CN113173860B - Preparation method of 2-methylalanine - Google Patents
Preparation method of 2-methylalanine Download PDFInfo
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- CN113173860B CN113173860B CN202110536544.XA CN202110536544A CN113173860B CN 113173860 B CN113173860 B CN 113173860B CN 202110536544 A CN202110536544 A CN 202110536544A CN 113173860 B CN113173860 B CN 113173860B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/12—Formation of amino and carboxyl groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
- C07C313/02—Sulfinic acids; Derivatives thereof
- C07C313/06—Sulfinamides
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Abstract
The invention specifically discloses a preparation method of 2-methylalanine, and belongs to the technical field of organic synthesis. The method comprises the steps of condensing 2, 2-dimethoxypropane serving as a raw material with tert-butyl sulfinamide or tert-butyl carbamate to generate Schiff base, performing nucleophilic addition with sodium cyanide or potassium cyanide under the action of phase transfer catalysis and ammonium chloride, and adding acid to hydrolyze cyano to obtain 2-methylalanine.
Description
Technical Field
The invention relates to a preparation method of 2-methylalanine, belonging to the technical field of organic synthesis.
Background
2-methylalanine, english name: 2-aminoisobutric acid, CAS: 62-57-7 with the structural formula of H2N-C(CH3)2-COOH, which is present in antibiotics of some fungal origin, for example from penicillins and some lantibiotics. Is not one of the proteinogenic amino acids and is rare in nature. 2-methylalanine is a strong helix inducer in peptides, and oligomers of AIB form 310 helices.
2-methylalanine is an important intermediate in the synthesis of pharmaceuticals, such as: CN110872258A 2-methyl alanine is an intermediate of an enzalutamide drug for treating prostatic cancer. The document [ Beilstein Journal of Organic Chemistry,2020, vol.16, p.1225-1233] 2-methyl alanine is an important intermediate for preparing pyrrolo [2,1-a ] isoquinoline medicaments, and the derivative thereof is also a fruit preservative which can avoid the infection of plant fungi.
The synthesis routes of 2-methyl alanine are many, and the literature [ Journal fur praktische Chemie (Leipzig 1954),1934, vol. <2>140, p.297,304] reports that dimethyl hydantoin is adopted to synthesize 2-methyl alanine by reaction at the temperature of 120-130 ℃ of sulfuric acid, so that the method has very important development value. But because the high-temperature reaction of sulfuric acid is adopted, the reaction is easy to solidify and has more impurities. The reaction equation is as follows:
patent CN201410133144.4 reports the use of acetone cyanohydrin reacted with ammonium carbonate in an aqueous medium with a yield of 65%. However, the method adopts a high-temperature and high-pressure mode, and carbon dioxide and ammonia gas are generated in the reaction process, so that the pressure relief and ammonia gas recovery are required, the requirement on equipment is high, and the amplification has certain limitation. The reaction equation is as follows:
aiming at the defects of the method, the invention adopts the preparation method which has simple and convenient flow, mild reaction conditions, low requirements on equipment and high total yield, and is suitable for factory production to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the invention takes 2, 2-dimethoxypropane as a raw material to be condensed with tert-butyl sulfinamide or tert-butyl carbamate to generate Schiff base, then the Schiff base is subjected to nucleophilic addition with sodium cyanide or potassium cyanide under the action of phase transfer catalysis and ammonium chloride, and then acid is added to hydrolyze cyano group to obtain 2-methylalanine.
The invention relates to a preparation method of 2-methylalanine, wherein the reaction equation is as follows:
compound 1: 2, 2-dimethoxypropane; compound 2: n-isopropylidene carbamic acid tert-butyl ester or N-isopropylidene-tert-butylsulfinamide; compound 3: (2-cyanopropan-2-yl) carbamic acid tert-butyl ester or N- (2-cyanopropan-2-yl) -2-methylpropan-2-sulfinamide; compound 4: 2-methylalanine
The invention relates to a preparation method of 2-methylalanine, which comprises the following steps:
a) the method comprises the following steps Mixing 2, 2-dimethoxypropane 1 serving as a raw material with tert-butyl sulfinamide or tert-butyl carbamate in an organic solvent, reacting at 35-110 ℃, and concentrating and distilling to remove the solvent to obtain a compound 2.
b) The method comprises the following steps Dissolving the compound 2, a phase transfer catalyst, ammonium chloride and sodium cyanide or potassium cyanide in water, heating to 40-50 ℃ for reaction, and extracting by an organic solvent to obtain an organic phase of a compound 3. Then adding acid to hydrolyze cyano, and adding sodium hydroxide to adjust to isoelectric point to obtain 2-methylalanine.
Further, in the above technical solution, in the step a), the organic solvent is selected from n-hexane, n-heptane, toluene or tetrahydrofuran.
Further, in the technical scheme, in the step a), a catalyst BPh is added in the reaction3Or B (C)6F5)3. Preferably, the molar ratio of the catalyst to the 2, 2-dimethoxypropane 1 is 0.002-0.05: 1. The method of adding solvent while distilling is adopted to ensure that tert-butyl sulfenamide or BocNH2There is no residue.
Further, in the technical scheme, in the step a), the molar ratio of the 2, 2-dimethoxypropane to the tert-butyl sulfinamide or tert-butyl carbamate is 1.1-1.3: 1.
Further, in the above technical scheme, in the step b), the phase transfer catalyst is selected from benzyltriethylammonium chloride or benzyltrimethylammonium chloride.
Further, in the above technical scheme, in the step b), the molar ratio of the compound 2, the phase transfer catalyst, and the ammonium chloride to the sodium cyanide or the potassium cyanide is 1:0.1-0.08:1.1-1.15: 1.05-1.10.
Further, in the above technical solution, in the step b), the organic solvent is selected from xylene or toluene.
Further, in the above technical scheme, in the step b), the acid is selected from 50-65% sulfuric acid or 20-33% hydrochloric acid, and the isoelectric point pH is 6.78-6.86.
Advantageous effects of the invention
Compared with the synthesis method reported in the literature, the method has the following beneficial effects:
1. high-pressure and high-temperature reaction is avoided, the requirement on equipment is relatively low, and the operation is simple.
2. The sodium cyanide/potassium cyanide waste water can reach the discharge standard through hydrolysis or oxidation treatment.
3. The total yield and the product purity are high, the impurities are few, and the product is directly separated out from water after being adjusted to an isoelectric point.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples. These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of Compound 2
Example 1
26g (0.25mol) of 2, 2-dimethoxypropane and 0.002mol of BPh under the protection of nitrogen3Mixing with 23.4g (0.2mol) of tert-butyl carbamate in 200mL of toluene, reacting at 90 ℃ for 2 hours, heating to 110 ℃ for 4 hours, adding toluene while distilling, sampling, detecting by TLC, concentrating and distilling off toluene after no raw material is left, pulping with N-hexane and dichloromethane (10/1), and obtaining 30.6g of N-isopropylidene tert-butyl carbamate with the yield of 97.3% and GC of 99.1%.1HNMR(400MHz,CDCl3):1.42(s,6H),1.94(s,9H).
Example 2
25g (0.24mol) of 2, 2-dimethoxypropane and 0.001mol of BPh are added under the protection of nitrogen3Reacting with 24.2g (0.2mol) of tert-butyl sulfinamide in 200mL of tetrahydrofuran at 35 ℃ for 2 hours, heating to 67 ℃ for 5 hours, adding tetrahydrofuran while distilling, sampling, detecting by TLC, concentrating and distilling off tetrahydrofuran after no residual raw material is left, pulping N-hexane and dichloromethane (8/1), and obtaining 30.8g of N-isopropylidene-tert-butyl sulfinamide with the yield of 95.6% and GC 98.7%.1HNMR(400MHz,CDCl3):1.32(s,6H),1.93(s,9H).
Synthesis of 2-methylalanine
Example 3
Dissolving 15.7g (0.1mol) of tert-butyl N-isopropylidene carbamate (TBC) 2.28g (0.01mol) of benzyltriethylammonium chloride, 6.2g of ammonium chloride and 5.6g (0.115mol) of sodium cyanide in 60mL of water, heating to 50 ℃ for reaction for 5 hours, extracting with toluene, washing an organic phase with 20mL of water, washing the organic phase for three times, heating the organic phase to 60 ℃, dropwise adding 60mL of 65% sulfuric acid, heating to 85-90 ℃ for reaction for 4 hours, detecting by TLC (thin layer chromatography), cooling to room temperature, layering, adding 10% sodium hydroxide aqueous solution into a lower layer to adjust the pH to 6.84, slowly cooling to 0 ℃, and filtering to obtain 9g of 2-methylalanine, the yield is 87.6%, and the yield is 99.7% by Fmoc-Cl derivative HPLC.1HNMR(400MHz,D2O):1.44(s,6H).
Example 4
Dissolving 16.1g (0.1mol) of N-isopropylidene-tert-butyl sulfinamide in 60mL of water, heating to 50 ℃ for 5 hours, extracting with xylene, washing an organic phase with 20mL of water for three times, heating the organic phase to 60 ℃, dropwise adding 75mL of 33% hydrochloric acid, heating to 90-95 ℃ for reaction for 7 hours, sampling, detecting by TLC (thin layer chromatography) that no raw material is left, cooling to room temperature, layering, adding 10% sodium hydroxide aqueous solution into a lower layer to adjust the pH to 6.84, slowly cooling to 0 ℃, and filtering to obtain 8.7g of 2-methylalanine, wherein the yield is 84.6%, and the purity is 99.6% through Fmoc-Cl derivative HPLC.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (7)
1. The preparation method of the 2-methylalanine is characterized by comprising the following steps:
a) the method comprises the following steps Mixing 2, 2-dimethoxypropane 1 serving as a raw material with tert-butyl sulfinamide or tert-butyl carbamate in an organic solvent, reacting at 35-110 ℃, and concentrating and distilling to remove the solvent to obtain a compound 2; in step a), the reaction is carried out with addition of the catalyst BPh3Or B (C)6F5)3(ii) a The molar ratio of the catalyst to the 2, 2-dimethoxypropane 1 is 0.002-0.05: 1;
b) the method comprises the following steps Dissolving the compound 2, a phase transfer catalyst, ammonium chloride and sodium cyanide or potassium cyanide in water, heating to 40-50 ℃ for reaction, and extracting by using an organic solvent to obtain an organic phase of a compound 3; then adding acid to hydrolyze cyano, and adding sodium hydroxide to adjust to isoelectric point to obtain 2-methylalanine.
2. The process for producing 2-methylalanine according to claim 1, characterized in that: in step a), the organic solvent is selected from n-hexane, n-heptane, toluene or tetrahydrofuran.
3. The process for producing 2-methylalanine according to claim 1, characterized in that: in step a), the molar ratio of 2, 2-dimethoxypropane to tert-butylsulfinamide or tert-butyl carbamate is 1.1-1.3: 1.
4. The process for producing 2-methylalanine according to claim 1, characterized in that: in step b), the phase transfer catalyst is selected from benzyltriethylammonium chloride or benzyltrimethylammonium chloride.
5. The process for producing 2-methylalanine according to claim 1, characterized in that: in the step b), the mol ratio of the compound 2, the phase transfer catalyst and the ammonium chloride to the sodium cyanide or the potassium cyanide is 1:0.1-0.08:1.1-1.15: 1.05-1.10.
6. The process for producing 2-methylalanine according to claim 1, characterized in that: in step b), the organic solvent is selected from xylene or toluene.
7. The method for producing 2-methylalanine according to claim 1, characterized in that: in step b), the acid is selected from 50-65% sulfuric acid or 20-33% hydrochloric acid, and the isoelectric pH is 6.78-6.86.
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