JP2004323518A - Method for producing 2'-deoxy-2'-fluorouridine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for industrially producing 2'-deoxy-2'-fluorouridine which is an important intermediate for a pharmaceutical. <P>SOLUTION: This method for producing the 2'-deoxy-2'-fluorouridine comprising reacting a 3',5'-hydroxy-protected compound of 1-β-D-arabinofuranosyluracil with a trifluoromethanesulfonylating agent in the presence of an organic base to convert the compound into a 2'-triflate compound thereof, then reacting the triflate compound with a fluorinating agent which comprises "a salt or a complex composed of an organic base and hydrofluoric acid" to produce a 3',5'-hydroxy-protected compound of the 2'-deoxy-2'-fluorouridine, and further acting a deprotecting agent on the produced compound. The obtained 2'-deoxy-2'-fluorouridine is once converted into a 3',5'-diacetyl compound thereof, and the 3',5'-diacetyl compound is deacetylated after it is recrystallized, so that the 2'-deoxy-2'-fluorouridine is efficiently purified to have high purity. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to a method for producing 2'-deoxy-2'-fluorouridine, which is an important intermediate of pharmaceuticals.

  2'-Deoxy-2'-fluorouridine, which is the subject of the present invention, is an important pharmaceutical intermediate. Conventional manufacturing methods can be broadly classified into the following two, and typical literatures are cited.

(1) A method of ring-opening and fluorinating 2,2′-anhydrouridine with hydrofluoric acid;
(2) A method of dehydroxyfluorinating a protected 3 ′, 5′-hydroxyl group of 1-β-D-arabinofuranosyluracil with DAST ((C ₂ H ₅ ) ₂ NSF ₃ );
Further, as a technique related to the present invention, in the synthesis of 2′-deoxy-2′-fluoroadenosine and 2′-deoxy-2′-fluoroguanosine, 3 ′ of the corresponding 9-β-D-arabinofuranosyl adenine respectively. The protected ', 5'-hydroxyl group and the protected 3', 5'-hydroxyl group of N ² -isobutyryl-9-β-D-arabinofuranosylguanine are reacted with trifluoromethanesulfonyl chloride in the presence of sodium hydride. Thus, a method has been disclosed in which each is converted into a corresponding 2′-triflate form and then reacted with tetrabutylammonium fluoride (TBAF) (Non-Patent Document 3, Non-Patent Document 4, and Non-Patent Document 5). Non-Patent Document 6).
J. Org. Chem. (USA), 1964, Vol. 29, No. 3, p. 558-564 Chem. Pharm. Bull. (Japan), 1994, Vol. 42, No. 3, p. 595-598 Tetrahedron Lett. (UK), 1977, Vol. 18, No. 15, p. 1291-1294 Chem. Pharm. Bull. (Japan), 1981, Vol. 29, No. 4, p. 1034-1038 J. Carbohyd. Nucl. Nucl. (UK), 1980, Volume 7, Issue 2, p. 131-140 Chem. Pharm. Bull. (Japan), 1981, Vol. 29, No. 11, p. 3281-3285

  An object of the present invention is to provide an industrial method for producing 2'-deoxy-2'-fluorouridine, which is an important intermediate of pharmaceuticals.

  In the method for producing 2′-deoxy-2′-fluorouridine disclosed in Non-Patent Document 1, the reaction is carried out using excessively hydrofluoric acid having a high corrosiveness at a high temperature, so that the material of the reactor is There were significant restrictions. Further, the productivity was poor because the substrate was highly diluted with the reaction solvent, and the reaction yield itself was low. Further, from an industrial point of view, an industrial production method uses hydrofluoric acid, which is difficult to handle in large quantities, and requires column chromatography to purify the obtained product. It was hard to say.

  On the other hand, in the production method of Non-Patent Document 2, it is necessary to use a special fluorinating agent which is industrially expensive and has a problem in handling a large amount. Was hard to say.

  The methods for synthesizing 2'-deoxy-2'-fluoroadenosine or 2'-deoxy-2'-fluoroguanosine disclosed in Non-Patent Documents 3 to 6 give the desired product only in a very low yield. Was.

The reaction disclosed in Non-Patent Documents 3 to 6 in which a 2′-triflate compound is fluorinated to obtain 2′-deoxy-2′-fluoroadenosine or 2′-deoxy-2′-fluoroguanosine is a fluorine anion It is considered to be a nucleophilic S _N 2 substitution reaction by (F ⁻ ). In this reaction, a “elimination reaction of a triflate group (CF ₃ SO ₃ ⁻ group)” competes as a side reaction, and 1 A compound in which the 'position carbon and the 2' carbon are connected by a double bond is by-produced. The cause of the low yield in Non-Patent Document 3 is also derived from this side reaction. This is an essential problem inherent in the nucleophilic S _N 2 substitution reaction with a fluorine anion (F ⁻ ), and the same problem is involved in the production of the target compound 2′-deoxy-2′-fluorouridine of the present invention. The same is true.

  Thus, a method for industrially advantageously producing 2'-deoxy-2'-fluorouridine has been strongly desired.

  Furthermore, since 2′-deoxy-2′-fluorouridine, which is the final target compound in the present invention, is a water-soluble and hardly crystallizable compound, in order to purify it with high recovery as a highly pure white crystalline powder, It required purification by column chromatography (Non-Patent Document 1 and Non-Patent Document 2), and the purification operation was burdensome. There has not yet been reported a method capable of purifying a highly pure white crystalline powder with high recovery by a simple purification operation such as recrystallization purification. Thus, an industrial purification method of 2'-deoxy-2'-fluorouridine has been strongly desired.

The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and as a result, the 1-β-D-arabinofuranosyluracil targeted 3 ′, 5′-protected hydroxyl group of the present invention was used as a substrate. In some cases, the desired trifluoromethanesulfonylation at the 2′-position and the subsequent nucleophilic _SN 2 -substitution reaction with the fluorine anion (F ⁻ ) at the 2′-position proceeds well under certain conditions. It revealed that.

  A particularly important point of the present invention lies in the use of a "salt or complex consisting of an organic base and hydrofluoric acid" as the fluorinating agent in the fluorination step of the 2'-triflate.

As described above, in the nucleophilic S _N 2 substitution reaction with the fluorine anion (F ⁻ ), the elimination reaction of the triflate group (CF ₃ SO ₃ ⁻ group) competes as a side reaction. However, the present inventors have found that this elimination reaction can be carried out by converting tetrabutylammonium fluoride (TBAF), which is a strongly basic fluorinating agent used in Non-patent Documents 3 to 6, into a fluorine anion (F ⁻ ). It has been clarified that the substitution can be highly suppressed by substituting "a salt or complex comprising an organic base and hydrofluoric acid", which is a fluorinating agent having relatively high nucleophilicity and weak basicity.

  Furthermore, the present inventors have found that "salt or complex consisting of pyridine or triethylamine and hydrofluoric acid" is particularly preferable as the fluorinating agent.

In particular, industrially inexpensively commercially available and and handling is relatively safe, "triethylamine 1 mol of hydrofluoric 3 consisting molar complex _{((C 2 H 5) 3} N · 3HF) " and "pyridine A complex comprising about 30% (about 10 mol%) and about 70% (about 90 mol%) of hydrofluoric acid (trade name: 〜１０10 mol% C ₅ H ₅ N · 〜90 mol% HF) is preferred. Clarified that it can be used.

In particular, a complex composed of 1 mol of triethylamine and 3 mol of hydrofluoric acid ((C ₂ H ₅ ) ₃ N.3HF) does not cause problems such as devitrification or corrosion even when a glass reaction vessel is used. It is particularly advantageous also from the viewpoint of the material.

In the synthesis of 2'-deoxy-2'-fluoroadenosine and 2'-deoxy-2'-fluoroguanosine in conventional techniques (Non-Patent Documents 3 to 6), tetrabutylammonium fluoride (TBAF) is used as a fluorinating agent. ) Was used. In this case, excess TBAF and used, tetrabutylammonium hydroxide produced in the post-treatment with water _{((n-Bu) 4 NOH} ) selectively removing it from the product is generally difficult. However, when the above fluorinating agent is used, the excess fluorinating agent used can be selectively removed from the product by a simple purification operation such as washing with water, and the great operability during industrial production can be achieved. Improvements have been achieved.

  Furthermore, in the present invention, new findings regarding a protecting agent for the hydroxyl group at the 3'-position and the 5'-position in the production of 2'-deoxy-2'-fluorouridine were obtained.

  Examples of the protecting agent for the hydroxyl group at the 3′-position and the 5′-position include the 3′-position and the 5′-position in the deprotection step in the synthesis of 2′-deoxy-2′-fluoroadenosine and 2′-deoxy-2′-fluoroguanosine. It has been disclosed that the protecting group for the hydroxyl group at the 5′-position is better for a tetrahydrofuranyl group (THF group) than for a tetrahydropyranyl group (THP group) (Non-Patent Documents 4 and 5). However, 2,3-dihydrofuran which is a protecting agent for a tetrahydrofuranyl group (THF group) has a boiling point higher than that of 3,4-dihydro-2H-pyran which is a protecting agent for a tetrahydropyranyl group (THP group). Low (54 ° C. vs. 86 ° C.) makes handling difficult and more expensive industrially.

  However, in the production of 2'-deoxy-2'-fluorouridine which is the object of the present invention, even if the protecting groups for the hydroxyl groups at the 3'-position and the 5'-position are tetrahydropyranyl groups (THP groups), deprotection is performed. It was found that the process proceeded well.

  When the THP group is used as a protecting group, the 2′-hydroxylated 3′- and 5′-hydroxyl groups represented by the formula [7] and protected with a tetrahydropyranyl group (THP group) represented by the formula [7] are produced as an intermediate. The "triflate" is a novel compound and is a suitable intermediate in an industrial production method of 2'-deoxy-2'-fluorouridine.

Furthermore, in the present invention, the trifluoromethanesulfonyl fluoride (CF ₃ SO _{2) is used} in the trifluoromethanesulfonylation reaction of the 2′-hydroxyl group of the protected 3 ′, 5′-hydroxyl group of 1-β-D-arabinofuranosyluracil. It has been clarified that F) can be suitably used.

The reaction proceeds even when trifluoromethanesulfonic anhydride ((CF ₃ SO ₂ ) ₂ O) is used as the trifluoromethanesulfonylating agent for the 2′-position hydroxyl group, but the reaction proceeds with trifluoromethanesulfonic anhydride ((CF ₃ SO ₂ ) ₂ O) has two trifluoromethanesulfonyl groups (CF ₃ SO ₂ groups), but only one is used in the reaction, and the rest is a triflate group (CF ₃ SO ₃ ^- group). Acts as a leaving group in the form. Therefore, from the viewpoint of atomic economy, the use of trifluoromethanesulfonic anhydride ((CF ₃ SO ₂ ) ₂ O) is not always efficient.

Although the reaction proceeds even when trifluoromethanesulfonyl chloride (CF ₃ SO ₂ Cl) is used, in the synthesis of 2′-deoxy-2′-fluoroguanosine, a chlorine anion (Cl ₂ ) by-produced as the reaction proceeds. ^-) is a product 2'triflate and subsequently undergoes a substitution reaction in the reaction system, chlorine atom is disclosed to give a by-product obtained by replacing the 2 'position (non-patent Document 6 ). Nucleophilic chlorine anions (Cl chromatography) fluorine anion ^- becomes serious side reactions due much higher than nucleophilic (F). Therefore, the use of trifluoromethanesulfonyl chloride (CF ₃ SO ₂ Cl) is also limited.

An industrial process for producing a series of trifluoromethanesulfonic acid derivatives is shown in Scheme 1. In this flow, trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is located more upstream, and the use of trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is most industrially advantageous. It is.

As a result of intensive studies based on this background, it has been found that trifluoromethanesulfonylation of the 3 ′, 5′-hydroxyl-protected form of 1-β-D-arabinofuranosyluracil, which is the object of the present invention, results in trifluoromethanesulfonation. It has been found that the reaction proceeds favorably even when sulfonyl fluoride (CF ₃ SO ₂ F) is used. As a result, the above problems, namely, (1) low utilization of the trifluoromethanesulfonyl group (CF ₃ SO ₂ group), and (2) by-product of the compound in which the chlorine atom is substituted at the 2′-position, are essential. Can be avoided. In addition, in the trifluoromethanesulfonylation reaction, it is necessary to allow a base to coexist. However, it is not necessary to use sodium hydride which is industrially expensive and has a risk of ignition, and is industrially inexpensive. It is possible to use an organic base such as pyridine or triethylamine which is safe and safe to handle.

  Furthermore, the present inventors have found a novel method for purifying the obtained 2'-deoxy-2'-fluorouridine. That is, focusing on the crystallinity of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine, a low-purity product of 2′-deoxy-2′-fluorouridine was once used as 3 ′, 5 ′. -To obtain a high-purity 2'-deoxy-2'-fluorouridine by inducing it into a diacetyl form, recrystallizing and purifying the 3 ', 5'-diacetyl form, and re-deacetylating it. Revealed. The 2'-deoxy-2'-fluorouridine thus obtained does not become amorphous but can be recovered in high yield as a high-purity white crystalline powder. Thus, it has been clarified that 2'-deoxy-2'-fluorouridine can be obtained as a high-purity white crystalline powder while avoiding a burdensome purification method such as purification by column chromatography.

  Finally, since the production method of the present invention hardly produces by-products which are highly selective and difficult to separate in each reaction step, the trifluoromethanesulfonylation step of the first step and the fluorination step of the second step are performed as a one-pot reaction. The deprotection step of the third step and the acetylation step of the fourth step can be performed as a one-pot reaction, and 2′-deoxy-2′-fluorouridine can be industrially produced. This is a very useful method.

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

[Wherein R represents a protecting group for a hydroxyl group] 1-β-D-arabinofuranosyluracil represented by the general formula [2] in the presence of an organic base.

Wherein X represents an F atom, a Cl atom or a CF ₃ SO ₃ group, by reacting with a trifluoromethanesulfonylating agent represented by the general formula [3]:

[Wherein R represents a hydroxyl-protecting group, and Tf represents a CF ₃ SO ₂ group], and then converted to a 2′-triflate compound represented by the following formula: By reacting with a fluorinating agent comprising a complex

[Wherein R represents a protecting group for a hydroxyl group], and a method for producing a protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine represented by the formula:

  Further, the present invention provides a compound represented by the general formula [1]:

[Wherein R represents a hydroxyl-protecting group], a protected 3 ', 5'-hydroxyl group of 1- [beta] -D-arabinofuranosyluracil represented by the formula [5] in the presence of triethylamine:

By reacting with a trifluoromethanesulfonylating agent represented by the general formula [3]

[Wherein R represents a hydroxyl-protecting group, and Tf represents a CF ₃ SO ₂ group], and then converted to a 2′-triflate compound represented by the formula “Salt or complex consisting of triethylamine and hydrofluoric acid” By reacting with a fluorinating agent comprising the general formula [4]

[Wherein R represents a protecting group for a hydroxyl group], and a method for producing a protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine represented by the formula:

  Further, the present invention provides a compound of the formula [6]

[Wherein THP represents a tetrahydropyranyl group], a protected 3 ', 5'-hydroxyl group of 1- [beta] -D-arabinofuranosyluracil is represented by the formula [5] in the presence of triethylamine.

By reacting with a trifluoromethanesulfonylating agent represented by the formula [7]

[Wherein THP represents a tetrahydropyranyl group, and Tf represents a CF ₃ SO ₂ group], and then converted to a salt or complex consisting of triethylamine and hydrofluoric acid. [8] by reacting with a fluorinating agent consisting of

[Wherein THP represents a tetrahydropyranyl group], a method for producing a protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine.

  In addition, the present invention provides a compound represented by the general formula [4], which is produced by any of the methods described above.

[Wherein, R represents a protecting group for a hydroxyl group], a protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine represented by the following formula:

[Wherein THP represents a tetrahydropyranyl group], by reacting the protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine with a deprotecting agent, ]

And a method for producing 2'-deoxy-2'-fluorouridine represented by the formula:

  Further, the present invention provides a compound represented by the formula [9]:

By reacting 2'-deoxy-2'-fluorouridine represented by the formula (10) with an acetylating agent in the presence of an organic base.

[Wherein Ac represents an acetyl group], 2'-deoxy-2'-fluorouridine represented by the following formula is converted to a 3 ', 5'-diacetyl form, and then 2'-deoxy-2'-fluorouridine is converted to The formula [9], wherein the 3 ′, 5′-diacetyl form is purified by recrystallization and further reacted with a deacetylating agent.

And a method for purifying 2'-deoxy-2'-fluorouridine represented by the formula:

  The present invention also provides a compound of formula [9] produced by the above method.

By reacting 2'-deoxy-2'-fluorouridine represented by the formula (10) with an acetylating agent in the presence of an organic base.

[Wherein Ac represents an acetyl group], 2'-deoxy-2'-fluorouridine represented by the following formula is converted to a 3 ', 5'-diacetyl form, and then 2'-deoxy-2'-fluorouridine is converted to The formula [9], wherein the 3 ′, 5′-diacetyl form is purified by recrystallization and further reacted with a deacetylating agent.

And a method for purifying 2'-deoxy-2'-fluorouridine represented by the formula:

  Further, the present invention provides a compound of the formula [7]

[Wherein THP represents a tetrahydropyranyl group, and Tf represents a CF ₃ SO ₂ group].

  Provided is a method for producing 2'-deoxy-2'-fluorouridine, which is an important intermediate of a medicine.

  Hereinafter, the method for producing 2'-deoxy-2'-fluorouridine of the present invention will be described in detail. As shown in Scheme 2, the present invention provides (1) a trifluoromethanesulfonylation step, (2) a fluorination step, (3) a deprotection step, (4) an acetylation step, (5) a recrystallization purification step, (6) It comprises six production steps of a deacetylation step.

  First, the trifluoromethanesulfonylation step of the first step will be described in detail. In the trifluoromethanesulfonylation step of the first step, the protected 3 ′, 5′-hydroxy group of 1-β-D-arabinofuranosyluracil represented by the general formula [1] is converted to a compound of the general formula [1] in the presence of an organic base. 2] to obtain a trifluoromethanesulfonylating agent.

  R of the protected 3 ′, 5′-hydroxyl group of 1-β-D-arabinofuranosyluracil represented by the general formula [1] as a starting material is a trityl group (triphenylmethyl group), a tetrahydropyranyl group Group (THP group), tetrahydrofuranyl group (THF group) and the like. Among them, a tetrahydropyranyl group (THP group) and a tetrahydrofuranyl group (THF group) are preferable, and a tetrahydropyranyl group (THP group) is more preferable. Compounds represented by the general formula [1] are described in Non-Patent Document 2 and Khim. Geterotsikl. Soedin. (Russia), 1996, No. 7, p. 975-977. According to the methods described in these documents, those in which the 3'-position and the 5'-position are selectively protected can be obtained.

Examples of the trifluoromethanesulfonylating agent represented by the general formula [2] include trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F), trifluoromethanesulfonyl chloride (CF ₃ SO ₂ Cl), and trifluoromethanesulfonic anhydride ((CF ₃ SO ₂ ) ₂ O). Among them, trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) and trifluoromethane sulfonic anhydride ((CF ₃ SO ₂ ) ₂ O) are preferred, and trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is more preferred. .

  The amount of the trifluoromethanesulfonylating agent represented by the general formula [2] to be used is 1 mol of the protected 3 ′, 5′-hydroxyl group of 1-β-D-arabinofuranosyluracil represented by the general formula [1]. 1 mol or more, and usually 1 to 20 mol is preferable, and 1 to 10 mol is more preferable.

  As the organic base, trimethylamine, triethylamine, diisopropylethylamine, tri-n-butylamine, dimethyllaurylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, dimethylbenzylamine, 1,5-diazabicyclo [4,3,0] Non-5-ene, 1,8-diazabicyclo [5,4,0] undec-7-ene, 1,4-diazabicyclo [2,2,2] octane, pyridine, 2,4-lutidine, 2,5- Lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-trimethylpyridine, imidazole, pyrimidine, pyridazine and the like. Among them, triethylamine and pyridine are preferable, and triethylamine is particularly preferable.

  The amount of the organic base used is usually 1 mol or more per 1 mol of the protected 3 ′, 5′-hydroxyl group of 1-β-D-arabinofuranosyluracil represented by the general formula [1]. , Preferably 2 to 20 mol, more preferably 3 to 10 mol.

  The reaction can be carried out without using a reaction solvent, but it is preferable to use it. Examples of such a reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, and n-heptane; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene; methylene chloride, chloroform; , 2-dichloroethane and other halogenated hydrocarbons, diethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane and other ethers, ethyl acetate and n-butyl acetate and other esters, hexamethylphosphoric triamide Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; nitriles such as acetonitrile and propionitrile; and dimethylsulfoxide. Among them, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and dimethylsulfoxide are preferred, and methylene chloride, N, N-dimethylformamide and acetonitrile are more preferred. These reaction solvents can be used alone or in combination.

  The reaction solvent is used in an amount of usually 0.1 L or more based on 1 mol of the protected 3 ′, 5′-hydroxyl group of 1-β-D-arabinofuranosyluracil represented by the general formula [1]. Often, 0.1 to 20 L is preferable, and especially 0.1 to 10 L is more preferable.

The temperature condition is generally -100 to + 50C, preferably -80 to + 20C, and more preferably -60 to -10C. Among the trifluoromethanesulfonylating agents represented by the general formula [2], when trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is used to carry out the reaction under a temperature condition of a boiling point (−21 ° C.) or higher, the pressure resistance is increased. A reaction vessel can be used.

  The reaction time is usually 0.1 to 24 hours, but varies depending on the substrate and the reaction conditions. Therefore, the progress of the reaction is tracked by analytical means such as gas chromatography, liquid chromatography, and NMR, and the raw material is almost completely consumed. It is preferable that the end point be the time point at which the operation is performed.

The post-treatment is not particularly limited, but usually, water, an aqueous solution of sodium hydrogen carbonate or saline is added to the reaction-terminated liquid, and the mixture is extracted with an organic solvent such as toluene, methylene chloride, or ethyl acetate. Alternatively, the crude product can be obtained by washing with a saline solution or the like, drying with a desiccant such as anhydrous sodium sulfate or anhydrous magnesium sulfate, filtering, concentrating, and vacuum drying. By subjecting the crude product to a purification operation such as treatment with activated carbon or recrystallization if necessary, the desired 2′-triflate represented by the general formula [3] can be obtained with high chemical purity. However, since the present 2'-triflate is highly reactive, a "salt or complex comprising an organic base and hydrofluoric acid" is directly added to the reaction-terminated liquid without post-treatment and isolation outside the system. It is effective to add a fluorinating agent and perform the trifluoromethanesulfonylation step of the first step and the fluorination step of the second step as a one-pot reaction. Further, a trifluoromethanesulfonylating agent represented by the general formula [2] is added in the presence of a fluorinating agent consisting of an organic base and a "salt or complex consisting of an organic base and hydrofluoric acid" to add trifluoromethanesulfonating agent of the first step. It is also effective to carry out the methanesulfonylation step and the fluorination step of the second step as a one-pot reaction. When trifluoromethanesulfonyl fluoride (CF ₃ SO ₂ F) is used as the trifluoromethanesulfonylating agent represented by the general formula [2], “composed of an organic base and hydrofluoric acid, Although a salt or complex is by-produced, the subsequent fluorination reaction hardly proceeds, and it is necessary to newly add a fluorinating agent consisting of a salt or complex consisting of an organic base and hydrofluoric acid.

  Next, the fluorination step of the second step will be described in detail. In the fluorination step of the second step, the 2′-triflate compound represented by the general formula [3] obtained in the first step is converted to a fluorine salt of “a salt or complex consisting of an organic base and hydrofluoric acid” It is achieved by reacting with an agent.

  Examples of the organic base in the fluorinating agent consisting of “a salt or a complex comprising an organic base and hydrofluoric acid” include trimethylamine, triethylamine, diisopropylethylamine, tri-n-butylamine, dimethyllaurylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, dimethylbenzylamine, 1,5-diazabicyclo [4,3,0] non-5-ene, 1,8-diazabicyclo [5,4,0] undec-7-ene, 1,4-diazabicyclo [2,2,2] octane, pyridine, 2,4-lutidine, 2,5-lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-trimethylpyridine, Imidazole, pyrimidine, pyridazine and the like. Among them, triethylamine and pyridine are preferable, and triethylamine is particularly preferable.

The molar ratio of the organic base and hydrofluoric acid in the fluorinating agent is usually in the range of 100: 1 to 1: 100, preferably in the range of 50: 1 to 1:50, and particularly preferably in the range of 25: 1 to 1: 1. A range of 25 is more preferred. Further, “complexes consisting of 1 mol of triethylamine and 3 mol of hydrofluoric acid ((C ₂ H ₅ ) ₃ N.3HF)” and “pyridine about 30” are commercially available from Aldrich (2003-2004 general catalog). % (About 10 mol%) and about 70% (about 90 mol%) of hydrofluoric acid (trade name: 〜１０10 mol% C ₅ H ₅ N · 〜90 mol% HF) ” Extremely convenient.

  The amount of the fluorinating agent consisting of “salt or complex consisting of an organic base and hydrofluoric acid” is usually 1 mol or more per 1 mol of the 2′-triflate compound represented by the general formula [3]. 1 to 20 mol is preferable, and 1 to 10 mol is more preferable.

  The reaction can be carried out without using a reaction solvent, but it is preferable to use it. Examples of such a reaction solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, and n-heptane; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene; methylene chloride, chloroform; , 2-dichloroethane and other halogenated hydrocarbons, diethyl ether, tetrahydrofuran, t-butyl methyl ether, 1,4-dioxane and other ethers, ethyl acetate and n-butyl acetate and other esters, hexamethylphosphoric triamide Amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone; nitriles such as acetonitrile and propionitrile; and dimethylsulfoxide. Among them, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and dimethylsulfoxide are preferred, and methylene chloride, N, N-dimethylformamide and acetonitrile are more preferred. These reaction solvents can be used alone or in combination.

  The amount of the reaction solvent to be used is generally 0.1 L or more per 1 mol of the 2'-triflate compound represented by the general formula [3], preferably 0.1 to 20 L, particularly preferably 0.1 to 20 L. 10 L is more preferred.

  The temperature condition is usually -100 to + 100C, preferably -80 to + 80C, and more preferably -60 to + 60C.

  The reaction time is usually 0.1 to 120 hours. However, since the reaction time varies depending on the substrate and the reaction conditions, the progress of the reaction is tracked by analysis means such as gas chromatography, liquid chromatography, and NMR, and the raw material is almost completely consumed. It is preferable that the end point be the time point at which the operation is performed.

  The post-treatment is not particularly limited, but usually, water, an aqueous solution of sodium hydrogen carbonate, an aqueous solution of potassium carbonate or a saline solution, etc. are added to the reaction-completed solution, and the mixture is extracted and recovered with an organic solvent such as toluene, methylene chloride or ethyl acetate. The organic layer is washed with water or a saline solution, dried with a drying agent such as anhydrous sodium sulfate or anhydrous magnesium sulfate, filtered, concentrated, and dried under vacuum to obtain a crude product. If necessary, the crude product may be subjected to a purification operation such as treatment with activated carbon or recrystallization to obtain the desired 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by the general formula [4]. Protected bodies can be obtained with high chemical purity.

  Next, the deprotection step of the third step will be described in detail. In the deprotection step of the third step, the protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine represented by the general formula [4] obtained in the second step is deprotected. Reached by reacting with an agent.

  The deprotection reaction preferably uses an acid catalyst as the deprotection agent, and is preferably performed in an alcohol-based reaction solvent.

  Examples of the acid catalyst include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, PPTS (pyridinium p-toluenesulfonate), and 10-camphorsulfonic acid. Organic acids, ion exchange resins such as Amberlyst H-15 and Dowex 50W-X8, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Among them, acetic acid, p-toluenesulfonic acid, hydrochloric acid and sulfuric acid are preferred, and p-toluenesulfonic acid and sulfuric acid are more preferred.

  The amount of the acid catalyst to be used is generally 3 ', 5'-hydroxyl-protected form of 2'-deoxy-2'-fluorouridine represented by the general formula [4], which may be used in an amount of the catalyst or more per 1 mol. , 0.01 to 100 mol, particularly preferably 0.03 to 50 mol.

  It is preferable to use an alcohol-based reaction solvent as the reaction solvent. Examples of such a reaction solvent include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, sec-butanol, and tert-butanol. And the like. Among them, methanol, ethanol, n-propanol and n-butanol are preferred, and methanol, ethanol and n-propanol are more preferred. These reaction solvents can be used alone or in combination.

  The reaction solvent may be used in an amount of usually 0.1 L or more per 1 mol of the protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine represented by the general formula [4]. , 0.1 to 20 L, more preferably 0.1 to 10 L.

  The temperature condition is usually −20 to + 100 ° C., preferably −10 to + 80 ° C., and particularly preferably 0 to + 60 ° C.

  The reaction time is usually 0.1 to 48 hours, but varies depending on the substrate and the reaction conditions. Therefore, the progress of the reaction is tracked by analytical means such as thin-layer chromatography, liquid chromatography, and NMR, and the raw material is used. It is preferable that the time when almost disappeared is the end point.

  The post-treatment is not particularly limited, but is usually performed by adding an organic base or an inorganic base to the reaction-terminated liquid and concentrating the alcohol-based reaction solvent to obtain the desired 2′-deoxy-formula represented by the formula [9]. A crude product of 2'-fluorouridine can be obtained. The acetylation reaction in the fourth step proceeds sufficiently well by reacting the crude product with an acetylating agent.

  Next, the acetylation step of the fourth step will be described in detail. The acetylation step of the fourth step is achieved by reacting the 2′-deoxy-2′-fluorouridine represented by the formula [9] obtained in the third step with an acetylating agent in the presence of an organic base. .

  Examples of the acetylating agent include acetic anhydride, acetyl fluoride, acetyl chloride, acetyl bromide and the like. Among them, acetic anhydride, acetyl chloride and acetyl bromide are preferable, and acetic anhydride and acetyl chloride are particularly preferable.

  The amount of the acetylating agent to be used may be generally 2 mol or more, preferably 2 to 20 mol, and more preferably 2 mol, per 1 mol of 2'-deoxy-2'-fluorouridine represented by the formula [9]. -10 mol is more preferred.

  As the organic base, trimethylamine, triethylamine, diisopropylethylamine, tri-n-butylamine, dimethyllaurylamine, 4-dimethylaminopyridine, N, N-dimethylaniline, dimethylbenzylamine, 1,5-diazabicyclo [4,3,0] Non-5-ene, 1,8-diazabicyclo [5,4,0] undec-7-ene, 1,4-diazabicyclo [2,2,2] octane, pyridine, 2,4-lutidine, 2,5- Lutidine, 2,6-lutidine, 3,4-lutidine, 3,5-lutidine, 2,4,6-trimethylpyridine, imidazole, pyrimidine, pyridazine and the like. Among them, triethylamine and pyridine are preferable, and pyridine is particularly preferable.

  The amount of the organic base used is usually 2 mol or more per 1 mol of 2′-deoxy-2′-fluorouridine represented by the formula [9], preferably 2 to 20 mol, and particularly preferably 2 to 10 mol. Molar is more preferred.

  As the reaction solvent, aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, and n-heptane; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene; methylene chloride, chloroform; Halogenated hydrocarbons such as 2-dichloroethane, ethers such as diethyl ether, tetrahydrofuran, t-butyl methyl ether, and 1,4-dioxane; esters such as ethyl acetate and n-butyl acetate; hexamethylphosphoric triamide; Examples include amides such as N, N-dimethylformamide, N, N-dimethylacetamide and N-methylpyrrolidone, nitriles such as acetonitrile and propionitrile, and dimethylsulfoxide. Among them, toluene, methylene chloride, tetrahydrofuran, ethyl acetate, N, N-dimethylformamide, N, N-dimethylacetamide, acetonitrile and dimethylsulfoxide are preferred, and methylene chloride and N, N-dimethylformamide are more preferred. These reaction solvents can be used alone or in combination. In addition, an excess amount of an acetylating agent and an organic base can be used as a reaction solvent.

  The temperature condition is usually −20 to + 100 ° C., preferably −10 to + 80 ° C., and more preferably 0 to + 60 ° C.

  The reaction time is usually 0.1 to 48 hours, but varies depending on the reaction conditions. Therefore, the progress of the reaction is tracked by analytical means such as gas chromatography, liquid chromatography, and NMR, and the raw material has almost disappeared. It is preferable that the time point be the end point.

  The post-treatment is not particularly limited, but usually the excess acetylating agent and the organic base and the reaction solvent in the reaction-finished solution are concentrated and the reaction solvent is added, water is added to the concentrated residue, and the precipitated crystals are filtered, After washing with water or an organic solvent such as toluene, methylene chloride or ethyl acetate and drying in vacuo, the desired 3 ′, 5′-form of 2′-deoxy-2′-fluorouridine represented by the formula [10] is obtained. Crude crystals of the diacetyl form can be obtained.

  Next, the fifth step of recrystallization and purification will be described in detail. In the recrystallization purification step of the fifth step, the crude crystal of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10], obtained in the fourth step, is recrystallized. Reached by purification.

  Examples of the recrystallization solvent include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, and n-heptane; aromatic hydrocarbons such as benzene, toluene, ethylbenzene, xylene, and mesitylene; methylene chloride, chloroform; Halogenated hydrocarbons such as 1,2-dichloroethane, etc., ethers such as diethyl ether, tetrahydrofuran, t-butylmethyl ether, 1,4-dioxane, ketones such as acetone, methyl ethyl ketone and methyl i-butyl ketone, ethyl acetate, acetic acid Examples include esters such as n-butyl, nitriles such as acetonitrile and propionitrile, alcohols such as methanol, ethanol, n-propanol, i-propanol, n-butanol and i-butanol, and water. Among them, n-hexane, n-heptane, methylene chloride, tetrahydrofuran, acetone, methyl ethyl ketone, ethyl acetate, acetonitrile, methanol, ethanol, n-propanol, i-propanol and water are preferable, and particularly n-heptane, acetone, acetonitrile, methanol , Ethanol, n-propanol, i-propanol and water are more preferred. These recrystallization solvents can be used alone or in combination.

  The amount of the recrystallization solvent used is usually 1 ml or more per 1 g of the crude crystal of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10]. , Preferably 1 to 100 ml, more preferably 1 to 50 ml.

  In the present recrystallization purification, crystals can be deposited smoothly and efficiently by adding seed crystals. The seed crystal may be used in an amount of usually 0.0001 g or more based on 1 g of the crude crystal of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10]. , 0.0001 to 0.1 g, more preferably 0.001 to 0.05 g.

  The temperature condition can be appropriately determined depending on the boiling point and the freezing point of the recrystallization solvent to be used. Usually, the crude crystal before purification is dissolved at a temperature of about 30 ° C. to a temperature near the boiling point of the recrystallization solvent, and the solution is left standing or stirred. Crystals are precipitated while gradually lowering the temperature, and finally cooled to −20 ° C. to room temperature (25 ° C.).

  In the present recrystallization purification, since the chemical purity of the precipitated crystal is improved, the precipitated crystal is recovered by filtration or the like, so that 2′-deoxy-2′-fluoro represented by the formula [10] having high chemical purity is obtained. A 3 ′, 5′-diacetyl form of uridine can be obtained. Further, by repeating this recrystallization operation, a product having a higher chemical purity can be obtained. Alternatively, the solution can be decolorized by treating a solution of the crude crystals before purification in a recrystallization solvent with activated carbon.

  The purification time is usually 0.1 to 120 hours. However, since the purification time varies depending on the purification conditions, the chemical purity of the precipitated crystals and the amount of precipitated crystals are monitored and analyzed. Is preferably the end point.

  Finally, the deacetylation step of the sixth step will be described in detail. In the deacetylation step of the sixth step, the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10] having high chemical purity and obtained in the fifth step is deacetylated. It is achieved by reacting with an acetylating agent.

  The deacetylation reaction preferably uses an acid catalyst or a base as the deacetylating agent, and is preferably performed in an alcohol-based reaction solvent.

  Examples of the acid catalyst include formic acid, acetic acid, propionic acid, trifluoroacetic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, PPTS (pyridinium p-toluenesulfonate), and 10-camphorsulfonic acid. Organic acids, ion exchange resins such as Amberlyst H-15 and Dowex 50W-X8, and inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid. Among them, acetic acid, p-toluenesulfonic acid, hydrochloric acid and sulfuric acid are preferred, and p-toluenesulfonic acid and hydrochloric acid are more preferred.

  The amount of the acid catalyst to be used may be at least the amount of the catalyst based on 1 mol of the highly pure 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10]. Usually, 0.01 to 100 mol is preferable, and particularly 0.03 to 50 mol is more preferable.

  Examples of the base include carbons such as methylamine, ethylamine, n-propylamine, i-propylamine, n-butylamine, i-butylamine, sec-butylamine, tert-butylamine, n-pentylamine, n-hexylamine, and cyclohexylamine. And lower alkyl primary amines of formulas 1 to 6, ammonia and the like. Among them, methylamine, ethylamine, n-propylamine, n-butylamine and ammonia are preferred, and methylamine, ethylamine and ammonia are more preferred.

  The amount of the base used is usually 2 mol or more per 1 mol of the highly pure 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10]. Preferably, it is preferably from 2 to 200 mol, and particularly preferably from 2 to 100 mol.

  It is preferable to use an alcohol-based reaction solvent as the reaction solvent. Examples of such a reaction solvent include methanol, ethanol, n-propanol, i-propanol, n-butanol, i-butanol, sec-butanol, and tert-butanol. And the like. Among them, methanol, ethanol, n-propanol and n-butanol are preferred, and methanol, ethanol and n-propanol are more preferred. These reaction solvents can be used alone or in combination.

  The amount of the reaction solvent to be used is usually 0.1 L or more per 1 mol of a highly pure 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10]. 0.1 to 20 L is preferable, and 0.1 to 10 L is more preferable.

  The temperature condition is usually −20 to + 100 ° C., preferably −10 to + 80 ° C., and more preferably 0 to + 60 ° C. When the reaction is carried out at a temperature higher than the boiling point of the base used, a pressure-resistant reaction vessel can be used.

  The reaction time is usually 0.1 to 120 hours. However, since the reaction time varies depending on the reaction conditions, the progress of the reaction is tracked by analysis means such as thin layer chromatography, liquid chromatography, and NMR, and the raw material is almost completely lost. It is preferable that the time point be the end point.

  The post-treatment is not particularly limited, but usually the excess acid catalyst and base in the reaction-finished solution and the reaction solvent are concentrated, and a high-purity white crystalline powder can be recovered with a high yield. The desired 2′-deoxy-2′-fluorouridine represented by the formula [9] can be further purified by subjecting the high-purity white crystalline powder to a purification operation such as activated carbon treatment or recrystallization, if necessary. Can be obtained at In particular, acetamide by-produced when ammonia is used as the base can be efficiently removed by recrystallization purification. This recrystallization purification can be performed in the same manner with reference to the fifth recrystallization purification step. In this case, a crude crystal of a 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula [10] is converted into a 2′-deoxy-2′-formula represented by the formula [9]. The procedure is carried out by replacing with high-purity white crystalline powder of fluorouridine.

  Hereinafter, embodiments of the present invention will be described specifically with reference to Examples, but the present invention is not limited to these Examples.

[Reference Example 1] Production of 3 ', 5'-protected hydroxyl group of 1-β-D-arabinofuranosyluracil as starting material

50.00 g (0.221 mol, 1 eq) of 2,2′-anhydrouridine, 320 ml of N, N-dimethylformamide and 129.08 g of 3,4-dihydro-2H-pyran (1.534 mol, 6.94 eq) ), Cooled to 0 ° C, added with 25.60 g (0.135 mol, 0.61 eq) of p-toluenesulfonic acid monohydrate, and stirred at room temperature for 18 hours and 50 minutes. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 98.1%, and the following formula:

It was confirmed that a protected 3 ', 5'-hydroxyl group of 2,2'-anhydrouridine represented by. 13.07 g (0.129 mol, 0.58 eq) of triethylamine was added to the reaction-terminated liquid, cooled to 0 ° C., 230 ml (0.460 mol, 2.08 eq) of a 2N aqueous sodium hydroxide solution was added, and the mixture was added at room temperature for 2 hours 15 minutes. Stirred. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 98.7% and the following formula was obtained.

It was confirmed that a protected 3 ', 5'-hydroxyl group of 1- [beta] -D-arabinofuranosyluracil represented by the formula was generated. 29.37 g (0.489 mol, 2.21 eq) of acetic acid and 200 ml of water were added to the reaction-terminated liquid, followed by extraction with 250 ml of ethyl acetate. The recovered aqueous layer was further extracted twice with 150 ml of ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, azeotroped three times with a small amount of toluene, and 3 ′, 1-β-D-arabinofuranosyluracil represented by the above formula. 196.12 g of a crude product of a protected 5′-hydroxyl group was obtained. The recovered amount of the crude product exceeded the theoretical yield of 91.15 g.

[Example 1] A trifluoromethanesulfonylation step of a first step and a fluorination step of a second step In a SUS pressure-resistant reaction vessel, the following formula prepared in Reference Example 1 was used.

142.90 g (1 eq to 0.145 mol, 1 eq) of a crude product of a protected 3 ′, 5′-hydroxy group of 1-β-D-arabinofuranosyluracil represented by the following formula: 290 ml of N, N-dimethylformamide and triethylamine 87.12 g (0.861 mol, 5.94 eq) was added, the internal temperature was cooled to −54 ° C., 45.00 g (0.296 mol, 2.04 eq) of trifluoromethanesulfonyl fluoride was added, and the mixture was stirred for 2 hours. The temperature was raised to −20 ° C. over 30 minutes. The reaction completed solution was analyzed by ¹⁹ F-NMR.

It was confirmed that the 2′-triflate represented by the formula was generated. The ¹⁹ F-NMR spectrum of the 2′-triflate is shown below.
¹⁹ F-NMR (reference substance: C ₆ F ₆ , solvent: CDCl ₃ ), δ ppm: 87.06, 87.09, 87.17, 87.20.
118.00 g (0.732 mol, 5.05 eq) of (C ₂ H ₅ ) ₃ N.3HF was added to the reaction completed solution at −20 ° C., and the mixture was stirred at room temperature for 62 hours and 45 minutes. The reaction complete solution was analyzed by liquid chromatography, and the conversion rate was> 99%.

It was confirmed that a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by was generated. An aqueous sodium hydrogen carbonate solution was added to the reaction-terminated liquid, and the mixture was extracted with ethyl acetate. The recovered aqueous layer was further extracted with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and a crude product of a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by the above formula was obtained. .18 g were obtained. The recovered amount of the crude product exceeded the theoretical yield of 60.09 g. The ¹⁹ F-NMR spectrum of the protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine is shown below.
¹⁹ F-NMR (reference substance: C ₆ F ₆ , solvent: CDCl ₃ ), δ ppm: −43.13 (dt, 51.9 Hz, 15.4 Hz), −42.50 (dt, 51.5 Hz, 15 .4 Hz), -37.62 (dt, 51.5 Hz, 15.0 Hz), -37.55 (dt, 51.9 Hz, 15.0 Hz).
[Example 2] Deprotection step of the third step and acetylation step of the fourth step In a glass reactor, the following formula prepared in [Example 1] was used.

177.18 g (0.145 mol, 1 eq) of a crude product of a protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine represented by the following formula, 150 ml of methanol and p-toluenesulfonic acid. 13.80 g (0.073 mol, 0.50 eq) of hydrate was added, and the mixture was stirred at room temperature for 16 hours and 30 minutes. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 99.0% and the following formula was obtained.

It was confirmed that 2'-deoxy-2'-fluorouridine represented by was produced. 6.88 g (0.087 mol, 0.60 eq) of pyridine was added to the reaction-terminated liquid, and the mixture was concentrated under reduced pressure to obtain a crude product of 2'-deoxy-2'-fluorouridine represented by the above formula.

  The whole amount of the crude product was added to a glass reaction vessel, cooled to 0 ° C., 68.46 g (0.865 mol, 5.97 eq) of pyridine and 54.10 g (0.530 mol, 3.66 eq) of acetic anhydride were added, and the mixture was added at room temperature. For 19 hours and 10 minutes. The reaction complete solution was analyzed by liquid chromatography, and the conversion rate was> 99%.

It was confirmed that a 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula was generated. The reaction-terminated liquid was concentrated under reduced pressure at 50 ° C., 80 ml of water was added to the concentrated residue, and the precipitated crystals were filtered, washed with 20 ml of ethyl acetate, dried in vacuo, and 2′-deoxy-2 represented by the above formula. 58.00 g of crude crystals of the 3 ', 5'-diacetyl form of' -fluorouridine were obtained. The recovered amount of the crude crystals exceeded the theoretical yield of 47.89 g. When the crude crystals were analyzed by liquid chromatography, the HPLC purity was 90.17%. The ¹ H, ¹⁹ F-NMR spectrum of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine is shown below.
¹ H-NMR (reference substance: TMS, solvent: DMSO-D ₆ ), δ ppm: 1.96 (s, 3H), 2.03 (s, 3H), 4.08 (dd, 5.6 Hz, 12 2.0 Hz, 1 H), 4.19 (ddd, 2.4 Hz, 5.6 Hz, 8.0 Hz, 1 H), 4.26 (dd, 2.4 Hz, 12.0 Hz, 1 H), 5.18 (ddd, 5.2 Hz, 8.0 Hz, 17.6 Hz, 1H), 5.46 (ddd, 2.0 Hz, 5.2 Hz, 52.4 Hz, 1H), 5.61 (d, 8.0 Hz, 1H), 5 .79 (dd, 2.0 Hz, 22.6 Hz, 1H), 7.64 (d, 8.0
Hz, 1H), 11.41 (br, 1H).
¹⁹ F-NMR (reference substance: C ₆ F ₆ , solvent: DMSO-D ₆ ), δ ppm: −35.34 (dt, 51.9 Hz, 21.4 Hz).
Example 3 Fifth Step of Recrystallization Purification Step The following formula prepared in Example 2 was placed in a glass reaction vessel.

58.00 g of crude crystals of the 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine represented by the following formula, 330 ml of methanol and 120 ml of water were added, and the mixture was dissolved by heating under reflux and stirred to room temperature. The temperature has dropped. The precipitated crystals were filtered, washed with methanol, and dried under vacuum to obtain 33.48 g of a highly pure 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the above formula. . From crude products of protected 3 ', 5'-hydroxyl group of 1-β-D-arabinofuranosyluracil to highly purified products of 3', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine Was 70% (weight of the theoretical yield: 47.89 g). When the high purity product was analyzed by liquid chromatography, the HPLC purity was 99.49%.

  Again, 33.48 g of the high-purity product was recrystallized and purified from 200 ml of methanol and 100 ml of water in the same manner, and 3 ′, 5′-diacetyl of 2′-deoxy-2′-fluorouridine represented by the above formula having higher purity was further purified. 31.51 g of a body was obtained. The recovery of the second recrystallization purification was 94%. Second recrystallization of 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine from a crude product of a protected 3', 5'-hydroxyl group of 1-β-D-arabinofuranosyluracil The total yield up to the product was 66% (the weight of the theoretical yield was 47.89 g). When the second recrystallized product was analyzed by liquid chromatography, the HPLC purity was 99.95%.

Example 4 Deacetylation Step of the Sixth Step In a SUS pressure-resistant reaction vessel, the following formula prepared in Example 3 was used.

The second recrystallized product of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by 5.00 g (15.14 mmol, 1 eq), methanol 50 ml and ammonia 12.89 g (756.90 mmol) , 49.99 eq) and stirred at room temperature for 6 hours 30 minutes. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 99.9% and the following formula was obtained.

It was confirmed that 2'-deoxy-2'-fluorouridine represented by was produced.

The reaction-terminated liquid was concentrated under reduced pressure to obtain 6.77 g of high-purity white crystalline powder. 6.77 g of high-purity white crystalline powder, 70 ml of i-propanol and 3 ml of n-heptane were added to a glass reaction vessel, and the mixture was heated and dissolved under reflux conditions, and the temperature was lowered to room temperature with stirring. The precipitated crystals were filtered, washed with i-propanol, and dried under vacuum to obtain 3.10 g of 2′-deoxy-2′-fluorouridine represented by the above formula, which was a higher purity white crystalline powder. The total yield of the deacetylation reaction and the recrystallization purification was 83%. 55% in terms of the total yield from the crude product of the protected 3 ', 5'-hydroxyl group of 1-β-D-arabinofuranosyluracil to the recrystallized product of 2'-deoxy-2'-fluorouridine. Met. When the recrystallized product was analyzed by liquid chromatography, the HPLC purity was 99.84%. The ¹ H, ¹⁹ F-NMR spectrum of 2′-deoxy-2′-fluorouridine is shown below.
¹ H-NMR (reference substance: TMS, solvent: DMSO-D ₆ ), δ ppm: 3.57 (d, 12.8 Hz, 1H), 3.75 (d, 12.8 Hz, 1H), 3.86 (D, 7.6 Hz, 1H), 4.13 (ddd, 4.4 Hz, 7.6 Hz, 20.8 Hz, 1H), 5.02 (ddd, 2.0 Hz, 4.4 Hz, 53.2 Hz, 1H) ), 5.20 (br-t, 1H), 5.61 (br, 1H), 5.61 (dd, 2.0 Hz, 8.0 Hz, 1H), 5.89 (dd, 2.0 Hz, 17 .6 Hz, 1H), 7.91 (d, 8.0 Hz, 1H), 11.38 (br-d, 1H).
¹⁹ F-NMR (reference substance: C ₆ F ₆ , solvent: DMSO-D ₆ ), δ ppm: −39.77 (dt, 51.5 Hz, 18.4 Hz).
Example 5 Deacetylation Step of Sixth Step In a glass reaction vessel, the following formula was prepared in the same manner with reference to [Example 1] and [Example 3] to [Example 3].

199.00 g (0.603 mol, 1 eq, HPLC purity 99.60%) of a highly purified 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by, and 4020 ml of methanol were added thereto. Stirred at C for 1 hour. The internal temperature was cooled to 55 ° C., 200 ml (0.422 mol, 0.70 eq) of 2.11 M hydrochloric acid methanol was added, and the mixture was stirred at 45 ° C. for 19 hours. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was> 99.5% and the following formula was obtained.

It was confirmed that 2′-deoxy-2′-fluorouridine represented by was produced. The reaction-terminated liquid was filtered and concentrated under reduced pressure to obtain 196.38 g of high-purity white crystalline powder. 196.38 g of high-purity white crystalline powder, 900 ml of i-propanol and 300 ml of n-heptane were added to a glass reaction vessel, washed with stirring under heating at 50 ° C. for 30 minutes, and cooled to room temperature. The precipitated crystals were filtered and dried under vacuum to obtain 137.51 g of 2′-deoxy-2′-fluorouridine represented by the above formula and a higher purity white crystalline powder. The total yield of the deacetylation reaction and the heating and stirring washing was 93%. When the washed product under heating and stirring was analyzed by liquid chromatography, the HPLC purity was 99.50%. The ¹ H, ¹⁹ F-NMR spectrum of 2′-deoxy-2′-fluorouridine was similar to that shown in [Example 4].

[Reference Example 2] Production of protected 3 ', 5'-hydroxyl group of 1-β-D-arabinofuranosyluracil as starting material In a glass reactor, 700 ml of N, N-dimethylformamide and 3,4- 235.00 g (2.794 mol, 4.00 eq) of dihydro-2H-pyran was added, cooled to 0 ° C., and 80.00 g (0.421 mol, 0.60 eq) of p-toluenesulfonic acid monohydrate was added. At the same temperature,

158.00 g (0.699 mol, 1 eq) of 2,2'-anhydrouridine represented by the formula was added, and the mixture was stirred at room temperature for 15 hours and 35 minutes. The reaction-terminated liquid was analyzed by liquid chromatography to find that the conversion was 99.3% and the following formula:

It was confirmed that a protected 3 ', 5'-hydroxyl group of 2,2'-anhydrouridine represented by. The reaction-terminated liquid was cooled to 0 ° C., and a 5N aqueous sodium hydroxide solution (360 ml, 1.800 mol, 2.58 eq) was added thereto, followed by stirring at room temperature for 1 hour and 55 minutes. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 98.7% and the following formula was obtained.

It was confirmed that a protected 3 ', 5'-hydroxyl group of 1- [beta] -D-arabinofuranosyluracil represented by the formula was generated. 89.17 g (1.485 mol, 2.12 eq) of acetic acid was added to the reaction-terminated liquid, and the mixture was extracted with 450 ml of ethyl acetate. The recovered aqueous layer was further extracted with 200 ml of ethyl acetate. The recovered organic layer was concentrated under reduced pressure to obtain 479.94 g of a crude product of a protected 3 ', 5'-hydroxyl group of 1-β-D-arabinofuranosyluracil represented by the above formula. The recovered amount of crude product exceeded the theoretical yield of 288.29 g.

[Example 6] First step of trifluoromethanesulfonylation step and second step of fluorination step In a SUS pressure-resistant reaction vessel, the following formula prepared in Reference Example 2 was used.

479.94 g (1 eq. Of 0.699 mol) of a protected 3 ′, 5′-hydroxy group of 1-β-D-arabinofuranosyluracil represented by the following formula, 880 ml of acetonitrile and 428.34 g of triethylamine (4 .233 mol, 6.06 eq), cooled to 0 ° C., added 451.00 g (2.797 mol, 4.00 eq) of (C ₂ H ₅ ) ₃ N.3HF, further cooled, and cooled to an internal temperature of -23 to At -45 ° C, 191.00 g (1.256 mol, 1.80 eq) of trifluoromethanesulfonyl fluoride was added, and the mixture was stirred at room temperature for 110 hours and 55 minutes. When the reaction-completed solution was analyzed by liquid chromatography, the conversion was 99.8%, and the following formula:

It was confirmed that a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by was generated. 350.00 g (2.532 mol, 3.62 eq) of potassium carbonate was dissolved in 3000 ml of water, and the reaction-terminated liquid was added to a two-phase solution prepared by adding 800 ml of ethyl acetate while stirring, followed by extraction with ethyl acetate. The recovered aqueous layer was further extracted with 500 ml of ethyl acetate. The recovered organic layer was concentrated under reduced pressure to obtain 794.54 g of a crude 3 ′, 5′-hydroxy group protected product of 2′-deoxy-2′-fluorouridine represented by the above formula. The recovered amount of crude product exceeded the theoretical yield weight of 289.69 g. The ¹⁹ F-NMR spectrum of the protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine was similar to that shown in [Example 1].

[Example 7] Deprotection step of the third step and acetylation step of the fourth step In a glass reaction vessel, the following formula prepared in [Example 6] was used.

794.54 g (0.699 mol, 1 eq) of a crude product of a protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine represented by the following formula, 700 ml of methanol and p-toluenesulfonic acid. 66.60 g (0.350 mol, 0.50 eq) of hydrate was added, and the mixture was stirred at room temperature for 40 hours and 30 minutes. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 100%,

It was confirmed that 2'-deoxy-2'-fluorouridine represented by was produced. 88.02 g (1.113 mol, 1.59 eq) of pyridine was added to the reaction-terminated liquid, and the mixture was concentrated under reduced pressure to obtain a crude product of 2'-deoxy-2'-fluorouridine represented by the above formula.

  The whole amount of the crude product was added to a glass reaction vessel, 489.00 g (6.182 mol, 8.84 eq) of pyridine was added, the mixture was cooled to 0 ° C., and 541.00 g (5.299 mol, 7.58 eq) of acetic anhydride was added. And stirred at room temperature for 40 minutes. When the reaction-terminated liquid was analyzed by liquid chromatography, the conversion was 96.6% and the following formula was obtained.

It was confirmed that a 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine represented by the formula was generated. The reaction-terminated liquid was concentrated under reduced pressure, the concentrated residue was cooled to 0 ° C, 160 ml of water and 160 ml of ethyl acetate were added, the mixture was stirred at the same temperature, and the precipitated crystals were filtered, dried in vacuo, and represented by the above formula. As a result, 175.36 g of crude crystals of the 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine obtained were obtained. The total yield from 2,2'-anhydrouridine to crude crystals of the 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine was 76% (weight of the theoretical yield 230. 86g). When the crude crystals were analyzed by liquid chromatography, the HPLC purity was 96.90%. The ¹ H, ¹⁹ F-NMR spectrum of the 3 ′, 5′-diacetyl form of 2′-deoxy-2′-fluorouridine was similar to that shown in [Example 2].

Example 8 Fifth Step of Recrystallization Purification Step The following formula prepared in Example 7 was placed in a glass reaction vessel.

175.36 g of crude crystals of the 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine represented by the formula (1) and 700 ml of acetonitrile were added, dissolved by heating under reflux, and cooled to room temperature with stirring. The precipitated crystals were filtered and dried under vacuum to obtain 143.22 g of a highly purified 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine represented by the above formula. The total yield from 2,2'-anhydrouridine to a highly pure 3 ', 5'-diacetyl form of 2'-deoxy-2'-fluorouridine was 62% (the weight of the theoretical yield was 230). .86 g). When the high purity product was analyzed by liquid chromatography, the HPLC purity was 99.80%.

[Example 9] Trifluoromethanesulfonylation step of the first step and fluorination step of the second step In a glass reactor, the following formula was produced in the same manner as in [Reference Example 1].

The crude product of 1-β-D-arabinofuranosyluracil protected 3 ', 5'-hydroxyl group shown by the formula: 0.412 g (0.999 mmol, 1 eq), 5 ml of N, N-dimethylformamide and triethylamine Add 0.799 g (7.896 mmol, 7.90 eq), cool to −78 ° C., add 0.335 g (1.187 mmol, 1.19 eq) of trifluoromethanesulfonic anhydride, and stir at −78 ° C. for 10 minutes did.

The reaction completed solution was analyzed by ¹⁹ F-NMR.

It was confirmed that the 2′-triflate represented by the formula was generated. The ¹⁹ F-NMR spectrum of the 2′-triflate was similar to that shown in [Example 1].

At -78 ° C., the complex containing “pyridine—30% (〜１０10 mol%) and hydrofluoric acid—70% (〜90 mol%) was added at −78 ° C. (〜１０10 mol% C ₅ H ₅ N · 〜90 mol) % HF) "and stirred at room temperature for 3 hours. The reaction completed solution was analyzed by liquid chromatography to find that the conversion was 62%,

It was confirmed that a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by was generated. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction-terminated liquid, and the mixture was extracted with ethyl acetate. The recovered organic layer is dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and crude product of a protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine represented by the above formula 0 0.816 g was obtained. The recovered amount of crude product exceeded the theoretical yield of 0.414 g in weight. Then, the product was subjected to a purification operation by column chromatography (silica gel / ethyl acetate: n-hexane = 1: 1), and the accurate weight of the purified product was measured. As a result, 0.324 g of the purified product was obtained. From crude products of protected 3 ', 5'-hydroxyl groups of 1-β-D-arabinofuranosyluracil to purified products of protected 3', 5'-hydroxyl groups of 2'-deoxy-2'-fluorouridine Was 78%. The ¹⁹ F-NMR spectrum of the protected 3 ′, 5′-hydroxy group of 2′-deoxy-2′-fluorouridine was similar to that shown in [Example 1].

Claims (7)

General formula [1]
[Wherein R represents a protecting group for a hydroxyl group] 1-β-D-arabinofuranosyluracil represented by the general formula [2] in the presence of an organic base.
Wherein X represents an F atom, a Cl atom or a CF ₃ SO ₃ group, by reacting with a trifluoromethanesulfonylating agent represented by the general formula [3]:
[Wherein R represents a hydroxyl-protecting group, and Tf represents a CF ₃ SO ₂ group], and then converted to a 2′-triflate compound represented by the following formula: By reacting with a fluorinating agent comprising a complex
[Wherein R represents a protecting group for a hydroxyl group], a method for producing a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by the formula: General formula [1]
[Wherein R represents a protecting group for a hydroxyl group] 1-β-D-arabinofuranosyluracil represented by the formula [5] in the presence of triethylamine in the presence of triethylamine.
By reacting with a trifluoromethanesulfonylating agent represented by the general formula [3]
[Wherein R represents a hydroxyl-protecting group, and Tf represents a CF ₃ SO ₂ group], and then converted to a 2′-triflate compound represented by the formula “Salt or complex consisting of triethylamine and hydrofluoric acid” By reacting with a fluorinating agent comprising the general formula [4]
[Wherein R represents a protecting group for a hydroxyl group], a method for producing a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine represented by the formula: Equation [6]
[Wherein THP represents a tetrahydropyranyl group] 1-β-D-arabinofuranosyluracil represented by the formula [5] in the presence of triethylamine by protecting the protected 3 ′, 5′-hydroxyl group.
By reacting with a trifluoromethanesulfonylating agent represented by the formula [7]
[Wherein THP represents a tetrahydropyranyl group, and Tf represents a CF ₃ SO ₂ group], and then converted to a salt or complex consisting of triethylamine and hydrofluoric acid. [8] by reacting with a fluorinating agent consisting of
[Wherein THP represents a tetrahydropyranyl group], a method for producing a protected 3 ′, 5′-hydroxyl group of 2′-deoxy-2′-fluorouridine. The general formula [4] produced by the method according to any one of claims 1, 2, and 3.
[Wherein, R represents a hydroxyl-protecting group] 2'-deoxy-2'-fluorouridine represented by the following formula: [3]
[Wherein THP represents a tetrahydropyranyl group], by reacting the protected 3 ', 5'-hydroxyl group of 2'-deoxy-2'-fluorouridine with a deprotecting agent, ]
A method for producing 2′-deoxy-2′-fluorouridine represented by the formula: Equation [9]
By reacting 2′-deoxy-2′-fluorouridine represented by the formula (10) with an acetylating agent in the presence of an organic base.
[Wherein Ac represents an acetyl group], 2'-deoxy-2'-fluorouridine represented by the following formula is converted to a 3 ', 5'-diacetyl form, and then 2'-deoxy-2'-fluorouridine is converted to The formula [9], wherein the 3 ′, 5′-diacetyl form is purified by recrystallization and further reacted with a deacetylating agent.
A method for purifying 2'-deoxy-2'-fluorouridine represented by the formula: Formula [9] produced by the method of claim 4
By reacting 2′-deoxy-2′-fluorouridine represented by the formula (10) with an acetylating agent in the presence of an organic base.
[Wherein Ac represents an acetyl group], 2'-deoxy-2'-fluorouridine represented by the following formula is converted to a 3 ', 5'-diacetyl form, and then 2'-deoxy-2'-fluorouridine is converted to The formula [9], wherein the 3 ′, 5′-diacetyl form is purified by recrystallization and further reacted with a deacetylating agent.
A method for purifying 2'-deoxy-2'-fluorouridine represented by the formula: Equation [7]
[Wherein THP represents a tetrahydropyranyl group, and Tf represents a CF ₃ SO ₂ group].