KR100396114B1 - Method for manufacturing d-cycloserine - Google Patents

Abstract

PURPOSE: Provided is a method for manufacturing D-cycloserine(D-4-amino-3-isoxazolidinone) of the formula(I) that is useful for the treatment of tuberculosis, massively. CONSTITUTION: A method for manufacturing D-cycloserine(D-4-amino-3-isoxazolidinone) of the formula(I) comprises the steps of; reacting a compound of the formula(II) with SOX2 and ROH to give a compound of the formula(IV); reacting the compound of the formula(IV) with hydroxylamine or its acid added salt to give an alkali salt compound of the formula(I); and neutralizing it with hydrobromic acid and hydroiodic acid.

Description

Production method of D-cycloserine

The present invention relates to a new and advanced method for economically and industrially mass-producing D-cycloserine (D-4-amino-3-isoxazolidinone).

D-Cycloserine is an antibiotic substance used in the treatment of tuberculosis and is a compound represented by the following structural formula (I).

D-Cycloserine is a known compound.

This compound is described in British Patent No. 1,223,887. According to this method, D-α-amino-β-chloropyropionic acid methyl ester hydrochloride is used as a starting material and reacted with hydroxylamine hydrochloride to obtain D- α-amino-β-chloropropiohydroxamic acid was prepared and cyclized in a caustic soda solution to prepare D-cycloserine. To separate and purify D-cycloserine, a large amount of 8-hydroxyquinoline A method for using the above-mentioned method is described. However, this method is not suitable as a mass production method because a large amount of expensive 8-hydroxyquinoline must be used.

In addition, U.S. Patent No. 3,517,099 and British Patent No. 768,007 disclose a method for producing D-cycloserine by a fermentation method using a Streptomyces oryzdecios strain, respectively, and this method has a low yield and is not economical It is known.

The inventors of the present invention conducted a long study to solve this problem and completed the present invention.

The object of the present invention is to provide a process for the preparation of a compound of general formula (III) by reacting SOX ₂ with D-serine of the formula (II) as starting material in the presence of ROH, followed by addition of SOX ₂ (IV), and reacting the intermediate compound with a hydroxylamine or an acid addition salt thereof to prepare a cycloserine of the formula (I) with high yield and purity. The reaction formula is as follows.

In the above formula, R represents a lower alkyl group having 1-5 carbon atoms, and X represents a halogen atom.

The lower alkyl group having 1-5 carbon atoms means an alkyl group such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl or n-pentyl and X represents a chlorine or bromine atom.

(A) Preparation of the compound of the general formula (III): < EMI ID =

In order to esterify a general carboxylic acid compound including an amino acid compound such as the general formula (II), it is generally obtained by carrying out a reflux reaction in an alcohol solvent in which hydrochloric acid gas is captured. However, this method is difficult to obtain the target in a completely quantitative yield because the ester target produced by the water produced during the reaction is hydrolyzed and returned to the original starting material.

These disadvantages can be overcome by using thionyl halides such as thionyl bromide, thionyl chloride and the like as reaction reagents and discharging them with hydrochloric acid and sulfur gas. That is, lower alcohol such as methyl alcohol, ethyl alcohol, n-propyl alcohol and the like is suitable as a reaction solvent, and it is preferable to use methyl alcohol.

As the reaction substance, thionyl bromide and thionyl chloride are preferable.

The reaction is carried out using 1 to 3 moles of thionyl halide per mole of D-serine.

It is advantageous to carry out the reaction at a temperature of from 20 캜 to the boiling point of the solvent used, preferably between 20 and 40 캜.

The reaction is usually completed quantitatively at 3 - 12 hours. After completion of the reaction, the compound is treated according to a conventional method, and the compound of the formula (III) is obtained almost quantitatively.

(B) Preparation of general formula (IV)

The compound of the general formula (IV) is a known method in which a compound of the general formula (III) is reacted in a chloroform solvent using a phosphorylating reagent as a halogenating reagent, but the phosphorylating agent used is very toxic as such It is very difficult to treat as a sublimation solid reagent and it is not suitable to apply to a mass production process as a dangerous substance. Thus, the inventors could overcome this disadvantage by using thionyl bromide and thionyl chloride as halogenating reagents. As the reaction solvent, dichloromethane, chloroform, ethyl acetate, tetrahydrofuran, dioxane, toluene and the like are suitable. The reaction uses 1 to 3 moles of thionyl chloride relative to the compound (III). The reaction temperature is 20 ° C - the boiling point of the solvent used, and preferably 30 to 60 ° C. The reaction is usually completed quantitatively at 4 - 15 hours and the compound of formula (IV) is obtained in a yield of 97% or more.

The preparation of the compounds of the general formula (III) and the general formula (IV) can be carried out in the presence of an equivalent amount of ROH in an organic solvent used in a reactor (b) to give thionyl halide to be prepared directly from the compound of the structural formula (II) It is possible.

(C) Preparation of compound (I)

The compound of formula (I) can be prepared by reacting a compound of formula (IV) with hydroxylamine hydrochloride to convert it to D- [alpha] -amino- [beta] -chloropropiohydroxamic acid and subsequently cyclizing And the reaction proceeds until it reaches the reaction. However, since this compound has a high solubility in water, it is extremely low in solubility in an organic solvent and relatively stable in a basic aqueous solution, but is unstable in an acidic aqueous solution. Therefore, it is very difficult to obtain this substance in pure form from a reaction solution .

As a known method for separating the compound (I) from the reaction solution, there are two methods.

First, a method of separating compound (I) using an ion exchange resin, which is unsuitable for industrialization due to low economical efficiency due to instability of compound (I) and low yield.

Secondly, a lower alcohol solvent is added to the alkali reaction solution in which the reaction is completed, and the resulting inorganic salt is removed by filtration, followed by adjusting to pH 6.0 with glacial acetic acid to separate the resulting compound (I) by filtration. However, this method is not only low in yield but also difficult to obtain a high purity D-cyclocerein because a large amount of acetic acid remains as a residual solvent in the final compound (I). Thus, the present inventors have studied various other methods of lowering the pH to 5.5 - 6.5 and found that adjusting the pH to inorganic acids such as hydrobromic acid, hydroiodic acid, etc. is the most suitable method. That is, when the pH was adjusted with hydrochloric acid, the produced sodium chloride was much lower in solubility than D-cycloserine in the alcohol solvent, so that the produced D-cycloserine contained a large amount of sodium chloride and thus had poor purity. However, when sodium hydrobromide or hydroiodic acid is used as a neutralizing agent, the inorganic salts such as sodium bromide and sodium iodide are much more soluble than D-cycloserine, so they are completely dissolved in the alcohol solvent and removed. Therefore, solid state high purity D- The yield was high.

The results obtained by this method are summarized as follows.

* After reacting with sodium nitroperi- canide, measurement of transmittance at 645 nm wavelength

As the reaction solvent for this reaction, it is preferable to use water, a lower alcohol such as methyl alcohol, ethyl alcohol, n-propyl alcohol, iso-propyl alcohol or a mixed solvent of water and a lower alcohol.

1.0 to 4.0 mol, preferably 1.0 to 2.0 mol, of hydroxylamine, which is a reagent for cyclizing to 1 mol of the compound of the general formula (IV), is used for cyclization. The reaction temperature is -10 to 40 ° C, preferably 0 to 20 ° C. The reaction time is preferably 2 to 18 hours, and the usual reaction pH is preferably 10.0 to 11.0.

In order to precipitate high-purity D-cycloserine as a solid, hydrobromic acid, hydroiodic acid, and the like are absolutely necessary as reagents for adjusting the pH to 5.5 to 6.5.

EXAMPLES The following examples illustrate the present invention in further detail, but are not intended to limit the scope of the present invention.

Example 1

Preparation of D-serine methyl ester hydrochloride:

D-serine (102.9 g, 0.979 mole) and methanol (1 liter) were added to the 3-liter reaction part and cooled to -10 ° C. Thionyl chloride (147.7 g, 1.468 mole) was slowly added dropwise and the temperature of the reaction part was raised The mixture is stirred at 30 DEG C for 8 hours. After cooling the reaction part, methanol and thionyl chloride were concentrated under reduced pressure to obtain D-serine methyl ester hydrochloride (152.3 g, in general).

Example 2

Preparation of D-α-amino-β-chloropropionic acid methyl ester hydrochloride:

1,4-dioxane (1.0 liter) was added to a 3-liter reaction portion containing D-serine methyl ester hydrochloride (152.3 g, 0.979 mole), and the mixture was cooled to 0 ° C. Thionyl chloride (151.4 g, 1.273 mole) Slowly. The reaction solution is heated to a temperature of 50 ° C, stirred for 5 hours, and then concentrated under reduced pressure. (1.0 liter) was added to the reaction part and stirred for 30 minutes, followed by filtration and drying to obtain solid D-α-amino-β-chloropropionic acid methyl ester hydrochloride (166.6 g, 97.8%).

Example 3

Preparation of D-Cycloserine (1):

(124.7 g, 3.113 mole) aqueous solution (150 ml) was slowly added dropwise while cooling the solution to 10 ° C or lower, and then stirred for 10 minutes. To this reaction solution An aqueous solution (242 ml) of D-? - amino -? - chloropyropionic acid methyl ester hydrochloride (146.65 g, 0.843 mole) is added dropwise while maintaining the temperature of the reaction solution at 5 ° C or lower. React at room temperature for 4.5 hours while supplementing the 50% caustic soda solution so that the pH of the reaction solution is in the range of 10 - 11. After the reaction was completed, ethanol (6.6 liters) was added to the reaction mixture, stirred for 20 minutes, and the resulting solid was filtered off.

The filtrate was cooled to 0 ° C and 48% hydrobromic acid solution was slowly added thereto to adjust the pH to 6.0-6.5. The resulting solid was filtered and dried to obtain D-cyclocerein (73.3 g, 85.2%).

Example 4

Preparation of D-Cycloserine (II):

(124.7 g, 3.113 mole) aqueous solution (150 ml) was slowly added dropwise to the aqueous solution (103.25 ml) of hydroxylamine hydrochloride (70.25 g, 1.011 mole) while maintaining the temperature at 10 ° C or lower, stirred for 10 minutes, An aqueous solution (242 ml) of D-? - amino-? - chloropyropionic acid methyl ester hydrochloride (146.65 g, 0.843 mole) is added dropwise while maintaining the temperature of the reaction solution at 5 ° C or lower. The reaction was carried out at room temperature for 4.5 hours while supplementing the 50% caustic soda solution so that the pH of the reaction solution was in the range of 10 -11. After the reaction was completed, ethanol (6.6 liters) was added to the reaction mixture, stirred for 20 minutes, and the resulting solid was filtered off.

The filtrate is cooled to 0 ° C, and 47% hydroiodic acid solution is slowly added to adjust pH to 6.0-6.5. The resulting solid is filtered and dried to obtain D-cyclocerein (71.5g, 83.1%).

Claims (1)

A compound of general formula (IV) obtained by reacting a compound of formula (II) with SOX ₂ and ROH is reacted with hydroxylamine or its acid addition salt in an alkaline to produce an alkaline salt compound of formula (I) (I) with an acid selected from hydroiodic acid, to produce D-cycloserine of structural formula (I). Wherein R is a lower alkyl group having 1-5 carbon atoms and X is a chlorine atom. The lower alkyl group having 1-5 carbon atoms means an alkyl group such as methyl, ethyl, n-propyl, isopropyl, n-biphenyl, isobutyl, n-pentyl and the like and X represents a chlorine or bromine atom.