KR100654923B1 - Process for continuously preparing high purity chiral amide compound - Google Patents

Abstract

Provided is a method for preparing an optically active amide compound which is used as an intermediate for the synthesis of cilastatin continuously and simply with a high yield and a high purity. The method comprises the steps of condensing the compound represented by the formula K and L-menthol to prepare an ester mixture comprising the compounds represented by the formulas L and M; separating the ester mixture by recrystallization and obtaining the concentrated compound represented by the formula M without purification by racemization to prepare a 1:1 mixture comprising the compounds represented by the formulas L and M; hydrolyzing the compound represented by the formula L to obtain the compound represented by the formula N; chlorinating the compound of the formula N and addition reacting it with ammonia to prepare the amide compound represented by the formula I; and completely dissolving the S-form amide compound containing a small amount of the R-form compound in a suitable solvent and crystallizing it to obtain a pure S-form compound.

Description

Process for continuously producing high purity optically active amide {PROCESS FOR CONTINUOUSLY PREPARING HIGH PURITY CHIRAL AMIDE COMPOUND}

The present invention relates to a new method for preparing a pharmaceutical intermediate. More specifically, the present invention relates to a method for continuously preparing high purity cilastatin intermediates.

Cilastatin is a compound that is mixed with Carbapenem antibiotic (Imipenem) to block the decomposition of imipenem by the action of microorganisms to exert antimicrobial activity. The chemical structure of the product is as follows.

European Patent No. 48301 discloses a method for preparing cilastatin, which is condensed with an intermediate of formula (I) with an alpha keto acid compound (A) to form compound (B), as shown in the following scheme. Then, L-cysteine (C), an amino acid, is added thereto.

Therefore, the chiral intermediate compound of the formula (I) is a key material for preparing the cilastatin, and thus, various methods for making the cilastatin have been studied. [Reference: US Patent No. 5166417, U.S.A. Patent 5243070 and US patent 5273903].

The compound (I) has optical activity and the product purity of the final product, cilastatin, is determined according to the optical purity of the compound.

The main method of making the compound is a method of separating the racemate (racemate) with a chiral separation reagent (Ref .: US Patent No. 5166417 and US Patent No. 5243070), in which case the racemate to obtain the target After combining with the chiral separation reagent, each isomer is separated and then the chiral separation reagent and the isomer are separated. The complex resolution process is performed. Generally, in order to separate from the racemate with the desired optical purity of 98% or more, 20% or less is required. The target product is produced in a low yield level, which is also the same as that used in the manufacture of silasstatin, which has an enantiomer present in the vicinity of 1%, which reduces the quality of the final product. Not suitable for use as an intermediate.

U.S. Patent No. 5273903 also discloses a process for preparing the compound of formula (I) through a biological resolution from racemate, which is shown in the following scheme to amidase Compound (I) is prepared through selective hydrolysis using an amidase enzyme.

However, the above method also manufactures a product with an optical purity of 93% level, so that the same enantiomeric impurity content of 3.5% is not suitable for use as a pharmaceutical intermediate in the same manner as the aforementioned chemical resolution.

Accordingly, it is an object of the present invention to provide a method for the purification of key chiral intermediates that can be used for the production of cilastatin, which can be easily and efficiently produced without high complexity and directly applied to pharmaceuticals with high optical purity.

The present invention relates to a novel process for preparing a compound represented by the following formula (I) as a pharmaceutical intermediate:

That is, the present invention combines the racemate with L-menthol, a relatively inexpensive chiral resolving agent, and separates each diastereomeric isomer by simple recrystallization to make the desired S-form as a product and the opposite isomer. It is possible to obtain only the product of the desired S-form continuously through the continuous recrystallization method after isomerizing it to racemate again in the same reactor without separating it from the chiral separation reagent L-menthol. A chiral purity of about 90-95% was obtained.

A simple diagram of this is as follows.

In addition, by using the very specific physical property difference between the two isomers found by the inventors, it was possible to manufacture a high purity product having a chiral purity of surprisingly 99.0 ~ 99.8% through a simple recrystallization process.

That is, even though the two enantiomers of the compound of formula (I), that is, the S-enantiomer represented by formula (I) and the R-enantiomer represented by formula (II), are enantiomers, respectively, In addition, it was possible to develop a method of purely obtaining useful S-enantiomers by newly discovering a difference in crystallinity for suitable solvents.

The S-enantiomer obtained as described above was able to manufacture high quality products with an antiisomer content of 0.1% or less, which is not a problem in product quality as impurities, and was able to expect excellent product quality compared to existing products.

The process for the continuous preparation and purification of the compound of formula (I) of the present invention comprises the following steps.

First, the continuous manufacturing method includes the following steps:

(i) obtaining an ester mixture of formula (L) and formula (M) by condensation of a compound of formula (K) with L-menthol;

(ii) a 1: 1 mixture of the compound of formula (L) and formula (M) was isolated by recrystallization to obtain only the compound of formula (L) as crystals, and the concentrated compound of formula (M) was purified without purification. Racemizing in the same reactor to obtain a 1: 1 mixture of formula (L) and formula (M) again;

(iii) hydrolyzing the compound of formula (L) to obtain a compound of formula (N);

(iv) chlorination of the compound of formula (N) followed by reaction with ammonia to obtain a compound of formula (I);

Second, the purification method of the compound of formula (I) comprises the following steps:

(v) S-form compound of formula (I) containing a small amount of R-form compound of formula (II) is completely dissolved in a suitable solvent, and then crystallized through appropriate temperature range and stirring range to form R-form enantio Filtering the mixture of R-forms and S-forms containing a large amount of mers to obtain a solution of the S-form compounds in which the amount of useful S-form compounds is of sufficient purity for commercial use for pharmaceutical use; And

(vi) purifying the S-foam product of sufficient purity to commercialize for pharmaceutical use using a suitable secondary solvent from the solution of the S-foam compound to obtain the compound of formula (I).

Hereinafter, a method for continuously preparing and purifying the compound of formula (I) of the present invention will be described in detail step by step.

First step: preparing a mixture of formula (L) and formula (M)

A mixture of formulas (L) and (M) is obtained by condensation reaction of a compound of formula (K) with L-menthol on an acid catalyst:

At this time, the acid catalyst is hydrochloric acid, sulfuric acid, nitric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, toluenesulfonic acid, trifluoromethanesulfonic acid, phosphoric acid, polyphosphic acid (PPA), silica impregnated with metals such as titanium, zeolite, etc. It may be used, it is preferably used 0.000005 ~ 0.5 equivalent based on the compound (K).

The reaction is carried out in the presence or absence of an aromatic solvent such as benzene, toluene, xylene, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene and the like. Is carried out under.

Second Step: Separation of Compounds of Formula (L) and Racemization of Formulas (L) and (M)

The compound of formula (L) is obtained by separating a 1: 1 mixture of formula (L) and formula (M) by simple recrystallization.

The recrystallization solvent that can be used at this time may be an ether solvent such as tetrahydrofuran, dioxane, petroleum ether, dialkyl ether, t-butylalkyl ether, alcohol solvent such as methanol, ethanol, propanol, t-butanol, n-butanol or the like. Can be used and compound (L) is prepared in a yield of up to 45% (theoretical yield: 50%) and an optical purity of about 95%.

The compound of formula (L) was obtained as crystals and the remaining concentrated compound of formula (M) was racemized in the same reactor without purification to obtain a 1: 1 mixture of formula (L) and formula (M) again. Through recrystallization, only compound (L) can be obtained continuously.

Reagents that can be used in the racemization process are alkali metal, carbonic acid, hydroxide, hydride, alkoxide, amide, substituted amide, alkyl compound or alkaline earth metal, carbonic acid, hydroxide, hydroxide of alkali earth metal. Leads, alkoxides, amides, substituted amides, alkyl compounds, or mixtures thereof and the like can be used, and preferably 0.000001 to 1.0 equivalents based on the mixture of compounds (L) and (M).

The reaction includes aromatic solvents such as benzene, toluene and xylene, ether solvents such as tetrahydrofuran, dioxane, petroleum ether, dialkyl ether and t-butylalkyl ether, dimethylformamide, dimethylacetamide and dimethylsulfooxide. Polar solvents such as methanol, ethanol, propanol, t-butanol, n-butanol and the like or in the presence or absence of an alcohol solvent.

The reaction temperature is preferably 200 ° C. or less, more preferably 100 to 150 ° C., but less than 100 ° C., the reaction rate becomes slow, and if it exceeds 150 ° C., a side reaction occurs.

Third Step: Preparation of Compound of Formula (N)

The compound of formula (N) is obtained via a hydrolysis reaction of a compound of formula (L):

Reagents that can be used in the hydrolysis reaction include alkali metal, carbonic acid, hydroxide, hydride, alkoxide, amide, substituted amide, alkyl compound or alkaline earth metal, carbonic acid, hydroxide, hydroxide of alkali metal Leads, alkoxides, amides, substituted amides, alkyl compounds, or mixtures thereof and the like can be used, preferably 0.000001 to 1.0 equivalents based on compound (L).

As a solvent, an alcohol solvent such as water, methanol, ethanol, propanol, t-butanol, n-butanol, or a mixture thereof may be used, and the reaction temperature is preferably 150 ° C. or lower, more preferably 120 to 60 ° C. If it is less than 60 ℃ reaction rate is slow, if it exceeds 120 ℃ there is a disadvantage that a side reaction occurs.

Fourth Step: Preparation of Compound of Formula (I)

Compounds of formula (I) are obtained through addition reactions of compounds of formula (N) with various chlorination reagents and ammonia:

As the chlorination reagent, chlorine, SOCl ₂ , SO ₂ Cl ₂ , POCl ₃ , PCl _5, etc. may be used, and 1.0 to 2.0 equivalents based on the compound (N) is preferably used.

The reaction solvent of the reaction is carried out in the presence or absence of a solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene and the like.

The reaction temperature is preferably 100 ° C. or lower, more preferably -30 ° C. to 60 ° C., but is lower than -30 ° C. to slow down the reaction rate.

5th Step: Preparation of S-Form Compound Solution of High Purity Formula (I)

After completely dissolving the S-form compound of Formula (I) containing a small amount (about 2 to 3%) of the R-form compound of Formula (II) in a suitable solvent and crystallizing through an appropriate temperature range and stirring range, Since the solubility of foam enantiomers is much lower than that of S-enantiomers, a mixture of R and S foams containing a large amount of R foam is crystallized and precipitated. Filtering out this mixture allows useful S-foam compounds to be present in the solution at a level of 99.5-99.9%, which is sufficient for commercial use in pharmaceutical applications, to enable the preparation of high purity S-foam compound solutions of Formula (I).

The solvent of the above step is a halogen solvent such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene, tetrahydrofuran, dioxane, petroleum ether, dialkyl Ether solvents such as ether and t-butylalkyl ether, polar solvents such as dimethylformamide, dimethylacetamide and dimethylsulfooxide, alcohol solvents such as methanol, ethanol, propanol, t-butanol and n-butanol and mixtures thereof Is carried out under.

The crystallization temperature is preferably 30 ° C. or lower, more preferably -80 ° C. to 20 ° C., but when the crystallization temperature is lower than −80 ° C., impurities of the R-form are not removed.

Sixth Step: Preparation of S-Form Compound of Formula (I) of High Purity

The high purity S-form compound of formula (I) is precipitated from the S-form compound solution of formula (I) using a suitable secondary solvent to precipitate an S-form product of sufficient purity for commercialization for pharmaceutical use. Compounds of formula (I) can be obtained.

The solvent of the step may be a hydrocarbon solvent such as pentane, hexane, heptane, octane, dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene, trichlorobenzene, or the like. Mixed solvents of these are possible.

The temperature of this step is preferably 40 ° C. or less, more preferably less than 30 ° C., but if it exceeds 30 ° C., the chiral purity is inferior.

The chiral compound of formula (I) of the present invention can be used as an intermediate to prepare the cilastatin as described above (see EP 48301).

Hereinafter, the present invention will be described in more detail with reference to Examples. These examples are only for illustrating the present invention, it will be apparent to those skilled in the art that the scope of the present invention is not limited to these examples.

Example 1

In a 2000 ml round flask equipped with a stirrer, a condenser and a thermometer, 100 g of 2,2-dimethylcyclopropane carboxylic acid (compound (K)), 125 g of L-menthol, 10 g of paratoluenesulfonic acid, and 500 g of toluene Input. Thereafter, the water was removed while refluxing the reaction while maintaining the reaction temperature at 110 ℃. After the reaction was completed, 300 g of water and 100 g of 10% sodium carbonate were slowly added to the reaction mixture, stirred for 15 minutes, the water layer and the organic layer were separated, and the organic layer was concentrated to give 2,2-dimethylcyclopropane carboxylic acid L-mentyl ester. (1: 1 mixture of compound (L) and compound (M)) was obtained by distillation under reduced pressure (100-101 ° C / 3.0mmHg; yield: 90.1%, purity: 99.0%). Rf = 0.85 (normal-hexane / ethylacetate, 4/1). ¹ H NMR (CDCl ₃ , 300 MHz): 4.68 (t, d, 1H, J = 11.1 Hz, J = 4.50 Hz); 1.92 (m, 2 H); 166 (m, 2 H); 1.50-1.35 (m, 3H); 1.17 (d, 6H, J = 10.8 Hz); 1.12-0.96 (m, 3H); 0.90 (d, 6H, J = 6.90 Hz); 0.85-0.81 (m, 3H); 0.76 (d, 3H, J = 6.90 Hz).

Example 2

200 g with 100 g of 2,2-dimethylcyclopropane carboxylic acid L-menthyl ester (a 1: 1 mixture of compound (L) and compound (M)) in a 1,000 ml round flask equipped with a stirring device, a condenser and a thermometer. Isopropanol was added. The temperature is then raised to 60 ° C. to dissolve the reactants, and then slowly cooled to 5 ° C. to precipitate crystals. The resulting crystals were filtered using a filter paper, washed with a small amount of isopropanol and dried to give S-2,2-dimethylcyclopropane carboxylic acid L-mentyl ester (Compound (L)). (Yield: 45.0 %, Purity: 99.1%, chiral purity: 95.2%).

The filtered solution was distilled under atmospheric pressure, concentrated, 1.5 g of t-butoxy potassium was added to the reaction product, the temperature was raised to 120 ° C., and then reacted to proceed with racemization. After racemization was completed, 45 g of 2,2-dimethylcyclopropane carboxylic acid L-mentyl ester (a 1: 1 mixture of compound (L) and compound (M)) prepared in Example 1 was added, followed by 200 g of isopropanol. Input.

The temperature is then raised to 60 ° C. to dissolve the reactants, and then slowly cooled to 5 ° C. to precipitate crystals. The resulting crystals were filtered using a filter paper, washed with a small amount of isopropanol and dried to yield S-2,2-dimethylcyclopropane carboxylic acid L-mentyl ester (Compound (L)) in succession (yield: 44.0%, purity 99.2%, chiral purity 95.2%). Rf = 0.85 (normal-hexane / ethylacetate, 4/1). ¹ H NMR (CDCl ₃ , 300 MHz): 4.68 (t, d, 1H, J = 11.1 Hz, J = 4.50 Hz); 1.92 (m, 2 H); 166 (m, 2 H); 1.50-1.35 (m, 3H); 1.17 (d, 6H, J = 10.8 Hz); 1.12-0.96 (m, 3H); 0.90 (d, 6H, J = 6.90 Hz); 0.85-0.81 (m, 3H); 0.76 (d, 3H, J = 6.90 Hz).

Example 3

Into a 2,000 ml round flask equipped with a stirrer, a condenser and a thermometer, 100 g of S-2,2-dimethylcyclopropane carboxylic acid L-mentyl ester (Compound (L)) and 500 g of methanol were added. Then, 70g of 50% aqueous sodium hydroxide solution was slowly added while maintaining the reaction temperature at room temperature. After the reaction was refluxed and the reaction was completed, the reaction was concentrated to remove methanol, and then 500 g of water and 500 g of dichloromethane were added to the reaction, stirred for 15 minutes, and then the organic layer and the water layer were separated. The water layer was acidified with 35% hydrochloric acid, dichloromethane was added to the water layer, stirred for 15 minutes, and the organic layer and the water layer were separated. In the organic layer, the solvent and the low boiling point organics were recovered by distillation to give S-2,2-dimethylcyclopropane carboxylic acid (Compound (N)) (yield: 93.3%, purity: 99.0%, chiral purity: 95.1%). Rf = 0.5 (n-hexane / ethyl acetate, 2/1). ¹ H NMR (CDCl ₃ , 300 MHz): 1.55 (dd, 1H, J = 7.95 Hz, J = 5.42 Hz); 1.19 (s, 3 H); 1.16 (s, 3 H); 1.13 (dd, 1H, J = 4.98 Hz, J = 4.89 Hz); 0.92 (dd, 1H, J = 7.98 Hz, J = 4.42 Hz).

Example 4

100 g of S-2,2-dimethylcyclopropane carboxylic acid (compound (N)) and 400 g of dichloromethane were added to a 2,000 ml round flask equipped with a stirrer, a condenser, and a thermometer. Then, 104 g of thionyl chloride was slowly added while maintaining the reaction temperature at room temperature. After gas evolution was completed, 45 g of ammonia was added while maintaining the reaction at -15 ° C. After the reaction was completed, 700 ml of water was added to the reaction mixture, the mixture was stirred for 15 minutes, the organic layer and the water layer were separated, and the solvent and the low-boiling organic substance were recovered by distillation. Compound (I)) was obtained (yield: 92.1%, purity: 99.2%, chiral purity: 95.0%). Rf = 0.3 (normal-hexane / ethyl acetate, 1/1). ¹ H NMR (CDCl ₃ , 300 MHz): 5.59 (br, s, 2H,); 1.29 (dd, 1H, J = 7.91 Hz, J = 5.40 Hz); 1.17 (s, 3 H); 1.12 (s, 3 H); 1.06 (dd, 1H, J = 5.40 Hz, J = 4.84 Hz); 0.74 (dd, 1H, J = 7.92 Hz, J = 4.34 Hz).

Example 5

100 g of S-2,2-dimethylcyclopropane carboxamide (Compound (I)) and 200 g of ethanol were charged into a 1,000 ml round flask equipped with a stirrer, a condenser and a thermometer. The reaction is then refluxed to dissolve completely. Precipitate the crystals while slowly cooling the reaction to 10 ° C. The crystals are filtered through filter paper and the filtered solution is concentrated by distillation under reduced pressure. 200 g of normal heptane was added to the concentrated reaction mixture, and the mixture was stirred vigorously to precipitate crystals. The crystals produced by the filtering paper were filtered and dried to obtain high purity S-2,2-dimethylcyclopropane carboxamide as a white crystal. (Yield 82.0%, Purity: 99.8%, Chiral Purity: 99.8%). Rf = 0.3 (normal-hexane / ethyl acetate, 1/1). ¹ H NMR (CDCl ₃ , 300 MHz): 5.59 (br, s, 2H,); 1.29 (dd, 1H, J = 7.91 Hz, J = 5.40 Hz); 1.17 (s, 3 H); 1.12 (s, 3 H); 1.06 (dd, 1H, J = 5.40 Hz, J = 4.84 Hz); 0.74 (dd, 1H, J = 7.92 Hz, J = 4.34 Hz).

As described above, according to the method for preparing a chiral intermediate compound of the present invention, an intermediate that can be used for the preparation of the cilastatin is continuously and simply without a dangerous reaction step, and has a high yield and a high purity of 99.8% or higher and a high of 99.8% or higher. It can be prepared by purification in chiral purity. Therefore, application of the method for preparing the intermediate compound of the present invention to the production of the cilastatin enables the production of the target economically and with high purity without dangerous steps, which is suitable for commercial production.

Although the above has been described with reference to a preferred embodiment of the present invention, those skilled in the art will be able to variously modify and change the present invention without departing from the spirit and scope of the invention described in the claims below. It will be appreciated.

Claims (3)

A process for preparing the compound of formula (I)

(i) obtaining an ester mixture of formula (L) and formula (M) by condensation of a compound of formula (K) with L-menthol:

(ii) a 1: 1 mixture of the compound of formula (L) and formula (M) was isolated by recrystallization to obtain only the compound of formula (L) as crystals, and the concentrated compound of formula (M) was purified without purification. Racemizing in the same reactor to obtain a 1: 1 mixture of formula (L) and formula (M) again;

(iii) hydrolyzing the compound of formula (L) to obtain a compound of formula (N);

(iv) subjecting the compound of formula (I) to a compound of formula (I) via chlorination reaction followed by addition with ammonia to obtain a compound of formula (I):

(v) The S-form compound of Formula (I), which contains a small amount of the R-form compound of Formula (II), is completely dissolved in a suitable solvent and crystallized through an appropriate temperature range and agitation range to form an R-form enantiomer. Filtering a mixture of the contained R-form and S-form and obtaining a solution of the S-form compound in which the amount of the useful S-form compound is of sufficient purity for commercial use;

(vi) purifying the S-foam product of a purity sufficient to be commercialized for pharmaceutical use using a suitable secondary solvent from the solution of the S-foam compound to obtain the compound of formula (I). The method of claim 1, wherein the solvent of step (v) is dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane, chlorobenzene, dichlorobenzene and trichlorobenzene as a halogen solvent, and tetrahydro as an ether solvent. Furan, dioxane, petroleum ether, dialkyl ether and t-butylalkyl ether, dimethylformamide as polar solvent, dimethylacetamide and dimethylsulfooxide, and methanol as alcohol solvent, ethanol, propanol, t-butanol and n- And a solvent selected from the group consisting of butanol and mixed solvents thereof. 3. The solvent of claim 1 or 2, wherein the solvent of step (vi) is pentane, hexane, heptane and octane as a hydrocarbon solvent, and dichloromethane, dichloroethane, chloroform, carbon tetrachloride, tetrachloroethylene, tetrachloroethane as a halogen solvent. , A solvent selected from the group consisting of chlorobenzene, dichlorobenzene and trichlorobenzene, or a mixed solvent thereof.