JPH10287678A - Pyranoazine derivatives - Google Patents

Abstract

(57) [Problem] To provide a novel pyranoazine derivative having antibacterial activity, antiestrogenic activity and antitumor activity. SOLUTION: The formula (I) (Wherein, R ¹ represents hydrogen, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkanoyl, lower alkoxycarbonyl, lower alkanoyloxy, NR ² R ³ , nitro or halogen; W, X, One of Y and Z represents N, and the other represents the same or different and represents N or CR ⁴ ) or a pharmacologically acceptable salt thereof.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a pyranoazine derivative having antibacterial activity, antiestrogenic activity and antitumor activity.

[0002]

2. Description of the Related Art As 2-phenylpyranoazine derivatives, for example, 2-phenyl-4H-pyrano [3,2-b]
Pyridin-4-one derivatives (Boll. Chim. Fa
rm. Chem., 130, 312, 1991;
Pharm. Bull. , 25, 1150, 197
7 years), 2-phenyl-4H-pyrano [3,2-c] pyridin-4-one derivative (J. Heterocyclic)
c Chem. 16, Vol. 939, 1979; Bu
ll. Soc. Chim. Fr. , 4, 1435,
1972), 2-phenyl-4H-pyrano [2,3-
b] Pyridin-4-one derivative (J. Org. Che
m. 35, 3596, 1970; Bull. C
him. Soc. Fr. , 2, 631, 1970
Year; Chem. Soc. (C), p. 1836, 19
67)), 2-phenyl-4H-pyrano [2,3-d]
Pyrimidin-4-one derivatives (Youji Huaxu
e, 8, 250, 1988).
However, a compound having a fluorine at the 3′-position of the phenyl group and a compound having an amino group at the 4′-position of the phenyl group are not known.

[0003]

SUMMARY OF THE INVENTION An object of the present invention is to provide a novel pyranoazine derivative having antibacterial activity, antiestrogenic activity and antitumor activity.

[0004]

According to the present invention, there is provided a compound of the formula (I)

[0005]

Embedded image

In the formula, R ¹ is hydrogen, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkanoyl, lower alkoxycarbonyl,
Lower alkanoyloxy, in NR ² R ³ (wherein, R ² and R ³ represents hydrogen, lower alkyl or lower alkanoyl substituted or unsubstituted identical or different, R ²
And R ³ together represent a heterocyclic group formed through a substituted or unsubstituted N), nitro or halogen, and one of W, X, Y and Z represents N; The others are the same or different and are N or CR ⁴ wherein R ⁴ is hydrogen,
A substituted or unsubstituted lower alkyl, hydroxy, during lower alkoxy, NR ⁵ R ⁶ (wherein R ⁵ and R ⁶ represents hydrogen, lower alkyl or lower alkanoyl substituted or unsubstituted same or different, and R ⁵ R ⁶ represents a heterocyclic group formed by substituting a substituted or unsubstituted N), nitro or halogen]] or a pharmaceutically acceptable salt thereof. About.

[0007]

BEST MODE FOR CARRYING OUT THE INVENTION In the definition of each group of the formula (I),
The lower alkyl moiety in the lower alkyl and the lower alkoxy and the lower alkoxycarbonyl includes a straight-chain or branched C1-C6 alkyl group such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl and sec-.
Butyl, tert-butyl, pentyl, hexyl and the like. The lower alkanoyl moiety in lower alkanoyl and lower alkanoyloxy includes a carbon atom of 1
To 7, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, hexanoyl, heptanoyl and the like. Examples of the heterocyclic group formed by sandwiching N include pyrrolidinyl, piperidino, piperazinyl, homopiperazinyl, morpholino, and thiomorpholino. Halogen means each atom of fluorine, chlorine, bromine and iodine.

The substituent in the substituted lower alkyl may be the same or different and has 1 to 3 substituents, for example, hydroxy, lower alkoxy, carboxy, lower alkanoyl, lower alkoxycarbonyl, lower alkanoyloxy, NR ⁷ R ⁸ (wherein R ⁷ and R ⁸ may be the same or different and represent hydrogen, lower alkyl or lower alkanoyl, or R ⁷ and R ⁸ together represent a heterocyclic group formed across N), halogen, vinyl, etc. Is mentioned. In the definition of the substituent, the lower alkoxy, the lower alkanoyl, the lower alkoxycarbonyl, the lower alkanoyloxy, the lower alkyl, the halogen and the heterocyclic group formed by sandwiching N are as defined above.

Substituents in the substituted heterocyclic group formed across N may be the same or different and have 1 to 3 substituents.
For example, the substituent and lower alkyl in the above-mentioned substituted lower alkyl can be mentioned, and the lower alkyl is as defined above. As the pharmacologically acceptable salt of compound (I),
Pharmacologically acceptable acid or base addition salts,
For example, inorganic acid salts such as hydrochloride, hydrobromide, sulfate, and phosphate, or methanesulfonate, oxalate, acetate, malonate, succinate, fumarate, and maleate And organic acid salts such as tartrate and citrate; and base addition salts such as sodium and potassium salts.

Next, a method for producing the compound (I) will be described. In the production method shown below, if the defined group changes under the conditions of the method of execution or is inappropriate to carry out the method, a method commonly used in organic synthetic chemistry,
For example, it can be easily carried out by applying means such as protection and deprotection of a functional group.

Production method 1 Compound (I) can be produced according to the following reaction steps.

[0012]

Embedded image

(Wherein R ⁹ represents lower alkyl, R ¹⁰
Represents a protecting group for hydrogen or a hydroxyl group, and R ¹ ,
W, X, Y and Z are as defined above. In the definition of R ⁹ , lower alkyl is as defined above for lower alkyl. Examples of the hydroxyl-protecting group in the definition of R ¹⁰ include those generally used as a phenol-protecting group.Examples thereof include tetrahydropyranyl, methoxymethyl, and lower alkyl. It is synonymous.

Step (1) The compound (IV) is prepared by subjecting the compound (II) obtained according to the method described in Reference Example 1 or the equivalent thereof to 1 equivalent to an excess amount of the compound (III) in the presence of 1 to 5 equivalents of a base. Below, it can be obtained by condensation in an inert solvent. As the base, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium tert
-Butoxide and the like, and as the inert solvent, tetrahydrofuran, dioxane, ethers such as dimethoxyethane, methanol, alcohols such as ethanol,
Benzene, toluene, dimethylformamide and the like are used alone or in combination. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably at a temperature between room temperature and 100 ° C., and is complete in 1 to 24 hours.

Step (2) Compound (I) can be obtained by cyclizing compound (IV) by treating it with an acid, if necessary, in a suitable solvent. Examples of the acid include hydrochloric acid, sulfuric acid, formic acid, acetic acid, and trifluoroacetic acid, and examples of the solvent include methanol, ethanol, and dioxane. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used and is completed in 1 to 12 hours.

Production Method 2 Compound (IV) can also be produced according to the following reaction steps.

[0017]

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(In the formula, R ¹¹ represents hydrogen or lower alkyl, and R ¹ , R ¹⁰ , W, X, Y and Z have the same meanings as described above.) In the definition of R ¹¹ , lower alkyl is the same as the above lower alkyl. It is synonymous.

Step (3) When R ¹⁰ and R ¹¹ are hydrogen, compound (VII) can be obtained by compound (V) obtained by the method described in Reference Example 2 or a method described in Reference Example 5 or by a method described in Reference Example 5 The compound (VI) or a reactive derivative thereof obtained can be obtained by condensing in an inert solvent in the presence of an appropriate condensing agent and 1 to 5 equivalents of a base, if necessary. Examples of the condensing agent include 2-chloro-N-methylpyridinium salt, dicyclohexylcarbodiimide and derivatives thereof, and carbonyldiimidazole. Examples of the base include triethylamine, 4-dimethylaminopyridine, sodium hydride, potassium hydride, and sodium hydride. Methoxide, sodium ethoxide, potassium tert
-Butoxide and the like. Examples of the reactive derivative of the compound (VI) include an acid halide and 4-nitrophenyl ester. As the inert solvent, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, alcohols such as methanol and ethanol, benzene, toluene, dimethylformamide, dichloromethane and the like are used alone or in combination. The reaction is 0 ° C ~
Temperature between the boiling points of the solvents used, preferably between room temperature and 100
Performed at a temperature between ° C and completed in 1-24 hours. In addition,
In this reaction, compound (IV) may be obtained in some cases.

When R ¹¹ is lower alkyl, compound (IV)
Can be obtained in the same manner as in the above step (1) from the compound (V) obtained according to the method described in Reference Example 2 or the compound (V) obtained according to the method described in Reference Example 5 or the compound (VI) obtained according to the method described in Reference Example 5. it can.

Step (4) Compound (IV) can be obtained by treating compound (VII) with a base in an inert solvent. As the base, sodium hydride, potassium hydride, sodium methoxide, sodium ethoxide, potassium tert
-Butoxide, lithium diisopropylamide and the like, and examples of the inert solvent include ethers such as tetrahydrofuran, dioxane and dimethoxyethane, dimethylsulfoxide, dimethylformamide, benzene and toluene. The reaction is carried out at a temperature between 0 ° C. and the boiling point of the solvent used, preferably at a temperature between room temperature and 100 ° C., and is complete in 1 to 24 hours.

Production Method 3 Compound (I) can also be produced according to the following reaction steps.

[0023]

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Wherein R ¹² is R ¹³ R ¹⁴ R ¹⁵ Si (CH ₂
CH ₂ ) _n (wherein R ¹³ , R ¹⁴ and R ¹⁵ are the same or different and represent lower alkyl or phenyl, and n represents 0 or 1), M represents an alkali metal,
R ¹ , W, X, Y and Z are the same as defined above.] In the definition of R ¹³ , R ¹⁴ and R ¹⁵ , lower alkyl has the same meaning as the above lower alkyl. Examples of the alkali metal in the definition of M include lithium, sodium, potassium, and the like.

Step (5) Compound (X) can be obtained by reacting compound (VIII) and compound (IX) obtained in the same manner as described in Reference Example 3 or an analogous method in an inert solvent. . Compound (IX) can be obtained by reacting the acetylene or dibromoethene derivative obtained according to the method described in Reference Example 4 or a derivative thereof with n-
It is prepared in a reaction system by reacting an alkyl lithium such as butyl lithium. As the inert solvent, ethers such as tetrahydrofuran, dioxane and dimethoxyethane, benzene, toluene, hexane and the like are used. The reaction is carried out at a temperature between -78 and 0 ° C and is completed in 0.5 to 12 hours.

Step (6) Compound (XI) can be obtained by treating compound (X) with an oxidizing agent in an inert solvent. Examples of the oxidizing agent include manganese dioxide, pyridine chromate, and Jones reagent, and examples of the inert solvent include dichloromethane, benzene, toluene, and acetone.
The reaction is carried out at a temperature between -78 ° C and the boiling point of the solvent used, preferably at a temperature between 0 ° C and room temperature, and is complete in 0.1 to 12 hours.

Step (7) Compound (I) can be obtained by converting compound (XI) into a compound (J. Org.
Chem. 59, p. 4360, 1994), by the action of potassium fluoride or the like (fluoride ion) in a solvent such as dimethylformamide in the presence of a crown ether such as 18-crown-6. It can be obtained by cyclization following silylation.

A part of the compound (I) obtained here can be used as a synthetic intermediate to further lead to a new derivative (I). For example, compound (Ia) in which R ¹ is amino in compound (I) can be obtained by treating compound (Ib) in which R ¹ is pivaloylamino with an acid, if necessary, in an inert solvent. As the acid,
Examples of the solvent include hydrochloric acid, hydrobromic acid, sulfuric acid, and trifluoroacetic acid. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and acetic acid. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used, preferably between 50 and 100 ° C., and is complete in 0.5 to 12 hours.

In the compound (I), W, X, Y or Z
Is C-NH ₂ , the corresponding W,
Compound (Id) wherein X, Y or Z is C-NHCOC (CH ₃ ) ₃ is treated in the same manner as described above, or compound (Ie) wherein W, X, Y or Z is C-OCH ₃ ) And excess ammonia in an inert solvent. Examples of the inert solvent include alcohols such as methanol and ethanol, ethers such as dioxane and tetrahydrofuran, and dimethylformamide. Ammonia may be used by dissolving a gas or may be used as aqueous ammonia. The reaction is carried out at a temperature between room temperature and the boiling point of the solvent used and is completed in 1 to 12 hours.

The intermediates and target compounds in each of the above production methods are isolated by purification methods commonly used in synthetic organic chemistry, for example, filtration, extraction, washing, drying, concentration, recrystallization, various types of chromatography, and the like. It can be purified. Also,
The intermediate can be subjected to the next reaction without purification. When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is, or if compound (I) is obtained in a free form,
The compound may be dissolved or suspended in a suitable solvent by a usual method, and a desired acid or base may be added to form a salt, followed by isolation and purification.

The compound (I) and a pharmaceutically acceptable salt thereof may exist in the form of adducts with water or various solvents, and these adducts are also included in the present invention.
Table 1 shows specific examples of the compound (I) obtained by the present invention.

[0032]

[Table 1]

The compound (I) of the present invention has an antiestrogenic activity. This is shown by the effect of administration of compound (I) to adult mice to reduce uterine weight. Compound (I) also suppresses the growth of human breast cancer cells in a medium in a microplate, and further suppresses the growth of human breast tumors transplanted into nude mice. Compounds having such biological activity are effective in treating the same conditions in which tamoxifen, a typical antiestrogen, is effective, for example, in treating breast tumors, nonovulatory infertility or irregular menstruation.

The compound (I) of the present invention has an antibacterial activity. Next, the activity of the representative compound (I) will be specifically shown by experimental examples. Experimental Example 1 Effect on uterine weight of mature mice Mature female BALB / c mice aged 7 to 9 weeks were divided into two groups.
The test compound was repeatedly orally administered to one group of 6 animals for 4 days. Five days later, the uterus was removed and weighed. Table 2 shows the results.

[0035]

[Table 2]

Experimental Example 2 Growth Inhibition Test of Human Breast Cancer Cells (MCF-7) In each well of a 96-well microtiter plate, RPMI1640 medium was added.
10% fetal bovine serum, 10 ^-8M estradiol (Sigma
100 units / ml penicillin and 100 μg / ml
Medium supplemented with streptomycin (hereinafter referred to as medium B)
U) at 5 × 10^Four0.1 ml of MCF-7 cells
Was dispensed. Place the plate in a carbon dioxide incubator
After culturing at 37 ° C for 20 hours, the sample was appropriately diluted with Medium B.
(Test compound) was added in an amount of 0.05 ml each, and
The cells were cultured at 37 ° C for 72 hours in a thermometer. After removing the culture supernatant,
Medium B containing 0.02% neutral red added to the residue was added to 0.1%.
Add 1 ml each, and incubate at 37 ° C for 1 hour
And stained the cells. After removing the culture supernatant, the residue
Was washed once with physiological saline. Then, 0.001N hydrochloric acid
After extracting the dye with 30% ethanol,
The absorbance at 550 nm was measured by a reader. With untreated cells
Comparing absorbance of cells treated with known concentrations of analyte
The concentration of the sample that inhibits cell growth by 50% (IC₅₀)
Was calculated. Table 3 shows the results.

[0037]

[Table 3]

Experimental Example 3 Antitumor Effect on Estrogen-Dependent Human Breast Cancer MCF-7 Tumor pieces (2 mm square) of human hormone-dependent breast cancer MCF-7 were prepared by
9-week-old female BALB / c-nu / nu mice (CLEA Japan) were implanted subcutaneously on the ventral side. In order to promote tumor growth, 12.5 μg of estradiol propionate was administered intramuscularly twice on the day of transplantation and twice a week after transplantation. Three to four weeks after the transplantation, mice whose tumor volume reached 25 to 200 mm ³ were selected, and five mice were treated with the test compound for 5 days per week for 2 days.
Oral administration was repeated weekly. On the day of administration, estradiol propionate was additionally administered again. The major axis and minor axis of the tumor were measured over time, and the tumor volume was calculated as the approximate value of an ellipsoid by the following formula.

[0039]

(Equation 1)

After measuring the tumor volume (V ₀ ) at the start of administration, the tumor volume (V) was measured daily to calculate V / V ₀ , and the V / V of the control group was calculated.
It was determined the ratio of V / V ₀ values of drug administration group relative to V ₀ value (T / C). Table 4 shows the results.

[0041]

[Table 4]

Experimental Example 4 Antibacterial Activity Antibacterial activity of compound (I) against Bacillus subtilis # 10107 [minimum inhibitory concentration (MIC; μg / m
l)] is shown in Table 5. The minimum growth inhibitory concentration was measured at pH 7.0 by the agar dilution method.

[0043]

[Table 5]

Examples and reference examples are shown below. The physicochemical data of each compound in the following Examples and Reference Examples were measured by the following instruments.

[0045]

【Example】

Example 1 (Compound 1) Under an argon atmosphere, 60% sodium hydride (1.50 g, 3
7.5 mmol) in dioxane-toluene mixed solvent (1: 1, 10 m
L), and heated under reflux with ethyl 3-methoxymethoxy-2-pyridinecarboxylate (3.80 g, 18.0 mmol) obtained in Reference Example 1-1 and 3′-fluoro-
4'-pivaloylaminoacetophenone (JP-A-5-5
No. 86962) (3.56 g, 15.0 mmol) of the above mixed solvent solution (70 mL) was added dropwise over 10 minutes. After further heating and refluxing for 50 minutes, the reaction solution was ice-cooled, water was added, and the mixture was washed with hexane. A 10% aqueous citric acid solution was added to the aqueous layer, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. Residue in ethanol (80
Dissolved in water, added hydrochloric acid (20 mL) and stirred at room temperature for 16 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain Compound 1 (3.29 g, 64% over two steps).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.37
(s, 9H), 6.94 (s, 1H), 7.5-8.1 (m, 5H), 8.61 (t, J
= 8.5 Hz, 1H), 8.84 (br, 1H) EIMS (m / z) 340 (M ⁺ ) Molecular formula C ₁₉ H ₁₇ FN ₂ O ₃ = 340

Example 2 (Compound 2) To compound 1 (2.27 g, 6.68 mmol) was added sulfuric acid (20 mL).
The mixture was stirred at 50 ° C for 7 minutes. The reaction solution was poured into ice water, made alkaline with a 10 N aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. Purification by silica gel column chromatography (chloroform: methanol = 40: 1 to 20: 1) and recrystallization from methanol gave Compound 2 (1.02 g,
60%).

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.90
(t, J = 8.9 Hz, 1H), 7.02 (s, 1H), 7.72 (dd, J =
8.4, 2.0 Hz, 1H), 7.83 (dd, J = 12.9, 2.0 Hz, 1H),
7.86 (dd, J = 8.4, 4.5 Hz, 1H), 8.32 (dd, J = 8.4,
1.5 Hz, 1H), 8.77 (dd, J = 4.5, 1.5 Hz, 1H) EIMS (m / z) 256 (M ⁺ ) Molecular formula C ₁₄ H ₉ FN ₂ O ₃ = 256

Example 3 (Compound 3) Under argon atmosphere, 60% sodium hydride (1.86 g, 4
6.5 mmol) was suspended in dioxane (20 mL) and heated under reflux.
3-acetyl-4-methoxypyridine (2.34 g, 15.5 mmol) obtained in Reference Example 2-1 and methyl 3-fluoro-4-pivaloylaminobenzoate (5.88 g, 23.3 mmol) obtained in Reference Example 5 Dioxane solution (60 mL)
It was added dropwise over 7 minutes. After heating under reflux for an additional 40 minutes, the reaction solution was ice-cooled, water was added, and the mixture was washed with ether. 10 for water layer
% Citric acid aqueous solution was added, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1),
3-[(3-fluoro-4-pivaloylaminobenzoyl) acetyl] -4-methoxypyridine (1.70 g, 30%)
I got

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.35
(s, 9H), 4.05 (s, 3H), 6.86 (d, J = 9.2 Hz, 1H), 6.
98 (s, 1H), 7.5-7.8 (m, 3H), 8.4-8.6 (m, 2H), 9.01
(s, 1H) FABMS (m / z) 373 (M + H ⁺ ) molecular formula C ₂₀ H ₂₁ FN ₂ O ₄ = 372

To the above compound (1.70 g, 4.57 mmol) was added sulfuric acid.
(20 mL) and stirred at 100 ° C. for 1.3 hours. The reaction solution was poured into ice water, the pH was adjusted to 9 with a 10 N aqueous sodium hydroxide solution, and the precipitated crystals were collected by filtration. Trituration with chloroform gave compound 3 (278 mg, 24%).

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.17
(br, 2H), 6.88 (t, J = 8.9 Hz, 1H), 6.95 (s, 1H),
7.71 (d, J = 9.9 Hz, 1H), 7.75 (d, J = 5.9 Hz, 1
H), 7.82 (d, J = 13.4 Hz, 1H), 8.82 (d, J = 4.4 H
z, 1H), 9.15 (s, 1H) EIMS (m / z) 256 (M ⁺ ) Molecular formula C ₁₄ H ₉ FN ₂ O ₃ = 256

Example 4 (Compound 4) Under an argon atmosphere, 60% sodium hydride (356 mg, 8.
89 mmol) was dissolved in dimethylformamide (15 mL), and ethyl 3-methoxymethoxy-4-pyridinecarboxylate (897 mg, 4.25 mg) obtained in Reference Example 1-2 was obtained under ice cooling.
mmol) and 3′-fluoro-4′-pivaloylaminoacetophenone (916 mg, 3.87 mmol) in dimethylformamide (23 mL) were added dropwise over 10 minutes. The temperature was raised to room temperature and stirred for 5 hours. The reaction solution was ice-cooled, water was added, and the mixture was washed with n-hexane. Add 10% citric acid aqueous solution to the aqueous layer,
The mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. Dissolve the residue in ethanol (16 mL), add hydrochloric acid (4 mL), and add
Stirred for 16 hours. Water was added to the reaction solution, and the precipitated crystals were collected by filtration to obtain Compound 4 (1.12 g, 49% in two steps).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.37
(s, 9H), 6.84 (s, 1H), 7.7-7.8 (m, 3H), 8.06 (br, 1
H), 8.6-8.7 (m, 2H), 9.12 (s, 1H) FABMS (m / z) 341 (M + H ⁺ ) Molecular formula C ₁₉ H ₁₇ FN ₂ O ₃ = 340

Example 5 (Compound 5) Compound 4 (1.12 g, 3.31 mmol) was treated with sulfuric acid in the same manner as in Example 2 and recrystallized from methanol.
Compound 5 (656 mg, 77%) was obtained.

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.89
(t, J = 8.9 Hz, 1H), 6.95 (s, 1H), 7.7-7.8 (m, 2
H), 7.75-7.85 (m, 1H), 8.63 (d, J = 5.0Hz, 1H), 9.
18 (s, 1H) FABMS (m / z) 257 (M + H ⁺ ) Molecular formula C ₁₄ H ₉ FN ₂ O ₂ = 256

Example 6 (Compound 6) 3-Fluoro-4-pivaloylaminobenzoic acid (364 mg, 1.52 mmol) obtained in Reference Example 5 was dissolved in dichloromethane, and thionyl chloride (0.183 mL, 2.5 mmol) was added. 2.
The mixture was refluxed for 5 hours. After unreacted thionyl chloride was distilled off under reduced pressure, the residue was dissolved in dichloromethane (10 mL), and the mixture was cooled under ice-cooling to obtain 4-acetyl-3-hydroxy-5-pivaloylaminopyridine obtained in Reference Example 2-2. (359 mg, 1.67 m
mol) and triethylamine (0.3 mL) were added, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give 3- (4-acetyl-5-pivaloylamino) pyridinyl 3-fluoro-
4-Pivaloylaminobenzoate (697 mg, 99%) was obtained.

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.33
(s, 9H), 1.37 (s, 9H), 2.52 (s, 3H), 7.8-8.1 (m, 3
H), 8.34 (s, 1H), 8.66 (t, J = 8.5 Hz, 1H), 9.66
(s, 1H), 10.00 (s, 1H)

Under an argon atmosphere, potassium tert-
Butoxide (682 mg, 6.08 mmol) in tetrahydrofuran
(20 mL) and the above compound (697 mg, 1.52
mmol) in tetrahydrofuran (10 mL) was added dropwise over 5 minutes. After 30 minutes, a saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure.
Dissolve the residue in acetic acid (10 mL), add sulfuric acid (0.5 mL),
The mixture was heated under reflux for 2 hours. After acetic acid was distilled off under reduced pressure, the mixture was neutralized with a 2 N aqueous sodium hydroxide solution and extracted with chloroform.
The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain Compound 6 (676 mg, 99%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.37
(s, 9H), 1.40 (s, 9H), 6.76 (s, 1H), 7.68-7.75 (m,
2H), 7.84 (d, J = 4.5 Hz, 1H), 8.65 (t, J = 8.4 H
z, 1H), 8.80 (br, 1H, NH), 9.95 (s, 1H), 12.24 (br,
1H) EIMS (m / z) 439 (M ⁺ ) Molecular formula C ₂₄ H ₂₆ FN ₃ O ₄ = 439

Example 7 (Compound 7) Compound 6 (676 mg, 42%) was treated with sulfuric acid in the same manner as in Example 2 and triturated with chloroform to give Compound 7 (176 mg, 42%). I got

¹ H NMR (90 MHz, DMSO-d ₆ ) δ (ppm) 6.08
(br, 2H), 6.72 (s, 1H), 6.86 (t, J = 8.9 Hz, 1H),
7.31 (br, 2H), 7.64 (dd, J = 8.4, 2.0 Hz, 1H), 7.7
4 (dd, J = 12.9, 2.0 Hz, 1H), 7.93 (s, 1H), 8.07
(s, 1H) FABMS (m / z) 272 (M + H ⁺ ) Molecular formula C ₁₄ H ₁₀ FN ₃ O ₂ = 271

Example 8 (Compound 8) Ethyl 3-methoxymethoxy-4-pyridinecarboxylate obtained in Reference Example 1-2 (200 mg, 0.947 mmo)
l) and 3'-fluoroacetophenone (131 mg, 0.94
Compound 8 (62 mmol) in the same manner as in Example 4 using 7 mmol).
mg, 2 steps 27%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 6.89
(s, 1H), 7.31 (dd, J = 8.9, 2.5 Hz, 1H), 7.55 (td,
J = 8.9, 5.9 Hz, 1H), 7.66 (dd, J = 10.4, 2.5 Hz,
1H), 7.74 (d, J = 8.9 Hz, 1H), 8.02 (d, J = 5.0 H
z, 1H), 8.69 (d, J = 5.0 Hz, 1H), 9.11 (s, 1H) FABMS (m / z) 242 (M + H ⁺ ) Molecular formula C ₁₄ H ₈ FNO ₂ = 241

Example 9 (compound 9) 60% sodium hydride (2.04 g, 5
1.0 mmol) in dioxane-toluene mixed solvent (1: 1, 20 m
L) and suspended under ice-cooling, ethyl 1- (2-tetrahydropyranyl) -2H-2-oxopyridine-3-carboxylate (7.94 g, 31.6 mmol) obtained in Reference Example 1-3.
l) and 3′-fluoro-4′-pivaloylaminoacetophenone (6.47 g, 27.3 mmol) in the above mixed solvent solution
(80 mL) was added dropwise over 10 minutes. After heating at 80 ° C. for 40 minutes under reflux, the reaction solution was ice-cooled. A 10% aqueous citric acid solution was added, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. Repeat the above operation, and combine the two residues with acetic acid (18
0 mL), sulfuric acid (20 mL) was added, and the mixture was stirred at 40 ° C for 2.5 hours. Add 10 N aqueous sodium hydroxide solution (80 m
L) was added, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform), and triturated with n-hexane to obtain Compound 9 (5.43 g, 30% over two steps).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.36
(s, 9H), 6.80 (s, 1H), 7.47 (dd, J = 7.7, 4.6 Hz, 1
H), 7.7-7.9 (m, 3H), 8.4-8.7 (m, 3H) EIMS (m / z) 340 (M ⁺ ) Molecular formula C ₁₉ H ₁₇ FN ₂ O ₃ = 340

Example 10 (Compound 10) Compound 9 (5.30 g, 15.6 mmol) was treated with sulfuric acid in the same manner as in Example 2 and recrystallized from methanol.
Compound 10 (2.13 g, 53%) was obtained.

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.14
(br, 2H), 6.89 (t, J = 8.9 Hz, 1H), 6.91 (s, 1H),
7.60 (dd, J = 7.9, 4.9 Hz, 1H), 7.69 (dd, J = 8.
4, 2.0Hz, 1H), 7.75 (dd, J = 12.9, 1.5 Hz, 1H), 8.
46 (dd, J = 7.9, 2.0 Hz, 1H), 8.77 (dd, J = 5.0,
2.0 Hz, 1H) EIMS (m / z) 256 (M ⁺ ) Molecular formula C ₁₄ H ₉ FN ₂ O ₂ = 256

Example 11 (Compound 11) Ethyl 2-hydroxy-6-methyl-3-pyridinecarboxylate (4.50 g, 24.8 mmol) under an argon atmosphere
l) and 3′-Fluoro-4′-pivaloylaminoacetophenone (2.95 g, 12.4 mmol) were dissolved in dimethylformamide (120 mL), and the mixture was dissolved in ice-cooled 60% sodium hydride.
(2.24 g, 56.0 mmol) and the mixture was stirred at room temperature for 1.5 hours. Water was added to the reaction solution, which was washed twice with n-hexane. To the aqueous layer was added a 10% aqueous citric acid solution, and the mixture was extracted with ethyl acetate.
The solvent was distilled off under reduced pressure. The residue was dissolved in acetic acid (45 mL), sulfuric acid (5 mL) was added, and the mixture was stirred at room temperature for 14 hours. 10 in the reaction solution
An aqueous solution of sodium hydroxide (20 mL) was added, and the mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to obtain Compound 11 (697 mg, 16% over two steps).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.36
(s, 9H), 2.71 (s, 3H), 6.78 (s, 1H), 7.31 (d, J =
7.9 Hz, 1H), 7.6-7.9 (m, 3H), 8.47 (d, J = 7.6 Hz,
1H), 8.59 (t, J = 7.0 Hz, 1H) EIMS (m / z) 354 (M ⁺ ) Molecular formula C ₂₀ H ₁₉ FN ₂ O ₃ = 354

Example 12 (Compound 12) Compound 11 (685 mg, 1.93 mmol) was treated with sulfuric acid in the same manner as in Example 2 and recrystallized from methanol / diisopropyl ether to give Compound 12 (310 mg, 59% )
I got

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 2.61
(s, 3H), 6.11 (br, 2H), 6.86 (s, 1H), 6.89 (t, J =
8.9 Hz, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.6-7.8
(m, 2H), 8.33 (d, J = 7.9 Hz, 1H) EIMS (m / z) 270 (M ⁺ ) Molecular formula C ₁₅ H ₁₁ FN ₂ O ₂ = 270

Example 13 (Compound 13) 60% sodium hydride (2.63 g, 6
5.8 mmol) was suspended in dioxane (20 mL) and heated under reflux.
Ethyl 2-methoxy-4-pivaloylamino-3-pyridinecarboxylate obtained in Reference Example 1-4 (5.53
g, 19.8 mmol) and a solution of 3′-fluoro-4′-pivaloylaminoacetophenone (3.90 g, 16.5 mmol) in dioxane (30 mL) were added dropwise over 7 minutes. After heating under reflux for another 4 hours, the reaction solution was ice-cooled, water was added, and the mixture was washed with n-hexane. A 10% aqueous citric acid solution was added to the aqueous layer, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was treated with acetic acid (90 m
L), sulfuric acid (10 mL) was added, and the mixture was stirred at room temperature for 24 hours. A 10 N aqueous solution of sodium hydroxide (40 mL) was added to the reaction solution, and the mixture was extracted with ethyl acetate. The residue was purified by silica gel column chromatography (n-hexane: acetone = 4: 1) and recrystallized from chloroform / n-hexane to give compound 13 (1.64 g, two steps).
23%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.36
(s, 9H), 1.39 (s, 9H), 6.72 (s, 1H), 7.6-7.9 (m, 3
H), 8.48 (d, J = 5.9 Hz, 1H), 8.61 (t, J = 7.3 Hz,
1H), 8.63 (d, J = 5.5 Hz, 1H) FABMS (m / z) 440 (M + H ⁺ ) Molecular formula C ₂₄ H ₂₆ FN ₃ O ₄ = 439

Example 14 (Compound 14) Compound 13 (1.62 g, 3.69 mmol) was treated with sulfuric acid in the same manner as in Example 2 and recrystallized from methanol / diisopropyl ether to give Compound 14 (707 mg, 71% )
I got

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.03
(br, 2H), 6.54 (d, J = 5.9 Hz, 1H), 6.67 (s, 1H),
6.86 (t, J = 8.6 Hz, 1H), 7.59 (dd, J = 8.6, 2.0
Hz, 1H), 7.65 (dd, J = 12.9, 2.0 Hz, 1H), 7.65 and 8.77 (br, 1H × 2), 7.92 (d, J = 5.9 Hz, 1H) FABMS (m / z) 272 (M + H ⁺ ) Molecular formula C ₁₄ H ₁₀ FN ₃ O ₂ = 272

Example 15 (Compound 15) Ethyl 1- (2-tetrahydropyranyl) -2H-2-oxopyridine-3-carboxylate (2.16 g, 8.60 mmol) obtained in Reference Example 1-3 and 3 ′ Compound 15 (177 mg, 10% over two steps) was obtained in the same manner as in Example 1 using -fluoroacetophenone (0.880 mL, 7.17 mmol).

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 7.23
(s, 1H), 7.48 (td, J = 8.9, 2.5 Hz, 1H), 7.66 (d
d, J = 7.9, 4.9 Hz, 1H), 7.67 (dd, J = 14.4, 7.9 H
z, 1H), 7.9-8.0 (m, 2H), 8.52 (dd, J = 7.9, 2.0 Hz,
1H), 8.82 (dd, J = 5.0, 2.0Hz, 1H) FABMS (m / z) 242 (M + H ⁺ ) Molecular formula C ₁₄ H ₈ FNO ₂ = 241

Example 16 (Compound 16) Under argon atmosphere, (3-fluoro-4-pivaloylaminophenyl) acetylene (306 m) obtained in Reference Example 4 was obtained.
g, 1.38 mmol) in tetrahydrofuran (7 mL).
Cooled to ° C. Add n-butyllithium (1.6 M n
-Hexane solution, 1.9 mL, 3.04 mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 30 minutes. 4- (2-trimethylsilylethoxy) -5 obtained in Reference Example 3-1
Pyrimidinecarboxaldehyde (282 mg, 1.26 mmol)
Of tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution,
The mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1 to 1: 1) to give 3- (3-fluoro-4-pivaloylaminophenyl) -1- [4- (2-
[Trimethylsilylethoxy) -5-pyrimidinyl] propynol (233 mg, 42%) was obtained.

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.10
(s, 9H), 1.2-1.3 (m, 2H), 1.33 (s, 9H), 2.93 (d, J
= 6.4 Hz, 1H), 4.6-4.7 (m, 2H), 5.79 (d, J = 5.9 H
z, 1H), 7.19 (dd, J = 11.4, 2.0 Hz, 1H), 7.2 (m, 1
H), 7.67 (br, 1H), 8.37 (t, J = 8.4 Hz, 1H), 8.70
(s, 1H), 8.75 (s, 1H) FABMS (m / z) 444 (M + H ⁺ ) Molecular formula C ₂₃ H ₃₀ FN ₃ O ₃ Si = 443

The above compound (233 mg, 0.526 mmol) was dissolved in dichloromethane (5 mL), and manganese dioxide (200 m
g) was added and stirred for 24 hours. The reaction solution was filtered through a radio light, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
4: 1) and purified by 3- (3-fluoro-4-pivaloylaminophenyl) -1- [4- (2-trimethylsilylethoxy) -5-pyrimidinyl] propynone (205 mg,
88%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.2-1.3 (m, 2H), 1.35 (s, 9H), 4.7-4.8 (m,
2H), 7.35 (d, J = 9.4 Hz, 1H), 7.38 (dd, J = 11.
4, 2.0Hz, 1H), 7.77 (br, 1H), 8.51 (t, J = 8.4 Hz,
1H), 8.87 (s, 1H), 9.13 (s, 1H) FABMS (m / z) 442 (M + H ⁺ ) Molecular formula C ₂₃ H ₂₈ FN ₃ O ₃ Si = 441

The above compound (163 mg, 0.370 mmol) was dissolved in dimethylformamide (3.7 mL), and 18-crown-6 (196 mg, 0.740 mmol) and potassium fluoride were added under ice-cooling.
(43.0 mg, 0.740 mmol) was added. Warm to room temperature, 4
Stirred for hours. After adding a saturated aqueous solution of ammonium chloride to the reaction solution, the mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to give Compound 16 (102
mg, 80%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.37
(s, 9H), 6.86 (s, 1H), 7.7-7.8 (m, 2H), 7.81 (br, 1
H), 8.65 (t, J = 8.4 Hz, 1H), 9.27 (s, 1H), 9.54
(s, 1H) FABMS (m / z) 342 (M + H ⁺ ) Molecular formula C ₁₈ H ₁₆ FN ₃ O ₃
= 341

Example 17 (Compound 17) Compound 16 (102 mg, 0.297 mmol) was treated with sulfuric acid in the same manner as in Example 2 and triturated with chloroform to give Compound 17 (21 mg, 27%). I got

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.24
(br, 2H), 6.89 (t, J = 8.9 Hz, 1H), 7.01 (s, 1H),
7.69 (dd, J = 8.4, 2.0 Hz, 1H), 7.76 (dd, J = 13.
3, 2.0Hz, 1H), 9.28 (s, 1H), 9.35 (s, 1H) FABMS (m / z) 258 (M + H ⁺ ) Molecular formula C ₁₃ H ₈ FN ₃ O ₂ = 257

Example 18 (Compound 18) Under argon atmosphere, 1,1-dibromo-2- (3-fluoro-4-pivaloylaminophenyl) ethene (134 mg, 0.355 mmol) obtained in Reference Example 4 was obtained. The solution of tetrahydrofuran (3 mL) was cooled to -78 ° C. Add n-butyllithium (1.6 M n-hexane solution, 0.70 mL, 1.06 mm)
ol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 10 minutes. 4-methoxy-6 obtained in Reference Example 3-2
A solution of (2-trimethylsilylethoxy) -5-pyrimidinecarboxaldehyde (90.3 mg, 0.355 mmol) in tetrahydrofuran (1 mL) was added dropwise, and the mixture was stirred for 30 minutes. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate = 6
: 1), and purified by 3- (3-fluoro-4-pivaloylaminophenyl) -1- [4-methoxy-6- (2-trimethylsilylethoxy) -5-pyrimidinyl] propynol (111 mg, 66%). ).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.2-1.3 (m, 2H), 1.32 (s, 9H), 3.57 (d, J
= 11.4 Hz, 1H), 4.06 (s, 3H), 4.5-4.6 (m, 2H), 5.8
7 (d, J = 10.9 Hz, 1H), 7.1-7.2 (m, 2H), 7.64 (br,
1H), 8.33 (t, J = 8.4 Hz, 1H), 8.39 (s, 1H)

The above compound (111 mg, 0.234 mmol) was dissolved in dichloromethane (5 mL), and manganese dioxide (100 m
g) was added and stirred for 6 hours. The reaction solution was filtered through a radio light, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
4: 1), and purified by 3- (3-fluoro-4-pivaloylaminophenyl) -1- [4-methoxy-6- (2-trimethylsilylethoxy) -5-pyrimidinyl] propynone (106 mg, 96) %).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.05
(s, 9H), 1.1-1.2 (m, 2H), 1.34 (s, 9H), 4.05 (s, 3
H), 4.5-4.6 (m, 2H), 7.1-7.2 (m, 2H), 7.75 (br, 1
H), 8.45 (s, 1H), 8.47 (t, J = 8.4 Hz, 1H)

The above compound (757 mg, 1.60 mmol) was dissolved in dimethylformamide (20 mL), and 18-crown-6 (848 mg, 3.21 mmol) and potassium fluoride (187
mg, 3.21 mmol). The temperature was raised to room temperature and stirred for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain Compound 18 (505 mg, 85%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.36
(s, 9H), 4.23 (s, 3H), 6.77 (s, 1H), 7.7-7.8 (m, 2
H), 7.81 (br, 1H), 8.59 (dd, J = 8.6, 7.6 Hz, 1H),
8.72 (s, 1H) FABMS (m / z) 372 (M + H ⁺ ) Molecular formula C ₁₉ H ₁₈ FN ₃ O ₄ = 371

Example 19 (Compound 19) Compound 18 (400 mg, 1.08 mmol) was suspended in a solution of ammonia in methanol (40 mL) and heated under reflux for 5 hours. After allowing to cool, the crystals were collected by filtration to give Compound 19 (343 mg,
89%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.36
(s, 9H), 6.06 (br, 1H), 6.74 (s, 1H), 7.7-7.8 (m,
2H), 7.80 and 9.13 (br, 1H × 2), 8.47 (s, 1H), 8.6
0 (t, J = 8.4 Hz, 1H) FABMS (m / z) 357 (M + H ⁺ ) Molecular formula C ₁₈ H ₁₇ FN ₄ O ₃ = 356

Example 20 (Compound 20) Compound 19 (323 mg, 0.907 mmol) was treated with sulfuric acid in the same manner as in Example 2 and triturated with chloroform to give Compound 20 (222 mg, 89%). I got

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.06
(br, 2H), 6.82 (s, 1H), 6.87 (t, J = 8.4 Hz, 1H),
7.58 (dd, J = 8.4, 2.0 Hz, 1H), 7.65 (dd, J = 12.
9, 2.0Hz, 1H), 8.35 (s, 1H), 8.41 and 8.87 (br, 1
H × 2) FABMS (m / z) 273 (M + H ⁺ ) Molecular formula C ₁₃ H ₉ FN ₄ O ₂ = 272

Example 21 (Compound 21) Under argon atmosphere, (3-fluoro-4-pivaloylaminophenyl) acetylene (650 m) obtained in Reference Example 4 was obtained.
g, 2.96 mmol) in tetrahydrofuran (7 mL).
Cooled to ° C. Add n-butyllithium (1.6 M n
-Hexane solution, 3.7 mL, 5.93 mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 10 minutes. 3- (2-trimethylsilylethoxy) -2- obtained in Reference Example 3-3
A solution of pyrazinecarboxaldehyde (664 mg, 2.96 mmol) in tetrahydrofuran (2 mL) was added dropwise, and the mixture was stirred for 1 hour. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1 to 3: 1) to give 3- (3-fluoro-
4-Pivaloylaminophenyl) -1- [3- (2-trimethylsilylethoxy) -2-pyrazinyl] propinol (638 mg, 49%) was obtained.

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.2-1.3 (m, 2H), 1.32 (s, 9H), 4.46 (d, J
= 8.4 Hz, 1H), 4.5-4.6 (m, 2H), 5.75 (d, J = 8.4 H
z, 1H), 7.1-7.2 (m, 2H), 7.63 (br, 1H), 8.08 (d, J
= 3.0 Hz, 1H), 8.11 (d, J = 3.0 Hz, 1H), 8.32 (t,
J = 7.9 Hz, 1H) FABMS (m / z) 444 (M + H ⁺ ) Molecular formula C ₂₃ H ₃₀ FN ₃ O ₃ Si = 443

The above compound (583 mg, 1.31 mmol) was dissolved in dichloromethane (10 mL), manganese dioxide (1.0 g) was added, and the mixture was stirred for 2 hours. The reaction solution was filtered through a radio light, and the solvent was distilled off under reduced pressure. The residue is subjected to silica gel column chromatography (n-hexane: ethyl acetate = 4: 1)
To give 3- (3-fluoro-4-pivaloylaminophenyl) -1- [3- (2-trimethylsilylethoxy) -2-pyrazinyl] propynone (489 mg, 84%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.2-1.3 (m, 2H), 1.34 (s, 9H), 4.6-4.7 (m,
2H), 7.40 (dd, J = 11.4, 2.0 Hz, 1H), 7.45 (d, J
= 8.4Hz, 1H), 7.75 (br, 1H), 8.30 (d, J = 2.5 Hz,
1H), 8.32 (d, J = 2.5 Hz, 1H), 8.48 (t, J = 8.4 H
(z, 1H) EIMS (m / z) 441 (M ⁺ ) Molecular formula C ₂₃ H ₂₈ FN ₃ O ₃ Si = 441

The above compound (585 mg, 1.32 mmol) was dissolved in dimethylformamide (15 mL), and under ice-cooling, 18-crown-6 (700 mg, 2.65 mmol) and potassium fluoride (154 mL).
mg, 2.65 mmol). The temperature was raised to room temperature and stirred for 5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain Compound 21 (357 mg, 79%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.37
(s, 9H), 7.00 (s, 1H), 7.77 (dd, J = 8.4, 2.0 Hz, 1
H), 7.8 (m, 1H), 8.65 (t, J = 8.4 Hz, 1H), 8.73
(d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H) FABMS (m / z) 342 (M + H ⁺ ) Molecular formula C ₁₈ H ₁₆ FN ₃ O ₃ = 341

Example 22 (Compound 22) Compound 21 (112 mg, 49%) was treated with sulfuric acid in the same manner as in Example 2 and triturated with chloroform to give Compound 22 (112 mg, 49%). I got

¹ H NMR (270 MHz, DMSO-d ₆ ) δ (ppm) 6.17
(br, 2H), 6.90 (t, J = 8.9 Hz, 1H), 7.06 (s, 1H),
7.70 (dd, J = 8.9, 2.0 Hz, 1H), 7.81 (dd, J = 11.
4, 2.0Hz, 1H), 8.82 (d, J = 2.0 Hz, 1H), 8.90 (d,
J = 2.0 Hz, 1H) FABMS (m / z) 258 (M + H ⁺ ) Molecular formula C ₁₃ H ₈ FN ₃ O ₂ = 257

Reference Example 1-1 Ethyl 3-methoxymethoxy-2-pyridinecarboxylate 3-hydroxy-2-picolinic acid (10.0 g, 71.9 mmol)
Add ethanol (150 mL) and sulfuric acid (3 mL) to the
Heated to reflux for an hour. After evaporating most of the ethanol under reduced pressure,
Ice and a saturated aqueous solution of sodium hydrogen carbonate were added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure to obtain ethyl ester (5.98 g, 50%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.49
(t, J = 7.0 Hz, 3H), 4.54 (q, J = 7.0 Hz, 2H), 7.3
-7.4 (m, 2H), 8.29 (dd, J = 3.5, 2.2 Hz, 1H), 10.7
(br, 1H)

The above compound (5.95 g, 35.6 mmol) was dissolved in dichloromethane (100 mL), and diisopropylamine (12.4 mL, 71.2 mmol) and chloromethyl methyl ether (4.9 mL, 64 mmol) were added under ice-cooling. Stir for 1 hour. Water was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the title compound (5.29 g, 70%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.43
(t, J = 7.0 Hz, 3H), 3.52 (s, 3H), 4.45 (q, J = 7.0
Hz, 2H), 5.26 (s, 2H), 7.3-7.6 (m, 2H), 8.33 (dd,
(J = 4.4, 1.5 Hz, 1H)

Reference Example 1-2 Ethyl 3-methoxymethoxy-4-pyridinecarboxylate Diisopropylamine (2.5 mL, 1
8.0 mmol) in tetrahydrofuran (30 mL).
Cooled to ° C. Add n-butyllithium (1.6 M n
-Hexane solution, 11.3 mL, 18.0 mmol) at -50 ℃
And stirred for 20 minutes. 3-pyridinyl N, N-diethyl carbamate (3.0 g, 15.5 mm
ol) in tetrahydrofuran (9 mL) was added dropwise over 5 minutes. After stirring for 30 minutes, dry ice (about 1 g) was added, and the mixture was stirred for 1 hour while warming to room temperature. The reaction solution was ice-cooled, adjusted to pH 4 with 1 N hydrochloric acid, and extracted with chloroform. The solvent was distilled off under reduced pressure to give 3-diethylcarbamoyloxy-4-pyridinecarboxylic acid (3.23 g, 88
%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.1-1.
4 (m, 6H), 3.4-3.6 (m, 4H), 7.88 (d, J = 5.0 Hz, 1
H), 8.58 (s, 1H), 8.6 (d, J = 5.0 Hz, 1H)

The above compound (1.64 g, 6.90 mmol) was added to methanol (15 mL) and a 2N aqueous sodium hydroxide solution (15 m
L) was added and the mixture was heated under reflux for 4.5 hours. Most of the methanol was distilled off under reduced pressure, cooled with ice, and acidified with hydrochloric acid. The precipitated crystals were collected by filtration to give 3-hydroxy-4-pyridinecarboxylic acid (956 mg, 99%).

Ethanol (15 mL) and sulfuric acid (3 mL) were added to the above compound (956 mg, 6.88 mmol), and the mixture was heated under reflux for 2.5 hours. After removing most of the ethanol under reduced pressure,
A 2N aqueous sodium hydroxide solution was added to adjust the pH to 8. Extraction was performed with chloroform, and the solvent was distilled off under reduced pressure to obtain ethyl ester (863 mg, 75%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.44
(t, J = 7.0 Hz, 3H), 4.46 (q, J = 7.0 Hz, 2H), 7.6
0 (d, J = 5.2 Hz, 1H), 8.21 (d, J = 5.2 Hz, 1H),
8.49 (s, 1H), 10.31 (s, 1H)

The above compound (187 mg, 1.12 mmol) was dissolved in dichloromethane (5 mL), and diisopropylamine (0.2 mL, 1.12 mmol) and chloromethyl methyl ether (0.085 mL, 1.12 mmol) were added under ice cooling. The mixture was stirred for 6 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (186 mg, 79%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.39
(t, J = 7.0 Hz, 3H), 3.54 (s, 3H), 4.40 (q, J = 7.0
Hz, 2H), 5.28 (s, 2H), 7.57 (d, J = 4.8 Hz, 1H),
8.37 (d, J = 4.8 Hz, 1H), 8.61 (s, 1H)

Reference Example 1-3 Ethyl 1- (2-tetrahydropyranyl) -2H-2
-Oxopyridine-3-carboxylate 2-Hydroxynicotinic acid (25.0 g, 180 mmol) was dissolved in ethanol (485 mL), sulfuric acid (15 mL) was added, and the mixture was heated under reflux for 18 hours. The reaction solution was ice-cooled, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. After evaporating the solvent under reduced pressure, the residue was dissolved in dichloromethane (200 mL),
3,4-Dihydro-2H-pyran (16 mL, 170 mmol) and dl-10-camphorsulfonic acid were added, and the mixture was added at room temperature.
Stir for 2 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the title compound (1
7.0 g, 34%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.38
(t, J = 7.0 Hz, 3H), 1.4-2.3 (m, 6H), 3.5-4.3 (m,
2H), 4.36 (q, J = 7.0 Hz, 2H), 5.91 (dd, J = 10.0,
2.1 Hz, 1H), 6.28 (t, J = 7.0 Hz, 1H), 7.80 (dd,
J = 6.8, 2.2 Hz, 1H), 8.11 (dd, J = 7.0, 2.2 Hz, 1
H) FABMS (m / z) 252 (M + H ⁺ ) Molecular formula C ₁₃ H ₁₇ NO ₄ = 251

Reference Example 1-4 Ethyl 2-methoxy-4-pivaloylamino-3-pyridinecarboxylate Under an argon atmosphere, 3-bromo-2,4-dichloropyridine (Synthetic Commun., Vol. 22,
2829, 1992) (9.08 g, 40.0 mmol) was dissolved in dimethylformamide (40 mL) and sodium azide was added.
(3.26 g, 50.0 mmol) was added, and the mixture was stirred at 70 ° C. for 2 hours.
Water was added to the reaction solution, and the precipitated crystals were collected by filtration to give 4-azido-3-bromo-2-chloropyridine (8.
10 g, 87%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 7.02
(d, J = 5.3 Hz, 1H), 8.26 (d, J = 5.5 Hz, 1H) FABMS (m / z) 237, 235, 233 (M + H ⁺ ) Molecular formula C ₅ H ₂ ⁷⁹ Br
³⁵ ClN ₄ = 232

The above compound (8.10 g, 34.8 mmol) was dissolved in tetrahydrofuran (150 mL), triphenylphosphine (1.00 g, 38.2 mmol) was added, and the mixture was stirred at room temperature for 2 hours. 1 N hydrochloric acid (50 mL) was added, and the mixture was further stirred for 30 minutes.
A 1 N aqueous sodium hydroxide solution (100 mL) was added, and the mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
3: 2) to give 4-amino-3-bromo-2-chloropyridine (6.91 g, 96%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 4.80
(br, 2H), 6.52 (d, J = 5.5 Hz, 1H), 7.90 (d, J =
5.5 Hz, 1H) FABMS (m / z) 211, 209, 207 (M + H ⁺ ) Molecular formula C ₅ H ₄ ⁷⁹ Br
³⁵ ClN ₂ = 206

The above compound (6.73 g, 32.5 mmol) was dissolved in methanol (100 mL), and sodium methoxide (28%
Methanol solution, 50 mL) was added, and the mixture was stirred at 140 ° C. in a sealed tube for 7 hours. After evaporating the solvent under reduced pressure, water was added and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (chloroform: acetone = 20: 1).
By purifying with 4-amino-3-bromo-2-
Methoxypyridine (6.09 g, 92%) was obtained.

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 3.96
(s, 3H), 4.67 (br, 2H), 6.27 (d, J = 5.7 Hz, 1H),
7.70 (d, J = 5.5 Hz, 1H) FABMS (m / z) 205, 203 (M + H ⁺ ) Molecular formula C ₆ H ₇ ⁷⁹ BrN ₂ O =
202

The above compound (6.09 g, 30.0 mmol) was dissolved in dichloromethane (100 mL), and triethylamine (21.0
mL, 150 mmol) and pivalic acid chloride (15.0 mL, 1
20 mmol) and stirred at room temperature for 31 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform) to give 3-bromo-2-methoxy-4-pivaloylaminopyridine (7.28
g, 85%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.35
(s, 9H), 4.01 (s, 3H), 7.98 (d, J = 5.7 Hz, 1H), 8.
06 (d, J = 5.7 Hz, 1H), 8.22 (br, 1H) FABMS (m / z) 289, 287 (M + H ⁺ ) Molecular formula C ₁₁ H ₁₅ ⁷⁹ BrN ₂ O
₂ = 286

The above compound (7.17 g, 25.0 mmol) was dissolved in tetrahydrofuran (100 mL) and cooled to -78 ° C.
Add n-butyllithium (1.6 M n-hexane solution,
39 mL, 62 mmol) was added dropwise over 25 minutes, and the mixture was further stirred for 5 minutes. Ethyl chloroformate (4.8 mL, 50 mmol) was added, and after stirring for 10 minutes, water was added, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (5.64 g, 81%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.31
(s, 9H), 1.40 (t, J = 7.3 Hz, 3H), 3.97 (s, 3H), 4.
40 (q, J = 7.3 Hz, 2H), 8.11 (d, J = 5.9 Hz, 1H),
8.21 (d, J = 5.9 Hz, 1H) FABMS (m / z) 281 (M + H ⁺ ) Molecular formula C ₁₄ H ₂₀ N ₂ O ₄ = 280

Reference Example 2-1 3-Acetyl-4-methoxypyridine Under an argon atmosphere, 4-methoxypyridine (10.9 g, 10
0 mmol) was dissolved in tetrahydrofuran (200 mL).
Cooled to 8 ° C. Add n-butyllithium (1.6 M n
-Hexane solution, 62 mL, 99 mmol) was added dropwise over 1 hour, and the mixture was further stirred for 10 minutes. Acetaldehyde (11 mL)
Was introduced in the gas phase and stirred for 2 hours. Add water to the reaction solution,
The mixture was extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to obtain 3- (1-hydroxyethyl) -4-methoxypyridine (3.38 g, 22%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.51
(d, J = 6.4 Hz, 3H), 3.22 (br, 1H), 3.89 (s, 3H),
5.11 (q, J = 6.4 Hz, 1H), 6.76 (d, J = 5.7 Hz, 1
H), 8.37 (d, J = 5.9 Hz, 1H), 8.48 (s, 1H) FABMS (m / z) 154 (M + H ⁺ ) Molecular formula C ₈ H ₁₁ NO ₂ = 153

The above compound (3.36 g, 22.0 mmol) was dissolved in toluene (100 mL), and manganese dioxide (15.3 g, 176
mmol) and heated under reflux for 2 hours. The reaction solution was filtered through a radio light, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1) to obtain the title compound (2.37 g, 71%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 2.61
(s, 3H), 3.98 (s, 3H), 6.89 (d, J = 5.9 Hz, 1H), 8.
57 (d, J = 5.9 Hz, 1H), 8.80 (s, 1H) FABMS (m / z) 152 (M + H ⁺ ) Molecular formula C ₈ H ₉ NO ₂ = 151

Reference Example 2-2 4-Acetyl-3-hydroxy-5-pivaloylaminopyridine 5-hydroxynicotinic acid (1.0 g, 7.19 mmol) was dissolved in methanol (15 mL), and sulfuric acid (3 mL) Was added and the mixture was refluxed for 4 hours. After cooling the reaction solution with ice, a 2 N aqueous solution of sodium hydroxide was added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure to obtain a methyl ester (1.01 g, 92%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 3.92
(s, 3H), 7.74 (m, 1H), 8.39 (s, 1H), 8.69 (s, 1H)

The above compound (1.37 g, 8.93 mmol) was dissolved in dichloromethane (50 mL), and diisopropylethylamine (1.87 mL, 10.7 mmol) and chloromethyl methyl ether (0.81 mL, 10.7 mmol) were added under ice cooling. The mixture was stirred for 10 hours. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate = 1: 1) gave methyl 5-methoxymethoxy-3-pyridinecarboxylate (1.57 g, 89%).
I got

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 3.50
(s, 3H), 3.96 (s, 3H), 5.25 (s, 2H), 7.96 (m, 1H),
8.56 (d, J = 2.2 Hz, 1H), 8.88 (d, J = 2.2 Hz, 1H)

To the above compound (1.57 g, 7.98 mmol) was added methanol (20 mL) and a 2 N aqueous sodium hydroxide solution (10
mL) and heated under reflux for 4 hours. Most of the methanol was distilled off under reduced pressure, cooled with ice, and acidified with hydrochloric acid. The precipitated crystals were collected by filtration to give 5-methoxymethoxynicotinic acid (1.52 g, 99%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 3.50
(s, 3H), 5.25 (s, 2H), 8.00 (m, 1H), 8.54 (d, J =
2.2 Hz, 1H), 8.91 (s, 1H)

The above compound (1.52 g, 8.28 mmol) was dissolved in acetone (25 mL), and triethylamine (1.38
mL, 9.94 mmol) and ethyl chloroformate (0.95 mL,
9.94 mmol) and stirred for 40 minutes. Further, an aqueous solution (6 mL) of sodium azide (834 mg, 12.8 mmol) was added,
Stir for 1 hour. Water was added to the reaction solution, extracted with dichloromethane, and the solvent was distilled off under reduced pressure. Benzyl alcohol (10 mL) was added to the residue, and the mixture was heated with stirring at 120 ° C. for 15 hours. Water was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-
Purification with hexane: ethyl acetate = 1: 1) afforded 3-benzyloxycarbonylamino-5-methoxymethoxypyridine (1.68 g, 71% over two steps).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 3.49
(s, 3H), 5.1-5.2 (m, 4H), 7.37 (s, 5H), 7.83 (m, 1
H), 8.1-8.2 (m, 2H) EIMS (m / s) 288 (M ⁺ ) Molecular formula C ₁₅ H ₁₆ N ₂ O ₄ = 288

The above compound (1.68 g, 5.84 mmol) was dissolved in methanol (50 mL), palladium carbon (250 mg) was added, and the mixture was stirred under a hydrogen atmosphere at room temperature for 1 hour. The reaction solution was filtered through a radio light, and the solvent was distilled off under reduced pressure. The residue was dissolved in dichloromethane (20 mL), and triethylamine (1.22 mL, 8.76 mmol) and pivalic acid chloride (1.08 mL, 8.76 mmol) were added under ice-cooling, and the mixture was stirred for 3 hours.
A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (n-hexane: ethyl acetate =
Purification by 1: 1) gave 3-methoxymethoxy-5-pivaloylaminopyridine (1.38 g, 99% in two steps).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.34
(s, 9H), 3.51 (s, 3H), 5.21 (s, 2H), 7.50 (br, 1
H), 8.11 (m, 2H), 8.34 (br, 1H) EIMS (m / s) 238 (M ⁺ ) Molecular formula C ₁₂ H ₁₈ N ₂ O ₃ = 238

The above compound (2.11 g,
8.85 mmol) was dissolved in tetrahydrofuran (30 mL).
Cooled to 8 ° C. Add n-butyllithium (1.6 M
n-Hexane solution, 13.8 mL, 22.1 mmol) was added dropwise over 10 minutes, and the mixture was further stirred for 15 minutes. Acetaldehyde (1.
0 mL) was introduced in the gas phase and stirred for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. Purification by silica gel column chromatography (chloroform: methanol = 20: 1) gave 4- (1-hydroxyethyl) -3-methoxymethoxy-5-pivaloylaminopyridine (1.90 g, 76%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.34
(s, 9H), 1.50 (d, J = 6.6 Hz, 3H), 3.49 (s, 3H), 5.
20 (s, 2H), 5.62 (m, 1H), 8.08 (s, 1H), 9.24 (s, 1
H) EIMS (m / s) 282 (M ⁺ ) Molecular formula C ₁₄ H ₂₂ N ₂ O ₄ = 282

The above compound (998 mg, 3.53 mmol) was dissolved in acetone (100 mL), and the mixture was cooled with ice and the Jones reagent (7 m
L) was added and the mixture was stirred for 2 hours. An aqueous solution of sodium hydrogen carbonate and water are added to the reaction solution until the reaction solution turns green-blue,
The mixture was extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1), and 4-acetyl-3-methoxymethoxy-5-pivaloylaminopyridine (902 mg, 91
%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.31
(s, 9H), 2.67 (s, 3H), 3.53 (s, 3H), 5.32 (s, 2H),
8.37 (s, 1H), 9.38 (s, 1H), 9.80 (br, 1H)

The above compound (1.27 g, 4.51 mmol) was dissolved in a mixed solvent of methanol (10 mL) and a 1N aqueous hydrochloric acid solution (10 mL), and the mixture was stirred at 80 ° C. for 30 minutes. After distilling off most of the methanol under reduced pressure, neutralize with 2 N aqueous sodium hydroxide,
Extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 9: 1) to give the title compound.
(1.03 g, 97%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.33
(s, 9H), 2.78 (s, 3H), 8.17 (s, 1H), 9.33 (s, 1H),
10.73 (s, 1H) EIMS (m / s) 236 (M ⁺ ) Molecular formula C ₁₂ H ₁₆ N ₂ O ₃ = 236

Reference Example 3-1 4- (2-Trimethylsilylethoxy) -5-pyrimidinecarboxaldehyde Under an argon atmosphere, 60% sodium hydride (1.4 g, 35.50 g) was used.
2 mmol) in tetrahydrofuran (5 mL).
Trimethylsilylethanol (5.05 mL, 35.2 mmol) was added, and the mixture was stirred at room temperature for 1 hour. This solution was added to a solution of 4,6-dichloropyrimidine (4.0 g, 35.2 mmol) in tetrahydrofuran (50 mL) under ice cooling, the temperature was raised to room temperature, and the mixture was stirred for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 8: 1) to obtain 4-chloro-6- (2-trimethylsilylethoxy) pyrimidine (5.59 g, 69%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.08
(s, 9H), 1.1-1.2 (m, 2H), 4.4-4.5 (m, 2H), 6.72
(d, J = 1.0 Hz, 1H), 8.56 (s, 1H) EIMS (m / z) 230 (M ⁺ ) Molecular formula C ₉ H ₁₅ ³⁵ ClN ₂ OSi = 230

Under an argon atmosphere, diisopropylamine
(3.6 mL, 26.0 mmol) was dissolved in tetrahydrofuran (50 mL) and cooled to -78 ° C. To this solution, n-butyllithium (1.6 M n-hexane solution, 16.2 mL, 26.0 mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 20 minutes.
Tetrahydrofuran of the above compound (5.0 g, 21.7 mmol)
(10 mL) solution was added dropwise over 10 minutes. After stirring for 30 minutes,
Ethyl chloroformate (2.5 mL, 26.0 mmol) was added, and the mixture was stirred for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give ethyl 4-chloro-6-.
(2-Trimethylsilylethoxy) -5-pyrimidine carboxylate (3.95 g, 64%) was obtained.

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.06
(s, 9H), 1.1-1.2 (m, 2H), 1.38 (t, J = 6.9 Hz, 3H),
4.41 (q, J = 6.9 Hz, 2H), 4.5-4.6 (m, 2H), 8.55
(s, 1H)

The above compound (4.0 g, 14.1 mmol) was dissolved in methanol (30 mL), and ammonium formate (2.0 g) and palladium on carbon (400 mg) were added. After stirring at room temperature for 4 hours, the reaction solution was filtered through radio light, and the solvent was distilled off under reduced pressure. Water was added to the residue, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give ethyl 4- (2-trimethylsilylethoxy).
-5-Pyrimidine carboxylate (3.05 g, 81%) was obtained.

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.2-1.3 (m, 2H), 1.39 (t, J = 6.9 Hz, 3H),
4.38 (q, J = 6.9 Hz, 2H), 4.6-4.7 (m, 2H), 8.82
(s, 1H), 8.95 (s, 1H) EIMS (m / z) 268 (M ⁺ ) Molecular formula C ₁₂ H ₂₀ N ₂ O ₃ Si = 268

Lithium aluminum hydride (70.7 mg, 6.86 mmol) in tetrahydrofuran under an argon atmosphere
(10 mL) The suspension was cooled to -78 ° C and the above compound (500 mg,
1.86 mmol) was added. After 1.5 hours, water was carefully added dropwise, sodium sulfate was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was filtered, the filtrate was extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the title compound (138 mg, 33%) and 5-hydroxymethyl-4.
-(2-trimethylsilylethoxy) pyrimidine (280
mg, 54%).

5-Hydroxymethyl-4- (2-trime
Tylsilylethoxy) pyrimidine ¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.05 (s, 9H), 1.1-
1.2 (m, 2H), 4.5-4.6 (m, 2H), 4.62 (s, 2H), 8.40
(s, 1H), 8.64 (s, 1H) FABMS (m / z) 227 (M + H ⁺ ) Molecular formula C ₁₀ H ₁₈ N ₂ O ₂ Si = 226

The above 5-hydroxymethyl-4- (2-trimethylsilylethoxy) pyrimidine (280 mg, 1.01 m
mol) was dissolved in dichloromethane (5 mL), manganese dioxide (160 mg) was added, and the mixture was stirred at room temperature for 24 hours. The reaction solution was filtered through a radio light, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 15: 1) to give the title compound (108 m
g, 39%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.2-1.3 (m, 2H), 4.6-4.7 (m, 2H), 8.898
(s, 1H), 8.903 (s, 1H), 10.35 (s, 1H) EIMS (m / z) 224 (M ⁺ ) Molecular formula C ₁₀ H ₁₆ N ₂ O ₂ Si = 224

Reference Example 3-2 4-methoxy-6- (2-trimethylsilylethoxy)
-5-pyrimidinecarboxaldehyde 60% sodium hydride (1.95 g, 4
8.9 mmol) in tetrahydrofuran (20 mL).
-Trimethylsilylethanol (5.60 mL, 39.1 mmol)
Was added and heated under reflux for 3 hours. This solution was treated with 4-chloro-
A solution of 6-methoxypyrimidine (4.71 g, 32.6 mmol) in tetrahydrofuran (50 mL) was added under ice-cooling, the temperature was raised to room temperature, and the mixture was stirred for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give 4-methoxy-
6- (2-trimethylsilylethoxy) pyrimidine (2.
69 g, 37%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 0.07
(s, 9H), 1.0-1.2 (m, 2H), 3.94 (s, 3H), 4.3-4.5 (m,
2H), 6.00 (d, J = 0.9 Hz, 1H), 8.42 (s, 1H)

Under an argon atmosphere, diisopropylamine
(4.9 mL, 35.4 mmol) was dissolved in tetrahydrofuran (60 mL) and cooled to -78 ° C. To this solution, n-butyllithium (1.6 M n-hexane solution, 22.1 mL, 35.4 mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 30 minutes.
Tetrahydrofuran of the above compound (5.34 g, 23.6 mmol)
(20 mL) solution was added dropwise over 10 minutes. After stirring for 30 minutes,
Dimethylformamide (3.0 mL) was added, and the mixture was stirred for 1 hour. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to obtain the title compound (4.04 g, 67%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 0.08
(s, 9H), 1.1-1.3 (m, 2H), 4.09 (s, 3H), 4.5-4.7 (m,
2H), 8.48 (s, 1H), 10.35 (s, 1H) EIMS (m / z) 254 (M ⁺ ) Molecular formula C ₁₁ H ₁₈ N ₂ O ₃ Si = 254

Reference Example 3-3 3- (2-Trimethylsilylethoxy) -2-pyrazinecarboxaldehyde Under an argon atmosphere, 60% sodium hydride (1.92 g, 48.0 mmol) was added to tetrahydrofuran.
(6 mL) and 2-trimethylsilylethanol
(6.30 mL, 43.7 mmol) and the mixture was stirred at room temperature for 1 hour.
This solution was added to a solution of 2-chloropyrazine (5.00 g, 43.7 mmol) in tetrahydrofuran (30 mL) under ice cooling, and the mixture was heated under reflux for 2.5 hours. After cooling, a saturated aqueous solution of ammonium chloride was added to the reaction solution, and the mixture was extracted with ethyl acetate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-
By purifying with hexane: ethyl acetate = 6: 1),
2- (2-trimethylsilylethoxy) pyrazine (8.17
g, 95%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.09
(s, 9H), 1.15 (t, J = 8.4 Hz, 2H), 4.42 (t, J = 8.4
Hz, 2H), 8.07 (s, 1H), 8.08 (s, 1H), 8.18 (s, 1H) Under an argon atmosphere, 2,2,6,6-tetramethylpiperidine (3.10 mL, 18.3 mmol) was added to tetrahydrofuran.
(30 mL) and cooled to -78 ° C. Add n-butyllithium (1.6 M n-hexane solution, 11.5 mL, 18.3
(mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 20 minutes. A solution of the above compound (3.00 g, 15.3 mmol) in tetrahydrofuran (10 mL) was added dropwise over 10 minutes. After stirring for 1 hour, ethyl formate (2.0 mL) was added, and the mixture was stirred for 30 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title compound (1.50 g, 44%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 0.08
(s, 9H), 1.2-1.3 (m, 2H), 4.5-4.6 (m, 2H), 8.22
(d, J = 2.5 Hz, 1H), 8.23 (d, J = 2.5 Hz, 1H), 10.
29 (s, 1H)

Reference Example 4 (3-Fluoro-4-pivaloylaminophenyl) acetylene Under argon atmosphere, 4-bromo-2-fluoro-N-pivaloylaniline (2.18 g, 7.96 mmol) in tetrahydrofuran (30 mL) ) The solution was cooled to -78 ° C. N-
Butyllithium (1.6 M n-hexane solution, 12.0 mL, 19.
(1 mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 40 minutes. Dimethylformamide (5 mL) was added, the temperature was raised to room temperature, and the mixture was stirred for 2.5 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, extracted with chloroform, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 4: 1) to give 3
-Fluoro-4-pivaloylaminobenzaldehyde
(1.21 g, 68%).

Carbon tetrabromide (7.08 g, 21.3 mmol) was dissolved in dichloromethane (15 mL), and triphenylphosphine (11.2 g, 42.6 mmol) in dichloromethane (15 mL) was added under ice-cooling.
The solution was added dropwise. After 5 minutes, the above compound (1.19 g, 5.33 m
mol) in dichloromethane (15 mL) was added dropwise and stirred for 15 minutes. Water (15 mL) was added to the reaction solution, extracted with chloroform, and washed with a saturated aqueous solution of sodium hydrogen carbonate and a saturated aqueous solution of ammonium chloride. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography (n-hexane:
Purification with ethyl acetate = 4: 1) gave 1,1-dibromo-2- (3-fluoro-4-pivaloylaminophenyl) ethene (1.37 g, 68%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.33
(s, 9H), 7.24 (m, 1H), 7.39 (s, 1H), 7.46 (dd, J =
12.4, 2.0 Hz, 1H), 7.67 (br, 1H), 8.39 (t, J = 8.
4 Hz, 1H) EIMS (m / z) 381, 379, 377 (M ⁺ ) Molecular formula C ₁₃ H ₁₄ ⁷⁹ Br ₂
FNO = 377

The above compound (1.00 g,
2.64 mmol) in tetrahydrofuran (20 mL) at -78 ° C
And cooled. To this solution, n-butyllithium (1.6 M n-hexane solution, 6.6 mL, 10.6 mmol) was added dropwise so that the internal temperature did not exceed -50 ° C, and the mixture was stirred for 20 minutes. A saturated aqueous solution of ammonium chloride was added to the reaction solution, extracted with ethyl acetate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 6: 1) to obtain the title compound (508 mg, 88%).

¹ H NMR (270 MHz, CDCl ₃ ) δ (ppm) 1.33
(s, 9H), 3.06 (s, 1H), 7.21 (dd, J = 11.4, 2.0 Hz,
1H), 7.27 (d, J = 9.4 Hz, 1H), 7.66 (br, 1H), 8.36
(t, J = 8.4 Hz, 1H) FABMS (m / z) 222 (M + H ⁺ ) Molecular formula C ₁₃ H ₁₄ FNO = 221

Reference Example 5 Methyl 3-fluoro-4-pivaloylaminobenzoate Under an argon atmosphere, 4-bromo-2-fluoropivaloylaniline (8.49 g, 31.0 mmol) was added to tetrahydrofuran.
(100 mL) and cooled to -78 ° C. N-
Butyllithium (1.6 M n-hexane solution, 43 mL, 68 mm
ol) was added dropwise over 1 hour, and the mixture was further stirred for 10 minutes. Dry ice (about 2 g) was added, and the mixture was stirred for 2 hours while warming to room temperature. After adding water to the reaction solution and washing with ethyl acetate, hydrochloric acid was added to the aqueous layer to adjust the pH to 3. The precipitated white crystals were collected by filtration to give 3-fluoro-4-pivaloylaminobenzoic acid (5.35 g, 72%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.34
(s, 9H), 7.6-7.9 (m, 3H), 8.49 (t, J = 8.2 Hz, 1H) EIMS (m / z) 239 (M ⁺ )

The above compound (12.3 g, 51.6 mmol) was dissolved in methanol (200 mL), sulfuric acid (4 mL) was added, and the mixture was heated under reflux for 18 hours. The reaction solution was ice-cooled, a saturated aqueous solution of sodium hydrogen carbonate was added, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography.
The residue was purified by (n-hexane: ethyl acetate = 6: 1) to give the title compound (13.0 g, 99%).

¹ H NMR (90 MHz, CDCl ₃ ) δ (ppm) 1.34
(s, 9H), 3.90 (s, 3H), 7.6-7.9 (m, 3H), 8.49 (t, J
= 8.2 Hz, 1H) EIMS (m / z) 253 (M ⁺ )

[0174]

According to the present invention, a novel pyranoazine derivative having antibacterial activity, antiestrogenic activity and antitumor activity can be provided.

 ──────────────────────────────────────────────────続 き Continued on the front page (72) Inventor Hiromitsu Saito 4-16-19 Nishiikuta, Tama-ku, Kawasaki-shi, Kanagawa

Claims (1)

[Claims] 1. A compound of the formula (I) Wherein R ¹ is hydrogen, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy, carboxy, lower alkanoyl, lower alkoxycarbonyl, lower alkanoyloxy, NR ² R ³ (wherein R ² and R ³ are the same Or differently represents hydrogen, substituted or unsubstituted lower alkyl or lower alkanoyl, or R ² and R ³ together represent a heterocyclic group formed by a substituted or unsubstituted N) Or halogen, W,
One of X, Y and Z represents N, and the other is the same or different and is N or CR ⁴ wherein R ⁴ is hydrogen, substituted or unsubstituted lower alkyl, hydroxy, lower alkoxy,
NR ⁵ R ^{6 wherein} R ⁵ and R ⁶ are the same or different and represent hydrogen, substituted or unsubstituted lower alkyl or lower alkanoyl, or R ⁵ and R ⁶ together form a substituted or unsubstituted N Represents a heterocyclic group formed by interposing a), represents nitro or halogen], or represents a pharmaceutically acceptable salt thereof.