High-yield C1 raw material oriented amino acid synthesis technology

Abstract

The invention relates to the field of new material chemicals, in particular to a new production technology of a plurality of amino acid substances. All C2 amino acid skeleton target compounds are flexibly and divergently prepared through direct addition reaction of simple carbonyl compound precursors such as formaldehyde and two high-yield C1 raw materials such as chloroform for the first time. The technology has excellent cost competitiveness, simplicity in operation, environmental friendliness and resource sustainability.

Description

Technical Field

[0001] The present invention relates to the field of new material chemicals, and in particular to a new production process technology for several amino acid substances. For the first time, it is disclosed that all the above C2 amino acid skeleton target compounds are prepared flexibly and divergently through direct addition reaction of simple carbonyl compound precursors such as formaldehyde and two types of abundant C1 raw materials such as chloroform. The technology has excellent cost competitiveness, simple operation, environmental friendliness, and resource sustainability. Background Art

[0002] Amino acids are well-known basic chemicals with a wide range of uses in physiological functions, nutritional metabolism, and nitrogen balance. Their simple, efficient, and low-cost synthesis methods have always been the goal of technological progress pursued by technical personnel in the industry. Traditionally, many amino acids are prepared using the so-called Strecker reaction, which is to add aldehydes or ketones to highly toxic substances such as hydrocyanic acid HCN or ammonium chloride / sodium (potassium) cyanide to obtain aminocyanide intermediates, which are then hydrolyzed to obtain amino acids.

[0003] The present application has unexpectedly discovered that a common intermediate of the C2 skeleton can be obtained by direct addition of commonly used carbonyl compounds (aldehydes or ketones) such as formaldehyde and chloroform and other bulk C1-rich chemicals, which can be used to flexibly and divergently prepare amino acids or their structural derivatives after aminolysis. This technical route has excellent cost competitiveness, simple operation, and resource sustainability. Summary of the invention

[0004] The present application has found that, as shown in reaction formula (I-II), trichloromethyl alcohol shown in structural formula A and ammonia source "NH 3 "The substitution reaction is carried out under reaction conditions to efficiently prepare the amino acid substance represented by structural formula B or its salt (general formula I). ​​The reaction conditions are at least one of solvent, temperature, pressure (or vacuum), and additives.

[0005]

[0006] Where R 1 or R 2 are independently hydrogen, or a branched or straight chain aliphatic hydrocarbon group containing 1 to 24 carbon atoms, or a (hetero) aromatic hydrocarbon group containing 4 to 24 carbon atoms; X is O, NH, S, NR 1 ; R 3 YesR 1 or metal or ammonium cation; ammonia source "NH 3 "It is ammonia gas, ammonia water, HNR 1 R 2 , H 2 NR1 , ammonium carbonate (bicarbonate), ammonium formate, ammonium chloride, ammonium sulfate, ammonium nitrate; the preferred ammonia source "NH 3 ” is ammonia gas or ammonia water.

[0007] The amino acid B that can be prepared by the present invention preferably includes 20 natural amino acids or non-natural amino acids known to practitioners; more preferably includes the following exemplary but non-limiting amino acid or derivative structures:

[0008]

[0009] In the general formula (I), the additive or promoter in the reaction conditions is preferably a base; the base is ammonia, ammonia water, a metal or its oxide, hydroxide, alkoxide, alkylamine, carbonate (bicarbonate), carboxylate, sulfonate, organic amine, or nitrogen-containing heterocyclic compound;

[0010] In the general formula (I), the additive or promoter in the reaction conditions is preferably an acid; the acid is hydrochloric acid, sulfuric acid, nitric acid, hydrohalic acid, sulfonic acid, carboxylic acid, metal or its halide, sulfide, oxide, carboxylate, (hydrogen) sulfate, nitrate, (hypo)halite.

[0011] The solvent is selected from at least one of substituted or unsubstituted aromatic hydrocarbons, linear or branched aliphatic hydrocarbons, (sub)sulfones, amides, ethers, alcohols, esters, ketones, nitriles, carboxylic acids, water, amines, carbonates, ionic liquids, and supercritical carbon dioxide containing 1-24 carbon atoms; or the substrate itself acts as a solvent medium at the same time.

[0012] In some preferred embodiments of the present invention, the solvent is selected from acetonitrile, ethanol, butanol, ethyl acetate, butyl acetate, water, dimethyl sulfoxide, dimethyl sulfone, benzyl sulfoxide, benzyl sulfone, cyclobutylene sulfoxide, cyclobutylene sulfone, trichlorosilane, dichloromethane, dichloroethane, dimethyl carbonate, diethyl carbonate, ethylene carbonate, propylene carbonate, chloroform, carbon tetrachloride, benzene, toluene, xylene, trimethylbenzene, tetramethylbenzene, acetonitrile, ethylbenzene, diethylbenzene, chlorobenzene, dichlorobenzene, anisole , nitrobenzene, heptane, hexane, petroleum ether, dioxane, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, bis(ethylene glycol) dimethyl ether, triethylene glycol dimethyl ether, propylene glycol methyl ether acetate, triethylamine, tributylamine, dimethylisopropylamine, pyridine, N,N-tetramethylethylenediamine, N-alkylmorpholine, N-alkylpyrrole, N,N-dimethylformamide, formylmorpholine, N,N-diethylformamide and N-methylpyrrolidone.

[0013] In the present invention, the reaction can also be carried out by using only a small amount of or even no conventional "solvent", and by adopting solid-phase heating and / or grinding of the raw materials, and / or promoting by ultrasonic and / or microwave irradiation, and by using supercritical carbon dioxide as the reaction medium.

[0014] The advantage of using supercritical carbon dioxide as the reaction medium is that it is green and environmentally friendly and is conducive to the occurrence of the reaction and the separation of the products. Such advantages are well known to technical personnel working in this profession.

[0015] The temperature is -70°C to 300°C. Preferably, the temperature is -30°C to 250°C. More preferably, the temperature is -20°C to 200°C.

[0016] The pressure is 0.001 atm-200 atm. Preferably, the pressure is 0.1 atm-100 atm.

[0017] The additives are reaction accelerators, synergists, catalysts, oxidants, polymerization inhibitors, reducing agents and / or functional additives.

[0018] Taking the molar amount of substrate A as the reference equivalent, the amount of the additive used is a catalytic amount, an equivalent amount, or an excess amount (0.001-1000 equivalents).

[0019] Taking the molar amount of substrate A as the reference equivalent, the ammonia source "NH 3 " is used in an amount of 0.1-1000 equivalents; preferably, the amount is 1-100 equivalents; more preferably, the amount is 2-50 equivalents.

[0020] Typically, the by-product produced by carrying out the reaction of formula (I) is ammonium chloride, which is a useful fertilizer and chemical.

[0021] Since compound A can be obtained via the carbonyl compound precursor R 1 C(O)R 2 and haloform HCCl 3 Direct addition reaction is carried out to prepare the carbonyl compound R. The present application also claims the following preparation process: As shown in reaction formula (IA), the carbonyl compound R 1 C(O)R 2 and haloform HCCl 3 Compound A is then added to the ammonia source "NH 3 ” is transformed into product B.

[0022]

[0023] The gist of the present invention is further explained below with reference to specific embodiments. DETAILED DESCRIPTION

[0024] Example:

[0025]

[0026] Add 3 g of paraformaldehyde, 27 g of chloroform and 40 ml of N,N-dimethylformamide to the reaction bottle in sequence under ice-water bath temperature, slowly add 12 ml of 32% sodium hydroxide aqueous solution for about half an hour under strong stirring, and continue to react for 2 hours after the addition. Add 30 ml of water and 6 ml of concentrated hydrochloric acid in sequence, continue stirring for 30 minutes, then add 120 ml of ethyl acetate for extraction, concentration, and separation to obtain about 13.8 g of trichloroethanol intermediate.

[0027] 8.2 g of trichloroethanol and 20 ml of 32% concentrated ammonia water were added to a sealed pressure reactor at room temperature. The mixture was stirred for reaction for half an hour and then gradually heated to 40-50 degrees Celsius within 2 hours. After the system was depressurized, the residue was concentrated to dryness under reduced pressure. The mixture was recrystallized in 95% ethanol to obtain 4.9 g of ammonium glycinate product.

[0028] Example:

[0029]

[0030] The above-mentioned example was followed except that formaldehyde was replaced by acetaldehyde, and 9.5 g of ammonium alanine product was prepared from 4.3 g of acetaldehyde.

[0031] Example:

[0032]

[0033] 6.4 g of trichloroethanol and 6.8 ml of 37% concentrated aqueous ammonia were added to a sealed pressure reactor at room temperature, the mixture was stirred and reacted overnight, and the pH of the system was adjusted to 5-6 with dilute hydrochloric acid. The reaction residue was concentrated to dryness under reduced pressure, and the mixture was recrystallized in 95% ethanol to obtain 3.1 g of glycine product.

[0034] Example:

[0035]

[0036] 4.1 g of trichloroethanol and 10 ml of liquid ammonia were placed in a sealed pressure reactor under Dewar cooling. The mixture was reacted at low temperature for one hour and then gradually returned to room temperature. After the pressure was released, the residue was recrystallized in methanol to obtain 1.9 g of needle-shaped crystals of glycineamide.

[0037] It should be emphasized that the above embodiments are merely illustrative and not restrictive. Based on the disclosure of this application, any adjustment or change in reaction conditions or parameters that may be commonly adopted by practitioners will not deviate from the gist of the present invention. The scope of protection of this patent shall be based on the relevant rights record items.

Claims

1. A new production process technology for amino acids and their derivatives. As shown in reaction formula (I), trichloromethyl alcohol shown in structural formula A and ammonia source "NH3" undergo substitution reaction under reaction conditions to efficiently prepare amino acid substances shown in structural formula B or their salts (general formula I). ​​The reaction conditions are at least one of solvent, temperature, pressure (or vacuum), and additives: Wherein R1 or R2 are independently hydrogen, or a branched or straight chain aliphatic hydrocarbon group containing 1 to 24 carbon atoms, or a (hetero) aromatic hydrocarbon group containing 4 to 24 carbon atoms; X is O, NH, S, NR1; R3 is R1 or a metal or ammonium salt cation; the ammonia source "NH3" is ammonia gas, ammonia water, HNR1R2, H2NR1, ammonium carbonate (bicarbonate), ammonium formate, ammonium chloride, ammonium sulfate; the preferred ammonia source "NH3" is ammonia gas or ammonia water; the preferred XR3 is OH, NH2, ONa, OK, ONH4, OLi, O(Ca) 1 / 2 ,O(Mg) 1 / 2 .

2. According to claim (1), the solvent is preferably selected from at least one of water, substituted or unsubstituted aromatic hydrocarbons, linear or branched aliphatic hydrocarbons, (sub)sulfones, amides, ethers, alcohols, esters, ketones, nitriles, carboxylic acids, amines, carbonates, ionic liquids, and supercritical carbon dioxide, or the substrate itself acts as a solvent medium. The temperature is -70°C-300°C. The pressure is 0.001atm-200atm. The additive refers to a reaction promoter, a synergist, a catalyst, an oxidant, an inhibitor, a reducing agent and / or a functional aid. Based on the substrate trihalomethyl alcohol A, the additive is used in an amount of 0.001-1000 equivalents.

3. According to claim (1), in the general formula (I), the additive or promoter in the reaction conditions is preferably a base; the base is ammonia, ammonia water, a metal or its oxide, hydroxide, alkoxide, alkylamine, carbonate (bicarbonate), carboxylate, sulfonate, organic amine, or a nitrogen-containing heterocyclic compound.

4. According to claim (1), in the general formula (I), the additive or promoter in the reaction conditions is preferably an acid; the acid is hydrochloric acid, sulfuric acid, nitric acid, a hydrohalic acid, a sulfonic acid, a carboxylic acid, a metal or its halide, sulfide, oxide, carboxylate, (hydrogen) sulfate, nitrate, (hypo)halate.

5. According to claim (1), the amino acid B that can be prepared by the technology of the present invention preferably includes 20 natural amino acids or unnatural amino acids known to practitioners; more preferably includes the following exemplary but non-limiting amino acid or derivative structures:

6. According to claim (1), a preferred execution mode of the general formula (I) is reaction (IA), i.e., a carbonyl compound R1C(O)R2 and a haloform HCCl3 undergo addition reaction to obtain a compound A, and then A reacts with an ammonia source "NH3" to convert into a product B:

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