Acylphenylalanine preparation process

FIELD: industrial organic synthesis.

SUBSTANCE: invention provides a simple method for preparing high-purity acylphenylalanine useful as starting material for pharmaceutical products. Process comprises Schotten-Bauman reaction stage wherein acid chloride reacts with phenylalanine in mixed solvent consisting of water-miscible organic solvent and water, while maintaining alkali pH (>10) of solvent medium with the aid of potassium hydroxide.

EFFECT: prevented formation of impurities.

13 cl, 4 tbl, 12 ex

 

The technical field

The present invention relates to a simple method of obtaining allenylidene with a high degree of purity, which is useful as a starting material for the pharmaceutical and similar products.

Background of the invention

In one of the ways to get acylaminoalkyl allumination containing as little impurities as possible, can be obtained by reaction of the carboxylic acid corresponding to the acyl group, with a complex ester of the amino acids in the presence of a condensing agent, such as dicyclohexylcarbodiimide (DCC), and then carrying out hydrolysis of ester. However, since the method requires a single preparation of ester of the amino acids and the use of expensive condensing agent, it has the disadvantage of high cost of production.

As to another method of obtaining acylaminoalkyl, which use amino acid instead of ester amino acids, it is known that allumination can be obtained by the reaction of carboxylic acid with N-hydroxysuccinimide in the presence of DCC or similar with the formation of the activated complex ether and then reaction of the activated complex ester with the amino acid. However, since the method requires the use of expensive congenerous what about the agent and its output is not high, it increases production costs.

Now, as for the method of obtaining acylaminoalkyl at a low cost is considered that the reaction of the Schotten's-Bauman is the most appropriate response in the industry, where the acid chloride acid and amino acid react in an aqueous solvent in an alkaline environment. The reaction is used to produce various acylaminoacyl.

Although the reaction of the Schotten's-Bauman tried to use to get allenylidene, it was found that in the reaction impurities and formed them difficult to remove.

Description of the invention

Therefore, the aim of the present invention is a method of preventing the formation of impurities, when you get allenylidenes using fine industry reaction the Schotten's-Bauman.

Have been carefully researched and impurities, which are the by-products formed when receiving allenylidene when using reaction Schotten's-Bauman, and it was found that these impurities are allenallenaleen (Acff), where allenylidenes additionally connected with phenylalanine.

To prevent the formation Acff was conducted intensive research and found that the purpose can be easily achieved using the reaction as a neutralizing agent Ki is rockside potassium. The present invention was made on the basis of this discovery. The present invention includes the following:

(1) a Method of producing allenylidene, which includes a step of reacting the carboxylic acid with phenylalanine in a mixed solvent consisting of an organic solvent and water, while maintaining the environment of the solvent alkaline using potassium hydroxide.

(2) the Method according to (1), where the pH of the mixed solvent is not less than 12.5.

(3) the Method according to (1), where the pH of the mixed solvent is not less than 13.5.

(4) the Method according to (1), where the ratio of organic solvent to water in the mixed solvent is from 10:90 to 80:20 by volume.

(5) the Method according to (1), where the ratio of organic solvent to water in the mixed solvent is from 15:85 to 40:60 by volume.

(6) the Method according to (1), where the acid chloride acid is the acid chloride saturated or unsaturated, having from 2 to 22 carbon atoms.

(7) the Method according to (1), where the acid chloride acid selected from the group consisting of Caproic acid, acid chloride, acid chloride Caprylic acid, capric acid chloride of the acid, acid chloride lauric acid, myristic acid chloride acid, palmitic acid chloride, acid chloride stearic acid, oleic acid chloride acid, C is kaheksanurkseid, methylcyclohexanecarboxylic, ethylcyclohexylamine, propylcyclohexanone, isopropylcyclohexane, benzoyl chloride, trouillard, salicylanilide, cinnamoroll, nafolklore and nicotinic acid chloride acid.

(8) the Method according to (1), where the acid chloride acid is isopropylcyclohexane.

(9) the Method according to (1), where the organic solvent in the mixed solvent selected from the group consisting of acetone, methyl ethyl ketone, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol and isopropyl alcohol.

(10) the Method according to (9), where the organic solvent in the mixed solvent is an acetone.

(11) the Method of producing allenylidene, which includes the stage of adding dropwise the carboxylic acid to a solution containing phenylalanine and potassium hydroxide in a mixed solvent consisting of an organic solvent and water, while maintaining the pH in the alkaline region, using potassium hydroxide.

(12) the Method according to (11), where the pH is not less than 12.5.

(13) the Method according to (11), where the ratio of organic solvent to water in the mixed solvent is from 10:90 to 80:20 by volume.

The best way of carrying out the invention

Used in the present invention chloramide the acid is not particularly limited, and usually represents the acid chloride saturated or unsaturated, having from 2 to 22 carbon atoms and preferably from 6 to 18 carbon atoms. His examples include the acid chloride of the acid derived from fatty acids such as Caproic acid, Caprylic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid and oleic acid; cyclohexylcarbonyl, methylcyclohexanecarboxylic, ethylcyclohexylamine, propylcyclohexanone, isopropylcyclohexane, benzoyl chloride, colorenhanced, salicylanilide, cinnamoroll, aftercare and the acid chloride of nicotinic acid. They may contain a substituent(s).

Further, the acid chloride of the acid of the present invention also includes allyloxycarbonyl, such as methoxycarbonylamino and tert-butoxycarbonylamino, and aryloxypropanolamine, such as benzyloxycarbonylamino, in addition to alkylcarboxylic and arylcarboxamide.

To regulate the pH in the reaction mixture using an aqueous solution of potassium hydroxide. If the pH of the reaction mixture is not less than 10, the reaction proceeds without any problems, however, a higher pH value of the reaction mixture is preferred because it pragotrade the education Asff. The preferred pH is not less than 12, more preferably, not less than 12.5, more preferably at least 13, and, most preferably, not less than 13.5. However, since the reaction mixture is sometimes painted in the event the pH is more than 14, it is necessary to carefully adjust the pH when necessary to avoid staining. Although pH may deviate from the above range when the regulation if it is temporarily, it does not cause any problems, because a temporary deviation has a negative impact. The pH value is determined by the readings of the pH-meter with glass electrodes. The concentration of an aqueous solution of hydroxide, particularly potassium, is not limited, but usually ranges from 2 to 50% mass, preferably from 5 to 25% of the mass.

Used in the present invention, organic solvents are solvents that can be mixed with water. For example, they include acetone, methyl ethyl ketone, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol, propanol and isopropanol, and particularly preferred is acetone.

The ratio of organic solvent to water in the mixture depends on the used acid anhydrides and therefore cannot be determined in General. However, it usually ranges from 10:90 to 80:20 and preferably from 15:85 to 40:60. Lower agains the organic solvent tends to prevent the formation of side product, Acff. However, when the acyl group contains a large number of carbon atoms that leads to the fact that the desired connection has a high hydrophobicity, the ratio of organic solvent must be improved in order to prevent the deposition and solidification of a connection in the course of the reaction. Specified in this description, the ratio shows the volume ratio of organic solvent to water and aqueous solution of potassium hydroxide, is added at the starting point of the reaction.

The temperature and concentration of the reaction mixture also can not be determined in the General case, since they depend on the used acids and anhydrides used in the reaction solvent. However, the temperature of the reaction mixture typically ranges from -5 to 25°and, preferably, from 0 to 15°C. the Concentration is usually from 1 to 20% and preferably from 2 to 10%. Data corresponding conditions can be defined, taking into account the outputs, efficiency and performance.

As a reaction methods can be used, for example, the following method. First, phenylalanine is dissolved in water, using approximately equivalent molar amount of an aqueous solution of potassium hydroxide, and to it add water, an organic solvent. Optionally, add an aqueous solution of potassium hydroxide to adjust the Finance pH. Then dropwise with stirring to the acid chloride acid. Added, preferably, is from about 15 minutes to 2 hours. The molar ratio of phenylalanine to the acid chloride acid, such as used in the reaction of TRANS-4-isopropylcyclohexane, respectively, is from 0.5:1 to 2:1, preferably from 0.9:1 to 1.5:1. Concentration in the reaction mixture of phenylalanine with the acid chloride of the acid, such as TRANS-4-isopropylcyclohexane, preferably equal to 2 wt.% up to 15 wt.% in units of concentration of phenylalanine when each substance is within the above range. The resulting allenylidenes can crystallize, podkisst the reaction mixture of hydrochloric acid and similar, filtering and removing after washing with water.

Examples

The following examples will further illustrate the present invention and in no way will be his limit.

Example 1

To 4.2 g of phenylalanine for its dissolution add 17 ml of water and 10.5 ml of 10% aqueous solution of potassium hydroxide. To this solution add 50 ml of acetone and cooled to approximately 10°C. To the reaction mixture are added dropwise 5.5 g of TRANS-4-isopropylcyclohexane (purity: about 95%). Meanwhile, to the reaction mixture is added 10% aqueous hydroxide solution is Aliya while maintaining the pH of the mixture in the range of 10.5-11. Then the reaction mixture was analyzed HPLC to calculate the ratio of the area of impurities TRANS-4-isopropylcyclopentadienyl (IFF) to the desired compound, TRANS-4-isopropylcyclopentadienyl. The result is shown in table 1.

Examples 2-6

The following reactions are examples 2-6 carried out using a 10% aqueous potassium hydroxide solution and the same procedure of example 1 except that in the reaction of changing the concentration of organic solvents and pH, as shown in table 1. The reaction mixture analyzed HPLC analogously to example 1. The results are shown in table 1.

Table 1
ExampleLyeOrganic solventpHOff
1KON65% acetone10,5-110,6
2KON60% acetone12-130,5
3KON50% acetone12-130,3
4KON40% acetone12-130,13
5KON30% acetone12-130,08
6 KON20% acetone12-130,05

Examples 7-9

To 4 g of phenylalanine for its dissolution add 44 ml of water and 16 ml of 10% aqueous solution of potassium hydroxide. To this solution add 15 ml of acetone and cooled to approximately 10°C. To the reaction mixture dropwise added to 5.3 g of TRANS-4-isopropylcyclohexane. Meanwhile, to the reaction mixture is added 10% aqueous potassium hydroxide solution while maintaining the mixture at pH values shown in table 2. Then the reaction mixture was analyzed HPLC in a similar manner as in example 1. The results are shown in table 2.

Table 2
ExampleLyeOrganic solventpHOff
7KON20% acetone12-12,50,13
8KON20% acetone13-13,20,07
9KON20% acetoneof 13.7 to 13.8Not defined

Examples 10-12

The following reactions are examples 10-12 spend analogous to the methods of examples 7 to 9 except that alter the concentration of organic solvents is her and the pH is 13.6 to 13.9. The reaction mixture analyzed HPLC analogously to example 1. The results are shown in table 3.

Table 3
ExampleLyeOrganic solventpHOff
10KON20% acetoneof 13.6 to 13.9Not defined
11KON30% acetoneof 13.6 to 13.9Not defined
12KON40% acetoneof 13.6 to 13.90,1

Comparative example 1

To 4.2 g of phenylalanine for its dissolution add 17 ml of water and 10.5 ml of 10% aqueous sodium hydroxide solution. To this solution add 50 ml of acetone and cooled to approximately 10°C. To the reaction mixture are added dropwise 5.5 g of TRANS-4-isopropylcyclohexane (purity: about 95%). Meanwhile, to the reaction mixture is added 10% aqueous sodium hydroxide solution while maintaining the pH of the mixture in the range of 10-10,5. Then the reaction mixture was analyzed HPLC to calculate the ratio of the area of impurities TRANS-4-isopropylcyclopentadienyl (IFF) to the desired compound, TRANS-4-isopropylcyclopentadienyl is. The result is shown in table 4.

Comparative examples 2-5

The following reactions are examples of comparisons 2-5 carried out using a 10% aqueous sodium hydroxide solution and the same procedure of comparative example 1 except that the reaction alter the ratio of organic solvents and pH. The reaction mixture analyzed HPLC analogously to example comparison 1. The results are shown in table 4.

Table 4
Comparative exampleLyeOrganic solventpHOff
1NaOH65% acetone10-10,51,9
2NaOH65% dioxane10-10,51,6
3NaOH65% acetonitrile10-10,51,8
4NaOH65% acetone12-12,53,5
5NaOH75% acetone10-10,5a 3.9

From the comparison of the results of each example and each comparative example are shown in tables 1-4, it is clear that it is possible to substantially prevent the formation of IFF, which are impurities which, applying an aqueous solution of potassium hydroxide as used in the reaction of alkali. Moreover, from examples 1-6, where the use of alkali water solution of potassium hydroxide, it is clear that lower concentrations of organic solvent (acetone) can more effectively prevent the formation of IFF. However, in the ways in which use of the source materials of examples 1-6, it was found that the amount of acetone as a solvent less than the number in example 6, for example, less than 10%, leads to the fact that the mixture thickens and the continuation of the reaction is difficult.

The method of the present invention can easily obtain allenylidenes with a high degree of purity with excellent industrially reaction Schotten's-Bauman.

1. The method of producing allenylidene, which includes a step of reacting the carboxylic acid with phenylalanine in a mixed solvent consisting of an organic solvent which is miscible with water, and water, while maintaining the environment of the solvent is alkaline (pH above 10) using potassium hydroxide.

2. The method according to claim 1, where the pH of the mixed solvent is not less than 12.5.

3. The method according to claim 1, where the pH of the mixed solvent is not less than 13.5.

4. The method according to claim 1, where the ratio of organic solvent to vodev mixed solvent is from 10:90 to 80:20 by volume.

5. The method according to claim 1, where the ratio of organic solvent to water in the mixed solvent is from 15:85 to 40:60 by volume.

6. The method according to claim 1, where the acid chloride acid is the acid chloride saturated or unsaturated, having from 2 to 22 carbon atoms.

7. The method according to claim 1, where the acid chloride acid selected from the group consisting of Caproic acid, acid chloride, acid chloride Caprylic acid, capric acid chloride of the acid, acid chloride lauric acid, myristic acid chloride acid, palmitic acid chloride, acid chloride stearic acid, oleic acid chloride acid, cyclohexylcarbodiimide, methylcyclohexanecarboxylic, ethylcyclohexylamine, propylcyclohexanone, isopropylcyclohexane, benzoyl chloride, trouillard, salicylanilide, cinnamoroll, nafolklore and nicotinic acid chloride acid.

8. The method according to claim 1, where the acid chloride acid is isopropylcyclohexane.

9. The method according to claim 1, where the organic solvent in the mixed solvent selected from the group consisting of acetone, methyl ethyl ketone, dioxane, tetrahydrofuran, acetonitrile, methanol, ethanol and isopropyl alcohol.

10. The method according to claim 9, where the organic solvent in the mixed p is storytale represents acetone.

11. The method of producing allenylidene, which includes the stage of adding dropwise the carboxylic acid to a solution containing phenylalanine and potassium hydroxide in a mixed solvent consisting of an organic solvent which is miscible with water, and water, while maintaining the environment of the solvent is alkaline (pH above 10) with the use of potassium hydroxide.

12. The method according to claim 11, where the pH is not less than 12.5.

13. The method according to claim 11, where the ratio of organic solvent to water in the mixed solvent is from 10:90 to 80:20 by volume.



 

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SUBSTANCE: invention relates to methods for preparing N-(trans-4-isopropylcyclohexylcarbonyl)-D-phenylalanine (nateglinide). Method for preparing nateglinide crystals of H-type is carried out by addition of inorganic acid to reaction mixture containing nateglinide to provide its acidification. The reaction mixture is prepared by interaction of trans-4-isopropylcyclohexylcarbonyl chloride with D-phenylalanine in a mixed solvent consisting of a ketone solvent and water in the presence of alkali. The ratio of water to ketone solvent is from 10:1 to 0.5:1. Temperature of the mixture is brought about to 58-72°C and concentration of ketone solvent - up to value above 8 wt.-% and less 22 wt.-% for carrying out precipitation of nateglinide crystals. Invention proposes variant for preparing nateglinide crystals of H-type. Also, invention proposes crystals of nateglinide of H-type showing average value of longitudinal axis from 1 to 5 mm and that for transverse axis from 0.1 to 0.5 mm. Invention provides enhancing effectiveness in isolation of nateglinide crystals.

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10 cl, 1 tbl, 13 ex

The invention relates to derivatives of amino, aminopentanoic, aminohexanoic acids of General formula I

< / BR>
where R1- A-COOR10; - (CH2)m-CONHOR10, -CONHNHR10, -(CH2)nSR50or-Y-P (OR51)2; m = 0, 1, 2; n = 0-3; each R2, R3, R4, R5, R6and R7independently is hydrogen, C1-8 alkyl, C2-8 alkenyl, -OR11, -SR11, -NR12R13, Cycle 1, C1-8 alkyl, substituted OR11, -SR11, -NR12R13, -COR14, guanidino or Cycle 1, or C2-8 alkenyl, substituted OR11, -SR11, -NR12R13, -COR14, guanidino or Cycle 1, or R3and R4taken together, represent a C1-8 alkylene, R5and R6taken together, represent a C1-8 alkylene, R3and R6taken together, represent a C1-8 alkylene, R2and R3taken together, represent a C2-8 alkylene, R4and R5taken together, represent a C2-8 alkylene or R6and R7taken together, represent a C2-8 alkylene, or (1) R8represents 1) hydrogen, 2) C1-8 alkyl, 3) C1-8 alkoxycarbonyl, 4) C1-8 alkyl, substituted OR26, -SR26, -NR27R28ips.ru/fullimg4/rupat5/2003/11/01/2215735-2t.gif" ALIGN="ABSMIDDLE">< / BR>
(2) R8represents a

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< / BR>
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5)< / BR>
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10 cl, 1 tbl, 13 ex

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18 cl, 3 tbl, 23 ex

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EFFECT: prevented formation of impurities.

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