Separation of 3-aminoalkylnitryles

FIELD: organic chemistry.

SUBSTANCE: invention relates to chiral N-acetyl-alpha-amino acid salts and optically active beta-aminoalkylnitriles, in particular compound of formula IIa , wherein R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; Q is N-acetyl-alpha-amino acid. Also invention relates to method for conversion of racemic 3-amino-(C3-C7)-alkylnitrile of formula I to corresponding (R) isomer of formula IIf. Claimed method includes interaction of racemic 3-amino-(C3-C7)-alkylnitrile of formula I with N-acetyl-alpha-amino acid of formula Q in solvent. Also disclosed is method for conversion of R or S 3-amino-(C3-C7)-alkylnitrile to racemic 3-amino-(C3-C7)-alkylnitrile by interaction of R or S 3-amino-(C3-C7)-alkylnitrile with aqueous ammonia at 30-200°C. Composition useful as structure units in synthesis of optically active beta-amino acids, enriched with compound of formula IIa and compound of formula I, wherein Q is N-acetyl-alpha-amino acid; and R is as defined above also are disclosed.

EFFECT: new method for separation of 3-aminoalkylnitryles.

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The scope of the invention

This invention relates to a method for producing optically active β-aminoalkylation, which are used as building blocks in the synthesis of optically active β-amino acids and pharmaceutical drugs, separation of the racemic β-aminoalkylation using as separating agents optically active N-acetyl-alpha-amino acids.

More specifically this invention relates to a chiral salts of N-acetyl-alpha-amino acids optically active β-aminoalkylation and also to a method for producing optically active β-aminoalkylation separation of racemic β-aminoalkylation using chiral salts of N-acetyl-alpha-amino acids as separating agents.

The level of technology

β-amino acids isolated in the free form, and they find useful pharmacological properties. For example, β-amino acids can be cyklinowanie to β-lactam, a well-known class of potential biologically active substances. These types of connections are also excellent building blocks for a variety of natural products and, as shown, are useful tools in the synthesis of modified peptides with high activity and stability in vivo.

Steer and the R. in the publication "the Use of β-amino acids in the creation of inhibitors of proteases and peptidases" reported that in recent years there have been coworkers peptide approach with considerable potential using β-amino acids. It is reported that one of the important features β-amino acids is their biological stability. This biological stability is a consequence of the fact that, although β-amino acids such α-amino acids that they contain terminal amino group and a carboxyl end group, they also have two carbon atoms that share these functional end groups. As such, β-amino acids with specific side chain may exist in the R or S isomers or when α (C2) carbon atom, or when β (C3) carbon atom, resulting in four possible isomers for each of the given side chain. This demonstrates that in β-amino acids significantly more isomers available than is possible for the respective α-amino acids. Steer, David L.; Lew, Rebecca A.; Perlmutter, Patrick; Smith, Ian A.; Aguilar, Marie-Isabel; Letters in Peptide Science (2002), Volume Date 2001, 8(3-5), 241-246.

In the publication "β-amino acids: multipurpose peptidomimetics" Steer, etc. give an overview of the application β-amino acids to create and synthesis of biologically active peptides. They reveal that the use of the group β -amino acids in the creation of biologically active peptides is expanding rapidly. Part β-amino acids, as noted, is successful in creating peptidomimetics that not only have strong biological activity, but also are resistant to proteolysis. Steer, David L.; Lew, Rebecca A.; Perlmutter, Patrick; Smith, Ian A.; Aguilar, Marie-Isabel; Current Medicinal Chemistry (2002), 9(8), 811-822.

Different ways of obtaining enantioface β-amino acids and their derivatives exist. Of these methods conjugated accession amines to unsaturated NITRILES or esters and subsequent hydrolysis is applicable due to the availability of source material. Although the reaction of the merger proceeds with high yield with the formation of racemic β-amino acids, most attempts to control the stereochemistry of the chiral center are the result of low yields and void enantiomeric excess.

Given the low cost of obtaining racemic mixtures β-aminoalkylation, their separation is an excellent opportunity to develop an affordable method for the synthesis of optically active β-aminoalkylation and their respective β-amino acids as building blocks to create a useful pharmaceutical compounds. But it is unlikely that such attempts have been reported in the scientific literature. Thus the m there is a need for effective budget process for the separation of racemic mixtures β-aminoalkylation.

The invention

According to one aspect of this invention relates to the compound of formula IIa or IIb

where R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, and Q denotes N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-asparagine, N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl-L-glutamine, N-acetyl-L-glutamic acid, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-Proline, N-acetyl-L-serine, N-acetyl-L-threonine, N-acetyl-L-tryptophan, N-acetyl-L-tyrosine, N-acetyl-L-valine, N-acetyl-D-alanine, N-acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N-acetyl-D-glutamine, N-acetyl-D-glutamic acid, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N-acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-methionine, N-acetyl-D-phenylalanin, N-acetyl-D-Proline, N-acetyl-D-serine, N-acetyl-D-threonine, N-acetyl-D-tryptophan, N-acetyl-D-tyrosine, N-acetyl-D-valine.

In a preferred embodiment Q is selected from the group consisting of N-acetyl-L-alanine, N-acetyl-L-cysteine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine and N-acetyl-L-valine.

In another predpochtitel the second embodiment Q means N-acetyl-L-isoleucine.

In another preferred embodiment Q means N-acetyl-L-valine.

According to another preferred embodiment R is ethyl.

According to another aspect of the present invention, a method for conversion of racemic 3-amino-(C3-C7)Alternaria formula I

where R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, in the appropriate (R) or (S) isomer of formula IIa or IIb,

containing a combination of solvent racemic 3-amino-(C3-C7)Alternaria formula I with N-acetyl-L-amino acid of formula Q, where Q denotes N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-asparagine, N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl-L-glutamine, N-acetyl-L-glutamic acid, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-Proline, N-acetyl-L-serine, N-acetyl-L-threonine, N-acetyl-L-tryptophan, N-acetyl-L-tyrosine, N-acetyl-L-valine, N-acetyl-D-alanine, N-acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N-acetyl-D-glutamine, N-acetyl-D-glutamic acid, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N-acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-methionine, N-acetyl-D-phenylalanin, N-acetyl-D-Proline, N-acetyl-D-serine, -acetyl-D-threonine, N-acetyl-D-tryptophan, N-acetyl-D-tyrosine or N-acetyl-D-valine, in a solvent, which is selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, methanol and water, or mixtures thereof.

In the preferred embodiment of the method Q is selected from the group consisting of N-acetyl-L-alanine, N-acetyl-L-cysteine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine and N-acetyl-L-valine.

In another preferred embodiment of the method Q means N-acetyl-L-isoleucine.

In another preferred embodiment of the method Q means N-acetyl-L-valine.

In another preferred embodiment R is ethyl.

According to another aspect of the invention, a method of transformation of R or S 3-amino-(C3-C7)Alternaria in racemic 3-amino-(C3-C7)alkynylaryl containing a combination of R or S 3-aminophthalonitrile with aqueous ammonia at a temperature of from 30 to 200°C.

According to another aspect of the invention racemic amino-(C3-C7)alkynylaryl is R-3-aminophthalonitrile.

According to another aspect of the invention proposed a composition enriched compound of formula IIa or IIb, as described above.

According to another aspect of the invention proposed compound of the formula I

where R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, and Q N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-asparagine, N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl-L-glutamine, N-acetyl-L-glutamic acid, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanin, N-acetyl-L-Proline, N-acetyl-L-serine, N-acetyl-L-threonine, N-acetyl-L-tryptophan, N-acetyl-L-tyrosine, N-acetyl-L-valine, N-acetyl-D-alanine, N-acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N-acetyl-D-glutamine, N-acetyl-D-glutamic acid, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N-acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-methionine, N-acetyl-D-phenylalanin, N-acetyl-D-Proline, N-acetyl-D-serine, N-acetyl-D-threonine, N-acetyl-D-tryptophan, N-acetyl-D-tyrosine or N-acetyl-D-valine.

Used herein, the term "division" has its conventional meaning, i.e. the transformation of racemic 3-aminoalkylsilyl formula I in the product (i.e. the composition), enriched with the appropriate (R) or (S) isomer. Enriched composition is a composition that contains a higher excess or higher relative proportion of one stereoisomer over the other. Thus, the enriched composition usually contains a higher relative proportion of the desired stereoisomer (e.g., enantiomer) with respect to the racemate.

In formulas here, unless otherwise specified, communication amino-carbon have Izv the STN in the technique stereochemical values. For example, in the formula I the relationship amino-carbon, indicated by the straight line represents the racemate. Communication amino-carbon indicated by thickened lines as in formula IIa (see below), is above the plane of the page. Communication amino-carbon, marked by a dotted or dashed line, as in the formula IIb (see below), is located behind the plane of the page.

Specialists in this field will readily understand that the symbol · in formulas I, IIa and IIb means salt pair.

The salt formed between the optically active N-acetyl-alpha-amino acid, Q, and (R)-stereoisomer or (S)-stereoisomer of substrate β-aminoacetonitrile, has the formula IIa or IIb

where Q, R and communication amino-carbon have the above values. Concrete formed by the Sol depends of course on the specific stereochemistry of N-acetyl-alpha-amino acids used to separate β-aminoacetonitrile. If desired stereoisomer found in salt, salt usually precipitates and can be isolated, for example, by filtration. Q can then be displaced to obtain the desired optically active β-aminoalkylsilyl. On the other hand, if the desired isomer is contained in the mother liquor, the mother liquor can be concentrated to obtain the desired optically active β-aminoalkylsilyl.

It is established that pricheski active N-acetyl-alpha-amino acids, denoted here as Q, can be used for the separation of racemic β-aminoalkylation formula I. Racemic β-aminoalkylsilyl subjected to reaction with (which is also referred to here as "handle") stereoisomer of N-acetyl-alpha-amino acids for the formation of one of the corresponding optically active salts of the formula IIa or IIb with excellent enantiomeric purity and overall yield. Typically, the salt of the formula IIa or IIb, which is formed, deposited, and the remaining stereoisomer β-aminoacetonitrile is dissolved in the mother liquor. If desired stereoisomer is contained in the salt, the salt can be separated, e.g. by filtration, and Q can then be substituted to obtain the desired optically active β-aminoalkylsilyl. On the other hand, if the desired isomer is contained in the mother liquor, it can be concentrated to obtain the desired optically active β-aminoalkylsilyl. Optional uterine fluid initially it may be extracted with a suitable (immiscible) with a solvent, for example a solvent having a low boiling temperature, and then concentrated by evaporating the low-boiling solvent.

A specific example embodiment of this invention relates to a method, which is described above, where L Is N-acetylcholin used to is the amount of separating agent and alcohol, for example ethanol, used as a solvent for crystallization of salt β-aminoacetonitrile with L-N-acetylamino. In another specific embodiment it is established that the method may be used to obtain (R)-3-aminophthalonitrile of the racemic mixture using N-acetylaminophenol. More specifically, L-N-acetylcholin used as a separating agent, followed by conversion of the salt of valinta a free base using well-known technique procedures.

Detailed description of the invention

Found that the separation of racemic 3-aminoalkylsilyl processing L-N-acetyl-amino acids can provide high-performance reaction gases with very high selectivity. In addition found that this approach provides cheap/efficient synthesis of interest compounds, such as R-3-aminopentanoic. Specific methods for obtaining optically active β-aminoalkylation provided as an additional characteristic features of the invention and described below in the experimental part.

All source materials are commercially available, moreover, their synthesis will be obvious to the expert. See, e.g., "Synthesis of N-acetyl-amino acids", Marshall, J.J. AM. Chem. Soc. 1956, 78, 4636.

SCHEME 1

On scheme R and Q have the previously indicated values.

Scheme 1 above provides the chiral salt of N-acetyl-amino acids and (R) or (S) 3-aminoalkylsilyl formula IIa or IIb, starting from the corresponding alkyl-2-ene-nitrile of the formula III. Alkyl-2-ene-nitrile of the formula III is subjected to reaction with aqueous ammonium hydroxide, preferably under pressure of approximately 12 bar and at a temperature of approximately 150°to obtain racemic 3-aminoalkyl formula I. Chiral salt of N-acetyl-alpha-amino and 3-aminoalkylsilyl formula IIa or IIb is then obtained by interaction of racemic 3-aminoalkylsilyl formula I with a suitable chiral N-acetyl-alpha-amino acid Q is preferably an alcohol or a water/alcohol solvent at a temperature from -20 to 120°C.

Education salt is most preferably carried out using a mixture of ethanol/water as solvent and in the range of 0.5 to 1.1 mol of the formula Q per mole β-aminoalkylsilyl formula I. the Reaction can be conducted at temperatures ranging from room temperature to 80°C. the Reaction is preferably carried out at a temperature of from 65 to 80°C. the Reaction continue until you get the solution. The mixture was then cooled, filtered and the desired isomer isolated, for example by filtration, if it is separated from the mother liquor in the form of the Oli, or by evaporation, if he remains in it as neozhidanny remaining stereoisomer β-aminoacetonitrile.

The preferred method of obtaining chiral salt of N-acetyl-alpha-amino and 3-aminoalkylsilyl formula IIa or IIb involves the interaction of 0.9 equivalents of the corresponding chiral N-acetyl-alpha-amino acids of formula Q with 1.0 equivalent of racemic 3-aminoacetonitrile in aqueous ethanol. More specifically, racemic 3-aminoalkylsilyl formula I add to chiral N-acetyl-alpha-amino acid Q in aqueous ethanol at approximately 65 to 70°C. the Reaction mixture is then heated to boiling with the return of phlegmy until you get a homogeneous solution. The reaction mixture is then cooled to about 60°C and maintained at this temperature for at least 30 minutes. The reaction mixture was then cooled to 0°and chiral salt of N-acetyl-alpha-amino and 3-aminoalkylsilyl formula I, which precipitates is separated and collected by filtration. The filtrate enriched remaining stereoisomer. If the filtrate enriched unwanted isomer, it can be processed as described above to racemethionine stereoisomer, and then returned into the cycle through the procedure division. If it contains the desired stereoisomer, he can be concentrated by evaporation to remove it, optional is entrusted with intermediate extraction.

Specialist in this field can easily understand that this procedure is generally applicable to any β-aminoalkylation applicable in this invention, with the implementation of such adjustments solvent (or solvents, if they use their mixture), temperature, and specific chiral N-acetyl-amino acids that may be required to optimize the output.

As previously mentioned, the maximizing of the nuclear power utilization of the invention provides a method of racemization unwanted isomer, as shown in scheme 2. Chiral 3-amino-(C3-C7)alkynylaryl subjected to reaction with aqueous ammonium hydroxide at about 12 bar at approximately 120 to 150°With from 2 to 24 hours. The reaction mixture was then concentrated in vacuo and the resulting crude racemic 3-amino-(C3-C7)alkynylaryl can optionally be separated by vacuum distillation.

SCHEME 2

The obtained racemic mixture can then be separated according to known procedures disclosed here, that is, the racemic mixture can be subjected to reaction with N-acetyl-amino acid, denoted here as Q, to obtain enantiomerically enriched salt of the formula IIa or IIb in accordance with the conditions described above in scheme 1.

EXAMPLES

Example I

Synthesis of N-ACET the l-L-valine

L-Valine (200 g, 1,7 molecu.) dissolved in water (500 ml), accompanying the addition of NaOH (30%, 170 ml). The mixture is cooled to 0-5°With accompanying addition of acetic anhydride (32 ml, 1.4 EQ.). Sodium hydroxide (30%, 34 ml) is added, keeping the temperature between 0-5°C. Alternating adding acetic anhydride and 30% NaOH repeat six times, keeping the temperature (acetic anhydride, 6×32 ml; 30% NaOH 6×34 ml). After all additions, the mixture is stirred for additional two hours at 0°C. Hydrochloric acid (32%, 380 ml) is added to reduce the pH below 3, maintaining the temperature 0°C. the resulting suspension granularit for 12 hours, filtered and the filter cake washed with HCl (0.1 n., 100 ml). Wet N-acetyl-L-valine dried, getting 233 g (yield 86%).

Example II

Division 3-aminophthalonitrile N-acetyl-L-valine

N-acetyl-L-valine (145,4 g, 0,91 molecu.) combine with ethanol (1425 ml) and water (75 ml) in a flask equipped with a stirrer and condenser unit. The mixture is heated to 65-70°With accompanying added (syringe) of racemic 3-aminophthalonitrile. The mixture was kept at boiling with the return of phlegmy until dissolved. The mixture is cooled to 60°C and maintained at this temperature at least 30 minutes. The mixture is cooled to 0°and salt is separated by filtration.

Example III

Division 3-aminopentyl the nitrile N-acetyl-L-isoleucine.

N-acetyl-L-isoleucine (157 g, 0,91 molecu.) combine with ethanol (250 ml) and water (75 ml) in a flask equipped with a stirrer and condenser unit. The mixture is heated to 65-70°With accompanying addition of racemic 3-aminophthalonitrile. The mixture was kept at boiling with the return of phlegmy until dissolved. The mixture is cooled to 60°C and maintained at this temperature at least 30 minutes. The mixture is cooled to 0°and salt is separated by filtration (yield 70%, with a maximum possible output from 50% to 99.8%).

Example IV

Racemization R-3-aminophthalonitrile

R-3-aminopentanoic (197 g, 2,1 molecu.) combined with 30% aqueous ammonia solution (930 ml, 14,7 molecu.) in a suitable pressure vessel and the mixture is heated to 130°C. After 6 hours the mixture is cooled and analyzed to complete racemization. The mixture was concentrated in vacuo (15 mm RT. Art., 88° (C) to 300 ml of the Crude product is distilled in vacuum for additional purification, receiving 160 g of racemic mixture (yield 77%, 95% GC purity, 50/50% R/S).

Example V

The transformation of a free base salt of N-acetyl-L-valine with 3-aminophthalonitrile

Salt of N-acetyl-L-valine with 3-aminophthalonitrile (230 g) are combined with dichloromethane (713 ml). To this mixture an aqueous solution of sodium hydroxide (98 ml, 30% wt./wt.) and the mixture is stirred at 20-25°C for 1 hour. The lower organic the positive phase is separated and the upper aqueous phase was washed with additional dichloromethane (2× 180 ml). The organic layers combine, concentrate, and optically active 3-aminopentanoic separated by distillation (yield 80%, 99.8 per cent)

Example VI

Obtaining salts of L-acetyl-L-valine with 3-aminophthalonitrile

A 3-liter flask equipped with stirrer, thermometer, addition funnel, oil bath, download N-acetyl-L-valine (145,4 g), denatured ethanol (denatured with about 5% methanol and 3% cyclohexane) (1425 ml) and water (75 ml). The mixture is heated under stirring up to 65-70°and add 150 g of 3-aminophthalonitrile. The solution is heated to boiling with the return of phlegmy (about 75° (C) to obtain a completely transparent solution, which is then slowly cooled to 65°C. With constant stirring in the mixture contribute diluted a bit diastereomers pure salt of L-acetyl-L-valine with 3-aminophthalonitrile and stirred at 60°C for 1 hour. The thick slurry is then cooled to 0°C for 3 hours and stirred at 0°C for 2 hours. The obtained salt is filtered off and washed with ethanol 2×75 ml. Optical purity wet product 89,8% (And%). Wet salt load in 2-liter flask with standard equipment and add 900 ml of denatured ethanol. The suspension is heated to boiling with the return of phlegmy, stirred for 1 hour at boiling temperature with the return of f is egmi and then cooled to room temperature within 2 hours. After more than 2 hours of stirring at room temperature the obtained salt is filtered off and washed with denatured ethanol 2×150 ml, the Product is dried at 40°receiving 118,3 g of salt of L-acetyl-L-valine with 3-aminophthalonitrile, crystalline solid white color (optical purity: 99,8%, yield: 60% of theoretical).

Example VII

Obtaining salts of L-acetyl-L-valine with 3-aminophthalonitrile

A 3-liter flask equipped with stirrer, thermometer, addition funnel, oil bath, download N-acetyl-L-valine (200,0 g), denatured ethanol (denatured with about 5% methanol and 3% cyclohexane) (2000 ml) and water (100 ml). The mixture is heated under stirring up to 65-70°and type 3-aminopentanoic (206,4 g) for 30 minutes the Solution is heated to boiling with the return of phlegmy (about 75° (C) to obtain a completely transparent solution, which is then slowly cooled to 65°C. With constant stirring in the mixture contribute diluted a bit diastereomers pure salt of L-acetyl-L-valine with 3-aminophthalonitrile and stirred at 60°C for 1 hour. The thick slurry is then slowly cooled to 20°C for 3 hours and stirred at 20°C for 18 hours (overnight). The suspension since that time, cooled to 5°C and stirred for 3 hours. The precipitated salt Hotfile revival and washed with denatured ethanol (3× 100 ml) and dried in a vacuum dryer at 40°With C/10 mbar until reaching constant weight, getting salt of L-acetyl-L-valine with 3-aminophthalonitrile (to 228.7 g), crystalline solid white (output 84,8%)having an optical purity of 97.7%.

Example VIII

Obtaining salts of L-acetyl-L-isoleucine with 3-aminophthalonitrile

In a flask with a capacity of 250 ml, equipped with a mechanical stirrer, thermometer, addition funnel, oil bath, load 3-aminopentanoic (5 g), N-acetyl-L-isoleucine (8.8 g) and denatured ethanol (denatured with about 5% methanol and 3% cyclohexane) (97 ml). The solution is heated to boiling with the return of phlegmy to a fully transparent solution, which is then slowly cooled to 68°C. With constant stirring in the mixture contribute diluted a bit diastereomeric enriched salt of L-acetyl-L-isoleucine with 3-aminophthalonitrile and stirred at 65-70°C for 2 hours. The thick slurry is then slowly cooled to room temperature. The obtained salt is filtered off and washed with ethanol. The product is dried at 50°receiving salt of L-acetyl-L-isoleucine with 3-aminophthalonitrile (7,3 g), crystalline solid white color (optical purity: 76% R; output 112% of theoretical).

The obtained salt is loaded into a flask with a capacity of 250 ml with standard equipment and adds methyl-ethyl-ketone (73 ml). The suspension is heated to boiling with the return of phlegmy, stirred for 1 hour at boiling temperature with the return of phlegmy and then slowly cooled to 60°C. the Obtained salt is filtered off and washed with methyl-ethyl-ketone. The product is dried at 50°receiving salt of L-acetyl-isoleucine with 3-aminophthalonitrile (5,2 g), crystalline solid white color (optical purity: 98.2% of R; output 71.9% of theoretical).

In this application there are links to various publications. The disclosure of these publications in their entirety attached thereby to this application for all purposes.

Professionals in this field should be clear that various modifications and changes may be made in this invention without leaving the scope and essence of the invention. Other embodiments of the invention will be obvious to experts in this area from consideration of the description and implementation in practice of the invention disclosed here. Understood that the description and examples should be considered only as examples, the true scope and nature of the invention is indicated by the following claims.

1. The compound of formula IIa

where R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; Q means N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-asparagine,N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl-L-glutamine, N-acetyl-L-glutamic acid, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-Proline, N-acetyl-L-serine, N-acetyl-L-threonine, N-acetyl-L-tryptophan, N-acetyl-L-tyrosine, N-acetyl-L-valine, N-acetyl-D-alanine, N-acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N-acetyl-D-glutamine, N-acetyl-D-glutamic acid, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N-acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-methionine, N-acetyl-D-phenylalanin, N-acetyl-D-Proline, N-acetyl-D-serine, N-acetyl-D-threonine, N-acetyl-D-tryptophan, N-acetyl-D-tyrosine, N-acetyl-D-valine.

2. The compound according to claim 1, where Q is selected from the group consisting of N-acetyl-L-alanine, N-acetyl-L-cysteine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine and N-acetyl-L-valine.

3. The compound according to claim 2, where Q denotes N-acetyl-L-isoleucine.

4. The compound according to claim 2, where Q denotes N-acetyl-L-valine.

5. The compound according to any one of claims 1 to 4, where R is ethyl.

6. The way of transformation of racemic 3-amino-(C3-C7)Alternaria formula I

where R is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, in the corresponding (R) isomer of formula IIa,

which conclusion is highlighted in the interaction of racemic 3-amino-(C 3-C7)Alternaria formula I with N-acetyl-L-amino acid of formula Q in the solvent, where Q denotes N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-asparagine, N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl-L-glutamine, N-acetyl-L-glutamic acid, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanin, N-acetyl-L-Proline, N-acetyl-L-serine, N-acetyl-L-tryptophan, N-acetyl-L-tryptophan, N-acetyl-L-tyrosine, N-acetyl-L-valine, N-acetyl-D-alanine, N-acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N-acetyl-D-glutamine, N-acetyl-D-glutamic acid, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N-acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-methionine, N-acetyl-D-phenylalanin, N-acetyl-D-Proline, N-acetyl-D-serine, N-acetyl-D-threonine, N-acetyl-D-tryptophan, N-acetyl-D-tyrosine or N-acetyl-D-valine, where the solvent is selected from the group consisting of ethanol, n-propanol, isopropanol, n-butanol, tert-butanol, methanol and water, or mixtures thereof.

7. The method according to claim 6, where Q is selected from the group consisting of N-acetyl-L-alanine, N-acetyl-L-cysteine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine and N-acetyl-L-valine.

8. The method according to claim 7, where Q denotes N-acetyl-L-isoleucine.

9. The method according to claim 7, where Q denotes N-acetyl-L-valine.

10. The method according to any of PP-9, where R snaketail.

11. The way of transformation of R or S 3-amino-(C3-C7)Alternaria in racemic 3-amino-(C3-C7)alkynylaryl, including the interaction of the R or S 3-amino-(C3-C7)Alternaria with aqueous ammonia at a temperature of from about 30°to 200°C.

12. The method according to claim 11, where the racemic amino-(C3-C7)alkynylaryl is R-3-aminophthalonitrile.

13. The composition for use as building blocks in the synthesis of optically active β-amino acids, enriched compound according to any one of claims 1 to 4.

14. The compound of the formula I

where

R means methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl; Q means N-acetyl-L-alanine, N-acetyl-L-arginine, N-acetyl-L-asparagine, N-acetyl-L-aspartic acid, N-acetyl-L-cysteine, N-acetyl-L-glutamine, N-acetyl-L-glutamic acid, N-acetyl-L-histidine, N-acetyl-L-isoleucine, N-acetyl-L-leucine, N-acetyl-L-lysine, N-acetyl-L-methionine, N-acetyl-L-phenylalanine, N-acetyl-L-Proline, N-acetyl-L-serine, N-acetyl-L-threonine, N-acetyl-L-tryptophan, N-acetyl-L-tyrosine, N-acetyl-L-valine, N-acetyl-D-alanine, N-acetyl-D-arginine, N-acetyl-D-asparagine, N-acetyl-D-aspartic acid, N-acetyl-D-cysteine, N-acetyl-D-glutamine, N-acetyl-D-glutamic acid, N-acetyl-D-histidine, N-acetyl-D-isoleucine, N-acetyl-D-leucine, N-acetyl-D-lysine, N-acetyl-D-met is onini, N-acetyl-D-phenylalanin, N-acetyl-D-Proline, N-acetyl-D-serine, N-acetyl-D-threonine, N-acetyl-D-tryptophan, N-acetyl-D-tyrosine or N-acetyl-D-valine.



 

Same patents:

FIELD: organic chemistry, chemical technology, catalysts.

SUBSTANCE: invention relates to a method for synthesis of aminonitrile from corresponding dinitrile. Method involves contacting dinitrile of the general formula R(CN)2 wherein R means alkylene group comprising from 2 to 25 carbon atoms with hydrogen-containing medium in the presence of a solvent, hydrogenation catalyst and an additive comprising tetralkyl ammonium cyanate for enhancing yield and/or selectivity by aminonitrile as the end product. Also, invention relates to the catalyst composition used in hydrogenation of dinitrile to aminonitrile comprising the combination (1) of the hydrogenation catalyst useful for hydrogenation of dinitrile of the general formula R(CN)2 wherein R means alkylene group comprising from 2 to 25 carbon atoms to aminonitrile, and (2) additive comprising compound of tetraalkyl ammonium cyanate.

EFFECT: improved method of synthesis.

15 cl, 10 ex

FIELD: organic chemistry, biochemistry.

SUBSTANCE: invention relates to compounds used as intermediates substances for inhibitors of transfer of cholesteryl ester protein (CETP) and methods for their preparing. Indicated compounds are represented by the following formulae:

, ,

wherein R is taken among methyl and benzyl and by the formula

wherein R represents methyl.

EFFECT: improved preparing method, valuable biochemical properties of inhibitors.

15 cl, 9 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for semi-hydrogenation of dinitrile of the general formula: NC-R-CN wherein R means linear or branched alkylene group comprising from 1 to 12 carbon atoms to the corresponding aminonitrile in the liquid medium. Method is carried out in the presence of a catalyst, such as nickel or Raney nickel comprising an activating element taken among rhodium or iridium wherein the weight ratio (Rh or Ir)/Ni is from 0.05% to 10%. Method provides enhancing yield of aminonitrile.

EFFECT: improved and enhanced method.

21 cl, 3 ex

FIELD: organic chemistry, chemical technology.

SUBSTANCE: invention relates to a method for semi-hydrogenation of dinitriles of the general formula: NC-R-CN (I) wherein R means linear or branched alkylene or alkenylene group comprising from 1 to 12 carbon atoms to the corresponding aminonitriles. Method involves using hydrogen in the presence of catalyst based on nickel, cobalt, Raney nickel or Raney cobalt comprising, possibly, an activating element that is taken among the 6 group of the Periodic system of element by the IUPAC nomenclature in the presence of strong mineral base representing a derivative of alkaline or earth-alkaline metal or ammonium hydroxide. In carrying out the hydrogenation process the parent mixture comprises water in the weight concentration at least 0.5 weight% of the total content of liquid components of the above said mixture, diamine and/or aminonitrile that can be form from the hydrogenating dinitrile and non-converted dinitrile wherein the weight concentration of all three indicated components is from 80% to 99.5%. The semi-hydrogenation reaction is carried out in the presence of at least one the selectivity-enhancing agent that is taken among the group comprising the following components: - compound comprising at least one cyano-group not bound with carbon atom that is taken among the group comprising hydrogen cyanide, lithium, sodium, potassium, copper cyanide, chelate cyanides of K3[Fe(CN)6], K4[Fe(CN)4], K3[Co(CN)6], K2[Pt(CN)6], K4[Ru(CN)6], ammonium or alkaline metal cyanides, tetrabutyl ammonium cyanide, tetramethyl ammonium thiocyanide, tetrapropyl ammonium thiocyanide; - organic isonitrile that is taken among the group including tert.-octylisonitrile, tert.-butylisonitrile, n-butylisonitrile, isopropylisonitrile, benzylisonitrile, ethylisonitrile, methylisonitrile and amylisonitrile; - tetraalkyl ammonium or tetraalkylphosphonium hydroxide or fluoride is taken among the group comprising tetramethyl ammonium, tetraethyl ammonium, tetrapropyl ammonium, tetrabutyl ammonium, tetrabutylphosphonium; - the chelate coordination compound formed by at least one metal atom and at least carbonyl radicals that is taken among the group comprising organic compounds including carbonyl, phosphine, arsine or mercapto-groups bound with metal and taken among the group comprising iron, ruthenium, cobalt, osmium, rhenium, iridium and rhodium. Method provides enhancing the selectivity by the aminonitrile group.

EFFECT: improved preparing method.

13 cl, 2 ex

The invention relates to a method of partial hydrogenation of dinitrile in aminonitriles, including the state of contact of dinitrile General formula R(CN)2where R represents alkylenes group, with a hydrogen containing medium in the presence of (a) solvent-containing liquid ammonia, alcohol, or both; catalytic composition (b) containing a hydrogenating catalyst, which may be in the form of a foam metal or supported on a carrier, and (C) additives to increase the output of aminonitriles and/or selectivity for aminonitriles selected from the group consisting of oxides of carbon, compounds of tetraalkylammonium hydroxide, connection hydroxide tetraallylsilane, polycentric cluster carbonyl metal containing (i) at least two transition metal atoms inside the cluster, (ii) at least three bridge between metal atoms inside the cluster, and (iii) at least one carbonyl group associated with the metal atom, where the metal is a metal of group VIII; organic isonitrile; cyanide compounds having at least one cyano associated with an atom other than carbon; and fluoride compounds
The invention relates to a method of providerone of dinitriles General formula NC-R-CN in which R is a normal or branched alkylenes group having from 1 to 12 carbon atoms into the corresponding aminonitriles in liquid medium at elevated temperature and pressure

The invention relates to variants of the method of selective hydrogenation of aliphatic dinitriles formula NCRCN, where R is alkylenes group having from 2 to 25 carbon atoms, to aminonitriles by shielding dinitrile with a hydrogen-containing fluid medium in the liquid phase in the presence of a hydrogenation catalyst on a carrier and solvent-containing liquid ammonia, alcohol or both of these substances, using a catalyst selected from the group consisting of Nickel, cobalt, iron or a combination of two or more of them, deposited on magnesium oxide, or in the presence of organic additives containing a carbonyl group selected from the group consisting of organic amides, such as formamide, N-methylformamide, N,N-dimethylformamide, N-methylacetamide, N-metalloceramic, ndimethylacetamide, organic esters of carboxylic acids, such as methylformate, ethyl formate, salts of carboxylic acids, such as formate, sodium formate, ammonium, and urea
The invention relates to a method of producing aminonitriles and diamine by catalytic hydrogenation of aliphatic dinitrile, in particular the production of 6-aminocaproate and diamine
The invention relates to the purification of acetonitrile through a process based on adsorption

The invention relates to a method of reducing leakage of ammonia and the corresponding reduction of ammonium sulfate and wastes derived from the unreacted ammonia in the production of Acrylonitrile direct oxidative ammonolysis of the unsaturated or saturated hydrocarbon, preferably propylene or propane, ammonia and oxygen in a reactor with a fluidized bed containing a catalyst of oxidative ammonolysis
The invention relates to the stabilization of the crude acetonitrile, in particular crude acetonitrile, obtained as a byproduct in the production of Acrylonitrile

FIELD: special methods in organic synthesis.

SUBSTANCE: known drug: racemic 1-(isopropylamino)-3-(1-naphthyloxy)-2-propanol, briefly called propranolol, is converted into propranolol hydrofluoride, which is dissolved in ethanol at 55-70оС to form concentrated solution. The latter is gradually cooled to 20-26оС, after which is added seed of one of enantiomers, solution is stirred for 30-60 min, filtered non-racemic propranolol hydrofluoride enantiomer having the same configuration as the seed previously added. Racemic compound is added to mother liquor in amount compensating separated precipitate, mother liquor is heated at 55-70оС to entirely dissolve added material and seed of the other enantiomer is added. Subsequent crystallization gives precipitate rich in the other enantiomer and process is several times repeated. Enantiomer purity is then raised by recrystallization. Non-racemic propranolol salts are finally converted into free propranolol enantiomers. Method of invention can be used in pharmaceutical practice.

EFFECT: enabled involvement method-assisted preparation of non-racemic propranolol.

6 ex

The invention relates to a method for separation of the enantiomers of racemic 3-(2-methoxyphenoxy)-1,2-propane diol and 3-(2-methylphenoxy)-1,2-propane diol, which can be used in the pharmaceutical industry in obtaining narramissic drugs

The invention relates to an improved method of isolation and purification of (RR, SS)-2-[(dimethylamino)methyl] -1-(3-methoxyphenyl)-cyclohexanol (tramadol) hydrochloride from technical mixtures containing tramadol, (RS, SR)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexanol [(RS,SR)-isomer] and by-products of the Grignard reaction using the selective deposition of a derivative of tramadol

The invention relates to a method for the splitting of the racemate tramadol

The invention relates to an improved process for the preparation of enantiomers of O-demethyltramadol, with a strong analgesic action, which unlike opioid analgesics has no known side effects

The invention relates to a method for the monohydrate of ropivacaine hydrochloride of the formula I, which comprises the following stages: stage 1: (i) racemic starting material hydrochloride of pipecoloxylidide formula II freed from Hcl, forming with it salt, by extraction with an organic solvent containing a diluted basis, (ii) received pipecoloxylidide process of the separating reagent and the diluent, forming a stable crystallization system with water, and produce a crystalline product (S)- pipecoloxylidide formula III by extraction with dilute base in an organic solvent that dissolves at least about 1 wt
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