JP2000290265A - Preparation of oxazolidine-2-ones - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain oxazolidine-2-ones in an excellent yield by reacting dioxolane-2-ones with isocyanates in the presence of a fluoride without reducing optical purity in the case of using an optical active starting material. SOLUTION: The oxazolidine-2-ones of formula III are obtained by reacting (A) the 1,3-dioxolane-2-ones of formula I (R1 to R4 are each H, an alkyl, an alkoxy, an aralkyl, an aryl or the like), (B) the isocyanates of formula II (R5 is H, an alkyl, an aralkyl, a halogenosulfonyl, a trialkylsillyl or the like) in the presence of (C) the fluorine salt [preferably, an alkali (alkaline earth) metal salt, especially CsF or KF]. This reaction is preferably carried out by using N,N'-dimethylformamide or dimethylsulfoxide as the reaction solvent The component B is preferably used in amount of 0.8-1.5 equivalent to the component A.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

[0001] The present invention relates to a novel method for producing oxazolidine-2-ones useful as synthetic intermediates for pharmaceuticals, agricultural chemicals and the like.

[0002]

2. Description of the Related Art Oxazolidin-2-ones are industrially useful compounds which have been known for a long time. In particular, its usefulness in the pharmaceutical field is high, and many pharmaceuticals using this compound as a synthetic intermediate have been developed in recent years. Therefore, there are many and various reports on the production method of this compound. Among them, one of the efficient production methods is oxazolidin-2-one by ring conversion from 1,3-dioxolan-2-ones. There is a method of leading to ons. This method uses 1,3-dioxolan-2 as a raw material.
-Ones are relatively easily available 1,2-diols, and are efficient in that they can be converted to oxazolidin-2-ones from the easily available 1,2-diols in a small number of steps. It can be said to be a manufacturing method. Particularly, a method of reacting 1,3-dioxolan-2-ones with an isocyanate derivative with ethylene carbonate or propylene carbonate in the presence of lithium chloride (Chem. Ber., 93 , 1975)
(1960)) is known.

[0003]

However, this method requires the reaction to be carried out under severe conditions because of the low activity of lithium chloride. When the optically active 1,3-dioxolan-2-ones are used as a raw material, the optical purity of the obtained target product is significantly reduced.

[0004]

Means for Solving the Problems The inventors of the present invention have prepared a fluorine salt of a 1,3-dioxolan-2-one represented by the following formula (1) and an isocyanate represented by the following formula (2). The present invention has been found that the oxazolidin-2-ones represented by the following formula (3) can be produced without impairing optical purity by using the optically active substance in a good yield by reacting in the presence of the compound. Was completed. That is, the present invention provides the following formula (1)

Embedded image (Wherein R ¹ , R ² , R ³ and R ⁴ are a hydrogen atom, a linear or branched alkyl group having a linear or branched or cyclic alkyl group, an alkoxy group, a substituted amino group or an alkylthio group, a substituted or 1,3-dioxolan-2-ones represented by an unsubstituted aralkyl group or a substituted or unsubstituted aryl group) or an optically active substance thereof, and the following formula (2)

Embedded image (Wherein R ⁵ represents a hydrogen atom, a linear, branched or cyclic alkyl group, a substituted or unsubstituted aralkyl group, a halogenosulfonyl group, a trialkylsilyl group, a substituted or unsubstituted arylsulfonyl group, or a substituted or unsubstituted Is substituted with an isocyanate represented by the following formula (3):

Embedded image (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ mean the same groups as described above) or a process for producing an optically active form thereof.

In the formula (1), specific examples of the groups represented by R ¹ , R ² , R ³ and R ⁴ include a hydrogen atom, methyl,
Linear, branched or cyclic alkyl groups such as ethyl, isopropyl, cyclopropyl, cyclohexyl groups, alkoxyalkyl groups such as methoxymethyl, methoxyethyl, benzyloxymethyl groups, dimethylaminomethyl, piperidinoethyl, morpholinoethyl, N-benzyloxy Substituted aminoalkyl groups such as carbonylpiperazinomethyl, N-methylpiperazinomethyl, N-ethoxycarbonylmethylpiperazinomethyl group, alkylthioalkyl groups such as methylthiomethyl and methylthioethyl groups, benzyl, methylbenzyl, methoxybenzyl And substituted or unsubstituted aryl groups such as phenyl, tolyl, and methoxyphenyl groups. Among them, preferred groups are a hydrogen atom, C ₁ -C ₄
Are a lower alkyl group, a methoxymethyl group, a benzyloxymethyl group, and a benzyl group.

In the formula (2), specific examples of the group represented by R ⁵ include a hydrogen atom, a linear, branched or cyclic alkyl group such as methyl, ethyl, isopropyl and cyclopropyl, benzyl and methylbenzyl. , A substituted or unsubstituted aralkyl group such as a methoxybenzyl group, a halogenosulfonyl group such as a chlorosulfonyl group, a trialkylsilyl group such as a trimethylsilyl group, benzenesulfonyl, o-toluenesulfonyl, p-toluenesulfonyl,
Substituted or unsubstituted arylsulfonyl group such as 4-chlorobenzenesulfonyl group, substituted or unsubstituted aryl group such as phenyl, cyanophenyl, tolyl, methoxyphenyl group, naphthalene, polycyclic aromatic group such as anthracene, Examples include aromatic heterocyclic groups such as furyl, thienyl, pyridyl, pyrimidyl, quinolyl, benzofuryl, and benzothienyl. Among them, preferred groups are
Hydrogen atom, a lower alkyl group of C ₁ -C _4, benzyl group, phenyl group, cyanophenyl group, a naphthyl group, a thienyl group.

The amount of isocyanates (2) used in this reaction is 1,3-dioxolan-2-ones (1)
0.5 equivalent or more, preferably 0.8 to 1.
It is 5 equivalents, more preferably 0.9 to 1.1 equivalents.

The fluorine salt used in this reaction is preferably a quaternary ammonium salt of fluorine, an alkali metal salt of fluorine or an alkaline earth metal salt of fluorine, particularly preferably an alkali metal salt of fluorine or alkaline earth metal of fluorine. It is a metal salt. In addition, the reaction can be carried out in the same manner by using them alone or as a mixture of two or more kinds, or by using those supported on a suitable carrier. Examples of the quaternary ammonium salt of fluorine include tetramethylammonium fluoride, tetraethylammonium fluoride, tetrabutylammonium fluoride, tetraoctylammonium fluoride, and benzyltrimethylammonium fluoride. Alkali metal salts of fluorine include sodium fluoride, potassium fluoride and cesium fluoride, and alkaline earth metal salts of fluorine include magnesium fluoride and calcium fluoride. Examples of the carrier that can be used include zeolite, alumina, silica gel, molecular sieves, and modified products thereof.

The amount of the fluorine salt is 0.001 to 10 based on the reaction substrate 1,3-dioxolan-2-ones (1).
The equivalent is preferable, and particularly preferably 0.01 to 1 equivalent. If the amount is less than 0.001 equivalent, the progress of the reaction is very slow.
Although it may be used in excess of 10 equivalents, it is not economical. Further, depending on the solvent, excess fluorine salt becomes insoluble, so that stirring becomes difficult.

Solvents used in this reaction include aprotic polar solvents such as N, N-dimethylformamide and dimethylsulfoxide, diglyme, triglyme, 1,4-dioxane, 1,2-dimethoxyethane, t Ether solvents such as -butyl methyl ether, chloroform, chlorine solvents such as dichloroethane and the like, and a mixed solvent thereof, and the like.
N, N-dimethylformamide and dimethylsulfoxide.

The reaction temperature ranges from 50 ° C. to the reflux temperature of the solvent under heating, preferably from 100 ° C. to 150 ° C. After completion of the reaction, insolubles such as metal salts of fluorine are removed by filtration, excess solvent is distilled off under reduced pressure, and the residue is subjected to purification treatment such as distillation, recrystallization, silica gel column chromatography, etc. Oxazolidin-2-ones (3) or an optically active form thereof are obtained.

[0012]

The present invention will be specifically described below with reference to examples. However, the present invention is not limited to these examples.

Example 1 Preparation of (R) -3-phenyl-5-methoxymethyloxazolidin-2-one: phenyl isocyanate
0 g (0.151 mol) of dimethyl sulfoxide 1
Dissolved in 100 mL, and 2.29 g of cesium fluoride (15.
1 mmol), (S) -4-methoxymethyl-1,3
-Dioxolan-2-one 20.0 g (0.151 m
ol and an optical purity of 98% ee) are sequentially added, and the mixture is stirred at 140 ° C. for 9 hours under an argon stream. After filtering off the insolubles and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R) -3-phenyl-
5-methoxymethyloxazolidin-2-one 29.9
g (yield 95.4%, optical purity 98% ee) was obtained.

Example 2 Preparation of (R) -3-phenyl-5-methoxymethyloxazolidin-2-one: phenyl isocyanate
0 g (0.151 mol) was dissolved in 100 mL of N, N-dimethylformamide, and 2.29 g of cesium fluoride was dissolved.
(15.1 mmol), 20.0 g of (S) -4-methoxymethyl-1,3-dioxolan-2-one (0.1
51 mol and an optical purity of 98% ee) are sequentially added, and the mixture is stirred at 140 ° C. for 8 hours under an argon stream. After filtering off the insoluble matter and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R) -3-
28.7 g of phenyl-5-methoxymethyloxazolidin-2-one (91.7% yield, 98% ee optical purity)
I got

Example 3 (S) -3-phenyl-5-methyloxazolidine-2
Preparation of -one: 23.3 g of phenyl isocyanate
(0.196 mol) in dimethyl sulfoxide 100
and dissolved in cesium fluoride 2.98 g (19.6).
mmol) and 20.0 g (0.196 mol, optical purity 99% ee) of (S) -4-methyl-1,3-dioxolan-2-one were added in succession, and 8
Stir for hours. After filtering off the insoluble matter and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give 32.0 g of the title (S) -3-phenyl-5-methyloxazolidine-2-one (yield). 92.1% and an optical purity of 99% ee) were obtained.

Example 4 Preparation of (R) -3- (2-naphthyl) -5-methoxymethyloxazolidine-2-one: 25.6 g (0.151 mol) of 2-naphthyl isocyanate was dissolved in 100 mL of dimethyl sulfoxide. , Cesium fluoride 2.2
9 g (15.1 mmol), (S) -4-methoxymethyl-1,3-dioxolan-2-one 20.0 g
(0.151 mol, 98% ee of optical purity) are sequentially added, and the mixture is stirred at 140 ° C. for 8 hours in an argon stream. After filtering off the insoluble matter and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R).
Thus, 34.0 g (yield: 87.3%, optical purity: 98% ee) of -3- (2-naphthyl) -5-methoxymethyloxazolidin-2-one was obtained.

Example 5 Preparation of (R) -5-benzyloxymethyl-3- (4-cyanophenyl) oxazolidine-2-one: 13.8 g (96.06 m) of 4-cyanophenylisocyanate
mol) in 100 mL of dimethyl sulfoxide,
1.46 g (9.606 mmol) of cesium fluoride,
20.0 g (96.06 mmol, optical purity 98% ee) of (S) -4-benzyloxymethyl-1,3-dioxolan-2-one were sequentially added, and the mixture was added under an argon stream at 140 ° C.
Stir at C for 8 hours. After filtering off the insolubles and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R) -5-benzyloxymethyl-3- (4-cyanophenyl) oxazolidin-2-
ON 23.1 g (yield 78.0%, optical purity 98% e
e) was obtained.

Example 6 (R) -3- (6-benzyloxy-2-naphthyl)-
Preparation of 5-methoxymethyloxazolidin-2-one:
6-benzyloxy-2-naphthyl isocyanate 4
1.7 g (0.151 mol) was dissolved in 100 mL of dimethyl sulfoxide, and 2.29 g of cesium fluoride (1
5.1 mmol), (S) -4-methoxymethyl-
20.0 g of 1,3-dioxolan-2-one (0.15
1 mol and 98% ee) are sequentially added, and the mixture is stirred at 140 ° C. for 8 hours under a stream of argon. Filter off insolubles,
After the filtrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R) -3- (6).
-Benzyloxy-2-naphthyl) -5-methoxymethyloxazolidin-2-one (45.2 g, yield 82.2)
3% and an optical purity of 98% ee) were obtained.

Example 7 Preparation of (R) -5-benzyloxymethyl-3- (2-thienyl) oxazolidine-2-one: Dissolve 12.0 g (96.06 mmol) of 2-thienyl isocyanate in 100 mL of dimethyl sulfoxide. Then, 1.46 g (9.606 mmol) of cesium fluoride, 20.0 g (96.06 mmol, (S) -4-benzyloxymethyl-1,3-dioxolan-2-one, optical purity 98% e) of (S) -4-benzyloxymethyl-1,3-dioxolan-2-one
e) is added in sequence, and the mixture is stirred at 140 ° C. for 9 hours under a stream of argon. After filtering off the insoluble matter and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R) -5-benzyloxymethyl-3- (2-
22.3 g of (thienyl) oxazolidin-2-one (yield: 80.3%, optical purity: 98% ee) were obtained.

Example 8 Preparation of (R) -3- (n-butyl) -5-methoxymethyloxazolidine-2-one: 11.3 g (0.114 mol) of n-butyl isocyanate was dissolved in 100 mL of dimethyl sulfoxide. 1.72 g of cesium fluoride
(11.4 mmol), 15.0 g of (S) -4-methoxymethyl-1,3-dioxolan-2-one (0.1
14 mol and 98% ee of optical purity are sequentially added, and the mixture is stirred at 140 ° C. for 9 hours under an argon stream. After filtering off the insolubles and concentrating the filtrate under reduced pressure, the residue was purified by silica gel column chromatography to give the title (R) -3-
(N-butyl) -5-methoxymethyloxazolidine-
18.7 g of 2-one (87.6% yield, 98% optical purity)
ee) was obtained.

[0021]

According to the method of the present invention, the desired oxazolidine-2-ones (3) or their optically active substances are obtained in good yield, and in the case of the optically active substances, the optical purity is not impaired. Can be manufactured.

Claims (6)

[Claims] [Claim 1] The following formula (1) (Wherein R ¹ , R ² , R ³ and R ⁴ are a hydrogen atom, a linear or branched alkyl group having a linear or branched or cyclic alkyl group, an alkoxy group, a substituted amino group or an alkylthio group, a substituted or 1,3-dioxolan-2-one represented by an unsubstituted aralkyl group or a substituted or unsubstituted aryl group) and the following formula (2): (In the formula, R ⁵ is a hydrogen atom, a linear, branched or cyclic alkyl group, a substituted or unsubstituted aralkyl group, a halogenosulfonyl group, a trialkylsilyl group, a substituted or unsubstituted arylsulfonyl group, or a substituted or unsubstituted group. Is substituted with an isocyanate represented by the following formula (3): (Wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ represent the same groups as described above). 2. The following formula (1a): (Wherein R ¹¹ , R ²¹ , R ³¹ and R ⁴¹ represent a hydrogen atom, C ₁
-C ₄ lower alkyl group, a methoxymethyl group, means a benzyloxymethyl group or a benzyl group. ) And 1,3-dioxolan-2-ones represented by the following formula (2)
a) embedded image (Wherein R ⁵¹ is a hydrogen atom, a C ₁ -C ₄ lower alkyl group,
It means a benzyl group, a phenyl group, a cyanophenyl group, a naphthyl group or a thienyl group. ) Is reacted with a isocyanate represented by the following formula (3a): (Wherein R ¹¹ , R ²¹ , R ³¹ , R ⁴¹ and R ⁵¹ mean the same groups as described above). 3. The method for producing oxazolidin-2-ones according to claim 1, wherein the fluorine salt is an alkali metal salt or an alkaline earth metal salt of fluorine. 4. The oxazolidine-2 according to claim 1, wherein the fluorine salt is cesium fluoride or potassium fluoride.
-A method for producing ons. 5. The process according to claim 1, wherein the reaction solvent is N, N-dimethylformamide or dimethylsulfoxide. 6. An optically active 1,3-dioxolan-2-amine.
The method for producing an oxazolidin-2-one according to any one of claims 1 to 5, wherein the optically active oxazolidine-2-one is produced using the one.