JPH06256318A - Method for synthesizing 5-carboalkoxypyrimidine derivative - Google Patents

Abstract

PURPOSE:To provide a method of synthesis capable of efficiently and industrially producing the subject compound being used as a raw material for a pyrimidine derivative useful as an HMG-CoA reductase inhibitor. CONSTITUTION:A compound of formula I (R<1> to R<2> are H or alkyl, aralkyl, aryl or heteroaryl which may be replaced, respectively) is reacted with a halophosphoric ester of the formula (R<4>O)2POX<1> (R<4> is alkyl, aralkyl, aryl or heteroaryl which may be replaced, respectively; X is halogen) preferably in the presence of triethylamine to give a phosphoric ester of formula II. Then the compound is reacted with an acid addition salt of amidine of formula III [A is alkyl, aralkyl, aryl, SR<5>, OR<6> or NR<7>R<8>(R<5> to R<8> are H or alkyl, aryl, heteroaryl, aralkyl, alkylsulfonyl or arylsulfonyl which may be replaced, respectively) in the presence of a base and a pyridine ring is formed to give the objective 5-carboalkoxypyrimidine derivative of formula IV.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a method for synthesizing a 5-carboalkoxypyrimidine derivative used as a raw material of a pyrimidine derivative useful as an inhibitor of hydroxymethylglutaryl CoA (HMG-CoA) reductase.

[0002]

HMG-CoA (3-hydroxy-3-methyl-glutaryl coenzyme A) reductase is a rate-limiting enzyme for cholesterol biosynthesis. Various pyrimidine derivatives are known as inhibitors of this HMG-CoA reductase. For example, Journal of Medicinal Chemistry, Vol. 33, pp. 52-60 (1990) (Journal
ofMedicinal Chemistry 33 , 52-60 (1990)), JP-A-1
No. 261,377, EP 0,367,895 and the like disclose derivatives of this type. Such a pyrimidine derivative or an intermediate for synthesizing it is also useful as an intermediate for various pharmaceuticals.

For example, the above-mentioned Journal of Medicinal Chemistry describes a 5-carboalkoxypyrimidine derivative represented by the following formula (X) as a raw material for the above pyrimidine derivative. This 5-carboalkoxypyrimidine derivative (X) is
As shown in the scheme below, a compound obtained by reacting a diketone represented by the following formula (VI) with an aldehyde represented by the following formula (VII) and an acid addition salt of an amidine represented by the following formula (VIII) to effect ring closure It is synthesized by dehydrogenating (IX).

[0004]

[Chemical 9]

In the above scheme, R ⁹ is, for example, alkyl such as methyl and isopropyl, R ¹⁰ is, for example, aryl such as 4-fluorophenyl and 4-chlorophenyl, and R ¹¹ is, for example, methyl, isopropyl and the like. Alkyl; cycloalkyl such as cyclohexyl; or aryl such as phenyl and 4-fluorophenyl; and R ¹² is alkyl such as ethyl.

The dehydrogenation of compound (IX) is carried out here with the dehydrogenating agent 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). However, since there is no good method for industrially carrying out this dehydrogenation reaction, the above-mentioned 5-carboalkoxypyrimidine derivative (X) cannot be efficiently industrially produced.

[0007]

DISCLOSURE OF THE INVENTION The present invention is intended to solve the above-mentioned conventional problems, and an object thereof is to synthesize a 5-carboalkoxypyrimidine derivative efficiently and industrially. To provide a method.

[0008]

The synthetic method of the present invention comprises the following formula (I):

[0009]

[Chemical 10]

(Wherein R ¹ , R ² and R ³ each independently represent a group selected from the group consisting of hydrogen, alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent) The compound represented by the formula (R ⁴ O) ₂ POX ¹ (wherein R ⁴ represents a group selected from the group consisting of alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent, X ¹
Is halogen) and is represented by halophosphate (I
Reacting I) in the presence of a base to obtain a phosphate ester represented by the following formula (III),

[0011]

[Chemical 11]

(Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined in the formula (I) or (II) respectively) The phosphoric acid ester (III) is added to the following formula (IV)

[0013]

[Chemical 12]

(In the formula, A represents alkyl, aralkyl, aryl, SR ⁵ , OR ⁶ or NR ⁷ R ⁸ , and R ⁵ , R ⁶ ,
R ⁷ and R ⁸ each independently represent a group selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, aralkyl, alkylsulfonyl or arylsulfonyl, and these groups having a substituent). By reacting an acid addition salt of the compound in the presence of a base to form a pyrimidine ring.

[0015]

[Chemical 13]

(Wherein R ¹ , R ² , R ³ and A are the same as defined in formula (I) or (IV), respectively), and a 5-carboalkoxypyrimidine derivative represented by the formula (I) or (IV) is obtained. However, the above-mentioned object is achieved thereby.

The compound of formula (I) has the following formula

[0018]

[Chemical 14]

As shown in the formula (wherein R ¹ , R ² and R ³ are the same as defined in the formula (I)), a tautomer (I ′) exists and usually the tautomer (I ′) is present. It is understood that it exists in the form of a mixture of the compound of I) and its tautomer (I ′). In the present specification, when simply referring to the compound of the formula (I), it means the compound of the formula (I) or its tautomer (I ′) or a mixture thereof.

Examples of the alkyl in the above formulas include linear, branched or cyclic alkyl, preferably C ₁ -C ₆ alkyl. For example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, t-butyl, n-pentyl, isopentyl, neopentyl, s-pentyl, t-pentyl, n-hexyl, isohexyl, neohexyl, Examples are s-hexyl and t-hexyl. The alkyl may have 1 to 3 substituents selected from the group consisting of halogen, amino and cyano.

The aryl in each of the above formulas is preferably a C _{6 to} C ₁₂ aryl such as phenyl, α-naphthyl or β-naphthyl. The above aryl may have 1 to 3 substituents selected from the group consisting of alkyl, halogen, amino and cyano.

Examples of the heteroaryl in each of the above formulas include heteroaryls containing N, S and / or O in the ring, and examples thereof include pyridinyl, pyrimidinyl, furyl, thienyl, pyrrolyl, quinolyl and isoquinolyl. To be done. The heteroaryl may have 1 to 3 substituents selected from the group consisting of alkyl, halogen, amino and cyano.

The aralkyl in each of the above formulas is a group in which the above alkyl is substituted with the above aryl group, and preferably a group in which a C _{1 to} C ₆ alkyl is substituted with a C _{6 to} C ₁₂ aryl is mentioned. . For example, benzyl, phenethyl and phenylpropyl are exemplified. The above aryl is
It may have 1 to 3 substituents selected from the group consisting of alkyl, halogen, amino and cyano.

According to the method of the present invention, as described above, first, the compound of formula (I) is added to the compound of formula (R ⁴ O) ₂ POX ¹ (wherein R ⁴ is alkyl) in the presence of a base. , Aralkyl, aryl, heteroaryl, and a group selected from the group consisting of these groups having a substituent, X ¹ represents halogen), and a halophosphate (II) represented by III) is obtained.

[0025]

[Chemical 15]

(In the formulas (I) and (III), R ¹ ,
R ² and R ³ each independently represent a group selected from the group consisting of hydrogen, alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent,
And R ⁴ represents a group selected from the group consisting of alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent).

Examples of the halogen contained in the halophosphate (II) include chlorine, bromine and iodine, and preferably chlorophosphate is used.

As the base used in the esterification reaction together with the halophosphate ester (II), an organic base or an inorganic base can be used. In the present invention,
Triethylamine, triisopropylamine, N, N-
Trialkylamines such as diisopropylethylamine and DBU are preferably used, and triethylamine is most preferably used.

Examples of the solvent used in the above phosphoric acid esterification reaction include acetonitrile, dichloromethane, dichloroethane, benzene, toluene and ethyl acetate, and preferably acetonitrile is used.

The reaction temperature for the above phosphoric acid esterification reaction is
It is usually -30 ° C to room temperature, and the reaction time is usually 1 to 6 hours.

Next, the above phosphoric acid ester (III) and the formula

[0032]

[Chemical 16]

(In the formula, A represents alkyl, aralkyl, aryl, SR ⁵ , OR ⁶ or NR ⁷ R ⁸ , and R ⁵ , R ⁶ ,
R ⁷ and R ⁸ each independently represent a group selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, aralkyl, alkylsulfonyl or arylsulfonyl, and these groups having a substituent). Reaction with an acid addition salt of amidine (IV)

[0034]

[Chemical 17]

A 5-carboalkoxypyridimine derivative (V) represented by the formula (wherein R ¹ , R ² , R ³ and A are the same as defined in formula (I) or (IV)) is obtained. The reaction is carried out in a solvent in the presence of a base. The amidine (IV) is preferably used in the form of an acid-added salt, and the acid may be either an organic acid or an inorganic acid. In the present invention, it is more preferable to use an inorganic acid, and for example, hydrochloric acid, nitric acid, carbonic acid, sulfuric acid and the like are particularly preferable. Depending on the kind of the substituent A of amidine (IV), the reaction conditions, that is, the kinds of base and solvent used,
And the reaction temperature and the reaction time are appropriately selected.

The substituent A in the amidine (IV) is alkyl, aralkyl, aryl, SR ⁵ or OR ⁶ (R
⁵ and R ⁶ each independently represent hydrogen, alkyl, aryl, heteroaryl, aralkyl, alkylsulfonyl or arylsulfonyl, and a group selected from the group consisting of these groups having a substituent). As the above base, an inorganic weak base is used, and preferably K ₂ CO ₃ , NaHCO ₃ or the like is used. As the solvent, a polar aprotic solvent is used, and for example, dimethyl sulfoxide (DMSO), N, N-dimethylformamide (DMF) and the like are used. Reaction temperature is usually 50
The reaction time is usually 3 to 10 hours.

The substituent A is NR ⁷ R ⁸ (R ⁷ and R ⁸ each independently represent a group selected from the group consisting of hydrogen, alkyl, aryl, heteroaryl, aralkyl and these groups having a substituent. ), MOR ⁹ (M represents an alkali metal or an alkaline earth metal and R ⁹ represents an alkyl) is used as the base.
Alcohol is preferably used as the solvent, and examples thereof include methanol, ethanol, and isopropanol. The reaction temperature is usually room temperature to the reflux temperature (boiling point) of the solvent, and the reaction time is usually 1 to 3 hours.

As described above, according to the method of the present invention, the 5-carboalkoxypyrimidine derivative (V) can be efficiently obtained, which is a pyrimidine derivative useful as an inhibitor of HMG-CoA reductase. It can be used as a raw material.

[0039]

EXAMPLES The present invention will be described below with reference to examples, but these are merely examples and the present invention is not limited thereto.

Example 1 (a) Synthesis of compound (I)

[0041]

[Chemical 18]

Methyl isobutyryl acetate (XI) 4.
To a solution prepared by dissolving 32 g (30 mmol) in 8.64 ml of toluene, 7.72 g of 10% sodium hydroxide aqueous solution
(18 mmol) was added dropwise under ice cooling over 10 minutes.
To the solution was further added 33% aqueous sodium hydroxide solution 7.
27 g (60 mmol) and p-fluorobenzoyl chloride (5.13 g, 32.4 mmol) were simultaneously added dropwise over 43 minutes, the temperature of the mixed solution was gradually raised to room temperature, and the mixed solution was stirred for 1 hour. Then, the toluene layer and the water layer were separated. The aqueous layer was acidified by adding 8.1 g of 20% hydrochloric acid, and toluene was further added to this aqueous layer for extraction.
These toluene layers were combined, washed with a saturated sodium hydrogen carbonate aqueous solution and a saturated sodium chloride aqueous solution, and then dried. Concentrate under reduced pressure to remove toluene, and remove methyl (E) -3-
(P-Fluorophenyl) -3-hydroxy-2-isobutyryl propenoate (Ia) (mixture of positional isomers of double bond) (hereinafter referred to as compound (Ia)) 6.83 g (yield 8
5.6%) was obtained as a liquid. The measurement results of the nuclear magnetic resonance spectrum (NMR) of the obtained compound (Ia) are shown below.

NMR (CDCl ₃ ): δ1.13 (6
H, d, J = 7Hz), 1.22 (6H, d, J = 7H
z), 2.45 to 2.60 (1H, m), 3.08 to
3.30 (1H, m), 3.53 (3H, s), 3.6
4 (3H, s), 7.01 to 8.0 (8H, m), 1
3.02 (1H, s), 17.41 (1H, s).

(B) Synthesis of phosphoric acid ester (III)

[0045]

[Chemical 19]

7.99 g of the compound (Ia) obtained in (a)
2.34 g (33 mmmo) of triethylamine was added to a solution of (30 mmol) in 80 ml of acetonitrile.
1) was added under ice cooling and stirred for 10 minutes. To this solution was added diphenyl chlorophosphate (IIa) 8.87 g (33 mmo).
l) Added and stirred for 4 hours. 5% hydrochloric acid was added to this mixed solution 10
After adding 0 ml and 100 ml of ethyl acetate and stirring, the ethyl acetate layer was separated. The obtained ethyl acetate solution was washed with a saturated sodium chloride aqueous solution and then dried. The ethyl acetate solution was concentrated under reduced pressure to remove ethyl acetate, and the obtained residue was washed with ethyl acetate-ethanol to give methyl (E) -2- (p-fluorobenzoyl) -3-diphenoxyphos Phenoyloxy-3-isopropylpropenoate (I
IIa) (hereinafter referred to as phosphate ester (IIIa)) 9.6
0 g (yield 64.2%) was obtained as crystals.

The results of nuclear magnetic resonance spectrum (NMR) measurement of the obtained phosphoric acid ester (IIIa) are shown below.

NMR (CDCl ₃ ): δ 1.30 (6
H, d, J = 7 Hz), 3.65 (3H, s), 3.8
5 (1H, m), 6.90 to 7.30 (12H, m),
7.80-7.92 (2H, m).

(C) Synthesis of 5-carboalkoxypyrimidine derivative (Va)

[0050]

[Chemical 20]

Phosphate ester (IIIa) obtained in (b)
1.99 g (4.00 mmol), 0.72 g (2.6 mmol) of s-methylisothiourea sulfate (IVa),
A mixture of 0.64 g (4.6 mmol) of anhydrous potassium carbonate and 10 ml of dimethyl sulfoxide was added, and the mixture was heated to 90 ° C.
The mixture was stirred for 7 hours and reacted. Add water to this reaction mixture,
Further, ethyl acetate was added for extraction. The ethyl acetate layer was separated, washed with water, and then concentrated under reduced pressure to obtain 1.46 g of a crude product. This crude product was subjected to silica gel column chromatography (silica gel 30 g, developing solvent:
Purified with n-hexane / dichloromethane = 3/1), methyl 4- (p-fluorophenyl) -6-isopropyl-2-methylthiopyrimidine-5-carboxylate (Va) (hereinafter referred to as 5
-Carboalkoxypyrimidine derivative (Va))
0.28 g (21% yield) was obtained as crystals.

The measurement results of the nuclear magnetic resonance spectrum (NMR) of the obtained 5-carboalkoxypyrimidine derivative (Va) are shown below.

NMR (CDCl ₃ ): δ1.31 (6
H, d, J = 7 Hz), 2.61 (3H, s), 3.1
4 (1H, hept, J = 7Hz), 3.70 (3H,
s), 7.13 (2H, m), 7.66 (2H, m).

(Example 2)

[0055]

[Chemical 21]

5.00 g (10.0 mmol) of the phosphoric ester (IIIa) obtained in (b) of Example 1 and 1.42 g (13.0 m) of 1-methylguanidine hydrochloride (IVb).
(mol) was suspended in 25 ml of anhydrous methanol under a nitrogen atmosphere. Sodium methoxide 2.8 was added to this suspension.
0 g (52.0 mmol) was added. The solution was heated to reflux for 1 hour 30 minutes. Methanol solution is ethyl acetate
It was partitioned in a 1% aqueous sodium chloride solution and the organic solvent layer was separated. This organic solvent layer was washed with a 5% aqueous sodium hydroxide solution and a 5% aqueous sodium chloride solution, and then dried using anhydrous magnesium sulfate. This organic solvent layer was concentrated under reduced pressure. Methanol-water was added to the obtained residue and the mixture was extruded and crystallized to give methyl 4- (p-fluorophenyl).
-6-isopropyl-2- (N-methylamino) pyrimidine-5-carboxylate (Vb) (hereinafter referred to as 5-carboalkoxypyrimidine derivative (Vb)) 1.27 g (yield 41.
7%) was obtained as white crystals.

The measurement results of the nuclear magnetic resonance spectrum (NMR) of the obtained 5-carboalkoxypyrimidine derivative (Vb) are shown below.

H-NMR (CDCl ₃ ): δ1.26
(6H, hept, J = 6.8Hz), 3.05 (3
H, d, J = 4.7 Hz), 3.16 (1H, hep
t, J = 6.8 Hz), 3.61 (3H, s), 5.3
0 (1H, b), 7.06 to 7.61 (4H, m).

(Example 3)

[0060]

[Chemical formula 22]

100 mg (0.2 mmol) of the phosphoric acid ester (IIIa) obtained in (b) of Example 1 was dissolved in 1.5 ml of anhydrous methanol, and 40 mg (0.4 mmol) of guanidine hydrochloride (IVc) was added to this solution. ) And 43 mg (0.8 mmol) of sodium methoxide were added. This solution was stirred at room temperature for 3 hours, and further heated under reflux for 2 hours for reaction. The solvent was distilled off from the reaction solution, water was added to the obtained residue, and the mixture was extracted with diethyl ether. The diethyl ether solution was washed with a saturated sodium chloride aqueous solution and dried. After concentration under reduced pressure, the resulting crude product was purified by silica gel column chromatography (developing solvent: methylene chloride / diethyl ether = 95/5) and methyl 4- (p-fluorophenyl) -6-isopropyl-2-aminopyrimidine- 5-carboxylate (Vc)
32 mg (hereinafter referred to as 5-carboalkoxypyrimidine derivative (Vc)) (yield 55.2%) was obtained as crystals.

The measurement results of the nuclear magnetic resonance spectrum (NMR) of the obtained 5-carboalkoxypyrimidine derivative (Vc) are shown below.

NMR (CDCl ₃ ): δ1.25 (6
H, d, J = 7 Hz), 3.13 (1H, m), 3.6
3 (3H, s), 5.24 (2H, bs), 7.10
(2H, m), 7.55 (2H, m).

[0064]

INDUSTRIAL APPLICABILITY According to the present invention, a compound (I) is used as an active ester and an acid addition salt of amidine is allowed to act thereon to form a pyrimidine ring in one step to efficiently synthesize a 5-carboalkoxypyrimidine derivative. can do.
According to the present invention, it is possible to efficiently obtain a 5-carboalkoxypyrimidine derivative on an industrial scale. The resulting 5-carboalkoxypyrimidine derivative is HMG-
It is preferably used as a raw material of a pyrimidine compound useful as an inhibitor of CoA reductase.

Claims (3)

[Claims] 1. The following formula (I): (In the formula, R ¹ , R ² and R ³ are each independently hydrogen,
Alkyl, aralkyl, aryl or heteroaryl, and a group selected from the group consisting of these groups having a substituent), a compound represented by the formula (R ⁴ O) ₂ P
Halo phosphate represented by OX ¹ (in the formula, R ⁴ represents a group selected from the group consisting of alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent, and X ¹ represents halogen) A step of reacting (II) in the presence of a base to obtain a phosphoric ester represented by the following formula (III): (Wherein R ¹ , R ² , R ³ and R ⁴ are the same as defined in formula (I) or (II), respectively) and the phosphoric acid ester (III) is represented by the following formula (IV): (In the formula, A is alkyl, aralkyl, aryl, S
R ⁵ , OR ⁶ or NR ⁷ R ⁸ is shown, and R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, alkyl, aryl,
Heteroaryl, aralkyl, alkylsulfonyl or arylsulfonyl, and a group selected from the group consisting of these groups having a substituent), which is reacted with an acid addition salt of amidine in the presence of a base to form a pyrimidine ring. And a step of forming the following formula (V): (In the formula, R ¹ , R ² , R ³ and A have the same definitions as in formula (I) or (IV), respectively), and a method for synthesizing the 5-carboalkoxypyrimidine derivative. 2. A phosphoric acid ester represented by the following formula (III): Wherein R ¹ , R ² and R ³ each independently represent a group selected from the group consisting of hydrogen, alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent, and R ⁴ represents a group selected from the group consisting of alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent). 3. A phosphoric acid ester represented by the following formula (III): Wherein R ¹ , R ² and R ³ each independently represent a group selected from the group consisting of hydrogen, alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent, and R ⁴ represents a group selected from the group consisting of alkyl, aralkyl, aryl or heteroaryl, and these groups having a substituent).
Is represented by the following formula (IV): (In the formula, A is alkyl, aralkyl, aryl, S
R ⁵ , OR ⁶ or NR ⁷ R ⁸ is shown, and R ⁵ , R ⁶ , R ⁷ and R ⁸ are each independently hydrogen, alkyl, aryl,
Heteroaryl, aralkyl, alkylsulfonyl or arylsulfonyl and a group selected from the group consisting of these groups having a substituent), which is reacted with an acid addition salt of amidine in the presence of a base to form a pyrimidine ring. The following formula (V) including the steps of (Wherein R ¹ , R ² , R ³ and A have the same definitions as in formula (III) or (IV), respectively).