KR950009857B1 - Process for preparing 5-fluorouracil derivatives - Google Patents

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Description

Method for preparing 5-fluorouracil derivative

The present invention relates to a method for preparing a 5-fluorouracil derivative useful as an anticancer component.

European Patent Application Publication No. 180,897 states that 5-fluorouracil derivatives have anticancer activity. European Patent Application Publication No. 180,188 describes a composition containing pyridine derivatives for enhancing the anticancer action of 5-fluorouracil and an anticancer compound selected from compounds capable of producing 5-fluorouracil in vivo. have.

The inventors have conducted studies on 5-fluorouracil derivatives to find several compounds that are not specifically described in the above European patent application, which compounds are described in detail in European Patent Application Publication No. 180,897, And pyridine derivatives described in European Patent Application Publication No. 180,188 and found to have significantly higher therapeutic indices than 5-fluorouracil with enhanced anticancer activity and compounds capable of producing 5-fluorouracil in vivo. .

The present invention relates to a 5-fluorouracil derivative represented by the following general formula (1),

In the above formula, R ^a is a C ₁ -C ₆ alkoxymethyl group.

The 5-fluorouracil derivatives of formula (1) have an anticancer effect, have low toxicity, and side effects such as weight loss are reduced, so the derivatives of formula (1) are very useful for treating cancer in humans and animals. It is a useful antitumor agent. The compounds of the present invention have distinct features as described below; (1) easy to absorb, (2) has a sustained effect, (3) has high stability, (4) shows little or no gastrointestinal toxicity, such as diarrhea, enema or gastrointestinal bleeding, (5) The safety margin is wide (i.e., the difference between the dose that exhibits anticancer activity and the dose that causes side effects such as toxicity) is excellent and the treatment index is excellent and very safe.

The present invention relates to an anticancer composition containing an effective amount of the 5-fluorouracil derivative of formula (1) and a pharmaceutically acceptable carrier.

The present invention also relates to a method of administering an effective amount of the 5-fluorouracil derivative of formula (1) to cancer patients for cancer treatment.

In the specification, examples of the C ₁ to C ₆ alkoxymethyl group in particular relating to the general formula (1) include methoxymethyl, ethoxymethyl, 1-propoxymethyl, isopropoxymethyl, 1-butoxymethyl, 2-part Methoxymethyl, tert-butoxymethyl, 1-pentyloxymethyl, 1-hexyloxymethyl and the like.

Among the compounds of the general formula (1), preferred are compounds in which R ^a is ethoxymethyl or methoxymethyl.

Among the compounds of the present invention, more preferred compounds to be described later in Example 1, namely 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1- Methoxymethyl-5-fluorouracil.

According to the present invention, the compound of the general formula (1) can be prepared by the method shown in the following reaction table-1 or reaction table-2.

[Reaction Chart 1]

[Step A]

[Step B]

Wherein R ^a is the same as defined above, X is a halogen atom such as fluorine, chlorine, bromine and the like, and R ^b is a hydrogen atom or a tri (lower alkyl) silyl group. Examples of lower alkyl groups in the tri (lower alkyl) silyl groups are C ₁ -C ₆ alkyl groups such as methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, pentyl, hexyl and the like.

(i) step A

According to the method shown in Reaction Table 1, when known compound (2) is reacted with known compound (3), an intermediate product (4) is produced.

The reaction is carried out in a suitable solvent in the presence of a suitable acid scavenger. Examples of useful acid scavengers include inorganic basic compounds such as sodium hydrogen carbonate, sodium carbonate, potassium carbonate and the like, and organic basic compounds such as triethylamine, N, N-dimethylaminopyridine, pyridine, and these are commonly used technically. do.

Examples of useful solvents include ethers such as dioxane and tetrahydrofuran, nitriles such as acetonitrile, aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride, pyridine, N, N -Dimethylformamide and the like, and these are organic solvents which do not adversely affect the reaction.

The amount of compound (3) relative to compound (2) is not specifically limited, but is generally at least about 1 mole, preferably about 1 to about 3 moles (amount of compound (3) per unit mole of compound (2)). ) Is used. The reaction is carried out at about −30 to about 100 ° C., the preferred temperature is from room temperature to about 100 ° C., and the reaction is completed between about 10 minutes and about 20 hours.

(ii) step B

When the intermediate (4) obtained above is reacted with known or novel compound (5), the expected compound of formula (I) according to the present invention is produced.

Depending on the kind of compound (5) to be used, in more detail, when using compound (5) in which R ^b is hydrogen, the reaction is the same as the reaction of compounds (2) and (3) in step (A). Can be performed under the following conditions.

When using compound (5) in which R ^b is a tri (lower alkyl) silyl group, an aprotic organic solvent (e.g., ethers such as diethyl ether, dioxane, tetrahydrofuran, nitriles such as acetonitrile, benzene, toluene The reaction can be carried out in the presence of a suitable solvent such as aromatic hydrocarbons such as, and halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride. It is preferable that the said solvent is used in anhydrous state.

In each case, the reaction is carried out at about -30 ° C to about 100 ° C, the preferred temperature is from room temperature to about 60 ° C, and the reaction is complete in about 1 to about 20 hours. In the reaction of the intermediate product 4 with compound 5 in which R ^b is a tri (lower alkyl) silyl group, a catalytic amount of Lewis acid such as aluminum chloride, ditin tin chloride, zinc chloride or the like may also be used.

The amount of compound (5) may be appropriately determined, and generally at least about 1 mole, preferably about 1 to about 3 moles, per mole of intermediate of formula (4) is used.

[Reaction Chart 2]

[Step A]

[Step B]

In the above formulas, R ^a and X are the same as defined in Reaction Table-1.

(i) step A

The reaction of Compound (6) and Compound (3) shown in Reaction Table 2 is carried out in the same manner as the reaction of Compound (2) and Compound (3) shown in Scheme Table 1.

(ii) step B

The reaction between the intermediate product 7 obtained above and compound (2) can also be carried out in the same manner as the reaction between compound (2) and compound (3) shown in the reaction table 1.

Compounds (2) and (3) used as starting materials in reaction schemes 1 or 2 are both known compounds that are readily available. On the other hand, compounds (5) and (6) used in reaction tables 1 or 2 include novel compounds. The above compounds can be prepared, for example, by method (a) or (b) or in combination, both methods (a) and (b) are described below.

(a) Introduction reaction of benzoyl group

The reaction to produce compound (5) or (6) having a pyridyl group substituted with a benzoyloxy group starts with the corresponding pyridine compound having a hydroxy group or a tri (lower alkyl) silyloxy group reacted with a suitable acylating agent (benzoylating agent). It is carried out using as a substance. The acylation reaction can be carried out in the same manner as the reaction of Compound (2) and Compound (3) shown in Reaction Chart 1.

(b) Introduction reaction of tri (lower alkyl) silyl group

For example, the reaction for preparing compound (5) wherein R ^b is a tri (lower alkyl) silyl group can be carried out by reacting the corresponding pyridine derivative having a hydroxy group with a silylating agent. Examples of useful silylating agents include, but are not limited to, tri (lower alkyl) halogenosilanes such as hexa (lower alkyl) disilazanes such as 1,1,1,3,3,3-hexamethyldisilazine, trimethylchlorosilane, and the like, Silylated acetamides such as N, O-bis (trimethylsilyl) acetamide and the like are included and these are commonly used technically. Silylation agents are typically used in amounts of about 1 to about 3 moles per unit mole of starting compound. When using tri (lower alkyl) halogenosilane as the silylating agent, the reaction system is more preferably about 1 to about 3 moles of amine (e.g. triethylamine, dimethylaniline, diethylaminopyridine, etc.) per mole of silylating agent or It contains pyridine. In the above cases or when silylated acetamide is used as the silylating agent, ethers such as diethyl ether, dioxane and tetrahydrofuran, nitriles such as acetonitrile, halogenated hydrocarbons such as methylene chloride and chloroform It is preferable to carry out the reaction in a suitable solvent including. When hexa (lower alkyl) disilazane is used as the silylating agent, hexa (lower alkyl) disilazane can also act as a solvent, without the need to use other solvents. The silylation reaction is carried out at a temperature between room temperature and near the boiling point of the solvent and is completed within about 1 to about 15 hours.

The final compound produced in each step and the resulting compound of the present invention can be separated from the reaction product by conventional methods and then purified. Useful separation and purification methods include reprecipitation, recrystallization, silica gel color chromatography, ion-exchange column chromatography, gel chromatography, affinity chromatography and the like.

The compounds of the present invention are commonly administered to mammals, including humans, in the form of generally acceptable pharmaceutical compositions prepared using diluents and excipients. Examples of diluents and excipients used include fillers, swelling agents, binders, disintegrants, surfactants, lubricants and the like. The dosage unit form of the pharmaceutical composition of the present invention can be changed and selected for various therapeutic purposes. Representative formulations of pharmaceutical compositions include tablets, pills, powders, solutions, suspensions, emulsions, granules, capsules, suppositories, injectables (liquids, suspensions and the like), ointments and the like. Examples of useful carriers for shaping into tablets include lactose, refined sugars, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid and other excipients; Sweet syrup, glucose solution, starch solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate, polyvinylpyrrolidone and other binders; Dry starch, sodium alginate, agar-agar powder, laminarin powder, sodium bicarbonate, calcium carbonate, fatty acid ester of polyoxyethylene sorbitan, sodium laurylsulfate, monoglyceride of stearic acid, starch, lactose and other boron release ; Refined sugars, stearin, cacao butter, hydrogenated oils and other disintegration inhibitors; Quaternary ammonium bases, sodium laurylsulfate and other absorption promoters; Glycerin, starch and other humectants; Starch, lactose, kaolin, bentonite, colloidal silicic acid and other adsorption accelerators; And refined talc powders, stearates, boric acid powders, polyethylene glycols and other glidants.

If desired, tablets may also be coated with a general coating to make coated tablets. Examples of coated tablets include sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, Or double layered, multi-layered and others.

Examples of useful carriers for molding into pills include glucose, lactose, starch, cacao butter, hydrogenated vegetable oils, kaolin, talc and other excipients; Arabian rubber powder, tragacanth rubber powder, gelatin and other binders: laminarin, agar-agar powder and other disintegrants. Examples of useful carriers for molding into suppositories include polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semisynthetic glycerides, and the like. A capsule is prepared by a conventional method. The above various kinds of carriers and the compound of the present invention are mixed to encapsulate the mixture into hard-gelatin capsules, soft-gelatin capsules and the like. In the preparation of injections, solutions, emulsions and suspensions, the preparation must be sterilized and isotonic with blood is preferred. Examples of useful diluents for preparing solutions, emulsions and suspensions include water, ethanol, macrogol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acids Esters and others. When preparing an isotonic solution, a sufficient amount of sodium chloride, glucose or glycerin may be added to make isotonic with blood. Pharmaceutical compositions for injection may also contain customary solubilizers, buffers, analgesics, and the like, as desired. The pharmaceutical compositions of the present invention may also contain colorants, preservatives, flavorings, seasonings, sweeteners and the like, as well as other pharmaceuticals, if necessary. In the preparation of pastes, creams, gels, white petrolatum, paraffin, glycerin, cellulose derivatives, polyethylene glycol, silica, bentonite, and the like can be used as the diluent.

The amount of the desired product according to the invention contained in the pharmaceutical composition as an active ingredient is not particularly limited and may be selected and used in a wide range, generally within 1 to 70% by weight.

The administration method of the above-mentioned pharmaceutical composition is not specifically limited, and may be administered by a method suitable for each dosage form, depending on the age, sex and other conditions of the patient, the condition of the patient and others. For example, tablets, pills, solutions, suspensions, emulsions, granules and capsules are administered orally; Injectables are injected intravenously, alone or in admixture with glucose solutions, amino acid solutions, and other conventional injectable fluids; And if necessary injections are given intramuscularly, intracutaneously, subcutaneously or intraperitoneally; And suppositories are administered rectally.

The dosage of the desired product of the present invention may be appropriately selected depending on the administration method, the age, sex and other conditions and symptom conditions of the patient, and generally the pharmaceutical composition of the present invention is about 0.5 mg to about 20 mg / day of body weight / day. It can divide and administer 1-4 times in the quantity of kg [calculated by the compound (active component) of this invention].

The following reference examples illustrate the preparation of starting materials used in the preparation of the compounds of the invention, and the preparation of the compounds of the invention is described by way of examples. In addition, the pharmacological tests performed on the compounds of the present invention are described below.

Reference Example, Regarding the NMR data of the Examples, the numbers written in the lower right of the symbol “C” are related to the position in the compound. Thus, for example, the indication “C ₆ -H” indicates that hydrogen is bonded to a 6-position carbon atom.

Reference Example 1

Preparation of 6-benzoyloxy-3-cyano-2-hydroxypyridine

To a solution of 1.00 g of 3-cyano-2,6-dihydroxypyridine in 40 ml of N, N-dimethylacetamide, 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride are added. The mixture is stirred at room temperature for 15 minutes. 0.51 ml of triethylamine and 0.43 ml of benzoyl chloride are added to the reaction solution. The mixture is stirred at room temperature for 15 minutes. The reaction mixture is filtered and the filtrate is concentrated under reduced pressure. Washing the residue with chloroform and water gave 1.06 g (yield: 60%) of the title compound.

¹ H-NMR (DMSO-d ₆ ) δ (ppm): 12.76 (1H, bs, OH or NH), 8.33 (1H, d, J = 8Hz, C ₄ -H of pyridine ring),

6.95 (1H, d, J = 8 Hz, C ₅ -H of pyridine ring)

Reference Example 2

Preparation of 6-benzoyloxy-3-cyano-trimethylsilyloxypyridine

A volume of 20 ml of 1,1,1,3,3,3-hexamethyldisilazane was added to 2.0 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine and the mixed solution was stirred at 140 ° C. for 20 minutes. do. Concentration of the reaction mixture under reduced pressure yields the title compound in quantitative quantities.

¹ H-NMR (CDCl ₃ ) δ (ppm):

6.85 (1H, d, J = 8 Hz, C ₅ -H), 0.40 (9H, s, CH ₃ × 3)

Example 1

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil

To a solution of 1.17 g of 1- (ethoxymethyl) -5-fluorouracil in 50 ml of anhydrous dioxane, 5.53 ml of triethylamine and 1.52 g of isophthaloyl chloride are added. The mixture is refluxed for 1 hour.

The reaction mixture is filtered and the filtrate is concentrated to dissolve the residue in 50 ml of acetonitrile. To the solution is added 3.46 ml of triethylamine and 2.10 g of 6-benzoyloxy-3-cyano-2-hydroxypyridine. The mixture is stirred at room temperature for 2 hours. The reaction mixture was concentrated by filtration, and the residue was purified by silica gel column chromatography using chloroform as eluent to give 860 mg (yield: 25%) of the title compound.

Melting Point: 162 ~ 164 ℃

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.15 (2H, s, N-CH ₂ ), 3.62 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 1.22 (3H, t, J = 7 Hz, -CH ₃ )

Example 2

Preparation of 3- [4- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil

The title compound is prepared by the general method of Example 1.

Yield: 24%

Form: Powder

¹ H-NMR (CDCl ₃ ) δ (ppm):

5.14 (2H, s, N-CH ₂ ), 3.61 (2H, q, J = 7 Hz, -CH ₂ CH ₃ ), 1.22 (3H, t, J = 7 Hz, CH ₃ )

Example 3

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -5-fluoro-1- (methoxymethyl) uracil

The title compound is prepared by the general method of Example 1.

Yield: 26%

Form: Powder

¹ H-NMR (DMSO-d ₆ ) δ (ppm):

Example 4

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil

To a solution of 1.07 g of 1-ethoxymethyl-5-fluorouracil in 40 ml of dioxane, 1.39 g of isophthaloyl chloride and 3.15 ml of triethylamine are added. The mixture is stirred at 80 ° C. for 30 minutes. The reaction mixture is filtered and concentrated.

30 ml of acetonitrile and 2.60 g of 6-benzoyloxy-3-cyano-2-trimethylsilyloxypyridine are added to the residue, and the mixture is stirred at room temperature overnight.

The reaction mixture was again filtered and concentrated, and the residue was placed on a silica gel column and eluted with ethyl acetate-methylene chloride to afford 0.43 g of the title compound (compound of Example 1).

Example 5

Preparation of 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5-fluorouracil

To a solution of 1.53 g of 6-benzoyloxy-2-cyano-2-hydroxypyridine in 30 ml of dioxane is added 1.30 g of isophthaloyl chloride and 2.68 ml of triethylamine. The mixture is stirred at room temperature for 3 hours. Concentration of the filtrate by filtration of insoluble material affords an intermediate, ie 3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl chloride.

The intermediate product is dissolved in 30 ml of dioxane. 1.00 g of 1-ethoxymethyl-5-fluorouracil and 2.68 ml of triethylamine are added to the solution, and the mixed solution is stirred at 60 ° C for 1 hour. The insoluble material is filtered off and the filtrate is concentrated. The residue was placed on a silica gel column and eluted with dichloromethane to afford the desired 3- [3- (6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl) benzoyl] -1-ethoxymethyl-5. 0.62 g (yield: 21%) of -fluorouracil (compound of Example 1) were obtained.

Pharmacological Test 1

Umbilical cord sarcoma-180 cultured in ascites of ICR mice was diluted with physiological saline and transplanted into 2 × 10 ⁷ cells in subcutaneous tissue of the back of ICR mice. 24 hours after implantation, a suspension of test compound is orally administered to each new rat once a day for 7 days. A suspension of the test compound is prepared by uniformly mixing the test compound with polyvinyl pyrrolidone by coprecipitation and suspending the mixture in 5% gum arabic.

To determine the weight of the tumor, solid tumors are removed under the eastern skin of the rats on day 10 post-transplant. The ratio (T / C) of the weight (T) of tumors extracted from the rat group treated with the test compound and the weight (C) of the tumors extracted from the rat control group not treated with the test compound is determined. Dose-dose response curves and ratios (T / C) determine the 50% tumor suppression (ED ₅₀ value) with a T / C of 0.5.

The results shown in Table 1 below compare the anticancer compositions containing 5-fluoro-1- (2-tetrahydrofuranyl) uracil and uracil in a ratio (molar ratio of 1: 4) in the group of young rats by the same method. The results obtained by administration with the drug are also described.

TABLE 1

Pharmacological Test 2

Yoshida sarcoma cultured in the ascites of rats (Donryu spp.) Is diluted with physiological saline and transplanted into the subepithelial tissues of Donryu mice in an amount of 1 × 10 ⁴ cells, respectively. 24 hours after transplantation, the test compound suspension is orally administered to each rat once daily for 7 days. A suspension of test compounds is prepared by uniformly mixing the test compound with polyvinyl pyrrolidone by coprecipitation and suspending the mixture in 5% gum arabic.

To determine the weight of the tumor, solid tumors are removed under the eastern skin of rats on day 10 post-transplant. The ratio (T / C) of the weight (T) of tumors extracted from a control group of mice not treated with a test compound is determined from the weight (T) of tumors extracted from a group of mice treated with a test compound. From the dose-administration response vacancy and ratio (T / C), a 50% tumor suppression amount (ED ₅₀ value) with a T / C of 0.5 is determined.

During the above test, a dose (single dose, mg / kg), which is effective for inhibiting the weight gain of the rats treated with the test compound by 10%, was also determined, compared to the weight gain of the rats not treated with the test compound. do. Subsequent doses refer to “10% weight inhibition”.

The treatment index is calculated from the ED ₅₀ value and the 10% weight inhibition, according to the following formula:

The results shown in Table 2 below also describe the results obtained by administering the following Comparative Drugs A-E (described below) administered in place of the compounds of the present invention.

Table 2 shows the comparative efficacy of each test drug and is expressed as the ratio of the treatment index of each test drug to the treatment index of comparative drug C (denoted by 1).

(1) Comparative Drug A

3- {3- [6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl] benzoyl} -1- [2- (tetrahydrofuranyl)]-5-fluorouracil

(2) Comparative Drug B

3- {3- [5-chloro-4-benzoyloxy-2-pyridyloxycarbonyl] benzoyl} -2'-deoxy-3'-O-benzyl-5-fluorouradine

(3) Comparative Drug C

3- {3- [6-benzoyloxy-3-cyano-2-pyridyloxycarbonyl] benzoyl} -2'-deoxy-3'-O-benzyl-5-fluorouridine

(4) Comparative Drug D

3- {3- [4-benzoyloxy-5-chloro-2-pyridyloxycarbonyl] benzoyl} -5-fluoro-1-ethoxymethyluracil

(5) Comparative Drug E

Combination of 1-ethoxymethyl-5-fluorouracil and 3-cyano-2,6-dihydroxypyridine

TABLE 2

As shown in Table 2, the compound of the present invention has a significantly higher therapeutic index than the comparative drugs A ~ E.

Pharmacological Test 3

Comparative Drug C used in Pharmacological Test 2 or the compound of Example 1 (25 mg / kg each) is orally administered to each normal rat. Blood is drawn from rats at regular intervals. The concentration of the test compound in blood was indexed (as a metabolite of rats treated with Comparative Drug C, rats treated with 3′-O-benzyl-2′-deoxy-5-fluorouridine and the compound of Example 1). As a metabolite of 1-ethoxymethyl-5-fluorouracil, the concentration of the metabolite in blood is measured and recorded, and the highest blood concentration is determined. The results are shown in Table 3 below.

TABLE 3

In the compound of Example 1, it can be seen from Table 3 that 5 times the amount absorbed by the comparative drug C is absorbed.

The formulation examples according to the present invention are described below.

[Example 1]

25 mg of the compound of Example 1

Starch 112mg

Magnesium Stearate 18mg

Lactose 45mg

200 mg total

Tablets each having the above composition are prepared by conventional methods.

[Example 2]

10 mg of the compound of Example 2

Starch 125mg

Magnesium Stearate 20mg

Lactose 45mg

200 mg total

Tablets each having the above composition are prepared by conventional methods.

Claims (2)

The compound represented by the following general formula (2) is reacted with the compound represented by the following general formula (3) in an organic solvent in the presence of an acid scavenger to obtain an intermediate product represented by the following general formula (4) A process for producing the 5-fluorouracil derivative represented by the following general formula (1), wherein the intermediate product of (4) is reacted with a compound represented by the following general formula (5) in an organic solvent.

[Wherein R ^a is an alkoxymethyl group having 1 to 6 carbon atoms, R ^b is a hydrogen atom or a tri (lower alkyl) silyl group, and X is a halogen atom]. The compound represented by the following general formula (6) is reacted with the compound represented by the following general formula (3) in an organic solvent in the presence of an acid scavenger to obtain an intermediate product represented by the following general formula (7). Of a 5-fluorouracil derivative represented by the following general formula (1), characterized in that the intermediate product of the general formula (7) is reacted with a compound represented by the following general formula (2) in an organic solvent in the presence of an acid scavenger: Method of manufacture:

[Wherein R ^a is an alkoxymethyl group having 1 to 6 carbon atoms, R ^b is a hydrogen atom or a tri (lower alkyl) silyl group, and X is a halogen atom.]