CN108299173B - Asymmetric synthesis method of dezocine key intermediate - Google Patents
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- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
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- C07C45/67—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton
- C07C45/673—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by isomerisation; by change of size of the carbon skeleton by change of size of the carbon skeleton
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Abstract
The invention discloses an asymmetric synthesis method of dezocine key intermediate (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecene-13-ketone, which comprises the following steps: the alkylation reaction intermediate (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone is synthesized stereoselectively by adopting 7-methoxy-1-methyl-2-tetralone as an initial raw material under the catalysis of cinchonidine derivative; cyclizing under the action of alkali, and recrystallizing to obtain (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxyl-5-methyl-5, 11-methylene benzocyclodecene-13-ketone with high chiral purity. The method has the advantages of high reaction yield, low cost and mild conditions, and is suitable for large-scale high-efficiency synthesis of dezocine.
Description
Technical Field
The invention relates to synthesis of a pharmaceutical compound, in particular to an asymmetric synthesis method of a chiral drug dezocine key intermediate (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxyl-5-methyl-5, 11-methylene benzocyclodecene-13-ketone.
Background
Dezocine, having the english name Dezocine, having the chemical name (-) - [5R- (5 α,11 α, 13S) ] -13-amino-5, 6,7,8,9,10,11, 12-octahydro-5-methyl-5, 11-methylenebenzocyclodecen-3-ol, having the chemical structural formula shown in formula i:
dezocine is developed by Astrazeneca company, belongs to a potent opioid analgesic, and mainly acts on mu receptors and kappa receptors. The dezocine has the analgesic effect equivalent to that of morphine, has small addiction and slight adverse reaction compared with similar medicines, is suitable for treating moderate to severe postoperative pain, visceral colic and pain of patients with late cancer, and becomes one of the medicines with wide postoperative analgesic application in recent years.
The dezocine structure has three continuous chiral centers, wherein 1 is a quaternary carbon center and has a bridged ring structure, so the synthesis difficulty is high. Few synthesis methods are published at home and abroad; U.S. Pat. No. 4,4001331 discloses a process for the synthesis of racemic dezocine starting from 7-methoxy-1-methyl-2-tetralone.
Chinese patent CN102503840A discloses a method for resolving dezocine, wherein intermediate 7 needs to be resolved by (+) L-tartaric acid and (-) D-tartaric acid to obtain dezocine precursor 8 with high optical purity, and the yield is only 34-37%.
5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecen-13-one is a key intermediate for synthesizing dezocine. U.S. Pat. No. 4,4001331 discloses a method for preparing an intermediate 5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylenebenzocyclodecene-13-ketone by cyclizing 7-methoxy-1-methyl-2-tetralone serving as a starting material and 1, 5-dichloropentane serving as an alkylating reagent under the action of NaH, wherein the obtained intermediate is a racemate, and the condition of the first-step alkylation reaction is too severe, so that other impurities are easily generated, and the process is difficult to industrially produce.
Chinese patent CN101671269A discloses a synthesis method of 5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecene-13-ketoxime, which has the advantages of simple operation, mild reaction conditions and high safety, but the prepared intermediate 5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecene-13-ketone is still a racemate.
Chinese patent CN102503840A adopts 1, 5-dibromopentane as an alkylating reagent to synthesize 1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone, and then cyclization is carried out under the action of NaH, and the prepared intermediate is racemate.
Win Nerinckx et al disclose an asymmetric synthesis method of dezocine (W.Nerinckx, M.Vandewale, Tetrahedron: Asymmetry 1990,1,265), which adopts a chiral catalysis method, takes 7-methoxy-1-methyl-2-tetralone as a starting material, and synthesizes the alkylated substituent with a yield of 71% and an ee value of 60% under the action of an cinchonidine derivative catalyst. According to the method, 75 times of toluene is used as a solvent in the first step of alkylation reaction, and the stereoselectivity is general; the second step of ring closing needs column chromatography purification, which greatly limits the industrial application of the process.
Although the asymmetric synthesis method can be used for efficiently synthesizing (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxyl-5-methyl-5, 11-methylene benzocyclodecene-13-ketone, the pollution and the cost caused by racemization resolution and low-selectivity asymmetric synthesis process can be avoided, and the production efficiency is greatly improved; however, the high stereoselectivity synthesis of (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecen-13-one (compound 3) has two difficulties: on the one hand, (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone (compound 2) structure, containing all-carbon chiral Quaternary carbon center, with considerable challenges for construction using asymmetric catalysis (see Quaternary stereographers: gallens and solutions for organic synthesis by Christoffset, J.; Baro, A.2005 WILEY-VCH Verlag GmbH & Co.KGaA, Weinheim); on the other hand, the racemization resolution process cannot be advanced, for example, the resolution of the penultimate step is advanced to the compound 2 or 3, the compound 2 and the compound 3 only have one phenolic hydroxyl and carbonyl, the phenolic hydroxyl is weak acid, and the effective resolution cannot be carried out by using the conventional chiral base.
Disclosure of Invention
The invention aims to provide a novel asymmetric synthesis method of a key intermediate of dezocine; the method not only establishes a chiral quaternary carbon center through stereoselective alkylation to obtain a chiral intermediate; meanwhile, the method has the advantages of high yield, low cost, environmental protection and suitability for large-scale production.
The invention aims to provide an asymmetric synthesis method of a dezocine key intermediate, namely (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecene-13-ketone.
In an embodiment of the present invention, the present invention provides an asymmetric synthesis method of a dezocine key intermediate, i.e., (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylenebenzocyclodecen-13-one (compound 3), comprising the steps of:
1) taking a compound 1, namely 7-methoxy-1-methyl-2-tetralone as a starting material, reacting the starting material with 1, 5-dibromopentane in an organic solvent A in the presence of an cinchonidine derivative catalyst and alkali to obtain a compound 2, namely (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone;
2) reacting the compound 2 obtained in the step 1), namely (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone, under the condition of sodium hydride to obtain a crude product of a compound 3, namely (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecene-13-ketone; crystallizing the crude product in an organic solvent B, and crystallizing to obtain a compound 3 of a white-like solid;
here, the structure of the cinchonidine derivative catalyst described in step 1) is as follows:
wherein R is selected from 3-fluoro-benzyl, 3, 4-difluorobenzyl, 3-fluoro-4-trifluoromethylbenzyl, 2, 4-difluorobenzyl;
x is an anion selected from halogen, BF4、SbF6Sulfonate or hexafluorophosphate;
the organic solvent A in the step 1) is selected from xylene, toluene, chlorobenzene, benzene, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane or trichloromethane;
the organic solvent B in the step 2) is methyl tert-butyl ether, acetonitrile, ethyl acetate or acetone.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a dezocine key intermediate, wherein the molar ratio of the compound 1, namely 7-methoxy-1-methyl-2-tetralone to 1, 5-dibromopentane in the step 1) is 1:1.5 to 1: 3.5.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key dezocine intermediate, wherein the mass-to-volume ratio of the compound 1 to the organic solvent A in the step 1) is 1:5-55 (unit is g/ml).
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key dezocine intermediate, wherein the molar ratio of the cinchonidine derivative catalyst to the compound 1 in the step 1) is 7.5-15: 100.
In an embodiment of the present invention, the present invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein, in step 1), the base is selected from lithium hydroxide, potassium hydroxide, cesium hydroxide; potassium hydroxide is preferred.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key dezocine intermediate, wherein the molar ratio of the compound 1 to the base in the step 1) is 1: 10-15.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein the temperature of the reaction in the step 1) is controlled between 5 and 15 ℃.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key dezocine intermediate, wherein the reaction in the step 1) is carried out under the protection of light and nitrogen.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein the reaction time in the step 1) is 1-6 hours.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein the reaction in the step 2) is carried out in dimethyl formamide DMF or dimethyl sulfoxide DMSO.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein the temperature of the reaction in the step 2) is controlled to be 70-80 ℃.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein the crystallization in the step 2) is carried out under a low temperature condition, wherein the low temperature is in a temperature range of 0-15 ℃.
In the embodiment of the invention, the asymmetric synthesis method of the key intermediate of dezocine is provided, wherein the crystallization time in the step 2) is 2-12 hours.
In the embodiment of the invention, the invention provides an asymmetric synthesis method of a key intermediate of dezocine, wherein the chiral purity of the compound 3 which is a white solid in the step 2) is more than 97%.
The term "halogen" (or "halo") as used herein refers to fluorine, chlorine, bromine or iodine (alternatively referred to as fluoro, chloro, bromo or iodo).
In the present invention, the HPLC conditions for detecting chiral purity are as follows: a chromatographic column: AS-H (4.6mm 250mm,5 μm); mobile phase: ethanol, 97: 3; detection wavelength: 214nm, 280 nm; flow rate: 1.0 ml/min; column temperature: 30 ℃; operating time: 16.0 min.
The invention adopts materials which are produced in large scale as starting materials, and obtains the key intermediate of dezocine synthesis with high optical purity by one-step crystallization and purification through asymmetric catalytic alkylation reaction and ring closing reaction. The asymmetric synthesis reaction has the advantages of simple steps, high yield, low cost, mild conditions and the like, and is suitable for large-scale high-efficiency synthesis of dezocine.
Compared with (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylene benzocyclodecene-13-ketone (a comparison group, an example is Formation of tricyclic ketone (-) -22) obtained by the prior art, namely W.Nerickx, M.Vandewale, Tetrahedron: Asymmetry 1990,1,265, the result shows that the purity and chiral purity of the product obtained by using the method are higher, and the RRT is not detected as 1.22 impurity, the operation is simple and convenient, the industrialization is easy, and the detection results are compared as follows:
| yield of | Purity of | Chiral purity | Specific rotation degree | Impurity (RRT 1.22) | |
| Example 5 | 88％ | 99.24％ | 99％ | -45 | Not detected out |
| Example 6 | 85％ | 99.47％ | 99％ | -45 | Not detected out |
| Example 7 | 89％ | 99.33％ | 98％ | -45 | Not detected out |
| Example 8 | 82.9％ | 99.51％ | 99％ | -46 | Not detected out |
| Control group | 43.02％ | 93.62％ | 86％ | -25 | 0.53％ |
Detailed Description
The following examples will help to understand the invention, but do not limit the scope of the invention. Some embodiments of the invention are disclosed below, and those skilled in the art can appropriately modify the process parameters to achieve the invention according to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included in the invention. While the methods and applications of this invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications in the methods and applications described herein, or appropriate variations and combinations thereof, may be made in implementing and using the techniques of this invention without departing from the spirit and scope of the invention.
The structural formula of the cinchonidine derivative catalyst used in the following examples is as follows, and specific meanings of R and X are given in the examples.
Example 1
Preparation of (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone
Adding 7-methoxy-1-methyl-2-tetralone (2.5g, 13mmol), 1, 5-dibromopentane (7.55g, 32.8mmol), an cinchonidine derivative catalyst (0.75g, 1.3mmol R is 2, 4-difluorobenzyl, X is Br) and methyl tert-butyl ether (150ml, 55V) in a 250ml three-neck flask in sequence, dropwise adding 40 wt% KOH aqueous solution (7.3 g, 130mmol) under the protection of nitrogen and in the dark condition, controlling the reaction temperature at 5-15 ℃, separating after reacting for 3h, extracting the aqueous phase with methyl tert-butyl ether for three times (10 ml each time), combining the organic phases, and washing the organic phase with 3% HCl; discarding the aqueous phase and washing the organic phase with saturated NaCl solution to pH 7.0-8.0; the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain oily substance 3.4g with yield of 78%; [ alpha ] to]D 20＝+24(c＝1.0.CHCl3) Ee value 85% by HPLC.
lH NMR(400MHz,CDC13):7.09(d,lH,J＝8.3Hz),6.80(d,lH,J＝2.3 Hz),6.75(dd,1H.J＝2.3and 8.3Hz),3.28(s,3H).3.30(t,2H,J＝6.8Hz). 2.99(dd,lH,J＝2.5and 6.0Hz),2.97(d,lH,J＝6.1Hz).2.68(m,lH),2.56(m, lH),2.11(m,lH),1.74(p,2H,J＝7.0Hz),1.63(m,lH),1.38(s,3H),1.31(m, 2H),0.96(m,2H).
MS:m/z 340(MH+).
Example 2
Preparation of (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone
In a 500ml three-necked flask were sequentially added 7-methoxy-1-methyl-2-tetralone (5.0g, 26.3mmol), 1, 5-dibromopentane (15.1g, 65.7mmol), and cinchonidine derivative catalyst (0.75g, 1.3mmol, R is 2-fluoro-4-trifluoromethylbenzyl, and X is BF4) And dichloromethane (150ml, 30V), under nitrogen protection and in the dark, dropwiseAdding 10 wt% LiOH aqueous solution (LiOH 9.4g, 394.5mmol), controlling reaction temperature at 5-15 deg.C, reacting for 6h, separating, extracting water phase with dichloromethane three times (25 ml each time), combining organic phases, and washing organic phase with 1% HCl; discarding the aqueous phase and washing the organic phase with saturated NaCl solution to pH 7.0-8.0; the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain 6.7g of oily substance with yield of 76%; [ alpha ] to]D 20＝+25(c＝1.0.CHC13) And ee value of 80% by HPLC.
Example 3
Preparation of (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone
Adding 7-methoxy-1-methyl-2-tetralone (50g, 263mmol), 1, 5-dibromopentane (151g, 657.5mmol), an cinchonidine derivative catalyst (14.1g, 26.3mmol, R is 3-fluoro-4-trifluoromethylbenzyl, and X is Br), and toluene (1.65L, 35V) in a 5L three-neck flask in sequence, dropping 30 wt% CsOH aqueous solution (CsOH 587g, 3.945mol) under the protection of nitrogen and in the dark condition, controlling the reaction temperature at 10-15 ℃, reacting for 1h, separating, extracting the aqueous phase with toluene three times (250 ml each time), combining the organic phases, and washing the organic phase with 5% HCl 2 times; discarding the aqueous phase and washing the organic phase with saturated NaCl solution to pH 7.0-8.0; the organic phase was dried over anhydrous sodium sulfate. Concentrating under reduced pressure to obtain oil 72.2g with yield of 81%; [ alpha ] to]D 20＝+23(c＝1.0.CHC13) Ee value 78% by HPLC.
Example 4
Preparation of (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone
Adding 7-methoxy-1-methyl-2-tetralone (50g, 263mmol), 1, 5-dibromopentane (181g, 788mmol), an cinchonidine derivative catalyst (14.1g, 26.3mmol, R is 3-fluorobenzyl, X is Br) and methyl tert-butyl ether (2.25L, 45V) into a 5L three-neck flask in sequence, under the protection of nitrogen and in a dark condition, dropwise adding 40 wt% KOH aqueous solution (KOH 221g, 3.945mol), controlling the reaction temperature at 5-15 ℃, after reacting for 4h, separating liquid, extracting the aqueous phase with methyl tert-butyl ether three times (100 ml each time), combining organic phases, and washing the organic phases with 3% HCl; discarding the aqueous phase and washing the organic phase with saturated NaCl solution to pH 7.0-8.0; is free ofThe organic phase was dried over sodium sulfate. Concentrating under reduced pressure to obtain oil 69.5g with yield of 78%; [ alpha ] to]D 20＝+25(c＝1.0.CHC13) Ee value of 82% by HPLC;
example 5
Preparation of (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylenebenzocyclodecen-13-one
A250 ml three-necked flask was charged with 60ml of DMF and (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone (10g, 29.5mmol, ee 82%) (prepared in example 4), and a solution of 5% NaH (1.4g, 59mmol in moles based on NaH) in DMF was added dropwise, heated to 75-80 deg.C and reacted for 3 h; adding methanol to quench the reaction; concentrating under reduced pressure to remove DMF, extracting the reaction solution with 80ml methyl tert-butyl ether for 3 times, separating the solution, and concentrating the organic phase to obtain crude oily substance; adding 50ml acetonitrile into the crude product, stirring and dissolving, cooling to 0-5 ℃, crystallizing for 12h, filtering and drying to obtain 6.72g of white solid, the melting point is 94 ℃, and the yield is 88%. [ alpha ] to]D 20＝-45(c＝1.0.CHC13) And the chiral purity is 99 percent by HPLC detection.
1H NMR(400MHz,CDC13):7.06(d.lH,J＝8.3),6.80(d,lH,J＝2.6), 6.74(dd,1H.J＝2.6and 8.3),3.82(s,3H),3.05(dd,1H.J＝5.7and 16.0). 2.98(dd,lH,1＝4.6and16.0),2.76(m,lH),2.41(m,lH),1.89(m,lH),1.74(m, 2H),1.56(m,4H),1.36(s,3H),1.30(m,2H).
MS:m/z 259(MH+),
Example 6
Preparation of (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylenebenzocyclodecen-13-one
60ml of DMSO and (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone (10g, 29.5mmol, ee value 80%) prepared in example 2 were placed in a 250ml three-necked flask, and a solution of 5% NaH (1.4g, 59mmol as NaH) in DMSO was added dropwise, heated to 75-80 ℃ and reacted for 3 h; adding methanol to quench the reaction; concentrating under reduced pressure to remove DMSO, extracting the reaction solution with 80ml methyl tert-butyl ether for 3 times, separating, and concentrating the organic phase to obtain crude oil; adding 50ml acetone into the crude product, stirring and dissolving, cooling to 5-10 deg.C, crystallizing for 24 hr, filtering, and drying to obtain white solid6.45g, melting point 94 ℃ and yield 85%. [ alpha ] to]D 20＝-45(c＝1.0.CHC13) And the chiral purity is 99 percent by HPLC detection.
Example 7
Preparation of (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylenebenzocyclodecen-13-one
A250 ml three-necked flask was charged with 60ml of DMF and (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone (10g, 29.5mmol, ee 85%) (prepared in example 1), and a solution of 5% NaH (1.4g, 59mmol as NaH) in DMF was added dropwise and heated to 70-75 deg.C for 3 h; adding methanol to quench the reaction; concentrating under reduced pressure to remove DMF, extracting the reaction solution with 80ml methyl tert-butyl ether for 3 times, separating the solution, and concentrating the organic phase to obtain crude oily substance; adding 50ml ethyl acetate into the crude product, stirring and dissolving, cooling to-5-0 ℃, crystallizing for 8h, filtering and drying to obtain 6.75g of white solid, the melting point is 94 ℃, and the yield is 89%. [ alpha ] to]D 20＝-45(c＝1.0.CHC13) And chiral purity is 98% by HPLC.
Example 8
Preparation of (5R,11S) -5,6,7,8,9,10,11, 12-octahydro-3-methoxy-5-methyl-5, 11-methylenebenzocyclodecen-13-one
150ml DMSO and (1R) -1- (5-bromopentyl) -7-methoxy-1-methyl-tetralone (50g, 147mmol, ee value 78%) (prepared in example 3) were placed in a 500ml three-necked flask, and a 5% NaH (7.0g, 294mmol as NaH) DMSO solution was added dropwise and heated to 70-75 ℃ for 2 h; adding methanol to quench the reaction; concentrating under reduced pressure to remove DMF, extracting the reaction solution with 80ml ethyl acetate, separating the solution, and concentrating the organic phase to obtain an oily crude product; adding 200ml acetone into the crude product, stirring and dissolving, cooling to 0-5 ℃, crystallizing for 6h, filtering and drying to obtain 31.4g of white solid, the melting point is 94 ℃, and the yield is 82.9%. [ alpha ] to]D 20＝-46(c＝1.0.CHC13) And the chiral purity is 99 percent by HPLC detection.
Claims (12)
1. An asymmetric synthesis method of a dezocine key intermediate, comprising the following steps:
1) taking a compound 1 as an initial raw material, and reacting the initial raw material with 1, 5-dibromopentane in an organic solvent A in the presence of an cinchonidine derivative catalyst and alkali to obtain a compound 2;
2) reacting the compound 2 obtained in the step 1) under the condition of sodium hydride to obtain a crude compound 3; crystallizing the crude product in an organic solvent B, and crystallizing to obtain a compound 3 of a white-like solid;
here, the structure of the cinchonidine derivative catalyst described in step 1) is as follows:
wherein R is selected from 3-fluoro-benzyl, 3, 4-difluorobenzyl, 3-fluoro-4-trifluoromethylbenzyl, 2, 4-difluorobenzyl;
x is an anion selected from halogen, BF4、SbF6Sulfonate or hexafluorophosphate;
the organic solvent A in the step 1) is selected from xylene, toluene, chlorobenzene, benzene, diethyl ether, isopropyl ether, methyl tert-butyl ether, dichloromethane or trichloromethane;
the organic solvent B in the step 2) is methyl tert-butyl ether, acetonitrile, ethyl acetate or acetone.
2. The synthesis method according to claim 1, wherein the molar ratio of the compound 1, i.e. 7-methoxy-1-methyl-2-tetralone to 1, 5-dibromopentane in step 1) is 1:1.5 to 1: 3.5.
3. The synthesis method according to claim 1, wherein the mass-to-volume ratio of the compound 1 to the organic solvent A in the step 1) is 1:5-55 in g/ml.
4. The synthesis method according to claim 1, wherein the molar ratio of the cinchonidine derivative catalyst to compound 1 in step 1) is 7.5-15: 100.
5. The synthesis of claim 1, wherein the base in step 1) is selected from lithium hydroxide, potassium hydroxide, cesium hydroxide.
6. The method of claim 5, wherein the base in step 1) is selected from potassium hydroxide.
7. The synthesis method according to claim 1, wherein the molar ratio of the compound 1 to the base in the step 1) is 1: 10-15.
8. The synthesis process according to claim 1, wherein the temperature of the reaction of step 1) is controlled between 5 and 15 ℃.
9. The synthesis process according to any one of claims 1 to 8, wherein the reaction of step 1) is carried out under protection from light and nitrogen.
10. The method of claim 9, wherein the reaction of step 2) is performed in dimethylformamide DMF or dimethylsulfoxide DMSO.
11. The synthesis process of claim 9, wherein the temperature of the reaction of step 2) is controlled at 70-80 ℃.
12. The synthesis method according to claim 9, wherein the time for crystallization in step 2) is 2 to 12 hours.
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| CN104910002A (en) * | 2015-05-28 | 2015-09-16 | 温州医科大学 | Dezocine key intermediate preparation method |
| WO2017118375A1 (en) * | 2016-01-04 | 2017-07-13 | 南京明德新药研发股份有限公司 | Dezocine analogue |
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| CN101671269A (en) * | 2009-10-26 | 2010-03-17 | 扬子江药业集团有限公司 | Preparation method of substituted methylene benzocyclodecene ketoxime |
| CN104910002A (en) * | 2015-05-28 | 2015-09-16 | 温州医科大学 | Dezocine key intermediate preparation method |
| WO2017118375A1 (en) * | 2016-01-04 | 2017-07-13 | 南京明德新药研发股份有限公司 | Dezocine analogue |
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