JPH0597847A - New process for producing nucleic acid compound - Google Patents

Abstract

PURPOSE:To obtain a 5'-ester derivative of 2',3'-dideoxy-2',3'-didehydrouridine useful as a production intermediate for pharmaceuticals in high yield with single step from an easily available inexpensive constituent component of ribonucleic acid. CONSTITUTION:A 2',3'-dideoxy-2',3'-didehydrouridine 5'-ester derivative of formula II (e.g. 5'-O-benzoyl-2',3'-dideoxy-2',3'didehydrouridine) is produced by reacting a compound of formula I (Ms is esters of e.g. methanesulfonyl, acetyl or benzoyl) (e.g. 5'-O-benzoyl-2'-bromo-2'-deoxy-3'-O-mesyluridine) with metallic zinc powder in a proper organic solvent such as ethyl acetate, methanol or tetrahydrofuran. Compounds of formula III, formula IV and formula V useful as synthetic intermediates for various nucleic acid compounds can easily be produced by using the above reaction as a key reaction.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for producing a useful nucleic acid compound as an intermediate in the production of pharmaceuticals.

[0002]

PRIOR ART AND PROBLEM TO BE SOLVED BY THE INVENTION General formula [I] (Wherein R represents an ester such as an acetyl group, a benzoyl group, etc.), that is, a 5'-ester derivative of 2 ', 3'-dideoxy-2', 3'-didehydrouridine is , Chem.Pharm.Bull., 18 , 554 (1970) and J.Org.C
hem., 53 , 5170 (1988), it is an intermediate useful for the production of nucleic acid compounds and antiviral agents using the same.

Further, the compounds [III], [IV] and [V]
Are, for example, J. Org. Chem., 32 , 817 (1967) (relative to compound [III]); JP-A-02-222695 and JP-A-03-47086 (above, compound [IV] ); JP 01-199991 A and JP 01-100191 A
It is a useful intermediate for the production of pyrimidine nucleoside analogues and purine nucleoside analogues, as described in Japanese Patent Publication (for compound [V] above).

The synthesis method of the compound represented by the general formula [I] is described in Shiragami et al., J. Org. Chem., 53 , 5170 (1).
988). According to them, they use orthoester 1
2 ', 3'-dideoxy-2', 3'-didehydrouridine 2 is synthesized.

However, although the yield of this reaction is about 50% when measured by HPLC or the like, it seems that 2 is obtained, but in reality, a by-product ( 1 unreacted material as a raw material is considerably A large amount) and must be purified by silica gel column chromatography. Therefore, although it may be a method that can be managed in the laboratory, industrially, it is not possible to isolate and operate a large amount of substances by column chromatography or the like. Therefore, this method is not industrially feasible. Also, 50% of one-step reaction is not completely satisfactory.

The industrially feasible method is a method in which the reaction proceeds cleanly and most of it is the target product in the state after completion of the reaction, and purification can be easily carried out by distillation or recrystallization, preferably in one step. Say.

Also, Shiragami et al. Used their reaction (a method for synthesizing 1 to 2 described above) as a key reaction, using uridine as a starting material, and producing compounds [III] and [IV]. The method of synthesizing the compound [II] is disclosed because the reaction of acetate 2 rather than orthoester 1 which is their key reaction is not industrial as described above.
The synthetic methods of [I] and [IV] are not industrially easy and inexpensive.

Further, as a method for synthesizing the compound represented by the general formula [I], MM Mansu
ri) et al. reported in J. Org. Chem., 54 , 4780 (1989). According to this report, they synthesize 4 from 3 ', 5'-O-diacetyl-2'-deoxy-2'-bromouridine 3 by the method shown below.

They use metallic zinc to eliminate the acetyl group and bromide of compound 3 , but 3 ', 5'-O
-Diacetyl-2'-deoxy-2'-bromouridine 3 is not very good as a raw material for elimination reaction by zinc. In fact, even in their report, the yield of 50-60 was obtained by this single step desorption.
% Is not good. The instability of the produced compound 4 (decomposed by the acidity of bromine or acetic acid added as a catalyst, which is produced at the same time) seems to be the main cause of the decrease in yield, but the acetyl group is essentially a leaving group. It is thought that one of the causes is that it is not very suitable.

Furukawa et al. Also reported Chem.Pharm.B.
ull., 18 , 554 (1970), as shown below, 2 '
-A method for obtaining dideoxyuridine-5'-benzoate 6 from -bromo-3'-O-mesyluridine derivative 5 is described.

However, palladium / barium sulfate (Pd
In the method of Furukawa et al. Using BaSO ₄ ), there is a considerable variation in the yield in the synthesis of 5 to 6 (20 to 60%). The reason for this is palladium (Pd)
It is thought that this is because when the bromide (Br) is desorbed by using as a catalyst, the decomposition of 6 produced at that acidity proceeds. Furthermore, since the bromide formed becomes a catalyst poison for the catalyst palladium, it seems that the reaction often stops halfway.

Furukawa et al. Also describe a method of using Raney-Ni instead of palladium. Although this method proceeds as a reaction more cleanly than the above method using palladium, the raw materials and products tend to be taken up and adsorbed in the Raney-Nickle swabs, so that the recovery is poor and the yield is low. Bad (40% or less). Therefore, neither method can be called an industrial manufacturing method. Furukawa et al. Use this reaction as a key reaction to synthesize dideoxyuridine, but it is not an industrial synthetic method for the reason described above.

On the other hand, JP Horwitz et al. Reported that 2'-deoxyuridine was used as a compound [III],
And a method for synthesizing compound [IV] [J. Org. Chem.,
32, 817 (1967)] to have, but their starting materials are readily difficult to obtain a 2'Deoshikiurijin, is unreasonable for an industrial synthesis method.

[0014]

According to the present invention, there is provided a method for producing a compound of the following general formula [I] from a compound of the following general formula [II] in high yield and in one step. It (However, Ms represents a methanesulfonyl group, R represents an ester such as an acetyl group, a benzoyl group, etc.)

Moreover, if the above reaction is used as a key reaction, the following compounds useful as synthetic intermediates for various nucleic acid compounds [II
A simple synthetic method of I], [IV], and [V] is provided. (However, R represents esters such as acetyl group, benzoyl group, etc.)

The present invention is particularly useful as an industrial production method of compound [IV], that is, dideoxyuridine.

Further, according to the present invention, the compound of the above formula [II] is dissolved in a suitable solvent, and zinc powder is allowed to act on the compound to reductively desorb bromide and mesylate at the same time. A method of making a compound of I] is provided. The reaction is preferably an organic solvent miscible with a small amount of water, for example, methanol, ethanol, tetrahydrofuran (THF), dioxane, acetone, methylisobutylketone (MIBK), dimethylformamide (D).
MF), dimethylsulfoxide (DMSO), ethyl acetate. Especially considering the treatment before and after the reaction, ethyl acetate is most preferable.

As a suitable zinc powder, commercially available zinc dust is sufficiently usable. An organic acid (such as acetic acid) may be added to activate zinc, but it is not always necessary when performing this reaction. Zinc powder is
From 50 to 1 mol of the compound represented by the above formula [II]
Present in an amount of 200 g. Even if the zinc powder is 50 g or less, the reaction proceeds sufficiently, but the reaction rate tends to be slow or stalled in the middle, so in that case, adding an organic acid (for example, acetic acid) gives good results. Sometimes. In addition, zinc powder 200 per 1 mol of compound [II]
The reaction proceeds normally even if more than g is added, but the reaction rate does not increase remarkably because of the added amount of zinc. Rather, when the amount of zinc is too large, the compounds [I], [I
Adsorption of [I] to zinc is not appropriate. Particularly preferably, the amount of zinc powder is about 100 g per mol of the compound [II].
Is.

In the above compound [II], R may be any ester, for example, acetyl group, propyl group, benzoyl group and the like.

The reaction is preferably carried out by stirring the reaction system at a temperature of 20 to 60 ° C. However, since the reaction itself is naturally accelerated as the reaction progresses, it is not necessary to heat the reaction apparatus with a jacket or the like.

The reaction can be started and stopped at room temperature. Preferably, the reaction is carried out for 30 minutes or longer, and usually within 30 hours. When the compound [II] is sufficiently pure and there is no problem such as impurities, the reaction is usually completed within 1 hour.

The above reaction is advantageous because it is suitable for large scale production of the compound of formula [I]. Furthermore, the present invention enables large-scale and inexpensive supply of the compounds represented by the formulas [III], [IV] and [V] by using the formula [I] obtained by the above reaction as a raw material. I chose

The compound of formula [III] can be easily obtained by treating the compound of formula [I] with a suitable alkali. In this case, examples of suitable alkalis include ammonia and sodium methoxide. The reaction is preferably carried out in alcohol. Since the compound of formula [I] synthesized according to the present invention has high purity, the reaction for obtaining the compound of formula [III] also proceeds in high yield.

The compound of formula [V] is obtained by subjecting the compound of formula [I] to catalytic hydrogenation in the presence of a suitable metal solvent. Palladium charcoal (Pd / C) and the like are particularly preferable as a suitable metal catalyst. Since the compound of the formula [I] obtained in the present invention has a high purity, it does not contain impurities that would poison the metal catalyst, and the reaction proceeds cleanly and almost quantitatively. Preferred solvents are alcohols such as methanol and ethanol.

The compound of formula [IV] can be produced from the compound of formula [III] or the compound of formula [V]. That is, the formula
Catalytic hydrogenation of a compound of formula [III] in the presence of a metal catalyst gives a compound of formula [IV]. Suitable metal catalysts include palladium charcoal (Pd /
C) and the like are particularly preferable. Since the compound of the formula [III] obtained in the present invention has a high purity, it does not contain impurities that would poison the metal catalyst, and the reaction proceeds cleanly and almost quantitatively. Preferred solvents are alcohols such as methanol and ethanol. Further, the compound of formula [IV] can be easily obtained by treating the compound of formula [V] with a suitable alkali. In this case, examples of suitable alkalis include ammonia and sodium methoxide.
The reaction is preferably carried out in alcohol. Since the compound of the formula [V] synthesized in the present invention has high purity, the reaction for obtaining the compound of the formula [IV] also proceeds in high yield.

The compound of the formula [II] used in the present invention can be prepared by a well-known method (Chem. Phar).
m.Bull. 18 , 554 (1970) and J.Org.Chim., 29 , 558 (19
64) and the like), or a method obtained by slightly modifying the existing method as described in the examples of the present invention can be used.

The present invention is particularly useful for useful synthetic intermediates for various antiviral agents (Japanese Patent Laid-Open Nos. 02-222695 and 03-
47086), which is useful as a method for industrially synthesizing 2 ', 3'-dideoxyuridine.

[0028]

The present invention will be described in more detail by the following examples.

Example 1 Synthesis of 5'-O-benzoyl-2'-bromo-2'-deoxy-3'-O-mesyluridine (Synthesis of starting material for elimination reaction with zinc)

A) Synthesis of 2 ', 3', 5'-tri-O-mesyluridine 2.44 kg (10 mol) of uridine in a sealable, 20 L flask.
[Rf value 0.05 (chloroform: ethanol = 9:
1)] and 7.5 L of pyridine are added and stirred. While cooling the outside of the flask with ice water, methanesulfonyl chloride 3.78k
g (33 mol) is slowly added dropwise. At this time, the internal temperature is 30 ℃
Be careful not to exceed the above. After dropping, TLC
After confirming the completion of the reaction by (silica gel thin layer chromatography), the reaction solution is slowly added dropwise to 100 L of ice water. At this time, the ice water is vigorously stirred. After completion of dropping, the mixture is stirred for 30 minutes as it is. The white solid obtained is filtered and washed thoroughly with water. After washing with water, the contents are thoroughly replaced with methanol to remove water, and dried at 50 ° C. for 6 hours.

The reaction proceeds quantitatively and the desired product, 2 ', 3
', 5'-Tri-O-mesyluridine was obtained. Rf value 0.61
(Chloroform: methanol = 9: 1). The white solid thus obtained was directly used in the next reaction.

B) Synthesis of 2,2'-anhydro-1- (5-O-benzoyl-3-O-mesyl-BD-arabinofuranosyl) uracil In a flask with a 30 L reflux tube, the aforesaid obtained in a)
2 ', 3', 5'- Tri-O-mesyluridine and the total amount of DMF
Add (15 L) of (dimethylformamide) and stir. Add 3.17 kg of sodium benzoate and heat the inner temperature to around 110 ° C. The reaction is terminated by keeping it for 30 minutes while stirring. After confirming the completion of the reaction by TLC (silica gel thin layer chromatography), the reaction solution is slowly added dropwise to 200 L of water with vigorous stirring to solidify the product. After the dropping, continue stirring for 30 minutes. The solids obtained are collected by filtration and washed well with water. Furthermore, the water is removed by thoroughly displacing and washing with methanol.

Thus, the desired product, 2,2'-anhydro-1- (5-O-benzoyl-3-O-mesyl-BD-arabinofuranosyl) uracil, was obtained from uridine in 95%. It was Yield 3.88 kg (9.5 mol). Rf value 0.50 (chloroform: methanol = 9: 1)

C) 5'-O-benzoyl-2'-bromo-2'-
Synthesis of deoxy-3'-O-mesyluridine In a 30 L flask equipped with a reflux tube, 2,2'-anhydro-1- (5-O-benzoyl-3-O-mesyl-B-D obtained in b) was obtained.
-Add the whole amount (3.88 kg) of arabinofuranosyl) uracil, add 26 L of ethyl acetate and 520 ml of methanol and stir. While stirring, heat the flask slowly and raise the temperature until the inside of the flask begins to reflux. When the reflux starts, 1.6 kg of acetyl bromide is slowly added dropwise while paying attention to bumping. The reaction temperature is controlled so that the inside of the flask is slightly refluxed.

After the completion of the dropping, the solution is further refluxed for about 30 minutes and reacted. After confirming the completion of the reaction by TLC (silica gel thin layer chromatography), the reaction solution is slowly dropped into 50 L of ice water while being vigorously stirred and blown. Add 24 L of ethyl acetate and separate and extract well. After discarding the aqueous layer, wash the ethyl acetate layer thoroughly with water to
Make sure that becomes neutral. The ethyl acetate layer was dehydrated and filtered with anhydrous sodium sulfate, and the filtered mother liquor was subjected to rotary filtration.
Concentrate with an evaporator until it becomes a candy.

When the concentrate was recrystallized from ethanol, the desired product, 5'-O-benzoyl-2'-bromo-2'-deoxy-3, was obtained.
'-O-Mesyl uridine needle crystals, 3.52kg (7.20mol)
Was obtained. When the recrystallization mother liquor is concentrated to dryness, a glassy 5'-
0.971 kg (1.98 mol) of O-benzoyl-2'-bromo-2'-deoxy-3'-O-mesyluridine was obtained. Rf value 0.92
(Chloroform: Methanol = 9: 1) Total yield 4.49k
g (9.18 mol). 92% total yield from uridine.

(Example 2) 5'-O-benzoyl-2 ', 3'
-Synthesis of dideoxy-2 ', 3'-didehydrouridine (elimination reaction using zinc powder) A 100 L flask was prepared, and 5'-O-benzoyl-2' synthesized by the method of Example 1 was prepared. -Bromo-2'-deoxy-3'-
A total of 4.49 kg (9.18 mol) of O-mesyluridine was dissolved in 40 L of ethyl acetate. While slowly stirring the solution, slowly add 1.0 kg of zinc powder little by little to react.
At this time, it is not necessary to heat the outside of the flask with a jacket or the like. The reaction solution generates heat due to its own reaction and rises from room temperature to about 50 ° C. Let it stand and confirm that the reaction temperature has settled to around room temperature again.
Confirm the completion of the reaction by (silica gel thin layer chromatography). Zinc is removed by filtration, water is added to the filtrate and the mixture is stirred, followed by extraction and separation operations and washing with water. At the time of this washing operation, the aqueous layer was weakly acidic (pH 2 to
3) and wash. Next, it is washed with water containing sodium hydrogen carbonate so that the aqueous layer becomes completely neutral (pH 6 to 7). The obtained ethyl acetate layer is concentrated to dryness.

The dried solid was recrystallized from isopropyl alcohol (IPA) to give 5'-O-benzoyl-2 ', 3'.
-Dideoxy-2 ', 3'- didehydrouridine 2.88 kg (8.26
mol) was obtained. Yield 90%. Rf value 0.54 (ethyl acetate only).

In addition, the mother liquor contained some product (5'-O).
-Benzoyl-2 ', 3'-dideoxy-2', 3'-didehydrouridine) is contained in several%, but since the following reaction involves catalytic reduction and other operations that dislike catalytic poisons, The collected product is not used in the next reaction. Only crystals were used in the following reactions. Also, instead of IPA, ethanol can be used as a solvent for recrystallization.

Example 3 2 ', 3'-dideoxy-2', 3'-
Synthesis of didehydrouridine (Production method 1) 1.0 kg (3.18 mol) of 5'-O-benzoyl-2 ', 3'-dideoxy-2', 3'-didehydrouridine obtained in Example 2 was mixed with 5 L of methanol. Dissolve in. Add 500 ml of 28% methanol solution of sodium methoxide to this and stir. T
After confirming the completion of the reaction by LC (silica gel thin layer chromatography), the pH is adjusted to 7.5 to 8.0 with an ion exchange resin IRC50 (manufactured by Organo). When the solution is concentrated and the methanol is distilled off, a solid content begins to precipitate. Recrystallization from methanol gave 2 ', 3'-dideoxy-2', 3'-didehydrouridine (0.602 kg, 2.86 mol). Yield 90%. Rf value 0.32
(Chloroform: methanol = 9: 1). The ¹ H NMR of the compound thus obtained was in agreement with the conventional one.

Only the crystal part was used in the following reaction. 0.015kg from the mother liquor when separated with a silica gel column
(0.07 mol) of 2 ', 3'-dideoxy-2', 3'-didehydrouridine was obtained (2.2%).

Example 4 2 ', 3'-dideoxy-2', 3'-
Synthesis of didehydrouridine (Production method 2) 5'-O-benzoyl-2 ', 3'-dideoxy-2', 3'-didehydrouridine obtained in Example 2 was placed in a 20 L eggplant flask.
0.500 kg (1.59 mol) is added, and 10 L of methanol containing 25% ammonia is further added and dissolved. Stir for 24 hours at room temperature to react. After confirming the completion of the reaction by TLC, when methanol and excess ammonia were distilled off, 2 ', 3
'-Dideoxy-2', 3'-didehydrouridine precipitates. 0.310k as crystals when treated with a small amount of methanol
g (1.48 mol) was obtained. Yield 93%. In addition, a small amount of product was confirmed in the mother liquor.

Example 5 Synthesis of 2 ', 3'-dideoxyuridine (Production Method A) The 2', 3'-dideoxy-2 ', 3'-obtained in Example 3 was placed in a 10 L round bottom flask. Add 0.600 kg (2.86 mol) of didehydrouridine and dissolve in 6 L of methanol. 25% of 5%
Add palladium charcoal (Pd / C). The inside of the reaction system is completely degassed by depressurization and then replaced with hydrogen. The reaction is carried out as it is under a hydrogen atmosphere for 2 hours at room temperature. At this time, if the reaction system leans toward acidity, it becomes a raw material2
Since the N-glycoside bond of ', 3'-dideoxy-2', 3'-didehydrouridine may be broken and decomposition may occur,
It is advisable to add a small amount of alkali (such as sodium hydrogen carbonate). After confirming the completion of the reaction by TLC, Pd / C is removed by filtration and the filtrate is concentrated.

The concentrated dried product was recrystallized from acetone to give 2
0.516 kg (2.43 mol) of ', 3'-dideoxyuridine was obtained.
Yield 85%. Rf value 0.44 (chloroform: methanol = 9: 1); 0.28 (ethyl acetate only). The ¹ H NMR of the compound thus obtained was in agreement with that reported previously.

(Example 6) 5'-O-benzoyl-2 ', 3'
-Synthesis of dideoxyuridine 5'-O-benzoyl-2 ', 3'-dideoxy-2', 3'-didehydrouridine 1.00 kg (3.18 mol) obtained in Example 2 was used.
It was dissolved in 10 L of methanol. Thereto, 100 g of 5% palladium charcoal (Pd / C) was added, and the mixture was stirred under a hydrogen atmosphere for 2 hours at room temperature. After confirming the completion of the reaction by TLC, the palladium catalyst was removed by filtration and the filtrate was concentrated. The concentrated dried product was recrystallized from isopropyl alcohol (IPA) to give 5'-O-benzoyl-2 ', 3'-.
Dideoxyuridine was obtained. Yield 94%. Rf value 0.7
5 (chloroform: methanol = 9: 1); 0.75 (ethyl acetate only)

(Example 7) Synthesis of 2 ', 3'-dideoxyuridine (Production method B) Crystal of 5'-O-benzoyl-2', 3'-dideoxyuridine obtained in Example 6 (0.900 kg ( 2.56 mol) is dissolved in 15 L of methanol containing 20% of ammonia and reacted in an autoclave at 60 ° C. for 1 hour. After confirming the completion of the reaction by TLC, the reaction mixture is concentrated to distill off methanol and excess ammonia. The obtained concentrate was recrystallized from acetone to obtain 0.486 kg (2.29 mol) of 2 ', 3'-dideoxyuridine. Rf value 0.44 (chloroform: methanol = 9:
1); 0.28 (ethyl acetate only). Yield 89.4%. 69% total yield from uridine.

[0047]

As described above, according to the production method of the present invention, 2 ', 3'-dideoxyuridine, 2, which is an important intermediate in the synthesis of pharmaceuticals, from the components of inexpensive ribonucleic acid is used.
', 3'-Dideoxy-2', 3'-didehydrouridine, 5'-O-
Benzoyl-2 ', 3'-dideoxyuridine, and 5'-O-
Benzoyl-2 ', 3'-dideoxy-2', 3'-didehydrouridine etc. can be easily produced in good yield without using any special reaction equipment, using only reagents that are easily available. It is an excellent production method that can be carried out economically and industrially. And, it is excellent as a method for industrially producing 2 ', 3'-dideoxyuridine, which has recently been highly demanded as an intermediate raw material for antiviral agents.

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[Procedure amendment]

[Submission date] January 8, 1992

[Procedure Amendment 1]

[Document name to be amended] Statement

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[Correction method] Change

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B) 2,2 ', anhydro-1- (5-
Synthesis of O-benzoyl-3-O-mesyl-β- _D -arabinofuranosyl) uracil In a 30 L flask equipped with a reflux tube, the 2 ', 3', 5'-tri-obtained in a) above was obtained. All of O-mesyluridine and 15 L of DMF (dimethylformamide) are added and stirred. Further, 3.17 kg of sodium benzoate is added, and the inner temperature is heated until it becomes around 110 ° C. The reaction is terminated as it is by holding for 30 minutes while stirring. T
After confirming the completion of the reaction by LC (silica gel thin layer chromatography), the reaction solution was slowly added to 200 L of water,
Slowly add dropwise with vigorous stirring to solidify the product. After the dropping is completed, the stirring is continued for 30 minutes. The solids obtained are collected by filtration and washed well with water. Furthermore, the water is removed by thoroughly displacing and washing with methanol.

[Procedure Amendment 2]

[Document name to be amended] Statement

[Name of item to be corrected] 0033

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Thus, the desired product, 2,2'-anhydro-1- (5-O-benzoyl-3-O-mesyl-, is obtained.
β- _D -arabinofuranosyl) uracil was obtained from uridine in 95%. Yield 3.88 kg (9.5 mol).
Rf value 0.50 (chloroform: methanol = 9: 1)

[Procedure 3]

[Document name to be amended] Statement

[Correction target item name] 0034

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C) Synthesis of 5'-O-benzoyl-2'-bromo-2'-deoxy-3'-O-mesyluridine In a 30 L flask equipped with a reflux tube, obtained in b) 2,
2'-anhydro-1- (5-O-benzoyl-3-O
-Mesyl-β- _D -arabinofuranosyl) uracil (3.88 kg) is added in total, ethyl acetate (26 L) and methanol (520 ml) are added, and the mixture is stirred. While stirring, heat the flask slowly and raise the temperature until the inside of the flask begins to reflux. When reflux begins, acetyl bromide 1.6k
g is slowly added dropwise while paying attention to bumping. The reaction temperature is controlled so that the inside of the flask is slightly refluxed.

Claims (21)

[Claims] 1. The general formula [II] (Wherein Ms is a methanesulfonyl group, R is an ester such as an acetyl group, a benzoyl group, etc.) and metallic zinc powder are reacted in a suitable organic solvent to synthesize a compound of the general formula [I ] (However, R represents an ester such as an acetyl group, a benzoyl group, etc.). 2. The method according to claim 1, wherein the suitable organic solvent is selected from any of the following solvents. i) Ethyl acetate ii) Methanol iii) Tetrahydrofuran iV) Dioxane V) Acetone Vi) Dimethylformamide Vii) Dimethylsulfoxide Viii) Methyl isobutyl ketone iX) Ethanol 3. The zinc metal powder is present in an amount of 50 to 200 g per mol of the compound of the formula [II].
The method described. 4. The method according to claim 1, wherein R is a benzoyl group. 5. The method according to claim 1, wherein R is an acetyl group. 6. A compound represented by the general formula [I] produced by the method according to any one of claims 1 to 5 is treated with an alkali in a suitable solvent to give a compound represented by the formula [III].
A method for producing a compound represented by: 7. The method according to claim 6, wherein the alkali is ammonia. 8. The method according to claim 6, wherein the alkali is sodium methoxide. 9. A suitable solvent is methanol.
9. The method according to any one of to 8. 10. A compound represented by the formula [III], which is produced by the method according to any one of claims 6 to 9, is dissolved in a solvent, and in the presence of a suitable metal catalyst, under a hydrogen atmosphere. A method of producing a compound represented by the formula [IV] by hydrogenating. 11. The method of claim 10 in which the suitable metal catalyst is palladium charcoal (Pd / C). 12. The solvent according to claim 10, wherein the solvent is methanol.
The method described. 13. The hydrogen pressure of the hydrogen atmosphere is 1 to 3 atm.
The method according to any one of claims 10 to 12, wherein 14. A compound represented by the general formula [I] produced by the method according to any one of claims 1 to 5,
A method for producing a compound represented by the formula [V] by dissolving in a solvent and hydrogenating in the presence of a suitable metal catalyst in a hydrogen atmosphere. (However, R represents esters such as acetyl group, benzoyl group, etc.) 15. The method of claim 14 wherein the suitable metal catalyst is palladium charcoal (Pd / C). 16. The method according to claim 14, wherein the solvent is methanol.
Method described in 15. 17. The hydrogen pressure of the hydrogen atmosphere is 1 to 3 atm.
The method according to any one of claims 14 to 16, wherein 18. A method for producing a compound represented by the formula [IV] by treating a compound represented by the formula [V] produced by the method according to claim 14 with an alkali in a suitable solvent. .. (However, R represents esters such as acetyl group, benzoyl group, etc.) 19. The method according to claim 18, wherein the alkali is ammonia.
The method described. 20. The method of claim 18, wherein the alkali is sodium methoxide. 21. A suitable solvent is methanol.
The method according to any one of 18 to 20.