JPH0733709A - Production of oxalic acid monoester compound - Google Patents

Abstract

PURPOSE:To selectively produce an oxalic acid monoester from oxalic acid in one step and high yield under mild condition. CONSTITUTION:An oxalic acid monoester of formula II is produced by reacting oxalic acid with a compound of formula I [R is residue obtained by removing hydroxyl group from corresponding alcohol (ROH); X is a reactive residue] in the presence of a base preferably in a proper solvent. The reaction is effective for producing the compound in high efficiency even when the ester residue is originated from an alcohol unstable to acid, alkali, etc., especially an ester residue for getting a prodrug to promote the peroral absorption of beta-lactam antibacterial agent. The compound of formula II is easily converted to an oxalic acid monoester halide compound of formula III (Y is halogen) by reacting with a halogenating agent and is usable for the production of a penem or cephem compound of formula IV (R<2> is OH-substituted alkyl; R<3> is organic group; Z is CH2CH2, SCH2, OCH2, CH2, etc.; R<4> is alkyl).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a method for producing an oxalic acid monoester compound.

[0002]

Oxalic acid monoester halides derived from oxalic acid monoesters are useful as synthetic intermediates for oral β-lactam antibacterial agents and the like. Above all, β
-In the field of lactam type antibacterial agents, it is useful as a synthetic intermediate for producing a compound which is converted into a prodrug to improve oral absorption (JP-A-62-99379, WO91).
/ 14691, JP-A-2-49783).

Oxalic acid monoester halides used for such purpose generally have unstable alcohols corresponding to ester residues (eg, pivaloyloxymethyl group, acetoxymethyl group, isobutyryloxymethyl group). , Its synthesis involved great difficulties.

For example, Japanese Patent Laid-Open No. 62-99379 discloses a method for producing oxalic acid monopivaloyloxymethyl chloride by reacting oxalyl chloride with benzyl alcohol to give oxalic acid monobenzyl chloride, which is then hydroxylated. Oxalic acid monobenzyl ester was hydrolyzed with an aqueous ammonium solution, then treated with tetrabutylammonium hydrogensulfate and sodium hydrogen carbonate, and then reacted with pivaloyloxymethyl chloride to give oxalic acid benzyl pivaloyloxymethyl. ,
Further, a method of chlorination after catalytic reduction is disclosed.

Further, WO 91/14691 discloses a method for producing oxalic acid monoacetoxymethyl chloride by reacting a potassium salt of glycolic acid with acetoxymethyl bromide to give acetoxymethyl glycolate, which is oxidized with chromium trioxide. A method of making monoacetoxymethyl oxalate and then chlorination is disclosed.

However, these known methods have drawbacks such as requiring multiple steps, requiring a purification step by silica gel column chromatography, and using a toxic oxidizing agent. Therefore, it has been desired to develop a production method capable of easily synthesizing oxalic acid monoester and its halide.

[0007]

DISCLOSURE OF THE INVENTION The present invention provides a novel industrially advantageous process for producing an oxalic acid monoester and its halide compound.

[0008]

As a result of various researches conducted by the present inventors, the ester residue of oxalic acid monoester is not only derived from a stable alcohol, but also unstable to, for example, acid or alkali. It has been found that oxalic acid monoesters can be selectively obtained from oxalic acid in a single step in a high yield even if they are derived from different alcohols.

That is, according to the present invention, the general formula [I]

[0010]

[Chemical 8]

(Where R is the corresponding alcohol (RO
H) represents a residue obtained by removing a hydroxyl group. ), An oxalic acid monoester compound represented by the following general formula [II]

[0012]

[Chemical 9]

(In the formula, X represents a reactive residue, and R has the same meaning as described above.).

In the starting compound [II], the symbol R, that is, the residue obtained by removing the hydroxyl group from the corresponding alcohol (ROH) is not particularly limited, and may be a residue obtained by removing the hydroxyl group from a stable alcohol. It may be a residue obtained by removing a hydroxyl group from an alcohol which is itself unstable, for example, an alcohol which is unstable to acid or alkali.

Examples of the residue obtained by removing a hydroxyl group from a stable alcohol include an alkyl group having 1 to 10 carbon atoms, an aryl lower alkyl group, a lower alkylthio lower alkyl group and the like. In addition, examples of the residue obtained by removing the hydroxyl group from the unstable alcohol include ester residues used for prodrugs to promote oral absorption especially in the field of β-lactam antibacterial agents. Specific examples include the general formula: -Q-OR ¹ (wherein R ¹ has a lower alkyl group which may have a substituent, an aryl group which may have a substituent, and a substituent which has a substituent). A heterocyclic group, which may be
A lower alkenyl group which may have a substituent, a lower alkynyl group which may have a substituent, a cycloalkyl group which may have a substituent, a lower alkanoyl which may have a substituent Group, an arylcarbonyl group which may have a substituent, a heterocyclic group which may have a substituent, a substituted carbonyl group, a lower alkenylcarbonyl group which may have a substituent, and a substituent. Optionally lower alkynylcarbonyl group, optionally substituted cycloalkylcarbonyl group, optionally substituted lower alkoxycarbonyl group, optionally substituted aryloxycarbonyl group Group, optionally substituted heterocyclic group, substituted oxycarbonyl group, optionally substituted lower alkenyloxycarbonyl group, optionally substituted Lower have a alkynyloxy group or substituent a good cycloalkyloxycarbonyl group, Q is straight or ester residue represented by branched lower alkylene group) is preferably mentioned.

As the aryl group, a phenyl group,
Examples thereof include a naphthyl group, and examples of the heterocyclic group include a pyridyl group, a thienyl group, a furyl group and a pyrrolidinyl group.

The substituent for R ¹ is, for example, a lower alkyl group or a heterocyclic group (eg pyridyl group,
(Thienyl group or furyl group), cycloalkyl group, lower alkoxy group, aryl group, lower alkenyl group, lower alkynyl group, lower alkanoyloxy group, lower alkoxycarbonyloxy group, arylcarbonyloxy group, lower alkylthio group, lower alkenylthio group Alternatively, a di-lower alkylamino group and the like can be mentioned. Further, the group R ¹ may contain a functional group such as an acid-labile acetal group, an imino group, an epoxy group or a cyano group and an alkali-labile ester.

Specific examples of R ¹ include a lower alkyl group,
Lower alkanoyloxy lower alkyl group, lower alkoxy lower alkyl group, lower alkoxycarbonyloxy lower alkyl group, arylcarbonyloxy lower alkyl group, aryl group, cycloalkyl group, lower alkanoyl group, lower alkoxy lower alkanoyl group, aralkylcarbonyl group, cyclo Alkyl lower alkanoyl group, arylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, cycloalkylcarbonyl group, lower alkoxycarbonyl group, lower alkoxy lower alkoxycarbonyl group, aralkyloxycarbonyl group, cycloalkyl lower alkoxycarbonyl group, lower alkenyl Examples thereof include an oxycarbonyl group, a lower alkynyloxycarbonyl group and a cycloalkyloxycarbonyl group.

Of these, preferred are lower alkyl groups, lower alkanoyloxy lower alkyl groups, lower alkoxy lower alkyl groups, lower alkanoyl groups, lower alkoxy lower alkanoyl groups, cycloalkylcarbonyl groups, lower alkenylcarbonyl groups, lower alkoxycarbonyl. Group or lower alkoxy lower alkoxycarbonyl group.

Particularly preferred R ¹ is a lower alkanoyl group or a lower alkoxycarbonyl group, especially an acetyl group, a pivaloyl group or an isobutyryl group.
A particularly preferred Q is a methylene group.

On the other hand, in the starting compound [II], as the reactive residue X, any of those capable of reacting with oxalic acid to produce an oxalic acid monoester compound [I] can be used. As the reactive residue X, a halogen atom, a lower alkylsulfonyloxy group, an arylsulfonyloxy group or the like can be preferably used, but a halogen atom such as a bromine atom or a chlorine atom is particularly preferable.

The reaction of the present invention can be suitably carried out in a suitable solvent in the presence of a base.

Any base can be used as long as it can form a salt with oxalic acid, and both organic and inorganic bases can be used.

Preferred bases include those in which a salt with oxalic acid is soluble in a reaction solvent, and a salt with oxalic acid and compound [II] can easily react to form a monoester. A base having a degree of basicity is more preferable. Examples of such base include, for example, organic amine compounds (for example, di-lower alkylamine, tri-lower alkylamine, N-lower alkylmorpholine, N-lower alkylpyrrolidine, pyridine, 4- (1-pyrrolidinyl) pyridine, lutidine, 4- Picoline, collidine, quinoline, N, N-dilower alkylaniline, 1,8-diazabicyclo [5.4.0] -7-undecene (DBU),
1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), morpholine, pyrrolidine, piperazine, piperidine or 4-N, N-di (lower alkylaminopyridine) and the like.

Of these, particularly preferred bases include triethylamine, diisopropylethylamine, DB
U, DBN, DABCO or 4-N, N-dimethylaminopyridine may be mentioned, and industrially inexpensive triethylamine is particularly preferable.

The amount of the base used is 1.5 to 3 molar equivalents, especially 2 to 3 molar equivalents, based on oxalic acid.
It is particularly preferable to use 2 molar equivalents or a small excess thereof.

Any solvent can be used as long as it does not adversely affect the reaction, but an aprotic polar solvent is preferable in consideration of the solubility of the salt with oxalic acid. As such a solvent, , For example methylene chloride,
Acetonitrile, acetone, chloroform, 1,2-dichloroethane, dimethylformamide, dimethylsulfoxide and the like can be mentioned, and among them, methylene chloride, acetonitrile or acetone can be preferably used.

Compound [II] is used in an amount of 0.4 to 0.9 molar equivalents, particularly 0.5 to 0.75 equivalents, particularly 0.5 molar equivalents or a small excess thereof, relative to oxalic acid. Is preferred. This reaction is carried out under cooling to heating, for example, at -20 ° C.
Suitably proceeds at room temperature, especially from 0 ° C to room temperature.

The oxalic acid monoester compound [I] thus obtained is reacted with a halogenating agent to give
General formula [III]

[0030]

[Chemical 10]

(In the formula, Y represents a halogen atom, and other symbols have the same meanings as described above.), And can be converted into an oxalic acid monoester halide compound.

The reaction between the compound [I] and the halogenating agent is
It can be carried out in the presence or absence of a solvent. As the halogenating agent, thionyl chloride, oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride and the like, particularly thionyl chloride or oxalyl chloride and the like can be preferably used, and when a solvent is used, as a solvent Is not limited as long as it does not adversely affect the reaction, and methylene chloride, 1,2-dichloroethane and the like can be preferably used. This reaction suitably proceeds at -20 ° C to room temperature, particularly 0 ° C to room temperature.

Compound [III] obtained by the above method
Is a conventional method (for example, JP-A-59-51286, WO91).
/ 14691), the general formula [I
V]

[0034]

[Chemical 11]

(In the formula, R ² is an optionally protected hydroxy-substituted lower alkyl group, R ³ is an organic group, and Z is a formula:
_{CH 2 -CH 2 -, - S} -CH 2 -, - O-CH 2 -,
It represents a group represented by —CH ₂ —, —CH (R ⁴ ) —, —S— or —O—, and R ⁴ represents a lower alkyl group. ) Can be introduced into a penem-based or cephem-based compound.

For example, compound [III] and general formula [V]

[0037]

[Chemical 12]

[Wherein the symbols have the same meanings as defined above] and are reacted with a compound of the general formula [VI]

[0039]

[Chemical 13]

A compound represented by the formula:

[0041]

[Chemical 14]

(Wherein R ⁵ represents a lower alkoxy group, an aryloxy group or a di-lower alkylamino group) is reacted with an organophosphorus compound, and then the ring is closed to form a penem-based compound useful as an antibacterial agent or The cephem compound [IV] can be used, and the product can be made into a pharmacologically acceptable salt thereof if desired.

In the above reaction, R ³ has the formula: —C
H ₂ OCONHR ^6, (R ⁶ represents a hydrogen atom or a lower alkyl ^{_{group.) - CH 2 OCOR 7,}} (R 7 represents a lower alkyl group.) - CH ₂ SR ^8, or -SR ⁸ (R ⁸ is heteroaryl Represents a 5-membered heterocyclic group having 1 to 4 N atoms as an atom and optionally an S atom, which may be optionally substituted with an oxo group or a thioxo group). A group can be preferably used, and a carbamoyloxymethyl group, an acetyloxymethyl group or a pyrrolidin-2-thion-4-ylthio group is particularly preferable.

In the present invention, the lower alkyl group, the lower alkylene group and the lower alkoxy group have 1 to 1 carbon atoms.
6, especially those having 1 to 4 carbon atoms, and examples of the lower alkanoyl group, lower alkenyl group and lower alkynyl group include those having 2 to 8 carbon atoms, especially 2 to 6 carbon atoms, and further lower alkenoyl groups. Examples of the lower alkinoyl group, cycloalkenyl group and cycloalkyl group include those having 3 to 8 carbon atoms, especially those having 3 to 6 carbon atoms.

[0045]

【Example】

Example 1 (1) To a suspension of 18 g of oxalic acid in 200 ml of methylene chloride, 41 g of triethylamine was added under ice cooling. The cooling was stopped, and after stirring at room temperature for 20 minutes, 80 ml of a methylene chloride solution containing 23 g of acetoxymethyl bromide was added under ice cooling. Stop cooling, stir at room temperature for 2 hours, then extract with water. Then acidify the aqueous solution with 150 ml of 10% hydrochloric acid,
After salting out with sodium chloride, extraction with ethyl acetate is performed. After drying the extract, the solvent is distilled off, 100 ml of methylene chloride is added to the residue, and the mixture is stirred under ice cooling for 15 minutes, and the precipitated oxalic acid is filtered off. The filtrate is concentrated, 20 ml of methylene chloride is added, and the mixture is diluted with 100 ml of n-hexane under ice cooling. The precipitated crystals were filtered, dried under reduced pressure and monoacetoxymethyl oxalate 18.
1 g is obtained as colorless crystals.

M. p. 57-61 ° C NMR (CDCl ₃ -DMSO-d ₆ ) δ: 2.14
(3H, s), 5.88 (2H, s), 10.55 (1
H, s).

(2) This product 10.54 g of methylene chloride 1
Oxalyl chloride 1 in a 00 ml suspension under ice cooling
A solution of 2.7 g of methylene chloride in 40 ml and 2 drops of N, N-dimethylformamide are added. The cooling was stopped, the mixture was stirred at room temperature for 4 hours, the solvent was distilled off, and the residue was distilled under reduced pressure to obtain 8.26 g of monoacetoxymethyl chloride oxalate as an oil.

B. p. 91-92 ° C (3-5mmH
g) NMR (CDCl ₃ ) δ: 2.18 (3H, s), 5.
94 (2H, s).

Example 2 (1) To a suspension of 9 g of oxalic acid in 80 ml of methylene chloride,
Under ice cooling, 20 g of triethylamine is added. The cooling was stopped, and after stirring at room temperature for 20 minutes, 8.14 g of acetoxymethyl chloride was added under ice cooling. Stop cooling and let go at room temperature 2
After stirring for 0 hour, extract with water. Then add 10
Acidify with 100 ml of hydrochloric acid, salt out with sodium chloride, and extract with ethyl acetate. After drying the extract, the solvent is distilled off, 100 ml of methylene chloride is added to the residue, and the mixture is stirred under ice cooling for 15 minutes, and the precipitated oxalic acid is filtered off.

After the filtrate is concentrated, 10 ml of methylene chloride is added and diluted with 50 ml of n-hexane under ice cooling. The precipitated crystals are filtered and dried under reduced pressure to obtain 6 g of monoacetoxymethyl oxalate as colorless crystals.

M. p. 57-61 ° C (2) To a suspension of 810 mg of this product in 15 ml of methylene chloride, 510 mg of triethylamine is added under ice cooling. The cooling was stopped, and after stirring at room temperature for 20 minutes, a solution of 830 mg of thionyl chloride in 5 ml of methylene chloride was added under ice cooling. The cooling is stopped, the mixture is stirred at room temperature for 2 hours, and then the solvent is distilled off. 30 ml of toluene is added to the residue and the precipitated triethylammonium salt is filtered off. The filtrate was concentrated and then distilled under reduced pressure to give oxalic acid monoacetoxymethyl chloride 44.
0 mg is obtained as an oil.

B. p. 91-92 ° C (3-5mmH
g) Example 3 To a suspension of 18 g of oxalic acid in 200 ml of methylene chloride, 41 g of triethylamine was added under ice cooling. Stop cooling,
After stirring at room temperature for 30 minutes, a solution of 23 g of acetoxymethyl bromide in 150 ml of methylene chloride is added under ice cooling.
After cooling is stopped, the mixture is stirred at room temperature for 2.5 hours, a solution of thionyl chloride (47.6 g) in methylene chloride (150 ml) is added under ice cooling, and the mixture is stirred under ice cooling for 2.5 hours. Evaporate the solvent,
400 ml of toluene is added to the residue and the precipitated triethylammonium salt is filtered off. The filtrate was concentrated and then distilled under reduced pressure to give oxalic acid monoacetoxymethyl chloride 14.7.
g is obtained as an oil.

B. p. 91-92 ° C (3-5mmH
g) Example 4 Using acetoxymethyl chloride instead of acetoxymethyl bromide and treating in the same manner as in Example 3, oxalic acid monoacetoxymethyl chloride is obtained as an oil.

B. p. 91-92 ° C (3-5mmH
g) Example 5 The corresponding starting compound was treated in the same manner as in Example 2- (1),
Monoisobutyryloxymethyl oxalate is obtained as an oil.

NMR (CDCl ₃ ) δ: 1.21 (6
H, d), 2.65 (1H, sep), 7.40 (1
H, brs) Example 6 The corresponding starting compound was treated in the same manner as in Example 2- (1),
Monopivaloyloxymethyl oxalate is obtained as an oil.

NMR (CDCl ₃ ) δ: 1.24 (9
H, s), 5.94 (2H, s), 8.98 (1H,
s) Examples 7 to 12 The corresponding starting material compounds were treated in the same manner as in Example 2- (1),
The compounds listed in Table 1 below are obtained.

[0057]

[Table 1]

[0058]

According to the present invention, oxalic acid and a compound [I
By reacting with [I], the oxalic acid monoester compound [I] can be produced efficiently and easily under mild conditions. Furthermore, by reacting the compound [I] with a halogenating agent after isolation or without isolation, an oxalic acid monoester halide compound [II
I] can also be produced.

Further, according to the present invention, the ester residue (R) has a hydroxyl group removed from an unstable alcohol such as a lower alkoxy lower alkyl group, a lower alkanoyloxy lower alkyl group or a lower alkoxycarbonyloxy lower alkyl group. Group of oxalic acid [I] and its halide compound [I] which can be efficiently and simply prepared under mild conditions using oxalic acid as a starting material.
II] can be produced. Therefore, the present invention is an industrially advantageous method for producing an oxalic acid monoester compound [I] and an oxalic acid monoester halide compound [III].

Claims (15)

[Claims] 1. Oxalic acid and a compound represented by the general formula [II]: (In the formula, R represents a residue obtained by removing a hydroxyl group from the corresponding alcohol (ROH), and X represents a reactive residue.) The compound represented by the general formula [I] is reacted. [Chemical 2] (In the formula, symbols have the same meanings as described above.) A method for producing an oxalic acid monoester compound. 2. The method according to claim 1, wherein R is a residue obtained by removing a hydroxyl group from an unstable alcohol (ROH). 3. R is of the formula: -Q-OR ¹ (wherein R ¹ is a lower alkyl group which may have a substituent, an aryl group which may have a substituent, and a substituent which has a substituent). Optionally substituted heterocyclic group, optionally substituted lower alkenyl group, optionally substituted lower alkynyl group, optionally substituted cycloalkyl group, substituted A lower alkanoyl group which may have a group, an arylcarbonyl group which may have a substituent, a heterocyclic group which may have a substituent, a substituted carbonyl group, which may have a substituent A good lower alkenylcarbonyl group, a lower alkynylcarbonyl group which may have a substituent,
A cycloalkylcarbonyl group which may have a substituent, a lower alkoxycarbonyl group which may have a substituent, an aryloxycarbonyl group which may have a substituent, and a substituent which may have a substituent Good heterocyclic group substituted oxycarbonyl group, optionally substituted lower alkenyloxycarbonyl group, optionally substituted lower alkynyloxycarbonyl group or optionally substituted cyclo group Represents an alkyloxycarbonyl group, Q
Represents a linear or branched lower alkylene group. The manufacturing method of Claim 1 which is a group shown by these. 4. A substituent for R ¹ is a lower alkyl group,
Heterocyclic group, cycloalkyl group, lower alkoxy group, aryl group, lower alkenyl group, lower alkynyl group, lower alkanoyloxy group, lower alkoxycarbonyloxy group, arylcarbonyloxy group, lower alkylthio group, lower alkenylthio group or dialkyl group. The process according to claim 3, wherein the process is a lower alkylamino group. 5. R ¹ is a lower alkyl group, a lower alkanoyloxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkoxycarbonyloxy lower alkyl group,
Arylcarbonyloxy lower alkyl group, aryl group, cycloalkyl group, lower alkanoyl group, lower alkoxy lower alkanoyl group, aralkylcarbonyl group,
Cycloalkyl lower alkanoyl group, arylcarbonyl group, lower alkenylcarbonyl group, lower alkynylcarbonyl group, cycloalkylcarbonyl group, lower alkoxycarbonyl group, lower alkoxy lower alkoxycarbonyl group, aralkyloxycarbonyl group, cycloalkyl lower alkoxycarbonyl group, lower The method according to claim 3, wherein the alkenyloxycarbonyl group, lower alkynyloxycarbonyl group or cycloalkyloxycarbonyl group. 6. R ¹ is a lower alkyl group, a lower alkanoyloxy lower alkyl group, a lower alkoxy lower alkyl group, a lower alkanoyl group, a lower alkoxy lower alkanoyl group, a cycloalkylcarbonyl group, a lower alkenylcarbonyl group, a lower alkoxycarbonyl group or The method according to claim 3, wherein the alkoxy group is a lower alkoxy lower alkoxycarbonyl group. 7. The method according to claim 3, wherein R ¹ is a lower alkanoyl group or a lower alkoxycarbonyl group, and Q is a methylene group. 8. The method according to claim 3, wherein R ¹ is an acetyl group, a pivaloyl group or an isobutyryl group. 9. The method according to claim 1, wherein X is a halogen atom, a lower alkylsulfonyloxy group or an arylsulfonyloxy group. 10. The method according to claim 1, which is carried out in a solvent in the presence of a base. 11. The method according to claim 10, wherein the solvent is an aprotic polar solvent. 12. The method according to claim 10, wherein the base is triethylamine and the solvent is an aprotic polar solvent. 13. Oxalic acid and a compound of the general formula [II]: (In the formula, R represents a residue obtained by removing a hydroxyl group from the corresponding alcohol (ROH), and X represents a reactive residue.), And reacted with a compound represented by the general formula [I] (Wherein the symbols have the same meanings as described above), an oxalic acid monoester compound is obtained, and then the oxalic acid monoester compound is reacted with a halogenating agent. (In the formula, Y represents a halogen atom, and other symbols have the same meanings as described above.) A method for producing an oxalic acid monoester halide compound. 14. The halogenating agent is thionyl chloride,
The method according to claim 13, which is oxalyl chloride, phosphorus trichloride, phosphorus pentachloride or phosphorus oxychloride. 15. A compound represented by the general formula [III] obtained by the process according to claim 13: (In the formula, R represents a residue obtained by removing a hydroxyl group from the corresponding alcohol (ROH) and Y represents a halogen atom.) An oxalic acid monoester halide compound represented by the general formula [IV] 7] (In the formula, R ² is an optionally protected hydroxy-substituted lower alkyl group, R ³ is an organic group, and Z is a formula: —CH ₂ —CH
_{2 -, - S-CH 2} -, - O-CH 2 -, - CH 2 -,
-CH (R ⁴⁾ -, - represents a group represented by S- or -O-, R ⁴ represents a lower alkyl group. The method for producing a penem-based or cephem-based compound is characterized by leading to a penem-based or cephem-based compound represented by (4).