CN110903205A - Preparation method of 2, 6-dimethyl-L-tyrosine - Google Patents
Preparation method of 2, 6-dimethyl-L-tyrosine Download PDFInfo
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Abstract
The invention discloses a preparation method of 2, 6-dimethyl-L-tyrosine, which comprises the following steps: dissolving camphor sulfonamide shown in a formula (I) in an organic solvent A, adding trimethyl aluminum under the protection of nitrogen, uniformly stirring to obtain a mixed solution A, then dissolving diphenyl imido ester shown in a formula (II) in an organic solvent B to obtain a mixed solution B, reacting the mixed solution A with the mixed solution B to obtain a chiral compound shown in a formula (III), dissolving the chiral compound in an organic solvent C, adding halide shown in a formula (IV) under the action of an alkaline substance A, carrying out nucleophilic substitution under the protection of inert gas to obtain a compound shown in a formula (V), dissolving the compound in an organic solvent D, carrying out imine hydrolysis reaction under the action of acid to obtain a compound shown in a formula (VI), dissolving the compound in an organic solvent E, and obtaining 2, 6-dimethyl-L-tyrosine shown in a formula (VII) under the action of an alkaline substance B. The invention has the advantages of cheap and easily obtained raw materials, short route, high yield and good stereoselectivity.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and particularly relates to a preparation method of a drug intermediate 2, 6-dimethyl-L-tyrosine.
Background
Opioid receptors are widely distributed and unevenly distributed in the nervous system. The density of grey opioid receptors in the brain, inside the thalamus, ventricles and around aqueducts is high, and these structures are involved in the integration and perception of pain sensation. The limbic system and the locus ceruleus opioid receptors are most dense and these structures are involved in emotional and mental activities. The midbrain anterior capping nucleus associated with miosis, the nucleus solitary tract of the prolongation of the brain associated with the cough reflex, respiratory center and sympathetic center, the posterolateral brain stem region associated with gastrointestinal activity (nausea, vomiting reflex), the dorsal vagus nerve nucleus, etc. all have opioid receptor distribution. The glial zone of the spinal cord and the glial zone of the tail nucleus of the trigeminal nerve spinal cord also have opioid receptor distribution, and these structures are important transfer sites for the afferent center of pain impulse and influence the afferent of the pain impulse. In addition, exogenous opioids, both naturally occurring and synthetic molecules, are effective in treating a number of human diseases. The dipeptide H-Tyr-Tic-OH is the smallest peptide fragment that has been found to be present that still retains the properties of an effective delta-opioid receptor antagonist. The substitution of the tyrosine moiety of this dipeptide with a single configuration of the unnatural amino acid 2, 6-dimethyl-L-tyrosine (DMT) further improves the affinity and selectivity of delta-opioids. The study of H-Dmt-Tic-OH by the researchers has designed nearly two thousand analogs and synthesized them for the development of pharmaceutically acceptable opioid receptor antagonists.
The asymmetric synthetic route of 2, 6-dimethyl-L-tyrosine mainly comprises the following steps:
the document (Synthesis,1992, (8):741-743) takes 3, 5-dimethylphenol as a raw material, and obtains the target product 2, 6-dimethyl-L-tyrosine hydrochloride through iodination, hydroxyl protection, Heck coupling reaction catalyzed by palladium acetate, asymmetric hydrogenation catalyzed by chiral rhodium and hydrolysis, wherein the total yield is 32.0 percent, but the chiral catalyst used in the reaction is expensive, the hydrogenation reaction needs to be carried out under strict oxygen-free conditions, the production cost is higher, and the industrial production is not easy.
The target product 2, 6-dimethyl-L-tyrosine is obtained by using 4-bromo-3, 5-dimethylphenol as a starting material through hydroxyl protection, Grignard addition, reduction, bromination, asymmetric alkyl induced by a chiral nickel reagent and debenzylation protecting group in the literature (Tetrahedron-Asymmetry,2000,11(14): 2917) -2925). The steps of the route are complicated, the reaction stereo selection is not good, a chiral column is required to be used for separation and purification, and the method is not suitable for industrial application.
The target product 2, 6-dimethyl-L-tyrosine is obtained by asymmetric double alkylation reaction of chiral reagent 2, 5-diketopiperazine derivative and iodide, acidic hydrolysis and purification by acidic ion exchange resin in the literature (Tetrahedron-Asymmetry,2009,20(12): 1398-. However, the reagent iodide is expensive, unstable, and easily decomposed, and is not suitable for mass production because of its high production cost.
In the literature (ACS Med. chem. Lett.,2015,6(12): 1199-ne 1203), Boc-protected L-serine methyl ester is used as a starting material, iodinated, catalyzed by tris (dibenzylideneacetone) dipalladium and 2-dicyclohexylphosphine-2 ', 6' -dimethoxybiphenyl under the assistance of microwave to complete Negishi cross-coupling reaction, and finally hydrolyzed to obtain 2, 6-dimethyl-L-tyrosine. However, the raw materials and reagents used in the route are expensive, the microwave reaction has high operation requirements, and the industrial production is difficult.
The literature (org.Lett.,2017,19(1):246-249) and the like take natural amino acid tyrosine derivatives as chiral sources, two methyl groups are introduced on an aromatic ring by direct C-H activation through palladium catalysis, and then a protecting group is removed through acidic hydrolysis to obtain the 2, 6-dimethyl-L-tyrosine. However, the catalyst used in the method is expensive, has low yield and is not suitable for industrial production.
In summary, since 2, 6-dimethyl-L-tyrosine is a component of a delta-opioid antagonist as a non-natural α -amino acid, it is a pharmacophore existing in many bioactive compounds (delta antagonists, delta agonists and delta antagonists/mu agonists), and is an important intermediate for drug synthesis, and has a good market prospect, there is a need to develop a simple, practical and effective method for synthesizing 2, 6-dimethyl-L-tyrosine.
Disclosure of Invention
The invention provides a method for preparing 2, 6-dimethyl-L-tyrosine by taking cheap and easily obtained camphor sulfonamide as a chiral source through condensation, asymmetric alkylation, hydrolysis and chiral auxiliary group removal.
The invention adopts the following technical scheme:
a preparation method of 2, 6-dimethyl-L-tyrosine comprises the following steps:
step A: dissolving camphor sulfonamide shown in a formula (I) in an organic solvent A, adding trimethylaluminum under the protection of nitrogen, uniformly stirring to obtain a mixed solution A, then dissolving diphenyl imine ester shown in a formula (II) in an organic solvent B to obtain a mixed solution B, carrying out a condensation reaction on the mixed solution A and the mixed solution B at a temperature of 25-80 ℃ (preferably 40-50 ℃) for 10-40 hours (preferably 15-20 hours), finishing a TLC detection reaction, and carrying out post-treatment on the obtained reaction solution A to generate a compound shown in a formula (III) and having chirality; the mass ratio of the camphor sulfonamide shown in the formula (I), the diphenyl imine ester shown in the formula (II) and the trimethyl aluminum is 1.0:1.0-1.5:1.0-1.5 (preferably 1.0:1.1: 1.2); in the same reaction, the organic solvent A and the organic solvent B are the same substance;
and B: dissolving the compound shown in the formula (III) obtained in the step A in an organic solvent C, adding a halide shown in the formula (IV) under the action of an alkaline substance A, carrying out nucleophilic substitution reaction for 1-6 hours (preferably 2-3 hours) at 20-25 ℃ under the protection of inert gas, finishing TLC detection reaction, and carrying out post-treatment on obtained reaction liquid B to obtain a compound shown in the formula (V); the alkaline substance A is organic alkali; the amount ratio of the compound shown in the formula (III), the compound shown in the formula (IV) and the alkaline substance A is 1.0:1.0-1.5:1.0-1.5 (preferably 1.0:1.1: 1.1);
and C: dissolving the compound shown in the formula (V) obtained in the step B in an organic solvent D, carrying out imine hydrolysis reaction for 1-8 hours (preferably 3-4 hours) at-10 ℃ (preferably 0-5 ℃) under the action of acid, and detecting the reaction result by TLC to obtain a reaction solution C, and carrying out post-treatment to obtain the compound shown in the formula (VI); the mass ratio of the compound (V) represented by the formula (V) to the acid is 1.0:1.0-2.0 (preferably 1.0: 1.5);
step D, dissolving the compound shown in the formula (VI) in an organic solvent E, reacting for 1-5 hours (preferably 2-3 hours) at-10 ℃ (preferably 0-5 ℃) under the action of an alkaline substance B, finishing TLC detection reaction, and carrying out aftertreatment on obtained reaction liquid D to obtain a target compound, namely the 2, 6-dimethyl-L-tyrosine shown in the formula (VII); the alkaline substance B is inorganic alkali, the alkaline substance B is added in the form of aqueous solution, the concentration of the alkaline substance B is 2.5mol/L,
the reaction equation is as follows:
wherein: in the formula (II), R1Selected from Me, Et, t-Bu; in the formula (IV), X is selected from Cl, Br or I; wherein R is2Methyl, ethyl, isobutyl, tert-butyl, benzyl, and the like.
Further, in step a, the organic solvent a or the organic solvent B is tetrahydrofuran, 2-methyltetrahydrofuran, toluene, or dimethyl sulfoxide.
Further, in the step A, the adding amount of the organic solvent A is 5-10mL/g based on the mass of the camphor sulfonamide shown in the formula (I); the adding amount of the organic solvent B is 5-10mL/g based on the mass of the diphenyl imine ester shown in the formula (II).
Further, in the step a, the post-treatment method of the reaction solution a comprises: and (2) sequentially adding saturated sodium bicarbonate and water into the obtained reaction liquid A, separating the liquid, extracting the water phase by using ethyl acetate, combining organic phases, washing the organic phases for three times, concentrating the organic phases, carrying out column chromatography separation, collecting eluent containing a target product by using a mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 4:1 as an eluent, and evaporating the solvent to obtain the compound shown in the formula (III).
Further, in step B, the basic substance A is selected from one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium bis (trimethylsilyl) amide or lithium hexamethyldisilazide, and is preferably lithium hexamethyldisilazide.
Further, in the step B, the organic solvent C is toluene, anhydrous tetrahydrofuran or 1, 4-dioxane.
Further, in the step B, the adding amount of the organic solvent C is 5-10mL/g based on the mass of the compound shown in the formula (III).
Further, in the step B, the post-treatment method of the reaction solution B comprises: quenching the reaction liquid B with glacial acetic acid, adding ethyl acetate and water for liquid separation, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated ammonium chloride, performing column chromatography separation, collecting eluent containing the target product by taking the mixed liquid of petroleum ether and ethyl acetate with the volume ratio of 2:1 as an eluent, and evaporating the solvent to obtain the compound shown in the formula (V).
Further, in step C, the concentration of the acid is preferably 1mol/L, and the acid is preferably one of hydrochloric acid or sulfuric acid, and most preferably hydrochloric acid.
Further, in step C, the organic solvent D is methanol, tetrahydrofuran or N, N-dimethylformamide.
Further, in the step C, the adding amount of the organic solvent D is 5-10mL/g based on the mass of the compound shown in the formula (V).
Further, in the step C, the post-treatment method of the reaction solution C comprises: and (2) distilling the obtained reaction liquid C under reduced pressure to remove the solvent, adding petroleum ether and ethyl acetate to wash off impurities, adjusting the pH of the water phase to be alkalescent by using saturated sodium bicarbonate, extracting a product by using ethyl acetate, performing column chromatography separation, collecting eluent containing the target product by using a mixed solution of the petroleum ether and the ethyl acetate with the volume ratio of 1:1 as an eluent, and evaporating the solvent to obtain the compound shown in the formula (VI).
Further, in step D, the alkaline substance B is selected from one of sodium hydroxide, lithium hydroxide, potassium hydroxide, calcium hydroxide or potassium carbonate, preferably lithium hydroxide.
Further, in the step D, the organic solvent E is methanol, tetrahydrofuran or N, N-dimethylformamide.
Further, in the step D, the adding amount of the organic solvent E is 5-10mL/g based on the mass of the compound shown in the formula (VI).
Further, in the step D, the post-treatment method of the reaction solution D includes: and (2) distilling the obtained reaction liquid D under reduced pressure to remove the solvent, adding 1M hydrochloric acid to adjust the pH to 1-2, adjusting the pH to 6-7 by using 1M sodium bicarbonate, distilling under reduced pressure to remove the solvent, carrying out column chromatography separation, collecting eluent containing the target product by using a mixed solution of ethyl acetate and methanol in a volume ratio of 2:1 as an eluent, and distilling off the solvent to obtain the 2, 6-dimethyl-L-tyrosine shown in the formula (VII).
Compared with the prior art, the invention has the beneficial effects that:
the raw materials are cheap and easy to obtain, the route is short, the yield is high, the stereoselectivity is good, the diphenylimine ester shown in the formula (II) and trimethylaluminum form a complex, and the purpose is to improve the nucleophilic ability of amino in camphor sultam and reduce the generation of byproducts. At present, 2, 6-dimethyl-L-tyrosine is an important chiral intermediate of a plurality of medicines and has good market prospect.
Detailed Description
The invention is further illustrated by the following examples, without restricting its scope.
In the examples, trimethylaluminum was purchased from Saien chemical technology (Shanghai) Co., Ltd, and was a 1.0mol/L n-hexane solution with a CAS number of 75-24-1;
sodium hydride was purchased from sahn chemical technology (shanghai) ltd, 60% mineral oil specification, CAS No. 7646-69-6;
the potassium tert-butoxide is purchased from Saen chemical technology (Shanghai) Co., Ltd, with the specification of 98% and the CAS number of 865-47-4;
the n-butyl lithium is purchased from Saen chemical technology (Shanghai) Co., Ltd, and is 2.5mol/L n-hexane solution with CAS number of 109-72-8;
lithium diisopropylamide was purchased from Saien chemical technology (Shanghai) Co., Ltd, 2.0mol/L n-hexane solution, CAS number 4111-54-0;
hexamethyldisilazane lithium amide was purchased from Sahn chemical technology (Shanghai) Co., Ltd, and was a 1.0mol/L tetrahydrofuran solution with CAS number 4039-32-1.
Example 1: synthesis of Compound (III)
According to the molar ratio, camphor sulfonamide: diphenylimidoesters: trimethylaluminum 1.0:1.0:1.0 the following reaction was carried out:
0.50g of camphorsulfonamide is dissolved in 5mL of toluene, and 2.33mL of trimethylaluminum n-hexane solution (1.0mol/L) is added dropwise at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.53g of a toluene solution of diphenylimidyl ester (5mL) was added to the reaction mixture, and the mixture was heated to 40 ℃ to react for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 0.82g of a pale yellow oily substance with a yield of 81.0%.
Example 2: synthesis of Compound (III)
According to the molar ratio, camphor sulfonamide: diphenylimidoesters: trimethylaluminum 1.0:1.5:1.0 the following reaction was carried out:
0.5g of camphorsulfonamide is dissolved in 5mL of toluene, and 2.33mL of trimethylaluminum n-hexane solution (1.0mol/L) is added dropwise at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.79g of a toluene solution of diphenylimidyl ester (5mL) was added to the reaction mixture, and the mixture was heated to 40 ℃ to react for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to purify the mixture to obtain 0.84g of a pale yellow oily substance, with a yield of 83.1%.
Example 3: synthesis of Compound (III)
According to the molar ratio, camphor sulfonamide: diphenylimidoesters: trimethylaluminum 1.0:1.1:1.0 the following reaction was carried out:
0.5g of camphorsulfonamide is dissolved in 5mL of toluene, and 2.33mL of trimethylaluminum n-hexane solution (1.0mol/L) is added dropwise at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.58g of a toluene solution of diphenylimidyl ester (5mL) was added to the reaction mixture, and the temperature was raised to 40 ℃ to react for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 0.86g of a pale yellow oily substance, with a yield of 85.6%.
Example 4: synthesis of Compound (III)
According to the molar ratio, camphor sulfonamide: diphenylimidoesters: trimethylaluminum 1.0:1.1:1.5 the following reaction was carried out:
0.5g of camphorsulfonamide is dissolved in 5mL of toluene, and 3.48mL of trimethylaluminum n-hexane solution (1.0mol/L) is added dropwise at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.58g of a toluene solution of diphenylimidyl ester (5mL) was added to the reaction mixture, and the temperature was raised to 40 ℃ to react for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 0.85g of a pale yellow oily substance, with a yield of 84.4%.
Example 5: synthesis of Compound (III)
According to the molar ratio, camphor sulfonamide: diphenylimidoesters: trimethylaluminum 1.0:1.1:1.2 the following reaction was carried out:
0.5g of camphorsulfonamide is dissolved in 5mL of toluene, and 2.79mL of trimethylaluminum n-hexane solution (1.0mol/L) is added dropwise at room temperature under nitrogen. After the reaction mixture was stirred at room temperature for 15 minutes, 0.58g of a toluene solution of diphenylimidyl ester (5mL) was added to the reaction mixture, and the temperature was raised to 40 ℃ to react for 20 hours. The reaction was completed by TLC detection. 10mL of saturated sodium bicarbonate and 10mL of water were added in this order, liquid separation was performed, the aqueous phase was extracted with 20mL of ethyl acetate, the organic phases were combined, washed with water three times, the organic phase was concentrated, and column chromatography (petroleum ether: ethyl acetate 4:1) was performed to obtain 0.91g of a pale yellow oily substance with a yield of 90.0%.
The analytical data for compound (III) are as follows: light yellow oil; rf＝0.30(Petroleum ether:EtOAc＝4:1)；1H NMR(500MHz,CDCl3)δ7.66(dd,J＝5.2,3.3Hz,2H),7.49-7.42(m,3H),7.38(dd,J＝4.9,3.6Hz,1H),7.33(t,J＝7.5Hz,2H),7.25–7.15(m,2H),4.63(d,J＝4.5Hz,2H),3.90(dd,J＝7.8,4.9Hz,1H),3.42(d,J＝12.4Hz,2H),2.14-2.03(m,1H),1.41-1.38(m,1H),1.35(d,J＝6.7Hz,1H),1.13(s,4H),0.95(s,6H)ppm.
Example 6: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): sodium hydride 1.0:1.0:1.0 the following reaction was carried out:
1.05g of compound (III) and 10mL of anhydrous THF solution are added, 58mg of sodium hydride are added under nitrogen, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 10mL (0.239mol/L) of anhydrous THF solution of chloride (IV) is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out to obtain 0.38g of white solid product, and the yield is 70.0%.
Example 7: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): potassium tert-butoxide ═ 1.0:1.0:1.0, the following reaction was carried out:
1.05g of compound (III) and 10mL of anhydrous THF solution are added, 0.27g of potassium tert-butoxide is added under nitrogen protection, and the reaction temperature is lowered to-78 ℃. After 20 minutes, 10mL (0.239mol/L) of chloride (IV) anhydrous THF solution is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out to obtain 0.35g of white solid product, and the yield is 64.2%.
Example 8: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): n-butyllithium was reacted at 1.0:1.0:1.0 as follows:
1.05g of the compound (III) and 10mL of an anhydrous THF solution were added, and 0.96mL of an n-butyllithium-n-hexane solution (2.5mol/L) was added under a nitrogen atmosphere to lower the reaction temperature to-78 ℃. After 20 minutes, 10mL (0.239mol/L) of chloride (IV) anhydrous THF solution is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 0.45g of white solid product, and the yield is 82.5%.
Example 9: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): lithium diisopropylamide was reacted at 1.0:1.0:1.0 as follows:
1.05g of the compound (III) and 10mL of an anhydrous THF solution were added, and 1.21mL of a lithium diisopropylamide n-hexane solution (2.0mol/L) was added under a nitrogen atmosphere to lower the reaction temperature to-78 ℃. After 20 minutes, 10mL (0.239mol/L) of chloride (IV) anhydrous THF solution is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 0.47g of white solid product, and the yield is 86.2%.
Example 10: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): hexamethyldisilazane lithium amide-base (1.0: 1.0: 1.0) was reacted as follows:
1.05g of the compound (III) and 10mL of an anhydrous THF solution were added, and 2.41mL of a lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under a nitrogen atmosphere, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 10mL (0.239mol/L) of anhydrous THF solution of chloride (IV) is added, the temperature is maintained for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 0.49g of white solid product, and the yield is 89.9%.
Example 11: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.0) was reacted as follows:
1.05g of the compound (III) and 10mL of an anhydrous THF solution were added, and 2.41mL of a lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under a nitrogen atmosphere, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 10mL (0.265mol/L) of chloride (IV) anhydrous THF solution is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 0.48g of white solid product, and the yield is 88.1%.
Example 12: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): hexamethyldisilazane lithium amide-base (1.0: 1.5: 1.0) was reacted as follows:
1.05g of the compound (III) and 10mL of an anhydrous THF solution were added, and 2.41mL of a lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under a nitrogen atmosphere, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 10mL (0.360mol/L) of anhydrous THF (IV) chloride is added, the temperature is maintained for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, the mixture is washed by saturated ammonium chloride, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out to obtain 0.47g of white solid product, and the yield is 86.2%.
Example 13: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): hexamethyldisilazane lithium amide-base (1.0: 1.1:1.1) was reacted as follows:
1.05g of the compound (III) and 10mL of an anhydrous THF solution were added, and 2.65mL of a lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) was added under a nitrogen atmosphere, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 10mL (0.265mol/L) of chloride (IV) anhydrous THF solution is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 0.50g of white solid product, and the yield is 91.8%.
Example 14: synthesis of Compound (V)
According to the molar ratio, the compound (III): chloride (IV): hexamethyldisilazane lithium amide-base (1.0: 1.1: 1.5) was reacted as follows:
1.05g of the compound (III) was added, and 10mL of an anhydrous THF solution and 3.62mL of a lithium hexamethyldisilazide tetrahydrofuran solution (1.0mol/L) were sequentially added under a nitrogen atmosphere, and the reaction temperature was lowered to-78 ℃. After 20 minutes, 10mL (0.265mol/L) of chloride (IV) anhydrous THF solution is added, the temperature is kept for reaction for 15 minutes, then the mixture is transferred to room temperature for reaction for 3 hours, TLC detection is carried out to detect the reaction is finished, glacial acetic acid is used for quenching, 20mL of ethyl acetate and water are added for liquid separation, the aqueous phase is extracted by ethyl acetate for 3 times, organic phases are combined, saturated ammonium chloride is used for washing, and column chromatography (petroleum ether: ethyl acetate: 2:1) is carried out for purification to obtain 0.45g of white solid product, and the yield is 83.3%.
Analytical data for compound (V) are as follows: white solid; m.p.102-103 ℃; rf＝0.33(Petroleumether:EtOAc＝2:1)；[α]D 20＝-88.5(c 1,CHCl3)；1H NMR(500MHz,CDCl3)δ7.66(dd,J＝5.2,3.3Hz,2H),7.42-7.34(m,4H),7.33-7.23(m,4H),6.35(s,2H),5.17(t,J＝7.7Hz,1H),3.92(dd,J＝7.7,4.7Hz,1H),3.34(s,2H),3.28(dd,J＝13.6,7.5Hz,1H),2.92-2.80(m,1H),2.65(d,J＝9.3Hz,1H),2.34(d,J＝24.7Hz,1H),1.99(d,J＝7.3Hz,6H),1.83(dd,J＝12.7,5.3Hz,2H),1.76(t,J＝3.8Hz,1H),0.94-0.80(m,6H),0.70(s,3H)ppm.13C NMR(125MHz,CDCl3)δ173.1,169.81,154.1,140.1,139.5,135.7,130.1,128.8,128.1,127.9,114.8,65.2,64.4,53.3,48.2,47.6,44.6,38.1,34.2,32.8,26.4,20.2,20.1,20.0,19.8ppm.HRMS(ESI):calcd.for C34H38N2O4S[M]+571.2625；found 571.2630.
Example 15: synthesis of Compound (VI)
Compound (V): the following reaction was carried out with hydrochloric acid 1.0:
0.42g of Compound (V) and 5mL of THF were added, and 0.73mL of concentrated hydrochloric acid (1mol/L) was added at 0 ℃ to keep the reaction at 0 ℃ for 4 hours. The reaction was completed by TLC and the solvent was distilled off under reduced pressure. Adding petroleum ether and ethyl acetate to wash off impurities, adjusting the pH of the water phase to be alkalescent by using saturated sodium bicarbonate, extracting a product by using ethyl acetate, and purifying by column chromatography (petroleum ether: ethyl acetate: 1) to obtain 0.24g of white solid with the yield of 84.4 percent.
Example 16: synthesis of Compound (VI)
Compound (V): the following reaction was carried out with sulfuric acid 1.0:
0.42g of Compound (V) and 5mL of THF were added, and 0.73mL of concentrated hydrochloric acid (1mol/L) was added at 0 ℃ to keep the reaction at 0 ℃ for 4 hours. The reaction was completed by TLC and the solvent was distilled off under reduced pressure. Adding petroleum ether and ethyl acetate to wash off impurities, adjusting the pH of the water phase to be alkalescent by using saturated sodium bicarbonate, extracting a product by using ethyl acetate, and purifying by column chromatography (petroleum ether: ethyl acetate: 1) to obtain 0.23g of white solid, wherein the yield of the product is 82.5%.
Example 17: synthesis of Compound (VI)
Compound (V): the following reaction was carried out with hydrochloric acid 1.0:1.5:
0.42g of Compound (V) and 5mL of THF were added, and 1.1mL of concentrated hydrochloric acid (1mol/L) was added at 0 ℃ to keep the reaction at 0 ℃ for 4 hours. The reaction was completed by TLC and the solvent was distilled off under reduced pressure. Adding petroleum ether and ethyl acetate to wash off impurities, adjusting the pH of the water phase to be alkalescent by using saturated sodium bicarbonate, extracting a product by using ethyl acetate, and purifying by column chromatography (petroleum ether: ethyl acetate: 1) to obtain 0.25g of white solid with the product yield of 88.0%.
Example 18: synthesis of Compound (VI)
Compound (V): the following reaction was carried out with hydrochloric acid 1.0: 2.0:
0.42g of Compound (V) and 5mL of THF were added, and 1.5mL of concentrated hydrochloric acid (1mol/L) was added at 0 ℃ to keep the reaction at 0 ℃ for 4 hours. The reaction was completed by TLC and the solvent was distilled off under reduced pressure. Adding petroleum ether and ethyl acetate to wash off impurities, adjusting the pH of the water phase to be alkalescent by using saturated sodium bicarbonate, extracting a product by using ethyl acetate, and purifying by column chromatography (petroleum ether: ethyl acetate: 1) to obtain 0.22g of white solid, wherein the yield of the product is 76.3%.
The analytical data for compound (VI) are as follows: white solid; m.p.208-209 ℃; rf＝0.23(Petroleumether:EtOAc＝1:1)；[α]D 20＝+23.5(c 1,MeOH)；1H NMR(500MHz,DMSO)δ6.34(s,2H),3.72(d,J＝14.1Hz,2H),3.06(q,J＝13.9Hz,1H),2.89(dd,J＝13.7,8.6Hz,1H),2.70(dd,J＝13.7,6.6Hz,1H),2.26(s,2H),2.19(s,6H),1.84-1.70(m,6H),1.64(s,1H),1.23-1.13(m,1H),1.04(s,1H),0.85(s,6H)ppm.13C NMR(125MHz,DMSO)δ167.4,155.4,138.0,124.3,114.8,62.0,54.2,49.9,47.0,44.2,35.3,31.5,26.4,20.4,20.3,20.1,20.0ppm.HRMS(ESI):calcd.for C21H30N2O4S[M]+407.1999；found 407.2012.
Example 19: synthesis of Compound (VII)2, 6-dimethyl-L-tyrosine
According to the molar ratio, the compound (VI): sodium hydroxide 1.0:3.0 the following reaction was carried out:
0.3g of Compound (VI) and 5mL of THF were added. 0.89mL of an aqueous NaOH solution (2.5mol/L) was added at 0 ℃ and the reaction was maintained at this temperature for 3 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, pH was adjusted to 1-2 by adding 1M hydrochloric acid, pH was adjusted to 6-7 by using 1M sodium bicarbonate, the solvent was distilled off under reduced pressure, and column chromatography (ethyl acetate: methanol 2:1) was performed to obtain 0.132g of a white solid product, yield 86.0%.
Example 20: synthesis of Compound (VII)2, 6-dimethyl-L-tyrosine
According to the molar ratio, the compound (VI): potassium hydroxide 1.0:3.0 the following reaction was carried out:
0.3g of Compound (VI) and 5mL of THF were added. 0.89mL of an aqueous KOH solution (2.5mol/L) was added thereto at 0 ℃ and the reaction was maintained at this temperature for 3 hours. After completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, pH was adjusted to 1-2 by adding 1M hydrochloric acid, pH was adjusted to 6-7 by using 1M sodium bicarbonate, the solvent was distilled off under reduced pressure, and column chromatography (ethyl acetate: methanol 2:1) was performed to obtain 0.128g of a white solid product, yield 83.4%.
Example 21: synthesis of Compound (VII)2, 6-dimethyl-L-tyrosine
According to the molar ratio, the compound (VI): lithium hydroxide 1.0:3.0 the following reaction was carried out:
0.3g of Compound (VI) and 5mL of THF were added. 0.89mL of an aqueous LiOH solution (2.5mol/L) was added at 0 ℃ and the reaction was maintained at this temperature for 3 hours. After completion of the reaction by TLC, the solvent was distilled off under reduced pressure. The pH was adjusted to 1-2 by adding 1M hydrochloric acid, to 6-7 with 1M sodium bicarbonate, the solvent was removed by distillation under the reduced pressure, and the product was purified by column chromatography (ethyl acetate: methanol ═ 2:1) to obtain 0.146g of a white solid product with a yield of 94.8%.
Example 22: synthesis of Compound (VII)2, 6-dimethyl-L-tyrosine
According to the molar ratio, the compound (VI): calcium hydroxide 1.0:3.0 the following reaction was carried out:
0.3g of Compound (VI) and 5mL of THF were added. 0.89mL Ca (OH) was added at 0 deg.C2Aqueous solution (2.5)mol/L) was added, the temperature was maintained and the reaction was continued for 3 hours. After completion of the reaction by TLC, the solvent was distilled off under reduced pressure. The pH was adjusted to 1-2 by adding 1M hydrochloric acid, to 6-7 with 1M sodium bicarbonate, the solvent was removed by distillation under reduced pressure, and the product was purified by column chromatography (ethyl acetate: methanol ═ 2:1) to give 0.139g of a white solid product, with a yield of 90.2%.
Example 23: synthesis of Compound (VII)2, 6-dimethyl-L-tyrosine
According to the molar ratio, the compound (VI): potassium carbonate 1.0:3.0 the following reaction was carried out:
0.3g of Compound (VI) and 5mL of THF were added. Adding 0.89Mlk at 0 deg.C2CO3An aqueous solution (2.5mol/L) was reacted at this temperature for 3 hours. After completion of the reaction by TLC, the solvent was distilled off under reduced pressure. The pH was adjusted to 1-2 by adding 1M hydrochloric acid, to 6-7 with 1M sodium bicarbonate, the solvent was removed by distillation under the reduced pressure, and the product was purified by column chromatography (ethyl acetate: methanol ═ 2:1) to obtain 0.123g of a white solid product with a yield of 80.3%.
Analytical data for 2, 6-dimethyl-L-tyrosine, Compound (VII), are White solid; m.p.247-248 ℃ (lit.[105]247-249℃)；Rf＝0.28(EtOAc:MeOH＝2:1)；[α]D 20＝+43.3(c 1,MeOH),lit.[99][α]D 25＝+39.41(c 1.017,MeOH)；_1H NMR(500MHz,D2O)δ6.38(s,2H),3.88(t,J＝8.1Hz,1H),3.01(dd,J＝14.7,8.4Hz,1H),2.86(dd,J＝14.7,7.9Hz,1H),2.01(s,6H).13C NMR(125MHz,D2O)δ＝171.8,154.2,139.4,123.3,115.0,52.5,29.6,19.2.
It should be noted that the above experimental examples are only for illustrating the concept and features of the present invention, and the purpose of the present invention is to provide the skilled in the art with an understanding of the experiment and to implement the experiment, and not to limit the protection scope of the present invention. All equivalent changes or modifications made according to the spirit of the present invention should be covered within the protection scope of the present invention.
Claims (10)
1. A preparation method of 2, 6-dimethyl-L-tyrosine is characterized in that: the method comprises the following steps:
step A: dissolving camphor sulfonamide shown in a formula (I) in an organic solvent A, adding trimethylaluminum under the protection of nitrogen, uniformly stirring to obtain a mixed solution A, then dissolving diphenyl imido ester shown in a formula (II) in an organic solvent B to obtain a mixed solution B, carrying out a condensation reaction on the mixed solution A and the mixed solution B at 25-80 ℃ for 10-40 hours to obtain a reaction solution A, and carrying out post-treatment to generate a chiral compound shown in a formula (III); the mass ratio of the camphor sulfonamide shown in the formula (I), the diphenyl imine ester shown in the formula (II) and the trimethylaluminum is 1.0:1.0-1.5: 1.0-1.5; in the same reaction, the organic solvent A and the organic solvent B are the same substance;
and B: dissolving the compound shown in the formula (III) obtained in the step A in an organic solvent C, adding a halide shown in the formula (IV) under the action of an alkaline substance A, and carrying out nucleophilic substitution reaction for 1-6 hours at 20-25 ℃ under the protection of inert gas to obtain a reaction liquid B, and carrying out aftertreatment to obtain the compound shown in the formula (V); the alkaline substance A is organic alkali; the mass ratio of the compound shown in the formula (III), the compound shown in the formula (IV) and the alkaline substance A is 1.0:1.0-1.5: 1.0-1.5;
and C: dissolving the compound shown in the formula (V) obtained in the step B in an organic solvent D, carrying out imine hydrolysis reaction for 1-8 hours at-10 ℃ under the action of acid, detecting the reaction result by TLC, and carrying out post-treatment on the obtained reaction liquid C to obtain the compound shown in the formula (VI); the mass ratio of the compound (V) shown in the formula (V) to the acid is 1.0: 1.0-2.0;
step D, dissolving the compound shown in the formula (VI) in an organic solvent E, reacting for 1-5 hours at the temperature of-10 ℃ to 10 ℃ under the action of an alkaline substance B, finishing TLC detection reaction, and carrying out post-treatment on the obtained reaction liquid D to obtain a target compound, namely the 2, 6-dimethyl-L-tyrosine shown in the formula (VII); the alkaline substance B is inorganic alkali, the alkaline substance B is added in the form of aqueous solution, the concentration of the alkaline substance B is 2.5mol/L,
wherein:in the formula (II), R1Selected from Me, Et, t-Bu; in the formula (IV), X is selected from Cl, Br or I; wherein R is2Is methyl, ethyl, isobutyl, tert-butyl or benzyl.
2. The method of claim 1, wherein: in the step A, the organic solvent A or the organic solvent B is tetrahydrofuran, 2-methyltetrahydrofuran, toluene or dimethyl sulfoxide; the adding amount of the organic solvent A is 5-10mL/g calculated by the mass of the camphor sulfonamide shown in the formula (I); the adding amount of the organic solvent B is 5-10mL/g based on the mass of the diphenyl imine ester shown in the formula (II).
3. The method of claim 1, wherein: in the step A, the post-treatment method of the reaction liquid A comprises the following steps: and (2) sequentially adding saturated sodium bicarbonate and water into the obtained reaction liquid A, separating the liquid, extracting the water phase by using ethyl acetate, combining organic phases, washing the organic phases for three times, concentrating the organic phases, carrying out column chromatography separation, collecting eluent containing a target product by using a mixed liquid of petroleum ether and ethyl acetate in a volume ratio of 4:1 as an eluent, and evaporating the solvent to obtain the compound shown in the formula (III).
4. The method of claim 1, wherein: in the step B, the alkaline substance A is selected from one of sodium hydride, potassium tert-butoxide, sodium tert-butoxide, n-butyllithium, tert-butyllithium, lithium diisopropylamide, potassium hexamethyldisilazide, sodium bis (trimethylsilyl) amide or lithium hexamethyldisilazide.
5. The method of claim 1, wherein: in the step B, the organic solvent C is toluene, tetrahydrofuran or 1, 4-dioxane; the adding amount of the organic solvent C is 5-10mL/g based on the mass of the compound shown in the formula (III).
6. The method of claim 1, wherein: in the step B, the post-treatment method of the reaction liquid B comprises the following steps: quenching the reaction liquid B with glacial acetic acid, adding ethyl acetate and water for liquid separation, extracting the water phase with ethyl acetate for 3 times, combining the organic phases, washing with saturated ammonium chloride, performing column chromatography separation, collecting eluent containing the target product by taking the mixed liquid of petroleum ether and ethyl acetate with the volume ratio of 2:1 as an eluent, and evaporating the solvent to obtain the compound shown in the formula (V).
7. The method of claim 1, wherein: in the step C, the organic solvent D is methanol, tetrahydrofuran or N, N-dimethylformamide; the adding amount of the organic solvent D is 5-10mL/g based on the mass of the compound shown in the formula (V).
8. The method of claim 1, wherein: in the step C, the post-treatment method of the reaction solution C comprises the following steps: and (2) distilling the obtained reaction liquid C under reduced pressure to remove the solvent, adding petroleum ether and ethyl acetate to wash off impurities, adjusting the pH of the water phase to be alkalescent by using saturated sodium bicarbonate, extracting a product by using ethyl acetate, performing column chromatography separation, collecting eluent containing the target product by using a mixed solution of the petroleum ether and the ethyl acetate with the volume ratio of 1:1 as an eluent, and evaporating the solvent to obtain the compound shown in the formula (VI).
9. The method of claim 1, wherein: in the step D, the organic solvent E is methanol, tetrahydrofuran or N, N-dimethylformamide; the adding amount of the organic solvent E is 5-10mL/g based on the mass of the compound shown in the formula (VI).
10. The method of claim 1, wherein: in the step D, the post-treatment method of the reaction solution D comprises the following steps: and (2) distilling the obtained reaction liquid D under reduced pressure to remove the solvent, adding 1M hydrochloric acid to adjust the pH to 1-2, adjusting the pH to 6-7 by using 1M sodium bicarbonate, distilling under reduced pressure to remove the solvent, carrying out column chromatography separation, collecting eluent containing the target product by using a mixed solution of ethyl acetate and methanol in a volume ratio of 2:1 as an eluent, and distilling off the solvent to obtain the 2, 6-dimethyl-L-tyrosine shown in the formula (VII).
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