KR820001460B1 - Process for manufacturing d-camphorate of l-carnitinamide and d-carnitinamide - Google Patents

Abstract

The title compds. were prepd. by resoln. of D,L-carnitine amide with D-camphoric acid. Thus, 500 g D,L-carnitinamide hydrochloride was treated with 550 g D-camphoric acid to give D,L-carnitinamide, D-camphoric acid, which was sepd. by fractional crystn. to give L-carnitinamide. D-camphoric acid, which was acidified with HCl gas to give L-carnitinamide-hydrochloride. The latter was hydrolyzed to give 150 g L-(-)-carnitinamide hydrochloride.

Description

D-camphorate preparation method of L-carnitine amide and D-carnitine amide

The present invention relates to a novel method for the preparation of D-camphorates of L-carnitineamides and D-camphorates of D-carnitineamides.

For example, as known from Belgian patent 660039, D-camphorates of L- and D-carnitineamides are important intermediates in the preparation of useful therapeutics. For example, D-camphorate of L-carnitineamide can be converted to L-carnitineamide with significant respiratory stimulating action. Moreover, L-carnitine amide as well as D-carnitine amide can be used to industrially produce, respectively, the left-handed and preferred carnitine hydrochloride known as useful therapeutic agents.

The methods proposed so far for the preparation of lecithin and preferential carnitine hydrochloride can be divided into two methods: using hydrochloride salt of D, L-carnitinenitrile as starting material and hydrochloride salt of D, L-carnitineamide as starting material. Can be divided into ways.

The former method, i.e. the use of hydrochloride salts of D, L-carnitinenitrile, Strak et al. (Z. Physiol. Chem. 318, 129, 1960), Horiji et al. (TOKIO KOHO SHO 40-3891), Ayada (YAKUGAKU ZASSHI 81, 778, 1961) and T. Methods proposed by Tohi et al. (Japan P.N. 63291/1965 of the OTSUKA Pharmaceutical Co., Ltd.).

Some of these methods require the formation of double salts to separate the left isomers (E. Strak's proposed method and Aida's proposed method) and the other two methods are L-camposulfonic acid (Horiji et al.) And Because of the use of expensive acids such as D-acetylglutamic acid (T. Tohi et al.), These methods have generally proved to be economically unsuitable for industrial production. Furthermore, the use of nitrile in carnitine is undesirable for this type of separation because the nitrile production process contains many salt impurities (10-15%) that are not easily separated and the impurities significantly complicate the two optically isolated separation processes.

In addition, racemization may occur during the continuous hydrolysis of the optically active carnitine nitrile into carnitine amide and carnitine.

This adverse effect occurs in particular upon conversion to carnitine amide so that the final compound obtained does not have the desired optical purity. The second method of using racemic carnitine amide as a starting material has the advantage of using a compound which can be easily obtained which is high in purity and easily hydrolyzed to carnitine without the risk of racemization.

The use of carnitine amide hydrochloride as starting material for separation is described in Belgian patent 660039, supra. This method also uses D-camphoric acid, which is readily available at low cost, for the production of camphorates of D and L-carnitineamides.

However, this method has a significant disadvantage. That is, in order to produce D-camphorate of D and L-carnitineamide, first, an ammonium salt of D-camphoric acid should be produced with ammonia, and the ammonium D-camphorate is reacted with silver nitrate to V) Industrial use is not very good since it has to be converted to D-camphorate. Since carnitine amide is in the hydrochloride form, the production of this silver salt is essential for the removal of chloride ions.

Therefore, this method also requires the use of a silver compound is very expensive and excessive silver chloride is formed, it is difficult to industrially perform various reaction processes to avoid the light to prevent the reaction vessel turns black.

Moreover, the final product is impure because of the presence of silver ions. It is therefore an object of the present invention to provide a process for the industrial preparation of D-camphorate of L-carnitineamide and D-camphorate of D-carnitineamide, which is free from the significant disadvantages of the prior art methods.

A more specific object of the present invention is to provide a method which is cheaper and time-saving than the prior art methods for producing D-camphorate of L-carnitineamide and D-camphorate of D-carnitineamide on an industrial scale. In particular, it is an object of the present invention to provide a method in which no expensive and troublesome silver compounds are used.

It is another object of the present invention to provide a method for using D, L-carnitine amide hydrochloride and D-camphoric acid as starting materials, which are inexpensive and easily available so far required to use silver compounds in order to obtain a desired object. .

The preliminary preparation of silver camphorate is not necessary and it is surprising that D-camphoric acid can be directly reacted with D, L-carnitineamide as long as D, L-carnitineamide is present in the free base form, not hydrochloride. Found.

According to the present invention, the method for preparing D-camphorate of L-carnitine amide and D-camphorate of D-chitinamide is:

(1) converting the D, L-carnitineamide hydrochloride solution to the D, L-cartinamide freebase solution,

(2) directly reacting the D, L-carnitineamide free base solution with D-camphoric acid to obtain a D-camphorate solution of D, L-carnitineamide,

(3) drying the solution of step (2) and recovering the residue with lower alkanol having 1 to 5 carbon atoms to form an alcohol solution, where the D-camphorate solid of L-carnitine amide is crystallized,

(4) A step of separating this solid from an alcohol solution containing D-camphorate of D-carnitine amide.

The preferred process for converting the D, L-carnitineamide hydrochloride solution to the D, L-carnitineamide freebase solution proceeds by contacting the aqueous D, L-carnitineamide hydrochloride solution with a strong acid or strongly basic ion exchange resin.

Gel-form Amberlite ion exchange resins prepared by Rohm and Haas are particularly suitable for the process of the invention. Specific examples of such Amberlite ion exchange resins are IRA 402, IRA 410 and IRA 401 / S.

By using a basic ion exchange resin, the D and L-carnitine amide free bases pass directly without remaining, while chlorine ions are fixed to the resin. On the contrary, when acidic ion exchange resin is used, D and L-carnitine amide are fixed. D, L-carnitine amide-fixed resin can be treated with D-camphoric acid solution to elute D, L-carnitine amide in the form of D-camphorate salt. Such ion exchange resins may be used directly in D, L-carnitineamide hydrochloride solution or may be used as a column. In general, use of the latter apparatus is more preferable because it is easier to control and has less loss during resin regeneration.

Once the resin is used, the resin can be easily recycled by a known method, so that it can be used in practically unlimited way. The average diameter of ion exchange resin varies from 0,39-0.46mm. A preferred method of use is one in which a strong basic ion exchange resin is charged into a chromatography column and passed through a solution containing D, L-carnitineamide hydrochloride.

The time the solution remains on the column should be 30-60 minutes and the preferred concentration range of the solution through the column is such that 500 g of D and L-carnitine amide are contained in 1.5-3 liters of a solvent such as water.

Since the D and L-carnitineamide free bases contained in the solution passing through the bottom of the chromatography column are unstable (carnitineamide tends to hydrolyze to carnitine), the preferred method of operation is to use D-camphoric acid as a solution. It is injected directly into the reaction vessel contained.

However, the solution may be stopped for 0.5-1 hours without any substantial risk of hydrolysis before reacting with D-camphor acid. D-camphoric acid can be used in suspension or solid form in a suitable suspending medium such as water, the latter method being vacuum dried to reduce the amount of moisture to evaporate in the next step of reducing the volume of the reaction mixture, and therefore less energy consumption. More preferred.

After drying the weight loss of the reaction mixture, the resultant residue is obtained as lower alkanol having 1 to 5 carbon atoms (isopropanol is particularly preferred). Separation of the optical isomer is performed by leaving the alcohol solution for 2-8 hours so that almost pure solid D-camphorate of L-carnitineamide is crystallized from the solution and D-camphorate of D-carnitineamide remains in the solution. do.

This solid can be separated from the liquid phase by filtration or the like, and the solid can then be recrystallized from the same alcohol used to recover the residue.

If isopropanol is used, simply washing with isopropanol is sufficient to obtain a high purity product. The following examples illustrate the invention in more detail without limiting its scope.

Example 1

Preparation of L-Carnitineamide Hydrochloride

Dissolving the D, L- carnitine amide hydrochloride of 500g in 2000ml of distilled water and OH ^- a basic ion exchange resin activated in the form (IRA 402, IRA 410, IRA or 401 / S, etc., Rohm & Haas) in diameter was charged with 4000ml 50mm Pass the 1.50m chromatographic glass column.

The residence time in the column of the solution is 30 minutes and the solution is kept at room temperature. The alkaline solution from the column is introduced directly into a suspension vessel in which 550 g of D-camphoric acid is suspended with 1200 ml of distilled water.

As D, L-carnitineamide free base seeps out of the column and reacts with D-camphor acid, D-camphor acid is dissolved and D, L-carnitineamide passes through the column (the pH of the solution is about 5-6). Thus all D-camphoric acid is dissolved.

D-camphor-containing aqueous solution of D, L-carnitineamide was vacuum dried to recover twice with 300 ml of isopropyl alcohol, and finally 4300 ml of isopropyl alcohol in which 10 g of D-camphoric acid was dissolved was added.

(C=2%수중)을 가진 L-카르니틴아마이드의 D-캄포레이트로 구성되어 있고 이소프로판올로 계속 결정화시켜

인 화합물 360g을 얻는다.In this state, when left at 0 ° C. overnight, 420 g of white compound crystallized,

Consisting of D-camphorate of L-carnitineamide with (C = 2% in water) and continuing crystallization with isopropanol

360 g of phosphorus compounds are obtained.

360 g of D-camphorate of this L-carnitine amide was dissolved in 3000 cc of isopropanol and treated with HCl gas to obtain acidic isopropanol.

(C=2 수중), M. P=239-241℃인 건조 화합물 150g을 얻는다.After about 12 hours at -4 ℃, excess L (-) carnitine amide hydrochloride is obtained, which is filtered and dried under vacuum at 40 ℃.

(C = 2 in water) and 150 g of a dry compound having M. P = 239-241 ° C.

); 3.30(s, 9H,

), 2.57(d, 2H, -CH₂-CONH₂); D₂OThe NMR of L-carnitineamide hydrochloride is as follows: δ 3.50 (d, 2H,

); 3.30 (s, 9 H,

), 2.57 (d, 2H, -CH ₂ -CONH ₂ ); D ₂ O

Example 2

Preparation of L (-) Carnitineamide Hydrochloride

The method of Example 1 was repeated except that the D, L-carnitineamide free base-containing solution from the chromatography column was introduced directly into the solid D-camphoric acid-containing reaction vessel.

Example 3

Preparation of L (-) Carnitine Hydrochloride

150 g of L (-) carnitine amide hydrochloride is dissolved in 310 ml of distilled water, heated to 98-100 ° C., 326 g of oxalic acid is added and the mixture is stirred for 6 hours while maintaining the temperature.

(C=5 수중)인 화합물 110g을 얻는다.The mixture was cooled for 12 hours, the ammonium oxalate precipitate was filtered off, the filtrate was concentrated to dryness and the residue was recovered twice with isopropyl alcohol and crystallized at 0 ° C.

110 g of a compound (C = 5 in water) is obtained.

All physicochemical properties (MP, IR, NMR and elemental analysis values) of the compounds thus obtained were the same as those of commonly known L (-) carnitine hydrochloride.

M. P = 140-142 ° C

L-carnitine amide hydrochloride has the following NMR.

); 3.32(s, 9H,

)2.73(d, 2H, CH₂-COOH); D₂Oδ 3,57 (d, 2H,

); 3.32 (s, 9 H,

) 2.73 (d, 2H, CH ₂ -COOH); D ₂ O

Example 4

Preparation of D (+) Carnitineamide Hydrochloride

700 ml of distilled water through a chromatographic column (120 cm high, 40 mm in diameter) packed with 1.35 kg of ion exchange resin in OH ^- activated base form (IRA 402 or IRA 401 / S or IRA 410, etc., Rohm & Haas) An aqueous solution containing 160 g of D L-carnitineamide hydrochloride in water is passed through. The residence time of the solution in the column is 1 hour. The solution is brought to room temperature.

인 45g의 백색 미정질 화합물을 얻는다.The solution which comes out of the column and contains D L-carnitineamide as free base is added directly to 185 g of D-campoic acid suspended in 400 ml of water. After filtration the aqueous solution is concentrated to dryness. Absorb with isopropyl alcohol and crystallize at 0 ° C. for 24 hours. The crystalline solid containing D-camphorate of L (-) carnitineamide was filtered and subjected to the same process as in Example 1. However, another 20 g of D-camphoric acid is added to the solution and crystallized for another 24 hours in isopropyl. The resulting solid compound is filtered and the clear solution is bubbled with cooled hydrous hydrogen chloride until a separate acid reaction is obtained. Chemical and physical properties (IR, NMR, MP and elemental analysis) were consistent with D (+) carnitine amide hydrochloride after standing in a refrigerator at -4 ° C for 12 hours.

45 g of white microcrystalline compound are obtained.

Example 5

Preparation of D (+) Carnitine Hydrochloride

(C=5%, 물)인 30g의 화합물을 얻었다. 다음의 실시예는 뒤에 L 및 D 광학적이성체의 후속적 용해를 위한 D, L-카르니틴아마이드 염산염으로 전환되는 D, L-카르니틴 염산염으로의 D-카르니틴아마이드의 라세미화를 설명한다.45 g of D (+) carnitineamide hydrochloride are dissolved in 100 ml of water and then heated to boiling and treated with 96 g of oxalic acid for 6 hours under constant stirring. The solution is cooled at 0 ° C. for 12 hours. The resulting ammonium oxalate is filtered and many of the solutions are concentrated to dryness in vacuo. The solid is well washed with isopropyl alcohol and then crystallized with the same solvent. Chemical-physical properties (IR, NMR, MP and elemental analysis) are consistent with D (+) carnitine hydrochloride

30 g of a compound (C = 5%, water) was obtained. The following examples illustrate the racemization of D-carnitineamide to D, L-carnitine hydrochloride, which is then converted to D, L-carnitineamide hydrochloride for subsequent dissolution of the L and D optical isomers.

Example 6

Method (a): D, L-carnitine hydrochloride preparation

을 표시한다.45 g of D-carnitineamide hydrochloride (prepared in Example 4) are dissolved in 200 cc of concentrated hydrogen chloride. And it is left at 100 degreeC for 60 hours. The solution is concentrated to dryness in vacuo. Residue 45g is D and L-carnitine hydrochloride. Residues are, in practice, the melting point and NMR of D, L-carnitine

Is displayed.

Method (b): Preparation of D, L-carnitineamide free base

10 g of D, L-carnitine hydrochloride are suspended in 100 cc absolute ethyl alcohol. The resulting suspension is saturated at 0 ° C. with gaseous hydrogen chloride. The suspension is then heated at reflux for about 3 hours until a solid phase is dissolved. The resulting solution is concentrated in vacuo to give 10 g of carnitine ethyl ester. Carnitine ethyl ester is treated with 100 cc of NH ₄ OH at room temperature for 40 hours. The solution is concentrated to dryness in vacuo. Residue is D, L-carnitineamide hydrochloride (12 g) containing about 10% NH ₄ Cl.

The above-mentioned D, L-carnitineamide hydrochloride is treated as in Example 1. For example D, L-carnitineamide free base and reacted with D-camphoric acid for dissolution of the optical isomer.

Claims (1)

The D, L-carnitineamide hydrochloride solution was connected with a strong acid or strong base ion exchange resin to obtain a D, L-carnitineamide free base solution which was reacted with D-camphoric acid to react D-camphorate and D- of L-carnitineamide. Process for preparing D-camphorate of carnitine amide.