JPH02273688A - Cyclic phosphite derivatives - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION Field of the Invention The present invention relates to novel cyclic phosphite derivatives.

Conventional techniques and their problems General formula O OO [wherein A may be substituted with a lower alkyl group 1,
Indicates a 3-propylene group. ] The acetonyl cyclic phosphate derivative represented by
It is an important compound as a raw material for synthesizing calcium channel blockers and antihypertensive agents (for example, JP-A-61-6368).
(See Publication No. 8).

Conventionally, the acetonyl cyclic phosphate derivative of the above general formula (1) has been produced according to the method shown in the following reaction formula (Chem, Pharm, Bull, 35(10)
.

4144-4154).

\ 1 OCH2C0CH5 c In the formula, A is the same as above. ] The above method requires special equipment because acetone bromide, which is a tear gas and has strong toxicity, is used as a raw material, and in addition, it requires special equipment to separate the toxic methyl bromide that is a by-product of the reaction from the target compound. This method has the drawback that the post-treatment becomes complicated, leading to a decrease in the yield of the target compound. Furthermore, the other starting material, phosphorous acid ester, has a unique bad odor and is a compound that is difficult to handle in large quantities.

In this way, in the above conventional method, the target general formula (1
) cannot be produced industrially advantageously.

Means for Solving the Problems In view of the current situation, the present inventor has conducted extensive research in order to develop an industrially advantageous method for producing the acetonyl cyclic phosphate derivative of the above general formula (1). I came. As a result, it has been found that a cyclic phosphite derivative represented by the following general formula (2), which has not been described in any literature, can be used as an intermediate for synthesizing the compound of the above general formula (1).

The present invention was completed based on this knowledge.

The cyclic phosphite derivative of the present invention is a compound that has not been described in any literature, and is represented by the following general formula (2)% [where A is the same as above]. ] In this specification, A is a 1,3-propylene group, and this group may be substituted with a lower alkyl group such as a methyl group, ethyl group, n-propyl group, or isopropyl group.

The cyclic phosphite derivative represented by the above general formula (2) is, for example, a general formula [where A is the same as above]. X represents a halogen atom. ] By reacting the compound represented by hydroxyacetone with hydroxyacetone! ! ! will be built.

In the reaction system of the above reaction, as a dehalogenating agent, organic tertiary amines, specifically aliphatic tertiary amines such as trimethylamine and triethylamine, pyridine, quinoline,
It is desirable to have an aromatic tertiary amine such as lutidine present. Further, the above reaction is usually carried out in a suitable solvent. The solvent is not particularly limited as long as it is inert to the reaction, and examples include ketones such as acetone and methyl ethyl ketone, aromatic hydrocarbons such as benzene, toluene, and xylene, dioxane, tetrahydrofuran, and diethyl ether. Ethers such as, halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform, etc. are used. The ratio of the compound of general formula (3) to hydroxyacetone is not particularly limited, but the ratio of the latter to the former is usually 0.5 to 2.
It is preferable to use about twice the molar amount, preferably about the same molar amount. The above reaction normally proceeds suitably at about -10 to 50°C, preferably about 0 to 20°C, and is generally completed in about 1 to 4 hours.

In the above reaction, the general formula (
The compound 3) is a known compound that is easily available.

The cyclic phosphite derivative (2) thus obtained can be easily isolated and purified from the reaction mixture according to commonly used industrial operations such as filtration, concentration, and distillation.

According to the present invention, the acetonyl cyclic phosphate derivative of the general formula (1) can be advantageously produced industrially by reacting the cyclic phosphite derivative of the general formula (2) with an alkyl halide. .

Examples of the alkyl halides used include iodides such as methyl iodide, ethyl iodide, butyl iodide, bromides such as methyl bromide, ethyl bromide, and propyl bromide, methyl chloride,
Examples include chlorides such as ethyl chloride and butyl chloride. The amount of such alkyl halide to be used may be a normal catalytic amount, preferably 0 to
．． It is 1 to 10 mol%.

Although the reaction between the compound of general formula (2) and the alkyl halide can be carried out without a solvent, it is usually carried out in a suitable solvent. As the solvent, a wide variety of known solvents can be used as long as they are inert to the above reaction, such as aromatic hydrocarbons such as benzene, toluene and xylene, ethers such as dioxane, tetrahydrofuran and diethyl ether,
Examples include ketones such as acetone, methyl ethyl ketone, and cyclohexanone. The above reaction is usually carried out at room temperature to 15
Proceeds at about 0'C, preferably about 70 to 120C,
Generally, the reaction is completed in about 4 to 5 hours9.

The acetonyl cyclic phosphate derivative (1) thus produced can be easily isolated and purified from the reaction mixture according to commonly used industrial operations such as filtration and distillation.

The above method eliminates all the drawbacks of conventional methods, and uses acetonyl cyclic phosphate derivative (1).
This is a far superior industrial manufacturing method.

Example Examples are given below to further clarify the present invention.

Reference example 1 3 neopentyl glycol in 100 mf2 methylene chloride
12.5 (J) was added, and 412 g of phosphorus trichloride was added dropwise with stirring while cooling the mixture to 10°C in an ice-water bath. Hydrogen chloride was generated and dissolved. After standing at room temperature overnight, the solvent was removed. The residue was distilled under reduced pressure (30 mmH).
c+) to obtain a colorless oil of 5,5-dimethyl-2-chloro-1,2°3-dioxaphosphorinane distilled at 88-90°C.

Yield: 477 g, yield: 94% Reference Example 2 138 q of phosphorus trichloride was added to 300 mQ of chloroform and dissolved therein, 76 C of 1,3-propanediol was added dropwise at 5 to 10'C under water cooling, and the mixture was heated at room temperature for 3 hours. Upon stirring, hydrogen chloride evolution stopped. When chloroform is distilled off under reduced pressure and the remaining oil is distilled under reduced pressure, the
C/ 2-chloro-1,2,3 distilled at 20 mmHg
-Dioxaphosphorinane was obtained as a colorless oil.

Yield 73.5 g, yield 52% Example 1 28.8 CI of hydroxyacetone was mixed with 34.8 CI of anhydrous pyridine.
8C] and 200 mQ of tetrahydrofuran), the mixture was cooled with water to 10°C, and at the same temperature, 5,5-dimethyl-2-chloro-1,2,3-dioxaphosphorinane 67
．． A solution of 4CJ dissolved in 50 m+2 of tetrahydrofuran was added dropwise. The reaction solution was stirred at room temperature for 2 hours, and then the precipitated pyridine hydrochloride was filtered. The solvent was concentrated under reduced pressure and the residue was vacuum distilled to give 5,5-dimethyl-2-acetonyloxy-1,2
, 3-dioxaphosphorinane was obtained.

Yield 69.8g, yield 84.5% IR spectrum: 2960.2880,1720,1350°1130.
720cm” Elemental analysis value (as C8H+ 30t P) CH Calculated value (%) 46.60 7.33 Experimental value (%)
46.55 7.28 Example 2 5. Dissolve 67 g of 5-dimethyl-2-chloro-1,2,3-dioxaphosphorinane in 200 mQ of toluene,
To this was added a solution of 28.8 g of hydroxyacetone and 34.8 C of pyridine in 50 ml of toluene under ice-water cooling for 5 to 10 minutes.
It was added dropwise at C. After stirring this at room temperature for 4 hours,
1'1II2 was added to dissolve the pyridine hydrochloride. The toluene layer was dried over anhydrous magnesium 5A acid and then concentrated under reduced pressure. Then vacuum distilled to 89-94°C/1
, 2 mmHc+ colorless oil to give 5,5-dimethyl-2-acetonyloxy-1,2,3-dioxaphosphorinane.

Yield 71C7, yield 86% Example 3 2-chloro-1,2,3-dioxaphosphorinane 76C
J was dissolved in ethyl ether 1901TIf2, and a mixed solution of 40 g of hydroxyacetone, 43 cx of pyridine, and 30 mQ of ethyl ether was added dropwise to the solution at 5° C. or below while cooling with water. After stirring overnight at room temperature, the precipitate was filtered and washed with ethyl ether. The mother liquor and washings were combined and concentrated. The residue was vacuum distilled to 83-86°C/1.5mm
2-a-cetonyloxy-1 as a colorless oil of Hg
, 2,3-dioxophosphorinane was obtained.

Yield: 64g, yield 68% IR spectrum: 2940.1725, 1340, 1135°750cm
' Elemental analysis value (as Cs Hs Oa P) CH Calculated value (%) 40,45 6.23 Experimental value (%)
40,25 6.20 Example 4 5.5-dimethyl-2-acetonyloxy-1°2.3
- Dioxaphosphorinane 69.80 to toluene 70mQ
1 mQ of methyl iodide was added to 100 mQ of methyl iodide.
The reaction was carried out at ℃ for 5 hours. After cooling, the precipitated crystals were filtered,
Recrystallized from 100ml of toluene to give 5 as white crystals.
,5-dimethyl-2-acetonyl-2,-oxo-1,
2,3-dioxaphosphorinane was obtained.

Yield: 47.7 CI, yield: 68% Melting point: 91.9°C (melting point did not drop even when mixed with separately synthesized sample) IR spectrum (KBr method): 2970.2890.1710, 1470°1280.
1105.820 cm” Example 5 5.5-dimethyl-2-acetonyloxy-1°2.3
- Dioxaphosphorinane 71.1 CI xylene 100
-, 5ml of ethyl bromide was added thereto, and the mixture was reacted at 105°C for 4 hours.

After cooling, filter the precipitated crystals and add 100 mf2 of toluene.
Recrystallized from 5,5-dimethyl-2- as white crystals.
Acetonyl-2-oxo-1,2,3-dioxaphosphorinane was obtained.

Yield 44.5C], yield 62% The melting point and IR spectrum of this compound matched those of the compound obtained in Example 4.

Example 6 35 Cl of 2-acetonyloxy-1,2,3-dioxaphosphorinane was mixed with 50 ml of toluene, 0.5 mQ of butyl iodide was added thereto, and the mixture was reacted at 95° C. for 8 hours. Toluene was distilled off under reduced pressure, and the residual oil was distilled under vacuum to obtain 2-acetonyl-2-okyne-1°2.3-dioxaphosphorinane as a pale yellow oil distilled at 164-b mmHg.

Yield 22.8g, yield 65% IR spectrum (liquid film); 2990.2910,1705° 1150, 805cm-1 1280° (Hereafter Up)

Claims (3)

[Claims] (1) General formula ▲ Numerical formula, chemical formula, table, etc. ▼ [In the formula, A may be substituted with a lower alkyl group 1,
Indicates a 3-propylene group. ] A cyclic phosphite derivative represented by: (2) General formula▲There are mathematical formulas, chemical formulas, tables, etc.▼ [In the formula, A is the same as above. X represents a halogen atom. ] A method for producing a cyclic phosphite derivative, which comprises reacting a compound represented by the following with hydroxyacetone to obtain the cyclic phosphite derivative according to claim (1). (3) A general formula characterized by reacting the cyclic phosphite derivative described in claim (1) with an alkyl halide ▲ There are numerical formulas, chemical formulas, tables, etc. ▼ [In the formula, A is the same as above. ] A method for producing an acetonyl cyclic phosphate derivative represented by: