CN110483315B - Preparation method of dezocine impurity C - Google Patents
Preparation method of dezocine impurity C Download PDFInfo
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Abstract
The invention discloses a preparation method of dezocine impurity C, which takes dezocine impurity A and homologues thereof as raw materials, and carries out rearrangement reaction in the presence of a catalyst, and the dezocine impurity C is prepared by separation. The invention has the advantages that: the method takes dezocine impurity A with an epoxy structure or homologues thereof as a raw material, realizes simple and efficient synthesis of dezocine impurity C by utilizing rearrangement reaction of epoxide, and has the advantages of simple and easily obtained reagent and simple and convenient operation.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of dezocine impurity C.
Background
Dezocine (Dezocine) is an artificially synthesized mixed opioid receptor agonist-antagonist alkaloid analgesic, has good tolerance and safety, continuously improves the acceptance, and gradually increases the clinical demand. Compared with opioid analgesics such as morphine, dezocine has the advantage of less addiction, and is clinically used for treating moderate to severe postoperative pain, visceral colic and pain of patients with advanced cancer. Currently, dezocine has been approved by the food and drug administration of China for marketing, and the synthesis process thereof has been industrialized (CN 102503840A).
Dezocine belongs to phenolic compounds, is easy to degrade in a small amount during long-term storage, possibly generates impurity C, and has the following chemical structure:
at present, no synthetic method of dezocine impurity C is reported in the literature. The dezocine impurity C is difficult to prepare using conventional prior art techniques due to the presence of phenolic hydroxyl and amino groups.
Disclosure of Invention
The inventor develops a preparation method of dezocine impurity C, uses dezocine impurity A and homologues thereof as raw materials, and realizes simple and efficient synthesis of dezocine impurity C by using rearrangement reaction of epoxide, and the preparation method is not reported in documents. Meanwhile, the dezocine impurity C provided by the invention has important significance on the quality research and stability of the dezocine, and can provide more support for the aspects of clinical medication safety and the like.
The invention aims to provide a preparation method of dezocine impurity C.
The invention is realized by the following technical scheme, and provides a preparation method of dezocine impurity C, which takes dezocine impurity A or homologues thereof as raw materials; the chemical structure of dezocine impurity C is shown as formula (I), and the chemical structure of dezocine impurity A or its homologue is shown as formula (II).
Wherein, in formula (II), R is selected from H, C1-C6 alkanoyl (such as formyl, acetyl, n-propionyl or n-butyryl), and R1One or more of-O-C (O); here, R is as defined1R in-O-C (O) -1Selected from C1-C6 alkyl, aryl, benzyl, fluorenylmethyl, etc.
The preparation method comprises the following steps:
1) adding a compound of formula (II), a reaction solvent and a catalyst into a reaction vessel, and reacting at-78-120 ℃;
or, under the condition of no reaction solvent, directly heating a mixture of the compound shown in the formula (II) and a catalyst for reaction, wherein the reaction temperature is 40-140 ℃;
2) carrying out post-treatment on the reaction mixture prepared in the step 1), and separating to obtain the compound shown in the formula (I).
In an embodiment of the present invention, the present invention provides a method for preparing dezocine impurity C, wherein, in the presence of the reaction solvent in step 1), the reaction solvent used is water, or an organic solvent, or a mixture of water and an organic solvent; here, the organic solvent is selected from the group consisting of C1-C4 alkanols (e.g., methanol, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, etc.), C5-C10 alkanes (e.g., pentane, isopentane, hexane, heptane, octane, nonane, decane, etc.) and C5-C10 cycloalkanes (e.g., cyclopentane, cyclohexane, cycloheptane, etc.), monohalogenated and polyhalogenated C1-C4 alkanes (e.g., dichloromethane, chloroform, carbon tetrachloride, monochlorobutane, etc.), unsubstituted and alkyl-substituted aromatic hydrocarbons (e.g., benzene, toluene, xylene, ethylbenzene, etc.), monohalogenated and polyhalogenated aromatic hydrocarbons (e.g., chlorobenzene, bromobenzene, dichlorobenzene, etc.), C4-C8 acyclic ethers and C4-C8 cyclic ethers (e.g., diethyl ether, tetrahydrofuran, or 1, 4-dioxane, etc.), C3-C7 saturated ketones (e.g., acetone, ethanol, propanol, isopropanol, butanol, isobutanol, tert-butanol, etc.), C5-C8525 cycloalkanes, and the like, Or butanone, etc.), esters of C1-C4 alkanoic acids with C1-C4 alkanols (e.g., ethyl formate, ethyl acetate, or isopropyl acetate, etc.), C2-C4 aliphatic nitriles (e.g., acetonitrile, or propionitrile, etc.), aromatic ethers (e.g., anisole, phenetole, or diphenyl ether, etc.), benzonitrile, dimethyl sulfoxide, and amide solvents (e.g., N-dimethylformamide, N-dimethylacetamide, or N-methylpyrrolidone, etc.); preferably, the organic solvent is one or a mixture of more of methanol, ethanol, dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, ethyl acetate, isopropyl acetate and acetonitrile.
In an embodiment of the present invention, in the case that the reaction solvent exists in step 1), when a mixture of water and an organic solvent is selected as the reaction solvent, the volume ratio of the water to the organic solvent is 0.1 to 50:1, preferably 0.1 to 10: 1.
In an embodiment of the present invention, the present invention provides a method for preparing dezocine impurity C, wherein, in the presence of a reaction solvent in step 1), the volume of the reaction solvent (unit: mL) and the mass of the compound of formula (II) (unit: g) the ratio of (A) to (B) is 1 to 500:1, preferably 5 to 200:1, more preferably 10 to 100: 1.
In an embodiment of the present invention, the present invention provides a method for preparing dezocine impurity C, wherein, in the presence of a reaction solvent in step 1), the catalyst may be a Bronsted acid or a Lewis acid or a mixture of both. Wherein the Bronsted acid is selected from one or more of hydrogen halide, sulfuric acid, sulfonic acid, phosphoric acid, carboxylic acid, perchloric acid, strong acidic ion exchange resin and weak acidic ion exchange resin; the Lewis acid is selected from one or a mixture of more of metal salt and oxide, boron halide, phosphorus halide and silica gel; the metal in the salts and oxides of the metals described herein is selected from Li, Mg, Al, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Pd, Ag, Sn, or Au; preferably, the catalyst is hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid, LiClO4、TiO2、BF3、MgSO4、TiCl4And silica gel, or a mixture of several of them.
In an embodiment of the invention, the preparation method of dezocine impurity C provided by the invention is characterized in that, under the condition that the reaction solvent exists in the step 1), the ratio of the addition amount of the catalyst to the equivalent of the compound of the formula (II) is 0.1-50: 1, preferably 1-20: 1, and more preferably 2-10: 1.
In an embodiment of the present invention, the present invention provides the process for preparing dezocine impurity C, wherein the catalyst selected from the group consisting of sparingly soluble metal oxide, sparingly soluble non-metal oxide, sparingly soluble metal oxide carrying acid, and sparingly soluble non-metal oxide carrying acid is not in accordance with claim 6, in the absence of a reaction solvent in step 1); the sparingly soluble metal oxide is selected from TiO2、ZnO、Al2O3And ZrO2One or a mixture of several of them; the insoluble non-metallic oxide is selected from B2O3And SiO2One or a mixture of both; the acid carried by the insoluble metal oxide or the insoluble nonmetal oxide is selected from soluble Bronsted acid or soluble Lewis acid or a mixture of the soluble Bronsted acid and the soluble Lewis acid; wherein the soluble Bronsted acid is selected from one or a mixture of more of hydrogen halide, sulfuric acid, sulfonic acid, phosphoric acid, carboxylic acid and perchloric acid, preferably hydrogen chloride, sulfuric acid or trifluoroacetic acid; wherein the soluble Lewis acid is selected from one or a mixture of more of soluble metal salt, soluble metal oxide and boron halide, and the metal in the soluble metal salt or the soluble metal oxide is selected from Li, Mg, Al, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Pd, Ag or Sn; preferably, the soluble Lewis acid is LiClO4、BF3、MgCl2、AlCl3、ZnCl2Or ZnI2。
In an embodiment of the invention, the preparation method of dezocine impurity C provided by the invention is that the weight ratio of the catalyst to the compound of formula (II) is 1-100: 1, preferably 2-50: 1, and more preferably 2-30: 1, under the condition of no reaction solvent in step 1).
In the embodiment of the present invention, the present invention provides a method for preparing dezocine impurity C, wherein, in step 2, the reaction mixture may further comprise a step of recovering unreacted raw materials after post-treatment.
In an embodiment of the present invention, the present invention provides a method for preparing dezocine impurity C, wherein dezocine impurity a or its homologue of formula (II) can be prepared by the following method:
i) adding a compound shown in formula (III), a transition metal catalyst, peroxide, a reaction auxiliary agent and a solvent 1 into a reaction vessel, and reacting at-40-90 ℃;
II) carrying out post-treatment on the reaction mixture prepared in the step i), and separating to obtain a compound shown as a formula (II);
wherein, R in the formula (III) is defined as the formula (II);
the transition metal catalyst is one or a mixture of more of transition metal oxide, transition metal hydroxide, transition metal salt and transition metal complex; here, the transition metal is Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, La, Ce, Sm, Hf, Ta, W, or Os; more preferably, the transition metal catalyst is scandium triflate, titanium tetraisopropoxide, titanium tartrate, TiO2、V2O5、NH4VO3、CrCl3、MnO2、FeCl3、Fe(OH)3Iron acetylacetonate, FeSO4、FeCl2Ferrocene, cobalt acetate, NiCl2Copper acetate, CuSO4、ZnO、ZrO2、RuCl3Palladium acetate, Pd (PPh)3)4Cl2、AgNO3、Rh(PPh3)4One or a mixture of more of Cl, ammonium ceric nitrate, phosphomolybdic acid and phosphotungstic acid;
the peroxide is one or a mixture of more of hydrogen peroxide, metal peroxide, peroxyalcohol, peroxyacid salt, dialkyl peroxide, ester of peroxyacid, diacyl peroxide and a peroxide compound; more preferably, the peroxide is hydrogen peroxide, sodium peroxide, barium peroxide, tert-butyl peroxy alcohol, cumene hydroperoxide, diisopropylbenzene hydroperoxide, m-chloroperoxybenzoic acid, sodium percarbonate, sodium perborate tetrahydrate, potassium peroxodisulfate, di-tert-butyl peroxide, tert-butyl peroxybenzoate, dibenzoyl peroxide, or urea hydrogen peroxide complex;
the reaction auxiliary agent is an alkaline reaction auxiliary agent or an acidic reaction auxiliary agent; wherein the alkaline reaction auxiliary agent is MOH, MOR, M2CO3、M3PO4、M2HPO4One or a mixture of more of trialkylamine with the total number of carbon atoms of 6-24, tetramethylguanidine, amidine and tetraalkylammonium hydroxide with the total number of carbon atoms of 4-24; wherein, the acidic reaction auxiliary agent is one or a mixture of more of inorganic and organic strong protonic acids; MOH, MOR, M2CO3、M3PO4、M2HPO4M in (1) is selected from Li, Na, K, Rb, Cs and Mg1/2、Ca1/2、Sr1/2Or Ba1/2(ii) a R in MOR is selected from C1-C5 alkyl; more preferably, the alkaline reaction auxiliary agent is NaOH or Na2CO3、NaOCH3Potassium tert-butoxide, N-diisopropylethylamine, tetrabutylammonium hydroxide, tetramethylguanidine, or 1, 8-diazabicyclo [ 5.4.0%]-undec-7-ene; more preferably, the acidic reaction auxiliary agent is hydrochloric acid, tetrafluoroboric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, tetrafluoroboric acid, or trifluoroacetic acid;
the solvent 1 is water, or an organic solvent, or a mixture of water and an organic solvent; the organic solvent is one or a mixture of more of C1-C4 alkanol, C5-C10 alkane or cycloalkane, halogenated alkane, aromatic hydrocarbon, halogenated aromatic hydrocarbon, C4-C8 ether or cyclic ether, C3-C7 saturated ketone, ester formed by C1-C4 alkanoic acid and C1-C4 alkanol, C2-C4 aliphatic nitrile or benzonitrile and amide solvents (such as N, N-dimethylformamide, N-dimethylacetamide and N-methylpyrrolidone); more preferably, the organic solvent is methanol, ethanol, N-hexane, N-heptane, dichloromethane, toluene, trifluoromethylbenzene, tetrahydrofuran, 1, 4-dioxane, acetone, ethyl acetate, isopropyl acetate, acetonitrile, N-dimethylformamide, or N, N-dimethylacetamide.
Compared with the prior art, the method has the advantages that the rearrangement reaction of the epoxide is creatively adopted, the dezocine impurity A with the epoxy structure and the homologue thereof are used as raw materials, the simple, convenient and efficient synthesis of the dezocine impurity C is realized, and meanwhile, part of unreacted raw materials can be recycled.
Detailed Description
The following examples will help to understand the present invention, but do not limit the contents thereof.
Example 1
Synthesis of dezocine impurity C: dezocine impurity a (10.1mg, i.e., R ═ H in formula (II)) was dissolved in CH2Cl2(1mL), the reaction temperature was reduced to-78 ℃ with dry ice, and BF was added3(0.05mL, 33% in ether, ca. 7.0 equiv.) after the addition, the reaction temperature was slowly raised to-20 ℃ for 60 minutes, the reaction was stopped, and 5% NaHCO was added to the reaction solution3Neutralizing with water solution to neutrality, separating, and adding CH to water phase2Cl2(2mL) for 2 times, and the organic phases are combined and subjected to column chromatography to obtain dezocine impurity C (formula I)5.3mg as a white solid with the yield of 52%. The ratio of the amount of reaction solvent dichloromethane (unit: mL) to the amount of dezocine impurity A (unit: g) was about 100: 1. Nuclear magnetic resonance hydrogen spectroscopy (DMSO-d)6500MHz) δ 8.29(s,1H),7.83(d, J ═ 8.5Hz,1H),6.83(d, J ═ 2.0Hz,1H),6.77(dd, J ═ 8.5,2.0Hz,1H),3.40(d, J ═ 7.5Hz,1H),2.85(dd, J ═ 7.5,5.5Hz,1H),2.04-1.89(m,3H), -1.60-1.48(m,4H),1.39(s,3H),1.18-1.15(m,1H),0.66-0.63(m,1H),0.43-0.39(m, 1H); nuclear magnetic resonance carbon spectrum (DMSO-d)6,125MHz)δ198.4,163.0,152.5,128.9,124.8,114.5,112.8,54.8,48.9,40.7,32.0,28.9,26.1,25.8,24.6；IR(KBr)ν3389,2926,2857,2724,1653,1645,1591,1472,1439,1385,1356,1292,1202,1142,1105,939,874,835,770,590cm-1(ii) a High resolution Mass Spectrometry (+ ESI, MeOH, C)16H21NO2Na+) Calculated 282.1465, found 282.1465.
Example 2
DezocineSynthesis of impurity C: dezocine impurity a (10.2mg, i.e., R ═ H in formula (II)) was dissolved in 10% aqueous sulfuric acid (0.2mL, H) previously cooled to-5 ℃2SO4Equivalent of (3) about 6.0), after 5 minutes the reaction was diluted with 2mL ice water and 5% NaHCO3Neutralizing with water solution to neutrality, adding CH2Cl2(5mL) for 2 times, and after the organic phases are combined and subjected to column chromatography, dezocine impurity C4.6 mg, white solid is obtained with yield of 45%. The ratio of the amount of aqueous sulfuric acid solution (unit: mL) as the reaction solvent to the amount of dezocine impurity A (unit: g) was about 20: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 3
Synthesis of dezocine impurity C: dezocine impurity a (30.4mg, i.e., R ═ H in formula (II)) was dissolved in dioxane (1mL), ZnO (0.1g, 10.5 equivalents) was added, the mixture was heated to 90 ℃ to react for 6 hours, and then the solvent was removed by concentration, and column chromatography was performed to obtain 24.6mg of dezocine impurity C (formula I) as a white solid in a yield of 81%. The ratio of the amount of dioxane (unit: mL) used as the reaction solvent to the amount of dezocine impurity A (unit: g) used was 33: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 4
Synthesis of dezocine impurity C: dissolving dezocine impurity a (500mg, i.e., R ═ H in formula (II)) in tetrahydrofuran (10mL), adjusting pH to 1-2 by adding concentrated hydrochloric acid (amount about 0.5mL, equivalent of HCl about 3.0), stirring at room temperature for 2 hours, adding 50mL of water, adjusting pH to 10 by 5% NaOH, extracting aqueous phase 3 times with dichloromethane (10mL), combining organic phases, concentrating to dryness, and recovering dezocine impurity a81 mg; the aqueous phase was adjusted to pH 7 with hydrochloric acid, extracted 4 times with dichloromethane (20mL), the organic phases combined and separated by column chromatography to give 253mg of dezocine impurity C (formula I), yield 60%. The ratio of the amount of tetrahydrofuran (unit: mL) as the reaction solvent to the amount of dezocine impurity A (unit: g) was 20: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 5
Synthesis of dezocine impurity C: the N-Boc dezocine impurity A (30.1mg, i.e., R ═ COO in formula (II)) was addedtBu) dissolved in 10% CF3CH of COOH2Cl2Solution (1mL, CF)3When of COOH10.5), stirring at 0-5 deg.C for 15min, and adding 5% NaHCO3Neutralizing the aqueous solution to neutrality, separating organic phase, and using CH as aqueous phase2Cl2The extraction is carried out for 2 times (5mL), and the organic phases are combined, dried by a small amount of anhydrous sodium sulfate and concentrated under reduced pressure to obtain dezocine impurity C13.5 mg, white solid with the yield of 62 percent. The ratio of the amount of reaction solvent dichloromethane (unit: mL) to the amount of N-Boc dezocine impurity A (unit: g) was about 33: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 6
Synthesis of dezocine impurity C: n-acetyldezocine impurity A (30.2mg, i.e. R ═ COCH in formula (II))3) Dissolving in 5% HBr methanol solution (1mL, HBr equivalent number is 6.2), reacting at room temperature for 5h, adding 10mL water, and adding 5% NaHCO3Neutralizing with water solution to neutrality, adding CH2Cl2Extracting for 3 times (5mL), combining organic phases, drying with small amount of anhydrous sodium sulfate, concentrating under reduced pressure, and separating by column chromatography to obtain dezocine impurity C (formula I)16.2mg, white solid, yield 62%. The ratio of the amount of methanol (unit: mL) as the reaction solvent to the amount of N-acetyldezocine as impurity A (unit: g) was about 33: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 7
Synthesis of dezocine impurity C: dezocine impurity a (20.5mg, i.e., R ═ H in formula (II)) was reacted with CH2Cl2Dissolving (0.5mL), adding silica gel 80mg (weight is about 4 times of the compound of formula (II)), concentrating under reduced pressure at room temperature to remove solvent, heating the residue at 140 deg.C for 25min, cooling, performing column chromatography, recovering dezocine impurity A2.1mg to obtain dezocine impurity C15.1 mg, with yield of 82%, and making into white solid. The weight ratio of catalyst (silica gel) to dezocine impurity a was about 4: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 8
Synthesis of dezocine impurity C (scheme B): dezocine impurity a (20.0mg, i.e., R ═ H in formula (II)) was reacted with CH2Cl2Dissolving in 0.5mL, adding 100mg ZnO (5 times of the weight of the compound of formula (II)), concentrating under reduced pressure at room temperature to remove solvent, heating the concentrate at 70 deg.C for 30min, cooling, and adding dichlorineAnd eluting with a mixed solvent (10mL, volume ratio of 2:1:0.1) of methane, methanol and triethylamine to obtain dezocine impurity C19.1 mg, yield 95.5% and white solid. The weight ratio of catalyst (ZnO) to dezocine impurity a was 5: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 9
Synthesis of dezocine impurity C: preparation of silica gel supported catalyst: mixing silica gel plate (model GF)254Silica gel with thickness of 0.5mm and length x width of 5cm x 5cm, wherein the weight of silica gel is about 80mg) is soaked in 10% sulfuric acid in dichloromethane for 1min, and dried by hot air to obtain silica gel-supported sulfuric acid which is used as a reaction catalyst, and the weight of a silica gel plate is increased by 15 mg.
20.1mg of N-Boc dezocine as impurity A (30.1mg, i.e. R ═ COO in formula (II)) was dissolvedtBu) CH2Cl2Coating the solution (0.3mL) on the surface of the prepared catalyst, drying the catalyst by hot air, placing the dried catalyst in an oven at 50 ℃ for heating for 10min, taking out the catalyst, fumigating the catalyst for 5min in an ammonia atmosphere, stripping silica gel, leaching the stripped silica gel by using a mixed solvent (10mL, the volume ratio is 2:1) of dichloromethane and methanol, and concentrating the leacheate to obtain dezocine impurity C12.1 mg, the yield is 83% and white solid. The weight ratio of catalyst (silica gel loaded with sulfuric acid) to N-Boc dezocine impurity A was 3.2: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 10
Preparation of silica gel supported catalyst: mixing silica gel plate (model GF)254Silica gel having a thickness of 0.5mm and a length x width of 5cm x 5cm, wherein the weight of the silica gel is about 80mg) in 5% AlCl3Soaking in dichloromethane solution for 1min, taking out, activating in a 110 deg.C oven for 10min to obtain AlCl loaded with silica gel3Used as a reaction catalyst, the weight of the silica gel plate is increased by 13 mg.
Synthesis of dezocine impurity C: dissolving 30.2mg dezocine impurity A in CH of sample2Cl2Coating the solution (0.3mL) on the surface of the prepared catalyst, drying the solvent with hot air, placing the dried solution in an oven at 50 ℃ for heating for 10min, taking out the heated solution, fumigating the solution for 5min in an ammonia atmosphere, stripping silica gel, leaching with a mixed solvent (10mL, volume ratio of 2:1) of dichloromethane and methanol, concentrating the leacheate to obtain dezocine impurity C22.9 mg,yield 76% as a white solid. Catalyst (loaded AlCl)3Silica gel) and the weight ratio of dezocine impurity a was 3.1: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 11
Preparation of silica gel supported catalyst: mixing silica gel plate (model GF)254Thickness 0.5mm, length x width 10cm x 10cm, where the weight of the silica gel is about 320mg) in 10% LiClO4Soaking in methanol solution for 1min, taking out, activating in a 110 deg.C oven for 10min to obtain LiClO loaded with silica gel4And is used as a reaction catalyst. The weight of the silica gel plate is increased by 48 mg.
Synthesis of dezocine impurity C: dissolving 120.6mg of dezocine impurity A in CH of sample2Cl2Coating the solution (2mL) on the surface of the prepared catalyst, drying the solvent with hot air, placing the dried solution in an oven at 70 ℃ for heating for 50min, stripping silica gel, leaching with a mixed solvent (30mL, volume ratio of 2:1) of dichloromethane and methanol, and concentrating the leacheate to obtain dezocine impurity C117.0 mg, yield of 97% and white solid. Catalyst (Supported LiClO)4Silica gel) and the weight ratio of dezocine impurity a was 3.1: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 12
TiO2Preparation of the supported catalyst: adding TiO into the mixture20.5g, dichloromethane 1mL, ZnI20.1g of the mixture is concentrated and dried at normal temperature to obtain the reaction catalyst.
Synthesis of dezocine impurity C: 126.1mg of N-Boc dezocine as impurity A (i.e. R ═ COO in formula (II))tBu) and the prepared catalyst, mechanically stirring, reacting at 60 ℃ for 1h, cooling, and leaching the reaction mixture with a mixed solvent of dichloromethane, methanol and triethylamine (30mL, volume ratio of 2:1:0.1) to obtain dezocine impurity C83.3 mg, yield 91%, and white solid. Catalyst (loaded ZnI)2Silica gel) and the weight ratio of N-Boc dezocine impurity a was 4.8: 1. Characterization data for dezocine impurity C are the same as in example 1.
Example 13
Synthesis of dezocine impurity a: to a500 mL three-necked bottle, 20.0g (1.0 equivalent) of dezocine and tetraisopropyl were added2.3g (0.1 equivalent) of titanium alkoxide, 6.0g (0.5 equivalent) of DBU and 200mL of dichloromethane, the temperature of the reaction solution is reduced to-10 ℃, 62.0g (4.0 equivalents) of 80% cumene hydroperoxide is slowly dripped for 2.0h, the reaction temperature is slowly increased to the room temperature after the dripping is finished, the reaction is carried out for 3h, the reaction temperature is increased to 75 ℃, and the reaction is carried out for 1 h. The reaction was stopped, the reaction mixture was extracted with 70mL of a 5% aqueous NaOH solution, the insoluble matter was filtered, the solution was separated, the organic phase was extracted twice with 50mL of a 5% aqueous NaOH solution and 5% Na2S2O3Extracting with 200mL of aqueous solution and 50mL of saturated salt solution, detecting organic phase with starch-KI test paper to remove peroxide residue, separating, and separating organic phase with anhydrous MgSO45.0g of the product was dried, concentrated to dryness under reduced pressure from an oil pump, and the residue was recrystallized from 50mL of a mixed solvent of dichloromethane and n-hexane (volume ratio: 1:7) to obtain 1.71g of an impurity dezocine. And separating the crystallization mother liquor by column chromatography to obtain dezocine impurity A0.39g. And mixing the NaOH aqueous solution extract, adjusting the pH value to 7 by using acetic acid, stirring in an ice water bath for 60min, carrying out suction filtration, drying a filter cake, and recovering 13.1g of dezocine. The charged amount of dezocine was 20g, the recovered amount was 13.1g, and the consumed amount was 6.9g, to obtain 2.1g of dezocine impurity (i.e., R ═ H in formula (II)), and the yield was 28.8%. Nuclear magnetic resonance hydrogen spectrum (500MHz, DMSO-d)6) δ 6.63(d, J ═ 9.85Hz,1H),6.42(dd, J ═ 9.85,1.7Hz,1H),6.32(d, J ═ 1.70Hz,1H),3.88(d, J ═ 2.40Hz,1H),3.13(d, J ═ 5.95Hz,1H),2.56(s,1H),2.06-2.01(m,1H),1.80-1.48(m,7H),1.30-1.21(m,1H),1.20(s,3H),1.19-1.10(m,1H),0.63-0.52(m, 1H); nuclear magnetic resonance carbon spectrum (125MHz, DMSO-d)6) δ 185.4,162.2,147.8,131.8,131.3,66.6,55.6,51.1,41.0,38.6,35.4,34.2,28.0,26.1,25.4, 22.5; mass spectrum (ESI +, CH)3OH) calculated value C16H22NO2 +[M+H]+260.17, found 260.16.
Example 14
N-Boc dezocine impurity A (i.e. R ═ COCH in formula (II))3) The synthesis of (2):
scheme 1-synthesis of N-acetyldezocine impurity a from N-acetyldezocine: 10.00g (1.0 equivalent) of dezocine, 50mL of methylene chloride and 5.00g (1.22 equivalent) of triethylamine were added to a 250mL single-neck flask, the temperature of the solution was lowered to 0 ℃ and 4.37g of acetic anhydride was slowly added dropwise(1.05 equiv.) of dichloromethane (50mL), adding dropwise, reacting for 30min, and detecting by thin layer chromatography (developing solvent is CH)2Cl2/CH3OH ═ 10:1), the reaction was complete. Stopping stirring, and sequentially using 1moL/L hydrochloric acid 50mL and 5% NaHCO to the organic phase350mL of the aqueous solution and 50mL of a saturated saline solution were washed once with anhydrous Na2SO45g of the product is dried and concentrated under reduced pressure to obtain 11.36g of N-acetyldezocine as a white solid with the yield of 97 percent.
To a50 mL single-neck flask were added 500mg (1.0 equivalent) of N-acetyldezocine, 25mg (0.08 equivalent) of cobalt acetate, 2mL of water, 3mL of tetrahydrofuran, and 2Na2CO3·3H2O21.09g (2.0 eq.) was allowed to react at room temperature for 4h, and the reaction was stopped. To the reaction flask was added 30mL of water, extracted three times with dichloromethane, and the organic phases were combined. The pH of the aqueous phase was adjusted to 4.0 with 2moL/L hydrochloric acid, filtered with suction, and 138mg of N-acetyldezocine was recovered. The organic phase is passed through anhydrous Na2SO4Drying, concentrating, and separating by column chromatography to obtain N-acetyldezocine impurity A87mg as white solid. The feeding amount of the N-acetyl dezocine is 500mg, the recovery amount is 138mg, the consumption amount is 362mg, and the N-acetyl dezocine impurity A87mg is obtained with the yield of 22.9 percent. Hydrogen nuclear magnetic resonance spectroscopy (500MHz, CDCl)3) δ 6.49(d, J ═ 9.85Hz,1H),6.45(d, J ═ 9.85Hz,1H),6.37(s,1H),5.68 to 5.66(d, J ═ 9.75Hz,1H),4.80(dd, J ═ 10.70,6.10Hz,1H),3.65(d, J ═ 2.35Hz),2.75(s,1H),2.10(s,3H),1.97 to 1.92(m,1H),1.84 to 1.62(m,7H),1.47 to 1.1.38(m,1H),1.25(s,3H),0.98 to 0.0.81(m, 2H); nuclear magnetic resonance carbon spectrum (125MHz, CDCl)3) Delta 185.9,169.4,160.4,146.9,132.6,131.6,66.5,55.6,48.9,40.6,36.5,36.3,35.3,28.8,26.7,25.5,23.6, 22.2; mass spectrum (ESI +, CH)3OH) calculated value C18H24NO3 +[M+H]+302.18, found 302.18. M is the molecular formula of N-acetyl dezocine impurity A.
Scheme 2-synthesis of N-acetyldezocine impurity a from dezocine impurity a: dezocine impurity A500mg (i.e. R ═ H in formula (II)) was dissolved in CH2Cl2To (10mL) was added triethylamine and acetic anhydride (0.5mL each), and the mixture was stirred at room temperature for 30 min. Stopping the reaction, and sequentially passing the reaction solution through 5% of Na2CO320mL of aqueous solution is used for extraction,20mL of extracted, anhydrous Na containing 1mol/L hydrochloric acid2SO42g of the product is dried and concentrated under reduced pressure to obtain 535mg of N-acetyldezocine impurity A as a white solid with the yield of 92 percent. The characterization data are the same as in scheme 1 of this example.
Example 15
N-Boc dezocine impurity A (i.e. R ═ COO in formula (II))tBu) synthesis:
scheme 1-Synthesis of N-Boc dezocine from N-Boc dezocine impurity A: to a 100mL single-necked flask were added 5.0g of dezocine, 20mL of dichloromethane, 3.09g (1.50 equivalents) of triethylamine, 375mg (0.15 equivalent) of 4-dimethylaminopyridine and Boc2O6.68 g (1.50 eq.) and reacted for 2h under reflux. Stirring was stopped, the reaction solution was concentrated under reduced pressure, and column chromatography was performed to obtain 6.41g of N-t-butoxycarbonyl dezocine as a white solid in a yield of 91%. Note: boc is tert-butyloxycarbonyl acyl.
To a 100mL single-necked flask were added 2.00g of N-Boc dezocine, 30mL of acetonitrile, and Pd (PPh)3)4Cl2350mg (0.05 equivalent), 1.33g (2.0 equivalent) of tetramethylguanidine, and 20mL of 70% t-butanol peroxide were reacted at room temperature for 3.5 hours, and the reaction was stopped. The reaction mixture was diluted with 300mL of methylene chloride, and 100mL of a 10% NaOH aqueous solution and 5% Na were added2S2O3100mL of each extract was extracted once with anhydrous Na2SO415g of the crude product was dried, concentrated and subjected to column chromatography to obtain 0.95g of N-Boc dezocine impurity A as a white solid with a yield of 45.7%. Hydrogen nuclear magnetic resonance spectroscopy (500MHz, CDCl)3) δ 6.49(dd, J ═ 9.85,1.5Hz,1H),6.42(d, J ═ 9.85Hz,1H),6.36(d, J ═ 1.5Hz,1H),4.62(d, J ═ 10.25Hz,1H),4.44(s,1H),3.63(d, J ═ 2.4Hz,1H),2.76(s,1H),1.97-1.90(m,1H),1.84-1.62(m,6H),1.47(s,9H),1.45-1.34(m,1H),1.27(s,3H),0.95-0.88(m,1H),0.83-0.78(m, 1H); nuclear magnetic resonance carbon spectrum (125MHz, CDCl)3) δ 186.0,160.7,155.3,146.9,132.7,131.7,79.8,66.1,55.7,50.7,41.1,36.9,36.4,35.5,28.4,27.4,26.8,25.6, 22.3; mass spectrum (ESI +, CH)3CN) calculated value C21H30NO4 +[M+H]+360.22, found 360.21, M is N-Boc dezocine impurity A molecular formula.
Scheme 2-synthesis of N-Boc dezocine impurity a from dezocine impurity a: 500mg of dezocine impurity A (namely, formula (II)Where R ═ H) is dissolved in CH2Cl2(10mL), Boc was added2O630mg (1.50 equiv.) and triethylamine 300mg (1.54 equiv.) were refluxed for 2 hours. Stopping the reaction, extracting the reaction solution once by 15mL of 1mol/L hydrochloric acid and then obtaining saturated NaHCO310mL of aqueous solution extracted once with anhydrous Na2SO42g was dried and concentrated under reduced pressure to give 651mg of N-Boc dezocine impurity A as a white solid in 93.8% yield. The characterization data are the same as in scheme 1 of this example.
Claims (16)
1. A method for preparing dezocine impurity C, which takes dezocine impurity A or homologues thereof as raw materials; the chemical structure of dezocine impurity C is shown as formula (I), and the chemical structure of dezocine impurity A or homologue thereof is shown as formula (II);
wherein, in formula (II), R is selected from H, C1-C6 alkanoyl and R1One or more of-O-C (O); here, R is as defined1R in-O-C (O) -1Selected from the group consisting of C1-C6 alkyl, aryl, benzyl, and fluorenylmethyl;
the preparation method comprises the following steps:
1) adding a compound of formula (II), a reaction solvent and a catalyst into a reaction vessel, and reacting at-78-120 ℃;
or, under the condition of no reaction solvent, directly heating a mixture of the compound shown in the formula (II) and a catalyst for reaction, wherein the reaction temperature is 40-140 ℃;
2) carrying out post-treatment on the reaction mixture prepared in the step 1), and separating to obtain a compound shown as a formula (I);
wherein, under the condition that a reaction solvent exists in the step 1), the catalyst is Bronsted acid or Lewis acid or a mixture of the Bronsted acid and the Lewis acid, wherein the Bronsted acid is selected from one or a mixture of more of hydrogen halide, sulfuric acid, sulfonic acid, phosphoric acid, carboxylic acid, perchloric acid, strong acidic ion exchange resin and weak acidic ion exchange resin; the Lewis acid is selected from one or a mixture of more of metal salt and oxide, boron halide, phosphorus halide and silica gel; the metal in the salts and oxides of the metals described herein is Li, Mg, Al, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Pd, Ag, Sn, or Au;
under the condition of no reaction solvent in the step 1), the catalyst is selected from a slightly soluble metal oxide or a slightly soluble nonmetal oxide, or a slightly soluble metal oxide loaded with acid, or a slightly soluble nonmetal oxide loaded with acid; the sparingly soluble metal oxide is selected from TiO2、ZnO、Al2O3And ZrO2One or a mixture of several of them; the insoluble non-metallic oxide is selected from B2O3And SiO2One or a mixture of both; here, the acid supported by the insoluble metal oxide or the insoluble nonmetal oxide is a soluble Bronsted acid or a soluble Lewis acid, or a mixture of the two; wherein the soluble Bronsted acid is selected from one or a mixture of more of hydrogen halide, sulfuric acid, sulfonic acid, phosphoric acid, carboxylic acid and perchloric acid; wherein the soluble Lewis acid is selected from one or a mixture of several of soluble metal salt or oxide and boron halide, and the metal in the soluble metal salt or oxide is Li, Mg, Al, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Pd, Ag or Sn.
2. The preparation process according to claim 1, wherein, in the presence of the reaction solvent in step 1), the reaction solvent used is water, or an organic solvent, or a mixture of water and an organic solvent; the organic solvent is selected from one or a mixture of several of C1-C4 alkanol, C5-C10 alkane, monohalogenated and polyhalogenated C1-C4 alkane, unsubstituted aromatic hydrocarbon and alkyl substituted aromatic hydrocarbon, monohalogenated and polyhalogenated aromatic hydrocarbon, C4-C8 acyclic ether and C4-C8 cyclic ether, C3-C7 saturated ketone, C1-C4 alkanoic acid ester with C1-C4 alkanol, C2-C4 aliphatic nitrile, aromatic ether, benzonitrile, dimethyl sulfoxide and amide solvent.
3. The method according to claim 2, wherein the organic solvent is selected from one or more of methanol, ethanol, dichloromethane, tetrahydrofuran, 1, 4-dioxane, acetone, ethyl acetate, isopropyl acetate, and acetonitrile.
4. The preparation method according to claim 2, wherein, in the presence of the reaction solvent in step 1), when a mixture of water and an organic solvent is selected as the reaction solvent, the volume ratio of water to the organic solvent is 0.1 to 50: 1.
5. The preparation method according to claim 4, wherein, in the presence of the reaction solvent in step 1), when a mixture of water and an organic solvent is selected as the reaction solvent, the volume ratio of water to the organic solvent is 0.1 to 10: 1.
6. The method according to claim 1, wherein, in the presence of the reaction solvent in step 1), the ratio of the volume of the reaction solvent to the mass of the compound of formula (II) is 1 to 500:1, wherein the volume is in mL and the mass is in g.
7. The method according to claim 6, wherein, in the presence of the reaction solvent in step 1), the ratio of the volume of the reaction solvent to the mass of the compound of formula (II) is 5 to 200:1, wherein the volume is in mL and the mass is in g.
8. The method according to claim 7, wherein, in the presence of the reaction solvent in step 1), the ratio of the volume of the reaction solvent to the mass of the compound of formula (II) is 10 to 100:1, wherein the volume is in mL and the mass is in g.
9. The process according to claim 1, wherein the catalyst is hydrochloric acid, sulfuric acid, trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, citric acid in the presence of the reaction solvent in step 1)Acid, LiClO4、TiO2、BF3、MgSO4、TiCl4And silica gel or a mixture of several thereof.
10. The process according to claim 1, wherein the catalyst is selected from the group consisting of a sparingly soluble metal oxide or a sparingly soluble non-metal oxide, or a sparingly soluble metal oxide carrying an acid, or a sparingly soluble non-metal oxide carrying an acid, in the absence of a reaction solvent in the step 1); the insoluble metal oxide is Al2O3Or ZnO; the insoluble non-metallic oxide is SiO2(ii) a Here, the acid supported by the insoluble metal oxide or the insoluble nonmetal oxide is a soluble Bronsted acid or a soluble Lewis acid, or a mixture of the two; wherein the soluble Bronsted acid is hydrogen chloride, sulfuric acid, or trifluoroacetic acid; wherein the soluble Lewis acid is LiClO4、BF3、MgCl2、AlCl3、ZnCl2Or ZnI2。
11. The preparation method according to claim 1, wherein the weight ratio of the catalyst to the compound of formula (II) is 1-100: 1 in the absence of a reaction solvent in step 1).
12. The method according to claim 11, wherein the weight ratio of the catalyst to the compound of formula (II) is 2-50: 1 in the absence of a reaction solvent in step 1).
13. The method according to claim 12, wherein the weight ratio of the catalyst to the compound of formula (II) is 2-30: 1 in the absence of a reaction solvent in step 1).
14. The method according to claim 1, wherein the step 2) further comprises a step of recovering the unreacted raw materials after the reaction mixture is post-treated.
15. The process according to claim 1, wherein dezocine impurity A of formula (II) or a homologue thereof is produced by:
i) adding a compound shown in formula (III), a transition metal catalyst, peroxide, a reaction auxiliary agent and a solvent 1 into a reaction vessel, and reacting at-40-90 ℃;
II) carrying out post-treatment on the reaction mixture prepared in the step i), and separating to obtain a compound shown as a formula (II);
wherein, R in the formula (III) is defined as the formula (II);
the transition metal catalyst is one or a mixture of more of transition metal oxide, transition metal hydroxide, transition metal salt and transition metal complex; here, the transition metal is Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, La, Ce, Sm, Hf, Ta, W, or Os;
the peroxide is one or a mixture of more of hydrogen peroxide, metal peroxide, peroxyalcohol, peroxyacid salt, dialkyl peroxide, ester of peroxyacid, diacyl peroxide and a peroxide compound;
the reaction auxiliary agent is an alkaline reaction auxiliary agent or an acidic reaction auxiliary agent; wherein the alkaline reaction auxiliary agent is MOH, MOR, M2CO3、M3PO4、M2HPO4One or a mixture of more of trialkylamine with the total number of carbon atoms of 6-24, tetramethylguanidine, amidine and tetraalkylammonium hydroxide with the total number of carbon atoms of 4-24; wherein, the acidic reaction auxiliary agent is one or a mixture of more of inorganic and organic strong protonic acids; MOH, MOR, M2CO3、M3PO4、M2HPO4M in (1) is selected from Li, Na, K, Rb, Cs and Mg1/2、Ca1/2、Sr1/2Or Ba1/2(ii) a R in MOR is selected from C1-C5 alkyl;
the solvent 1 is water, or an organic solvent, or a mixture of water and an organic solvent; the organic solvent is one or a mixture of more of C1-C4 alkanol, C5-C10 alkane, halogenated alkane, aromatic hydrocarbon, halogenated aromatic hydrocarbon, C4-C8 ether or cyclic ether, C3-C7 saturated ketone, ester formed by C1-C4 alkanoic acid and C1-C4 alkanol, C2-C4 aliphatic nitrile or benzonitrile and amide solvent.
16. The production method according to claim 15, wherein,
the transition metal catalyst is scandium trifluoromethanesulfonate, titanium tetraisopropoxide, titanium tartrate or TiO2、V2O5、NH4VO3、CrCl3、MnO2、FeCl3、Fe(OH)3Iron acetylacetonate, FeSO4、FeCl2Ferrocene, cobalt acetate, NiCl2Copper acetate, CuSO4、ZnO、ZrO2、RuCl3Palladium acetate, Pd (PPh)3)4Cl2、AgNO3、Rh(PPh3)4One or a mixture of more of Cl, ammonium ceric nitrate, phosphomolybdic acid and phosphotungstic acid;
the peroxide is hydrogen peroxide, sodium peroxide, barium peroxide, tert-butyl peroxy alcohol, cumene hydroperoxide, diisopropylbenzene hydroperoxide, m-chloroperoxybenzoic acid, sodium percarbonate, sodium perborate tetrahydrate, potassium peroxodisulfate, di-tert-butyl peroxide, tert-butyl peroxybenzoate, dibenzoyl peroxide or a hydrogen peroxide urea compound;
the reaction auxiliary agent is an alkaline reaction auxiliary agent or an acidic reaction auxiliary agent; wherein, the alkaline reaction auxiliary agent is NaOH and Na2CO3、NaOCH3Potassium tert-butoxide, N-diisopropylethylamine, tetrabutylammonium hydroxide, tetramethylguanidine, or 1, 8-diazabicyclo [ 5.4.0%]-undec-7-ene; the acidic reaction auxiliary agent is hydrochloric acid, tetrafluoroboric acid, sulfuric acid, methanesulfonic acid, p-toluenesulfonic acid, tetrafluoroboric acid or trifluoroacetic acid;
the solvent 1 is water, or an organic solvent, or a mixture of water and an organic solvent; here, the organic solvent is methanol, ethanol, N-hexane, N-heptane, dichloromethane, toluene, trifluoromethylbenzene, tetrahydrofuran, 1, 4-dioxane, acetone, ethyl acetate, isopropyl acetate, acetonitrile, N-dimethylformamide, or N, N-dimethylacetamide.
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