CN112321515A - Preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate - Google Patents
Preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate Download PDFInfo
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Abstract
The invention provides a preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate, and particularly relates to a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate. The preparation method comprises the steps of taking Boc-D-alanine and L-serine methyl ester hydrochloride as initial raw materials, and preparing chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate through condensation reaction, deamination protection, ring closing reaction, reduction reaction, amino protection, oxidation reaction, ring closing reaction and ring opening reaction. According to the preparation method provided by the invention, the Boc amino protective agent is used for protecting the amino, so that the production cost is reduced, the raw materials are easy to obtain, the conditions are mild, the yield is high, and the preparation method can be applied to large-scale industrial production.
Description
Technical Field
The invention belongs to the technical field of organic compound synthesis, and particularly relates to a preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate.
Background
The piperazine compound is an important nitrogen-containing heterocycle in heterocyclic compounds, piperazine derivatives are regarded as important compounds with activities of resisting depression, diminishing inflammation, relieving pain, resisting tumors and the like, and in addition, 1, 4-positions of piperazine rings are basic groups and have better water solubility and alkalinity, so that the piperazine derivatives can be introduced into drug molecules to increase the water solubility of the drugs and effectively adjust the acid-base balance of the drugs, thereby enhancing the biological activity of the drug molecules in animals and plants.
CN110183471A discloses a novel piperazine derivative and its preparation method and application, the compound is (R) -6-methyl-3- (4- (isopropylsulfonyl) phenyl) -6-chloro-1H-pyrrolo [2,3-b ] pyridine) -4,5,6, 7-tetrahydropyrazolo [1,5-a ] piperazine, the technique uses 1((R) -2- (benzylamino) propan-1-ol) and 2 (3-aldehyde-4-bromopyrazole) as initial raw materials, the prepared novel piperazine derivative can effectively inhibit proliferation of human breast cancer cells, and has better synergistic anti-human breast cancer cell effect when combined with adriamycin for use, and the preparation process condition of the compound is mild, thereby overcoming the harsh synthesis condition of the piperazine compound, Low yield and unsuitability for industrialized production.
CN111253325A discloses an amino quinazoline aryl piperazine compound, a pharmaceutical composition and an application thereof, wherein the amino quinazoline aryl piperazine compound provided by the invention has the following compounds or pharmaceutically acceptable salts thereof:
wherein R is1～R10Each independently represents hydrogen, halogen, amino, nitro, hydroxyamino, guanidino, ureido, trifluoromethyl, arylsulfonyl, substituted aryl, C1～C10Alkoxy radical, C1～C10Aminoalkyl radical, C1～C10Alkyl or C1～C10An amide group; n is an integer of 0 to 5; x is C, N, O or S; y ═ C or N; z ═ H, OH, halogen, or ester group. The compound has a certain cytotoxic effect in vitro, can obviously inhibit the stem cell balling of breast cancer, inhibit the clone formation of tumor cells and inhibit the migration and invasion of the tumor cells; can obviously inhibit the lung metastasis of breast cancer, the growth of breast tumor and non-small cell lung cancer tumor in vivo, has good safety, and does not cause the abnormality of animal body weight, hemogram and various major organs.
The prior art also discloses a synthetic route for preparing (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate by using Cbz-serine as a starting material, which comprises the following specific steps:
the preparation method needs 8 reaction processes, comprises two Cbz protected amino removing processes, and uses palladium carbon as a catalyst in the Cbz protected amino removing process, so that the palladium carbon is expensive, the production cost is increased, and the industrial production is not facilitated.
Because piperazine derivatives have wide application in aspects of depression resistance, inflammation diminishing, pain relieving, tumor resistance and the like, the development of a preparation method with easily available raw materials, simple process route and low production cost to realize high-purity preparation of piperazine compounds is a problem to be solved in the field.
Disclosure of Invention
Aiming at the defects in the prior art, the invention aims to provide a preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate, wherein the preparation method takes chiral Boc-D-alanine and chiral L-serine methyl ester hydrochloride as starting raw materials and obtains a target product with high yield through condensation reaction, deamination protection reaction, ring closing reaction, reduction reaction, amino protection reaction, oxidation reaction, ring closing reaction and ring opening reaction; the preparation method has the advantages of easily available raw materials and mild reaction conditions, and is suitable for industrial production.
In order to achieve the purpose, the invention adopts the following technical scheme:
the invention provides a preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate, which comprises the following steps:
(1) carrying out condensation reaction on Boc-D-alanine and L-serine methyl ester hydrochloride to obtain a compound shown in a formula I, wherein the reaction formula is as follows:
(2) carrying out deprotection reaction on the compound shown in the formula I obtained in the step (1) and a deprotection agent, and carrying out ring closing reaction on a generated product to obtain a compound shown in a formula II, wherein the reaction formula is as follows:
(3) and (3) carrying out reduction reaction on the compound shown in the formula II obtained in the step (2), and reacting the generated product with hydrochloric acid to obtain a compound shown in a formula III, wherein the reaction formula is as follows:
(4) reacting the compound shown in the formula III obtained in the step (3) with an acid binding agent, and carrying out amino protection reaction on the generated product and a Boc amino protective agent to obtain a compound shown in a formula IV, wherein the reaction formula is as follows:
(5) carrying out oxidation reaction on the compound shown in the formula IV obtained in the step (4) to obtain a compound shown in a formula V, wherein the reaction formula is as follows:
(6) carrying out a ring closing reaction on the compound shown in the formula V obtained in the step (5) to obtain a compound shown in a formula VI, wherein the reaction formula is as follows:
(7) carrying out ring-opening reaction on the compound shown in the formula VI obtained in the step (6) to obtain the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate;
the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate is (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate, and the preparation method comprises the steps of taking chiral Boc-D-alanine and chiral L-serine methyl ester hydrochloride as initial raw materials, and carrying out condensation reaction, deamination protection reaction, ring closing reaction, reduction reaction, amino protection reaction, oxidation reaction, ring closing reaction and ring opening reaction to obtain a target product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate. The invention uses Boc amino protective agent to protect amino, reduces production cost, has easily obtained raw materials and mild reaction conditions, and can be applied to large-scale industrial production.
As a preferred embodiment of the present invention, the condensation reaction in the step (1) is carried out in the presence of a condensing agent and an acid-binding agent.
Preferably, the mole ratio of Boc-D-alanine to L-serine methyl ester hydrochloride is (0.8-1.2): 1, and may be, for example, 0.8:1, 0.85:1, 0.9:1, 0.95:1, 1:1, 1.05:1, 1.1:1, 1.15:1, or 1.2: 1.
Preferably, the condensing agent is selected from any one or a combination of at least two of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate.
Preferably, the molar ratio of the condensing agent to Boc-D-alanine is 1 (1 to 1.2), and may be, for example, 1:1, 1:1.02, 1:1.04, 1:1.06, 1:1.08, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, or 1: 1.2.
Preferably, the acid scavenger is selected from any one or a combination of at least two of triethylamine, N-methylmorpholine or diisopropylethylamine.
Preferably, the molar ratio of the acid-binding agent to Boc-D-alanine is 1 (1.1-1.3), and may be, for example, 1:1.1, 1:1.12, 1:1.14, 1:1.16, 1:1.18, 1:1.2, 1:1.22, 1:1.24, 1:1.26, 1:1.28, or 1: 1.3.
Preferably, the condensation reaction in step (1) is carried out at a temperature of 23 to 28 ℃, for example, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃ or 28 ℃.
Preferably, the condensation reaction time in step (1) is 9-11 h, for example, 9h, 9.2h, 9.4h, 9.6h, 9.8h, 10h, 10.2h, 10.4h, 10.6h, 10.8h, or 11h, etc.
Preferably, the condensation reaction of step (1) is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
Preferably, the condensation reaction in the step (1) further comprises the mixing of Boc-D-alanine, L-serine methyl ester hydrochloride, a condensing agent, an acid-binding agent and an organic solvent before the condensation reaction.
Preferably, the mixing temperature is-5 to 5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃.
Preferably, the mixing time is 5-15 min, for example, 5min, 6min, 7min, 8min, 9min, 10min, 11min, 12min, 13min, 14min or 15 min.
Preferably, the condensation reaction in step (1) further comprises a post-treatment step after completion.
Preferably, the method of post-processing comprises: extracting, washing, drying and concentrating to obtain the compound shown in the formula I.
As a preferred embodiment of the present invention, the deprotecting agent in step (2) is selected from trifluoroacetic acid, HCl or H2SO4Any one or a combination of at least two of them.
Preferably, the mass ratio of the deprotection agent to the compound represented by the formula I in the step (2) is (8-10.5):1, and for example, may be 8:1, 8.5:1, 9:1, 9.5:1, 10:1 or 10.5: 1.
Preferably, the addition temperature of the deprotection agent in the step (2) is-5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃ and the like.
Preferably, the deprotection reaction temperature is 23 ~ 28 ℃, for example can be 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃ or 28 ℃.
Preferably, the deprotection reaction time is 3-5 h; for example, it may be 3h, 3.2h, 3.4h, 3.6h, 3.8h, 4h, 4.2h, 4.4h, 4.6h, 4.8h, 3h, or the like.
Preferably, the deprotection reaction is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
Preferably, the deprotection reaction is followed by a step of removing the organic solvent.
Preferably, the ring closure reaction in step (2) is carried out in the presence of a basic substance.
Preferably, the alkaline substance is selected from any one of potassium carbonate, sodium carbonate or cesium carbonate or a combination of at least two thereof.
Preferably, the mass ratio of the basic substance to the compound represented by formula I is (0.8-1.1):1, and may be, for example, 0.8:1, 0.83:1, 0.85:1, 0.88:1, 0.92:1, 0.95:1, 0.98:1, 1:1, 1.02:1, 1.05:1, 1.07:1, or 1.1:1, etc.
Preferably, the temperature of the ring closure reaction in step (2) is 55 to 75 ℃, and may be, for example, 55 ℃, 57 ℃, 59 ℃, 61 ℃, 63 ℃, 65 ℃, 67 ℃, 69 ℃, 71 ℃, 73 ℃, or 75 ℃.
Preferably, the time of the ring closure reaction in the step (2) is 3 to 5 hours, for example, 3 hours, 3.2 hours, 3.4 hours, 3.6 hours, 3.8 hours, 4 hours, 4.2 hours, 4.4 hours, 4.6 hours, 4.8 hours or 3 hours, etc.
Preferably, the ring closure reaction of step (2) is carried out in the presence of a solvent.
Preferably, the solvent is selected from any one of methanol, ethanol or acetonitrile or a combination of at least two thereof.
Preferably, the step (2) further comprises a post-treatment step after the ring closing reaction is completed.
Preferably, the method of post-processing comprises: concentrating, filtering, pulping, filtering, and drying to obtain the compound shown in formula II.
As a preferred embodiment of the present invention, the reduction reaction in the step (3) is carried out in the presence of a reducing agent.
Preferably, the reducing agent is selected from any one or a combination of at least two of borane tetrahydrofuran, borane dimethylsulfide, lithium aluminum hydride or red aluminum.
Preferably, the molar ratio of the reducing agent to the compound represented by formula II is (5-7: 1), and may be, for example, 5:1, 5.2:1, 5.4:1, 5.6:1, 5.8:1, 6:1, 6.2:1, 6.4:1, 6.6:1, 6.8:1, or 7: 1.
Preferably, the reducing agent is added at a temperature of-5 to 5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃.
Preferably, the temperature of the reduction reaction is 35-45 ℃, for example, 35 ℃, 36 ℃, 37 ℃, 38 ℃, 39 ℃, 40 ℃, 41 ℃, 42 ℃, 43 ℃, 44 ℃ or 45 ℃.
Preferably, the time of the reduction reaction is 3 to 5 hours, for example, 3 hours, 3.2 hours, 3.4 hours, 3.6 hours, 3.8 hours, 4 hours, 4.2 hours, 4.4 hours, 4.6 hours, 4.8 hours, or 3 hours.
Preferably, the reduction reaction is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
Preferably, step (3) further comprises mixing the compound represented by formula II with a reducing agent before the reduction reaction.
Preferably, the mixing temperature is 23-28 ℃, for example, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃ or 28 ℃.
Preferably, the mixing time is 4-6 h, for example, 4h, 4.2h, 4.4h, 4.6h, 4.8h, 5h, 5.2h, 5.4h, 5.6h, 5.8h or 6 h.
Preferably, the molar ratio of the hydrochloric acid to the compound of formula II in step (3) is (9-11):1, and may be, for example, 9:1, 9.2:1, 9.4:1, 9.6:1, 9.8:1, 10:1, 10.2:1, 10.4:1, 10.6:1, 10.8:1, or 11: 1.
Preferably, the gram-equivalent concentration of the hydrochloric acid in the step (3) is 4-6N, and may be, for example, 4N, 4.2N, 4.4N, 4.6N, 4.8N, 5N, 5.2N, 5.4N, 5.6N, 5.8N, or 6N.
Preferably, the hydrochloric acid in the step (3) is added at a temperature of-5 to 5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃.
Preferably, the reaction temperature of the product of step (3) and hydrochloric acid is 35-45 deg.C, such as 35 deg.C, 36 deg.C, 37 deg.C, 38 deg.C, 39 deg.C, 40 deg.C, 41 deg.C, 42 deg.C, 43 deg.C, 44 deg.C or 45 deg.C.
Preferably, the reaction time of the product in the step (3) and hydrochloric acid is 1.5-2.5 h, for example, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h or 2.5h, etc.
Preferably, the product of the step (3) is reacted with hydrochloric acid, and then a post-treatment step is included.
Preferably, the method of post-processing comprises: and (3) cooling, filtering, washing and drying the system after the reaction of the product and hydrochloric acid is finished to obtain the compound shown in the formula III.
As a preferable technical scheme of the invention, the acid-binding agent in the step (4) is selected from any one or a combination of at least two of triethylamine, diisopropylethylamine or N-methylmorpholine.
Preferably, the molar ratio of the acid-binding agent in the step (4) to the compound represented by the formula III is 1 (0.3-0.5), and may be, for example, 1:0.3, 1:0.32, 1:0.34, 1:0.36, 1:0.38, 1:0.4, 1:0.42, 1:0.44, 1:0.46, 1:0.48, or 1: 0.5.
Preferably, the temperature of the reaction between the acid-binding agent in step (4) and the compound represented by formula III is-5 to 5 ℃, and may be, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃.
Preferably, the acid-binding agent in the step (4) reacts with the compound represented by the formula III for 20-40 min, for example, 20min, 22min, 24min, 26min, 28min, 30min, 32min, 34min, 36min, 38min or 40 min.
Preferably, the reaction of the acid-binding agent in the step (4) and the compound shown in the formula III is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
Preferably, the mole ratio of the Boc amino protecting agent to the compound represented by formula III in step (4) is (2.1-3.1: 1, and may be, for example, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1, or 3.1: 1.
Preferably, the temperature of the amino protection reaction is 23 to 28 ℃, and may be 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃ or 28 ℃ for example.
Preferably, the time of the amino protection reaction is 11 to 13 hours, and may be, for example, 11 hours, 11.2 hours, 11.4 hours, 11.6 hours, 11.8 hours, 12 hours, 12.2 hours, 12.4 hours, 12.6 hours, 12.8 hours, or 13 hours.
Preferably, the amino protection reaction also comprises a post-treatment step after the completion.
Preferably, the method of post-processing comprises: washing, concentrating, pulping, filtering and drying to obtain the compound shown in the formula IV.
As a preferred technical scheme of the invention, the oxidant of the oxidation reaction in the step (5) is a TEMPO co-oxidation system, and the TEMPO co-oxidation system comprises a combination of TEMPO, alkali metal bromide salt and sodium hypochlorite.
Preferably, the oxidizing agent is an oxidizing agent solution.
Preferably, the solvent of the oxidant solution is deionized water.
Preferably, the molar ratio of TEMPO, alkali metal bromide salt and sodium hypochlorite is 1 (10-40): (190-300), and may be, for example, 1:10:190, 1:12:200, 1:15:210, 1:18:220, 1:20:230, 1:22:240, 1:25:190, 1:28:250, 1:30:260, 1:32:270, 1:35:280, 1:37:290 or 1:40: 300.
Preferably, the molar ratio of the oxidizing agent to the compound represented by formula IV is (2.1-3.4): 1, and may be, for example, 2.1:1, 2.2:1, 2.3:1, 2.4:1, 2.5:1, 2.6:1, 2.7:1, 2.8:1, 2.9:1, 3:1, 3.1:1, 3.2:1, 3.3:1, or 3.4: 1.
Preferably, the oxidation reaction is carried out in the presence of a basic substance.
Preferably, the alkaline substance is selected from potassium bicarbonate and/or sodium bicarbonate.
Preferably, the molar ratio of the basic substance to the compound represented by formula IV is (1.5-2.5):1, and may be, for example, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, or 2.5: 1.
Preferably, the oxidation reaction is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
As a preferred technical scheme of the invention, the oxidation reaction in the step (5) comprises a first reaction stage and a second reaction stage.
Preferably, the temperature of the first reaction stage is-5 to 5 ℃, and may be, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃.
Preferably, the time of the first reaction stage is 1.5 to 2.5 hours, and may be, for example, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, 2:1, 2.1:1, 2.2:1, 2.3:1, 2.4:1, or 2.5: 1.
Preferably, the temperature of the second reaction stage is 23 to 28 ℃, and may be 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃ or 28 ℃ for example.
Preferably, the temperature of the second reaction stage is 11-13 h, for example, 11h, 11.2h, 11.4h, 11.6h, 11.8h, 12h, 12.2h, 12.4h, 12.6h, 12.8h or 13h, etc.
Preferably, the oxidation reaction in the step (5) is completed and then a post-treatment step is included.
Preferably, the method of post-processing comprises: and adding a reducing solution into the system after the oxidation reaction, mixing, separating, reserving an organic phase, concentrating and drying to obtain the compound shown in the formula V.
As a preferred embodiment of the present invention, the ring-closing reaction in step (6) is carried out in the presence of a chlorinating agent.
Preferably, the chlorinating agent is selected from any one of oxalyl chloride, phosphorus trichloride, thionyl chloride or phosphorus pentachloride or a combination of at least two of them.
Preferably, the molar ratio of the chlorinating reagent to the compound represented by formula V is (1.1-1.3):1, and may be, for example, 1.1:1, 1.12:1, 1.14:1, 1.16:1, 1.18:1, 1.2:1, 1.22:1, 1.24:1, 1.26:1, 1.28:1, or 1.3: 1.
Preferably, the temperature of the chlorination reagent is-5 to 5 ℃, for example, -5 ℃, -4 ℃, -3 ℃, -2 ℃, -1 ℃, 0 ℃, 1 ℃, 2 ℃,3 ℃,4 ℃ or 5 ℃.
Preferably, the temperature of the ring closure reaction in the step (6) is 23-28 ℃, for example, 23 ℃, 24 ℃, 25 ℃, 26 ℃, 27 ℃ or 28 ℃.
Preferably, the time of the ring closure reaction in the step (6) is 1.5-2.5 h, for example, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h or 2.5h, etc.
Preferably, the ring closure reaction of step (6) is carried out in the presence of an organic solvent.
Preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
Preferably, the step (6) further comprises a post-treatment step after the ring closing reaction is completed.
Preferably, the method of post-processing comprises: concentrating, pulping, filtering, and drying to obtain the compound shown in formula VI.
As a preferred embodiment of the present invention, the ring-opening reaction in step (7) is carried out in the presence of methanol.
Preferably, the mass ratio of the methanol to the compound represented by the formula VI is (9-11: 1), and may be, for example, 9:1, 9.2:1, 9.4:1, 9.6:1, 9.8:1, 10:1, 10.2:1, 10.4:1, 10.6:1, 10.8:1 or 11: 1.
Preferably, the ring-opening reaction temperature is 55 ~ 75 ℃, for example can be 55 ℃, 57 ℃, 59 ℃, 61 ℃, 63 ℃, 65 ℃, 67 ℃, 69 ℃, 71 ℃, 73 ℃ or 75 ℃.
Preferably, the ring-opening reaction time is 4-6 h, for example, 4h, 4.2h, 4.4h, 4.6h, 4.8h, 5h, 5.2h, 5.4h, 5.6h, 5.8h or 6 h.
Preferably, the ring-opening reaction also comprises a post-treatment step after the ring-opening reaction is completed.
Preferably, the method of post-processing comprises: concentrating, washing and drying to obtain the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) mixing Boc-D-alanine, L-serine methyl ester hydrochloride, a condensing agent, an acid-binding agent and an organic solvent at the temperature of-5 ℃ for 5-15 min, heating to 23-28 ℃ and reacting for 9-11 h to obtain a compound
The mole ratio of the Boc-D-alanine to the L-serine methyl ester hydrochloride is (0.8-1.2) 1, the mole ratio of the condensing agent to the Boc-D-alanine is 1 (0.8-1.2), and the mole ratio of the acid-binding agent to the Boc-D-alanine is 1 (0.8-1.2);
(2) the compound obtained in the step (1) is
Mixing with an organic solvent, dropwise adding a deprotection agent at-5 ℃, heating to 23-28 ℃ after dropwise adding, reacting for 3-5 h, adding a solvent and an alkaline substance after desolventizing, and reacting for 3-5 h at 55-75 ℃ to obtain a compound
The deprotecting agents and compounds
The mass ratio of the basic substance to the compound is (7.5-11): 1
The mass ratio of (1) to (1-1.2);
(3) the compound obtained in the step (2)
Mixing with an organic solvent, dropwise adding a reducing agent into the mixture at the temperature of-5 ℃, heating to 23-28 ℃ after dropwise adding, mixing for 4-6 h, heating to 35-45 ℃ for reaction for 3-5 h, cooling to-5 ℃, dropwise adding hydrochloric acid into the mixture, heating to 35-45 ℃ after dropwise adding, and reacting for 1.5-2.5 h to obtain a compound
(ii) a The reducing agents and compounds
In a molar ratio of (5-7) to 1, said hydrochloric acid and compound
The molar ratio of (9-11) to (1);
(4) the compound obtained in the step (3)
Mixing an acid-binding agent and an organic solvent, reacting for 20-40 min at-5 ℃, dropwise adding a Boc amino protective agent, heating to 23-28 ℃ after dropwise adding, and reacting for 11-13 h to obtain a compound
(ii) a The acid-binding agent and the compound
The mole ratio of the Boc amino protective agent to the compound is 1 (0.3-0.5)
The molar ratio of (2.1-3.1) to (1);
(5) the compound obtained in the step (4) is
Mixing an oxidant, an alkaline substance and an organic solvent, reacting for 1.5-2.5 h at-5 ℃, heating to 23-28 ℃, and reacting for 11-13 h to obtain a compound
(ii) a Said oxidizing agents and compounds
The molar ratio of the basic substance to the compound is (2.1-3.4): 1
The molar ratio of (1.5-2.5) to (1);
(6) the compound obtained in the step (5)
Mixing with an organic solvent, dropwise adding a chlorinating agent at-5 ℃, heating to 23-28 ℃ after dropwise adding, and reacting for 1.5-2.5 h to obtain a compound
(ii) a The chlorinating agents and compounds
The molar ratio of (1.1-1.3) to 1;
(7) the compound obtained in the step (6)
Mixing the mixture with methanol, and reacting for 4-6 h at the temperature of 55-75 ℃ to obtain the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate
(ii) a The methanol and the compound
The mass ratio is (9-11) to 1; the process route of the reaction is as follows:
compared with the prior art, the invention has at least the following beneficial effects:
the preparation method provided by the invention takes chiral Boc-D-alanine and chiral L-serine methyl ester hydrochloride as initial raw materials, and obtains the target product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate through condensation reaction, deamination protection reaction, ring closure reaction, reduction reaction, amino protection reaction, oxidation reaction, ring closure reaction and ring opening reaction, and in the process of preparing the target product, the yield of each step is higher and is more than or equal to 88%. The invention uses Boc amino protective agent to protect amino, reduces production cost, has easily obtained raw material and mild reaction condition, and can be applied to large-scale industrial production.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitations of the present invention.
Example 1
The embodiment provides a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate, which specifically includes the following steps:
(1)
adding Boc-D-alanine (183.5g, 0.97mol) into 2.5L dichloromethane, dropwise adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (205g, 1.07mol) under ice bath, stirring for 10min, further dropwise adding L-serine methyl ester hydrochloride (158.7g, 1.02mol) and triethylamine (161mL, 1.16mol), naturally heating to room temperature, and reacting for 10 h; towards the reactionAdding 3L of pure water into the system, standing, separating to obtain an organic phase and an aqueous phase, extracting the aqueous phase with 1L of dichloromethane for 1 time, combining the organic phases, washing with 1N hydrochloric acid, saturated sodium bicarbonate, pure water and saturated salt solution in sequence, drying with anhydrous sodium sulfate, and concentrating to obtain 253g of product
The yield thereof was found to be 90%.
And (3) detecting a product:1H-NMR(CDCl3，400MHz)：δ7.17(d,1H),5.18(br,1H),4.64-4.61(m,1H),4.18-4.15(m,1H),3.96(br,2H),3.76(s,3H),1.44(s,9H),1.39(d,3H)。
(2)
dissolving the product (250g, 0.86mol) obtained in the step (1) in 1.5L of dichloromethane, dropwise adding 1.5L of trifluoroacetic acid under ice bath, naturally heating to room temperature, and reacting for 4 h; after the raw material disappeared by detection of Thin Layer Chromatography (TLC), desolventizing under reduced pressure, adding 2L of methanol and potassium carbonate (237g, 1.72mol), stirring at room temperature for 30min, and then heating under reflux for 4 h; concentrating, adding 3L pure water under stirring, filtering, pulping the filter cake with petroleum ether, filtering, and oven drying to obtain 129g product
The yield thereof was found to be 95%.
And (3) detecting a product:1H-NMR(CDCl3，400M)：δ1.25(d,3H).3.54(m,1H),3.70(m,1H),3.76(m,1H),3.94(m,1H),5.11(t,1H),7.90(s,1H),8.10(s,1H)。
(3)
adding the product (120g, 0.76mol) obtained in the step (2) into 2L of dichloromethane, dropwise adding 4.56L of borane tetrahydrofuran with the substance amount concentration of 1M under ice bath, naturally heating to room temperature, stirring for 5h, and heating and refluxing for 4 h; cooling to 0 ℃, and dropwise adding salt with gram equivalent concentration of 5N into the reaction system1.5L of acid, and heating and refluxing for 2 h; cooling to 0 ℃, stirring for 2h, filtering, washing a filter cake with tetrahydrofuran, and drying to obtain 139g of a product
The yield thereof was found to be 90%.
And (3) detecting a product:1H-NMR(DMSO-D6，400M)：δ1.33(d,3H),3.12(m,2H),3.39-3.78(m,6H),5.62(s,1H)，10.03(brs,4H)。
(4
adding the product (130g, 0.64mol) obtained in the step (3) into 2.5L dichloromethane, adding triethylamine (222mL, 1.6mol) under ice bath, and reacting for 30 min; dropwise adding Boc anhydride (293g, 1.34mol) into the reaction system, and reacting for 12h at room temperature; washing with 300mL pure water for 2 times, washing with 400mL hydrochloric acid with gram equivalent concentration of 1N for 2 times, washing with 200mL pure water for 2 times, washing with saturated saline solution for 1 time, concentrating to dryness, pulping with 600mL petroleum ether, filtering, and oven drying to obtain 211g product
The yield thereof was found to be 96%.
And (3) detecting a product:1H-NMR(CDCl3，400M)：δ1.22(d,3H),1.50(s,18H),3.10-3.30(m,2H),3.42-3.73(m,3H),3.80-4.02(m,1H),4.03-4.24(m,1H),4.25-4.43(m,1H)。
(5)
adding the product (209g, 0.63mol) obtained in the step (4) into 2L dichloromethane, adding 2.5L pure water in an ice bath, dissolving potassium bromide (15g, 0.126mol), TEMPO (2g, 0.0126mol) and potassium bicarbonate (126g, 1.26mol) in 1L water, dropwise adding into a reaction system, stirring for 20min, adding 880mL of sodium hypochlorite solution with the mass concentration of 10%, after dropwise adding, keeping an ice bath for 2h, naturally heating to room temperature, and reacting overnight; dropwise adding 10% sodium thiosulfate solution 1L, and stirringStanding for 30min, separating, adjusting pH of water phase to 1-2 with hydrochloric acid with gram equivalent concentration of 1N, extracting with 800mL dichloromethane twice, combining organic phases, drying, and concentrating to obtain 184g product
The yield thereof was found to be 90%.
And (3) detecting a product:1H-NMR(CDCl3，400M)：δ1.23(d,3H),1.50(s,18H),3.16-3.37(m,2H),3.45-3.84(m,2H),4.09-4.28(m,1H),4.78-4.89(m,1H)。
(6)
adding the product (180g, 0.52mol) obtained in the step (5) into 2L dichloromethane, dropwise adding oxalyl chloride (55mL, 0.65mol) at 0 ℃, naturally heating to room temperature, and reacting for 2 h; concentrating under reduced pressure, pulping residue with n-hexane, filtering, and vacuum drying to obtain 126g product
The yield thereof was found to be 90%.
(7)
Adding the product (120g, 0.44mol) obtained in the step (6) into 1.5L of methanol, and heating and refluxing for 5 h; concentrating, dissolving the residue in dichloromethane, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and vacuum drying to obtain 106g of the desired product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate
The yield thereof was found to be 93%.
Detecting a target product:1H NMR(DMSO-D6，400MHz)：δ1.14(d,3H),1.39(s,9H),2.46(dd,1H),2.68(s,1H),2.95(dd,1H),3.17(dd,1H),3.58(d,1H),3.66(s,3H),3.98-4.10(m,1H),4.11-4.18(m,1H)。
example 2
The embodiment provides a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate, which specifically includes the following steps:
(1)
adding Boc-D-alanine (189g, 1mol) into 2.5L dichloroethane, dropwise adding dicyclohexylcarbodiimide (206g, 1mol) under ice bath, stirring for 5min, further dropwise adding L-serine methyl ester hydrochloride (176.8g, 1.14mol) and N-methylmorpholine (148mL, 1.7mol), naturally heating to room temperature, and reacting for 9.5 h; adding 3L of pure water into the reaction system, standing, separating liquid to obtain an organic phase and an aqueous phase, extracting the aqueous phase for 1 time by using 1L of dichloroethane, combining the organic phases, washing the organic phases by sequentially using 1N hydrochloric acid, saturated sodium bicarbonate, pure water and saturated salt solution, drying the organic phases by using anhydrous sodium sulfate, and concentrating to obtain 258g of a product
The yield thereof was found to be 89%.
(2)
Adding the product (255g, 0.88mol) obtained in the step (1) into 1.5L of dichloroethane, dropwise adding 11.5L of hydrochloric acid solution with the substance amount concentration of 5M under ice bath, naturally heating to room temperature, and reacting for 4.5 h; after the raw material disappears by Thin Layer Chromatography (TLC), performing desolventizing under reduced pressure, adding 2L ethanol and sodium carbonate (128.26g, 1.21mol), stirring at room temperature for 30min, and heating and refluxing for 3 h; concentrating, adding 3L pure water under stirring, filtering, pulping the filter cake with petroleum ether, filtering, and oven drying to obtain 130.8g product
The yield thereof was found to be 94%.
(3)
Obtained in the step (2)Adding the product (125g, 0.79mol) into 2L of dichloroethane, dropwise adding 4.34L of borane dimethyl sulfide with the substance amount concentration of 1M under ice bath, naturally heating to room temperature, stirring for 4h, and heating and refluxing for 4.5 h; cooling to 0 ℃, dropwise adding 1.5L of hydrochloric acid with the gram-equivalent concentration of 4N into the reaction system, and heating and refluxing for 1.8 h; cooling to 0 ℃, stirring for 2h, filtering, washing a filter cake with tetrahydrofuran, and drying to obtain 147.5g of a product
The yield thereof was found to be 92%.
(4)
Adding the product (124g, 0.61mol) obtained in the step (3) into 2.5L dichloroethane, adding N-methylmorpholine (187.3mL, 1.35mol) under ice bath, and reacting for 20 min; dropwise adding Boc anhydride (373.3g, 1.708mol) into the reaction system, and reacting for 11h at room temperature; washing with 300mL pure water for 2 times, washing with 400mL hydrochloric acid with gram equivalent concentration of 1N for 2 times, washing with 200mL pure water for 2 times, washing with saturated saline solution for 1 time, concentrating to dryness, pulping with 600mL petroleum ether, filtering, and oven drying to obtain 194.4g product
The yield thereof was found to be 95%.
(5)
Adding the product (210g and 0.64mol) obtained in the step (4) into 2L of dichloroethane, adding 2.5L of pure water in an ice bath, dissolving potassium bromide (15g and 0.126mol), TEMPO (2g and 0.0126mol) and sodium bicarbonate (91.6g and 1.09mol) in 1L of water, dropwise adding the solution into a reaction system, stirring for 20min, adding 880mL of sodium hypochlorite solution with the mass concentration of 10%, keeping the ice bath for 2h after dropwise adding is finished, naturally heating to room temperature, and reacting overnight; dropwise adding 10% sodium thiosulfate solution 1L, stirring for 30min, standing, separating, adjusting pH of water phase to 1-2 with 1N hydrochloric acid, extracting with 800mL dichloroethane twiceThe organic phases are combined, dried and concentrated to give 194g of product
The yield thereof was found to be 88%.
(6)
Adding the product (178g, 0.517mol) obtained in the step (5) into 2L dichloroethane, dropwise adding phosphorus trichloride (60mL, 0.57mol) at 0 ℃, naturally heating to room temperature, and reacting for 1.5 h; concentrating under reduced pressure, pulping residue with n-hexane, filtering, and vacuum drying to obtain 127g product
The yield thereof was found to be 91%.
(7)
Adding the product (117g, 0.43mol) obtained in the step (6) into 1.33L of methanol, and heating and refluxing for 4 h; concentrating, dissolving the residue in dichloroethane, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and vacuum drying to obtain 102g of the desired product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate
The yield thereof was found to be 92%.
Example 3
The embodiment provides a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate, which specifically includes the following steps:
(1)
Boc-D-alanine (200g, 1.06mol) was added to 2.5L of chloroform, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate (334.6g, 0.88mol) was added dropwise under ice bath, stirred for 15min, and added dropwiseL-serine methyl ester hydrochloride (206g, 1.33mol) and diisopropylethylamine (162.4mL, 1.17mol) are naturally heated to room temperature and reacted for 10.5 h; adding 3L of pure water into the reaction system, standing, separating to obtain an organic phase and an aqueous phase, extracting the aqueous phase for 1 time by using 1L of trichloromethane, combining the organic phases, washing the organic phases by using 1N hydrochloric acid, saturated sodium bicarbonate, pure water and saturated salt solution in sequence, drying the organic phases by using anhydrous sodium sulfate, and concentrating to obtain 280g of a product
The yield thereof was found to be 91%.
(2)
Adding the product (245g, 0.84mol) obtained in the step (1) into 1.5L of trichloromethane, dropwise adding 7.2L of sulfuric acid solution with the substance amount concentration of 3M under ice bath, naturally heating to room temperature, and reacting for 5 h; after the raw material disappeared by detection of Thin Layer Chromatography (TLC), desolventizing under reduced pressure, adding 2L of acetonitrile and cesium carbonate (606g, 1.86mol), stirring at room temperature for 30min, and then heating under reflux for 3.5 h; concentrating, adding 3L pure water under stirring, filtering, pulping the filter cake with petroleum ether, filtering, and oven drying to obtain 127.5g product
The yield thereof was found to be 96%.
(3)
Adding the product (128g, 0.81mol) obtained in the step (2) into 2L of trichloromethane, dropwise adding 4.05L of 1M lithium aluminum hydride under ice bath, naturally heating to room temperature, stirring for 4.5h, and heating and refluxing for 3 h; cooling to 0 ℃, dropwise adding 1.5L of hydrochloric acid with gram-equivalent concentration of 4.5N into the reaction system, and heating and refluxing for 1.5 h; cooling to 0 ℃, stirring for 2h, filtering, washing a filter cake with tetrahydrofuran, and drying to obtain 146.3g of a product
The yield thereof was found to be 89%.
(4)
Adding the product (128g and 0.63mol) obtained in the step (3) into 2.5L of trichloromethane, adding diisopropylethylamine (174mL and 1.26mol) under ice bath, and reacting for 25 min; boc anhydride (426.9g, 1.95mol) is added into the reaction system dropwise and reacted for 11.5h at room temperature; washing with 300mL pure water for 2 times, washing with 400mL hydrochloric acid with gram equivalent concentration of 1N for 2 times, washing with 200mL pure water for 2 times, washing with saturated saline solution for 1 time, concentrating to dryness, pulping with 600mL petroleum ether, filtering, and oven drying to obtain 202g product
The yield thereof was found to be 97%.
(5)
Adding the product (200g, 0.61mol) obtained in the step (4) into 2L of trichloromethane, adding 2.5L of pure water in an ice bath, dissolving potassium bromide (15g, 0.126mol), TEMPO (2g, 0.0126mol) and potassium bicarbonate (133g, 1.33mol) in 1L of water, dropwise adding the solution into a reaction system, stirring for 20min, adding 880mL of sodium hypochlorite solution with the mass concentration of 10%, keeping an ice bath for 2h after dropwise adding, naturally heating to room temperature, and reacting overnight; dropwise adding 10% sodium thiosulfate solution 1L, stirring for 30min, standing, separating, adjusting pH of water phase to 1-2 with 1N hydrochloric acid, extracting with 800mL chloroform twice, mixing organic phases, drying, and concentrating to obtain 186.8g product
The yield thereof was found to be 89%.
(6)
The product obtained in step (5) (185g, 0.54mol) was added to 2L of trichloromethylAdding thionyl chloride (58mL, 0.62mol) dropwise into the alkane at 0 ℃, naturally heating to room temperature, and reacting for 1.8 h; concentrating under reduced pressure, pulping residue with n-hexane, filtering, and vacuum drying to obtain 129.8g product
The yield thereof was found to be 89%.
(7)
Adding the product (124g, 0.46mol) obtained in the step (6) into 1.57L of methanol, and heating and refluxing for 6 h; concentrating, dissolving the residue in dichloromethane, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and vacuum drying to obtain 111.6g of the desired product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate
The yield thereof was found to be 94%.
Example 4
The embodiment provides a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate, which specifically includes the following steps:
(1)
adding Boc-D-alanine (180g, 0.95mol) into 2.5L dichloromethane, dropwise adding benzotriazole-1-yl-oxy tripyrrolidinophosphonium hexafluorophosphate (468.3g, 0.9mol) under ice bath, stirring for 12min, further dropwise adding L-serine methyl ester hydrochloride (133.8g, 0.86mol) and triethylamine (176.3mL, 1.27mol), naturally heating to room temperature, and reacting for 9 h; adding 3L of pure water into the reaction system, standing, separating to obtain an organic phase and an aqueous phase, extracting the aqueous phase for 1 time by using 1L of dichloromethane, combining the organic phases, washing the organic phases by sequentially using 1N hydrochloric acid, saturated sodium bicarbonate, pure water and saturated common salt solution, drying the organic phases by using anhydrous sodium sulfate, and concentrating to obtain 242.7g of a product
The yield thereof was found to be 88%.
(2)
Adding the product (240g, 0.83mol) obtained in the step (1) into 1.5L of dichloromethane, dropwise adding 1.57L of trifluoroacetic acid under ice bath, naturally heating to room temperature, and reacting for 3.5 h; after the raw material disappeared by detection of Thin Layer Chromatography (TLC), desolventizing under reduced pressure, adding 2L of methanol and potassium carbonate (192g, 1.39mol), stirring at room temperature for 30min, and then heating under reflux for 4.5 h; concentrating, adding 3L pure water under stirring, filtering, pulping the filter cake with petroleum ether, filtering, and oven drying to obtain 122g product
The yield thereof was found to be 93%.
(3)
Adding the product (122g, 0.77mol) obtained in the step (2) into 2L of dichloromethane, dropwise adding 1.44L of a 3.46M red aluminum toluene solution under ice bath, naturally heating to room temperature, stirring for 5h, and heating and refluxing for 3.5 h; cooling to 0 ℃, dropwise adding 1.5L of hydrochloric acid with the gram-equivalent concentration of 6N into the reaction system, and heating and refluxing for 2.3 h; cooling to 0 ℃, stirring for 2h, filtering, washing a filter cake with tetrahydrofuran, and drying to obtain 142.2g of a product
The yield thereof was found to be 91%.
(4)
Adding the product (132g, 0.65mol) obtained in the step (3) into 2.5L dichloromethane, adding triethylamine (258mL, 1.86mol) under ice bath, and reacting for 35 min; dropwise adding Boc anhydride (354g, 1.63mol) into the reaction system, and reacting for 13h at room temperature; washing with 300mL of pure water 2 times, and washing with 400mL of hydrochloric acid having a gram-equivalent concentration of 1N 2 times200mL of pure water for 2 times, saturated brine for 1 time, concentrating to dryness, pulping with 600mL of petroleum ether, filtering, and drying to obtain 201.6g of product
The yield thereof was found to be 94%.
(5)
Adding the product (205g, 0.62mol) obtained in the step (4) into 2L dichloromethane, adding 2.5L pure water in an ice bath, dissolving potassium bromide (15g, 0.126mol), TEMPO (2g, 0.0126mol) and potassium bicarbonate (155g, 1.55mol) in 1L water, dropwise adding into a reaction system, stirring for 20min, adding 880mL of sodium hypochlorite solution with the mass concentration of 10%, after dropwise adding, keeping an ice bath for 2h, naturally heating to room temperature, and reacting overnight; dropwise adding 10% sodium thiosulfate solution 1L, stirring for 30min, standing, separating, adjusting pH of water phase to 1-2 with 1N hydrochloric acid, extracting with 800mL dichloromethane twice, mixing organic phases, drying, and concentrating to obtain 194.3g product
The yield thereof was found to be 91%.
(6)
Adding the product (174g, 0.51mol) obtained in the step (5) into 2L dichloromethane, dropwise adding phosphorus pentachloride (53mL, 0.66mol) at 0 ℃, naturally heating to room temperature, and reacting for 2.5 h; concentrating under reduced pressure, pulping residue with n-hexane, filtering, and vacuum drying to obtain 126.7g product
The yield thereof was found to be 92%.
(7)
Adding the product (115g, 0.426mol) obtained in the step (6) into 1.52L of methanol, and heating and refluxing for 6 h; concentrating, dissolving the residue in dichloromethane, washing with saturated brine, drying over anhydrous sodium sulfate, concentrating, and vacuum drying to obtain 100g of the desired product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate
The yield thereof was found to be 91%.
Example 5
The embodiment provides a preparation method of (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate, which specifically includes the following steps:
(1)
adding Boc-D-alanine (185g, 0.98mol) into 2.5L dichloromethane, dropwise adding 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide (162.8g, 0.85mol) under ice bath, stirring for 10min, further dropwise adding L-serine methyl ester hydrochloride (127.6g, 0.82mol) and triethylamine (169.3mL, 1.22mol), naturally heating to room temperature, and reacting for 11 h; adding 3L of pure water into the reaction system, standing, separating to obtain an organic phase and an aqueous phase, extracting the aqueous phase for 1 time by using 1L of dichloromethane, combining the organic phases, washing the organic phases by sequentially using 1N hydrochloric acid, saturated sodium bicarbonate, pure water and saturated common salt solution, drying the organic phases by using anhydrous sodium sulfate, and concentrating to obtain 261.7g of a product
The yield thereof was found to be 92%.
(2)
Adding the product (260g, 0.9mol) obtained in the step (1) into 1.5L of dichloromethane, dropwise adding 1.78L of trifluoroacetic acid under ice bath, naturally heating to room temperature, and reacting for 3 h; after disappearance of the starting material as detected by Thin Layer Chromatography (TLC), the mixture was desolventized under reduced pressure, 2L of methanol and potassium carbonate (286g, 2.07mol) were added, and the mixture was stirred at room temperature for 30 minutesmin, then heating and refluxing for 5 h; concentrating, adding 3L pure water under stirring, filtering, pulping the filter cake with petroleum ether, filtering, and oven drying to obtain 135.2g product
The yield thereof was found to be 95%.
(3)
Adding the product (118g, 0.75mol) obtained in the step (2) into 2L of dichloromethane, dropwise adding 4.05L of borane tetrahydrofuran with the substance amount concentration of 1M under ice bath, naturally heating to room temperature, stirring for 5h, and heating and refluxing for 5.5 h; cooling to 0 ℃, dropwise adding 1.5L of hydrochloric acid with gram-equivalent concentration of 5N into the reaction system, and heating and refluxing for 2.5 h; cooling to 0 ℃, stirring for 2.5h, filtering, washing a filter cake with tetrahydrofuran, and drying to obtain 134g of a product
The yield thereof was found to be 88%.
(4)
Adding the product (136g, 0.67mol) obtained in the step (3) into 2.5L dichloromethane, adding triethylamine (291mL, 2.1mol) under ice bath, and reacting for 40 min; dropwise adding Boc anhydride (321g, 1.47mol) into the reaction system, and reacting at room temperature for 13 h; washing with 300mL pure water for 2 times, washing with 400mL hydrochloric acid with gram equivalent concentration of 1N for 2 times, washing with 200mL pure water for 2 times, washing with saturated saline solution for 1 time, concentrating to dryness, pulping with 600mL petroleum ether, filtering, and oven drying to obtain 210g product
The yield thereof was found to be 95%.
(5)
The product obtained in step (4) (208g, 0.63mol) was addedAdding 2.5L of pure water into 2L of dichloromethane in an ice bath, dissolving potassium bromide (15g, 0.126mol), TEMPO (2g, 0.0126mol) and potassium bicarbonate (97.5g, 0.975mol) into 1L of water, dropwise adding the solution into a reaction system, stirring for 20min, adding 880mL of sodium hypochlorite solution with the mass concentration of 10%, keeping an ice bath for 2h after dropwise adding, naturally heating to room temperature, and reacting overnight; dropwise adding 10% sodium thiosulfate solution 1L, stirring for 30min, standing, separating, adjusting pH of water phase to 1-2 with 1N hydrochloric acid, extracting with 800mL dichloromethane twice, mixing organic phases, drying, and concentrating to obtain 199.6g product
The yield thereof was found to be 92%.
(6)
Adding the product (183g, 0.53mol) obtained in the step (5) into 2L dichloromethane, dropwise adding oxalyl chloride (52mL, 0.61mol) at 0 ℃, naturally heating to room temperature, and reacting for 2.5 h; concentrating under reduced pressure, pulping residue with n-hexane, filtering, and vacuum drying to obtain 126g product
The yield thereof was found to be 88%.
(7)
Adding the product (110g, 0.41mol) obtained in the step (6) into 1.53L of methanol, and heating and refluxing for 6 h; concentration, the residue was dissolved in methylene chloride, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated and dried under vacuum to give 100.5g of the aimed product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate
The yield thereof was found to be 95%.
In conclusion, the target product (3R,6R) -1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate is prepared by taking chiral Boc-D-alanine and chiral L-serine methyl ester hydrochloride as starting raw materials through condensation reaction, deamination protection reaction, ring closure reaction, reduction reaction, amino protection reaction, oxidation reaction, ring closure reaction and ring opening reaction, and in the process of preparing the target product, the yield of each step is more than or equal to 88%, the raw materials are easy to obtain, the reaction conditions are mild, and the method can be applied to large-scale industrial production.
The applicant states that the present invention is illustrated by the above examples to show the detailed process equipment and process flow of the present invention, but the present invention is not limited to the above detailed process equipment and process flow, i.e. it does not mean that the present invention must rely on the above detailed process equipment and process flow to be implemented. It should be understood by those skilled in the art that any modification of the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
Claims (10)
1. A preparation method of chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-dicarboxylate is characterized by comprising the following steps:
(1) carrying out condensation reaction on Boc-D-alanine and L-serine methyl ester hydrochloride to obtain a compound shown in a formula I, wherein the reaction formula is as follows:
(2) carrying out deprotection reaction on the compound shown in the formula I obtained in the step (1) and a deprotection agent, and carrying out ring closing reaction on a generated product to obtain a compound shown in a formula II, wherein the reaction formula is as follows:
(3) and (3) carrying out reduction reaction on the compound shown in the formula II obtained in the step (2), and reacting the generated product with hydrochloric acid to obtain a compound shown in a formula III, wherein the reaction formula is as follows:
(4) reacting the compound shown in the formula III obtained in the step (3) with an acid binding agent, and carrying out amino protection reaction on the generated product and a Boc amino protective agent to obtain a compound shown in a formula IV, wherein the reaction formula is as follows:
(5) carrying out oxidation reaction on the compound shown in the formula IV obtained in the step (4) to obtain a compound shown in a formula V, wherein the reaction formula is as follows:
(6) carrying out a ring closing reaction on the compound shown in the formula V obtained in the step (5) to obtain a compound shown in a formula VI, wherein the reaction formula is as follows:
(7) carrying out ring-opening reaction on the compound shown in the formula VI obtained in the step (6) to obtain the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate;
2. the process according to claim 1, wherein the condensation reaction of step (1) is carried out in the presence of a condensing agent and an acid-binding agent;
preferably, the mole ratio of the Boc-D-alanine to the L-serine methyl ester hydrochloride is (0.8-1.2): 1;
preferably, the condensing agent is selected from any one or a combination of at least two of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, dicyclohexylcarbodiimide, O-benzotriazole-tetramethylurea hexafluorophosphate, 2- (7-azabenzotriazole) -N, N, N ', N' -tetramethylurea hexafluorophosphate, benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate or benzotriazol-1-yl-oxytripyrrolidinylphosphine hexafluorophosphate;
preferably, the molar ratio of the condensing agent to the Boc-D-alanine is 1 (1-1.2);
preferably, the acid-binding agent is selected from any one or a combination of at least two of triethylamine, N-methylmorpholine or diisopropylethylamine;
preferably, the molar ratio of the acid-binding agent to the Boc-D-alanine is 1 (1.1-1.3);
preferably, the condensation reaction in the step (1) is carried out at the temperature of 23-28 ℃;
preferably, the condensation reaction time in the step (1) is 9-11 h;
preferably, the condensation reaction of step (1) is carried out in the presence of an organic solvent;
preferably, the organic solvent is selected from any one or a combination of at least two of dichloromethane, dichloroethane or chloroform;
preferably, the condensation reaction in the step (1) further comprises the mixing of Boc-D-alanine, L-serine methyl ester hydrochloride, a condensing agent, an acid-binding agent and an organic solvent before the condensation reaction;
preferably, the mixing temperature is-5 ℃;
preferably, the mixing time is 5-15 min;
preferably, the condensation reaction in the step (1) is completed and then a post-treatment step is included;
preferably, the method of post-processing comprises: extracting, washing, drying and concentrating to obtain the compound shown in the formula I.
3. The method according to claim 1 or 2, wherein the deprotecting agent in step (2) is selected from trifluoroacetic acid, HCl or H2SO4Any one or a combination of at least two of;
preferably, the mass ratio of the deprotection agent to the compound shown in the formula I in the step (2) is (8-10.5): 1;
preferably, the adding temperature of the deprotection agent in the step (2) is-5 ℃;
preferably, the temperature of the deprotection reaction is 23-28 ℃;
preferably, the deprotection reaction time is 3-5 h;
preferably, the deprotection reaction is carried out in the presence of an organic solvent;
preferably, the organic solvent is selected from any one or a combination of at least two of dichloromethane, dichloroethane or chloroform;
preferably, the deprotection reaction further comprises a step of removing the organic solvent;
preferably, the ring closure reaction of step (2) is carried out in the presence of a basic substance;
preferably, the alkaline substance is selected from any one or a combination of at least two of potassium carbonate, sodium carbonate or cesium carbonate;
preferably, the mass ratio of the alkaline substance to the compound shown in the formula I is (0.8-1.1): 1;
preferably, the temperature of the ring closing reaction in the step (2) is 55-75 ℃;
preferably, the time of the ring closing reaction in the step (2) is 3-5 h;
preferably, the ring closure reaction of step (2) is carried out in the presence of a solvent;
preferably, the solvent is selected from any one of methanol, ethanol or acetonitrile or a combination of at least two of the above;
preferably, the step (2) further comprises a post-treatment step after the ring closing reaction is completed;
preferably, the method of post-processing comprises: concentrating, filtering, pulping, filtering, and drying to obtain the compound shown in formula II.
4. The production method according to any one of claims 1 to 3, wherein the reduction reaction in step (3) is carried out in the presence of a reducing agent;
preferably, the reducing agent is selected from any one or a combination of at least two of borane tetrahydrofuran, borane dimethylsulfide, lithium aluminum hydride or red aluminum;
preferably, the molar ratio of the reducing agent to the compound shown in the formula II is (5-7): 1;
preferably, the adding temperature of the reducing agent is-5 ℃;
preferably, the temperature of the reduction reaction is 35-45 ℃;
preferably, the time of the reduction reaction is 3-5 h;
preferably, the reduction reaction is carried out in the presence of an organic solvent;
preferably, the organic solvent is selected from any one or a combination of at least two of dichloromethane, dichloroethane or chloroform;
preferably, step (3) further comprises mixing the compound represented by formula II with a reducing agent before the reduction reaction;
preferably, the mixing temperature is 23-28 ℃;
preferably, the mixing time is 4-6 h;
preferably, the molar ratio of the hydrochloric acid to the compound shown in the formula II in the step (3) is (9-11): 1;
preferably, the gram-equivalent concentration of the hydrochloric acid in the step (3) is 4-6N;
preferably, the adding temperature of the hydrochloric acid in the step (3) is-5 ℃;
preferably, the reaction temperature of the product obtained in the step (3) and hydrochloric acid is 35-45 ℃;
preferably, the reaction time of the product in the step (3) and hydrochloric acid is 1.5-2.5 h;
preferably, the product of the step (3) is reacted with hydrochloric acid, and then a post-treatment step is included;
preferably, the method of post-processing comprises: and (3) cooling, filtering, washing and drying the system after the reaction of the product and hydrochloric acid is finished to obtain the compound shown in the formula III.
5. The preparation method according to any one of claims 1 to 4, wherein the acid scavenger in step (4) is selected from any one or a combination of at least two of triethylamine, diisopropylethylamine or N-methylmorpholine;
preferably, the molar ratio of the acid-binding agent in the step (4) to the compound shown in the formula III is 1 (0.3-0.5);
preferably, the reaction temperature of the acid-binding agent in the step (4) and the compound shown in the formula III is-5 ℃;
preferably, the acid-binding agent in the step (4) reacts with the compound shown in the formula III for 20-40 min;
preferably, the reaction of the acid-binding agent in the step (4) and the compound shown in the formula III is carried out in the presence of an organic solvent;
preferably, the organic solvent is selected from any one or a combination of at least two of dichloromethane, dichloroethane or chloroform;
preferably, the mole ratio of the Boc amino protective agent in the step (4) to the compound shown in the formula III is (2.1-3.1): 1;
preferably, the temperature of the amino protection reaction is 23-28 ℃;
preferably, the time of the amino protection reaction is 11-13 h;
preferably, the amino protection reaction also comprises a post-treatment step after the completion;
preferably, the method of post-processing comprises: washing, concentrating, pulping, filtering and drying to obtain the compound shown in the formula IV.
6. The process according to any one of claims 1 to 5, wherein the oxidizing agent of the oxidation reaction in step (5) is a TEMPO co-oxidation system comprising a combination of TEMPO, an alkali metal bromide salt and sodium hypochlorite;
preferably, the oxidant is an oxidant solution;
preferably, the solvent of the oxidant solution is deionized water;
preferably, the molar ratio of TEMPO, alkali metal bromine salt and sodium hypochlorite is 1 (10-40) to (190-300);
preferably, the molar ratio of the oxidant to the compound shown in the formula IV is (2.1-3.4): 1;
preferably, the oxidation reaction is carried out in the presence of a basic substance;
preferably, the alkaline substance is selected from potassium bicarbonate and/or sodium bicarbonate;
preferably, the molar ratio of the alkaline substance to the compound shown in the formula IV is (1.5-2.5): 1;
preferably, the oxidation reaction is carried out in the presence of an organic solvent;
preferably, the organic solvent is selected from any one of dichloromethane, dichloroethane or chloroform or a combination of at least two thereof.
7. The production method according to any one of claims 1 to 6, wherein the oxidation reaction of step (5) comprises a first reaction stage and a second reaction stage;
preferably, the temperature of the first reaction stage is-5 to 5 ℃;
preferably, the time of the first reaction stage is 1.5-2.5 h;
preferably, the temperature of the second reaction stage is 23-28 ℃;
preferably, the temperature of the second reaction stage is 11-13 h;
preferably, the oxidation reaction in the step (5) is completed and then a post-treatment step is included;
preferably, the method of post-processing comprises: and adding a reducing solution into the system after the oxidation reaction, mixing, separating, reserving an organic phase, concentrating and drying to obtain the compound shown in the formula V.
8. The production method according to any one of claims 1 to 7, wherein the ring-closing reaction in step (6) is carried out in the presence of a chlorinating agent;
preferably, the chlorinating agent is selected from any one or a combination of at least two of oxalyl chloride, phosphorus trichloride, thionyl chloride or phosphorus pentachloride;
preferably, the molar ratio of the chlorinating reagent to the compound shown in the formula V is (1.1-1.3): 1;
preferably, the adding temperature of the chlorinating agent is-5 ℃;
preferably, the temperature of the ring closing reaction in the step (6) is 23-28 ℃;
preferably, the time of the ring closing reaction in the step (6) is 1.5-2.5 h;
preferably, the ring closure reaction of step (6) is carried out in the presence of an organic solvent;
preferably, the organic solvent is selected from any one or a combination of at least two of dichloromethane, dichloroethane or chloroform;
preferably, the step (6) further comprises a post-treatment step after the ring closing reaction is completed;
preferably, the method of post-processing comprises: concentrating, pulping, filtering, and drying to obtain the compound shown in formula VI.
9. The production method according to any one of claims 1 to 8, wherein the ring-opening reaction of step (7) is carried out in the presence of methanol;
preferably, the mass ratio of the methanol to the compound shown as the formula VI is (9-11): 1;
preferably, the temperature of the ring-opening reaction is 55-75 ℃;
preferably, the ring-opening reaction time is 4-6 h;
preferably, the ring-opening reaction also comprises a post-treatment step after the ring-opening reaction is completed;
preferably, the method of post-processing comprises: concentrating, washing and drying to obtain the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate.
10. The method according to any one of claims 1 to 9, comprising the specific steps of:
(1) mixing Boc-D-alanine, L-serine methyl ester hydrochloride, a condensing agent, an acid-binding agent and an organic solvent at the temperature of-5 ℃ for 5-15 min, heating to 23-28 ℃ and reacting for 9-11 h to obtain a compound
The mole ratio of the Boc-D-alanine to the L-serine methyl ester hydrochloride is (0.8-1.2) 1, the mole ratio of the condensing agent to the Boc-D-alanine is 1 (0.8-1.2), and the mole ratio of the acid-binding agent to the Boc-D-alanine is 1 (0.8-1.2);
(2) the compound obtained in the step (1) is
Mixing with an organic solvent, dropwise adding a deprotection agent at-5 ℃, heating to 23-28 ℃ after dropwise adding, reacting for 3-5 h, adding a solvent and an alkaline substance after desolventizing, and reacting for 3-5 h at 55-75 ℃ to obtain a compound
The deprotecting agents and compounds
The mass ratio of the basic substance to the compound is (7.5-11): 1
The mass ratio of (1) to (1-1.2);
(3) the compound obtained in the step (2)
Mixing with organic solvent, and dropwise adding into the mixture for reduction at-5 to 5 DEG CAfter the dropwise addition, heating to 23-28 ℃, mixing for 4-6 h, heating to 35-45 ℃, reacting for 3-5 h, cooling to-5 ℃, dropwise adding hydrochloric acid, after the dropwise addition, heating to 35-45 ℃, reacting for 1.5-2.5 h, and obtaining the compound
The reducing agents and compounds
In a molar ratio of (5-7) to 1, said hydrochloric acid and compound
The molar ratio of (9-11) to (1);
(4) the compound obtained in the step (3)
Mixing an acid-binding agent and an organic solvent, reacting for 20-40 min at-5 ℃, dropwise adding a Boc amino protective agent, heating to 23-28 ℃ after dropwise adding, and reacting for 11-13 h to obtain a compound
The acid-binding agent and the compound
The mole ratio of the Boc amino protective agent to the compound is 1 (0.3-0.5)
The molar ratio of (2.1-3.1) to (1);
(5) the compound obtained in the step (4) is
Mixing an oxidant, an alkaline substance and an organic solvent, reacting for 1.5-2.5 h at-5 ℃, heating to 23-28 ℃, reacting for 11-13 h,to obtain the compound
Said oxidizing agents and compounds
The molar ratio of the basic substance to the compound is (2.1-3.4): 1
The molar ratio of (1.5-2.5) to (1);
(6) the compound obtained in the step (5)
Mixing with an organic solvent, dropwise adding a chlorinating agent at-5 ℃, heating to 23-28 ℃ after dropwise adding, and reacting for 1.5-2.5 h to obtain a compound
The chlorinating agents and compounds
The molar ratio of (1.1-1.3) to 1;
(7) the compound obtained in the step (6)
Mixing the mixture with methanol, and reacting for 4-6 h at the temperature of 55-75 ℃ to obtain the chiral 1-tert-butyl-3-methyl-6-methylpiperazine-1, 3-diformate
The methanol and the compound
The mass ratio is (9-11): 1.
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