this advantage, the amount of trifluoromethanesulfonyl fluoride used is more preferably an equimolar to small excess of 1 to 3 moles per mole of 4-hydroxyproline protector.

  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, and triethylamine, diisopropylethylamine, pyridine, 2,4-lutidine, 2,6-lutidine, 3,5-lutidine and 2,4,6-collidine are more preferred.

  Although there is no restriction | limiting in particular as the usage-amount of an organic base, 1 mol or more should just be used with respect to 1 mol of 4-hydroxyproline protectors shown by General formula [1], and 1-10 mol is preferable normally. In particular, 1 to 5 mol is more preferable. In the production method of the present invention, side reactions such as elimination of trifluoromethanesulfonic acid from the trifluoromethanesulfonic acid ester and generation of unsaturated compounds are likely to occur, but this side reaction can be achieved by using a minimal excess of organic base. Can be controlled significantly. Therefore, 1.0-1.5 mol is still more preferable with respect to 1.0 mol of 4-hydroxyproline protectors.

  Examples of the reaction solvent include aliphatic hydrocarbons such as n-hexane, cyclohexane and n-heptane, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated carbonization such as methylene chloride, chloroform and 1,2-dichloroethane. Hydrogen type, diethyl ether, tetrahydrofuran, ether type such as tert-butyl methyl ether, ester type such as ethyl acetate, n-butyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, N-methylpyrrolidone, etc. Examples thereof include amides, 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, methylene chloride, tetrahydrofuran, N, N-dimethylformamide and acetonitrile are more preferable. 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, What is necessary is just to use 0.1L (liter) or more with respect to 1 mol of 4-hydroxyproline protectors shown by General formula [1]. 1-20L is preferable and especially 0.1-10L is more preferable.

  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. A pressure-resistant reaction vessel can be used when the reaction is performed under temperature conditions equal to or higher than the boiling point of trifluoromethanesulfonyl fluoride.

  The reaction time is 0.1 to 72 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 is no particular limitation on the post-treatment, but usually the reaction end solution is poured into an aqueous solution of an alkali metal inorganic base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate or potassium carbonate) and an organic solvent (for example, The crude product can be obtained by extraction with toluene, methylene chloride or ethyl acetate). Since salts or alkali metal salts composed of trifluoromethanesulfonic acid and an organic base by-produced from trifluoromethanesulfonyl fluoride are remarkably highly distributed to water, these salts can be efficiently removed by washing with water such as distillation. By adopting a purification method that does not impose a load, the desired 4-fluoroproline derivative represented by the general formula [2] can be obtained with high chemical purity.

Furthermore, by selectively or simultaneously deprotecting the protecting group R of the secondary amino group and the protecting group R ¹ of the carboxyl group of the obtained 4-fluoroproline derivative, the general formula [5]

［式中、Ｒ¹はカルボキシル基の保護基を表し、＊は不斉炭素を表す］で示される４−フルオロプロリンのカルボキシル基保護体、一般式［６］

[Wherein R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon], a protected carboxyl group of 4-fluoroproline represented by the general formula [6]

［式中、Ｒは二級アミノ基の保護基を表し、＊は不斉炭素を表す］で示される４−フルオロプロリンの二級アミノ基保護体、または式［７］

[Wherein R represents a protective group for a secondary amino group, and * represents an asymmetric carbon], or a protected secondary amino group of 4-fluoroproline represented by formula [7]

［式中、＊は不斉炭素を表す］で示される４−フルオロプロリンに変換できる。二級アミノ基の保護基Ｒとカルボキシル基の保護基Ｒ¹の脱保護反応は、第４版 実験化学講座 ２２ 有機合成ＩＶ 酸・アミノ酸・ペプチド（丸善、１９９２年、ｐ．１９３−３０９）を参考にして行うことができる。また式［４］で示される４−フルオロプロリン誘導体（二級アミノ基の保護基Ｒがｔｅｒｔ−ブトキシカルボニル基、カルボキシル基の保護基Ｒ¹がメチル基）は、上記の非特許文献１に従い、式［８］

[Wherein, * represents an asymmetric carbon]. The deprotection reaction of the protecting group R of the secondary amino group and the protecting group R ¹ of the carboxyl group is carried out by the 4th edition Experimental Chemistry Course 22 Organic Synthesis IV Acid / Amino Acid / Peptide (Maruzen, 1992, p.193-309) This can be done with reference. Further, the 4-fluoroproline derivative represented by the formula [4] (secondary amino group protecting group R is tert-butoxycarbonyl group, carboxyl group protecting group R ¹ is methyl group) Formula [8]

［式中、Ｂｏｃはｔｅｒｔ−ブトキシカルボニル基を表す］で示される４−フルオロプロリンの二級アミノ基保護体に変換できる。

[Wherein Boc represents a tert-butoxycarbonyl group] can be converted into a protected secondary amino group of 4-fluoroproline.

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

で示される４−ヒドロキシプロリン保護体 ３．４４ｇ（ガスクロマトグラフィー純度８７．２９％、１２．２３ｍｍｏｌとする、１．００ｅｑ）、アセトニトリル ２４．５ｍｌとトリエチルアミン ２．４８ｇ（２４．４６ｍｍｏｌ、２．００ｅｑ）を加え、内温を−７８℃に冷却してトリフルオロメタンスルホニルフルオリド ３．７２ｇ（２４．４６ｍｍｏｌ、２．００ｅｑ）をボンベより吹き込んだ。同温度で３時間２５分攪拌し、さらに３５℃で１７時間５５分攪拌した。反応の変換率をガスクロマトグラフィーにより測定したところ９９％以上であった。反応終了液を炭酸カリウムの水溶液［炭酸カリウム １０．１４ｇ（７３．３７ｍｍｏｌ、６．００ｅｑ）と水 １３０ｍｌから調製］に注ぎ込み、酢酸エチル １００ｍｌで２回抽出した。回収有機層は、無水硫酸ナトリウムで乾燥し、濾過し、減圧下濃縮し、真空乾燥し、下記式

Protected by 4-hydroxyproline represented by 3.44 g (gas chromatographic purity 87.29%, 12.23 mmol, 1.00 eq), acetonitrile 24.5 ml and triethylamine 2.48 g (24.46 mmol, 2.00 eq) ), The internal temperature was cooled to −78 ° C., and 3.72 g (24.46 mmol, 2.00 eq) of trifluoromethanesulfonyl fluoride was blown from the cylinder. The mixture was stirred at the same temperature for 3 hours and 25 minutes, and further stirred at 35 ° C. for 17 hours and 55 minutes. The conversion rate of the reaction was measured by gas chromatography and found to be 99% or more. The reaction-terminated liquid was poured into an aqueous solution of potassium carbonate [prepared from 10.14 g (73.37 mmol, 6.00 eq) of potassium carbonate and 130 ml of water], and extracted twice with 100 ml of ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, vacuum dried,

で示される４−フルオロプロリン誘導体の粗生成物 ３．８６ｇを褐色の油状物質として得た。粗生成物のガスクロマトグラフィー純度は６７．５２％であった。

The crude product of 4-fluoroproline derivative represented by the formula (3) was obtained as a brown oily substance. The gas chromatographic purity of the crude product was 67.52%.

There are three main impurities, and when impurities A to C are named, impurities A, B and C were included at 12.05%, 11.57% and 0.83%, respectively. The theoretical recovery amount of organic matter was 3.02 g, which suggested that the salt of trifluoromethanesulfonic acid was hardly contained. Therefore, when the molar ratio of the target product to the salt of trifluoromethanesulfonic acid in the crude product was measured by ¹⁹ F-NMR spectrum, the target product: salt of trifluoromethanesulfonic acid was 10: 1. The ¹ H-NMR and ¹⁹ F-NMR spectra of the 4-fluoroproline derivative are shown below (as a mixture of isomers attributable to the Boc group).
¹ H-NMR (reference substance: (CH ₃ ) ₄ Si, heavy solvent: CDCl ₃ ), δ ppm: 1.43 & 1.49 (s × 2, total 9H), 1.95-2.55 (total 2H) 3.51-3.94 (total 2H), 3.75 (S, 3H), 4.36-4.58 (total 1H), 5.10-5.31 (total 1H),
¹⁹ F-NMR (reference substance: C ₆ F ₆ , heavy solvent: CDCl ₃ ), δ ppm: -11.27 (total 1F).
The ¹⁹ F-NMR spectrum of the salt of trifluoromethanesulfonic acid is shown below.
¹⁹ F-NMR (reference material: C ₆ F ₆ , heavy solvent: CDCl ₃ ), δ ppm: +83.36 (s, 3F).
[Comparative Example 1]
In a glass reaction vessel,

で示される４−ヒドロキシプロリン保護体 ３．００ｇ（ガスクロマトグラフィー純度８３．３０％、１０．１９ｍｍｏｌとする、１．００ｅｑ）、アセトニトリル １５．３ｍｌとトリエチルアミン １．３６ｇ（１３．４５ｍｍｏｌ、１．３２ｅｑ）を加え、室温でパーフルオロブタンスルホニルフルオリド ３．６９ｇ（１２．２１ｍｍｏｌ、１．２０ｅｑ）を加えた。同温度で１９時間５５分攪拌した。反応の変換率をガスクロマトグラフィーにより測定したところ９７％以上であった。反応終了液を炭酸カリウムの水溶液［炭酸カリウム ３．３８ｇ（２４．４６ｍｍｏｌ、２．４０ｅｑ）と水 １００ｍｌから調製］に注ぎ込み、酢酸エチルで抽出した。回収有機層は、無水硫酸ナトリウムで乾燥し、濾過し、減圧下濃縮し、真空乾燥し、下記式

Protected by 4-hydroxyproline represented by the following formula: 3.00 g (gas chromatographic purity 83.30%, 10.19 mmol, 1.00 eq), 15.3 ml of acetonitrile and 1.36 g (13.45 mmol, 1.32 eq) of triethylamine ) And 3.69 g (12.21 mmol, 1.20 eq) perfluorobutanesulfonyl fluoride at room temperature. The mixture was stirred at the same temperature for 19 hours and 55 minutes. The conversion rate of the reaction was measured by gas chromatography and found to be 97% or more. The reaction-terminated liquid was poured into an aqueous solution of potassium carbonate [prepared from 3.38 g (24.46 mmol, 2.40 eq) of potassium carbonate and 100 ml of water] and extracted with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, vacuum dried,

で示される４−フルオロプロリン誘導体の粗生成物 ６．６９ｇを白色の結晶として得た（目的生成物の純品は無色澄明の油状物質である）。粗生成物のガスクロマトグラフィー純度は６０．２２％であった。

6.69 g of a crude product of a 4-fluoroproline derivative represented by the formula (1) was obtained as white crystals (a pure product of the desired product is a colorless and clear oily substance). The gas chromatographic purity of the crude product was 60.22%.

There are three main impurities, and when impurities A to C are named as in Example 1, impurities A, B and C were contained in 17.19%, 17.03% and 2.86%, respectively. . The theoretical recovery amount of organic matter was 2.52 g, suggesting that a large amount of perfluorobutanesulfonic acid salt was contained. Therefore, when the molar ratio of the target product to the perfluorobutanesulfonic acid salt in the crude product was measured by ¹⁹ F-NMR spectrum, the target product: perfluorobutanesulfonic acid salt = 2: 1. The ¹ H-NMR and ¹⁹ F-NMR spectra of the 4-fluoroproline derivative were the same as those obtained in Example 1. The ¹⁹ F-NMR spectrum of the salt of perfluorobutanesulfonic acid is shown below.
¹⁹ F-NMR (reference material: C ₆ F ₆ , heavy solvent: CDCl ₃ ), δ ppm: +35.79 (2F), +40.12 (2F), +47.26 (2F), +80.90 (3F) .
[Example 2]
In a pressure resistant reaction vessel made of stainless steel (SUS), the following formula

で示される４−ヒドロキシプロリン保護体 ２０．０５ｇ（ガスクロマトグラフィー純度９９．７７％、８１．５６ｍｍｏｌとする、１．００ｅｑ）、アセトニトリル １１６．０ｍｌとトリエチルアミン ９．０８ｇ（８９．７３ｍｍｏｌ、１．１０ｅｑ）を加え、内温を−３５℃に冷却してトリフルオロメタンスルホニルフルオリド １６．２３ｇ（１０６．７３ｍｍｏｌ、１．３１ｅｑ）をボンベより吹き込んだ。同温度で３０分間攪拌し、さらに室温で１６時間攪拌した。反応の変換率をガスクロマトグラフィーにより測定したところ９９％以上であった。反応終了液を炭酸カリウムの水溶液［炭酸カリウム ４５．２１ｇ（３２７．１１ｍｍｏｌ、４．０１ｅｑ）と水 １８０ｍｌから調製］に注ぎ込み、酢酸エチル ２００ｍｌで２回抽出した。さらに、有機層を１０％食塩水 ６１２ｍｌで２回洗浄した。回収有機層は、無水硫酸ナトリウムで乾燥し、濾過し、減圧下濃縮し、真空乾燥し、下記式

Protected by 4-hydroxyproline represented by 20.05 g (gas chromatography purity 99.77%, 81.56 mmol, 1.00 eq), acetonitrile 116.0 ml and triethylamine 9.08 g (89.73 mmol, 1.10 eq) ) Was added, the internal temperature was cooled to -35 ° C., and 16.23 g (106.73 mmol, 1.31 eq) of trifluoromethanesulfonyl fluoride was blown from the cylinder. The mixture was stirred at the same temperature for 30 minutes and further stirred at room temperature for 16 hours. The conversion rate of the reaction was measured by gas chromatography and found to be 99% or more. The reaction-terminated liquid was poured into an aqueous solution of potassium carbonate [prepared from 45.21 g (327.11 mmol, 4.01 eq) of potassium carbonate and 180 ml of water], and extracted twice with 200 ml of ethyl acetate. Further, the organic layer was washed twice with 612 ml of 10% saline. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, vacuum dried,

で示される４−フルオロプロリン誘導体の粗生成物 ２１．５９ｇを褐色の油状物質として得た。粗生成物のガスクロマトグラフィー純度は８５．２１％であった。主な不純物は３種類あり、不純物Ａ〜Ｃと命名すると、不純物Ａ、不純物Ｂおよび不純物Ｃはそれぞれ６．４７％、２．８０％、４．６８％含まれていた。生成物の理論収量は２０．１７ｇで、粗生成物にはトリフルオロメタンスルホン酸の塩が殆ど含まれていないことが示唆された。そこで粗生成物中の目的生成物とトリフルオロメタンスルホン酸の塩のモル比を¹⁹Ｆ−ＮＭＲスペクトルにより測定したところ、目的生成物：トリフルオロメタンスルホン酸の塩＝９７．６：２．４であった。

21.59 g of a crude product of the 4-fluoroproline derivative represented by the formula (1) was obtained as a brown oily substance. The gas chromatographic purity of the crude product was 85.21%. There are three types of main impurities. When the impurities A to C are named, the impurities A, B and C were contained in 6.47%, 2.80% and 4.68%, respectively. The theoretical yield of product was 20.17 g, suggesting that the crude product contained almost no salt of trifluoromethanesulfonic acid. Therefore, when the molar ratio of the target product to the trifluoromethanesulfonic acid salt in the crude product was measured by ¹⁹ F-NMR spectrum, the target product: trifluorotrifluorosulfonic acid salt = 97.6: 2.4. It was.

  The entire amount of the crude product was purified by distillation (decompression degree 300 Pa, boiling point 110-115 ° C., oil bath temperature 125-135 ° C.) to obtain 16.82 g of a distilled purified product as a pale yellow oily substance. The purity of the distilled purified product was 88.33% (impurities A, B and C were 5.39%, 1.74% and 4.54%, respectively). Since the crude product contained almost no salt of trifluoromethanesulfonic acid, no de-Boc formation by distillation purification was observed. The total yield considering gas chromatographic purity was 73.7%.

¹ H-NMR and ¹⁹ F-NMR spectrum of 4-fluoro-proline derivative, and ¹⁹ F-NMR spectrum of the salt of trifluoromethanesulfonic acid were the same as those obtained in Example 1.

[Comparative Example 2]
In a glass reaction vessel,

で示される４−ヒドロキシプロリン保護体 ２０．０２ｇ（ガスクロマトグラフィー純度９９．７７％、８１．４４ｍｍｏｌとする、１．００ｅｑ）、アセトニトリル １１６．０ｍｌとトリエチルアミン ９．０８ｇ（８９．７３ｍｍｏｌ、１．１０ｅｑ）を加え、内温を−３５℃に冷却してパーフルオロブタンスルホニルフルオリド ３２．０５ｇ（１０６．０９ｍｍｏｌ、１．３０ｅｑ）を加えた。同温度で３０分間攪拌し、さらに室温で１７．５時間攪拌した。反応の変換率をガスクロマトグラフィーにより測定したところ９９％以上であった。反応終了液を炭酸カリウムの水溶液［炭酸カリウム ４５．１０ｇ（３２６．３２ｍｍｏｌ、４．０１ｅｑ）と水 １８０ｍｌから調製］に注ぎ込み、酢酸エチル ２００ｍｌで２回抽出した。さらに、有機層を１０％食塩水 ６１３ｍｌで２回洗浄した。回収有機層は、無水硫酸ナトリウムで乾燥し、濾過し、減圧下濃縮し、真空乾燥し、下記式

Protected by 4-hydroxyproline represented by the following formula: 20.02 g (gas chromatographic purity 99.77%, 81.44 mmol, 1.00 eq), 116.0 ml of acetonitrile and 9.08 g (89.73 mmol, 1.10 eq) of triethylamine ), The internal temperature was cooled to −35 ° C., and 32.05 g (106.09 mmol, 1.30 eq) of perfluorobutanesulfonyl fluoride was added. The mixture was stirred at the same temperature for 30 minutes and further stirred at room temperature for 17.5 hours. The conversion rate of the reaction was measured by gas chromatography and found to be 99% or more. The reaction-terminated liquid was poured into an aqueous solution of potassium carbonate [prepared from 45.10 g (326.32 mmol, 4.01 eq) of potassium carbonate and 180 ml of water] and extracted twice with 200 ml of ethyl acetate. Further, the organic layer was washed twice with 613 ml of 10% saline. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, vacuum dried,

で示される４−フルオロプロリン誘導体の粗生成物 ６８．９２ｇを淡黄色のワックス状物質として得た。粗生成物のガスクロマトグラフィー純度は６４．４８％であった。主な不純物は３種類あり、不純物Ａ〜Ｃと命名すると、不純物Ａ、不純物Ｂおよび不純物Ｃはそれぞれ１４．８１％、１７．３３％、３．３８％含まれていた。生成物の理論収量は２０．１４ｇで、粗生成物にはパーフルオロブタンスルホン酸の塩が多量に含まれていることが示唆された。そこで粗生成物中の目的生成物とパーフルオロブタンスルホン酸の塩のモル比を¹⁹Ｆ−ＮＭＲスペクトルにより測定したところ、目的生成物：パーフルオロブタンスルホン酸の塩＝３２．５：６７．５であった。

As a pale yellow waxy substance, 68.92 g of a crude product of a 4-fluoroproline derivative represented by the formula: The gas chromatographic purity of the crude product was 64.48%. There are three main impurities, and when impurities A to C are named, impurities A, B and C contained 14.81%, 17.33% and 3.38%, respectively. The theoretical yield of the product was 20.14 g, suggesting that the crude product contained a large amount of perfluorobutanesulfonic acid salt. Therefore, when the molar ratio of the target product to the perfluorobutanesulfonic acid salt in the crude product was measured by ¹⁹ F-NMR spectrum, the target product: perfluorobutanesulfonic acid salt = 32.5: 67.5. Met.

  The whole crude product was purified by distillation [depressurization degree 530 Pa (not distilled even if the depressurization degree was further increased), boiling point 93-98 ° C, oil bath temperature 145-150 ° C], and 4.30 g of distilled purified product was pale yellow Obtained as an oil. The purity of the distilled product by gas chromatography was 47.71% (impurities A, B and C were 26.83%, 9.60% and 4.01%, respectively). Since the crude product contained a large amount of perfluorobutanesulfonic acid salt, de-Boc formation by distillation purification was considerably recognized (11.48%, the following formula structure).

ガスクロマトグラフィー純度を考慮したトータル収率は１０．２％であった。４−フルオロプロリン誘導体の¹Ｈ−ＮＭＲと¹⁹Ｆ−ＮＭＲスペクトルは実施例１で得られたものと同様であった。パーフルオロブタンスルホン酸の塩の¹⁹Ｆ−ＮＭＲスペクトルは比較例１で得られたものと同様であった。

The total yield considering gas chromatographic purity was 10.2%. The ¹ H-NMR and ¹⁹ F-NMR spectra of the 4-fluoroproline derivative were the same as those obtained in Example 1. The ¹⁹ F-NMR spectrum of the salt of perfluorobutanesulfonic acid was the same as that obtained in Comparative Example 1.

[Reference Example 1]
To a glass reaction vessel, 2.02 g (5.97 mmol) of potassium perfluorobutanesulfonate (C ₄ F ₉ SO ₃ K), 30 ml of water and 30 ml of ethyl acetate were added and stirred at room temperature for 2 hours. After standing, the organic layer and the aqueous layer were separated, and the molar ratio of potassium perfluorobutanesulfonate contained in each layer was measured by ¹⁹ F-NMR spectrum. Organic layer: aqueous layer = 26.0: It was 74.0.

[Reference Example 2]
To a glass reaction vessel, 1.13 g (6.01 mmol) of potassium trifluoromethanesulfonate (CF ₃ SO ₃ K), 30 ml of water and 30 ml of ethyl acetate were added and stirred at room temperature for 2 hours. After standing, the organic layer and the aqueous layer were separated, and the molar ratio of potassium trifluoromethanesulfonate contained in each layer was measured by ¹⁹ F-NMR spectrum. Organic layer: aqueous layer = 0.8: 99 .2.

Claims (6)

General formula [1]

[In the formula, R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon.] Is reacted with trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) to give a general formula [2]

[Wherein R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon]. General formula [1]

[Wherein, R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon.] A protected 4-hydroxyproline represented by triethylamine [(C ₂ H ₅ ) ₃ N] is reacted with trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) in the presence of general formula [2]

[Wherein R represents a protecting group for a secondary amino group, R ¹ represents a protecting group for a carboxyl group, and * represents an asymmetric carbon]. Formula [3]

[Wherein Boc represents a tert-butoxycarbonyl group] A protected 4-hydroxyproline represented by trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) in the presence of triethylamine [(C ₂ H ₅ ) ₃ N] ) To give the formula [4]

[Wherein Boc represents a tert-butoxycarbonyl group] A method for producing a 4-fluoroproline derivative represented by the formula: 4. The method according to claim 1, wherein only trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is used as a fluorinating agent and no other fluorinating agent is used in combination. Item 4. The method according to any one of Items 3. The organic base or triethylamine is used in any one of claims 1 to 4 in an amount of 1.0 to 1.5 mol per 1.0 mol of the 4-hydroxyproline protector. Item 5. The method according to any one of Items 4. The 4-fluoroproline derivative is synthesized by the method according to any one of claims 1 to 5, and the resulting reaction mixture is washed with water or an aqueous solution of an inorganic base. 6. The method according to any one of items 5.