CN112920086A - Preparation method of L-tyrosine derivative - Google Patents
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Abstract
The invention discloses a preparation method of an L-tyrosine derivative, wherein the L-tyrosine derivative is O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine, the O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine is prepared by taking L-tyrosine as an initial raw material and sequentially carrying out esterification, amidation, etherification/hydrolysis and amidation, the total yield of a target product can reach 61.5%, and the ee value can reach more than 99%. The preparation method has the advantages of cheap and easily obtained raw materials, low cost and the like, for example, the separation of triphenyl phosphine oxide is avoided in the etherification reaction; the method has the advantages of simple process, short route, mild reaction conditions and the like, for example, the etherification and the hydrolysis adopt a one-pot method; the three wastes generated in the whole process are less, the product yield and purity are higher, and the method is suitable for industrial production.
Description
Technical Field
The invention belongs to the field of synthesis of medical intermediates, and particularly relates to a preparation method of an L-tyrosine derivative for synthesizing polypeptide and bioactive small molecules.
Background
In nature, only 20 natural amino acids synthesize diverse proteins for the life activities of organisms. However, with the development of chemical and biological research and application, natural amino acids have failed to meet the needs of protein engineering, enzyme engineering, directed evolution, and the like. Over the last decade, advances in the field of genetic code reprogramming have rapidly brought hundreds of unnatural amino acids into protein structure and manipulated with unprecedented precision at the monoatomic level. Thus, unnatural amino acids have great potential for development in the biotechnology, biocatalysis, and biomedical fields.
The synthesis of unnatural amino acids is mainly carried out by chemical synthesis, biosynthesis, microinjection, auxotrophy, posttranslational modification, and the like. The currently reported unnatural amino acids mainly include phenylalanine derivatives, tyrosine derivatives, glutamine derivatives, alanine derivatives, and the like, and the unnatural amino acids generally need protection groups to form protected amino acids for polypeptide synthesis. Among them, O-alkyl-L-tyrosine derivatives are present in a variety of polypeptides and drug molecules, such as PPAR-gamma inhibitor GW1929, polycyclic peptides, etc.
O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine is an important protected amino acid for synthesizing O-alkyl-L-tyrosine derivatives, wherein O2amY is not only applied to a novel peptide inhibitor of interleukin-23 receptor, but also O2 amY-mediated polycyclic peptide has strong binding affinity to streptavidin, and the structural formula is shown as (I):
at present, no literature is reported about the synthesis process of O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine. The key of the preparation method of the general O-alkyl-L-tyrosine derivative is the reaction of phenolic hydroxyl and alkyl halide, and the two main methods are as follows:
douglas D.Young et al reported the synthesis of O- (4-alkynylpropyl) -L-tyrosine. The method is mainly characterized in that N-tert-butyloxycarbonyl-L-tyrosine methyl ester and alkyl halide are subjected to nucleophilic substitution reaction to generate ether, and the reaction yield of the step is only 3.9%. The method has the defects of extremely low yield, unsuitability for industrial production and the like. (Bioconjugate chem.2015,26,1884-1889.)
Fang Hao et al reported the synthesis of O-benzyl-N-t-butyloxycarbonyl-L-tyrosine. The method has a short route, the yield is 46%, but the operation is complicated, heavy metal salt is used, and the separation cost is high. (bioorg. Med. chem.2017,25, 138-
Aiming at the problems of lower yield, fussy steps, poor safety, difficult separation and the like in the synthetic method. The invention develops a synthesis process of O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine, which has the advantages of easily obtained raw materials, simple process, economy and environmental protection.
Disclosure of Invention
The invention aims to provide a method for preparing O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine by taking L-tyrosine as an initial raw material, which has the characteristics of simple process, convenient operation, higher yield, lower cost and the like.
The preparation method of the L-tyrosine derivative is characterized in that the L-tyrosine derivative is O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine shown in a formula (I), and the L-tyrosine derivative is obtained by taking L-tyrosine shown in a formula (II) as an initial raw material and sequentially carrying out esterification, amidation, etherification/hydrolysis and amidation reactions, and is characterized by specifically comprising the following steps:
s1: the L-tyrosine shown in the formula (II) is used as an initial raw material and is obtained through esterification reaction, and the method specifically comprises the following steps: starting L-tyrosine shown in a formula (II) as a raw material, carrying out esterification reaction with methanol at a reflux temperature in the presence of a catalyst, cooling and concentrating to remove the methanol after the reaction is finished, and drying to obtain L-tyrosine ester hydrochloride shown in a formula (III);
s2: adding a compound shown as a formula (III) into a solvent A, carrying out amidation reaction with trifluoroacetic anhydride in the solvent A at a reflux temperature in the presence of alkali A, concentrating to remove the solvent A after the reaction is finished, washing with water, filtering, and drying to obtain a compound shown as a formula (IV);
s3: adding a compound shown in a formula (IV) into a solvent B, carrying out etherification reaction with alcohol ROH in the solvent B in the presence of triphenylphosphine and azodicarbonic diester compounds, and concentrating to obtain a crude compound shown in a formula (V) after the reaction is finished; directly adding the obtained crude product of the compound shown in the formula (V) into a mixed solvent of lower alcohol and water, adding alkali B for hydrolysis reaction, acidifying the reaction solution with acid until the pH value is 5-6 after the reaction is finished, filtering, pulping with a halogenated hydrocarbon solvent, filtering, and drying to obtain the compound shown in the formula (VI);
s4: adding a compound shown as a formula (VI) and a sodium carbonate aqueous solution into a solvent D, adding 9-fluorenylmethyl-N-succinimidyl carbonate to perform amidation reaction, concentrating to remove part of the solvent after the reaction is finished, acidifying with acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, and concentrating to obtain a compound shown as a formula (I), namely O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine;
in the formulas (I), (IV), (V) and (VI), a substituent R is C1-C9 alkyl or substituted alkyl, and the substituent of the substituted alkyl is C2-C4 alkynyl or N-tert-butyloxycarbonyl; for example, the substituent R may be selected from ethyl, isopropyl, (N-t-butoxycarbonyl) ethyl, 3-alkynyl-butyl, and the like;
the substituents R in the alcohol ROH are the same as R in formula (I);
in step S3, the halogenated hydrocarbon solvent is selected from dichloromethane.
The preparation method of the L-tyrosine derivative is characterized in that in the step S1, the catalyst is concentrated sulfuric acid, thionyl chloride or anhydrous hydrogen chloride, and is preferably thionyl chloride; the amount ratio of the catalyst to the amount of the substance of tyrosine represented by formula (II) is 1.5-2.5: 1, preferably 1.7-2.0: 1.
The preparation method of the L-tyrosine derivative is characterized in that in the step S2, the base A is pyridine, triethylamine or N, N-diisopropylethylamine, and pyridine is preferred; the solvent A is ethyl acetate, tetrahydrofuran, methyl acetate, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the mass ratio of the base A to the compound represented by the formula (III) is 2.1 to 3.5:1, preferably 2.2 to 2.8: 1; the mass ratio of trifluoroacetic anhydride to the compound represented by formula (III) is 1.2 to 1.8:1, preferably 1.3 to 1.6: 1.
The preparation method of the L-tyrosine derivative is characterized in that in the step S3, the solvent B is ethyl acetate, tetrahydrofuran, methyl acetate, toluene, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the azodicarboxylic acid diester compound is dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate, preferably diethyl azodicarboxylate; the alcohol ROH is ethanol, tert-butyl alcohol, N-propanol, N- (tert-butoxycarbonyl) ethanolamine, 3-cyclopropyl-2-propyn-1-ol or 3-butyn-1-ol; the alkali B is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or potassium tert-butoxide, and potassium carbonate is preferred;
the mass ratio of triphenylphosphine to the compound of formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the azodicarboxylic acid diester compound to the compound represented by the formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the alcohol ROH to the compound represented by the formula (IV) is 1.2-1.8: 1, preferably 1.3-1.5: 1;
the lower alcohol is methanol or ethanol, and the mixed solvent of the lower alcohol and water is a methanol-water mixed solution with a volume ratio of 1-5: 1 or an ethanol-water mixed solution with a volume ratio of 1-4: 1, preferably a methanol-water mixed solution with a volume ratio of 1-3: 1; the ratio of the amount of the base B to the amount of the compound represented by the formula (V) is 2.5 to 5.0:1, preferably 3.0 to 4.0: 1.
The preparation method of the L-tyrosine derivative is characterized in that in the step S4, a solvent D is tetrahydrofuran, dioxane or acetone, and tetrahydrofuran is preferred; the mass ratio of sodium carbonate to the compound of formula (VI) is 1.1-2.5: 1, preferably 1.3-2.0: 1; the ratio of the amount of the 9-fluorenylmethyl-N-succinimidyl carbonate to the amount of the compound represented by the formula (VI) is 1.0 to 1.3:1, preferably 1.05 to 1.20: 1.
By adopting the technology, compared with the prior art, the invention has the beneficial effects that:
(1) the synthetic route is short, the process is simple, and the reaction conditions are mild;
(2) the raw materials are cheap, the cost is low, and the environment is friendly;
(3) the three wastes generated in the whole process are less, the product yield and purity are higher, and the method is suitable for industrial production.
Detailed Description
The present invention is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.
Example 1:
taking ROH as N-tert-butyloxycarbonyl-ethanolamine as a specific example, O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine is prepared according to the following synthetic route:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Adding L-tyrosine (1.81g, 10mmol) and 20mL of methanol into a 50mL three-neck flask with a magnetic stirring thermometer, slowly dropwise adding thionyl chloride (1.78g, 15mmol) in an ice bath at-10 ℃, ensuring the temperature of the reaction liquid to be below room temperature, after dropwise adding, heating to reflux for esterification reaction, and monitoring by TLC until the reaction is finished. After cooling, concentration to remove methanol and drying, 2.21g of white solid L-tyrosine methyl ester hydrochloride is obtained, the yield is 95.5 percent and the HPLC purity is 98.6 percent.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Adding L-tyrosine methyl ester hydrochloride (2.32g, 10mmol) and 25mL of tetrahydrofuran into a 50mL three-neck flask with a magnetic stirring thermometer, placing the reaction flask in an ice-water bath at 0-5 ℃, adding pyridine (1.18g, 21mmol), then dropwise adding trifluoroacetic anhydride (2.52g, 12mmol), ensuring that the temperature of the reaction solution is below room temperature, after dropwise adding, heating to reflux for amidation reaction, and monitoring by TLC until the reaction is finished. Cooling, concentrating to remove tetrahydrofuran, washing with water, filtering and drying to obtain white solid N-trifluoroacetyl-L-tyrosine methyl ester 2.69g with yield 92.2% and HPLC purity 99.4%,1H NMR(400MHz,DMSO-d6)δ9.90(d,J＝8.0Hz,1H),9.30(s,1H),7.04(d,J＝8.0Hz,2H),6.68(d,J＝7.2Hz,2H),4.56–4.49(m,1H),3.67(s,3H),3.08(dd,J＝13.6,4.4Hz,1H),2.91(m,1H).
3. preparation of O- [2- [ [ (tert-butoxy) carbonyl ] amino ] ethyl ] -L-tyrosine (VI-a)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and tetrahydrofuran (30 mL) into a 100mL three-neck flask with a magnetic stirring thermometer, adding N-tert-butoxycarbonyl-ethanolamine (1.93g, 12mmol) and triphenylphosphine (3.15g, 12mmol), placing the reaction bottle in an ice-water bath at 0-5 ℃, dropwise adding di-tert-butyl azodicarboxylate (2.76g, 12mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of N-trifluoroacetyl-L-tyrosine methyl ester is 96%. Concentrating to remove tetrahydrofuran to obtain (S) -3- (4- [2- [ [ tert-butoxycarbonyl group)]Amino group]Ethoxy radical]Phenyl) -2- (2,2, 2-trifluoroacetamido) propionic acid methyl ester crude product (V-a). To the crude product (V-a), 20mL of methanol was added, and 27.0g of an aqueous solution of potassium carbonate having a mass concentration of 25.6% was added to conduct hydrolysis reaction at room temperature, followed by TLC until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white-like solid, filtering, pulping with dichloromethane, filtering, and drying to obtain a white solid O- [2- [ [ tert-butoxycarbonyl group]Amino group]Ethyl radical]2.64g of L-tyrosine, two-step yield 81.4% and HPLC purity 99.3%. LC-MS (ESI) m/z calcd for C16H25N2O5[M+H]+:325.18,found:325.06.
4. Preparation of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine (I-a)
A100 mL three-neck flask with a magnetic stirring thermometer is charged with O- [2- [ [ tert-butoxy carbonyl ] carbonyl]Amino group]Ethyl radical]L-tyrosine (3.24g, 10mmol), 21.2g of sodium carbonate aqueous solution with mass concentration of 5.5%, 20mL of tetrahydrofuran solution of 9-fluorenylmethyl-N-succinimidyl carbonate (3.37g, 10mmol) was added dropwise at room temperature, after the addition, amidation reaction was carried out at room temperature, and TLC was monitored until the reaction was completed. Concentrating to remove partial solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethyloxycarbonyl ]]4.68g of L-tyrosine, yield 85.7%, HPLC purity 99.8%, ee value 99.8%.1H NMR(400MHz,DMSO-d6)δ12.75(s,1H),7.89(d,J＝7.6Hz,2H),7.72–7.64(m,3H),7.44–7.40(t,J＝7.6Hz,2H),7.35–7.28(m,2H),7.19(d,J＝8.0Hz,2H),7.00(t,J＝5.6Hz,1H),6.84(d,J＝8.4Hz,2H),4.24–3.90(m,4H),3.91(t,J＝6.0Hz,2H),3.29(q,J＝6.0Hz,2H),3.03(m,J＝14.0,4.4Hz,1H),2.82(m,1H),1.39(s,9H).
Example 2:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Adding L-tyrosine (1.81g, 10mmol) and 20mL of methanol into a 50mL three-neck flask with a magnetic stirring thermometer, slowly dropwise adding thionyl chloride (2.97g, 25mmol) in an ice bath at-10 ℃, ensuring the temperature of the reaction liquid to be below room temperature, after dropwise adding, heating to reflux for esterification reaction, and monitoring by TLC until the reaction is finished. Cooling, concentrating to remove methanol, and drying to obtain white solid L-tyrosine methyl ester hydrochloride 2.25g, yield 97.2%, and HPLC purity 99.3%.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Adding L-tyrosine methyl ester hydrochloride (2.32g, 10mmol) and 25mL of dichloromethane into a 50mL three-neck flask with a magnetic stirring thermometer, placing the reaction bottle in an ice-water bath at 0-5 ℃, adding pyridine (2.77g, 35mmol), dropwise adding trifluoroacetic anhydride (3.15g, 15mmol), ensuring the temperature of the reaction solution to be below room temperature, after dropwise adding, heating to reflux for amidation reaction, and monitoring by TLC until the reaction is finished. After cooling, concentration to remove dichloromethane, water washing, filtration and drying, 2.73g of white-like solid N-trifluoroacetyl-L-tyrosine methyl ester is obtained, the yield is 93.6 percent, and the HPLC purity is 99.2 percent.
3. Preparation of O- [2- [ [ (tert-butoxy) carbonyl ] amino ] ethyl ] -L-tyrosine (VI-a)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and 30mL of toluene into a 100mL three-neck flask with a magnetic stirring thermometer, adding N-tert-butoxycarbonyl-ethanolamine (2.90g, 18mmol) and triphenylphosphine (5.24g, 20mmol), placing the reaction bottle in an ice-water bath at 0-5 ℃, dropwise adding diethyl azodicarboxylate (3.48g, 20mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of N-trifluoroacetyl-L-tyrosine methyl ester is 97%. The toluene was removed by concentration to obtain a crude methyl (S) -3- (4- [2- [ [ tert-butoxycarbonyl ] amino ] ethoxy ] phenyl) -2- (2,2, 2-trifluoroacetamido) propionate product (V-a). To the crude product (V-a), 20mL of ethanol was added, and 21g of an aqueous solution of sodium hydroxide having a mass concentration of 4.7% was added to conduct hydrolysis reaction at room temperature, followed by TLC until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white solid, filtering, pulping with dichloromethane, filtering, and drying to obtain 2.78g of white solid O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -L-tyrosine, wherein the yield of the two steps is 85.8%, and the HPLC purity is 99.1%.
4. Preparation of O- [2- [ [ (tert-butyloxycarbonyl) amino ] ethyl ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine (I-a)
O- [2- [ [ tert-butoxycarbonyl ] amino ] ethyl ] -L-tyrosine (3.24g, 10mmol) and 22.6g of an aqueous solution of sodium carbonate having a mass concentration of 11.7% were charged into a 100mL three-necked flask equipped with a magnetic stirrer and a thermometer, 20mL of a tetrahydrofuran solution of 9-fluorenylmethyl-N-succinimidyl carbonate (4.38g, 13mmol) was added dropwise at room temperature, and after completion of the addition, amidation reaction was carried out at room temperature, and TLC was monitored until the reaction was completed. Concentrating to remove part of solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine 4.51g, the yield is 82.6%, the HPLC purity is 99.5%, and the ee value is 99.6%.
Example 3:
example 1 was repeated with ROH as ethanol, but mainly N-tert-butoxycarbonyl-ethanolamine was replaced with an equimolar amount of ethanol during the preparation of compound (vi);
the synthetic route of example 3 is as follows:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Preparation of L-tyrosine methyl ester hydrochloride (III) in example 3 example 1 was repeated.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Example 3 preparation of methyl N-trifluoroacetyl-L-tyrosine (IV) example 1 is repeated.
3. Preparation of 4-ethoxy-L-phenylalanine (VI-b)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and tetrahydrofuran (30 mL) into a 100mL three-neck flask with a magnetic stirring thermometer, adding ethanol (0.55g, 12mmol) and triphenylphosphine (3.15g, 12mmol), placing the reaction flask in an ice-water bath at 0-5 ℃, dropwise adding di-tert-butyl azodicarboxylate (2.76g, 12mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of the N-trifluoroacetyl-L-tyrosine methyl ester is 98%. The tetrahydrofuran was removed by concentration to give a crude (S) -methyl 3- (4-ethoxy ] phenyl) -2- (2,2, 2-trifluoroacetamido) propionate (V-b). To the crude product (V-b), 20mL of methanol was added, 23.5g of an aqueous solution of potassium carbonate having a mass concentration of 14.7% was added, hydrolysis reaction was carried out at room temperature, and TLC was carried out until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white solid, filtering, pulping with dichloromethane, filtering, and drying to obtain 1.78g of white solid 4-ethoxy-L-phenylalanine, wherein the yield of the two steps is 85.2%, and the HPLC purity is 99.5%.
4. Preparation of 4-ethoxy-N- [ fluorenylmethoxycarbonyl ] -L-phenylalanine (I-b)
A100 mL three-necked flask equipped with a magnetic stirrer and a thermometer was charged with 4-ethoxy-L-phenylalanine (2.09g, 10mmol) and 22.1g of a 9.6% aqueous sodium carbonate solution, 20mL of an acetone solution of 9-fluorenylmethyl-N-succinimidyl carbonate (3.71g, 11mmol) was added dropwise at room temperature, after completion of the addition, amidation reaction was carried out at room temperature, and TLC was carried out until the reaction was completed. Concentrating to remove part of solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine 3.74g, with the yield of 86.6%, the HPLC purity of 99.6% and the ee value of 99.7%.
Example 4:
example 1 was repeated with the experimental procedure of example 3 using ROH as 3-butyn-1-ol, except that in the preparation of compound (VI), N-tert-butoxycarbonyl-ethanolamine was replaced with an equimolar amount of 3-butyn-1-ol;
the synthetic route of example 4 is as follows:
1. preparation of L-tyrosine methyl ester hydrochloride (III)
Preparation of L-tyrosine methyl ester hydrochloride (III) in example 4 example 1 was repeated.
2. Preparation of N-trifluoroacetyl-L-tyrosine methyl ester (IV)
Example 4 preparation of methyl N-trifluoroacetyl-L-tyrosine (IV) example 1 is repeated.
3. Preparation of O- [ 3-butynyl ] -L-tyrosine (VI-c)
Adding N-trifluoroacetyl-L-tyrosine methyl ester (2.91g, 10mmol) and tetrahydrofuran (30 mL) into a 100mL three-neck flask with a magnetic stirring thermometer, adding 3-butyn-1-ol (0.84g, 12mmol) and triphenylphosphine (3.15g, 12mmol), placing the reaction bottle in an ice-water bath at 0-5 ℃, dropwise adding di-tert-butyl azodicarboxylate (2.76g, 12mmol) to ensure that the temperature of the reaction solution is below room temperature, reacting at room temperature after dropwise adding, and monitoring by HPLC until the reaction conversion rate of N-trifluoroacetyl-L-tyrosine methyl ester is 97%. The tetrahydrofuran was removed by concentration to obtain a crude product of (S) -methyl 3- (4- [ 3-butyn-1-oxy ] phenyl) -2- (2,2, 2-trifluoroacetamido) propionate (V-c). To the crude product (V-c), 20mL of methanol was added, 22g of an aqueous solution of 9.1% by mass sodium hydroxide was added, hydrolysis reaction was carried out at room temperature, and TLC was carried out until the reaction was completed. Acidifying with 2N hydrochloric acid until the pH value is 5-6, separating out a white solid, filtering, pulping with dichloromethane, filtering, and drying to obtain 1.96g of white solid O- [ 3-butyne ] -L-tyrosine, wherein the yield of the two steps is 84.1%, and the HPLC purity is 99.2%.
4. Preparation of O- [ 3-butyne ] -N- [ fluorenylmethoxycarbonyl ] -L-tyrosine (I-c)
O- [ 3-butyne ] -L-tyrosine (2.33g, 10mmol) and 22.1g of 9.6% sodium carbonate aqueous solution are added into a 100mL three-neck flask with a magnetic stirring thermometer, 20mL of 9-fluorenylmethyl-N-succinimidyl carbonate (3.71g, 11mmol) acetone solution is added dropwise at room temperature, after the addition, amidation reaction is carried out at room temperature, and TLC is monitored until the reaction is finished. Concentrating to remove part of solvent, acidifying with 2N hydrochloric acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline, concentrating, pulping with petroleum ether, filtering, and drying to obtain white solid O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine 3.81g, wherein the yield is 83.7%, the HPLC purity is 99.5%, and the ee value is 99.7%.
The statements in this specification merely set forth a list of implementations of the inventive concept and the scope of the present invention should not be construed as limited to the particular forms set forth in the examples.
Claims (7)
1. A preparation method of L-tyrosine derivative is characterized in that the L-tyrosine derivative is O-alkyl-N- [ fluorenylmethyloxycarbonyl ] -L-tyrosine shown in formula (I), which is obtained by taking a compound shown in formula (III) as a raw material and sequentially carrying out amidation, etherification/hydrolysis and amidation reactions, and specifically comprises the following steps:
1) adding a compound shown as a formula (III) into a solvent A, carrying out amidation reaction with trifluoroacetic anhydride in the solvent A at a reflux temperature in the presence of alkali A, concentrating to remove the solvent A after the reaction is finished, washing with water, filtering, and drying to obtain a compound shown as a formula (IV);
2) adding a compound shown in a formula (IV) into a solvent B, carrying out etherification reaction with alcohol ROH in the solvent B in the presence of triphenylphosphine and azodicarbonic diester compounds, and concentrating to obtain a crude compound shown in a formula (V) after the reaction is finished; directly adding the obtained crude product of the compound shown in the formula (V) into a mixed solvent of lower alcohol and water, adding alkali B for hydrolysis reaction, acidifying the reaction solution with acid until the pH value is 5-6 after the reaction is finished, filtering, pulping with a halogenated hydrocarbon solvent, filtering, and drying to obtain the compound shown in the formula (VI);
3) adding a compound shown as a formula (VI) and a sodium carbonate aqueous solution into a solvent D, adding 9-fluorenylmethyl-N-succinimidyl carbonate to perform amidation reaction, concentrating to remove part of the solvent after the reaction is finished, acidifying with acid until the pH value is 6-7, extracting with ethyl acetate, washing with saturated saline solution, and concentrating to obtain a compound shown as a formula (I), namely O-alkyl-N- [ fluorenylmethoxycarbonyl ] -L-tyrosine;
in the formulas (I), (IV), (V) and (VI), a substituent R is C1-C9 alkyl or substituted alkyl, and the substituent of the substituted alkyl is C2-C4 alkynyl or N-tert-butyloxycarbonyl;
the substituents R in the alcohol ROH are the same as R in formula (I).
2. The process for preparing L-tyrosine derivative according to claim 1, wherein the compound of formula (III) is prepared by esterification of L-tyrosine of formula (II) as starting material, which comprises the following steps: starting L-tyrosine shown in a formula (II) as a raw material, carrying out esterification reaction with methanol at a reflux temperature in the presence of a catalyst, cooling and concentrating to remove the methanol after the reaction is finished, and drying to obtain L-tyrosine ester hydrochloride shown in a formula (III);
3. the process for preparing an L-tyrosine derivative according to claim 2, wherein the catalyst is concentrated sulfuric acid, thionyl chloride or anhydrous hydrogen chloride, preferably thionyl chloride; the amount ratio of the catalyst to the amount of the substance of tyrosine represented by formula (II) is 1.5-2.5: 1, preferably 1.7-2.0: 1.
4. The process for preparing an L-tyrosine derivative according to claim 1, wherein in step 1), the base a is pyridine, triethylamine or N, N-diisopropylethylamine, preferably pyridine; the solvent A is ethyl acetate, tetrahydrofuran, methyl acetate, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the mass ratio of the base A to the compound represented by the formula (III) is 2.1 to 3.5:1, preferably 2.2 to 2.8: 1; the mass ratio of trifluoroacetic anhydride to the compound represented by formula (III) is 1.2 to 1.8:1, preferably 1.3 to 1.6: 1.
5. The process for preparing an L-tyrosine derivative according to claim 1, wherein in step 2), the solvent B is ethyl acetate, tetrahydrofuran, methyl acetate, toluene, chloroform, dichloromethane or 1, 2-dichloroethane, preferably tetrahydrofuran; the azodicarboxylic acid diester compound is dimethyl azodicarboxylate, diethyl azodicarboxylate, diisopropyl azodicarboxylate, di-tert-butyl azodicarboxylate or dibenzyl azodicarboxylate, preferably diethyl azodicarboxylate; the alcohol ROH is ethanol, tert-butyl alcohol, N-propanol, N- (tert-butoxycarbonyl) ethanolamine, 3-cyclopropyl-2-propyn-1-ol or 3-butyn-1-ol; the alkali B is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide or potassium tert-butoxide, and potassium carbonate is preferred;
the mass ratio of triphenylphosphine to the compound of formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the azodicarboxylic acid diester compound to the compound represented by the formula (IV) is 1.2-2.0: 1, preferably 1.3-1.6: 1; the mass ratio of the alcohol ROH to the compound represented by the formula (IV) is 1.2-1.8: 1, preferably 1.3-1.5: 1;
the lower alcohol is methanol or ethanol, and the mixed solvent of the lower alcohol and water is a methanol-water mixed solution with a volume ratio of 1-5: 1 or an ethanol-water mixed solution with a volume ratio of 1-4: 1, preferably a methanol-water mixed solution with a volume ratio of 1-3: 1; the ratio of the amount of the base B to the amount of the compound represented by the formula (V) is 2.5 to 5.0:1, preferably 3.0 to 4.0: 1.
6. The process for preparing an L-tyrosine derivative according to claim 1, wherein in step 3), the solvent D is tetrahydrofuran, dioxane or acetone, preferably tetrahydrofuran; the mass ratio of sodium carbonate to the compound of formula (VI) is 1.1-2.5: 1, preferably 1.3-2.0: 1; the ratio of the amount of the 9-fluorenylmethyl-N-succinimidyl carbonate to the amount of the compound represented by the formula (VI) is 1.0 to 1.3:1, preferably 1.05 to 1.20: 1.
7. The process of claim 1, wherein in step 2), the halogenated hydrocarbon solvent is dichloromethane.
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