KR20120131646A - A process for the preparation of isoxazolidinone derivative, D-cycloserine - Google Patents

Abstract

PURPOSE: A method for preparing 3-isoxazole dinone derivative is provided to effectively control heat generation during neutralization and to industrially produce a large amount of D-cycloserine. CONSTITUTION: A method for preparing D-cycloserine which is a 3-isoxazole dinone derivative of structural formula I comprises: a step of reacting D-alpha-amino-beta-chloropropionic acid alky ester of structural formula II with hydroxyl amine under the presence of alkali to prepare alkali salts of structural formula II; and a step of neutralizing the alkali salts with formic acid or a mixture of formic acid and low carbon number alcohol. The alkali is caustic soda, caustic potash, or lithium hydroxide. The low carbon number alcohol is methanol, ethanol, n-propanol, or iso-propanol. [Reference numerals] (AA) NH_2OH. salt/alkali solution

Description

A process for the preparation of isoxazolidinone derivative, D-cycloserine}

The present invention relates to an improved method for preparing D-cycloserine, a isoxazolidinone derivative, and the present invention relates to D-cycloserine (D-4-amino-3-isoxazole, a 3-isoxazolidinone derivative). The present invention relates to an economic method newly designed to allow mass production of lidinone) in an efficient manner such as shortening the reaction time.

D-cycloserine is a drug widely used as a drug for treating tuberculosis and is a compound represented by the following structural formula (I), and also applied to research for use as a medicament for increasing memory for other uses. [US Patent No. 00/27204 A1 ( 2001)].

The compounds are known compounds such as Helvetica chemica Acta., "Oxazolidinone" 40, 1531-1532 (1957), US Patent Nos. 2,772,280 (1956), 2,845,433 (1958), German Patent No. 1,044,086 (1957), Switzerland Patent No. 1,223,887 (1968), Korean Patent No. 10-0330903 (2002) and (KR) No. 10-0522246 (2005) are described.

According to most preparation methods, hydroxylamine hydrochloride or 50% hydroxylamine aqueous solution is used as aqueous solution of D-α-amino-β using D-α-amino-β-chloropropionic acid methyl ester hydrochloride as a starting material. It describes a method for preparing D-cycloserine by preparing a chloropropion hydroxamic acid and performing a cyclization reaction by continuously adjusting the pH with an alkali solution in a base solution without cyclization or separation.

According to Swiss Patent No. 1,223,887, an expensive 8-hydroxy quinoline is used to separate the target product after the reaction, and the reaction solution is concentrated with a strong base to increase the yield to concentrate the reaction solution containing a large amount of water. Since the post-treatment process is increased and the post-treatment process is complicated, in particular, the target product has high solubility in water, and when heat is applied in an aqueous solution, hydrolysis, etc., may easily occur, resulting in the formation of by-products. Not desirable

According to the manufacturing method described in Korean Patent (KR 10-0,522,246) and the like, when the hydroxyl amine hydrochloride is dissolved in water and neutralized by adding a caustic soda solution, the acid and alkali neutralization reaction of the hydrochloride and caustic soda solution as salts is neutralized. Pointed out that it has a disadvantage of requiring a powerful cooling device due to the slow input time due to the generation of a considerable amount of heat. Therefore, the commercially available 50% hydroxyl amine solution can be used to solve the above problems. It is described.

However, even if the 50% hydroxylamine aqueous solution reduces the amount of salt produced and slightly reduces the neutralization time, it uses a 50% hydroxylamine freebase aqueous solution, which is expensive compared to hydroxylamine hydrochloride, and after the reaction, 48% Hydrogen bromide solution is adjusted to pH 5.5 ~ 6.5 to prepare the target product. Hydrobromic acid (HBr) can bring the decomposition of the product into strong acid. It is possible to separate the target purely because it is high, but it is a method that can lower the yield.

This patent proposes a way to overcome the various disadvantages noted above.

The present inventors have carefully examined the time and temperature for neutralizing hydroxyl amine hydrochloride, and use a basic aqueous solution such as an aqueous solution of caustic soda when neutralizing the hydroxyl amine hydrochloride. It was found that the heat generated when the heat of neutralization and caustic soda solution is hydrated in water is duplicated and causes high heat.

Therefore, using a solution of caustic soda that has been sufficiently diluted and cooled so as not to generate heat in such a manner generates a small amount of heat, which is pointed out as a disadvantage. Found out.

In addition, as the acid required for neutralization after the reaction, inorganic and organic acids were examined, and examples of usable inorganic acids include sulfuric acid hydrochloric acid, hydrofluoric acid (hydrobromic acid), phosphoric acid, acetic acid and organic acid, and most of the patents mention acetic acid.

However, when acetic acid is used, the salt and sodium acetate produced after pH adjustment have poor solubility in water or alcohol, and thus the above products are mixed in the product to obtain a pure object. Should be used in this case, the yield is lower.

In addition, when hydrochloric acid is used, it is a 35% aqueous solution, so that the target product has high solubility in water, which causes a lower yield. do.

When hydrofluoric acid (aqueous 48% hydrobromic acid solution) is used, the same phenomenon is observed. Also, the patent claims that the resulting sodium bromide has good solubility so that no salt is formed in the target product. Has the potential to be lowered.

Therefore, the inventors of the present invention have studied a variety of usable acids, and have obtained good results by using formic acid (formic acid), which is a weak acid and the salt produced is soluble in water or lower alcohol.

The produced sodium formate was relatively well soluble in water, and was also soluble in organic solvents such as lower alcohols to obtain the target product more purely, and because it was not a water-soluble reagent, it had no effect on the yield of the target product.

The present invention reacts the D-α-amino-β-chloropropionic acid alkyl ester of formula (II) with a hydroxylamine salt in the presence of alkali to prepare an alkali salt of formula (I), followed by mixing formic acid or formic acid with lower alcohol. A method of preparing D-cycloserine, a 3-isoxazolidinone derivative of formula (I), by neutralization with a solution, wherein the reaction scheme is as follows.

In the formula, R represents a lower alkyl group of 1 to 4 carbon atoms, that is, methyl, ethyl, n-propyl, iso-propyl, and X represents a chlorine or bromine atom as a halogen atom.

This invention is comprised by the following process 1) -4) in detail.

1) Dissolve one alkali selected from caustic soda, caustic or lithium hydroxide in a mole, cool it to 5 ° C or lower, and then add a solid hydroxylamine or an acid addition salt thereof to react with hydroxylamine. Get the liquid. Hydroxylamine acid addition salts include hydrochloric acid, sulfuric acid, phosphoric acid or nitrate.

   The hydroxylamine produced by neutralizing the hydroxylamine hydrochloride must be kept at a low temperature because it is unstable in a strong alkaline aqueous solution and decomposes into ammonia. In consideration of reactivity, solubility, etc., -30 degrees or less is not considered.

2) D-α-amino-β-chloropropionic acid alkyl ester of formula (II) is reacted with the reaction solution obtained in 1) at 5 degrees or less,

3) The D-α-amino-β-chloropropiohydramic acid obtained in 2) is cyclized at room temperature -35 degrees while maintaining the pH typically at 10-11 in the same reactor. The resulting compound (I) is relatively stable in alkaline aqueous solution, but is unstable in acidic aqueous solution, producing various by-products, making it difficult to separate them into pure substances.

4) Remove the inorganic salt formed by adding lower alcohol to the alkali reaction solution obtained in 3), and add formic acid or a mixture of formic acid and lower alcohol to the alkaline filtrate at low temperature to adjust the pH to 5.5-6.5. ) Is filtered to separate D-cycloserine, a 3-isoxazolidinone derivative of formula (I).

As the lower alcohol, methanol, ethanol, n-propanol, iso-propanol and the like can be used.

According to the above process, it is possible to quickly neutralize hydroxylamine hydrochloride without exotherm while maintaining low temperature in a short time, and easy to control temperature by using relatively inexpensive hydroxylamine instead of expensive 50% hydroxylamine aqueous solution. In addition, the resulting reaction by-product formic acid salt is easily dissolved in water and ethanol to produce a pure target, and has the advantage of mass production of the target on a large scale in a high yield.

( Reference Example ) General formula ( II ) Preparation of compound

The preparation of the compound of formula (II) is described in detail in Helvetica chemie Acta., "Oxazolidinone" 40, 1531-1552, (1957), as follows.

D-α-amino-β- Chloropropionic acid Methyl ester  Preparation of Hydrochloride

D-serine is reacted in the presence of a lower alcohol such as methanol in the presence of an acid such as phosphorus contaminated or thionyl chloride to prepare an ester, thereby obtaining D-serine methyl ester hydrochloride, and chloroform, methylene chloride and tetrahydro. After reaction with a halogenating agent selected from phosphorus, thionyl chloride or thionyl bromide selected from furan or benzene in the presence of one organic solvent, between 0 degrees and room temperature, the solvent is removed under concentration, and dichloromethane After crystallization by adding a solvent such as or acetone, and purifying with a lower alcohol, ethyl acetate, or the like, a high-purity target product, which is a white to off-white powder, can be obtained quantitatively.

D-α-amino-β-chloropropionic acid methyl ester hydrochloride

¹ H NMR (400 MHz, DMSO-d ₆ ): δ 3.77 (s, 3H, -OCH ₃ ),

4.13 (dd, J = 12.4 and 3.2 Hz, 1H, -CH _a Cl), 4.20 (dd, J = 12.4 and 3.2 Hz, 1H, -CH _b Cl), 4.71 (t, J = 3.2 Hz, 1H,- CHN), 9.13 (brs, 3H, -NH ₃ Cl)

Example  One

D- Cycloserine  Produce

Caustic soda (69 g, 1.72 mole) is added to 100 ml of water, 40 g (0.576 mole) of hydroxylamine hydrochloride is slowly added while stirring and kept at 5 degrees or less and stirred for 10 minutes. The reaction solution is cooled and added dropwise to D-α-amino-β-chloropropionic acid methyl ester hydrochloride (100 g, 0.575 mole) while maintaining it at 0 degrees or less.

The reaction solution is reacted at 35 ° C. for 10 hours while supplementing with 50% aqueous solution of caustic soda to maintain a pH of 10-11. After the reaction was completed, ethanol (3 L) was added to the reaction solution, stirred for 20 minutes, and filtered.

While maintaining the filtrate at 0 ° C. and slowly adding 99% formic acid to pH 6.0-6.5 and stirring for 2 hours, the resulting solid was dried at 40 ° C. or less and 47 g of pure D-cycloserine as a white solid (yield, 80%).

¹ H NMR (400 MHz, D ₂ O): δ 4.04 (dd, J = 14.8, 10.0 Hz, 1H, -CH ₂ O), 4.14 (dd, J = 14.8, 8.0 Hz, 1H, -CH ₂ O) , 4.36 (dd, J = 10.0, 8.0 Hz, 1H, -CHN)

[α] _D ²⁵ +116 ^o (C = 1, H ₂ O)

Example  2

D- Cycloserine  Produce

Caustic soda (69 g, 1.72 mole) is added to 100 ml of water, 40 g (0.576 mole) of hydroxylamine hydrochloride is slowly added while stirring and kept at 5 degrees or less and stirred for 10 minutes. D-α-amino-β-chloropropionic acid methyl ester hydrochloride (100 g, 0.575 mole) is added dropwise to the reaction solution rapidly, keeping the reaction solution at 0 degrees or less.

The reaction solution is reacted at 35 ° C. for 10 hours while supplementing with 50% aqueous solution of caustic soda to maintain a pH of 10-11. After the reaction was completed, ethanol (3 L) was added to the reaction solution, stirred for 20 minutes, and filtered.

While maintaining the filtrate at 0 degrees or less, a mixture of 99% formic acid and methanol (1: 1) was gradually added to adjust the pH to 6.0-6.5, followed by stirring for 2 hours. The resulting solid was dried at 40 degrees or less to obtain a pure white solid. 47 g (yield, 80%) of D-cycloserine are obtained.

Example  3

D- Cycloserine  Produce

Caustic soda (69 g, 1.72 mole) is added to 100 ml of water, 40 g (0.576 mole) of hydroxylamine hydrochloride is slowly added while stirring and kept at 5 degrees or less and stirred for 10 minutes. D-α-amino-β-chloropropionic acid methyl ester hydrochloride (100 g, 0.575 mole) is added dropwise to the reaction solution rapidly, keeping the reaction solution at 0 degrees or less.

The reaction solution is reacted at 35 ° C. for 10 hours while supplementing with 50% aqueous solution of caustic soda to maintain a pH of 10-11. After the reaction was completed, ethanol (3 L) was added to the reaction solution, stirred for 20 minutes, and filtered.

While maintaining the filtrate at 0 degrees or less, a mixture of 99% formic acid and ethanol (1: 1) was slowly added to adjust the pH to 6.0-6.5, followed by stirring for 2 hours. The resulting solid was dried at 40 degrees or less to obtain a pure white solid. 47 g (yield, 80.1%) of D-cycloserine are obtained.

Claims (5)

The alkyl salt of the structural formula (I) is prepared by reacting the D-α-amino-β-chloropropionic acid alkyl ester of the following formula (II) with the hydroxylamine salt in the presence of alkali, and then using formic acid or formic acid and a lower alcohol mixture solution. A method for producing D-cycloserine, which is neutralized to be a 3-isoxazolidinone derivative of formula (I).

In the formula, R represents a lower alkyl group of 1 to 4 carbon atoms, that is, methyl, ethyl, n-propyl, iso-propyl, and X represents a chlorine or bromine atom as a halogen atom.
The method according to claim 1, wherein the alkali is selected from caustic soda, caustic or lithium hydroxide, and the lower alcohol is selected from methanol, ethanol, n-propanol or iso-propanol.
The method according to claim 1, wherein the solid hydroxylamine salt is added to the cooled aqueous alkali solution by neutralizing the hydroxylamine salt to neutralize the hydroxylamine salt.
The hydroxylamine salt of claim 3 which can be used is hydrochloric acid, sulfuric acid, phosphoric acid, nitrate and the like.
The method according to claim 3, wherein the reaction temperature is -30 ~ 5 degrees.