CN109206385B - Preparation method of dezocine impurity A and homologues thereof - Google Patents
Preparation method of dezocine impurity A and homologues thereof Download PDFInfo
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- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/19—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic hydroperoxides
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- C07D—HETEROCYCLIC COMPOUNDS
- C07D301/00—Preparation of oxiranes
- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/12—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with hydrogen peroxide or inorganic peroxides or peracids
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- C07D301/02—Synthesis of the oxirane ring
- C07D301/03—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds
- C07D301/14—Synthesis of the oxirane ring by oxidation of unsaturated compounds, or of mixtures of unsaturated and saturated compounds with organic peracids, or salts, anhydrides or esters thereof
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- C07D303/02—Compounds containing oxirane rings
- C07D303/12—Compounds containing oxirane rings with hydrocarbon radicals, substituted by singly or doubly bound oxygen atoms
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Abstract
The invention discloses a preparation method of dezocine impurity A and homologues thereof, which comprises the following steps: dezocine and homologs thereof are used as raw materials, transition metal is used as a catalyst, peroxide is used as an oxidant, and dezocine impurity A and homologs thereof are obtained through reaction. The invention has the advantages that: provides a new chemical method for converting phenolic substances into epoxide, simultaneously, the used reagent is simple and easy to obtain, the operation is simple and convenient, and part of unreacted raw materials can be recycled.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of dezocine impurity A and homologues thereof.
Background
Dezocine (Dezocine) is a typical opioid alkaloid analgesic developed by the company Astrazeneca, and belongs to an artificially synthesized mixed opioid receptor agonist-antagonist. Due to the good tolerance and safety of dezocine, the acceptance of markets and medical institutions is continuously improved, and the clinical demand is continuously increased. Dezocine is less addictive and is used for treating moderate to severe postoperative pain, visceral colic, and pain in patients with advanced cancer. Currently, dezocine has been approved by the food and drug administration of China to be marketed, and the synthesis process thereof has been industrialized (CN 102503840A). Dezocine is easy to generate degradation reaction in the stability experiment process to generate impurity A, and the chemical structure of the dezocine is as follows:
at present, there are 6 academic articles and 1 patent which reports methods for converting phenolic substances into corresponding epoxides, and the methods are classified into chemical methods and fermentation methods. In the structure of the raw material, the chemical method requires that the saturated carbon atom at the para position of the phenolic hydroxyl contains hydroxyl; in the oxidation process, the chemical process is further classified as NaBiO3Method and t-BuOK/O2Methods (WO2013/10102A2,2013; J.Am.Chem.Soc,2014,126, 16783-16792; J.Am.Chem.Soc,1997,119, 11315-11316; J.org.Chem.,1986,51, 2257-2266). For starting materials which contain no hydroxyl groups on the carbon atom opposite the phenolic hydroxyl group or double bonds on the carbon atom, the preparation of the corresponding epoxides is carried out by fermentation (Bioscience, biotechnology, and biochemistry,1993,57, 1387-.
At present, no report is available on the conversion of phenolic substances without hydroxyl group on saturated carbon atom para to phenolic hydroxyl group into corresponding epoxide by chemical method.
Disclosure of Invention
The invention takes the synthesis example of dezocine impurity A and homologues thereof, and adopts a chemical method to convert phenolic substances without hydroxyl on the para-saturated carbon atom of phenolic hydroxyl into corresponding epoxides. Meanwhile, the dezocine impurity A synthesized by the method and the homologues thereof have important significance for promoting the quality research of dezocine and provide more guiding significance for the clinical medication safety of the dezocine.
The invention aims to provide a preparation method of dezocine impurity A and homologues thereof, wherein the method has the advantages of simple and easily obtained reagents, simple and convenient operation and capability of recycling part of unreacted raw materials.
The invention is realized by the following technical scheme, and provides a preparation method of dezocine impurity A and homologues thereof, wherein the dezocine impurity A and the homologues thereof are shown as formula (I):
the preparation method comprises the following steps:
1) adding a compound shown in formula (II), a transition metal catalyst, peroxide, a reaction auxiliary agent and a reaction solvent into a reaction vessel, and reacting at-40-90 ℃;
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 process for the preparation of dezocine impurity a and its homologues, wherein, in formula (I) and formula (II), a single bond or a double bond is formed between C-13 and R; when C-13 forms a single bond with R, R is selected from the group consisting of a hydrogen atom, a hydroxyl group, and-N (R)1)(R2) Preferably is-N (R)1)(R2) And C-13 is in the S configuration; when a double bond is formed between C-13 and R, R is selected from oxygen atom, ═ N (R)1) (ii) a Wherein, N (R)1) and-N (R)1)(R2) R in (1)1Or R2Each independently selected from hydrogen, unsubstituted C1-C6 alkanoyl (e.g. formyl, acetyl, n-propionyl or n-butyryl, etc.), R3-O-c (O) -, phenylsulfonyl, p-toluenesulfonyl, or benzyl; wherein R is3Selected from methyl, ethyl, tert-butyl, benzyl, or fluorenylmethyl, preferably tert-butyl.
In the embodiment of the invention, the invention provides a preparation method of dezocine impurity A and homologues thereof, wherein the transition metal catalyst is one or a mixture of several of transition metal oxide, hydroxide, salt or 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, 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)4Cl, ammonium ceric nitrate, phosphomolybdic acid and phosphotungstic acid.
In the embodiment of the invention, the preparation method of dezocine impurity A and homologues thereof is provided, wherein 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, urea hydrogen peroxide complex.
In the embodiment of the invention, the invention provides a preparation method of dezocine impurity A and homologues thereof, wherein the reaction auxiliary agent comprises 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 or organic strong protonic acid; MOH, MOR, M2CO3、M3PO4、M2HPO4M in (1) is selected from Li, Na, K, Rb, Cs and Mg1/2、Ca1/2、Sr1/2、Ba1/2(ii) a R in MOR is selected from C1-C5 alkyl; furthermore, the utility modelPreferably, the alkaline reaction auxiliary agent is NaOH or Na2CO3、NaOCH3Potassium tert-butoxide, N-diisopropylethylamine, tetrabutylammonium hydroxide, tetramethylguanidine, 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.
In the embodiment of the invention, the invention provides a preparation method of dezocine impurity A and homologues thereof, wherein the reaction solvent 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, N-dimethylacetamide.
In the embodiment of the invention, the invention provides a preparation method of dezocine impurity A and homologues thereof, wherein, in the step 2), after the reaction mixture is subjected to post-treatment, the step can further comprise a step of recovering unreacted raw materials.
Compared with the prior art, the invention has the advantages that a novel chemical method is provided, and phenolic substances are converted into epoxide under the condition that the para-position carbon atom of phenolic hydroxyl does not contain hydroxyl; the method has important research significance for the diversified transformation of the phenolic substances. Meanwhile, the used reagent is simple and easy to obtain, the operation is convenient, and 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
To a 25mL single-necked round-bottomed flask was added 1g (1.0 equivalent) of dezocine, 0.1g (0.05 equivalent) of scandium trifluoromethanesulfonate, and 1, 8-diazabicyclo [5.4.0 ]]0.93g (1.5 equivalents) of-undec-7-ene, 10mL of dichloromethane, and 2.62g (5.0 equivalents) of 70% t-butanol peroxide were stirred at room temperature for 5 hours, and then the reaction was stopped. The reaction solution was diluted with 40mL of methylene chloride, and 20mL of a 5% NaOH aqueous solution and 5% Na were added in this order2S2O3Washing with 20mL of aqueous solution, separating liquid, and passing organic phase through anhydrous Na2SO42g of the extract is dried, concentrated to dryness under reduced pressure, and the residue is separated by column chromatography to obtain dezocine impurity A93 mg as off-white solid. Adjusting the pH value of the NaOH aqueous solution extract to 7 by using acetic acid, stirring for 30min in ice-water bath, filtering, drying a filter cake, and recovering 0.52g of dezocine. The charging amount of dezocine is 1.0g, the recovery amount is 0.52g, the consumption amount is 0.48g, and dezocine impurity A (namely the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 93mg, yield 18.4%. 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, M is dezocine impurity A molecular formula. Note: 1, 8-diazabicyclo [5.4.0 ]]The-undec-7-ene is abbreviated DBU in the examples which follow.
Example 2
20.0g (1.0 equivalent) of dezocine, 2.3g (0.1 equivalent) of titanium tetraisopropoxide, 6.0g (0.5 equivalent) of DBU and 200mL of dichloromethane are added into a 500mL three-necked flask, the temperature of a reaction solution is reduced to-10 ℃, 62.0g (4.0 equivalent) of 80% cumene hydroperoxide is slowly dripped, the reaction solution takes 2.0 hours, the reaction temperature is slowly increased to the room temperature after the dripping is finished, the reaction solution reacts for 3 hours, the reaction temperature is increased to 75 ℃, and the reaction solution reacts for 1 hour. The reaction is stopped, and the reaction mixture is stirred,the reaction mixture was extracted with 70mL of 5% aqueous NaOH solution, the insoluble matter was filtered, the solution was separated, and the organic phase was extracted twice with 50mL of 5% aqueous NaOH solution and 5% Na solution2S2O3Extracting 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 using 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 dezocine as an impurity A. The crystallization mother liquor is separated by column chromatography to obtain 0.39g of dezocine impurity A. 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 charging amount of dezocine is 20g, the recovery amount is 13.1g, the consumption amount is 6.9g, and dezocine impurity A (namely the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2All are hydrogen) 2.1g, yield 28.8%. The product characterization data were the same as in example 1.
Example 3
2g (1.0 equivalent) of dezocine, 0.23g (0.1 equivalent) of titanium tetraisopropoxide, 0.6g (0.5 equivalent) of DBU and 10mL of isopropyl acetate were added to 50mL of a single port, the temperature of the reaction mixture was lowered to-10 ℃, 6.2g (4.0 equivalents) of 80% cumene hydroperoxide was slowly added dropwise, and the reaction was carried out at 60 ℃ for 3 hours after the completion of the addition. Stirring was stopped, the reaction mixture was extracted with 20mL of a 5% aqueous NaOH solution, the insoluble matter was filtered, the solution was separated, and the organic phase was successively extracted with 10mL of a 5% aqueous NaOH solution and 5% Na2S2O3Washing with 30mL of aqueous solution, detecting that the organic phase has no peroxide residue by using starch-KI test paper, separating liquid, concentrating the organic phase to dryness, and separating the residue by column chromatography to obtain dezocine impurity A192 mg. 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 and recovering 1.2g of dezocine. The charging amount of dezocine is 2.0g, the recovery amount is 1.2g, the consumption amount is 0.8g, and the impurity A (namely the compound of the formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 192mg, yield 22.8%. The product characterization data were the same as in example 1.
Example 4
10g (1.0 equivalent) of dezocine, 1.16g (0.1 equivalent) of titanium tetraisopropoxide, 3.0g (0.5 equivalent) of DBU and 100mL of toluene were added to a 250mL three-necked flask, the temperature of the reaction solution was lowered to 0 ℃, 31.1g (4.0 equivalents) of 80% cumene hydroperoxide was slowly added dropwise over 1.0 hour, the reaction temperature was raised to 90 ℃ after the completion of the addition, and the mixture was stirred for 45 min. The reaction was stopped, the reaction mixture was extracted with 50mL of a 5% aqueous NaOH solution, insoluble materials were removed by filtration, the mixture was separated, and the organic phase was separated with 50mL of a 5% aqueous NaOH solution and 5% Na2S2O3Washing with 100mL of aqueous solution, detecting that the organic phase has no peroxide residue by using starch-KI test paper, separating the liquid, and carrying out anhydrous MgSO on the organic phase45.0g of the product is dried, the oil pump is decompressed and concentrated to dryness, and the residue is recrystallized by 25mL of mixed solvent of dichloromethane and normal hexane (the volume ratio is 1:7) to obtain 0.63g of dezocine impurity A. The crystallization mother liquor is separated by column chromatography to obtain 0.19g of dezocine impurity A. And mixing the NaOH aqueous solution extract, adjusting the pH value to 7 by using acetic acid, stirring in an ice water bath for 30min, carrying out suction filtration, and carrying out column chromatography separation on a filter cake to recover 6.2g of dezocine. The charging amount of dezocine is 10.0g, the recovery amount is 6.2g, the consumption amount is 3.8g, and the impurity A (namely the compound of the formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 0.82g, yield 20.4%. The product characterization data were the same as in example 1.
Example 5
A100 mL three-necked flask was charged with 5g (1.0 equivalent) of dezocine, 1.16g (0.1 equivalent) of titanium tetraisopropoxide, 0.42g (0.1 equivalent) of diethyl D, L-tartrate, 2.63g (1.0 equivalent) of N, N-diisopropylethylamine, 0.5g (0.21 equivalent) of tetramethylguanidine, and 50mL of trifluoromethylbenzene, and the reaction temperature was lowered to 0 ℃ and 7.42g (1.5 equivalents) of 80% diisopropylbenzene hydroperoxide was slowly added dropwise over 1.0 hour, followed by stirring at room temperature for 24 hours after completion of the dropwise addition. Stirring was stopped, the reaction solution was extracted with 50mL of a 5% aqueous NaOH solution, insoluble matter was removed by filtration, the mixture was separated, and the organic phase was separated with 30mL of a 5% aqueous NaOH solution and 5% Na2S2O3Extracting with 30mL of water solution once, detecting that the organic phase has no peroxide residue by using starch-KI test paper, separating the liquid, and using anhydrous MgSO for the organic phase45.0g of the extract is dried, concentrated to dryness under reduced pressure, and the residue is filtered offColumn chromatography separation to obtain dezocine impurity A0.64 g. And mixing the NaOH aqueous solution extract, adjusting the pH value to 7 by using acetic acid, stirring in an ice water bath for 30min, carrying out suction filtration, and carrying out column chromatography separation on a filter cake to recover 3.3g of dezocine. The charging amount of dezocine is 5.0g, the recovery amount is 3.3g, the consumption amount is 1.7g, and dezocine impurity A (namely the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 0.64g, yield 35.6%. The product characterization data were the same as in example 1.
Example 6
To a 1L three-necked bottle was added dezocine 10g (1.0 equivalent), V2O50.75g (0.10 equivalent) of 10 percent NaOH aqueous solution 50mL, controlling the temperature in an ice-water bath, dropwise adding 30 percent hydrogen peroxide 20mL into a reaction bottle, reacting for 3 hours, and suspending the reaction; extracting the reaction solution by using 50mL of dichloromethane, separating the solution, extracting an organic phase by using 10mL of 10% NaOH aqueous solution, combining the obtained aqueous phase with the first extracted aqueous phase, pouring the combined aqueous phase into a reaction bottle, continuously dropwise adding 20mL of 30% hydrogen peroxide into the reaction bottle, reacting for 3h, and operating according to the first post-treatment; the reaction was repeated for 6 cycles to stop the reaction. The organic phases are combined, extracted twice by 50mL of 5% NaOH aqueous solution, separated, and the organic phase is extracted by anhydrous Na2SO410g of the dezocine is dried, concentrated and separated by column chromatography to obtain 3.63g of dezocine impurity A. Cooling the rest reaction solution to 0 deg.C, controlling temperature in ice-water bath, and slowly adding Na2S2O3Solid to peroxide (starch-KI test paper detection), adjusting pH to 7 with acetic acid, stirring for 60min, filtering, separating filter cake by column chromatography, and recovering 3.37g dezocine. The charging amount of dezocine is 10.0g, the recovery amount is 3.37g, the consumption amount is 6.63g, and dezocine impurity A (namely the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 3.63g, yield 51.8%. The product characterization data were the same as in example 1.
Example 7
To a 50mL single-necked flask was added 1g (1.0 equivalent) of dezocine and CrCl3100mg (0.15 equivalent) of 10mL of 10% NaOH aqueous solution, dropwise adding 10mL of 30% hydrogen peroxide into a reaction bottle, reacting for 20min after dropwise adding, and reacting with dichloromethane and n-hexane50mL of the reaction mixture (volume ratio: 1) was extracted three times. Anhydrous Na for organic phase2SO42.0g of the crude product is dried and concentrated to dryness under reduced pressure to obtain dezocine impurity A (i.e. the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 48mg, yield 4.5%. The product characterization data were the same as in example 1.
Example 8
To a 250mL beaker was added 1g (1.0 equivalent) of dezocine and MnO250mg (0.14 equivalent), 10mL of 10% NaOH aqueous solution and 50mL of mixed solvent of dichloromethane and n-hexane (volume ratio is 1:1), mechanically stirring, dropwise adding 50mL of 30% hydrogen peroxide into a beaker, reacting for 20min after dropwise adding, stopping stirring until no bubbles are generated, and separating an organic phase; the remaining aqueous phase was continuously mixed with 50mL of a solvent mixture of dichloromethane and n-hexane (volume ratio: 1), MnO250mg, dropwise adding 50mL of hydrogen peroxide, reacting until no bubbles are generated, and separating an organic phase; combining the two organic phases, adding anhydrous Na2SO45.0g, concentrated to dryness to obtain dezocine impurity A (i.e. compound of formula (I), wherein, C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 247mg, yield 23.4%. The product characterization data were the same as in example 1.
Example 9
To a 250mL beaker was added 1g (1.0 equivalent) of dezocine and MnO254mg (0.15 equivalent), 10mL of 20% NaOH aqueous solution and 50mL of mixed solvent of dichloromethane and N-hexane (volume ratio is 1:1), mechanically stirring, adding 1.99g (2.0 equivalent) of dibenzoyl peroxide in batches into a reaction bottle, reacting at 35 ℃ for 2h after the addition is finished, separating an organic phase, concentrating to dryness, and performing column chromatography separation to obtain dezocine impurity A (namely the compound of the formula (I), wherein a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 134mg, yield 12.7%. The product characterization data were the same as in example 1.
Example 10
To a 250mL beaker were added 1g (1.0 equivalent) of dezocine, 10mL of a 10% aqueous NaOH solution, and FeCl350mg (0.08 eq.) of50mL of chloromethane is mechanically stirred, 50mL of 30% hydrogen peroxide is dripped into a reaction bottle, the reaction is carried out for 10min after the dripping is finished, no bubble is generated in the system, the stirring is stopped, the organic phase is separated, the water phase is extracted once by 50mL of dichloromethane, the organic phases are combined and are subjected to anhydrous Na2SO45.0g of the crude product is dried, concentrated and separated by column chromatography to obtain dezocine impurity A (i.e. the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 75mg, yield 7.1%. The product characterization data were the same as in example 1.
Example 11
To a 250mL beaker were added 1g (1.0 equivalent) of dezocine, 10mL of a 10% aqueous NaOH solution, and ZrO225mg (0.05 equivalent) of dichloromethane and 50mL of dichloromethane are mechanically stirred, 30 percent hydrogen peroxide solution is dropwise added into a reaction bottle for 50mL, the reaction is carried out for 30min after the dropwise addition, the system does not generate bubbles any more, the stirring is stopped, the organic phase is separated, the water phase is extracted once by 50mL of dichloromethane, the organic phase is merged, and anhydrous Na2SO45.0g of the crude product is dried, concentrated and separated by column chromatography to obtain dezocine impurity A (i.e. the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 102mg, yield 9.7%. The product characterization data were the same as in example 1.
Example 12
To a 250mL beaker were added 1g (1.0 equivalent) of dezocine, 10mL of a 10% aqueous NaOH solution, and ZrO225mg (0.05 equivalent) of dichloromethane and 50mL of dichloromethane are added into a reaction bottle by a mechanical stirring way, 20g of hydrogen peroxide-urea compound is added into the reaction bottle in batches, the reaction is continued for 60min after the addition, the stirring is stopped, the organic phase is separated, the water phase is extracted once by 50mL of dichloromethane, the organic phase is combined, and anhydrous Na is added2SO45.0g of the crude product is dried, concentrated and separated by column chromatography to obtain dezocine impurity A (i.e. the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 153mg, yield 14.5%. The product characterization data were the same as in example 1.
Example 13
To a 250mL beaker was added 1g (1.0 equivalent) of dezocine, 10% NaOH waterSolution 15mL, RuCl342mg (0.05 equivalent) of dichloromethane and 50mL of dichloromethane are mechanically stirred, 50mL of 30 percent hydrogen peroxide is dripped into a reaction bottle under ice bath, the reaction is continued for 30min after the dripping is finished, no bubble is generated in the system, the stirring is stopped, an organic phase is separated, 50mL of normal hexane is added into the organic phase, the organic phase is extracted by 5 percent NaOH aqueous solution, and anhydrous Na2SO45.0g of the crude product was dried and concentrated to dryness to give dezocine as impurity A (i.e., a compound of formula (I) wherein C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 283mg, yield 26.8%. The product characterization data were the same as in example 1.
Example 14
Into a 250mL three-necked flask were added 3.5g (1.0 equivalent) of dezocine, 40mg (0.01 equivalent) of ferrous sulfate heptahydrate, and 10mL of water, followed by 30% H2SO4Adjusting the pH value of the aqueous solution to 3.5, mechanically stirring, reducing the reaction temperature to-40 ℃ to solidify the reaction solution, dropwise adding 50mL of 30% hydrogen peroxide into the reaction bottle, reacting at-30 ℃ for 6h after dropwise adding, and stopping stirring. Adding the reaction mixture into 300mL of a mixed aqueous solution of 15% NaOH and 15% sodium thiosulfate in batches, controlling the internal temperature to be lower than-15 ℃, extracting the mixture for four times by using 100mL of a mixed solvent of methyl tert-butyl ether and dichloromethane (the volume ratio is 3:1) after the addition is finished, combining organic phases, and adding anhydrous Na2SO45.0g of the mixture is dried and concentrated to be dry, thus obtaining 453mg of dezocine impurity A; adjusting the pH value of the water phase to 7 with acetic acid, stirring for 60min in an ice-water bath, filtering, recovering 2.59g of dezocine, extracting the filtrate for three times with 50mL of dichloromethane, concentrating under reduced pressure to dryness, recovering 0.42g of dezocine, and recovering 3.01g of the dezocine. The charging amount of dezocine is 3.5g, the consumption amount is 0.49g, and dezocine impurity A (namely the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2All were hydrogen) 453mg, yield 87.5%. The product characterization data were the same as in example 1.
Example 15
Adding dezocine 3.5g (1.0 equivalent), ferrous sulfate heptahydrate 40mg (0.01 equivalent) and water 10mL into a 250mL three-necked flask, adjusting pH to 4.0 with concentrated hydrochloric acid, mechanically stirring, reducing reaction temperature to-30 deg.C, and adding dropwise into the reaction flaskAdding 50mL of 30% hydrogen peroxide, reacting at-20 ℃ for 5h after the dropwise addition is finished, and stopping stirring. Adding the reaction mixture into 300mL of a mixed aqueous solution of 15% NaOH and 15% sodium thiosulfate in batches, controlling the internal temperature to be lower than-15 ℃, extracting the mixture for four times by using 100mL of a mixed solvent of methyl tert-butyl ether and dichloromethane (the volume ratio is 3:1) after the addition is finished, combining organic phases, and adding anhydrous Na2SO45.0g of the crude product is dried and concentrated to dryness to obtain dezocine impurity A (i.e. the compound of formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 397mg, yield 10.8%. The product characterization data were the same as in example 1.
Example 16
Adding 2.0g (1.0 equivalent) of dezocine, 150mg (0.1 equivalent) of ferrocene, 20mL of methanol and 2.20g (5.0 equivalent) of sodium methoxide into a 100mL single-neck bottle, cooling the temperature of the reaction solution to-20 ℃, dropwise adding a dichloromethane (20mL) solution of 3.44g (2.0 equivalent) of 85% m-chloroperoxybenzoic acid into the reaction solution, slowly heating to 0 ℃ after dropwise adding, reacting for 2h, and dropwise adding 10% Na into the reaction solution2S2O3The reaction was quenched with 30mL of aqueous solution. After quenching was complete, the organic phase was separated and the remaining aqueous phase was extracted twice with 50mL of dichloromethane. The organic phases are combined and passed through anhydrous Na2SO4Drying, concentrating, and separating by column chromatography to obtain dezocine impurity A (i.e. compound of formula (I), wherein C-13 forms single bond with R, and R is-N (R)1)(R2)，R1And R2Both hydrogen) 198mg, yield 9.4%. The product characterization data were the same as in example 1.
Example 17
Adding 10.00g (1.0 equivalent) of dezocine, 50mL of dichloromethane and 5.00g (1.22 equivalent) of triethylamine into a 250mL single-neck bottle, reducing the temperature of the solution to 0 ℃, slowly adding 4.37g (1.05 equivalent) of acetic anhydride in 50mL of dichloromethane, continuing the reaction for 30min after the dropwise addition is finished, and detecting the reaction by thin-layer chromatography (a developing agent 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 dryConcentrating under reduced pressure to obtain N-acetyldezocine (compound of formula (II), wherein C-13 forms single bond with R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Is acetyl) 11.36g, white solid, yield 97%.
To a 50mL 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 A87 mg, white solid. The N-acetyl dezocine has the material feeding amount of 500mg, the recovery amount of 138mg and the consumption amount of 362mg to obtain N-acetyl dezocine impurity A (namely the compound of the formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Is an acetyl group) 87mg, yield 22.9%. 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.
Example 18
Adding 5.00g (1.0 equivalent) of dezocine, 50mL of dichloromethane and 2.47g (1.20 equivalent) of triethylamine into a 100mL single-neck bottle, reducing the temperature of the solution to 0 ℃, slowly dropwise adding a dichloromethane (20mL) solution of 4.08g (1.05 equivalent) of p-toluenesulfonyl chloride, continuing the reaction at room temperature for 45min after the dropwise addition is finished, and detecting the reaction by thin-layer chromatography (a developing agent is CH)2Cl2/CH3OH ═ 10:1), the reaction was complete. Stopping stirring, and sequentially using 1moL/L hydrochloric acid 30mL and 5% NaHCO to the organic phase3Washed once with 30mL of an aqueous solution and 30mL of a saturated saline solution, and washed with anhydrous Na2SO4Drying 5g, concentrating under reduced pressure to obtain N-p-toluenesulfonyldiazocine (compound of formula (II), wherein, C-13 and R form a single bond, and R is-N (R)1)(R2)，R1Is hydrogen, R2Is p-toluenesulfonyl) 7.74g, white solid, yield 95%.
To a 50mL single neck flask was added 800mg (1.0 eq) of N-p-toluenesulfonyldiazocin, NiCl2·6H2O50 mg (0.11 eq), AgNO320mg (0.06 equiv.), 5mL of 10% NaOH aqueous solution and 5mL of acetone were added in portions with K2S2O81.2g (2.2 equiv.) of the reaction mixture, stirring at room temperature for 6 hours, stopping the reaction, diluting the reaction mixture with 30mL of water, filtering the insoluble matter, extracting the filtrate with 50mL of dichloromethane three times, combining the organic phases, anhydrous Na2SO4Drying, concentrating to dry, and separating by column chromatography to obtain N-p-toluenesulfonyldiazocine impurity A (i.e. compound of formula (I), wherein, C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1Is hydrogen, R2P-toluenesulfonyl) 190mg, white solid, yield 22.9%. Hydrogen nuclear magnetic resonance spectroscopy (500MHz, CDCl)3) δ 7.84(d, J ═ 7.95Hz,2H),7.32(d, J ═ 7.95Hz,2H),6.45(d, J ═ 9.65Hz,1H),6.34(d, J ═ 9.80Hz,1H),6.32(d, J ═ 1.65Hz,1H),5.06-4.94(m,1H),3.91(dd, J ═ 11.00,6.05Hz,1H),3.51(d, J ═ 2.6Hz,1H),2.44(s,3H),2.41(s,1H),1.88-1.75(m,1H),1.65-1.55(m,4H),1.44-1.25(m,3H),1.06(s,3H),1.05-0.83(m, 0.73H); nuclear magnetic resonance carbon spectrum (125MHz, CDCl)3) Delta 185.8,159.8,146.3,143.7,137.6,132.8,131.9,130.8,129.8,128.8,127.1,66.3,65.5,55.7,54.9,40.8,36.7,36.2,35.0,29.6,25.5,22.1, 21.5; mass spectrum (ESI +, CH)3CN) calculated value C23H28NO4S+[M+H]+414.17, found 414.20, M is N-p-toluenesulfonyldiazocine impurity A molecular formula.
Example 19
Into a 100mL single-necked flask were added dezocine 5.0g and methylene chloride30mL and 2.47g (1.20 equiv) of triethylamine, reducing the temperature of the solution to 0 ℃, slowly dropwise adding a dichloromethane (20mL) solution of 2.78g of propionic anhydride, continuously reacting at room temperature for 50min after dropwise adding, and detecting the reaction by thin-layer chromatography (a developing agent 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 phase3Washed once with 50mL of aqueous solution and 50mL of saturated saline solution and anhydrous Na2SO4Drying 5g, concentrating under reduced pressure to obtain N-propionyl dezocine (i.e. compound of formula (II), wherein, C-13 forms single bond with R, R is-N (R)1)(R2)，R1Is hydrogen, R2Propionyl) 5.77g, white solid, yield 94%.
To a 5mL vial was added 200mg (1.0 equivalent) of N-propionidizocine, 5mg (0.024 equivalent) of iron acetylacetonate, Rh (PPh)3)4Cl 5.0mg (0.006 eq), Na2CO377mg (1.1 equiv.), 410mg (4.0 equiv.) of sodium perborate tetrahydrate, 1mL of water, 0.2mL of N, N-dimethylformamide and 2mL of butanone were stirred at room temperature for 4 hours to stop the reaction, the reaction solution was diluted with 30mL of water, insoluble materials were removed by filtration, the filtrate was extracted three times with 20mL of dichloromethane, the organic phases were combined, and anhydrous Na was added2SO4Drying 5g, concentrating to dry, and separating by column chromatography to obtain N-propionyl dezocine impurity A (i.e. compound of formula (I), wherein, C-13 forms single bond with R, R is-N (R)1)(R2)，R1Is hydrogen, R2Is propionyl) sample 73mg, white solid, yield 34.9%. Hydrogen nuclear magnetic resonance spectroscopy (500MHz, CDCl)3) δ 6.49(dd, J ═ 9.85,1.65Hz,1H),6.44(d, J ═ 9.85Hz,1H),5.57(d, J ═ 10.6Hz,1H),4.81(dd, J ═ 10.7,6.05Hz,1H),3.65(d, J ═ 2.6Hz,1H),2.75(s,1H),2.35-2.31(m,2H),2.03-1.93(m,1H),1.84-1.61(m,7H),1.48-1.38(m,1H),1.25(s,3H),1.21(t, J ═ 7.60Hz,3H),0.93-0.81(m, 2H); nuclear magnetic resonance carbon spectrum (125MHz, CDCl)3) δ 186.0,173.1,160.4,146.9,132.6,131.6,66.5,55.7,48.6,40.7,36.6,36.4,30.1,28.9,26.8,25.5,22.2, 10.0; mass spectrum (ESI +, CH)3CN) calculated value C19H26NO3 +[M+H]+316.19, found value is 316.20, M is N-propionyl dezocine impurity A molecular formula.
Example 20
A5 mL vial was charged with 12mg (0.10 equiv.) of copper acetate, 5.0mg (0.034 equiv.) of palladium acetate, 3mL of methanol, and PPh360mg (0.35 equivalent), stirring for 30min, adding 200mg (1.0 equivalent) of N-propionyl dezocine, 72mg (2.0 equivalent) of sodium methoxide and 300mg (3.5 equivalent) of 70% tert-butyl peroxide, stirring at room temperature for 8h, stopping reaction, diluting the reaction solution with 30mL of water, extracting with 10mL of dichloromethane for three times, combining organic phases, and carrying out column chromatography separation to obtain N-propionyl dezocine impurity A (namely the compound of formula (I), wherein a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Is propionyl) sample 65mg, white solid, yield 31.1%. The product characterization data were the same as in example 19.
Example 21
A5 mL vial was charged with 12mg (0.1 eq) of copper acetate, 5mg (0.034 eq) of palladium acetate, 2mL of toluene, and PPh360mg (0.35 equivalent), stirring for 30min, adding 200mg (1.0 equivalent) of N-propionyl dezocine, 110mg (1.2 equivalent) of potassium tert-butoxide and 300mg (3.5 equivalent) of 70% tert-butyl alcohol peroxide, stirring at room temperature for 8h, stopping reaction, diluting the reaction solution with 30mL of water, extracting with 10mL of dichloromethane for three times, combining organic phases, and carrying out column chromatography separation to obtain N-propionyl dezocine impurity A (namely the compound of formula (I), wherein a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Is propionyl) sample 58mg, white solid, yield 27.8%. The product characterization data were the same as in example 18.
Example 22
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 equivalent), refluxing for 2h, detecting the reaction by thin layer chromatography (the developing solvent is CH)2Cl2/CH3OH ═ 10:1), the reaction was complete. Stopping stirring, concentrating the reaction solution under reduced pressure, and separating by column chromatography to obtain N-tert-butoxycarbonyl dezocine (i.e. compound of formula (II) wherein C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Is tert-butoxycarbonylacyl) 6.41g, white solid, yield 91%. Note: boc is tert-butyloxycarbonyl acyl.
To a 5mL vial was added N-Boc dezocine 200mg, acetonitrile 2mL, Pd (PPh)3)4Cl235mg (0.05 equivalent), 133mg (2.0 equivalent) of tetramethylguanidine, and 2mL 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 50mL of methylene chloride, and 10mL of a 10% NaOH aqueous solution and 5% Na were added2S2O310mL of each extract was extracted once with anhydrous Na2SO42g of the crude product is dried, concentrated and separated by column chromatography to obtain N-tert-butoxycarbonyl dezocine impurity A (namely the compound of the formula (I), wherein, a single bond is formed between C-13 and R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Was t-butoxycarbonylacyl) 71mg, a white solid, yield 34.1%. 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-tert-butoxycarbonyl dezocine impurity A molecular formula.
Example 23
Into a 5mL vial were added 200mg of N-Boc dezocine and 10mg of phosphomolybdic acid (molecular formula H)3PO4·12MoO3·H2O, 0.0094 equivalent), 10mg of phosphotungstic acid (molecular formula is P)2O5·24(WO3)·44(H2O), 0.0060 equivalent), 133mg (2.0 equivalent) of tetramethylguanidine, and 2mL of 70% t-butyl alcohol peroxide, and the reaction was stopped after 5.5 hours at room temperature. The reaction mixture was diluted with 50mL of methylene chloride, and 10mL of a 10% NaOH aqueous solution and 5% Na were added2S2O310mL of each extract was extracted once with anhydrous Na2SO42g of the crude product is dried, concentrated and separated by column chromatography to obtain N-Boc dezocine impurity A (namely, the compound of formula (I))A compound wherein C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Was t-butoxycarbonylacyl) 77mg, a white solid, yield 37.0%. Product characterization data were the same as for example 22.
Example 24
To a 5mL vial was added N-Boc dezocine 100mg, 10% Na2CO31mL of an aqueous solution, and 5mg of phosphomolybdic acid (molecular formula: H)3PO4·12MoO3·H2O, 0.0094 equivalent), 1mL of 70% tert-butyl peroxy-alcohol, reacting for 5.5h at normal temperature, and stopping the reaction. The reaction mixture was diluted with 10mL of methylene chloride, and then, 5mL of a 10% NaOH aqueous solution and 5% Na were added2S2O3Extracting 5mL of the extract once, concentrating, and separating by column chromatography to obtain N-Boc dezocine impurity A (i.e. compound of formula (I), wherein C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Was t-butoxycarbonylacyl) 46mg, a white solid, yield 43.7%. Product characterization data were the same as for example 22.
Example 25
In operation similar to example 22, a 5mL vial was charged with N-Boc dezocine 100mg, 10% Na2CO31mL of an aqueous solution, and 5mg of phosphomolybdic acid (molecular formula: H)3PO4·12MoO3·H2O, 0.0094 equivalent), 13mg of tetrabutylammonium chloride and 1mL of 70% tert-butyl peroxy alcohol, reacting for 5.5h at normal temperature, and stopping the reaction. The reaction mixture was diluted with 10mL of methylene chloride, and then, 5mL of a 10% NaOH aqueous solution and 5% Na were added2S2O3Extracting 5mL of the extract once, concentrating, and separating by column chromatography to obtain N-Boc dezocine impurity A (i.e. compound of formula (I), wherein C-13 forms a single bond with R, and R is-N (R)1)(R2)，R1Is hydrogen, R2Tert-butoxycarbonyl) 64mg, white solid, yield 60.8%. Product characterization data were the same as for example 22. Comparison of this example with example 24 shows that the addition of a phase transfer catalyst (such as tetrabutylammonium chloride in this example) in some examples improves the yield.
Example 26
Adding C-13-iminooxazone into a 25mL single-mouth bottleOctyl (i.e., a compound of formula (II) wherein a double bond is formed between C-13 and R, R is ═ N (R1), and R1 is hydrogen) 100mg, 0.5mL of a 10% aqueous NaOH solution, 1.0mg (0.013 equivalent) of iron sulfate heptahydrate, cooling in an ice-water bath for 30min, adding 2.5mL of 30% hydrogen peroxide, reacting for 2.5h, and stopping the reaction. Diluting the reaction solution with 10mL of water, extracting with 10mL of dichloromethane, concentrating, and separating by column chromatography to obtain C13-iminodezocine impurity A (i.e. a compound of formula (I), wherein a double bond is formed between C-13 and R, and R is ═ N (R)1)，R1Is hydrogen) 41mg, white solid, yield 38.8%. Hydrogen nuclear magnetic resonance spectroscopy (500MHz, CDCl)3) δ 6.47(dd, J ═ 9.85,1.5Hz,1H),6.40(d, J ═ 9.85Hz,1H),6.35(d, J ═ 1.5Hz,1H),6.00(br,1H),2.68(s,1H),2.00-1.92(m,1H),1.88-1.59(m,6H),1.44-1.30(m,1H),1.28(s,3H),1.20-1.01(m,1H),0.91-0.83(m, 2H); nuclear magnetic resonance carbon spectrum (125MHz, CDCl)3) Delta 186.0,169.9,160.5,147.0,132.6,131.7,66.8,56.2,45.4,43.4,34.4,29.2,28.5,25.6,23.0, 21.4; mass spectrum (ESI +, CH)3OH) calculated value C16H20NO2 +[M+H]+258.15, found in 258.22, M is C13-iminodezocine impurity A molecular formula.
Example 27
100mg of C-13-oxodezocine (i.e., a compound of formula (II) wherein a double bond is formed between C-13 and R, and R is ═ O), 1mL of a 10% NaOH aqueous solution, and 1.5mg (0.013 equivalent) of iron sulfate heptahydrate were added to a 25mL single-neck flask, and after cooling in an ice-water bath for 30min, 2.5mL of 30% hydrogen peroxide was added, and the reaction was stopped for 2.5 h. The reaction mixture was diluted with 10mL of water, extracted with 10mL of dichloromethane, concentrated, and subjected to column chromatography to obtain 38mg of C-13-oxodezocine impurity a (i.e., a compound of formula (I) wherein a double bond is formed between C-13 and R, and R is ═ O) as a white solid, with a yield of 35.9%. Hydrogen nuclear magnetic resonance spectroscopy (500MHz, CDCl)3) δ 6.49(dd, J ═ 9.85,1.5Hz,1H),6.43(d, J ═ 9.85Hz,1H),6.39(d, J ═ 1.5Hz,1H),2.73(s,1H),2.20 to 1.94(m,1H),1.94 to 1.64(m,6H),1.47 to 1.37(m,1H),1.31(s,3H),1.22 to 1.07(m,1H),0.94 to 0.87(m, 2H); nuclear magnetic resonance carbon spectrum (125MHz, CDCl)3) δ 219.3,185.8,161.3,148.6,133.6,132.6,66.8,56.4,46.1,44.1,35.1,29.3,28.6,25.6,23.1, 21.6; mass spectrum (ESI +, CH)3OH) calculated value C16H18O3Na+[M+H]+281.11, found 281.20, M is C-13-oxo dizocine impurity A molecular formula.
Claims (8)
1. A method for preparing dezocine impurity a and homologs thereof, wherein the dezocine impurity a and homologs thereof are represented by formula (I):
the preparation method comprises the following steps:
1) adding a compound shown in formula (II), a transition metal catalyst, peroxide, a reaction auxiliary agent and a reaction solvent into a reaction vessel, and reacting at-40-90 ℃;
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);
in formula (I) and formula (II): c-13 forms a single bond or a double bond with R; when C-13 forms a single bond with R, R is selected from the group consisting of a hydrogen atom, a hydroxyl group, and-N (R)1)(R2) And C-13 is in the S configuration; when a double bond is formed between C-13 and R, R is selected from oxygen atom, ═ N (R)1) (ii) a Wherein, N (R)1) and-N (R)1)(R2) R in (1)1Or R2Each independently selected from hydrogen, unsubstituted C1-C6 alkanoyl, R3-O-c (O) -, phenylsulfonyl, p-toluenesulfonyl, or benzyl; wherein R is3Selected from methyl, ethyl, tert-butyl, benzyl, or fluorenylmethyl,
wherein, the transition metal catalyst is one or a mixture of several of transition metal oxides, hydroxides, salts or complexes; 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, 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 comprises 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 or organic strong protonic acid; MOH, MOR, M2CO3、M3PO4、M2HPO4M in (1) is selected from Li, Na, K, Rb, Cs and Mg1/2、Ca1/2、Sr1/2、Ba1/2(ii) a R in MOR is selected from C1-C5 alkyl;
the reaction solvent 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 solvent.
2. The process according to claim 1, wherein, in formula (I) and formula (II): when C-13 forms a single bond with R, R is-N (R)1)(R2)。
3. The process according to claim 1, wherein R is3Is a tert-butyl group.
4. The process according to any one of claims 1 to 3, wherein 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)4Cl, ammonium ceric nitrate, phosphomolybdic acid and phosphotungstic acid.
5. The process according to any one of claims 1 to 3, wherein the peroxide is hydrogen peroxide, sodium peroxide, barium peroxide, t-butyl peroxy-alcohol, cumene hydroperoxide, diisopropylbenzene hydroperoxide, m-chloroperoxybenzoic acid, sodium percarbonate, sodium perborate tetrahydrate, potassium peroxodisulfate, di-t-butyl peroxide, t-butyl peroxybenzoate, dibenzoyl peroxide, urea hydrogen peroxide complex.
6. The method according to any one of claims 1 to 3, wherein the alkaline reaction promoter is NaOH or Na2CO3、NaOCH3Potassium tert-butoxide, N-diisopropylethylamine, tetrabutylammonium hydroxide, tetramethylguanidine, 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 and trifluoroacetic acid.
7. The process according to any one of claims 1 to 3, wherein 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, N-dimethylacetamide.
8. The production method according to any one of claims 1 to 3, wherein the step 2) further comprises a step of recovering a part of the unreacted raw materials after the reaction mixture is post-treated.
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| CN104910002A (en) * | 2015-05-28 | 2015-09-16 | 温州医科大学 | Dezocine key intermediate preparation method |
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