CN114524717A - 1,2,3, 4-tetrahydronaphthalene derivative and preparation method and application thereof - Google Patents
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Abstract
The invention provides a 1,2,3, 4-tetrahydronaphthalene derivative, a preparation method and application thereof, wherein the structure of the 1,2,3, 4-tetrahydronaphthalene derivative is shown as a formula I, wherein X is selected from any one of Cl, Br or I; the preparation method comprises the following steps: mixing the compound A1, 2-dihydro-6-methoxy-4-methylnaphthalene, a halogenating agent and a catalyst for reaction to obtain the compound B1,2,3, 4-tetrahydronaphthalene derivative. The 1,2,3, 4-tetrahydronaphthalene derivative and the preparation method and application thereof provided by the invention are simple to operate, low in risk, environment-friendly and suitable for continuous and stable scale-up production.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a 1,2,3, 4-tetrahydronaphthalene derivative, a preparation method and an application thereof, in particular to a safe and high-purity 1,2,3, 4-tetrahydronaphthalene derivative, a preparation method and an application thereof.
Background
Dezocine is widely used for general anesthesia induction, postoperative analgesia, and advanced analgesia, and for the treatment of visceral pain and cancer pain. The dezocine has the analgesic activity equivalent to that of morphine, but has less adverse reactions such as respiratory depression, constipation, analgesic tolerance, addiction and the like. The synthesis of dezocine requires the intermediate of dezocine oxime, and dezocine is obtained by reduction, resolution and demethylation of dezocine oxime.
In the existing dezoxime process, peroxide is needed for preparing epoxide, and the peroxide is easy to decompose and has the characteristics of explosiveness and inflammability, and has potential risks of fire and explosion in the production process, so that great safety risk exists; sodium hydride is used as a base in the synthesis of the dezoxone, the cyclization reaction is carried out under the heating condition, and the sodium hydride reacts violently with water to generate hydrogen and release heat violently, so that the potential risks of combustion and explosion are high; the use of a large excess of hydroxylamine hydrochloride is prone to decomposition and even to explosion, and presents no small safety risk.
CN108299173A 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-methylenebenzocyclodecen-13-one, which comprises: 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 and high-efficiency synthesis of dezochromanone oxime. However, the use of sodium hydride in the reaction is liable to cause safety accidents. The reaction route is as follows:
chiral quaternary ammonium salt catalyzed asymmetric phase transfer catalysis is adopted in Tetrahedron Asymmetry,1990, p265-270, Beilstein, J, org, chem, 2018, p 1421-1427. In the substitution reaction of the compound C to the compound D1, in the presence of a chiral phase transfer catalyst, a nucleophilic substitution reaction is carried out to obtain a chiral compound D1, and the chiral compound D1 is subjected to cyclization and oximation reactions to obtain chiral dezochromone oxime. The method has certain advantages in yield, but the enantioselectivity is not high, the ee is only about 60%, and the optically pure product can be obtained by crystallization, resolution and other means in the later stage. In addition, the chiral quaternary ammonium salt derived from cinchona alkaloid used in the method is not expensive and has no advantage in price, so that the application of the method is limited. The reaction route is as follows:
in the prior art, because a large number of dangerous factors exist in raw material selection, the production process is easy to have a safety problem, so that how to provide a safe, efficient, environment-friendly method for preparing dezochytonone oxime with remarkable cost advantage becomes a problem to be solved urgently.
Disclosure of Invention
Aiming at the defects of the prior art, the invention aims to provide a 1,2,3, 4-tetrahydronaphthalene derivative and a preparation method and application thereof, and particularly provides a safe and high-purity 1,2,3, 4-tetrahydronaphthalene derivative and a preparation method and application thereof. The preparation method of the 1,2,3, 4-tetrahydronaphthalene derivative provided by the invention is safe, green and environment-friendly.
In order to achieve the purpose, the invention adopts the following technical scheme:
in a first aspect, the present invention provides a 1,2,3, 4-tetrahydronaphthalene derivative, wherein the structure of the 1,2,3, 4-tetrahydronaphthalene derivative is represented by formula I:
wherein X is selected from any one of Cl, Br or I.
The 1,2,3, 4-tetrahydronaphthalene derivative provided by the invention can be used for preparing dezochytonoxime, can reduce the risk in the preparation process of the dezocanone oxime, and is environment-friendly.
In a second aspect, the present invention provides a method for preparing a 1,2,3, 4-tetrahydronaphthalene derivative as described above, comprising the steps of: mixing and reacting a compound A1, 2-dihydro-6-methoxy-4-methylnaphthalene, a halogenating agent and a catalyst to obtain a compound B1,2,3, 4-tetrahydronaphthalene derivative, wherein the reaction formula is shown as a formula II:
wherein X is selected from any one of Cl, Br or I.
The preparation method is simple and easy to operate, and has good safety and stability.
Preferably, the catalyst is selected from any one or a combination of at least two of ammonium acetate, ammonium chloride, ammonium sulfate or protonic acid, such as a combination of ammonium acetate and ammonium chloride, a combination of ammonium chloride and ammonium sulfate, or a combination of ammonium sulfate and protonic acid, and the like, but is not limited to the listed combinations, and other combinations not listed in the above combination range are also applicable.
Preferably, the protic acid is selected from hydrochloric acid and/or acetic acid.
Preferably, the halogenating agent is selected from N-halosuccinimide or N-halohydantoin.
Preferably, the molar ratio of the 1, 2-dihydro-6-methoxy-4-methylnaphthalene to the halogenating agent is 1:0.9-1: 1.2.
Preferably, the molar ratio of the 1, 2-dihydro-6-methoxy-4-methylnaphthalene to the catalyst is from 1:0.05 to 1: 0.25.
Preferably, the temperature of the reaction is 0-40 ℃.
Preferably, the reaction time is 0.5 to 20 hours.
The molar ratio of 1, 2-dihydro-6-methoxy-4-methylnaphthalene to N-halosuccinimide may be 1:0.9, 1:1, 1:1.1 or 1:1.2, the molar ratio of 1, 2-dihydro-6-methoxy-4-methylnaphthalene to the catalyst may be 1:0.05, 1:0.07, 1:0.1, 1:0.12, 1:0.14, 1:0.16, 1:0.18, 1:0.2, 1:0.22 or 1:0.25, the temperature may be 0 ℃,5 ℃,10 ℃, 15 ℃, 20 ℃, 25 ℃, 30 ℃, 35 ℃ or 40 ℃, the time may be 0.5h, 1h, 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h or 20h, but the above-mentioned values are not limited to the other values in the above-mentioned range.
In a third aspect, the present invention provides the use of a 1,2,3, 4-tetrahydronaphthalene derivative as described above in the preparation of dezocanone oxime.
In a fourth aspect, the present invention provides a method for preparing dezoketoxime, comprising the steps of:
(1) reacting a compound B1, a 2,3, 4-tetrahydronaphthalene derivative with a base in a solvent and water to obtain a compound C;
(2) reacting the compound C obtained in the step (1) with boron trifluoride ethyl ether or protonic acid in a solvent to obtain a compound D;
(3) reacting the compound D obtained in the step (2) with 1, 5-dibromopentane and potassium iodide under the alkali condition to obtain a compound E;
(4) reacting the compound E obtained in the step (3) with alkali in an alcoholic solution to obtain dezoxone;
(5) and (3) carrying out reaction on the dezoketone obtained in the step (4) to obtain the dezoketoxime.
The reaction route is shown as formula III:
wherein X is selected from any one of Cl, Br or I.
According to the preparation method, the reaction conditions are optimized, and safer reagents are selected for reaction, so that the safety risk of the process is greatly reduced, the preparation process is easier to control and amplify, the continuous, stable and smooth production is ensured, and the safety and occupational health of production operators are ensured; meanwhile, the preparation method has high yield, is environment-friendly and reduces the pressure of environmental protection.
Preferably, the base in step (1) is selected from any one or a combination of at least two of sodium hydroxide, potassium hydroxide, ammonium acetate, ammonium chloride, lithium hydroxide or calcium hydroxide, such as a combination of sodium hydroxide and potassium hydroxide, a combination of potassium hydroxide and ammonium acetate, or a combination of ammonium acetate and ammonium chloride, but not limited to the listed combinations, and other combinations not listed within the above-mentioned combinations are also applicable.
The preparation of the epoxy intermediate by adopting the halogenating agent to replace a peroxide compound can obviously improve the product purity, simultaneously avoid potential fire and explosion risks caused by the instability of the peroxide compound, and improve the safety and stability of the reaction.
Preferably, the molar ratio of the compound B to the base in the step (1) is 1:2-1: 4.
Preferably, the temperature of the reaction of step (1) is 0-40 ℃.
Preferably, the reaction time of step (1) is 2-40 h.
Wherein the molar ratio of compound A to base may be 1:2, 1:2.5, 1:3, 1:3.5 or 1:4, etc., the temperature may be 0 ℃,4 ℃,8 ℃,12 ℃, 16 ℃, 20 ℃, 24 ℃, 28 ℃, 32 ℃, 36 ℃ or 40 ℃, etc., and the time may be 2h, 6h, 10h, 14h, 18h, 22h, 26h, 30h, 34h, 38h or 40h, etc., but is not limited to the recited values, and other values not recited within the above numerical range are also applicable.
Preferably, the protic acid of step (2) is selected from p-toluenesulfonic acid or concentrated hydrochloric acid.
Preferably, the alcohol solution in step (4) is selected from any one or a combination of at least two of tert-butyl alcohol, tert-amyl alcohol, n-butyl alcohol, cyclopentanol, n-amyl alcohol and cyclohexanol, such as a combination of tert-butyl alcohol and tert-amyl alcohol, a combination of tert-butyl alcohol and n-butyl alcohol, or a combination of tert-amyl alcohol and n-butyl alcohol, and the like, but is not limited to the listed combinations, and other combinations not listed in the above combination range are also applicable.
Preferably, the base in step (4) is selected from sodium salt and/or potassium salt of any one of ethanol, tert-butanol, tert-amyl alcohol or methanol, such as sodium ethoxide, potassium ethoxide, sodium tert-butoxide or potassium tert-butoxide, but not limited to the listed substances, and other substances not listed in the above range are also applicable.
Sodium alkoxide and potassium alkoxide are adopted to replace sodium hydride, and alcohol is adopted to replace DMF or DMSO, so that the safety of the reaction can be improved, the potential safety hazard is reduced, the safe, continuous and stable production is ensured, and the method is environment-friendly and environment-friendly.
Preferably, the temperature of the reaction of step (4) is 90-110 ℃.
Preferably, the reaction time of the step (4) is 2-24 h.
Wherein the temperature can be 90 ℃, 91 ℃, 92 ℃, 93 ℃, 94 ℃, 95 ℃, 96 ℃, 97 ℃, 98 ℃, 99 ℃, 100 ℃, 101 ℃, 102 ℃, 103 ℃, 104 ℃, 105 ℃, 106 ℃, 107 ℃, 108 ℃, 109 ℃ or 110 ℃, and the time can be 2h, 4h, 6h, 8h, 10h, 12h, 14h, 16h, 18h, 20h, 22h or 24h, and the like, but the method is not limited to the enumerated values, and other unrecited values in the numerical range are also applicable.
Preferably, the reaction of step (5) comprises the following two schemes:
firstly, the reaction in the step (5) comprises the following steps: and (3) carrying out oximation reaction on the dezocanone obtained in the step (4), specifically reacting the dezocanone with hydroxylamine hydrochloride and alkali to obtain the dezocanone oxime.
Preferably, the molar ratio of the dezoxone to the hydroxylamine hydrochloride is from 1:8 to 1: 20.
Preferably, the molar ratio of dezoxone to base is from 1:2 to 1: 20.
The molar ratio of dezoxone to hydroxylamine hydrochloride may be 1:8, 1:9, 1:10, 1:11, 1:12, 1:13, 1:14, 1:15, 1:16, 1:17, 1:18, 1:19 or 1:20, and the molar ratio of dezoxone to base may be 1:2, 1:4, 1:6, 1:8, 1:10, 1:12, 1:14, 1:16, 1:18 or 1:20, but is not limited to the recited values, and other non-recited values within the above numerical ranges are also applicable.
Preferably, the base is selected from pyridine and/or sodium acetate.
Preferably, the temperature of the reaction is 100-.
Preferably, the reaction time is 8-48 h.
The temperature may be 100 ℃, 102 ℃, 104 ℃, 106 ℃, 108 ℃, 110 ℃, 112 ℃, 114 ℃, 116 ℃, 118 ℃, 120 ℃, 122 ℃, 124 ℃, 126 ℃, 128 ℃ or 130 ℃, and the time may be 8h, 12h, 16h, 20h, 24h, 28h, 32h, 36h, 40h, 44h or 48h, but the method is not limited to the recited values, and other values not recited in the above numerical range are also applicable.
Secondly, the reaction in the step (5) comprises the following steps: and (3) reacting the dezoketone obtained in the step (4) with acetone oxime and acid to obtain the dezoketone oxime.
The process for preparing dezochytinone oxime by carrying out oxime exchange reaction on acetone oxime and dezocinone under acid catalysis can greatly reduce the use of hydroxylamine hydrochloride, greatly reduce the safety risk, relieve the environmental protection pressure and be more environment-friendly.
Preferably, the molar ratio of dezoxone to acetoxime is from 1:1.5 to 1: 10.
Preferably, the molar ratio of dezoxone to acid is from 1:0.1 to 1:1.
The molar ratio of dezoketone to acetoxime may be 1:1.5, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, and the molar ratio of dezoketone to acid may be 1:0.1, 1:0.2, 1:0.3, 1:0.4, 1:0.5, 1:0.6, 1:0.7, 1:0.8, 1:0.9 or 1:1, but is not limited to the enumerated values, and other unrecited values within the above numerical range are also applicable.
Preferably, the acid is selected from any one or a combination of at least two of p-toluenesulfonic acid, sulfuric acid, perchloric acid or periodic acid, such as a combination of p-toluenesulfonic acid and sulfuric acid, a combination of sulfuric acid and perchloric acid or a combination of perchloric acid and periodic acid, and the like, but is not limited to the listed combinations, and other combinations not listed in the above combinations are also applicable.
Preferably, the temperature of the reaction is 50-70 ℃.
Preferably, the reaction time is 16-48 h.
The temperature may be 50 ℃, 52 ℃, 54 ℃, 56 ℃, 58 ℃, 60 ℃, 62 ℃, 64 ℃, 66 ℃, 68 ℃ or 70 ℃ and the time may be 16h, 20h, 24h, 28h, 32h, 36h, 40h, 44h or 48h, but the method is not limited to the recited values, and other values not recited in the above numerical range are also applicable.
As a preferred technical scheme of the invention, the preparation method comprises the following steps:
(1) reacting a compound B1, a 2,3, 4-tetrahydronaphthalene derivative with alkali in a solvent and water at 0-40 ℃ for 2-40h to obtain a compound C;
(2) reacting the compound C obtained in the step (1) with boron trifluoride ethyl ether or protonic acid in a solvent to obtain a compound D;
(3) reacting the compound D obtained in the step (2) with 1, 5-dibromopentane under the alkali condition to obtain a compound E;
(4) reacting the compound E obtained in the step (3) with alkali in an alcohol solution at 90-110 ℃ for 2-24h to obtain dezozanone;
(5) and (3) carrying out reaction on the dezoketone obtained in the step (4) to obtain the dezoketoxime.
In a fifth aspect, the present invention also provides the use of the 1,2,3, 4-tetrahydronaphthalene derivatives as described above in the preparation of dezocine.
Compared with the prior art, the invention has the following beneficial effects:
the invention develops a safe, high-yield, green and environment-friendly method for preparing dezoxime by optimizing reaction conditions and reaction reagents; the halogenated agent is adopted to replace a peroxy compound to prepare an epoxy intermediate, so that the product purity can be obviously improved, the potential fire and explosion risks caused by the instability of the peroxy compound are avoided, and the safety and the stability of the reaction are improved; sodium alkoxide or potassium alkoxide is adopted to replace sodium hydride, and alcohol is adopted to replace DMF or DMSO, so that the safety of the reaction can be improved, the potential safety hazard is reduced, the safe, continuous and stable production is ensured, and the method is environment-friendly and environment-friendly; the process for preparing dezochytinone oxime by carrying out oxime exchange reaction on acetone oxime and dezocinone under acid catalysis is developed and utilized, so that the use of hydroxylamine hydrochloride can be greatly reduced, the safety risk is greatly reduced, the environmental protection pressure is relieved, and the process is more environment-friendly.
Drawings
FIG. 1 is a drawing showing a preparation of Compound B in example 1-11A HNMR map;
FIG. 2 is a drawing showing a scheme of preparation of Compound B in example 1-113A CNMR map;
FIG. 3 is a drawing showing a preparation of Compound D in example 3-11A HNMR map;
FIG. 4 is a drawing showing a scheme of preparing a compound E in example 4-11A HNMR map;
FIG. 5 is a process for preparing dezocanone oxime in example 6-11HNMR map.
Detailed Description
The technical solution of the present invention is further explained by the following embodiments. It should be understood by those skilled in the art that the examples are only for the understanding of the present invention and should not be construed as the specific limitation of the present invention.
The starting materials and reagents are commercially available in the following examples.
In the following examples, the reaction scheme is as follows:
EXAMPLES 1-1 TO 1-4 Synthesis of Compound B
Examples 1 to 1
To a reaction flask, 10g of Compound A, 1g of ammonium acetate, 200mL of acetonitrile and 50mL of water were added and dissolved with stirring until completion. Adding 11.2g N-bromosuccinimide into a reaction bottle, preserving the temperature at 10 ℃ for reaction for 20h after the addition is finished, and then adding sodium thiosulfate to quench the reaction. The reaction mixture was extracted with dichloromethane, dried and concentrated to obtain 15.5g of an oily liquid. After the sample is purified by column chromatography, the sample is sent to nuclear magnetic detection, and the detection result shows that the product has a correct structure, and the nuclear magnetic resonance hydrogen spectrum and the nuclear magnetic resonance carbon spectrum of the product are respectively shown in the figure 1 and the figure 2. The nuclear magnetic data was resolved as follows:1H-NMR(CDCl3,400Hz)δppm:7.16(1H,d,J＝2.7Hz),6.95(1H,d,J＝8.4Hz),6.77(1H,dd,J＝8.4,2.7Hz),4.47(1H,dd,J＝12.1,3,64Hz),3.79(1H,s),2.86-2.91(2H,m),2.44-2.51(2H,m),2.27-2.38(2H,m),1.62(3H,s).13C-NMR(CDCl3,100Hz)δppm:158.3,141.8,129.5,125.7,114.5,110.7,73.5,55.4,31.3,28.6,28.1。
examples 1 to 2:
to a reaction flask were added 6g of Compound A, 0.3g of ammonium acetate, 100mL of methylene chloride and 20mL of water, and the mixture was dissolved with stirring. Controlling the temperature below 10 ℃, adding 7.9g N-iodosuccinimide into the reaction flask, and preserving the temperature at 25 ℃ for 2 hours after the addition is finished. The layers were separated, and the aqueous layer was extracted with dichloromethane, dried, and concentrated to obtain 11.2g of compound B. The nmr hydrogen and carbon spectra data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.16(1H,d,J＝2.7Hz),6.95(1H,d,J＝8.4Hz),6.77(1H,dd,J＝8.4,2.7Hz),4.47(1H,dd,J＝12.1,3,64Hz),3.79(1H,s),2.86-2.91(2H,m),2.44-2.51(2H,m),2.27-2.38(2H,m),1.62(3H,s).13C-NMR(CDCl3,100Hz)δppm:158.3,141.8,129.5,125.7,114.5,110.7,73.5,55.4,31.3,28.6,28.1。
examples 1 to 3:
to a reaction flask were added 6g of Compound A, 0.11g of ammonium chloride, 0.05g of ammonium acetate, 100mL of dichloromethane, and 20mL of water, and the mixture was dissolved completely with stirring. Controlling the temperature below 20 ℃, adding 7.5g of dibromohydantoin into the reaction flask, and keeping the temperature at 35 ℃ for reaction for 0.5h after the addition is finished. Sodium thiosulfate is added, the mixture is stirred for 1 hour and then is kept stand for layering, and a water layer is extracted by dichloromethane, dried and concentrated to obtain 8.7g of a compound B. The nmr hydrogen and carbon spectra data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.16(1H,d,J＝2.7Hz),6.95(1H,d,J＝8.4Hz),6.77(1H,dd,J＝8.4,2.7Hz),4.47(1H,dd,J＝12.1,3,64Hz),3.79(1H,s),2.86-2.91(2H,m),2.44-2.51(2H,m),2.27-2.38(2H,m),1.62(3H,s).13C-NMR(CDCl3,100Hz)δppm:158.3,141.8,129.5,125.7,114.5,110.7,73.5,55.4,31.3,28.6,28.1。
examples 1 to 4:
to a reaction flask were added 6g of Compound A, 0.3g of ammonium chloride, 100mL of dichloromethane, and 20mL of water, and the mixture was dissolved completely with stirring. Controlling the temperature below 20 ℃, adding 6.1g N-bromosuccinimide into a reaction bottle, and keeping the temperature at 35 ℃ until the raw materials disappear after the addition. Sodium thiosulfate is added, the mixture is stirred for 1 hour and then is kept stand for layering, and the water layer is extracted by dichloromethane, dried and concentrated to obtain 9.3g of a compound B. The nmr hydrogen and carbon spectra data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.16(1H,d,J＝2.7Hz),6.95(1H,d,J＝8.4Hz),6.77(1H,dd,J＝8.4,2.7Hz),4.47(1H,dd,J＝12.1,3,64Hz),3.79(1H,s),2.86-2.91(2H,m),2.44-2.51(2H,m),2.27-2.38(2H,m),1.62(3H,s).13C-NMR(CDCl3,100Hz)δppm:158.3,141.8,129.5,125.7,114.5,110.7,73.5,55.4,31.3,28.6,28.1。
example 2-1 to 2-4 Synthesis of Compound C
Example 2-1:
150mL of isopropyl alcohol and then 20% by mass of an aqueous solution of potassium hydroxide were added to the oily substance obtained in example 1-2 to conduct a cyclization reaction at 20 ℃ for 4 hours, followed by extraction with methylene chloride, drying and concentration to obtain compound C10.5g.
Example 2-2:
a mixed solvent of 200g of Compound A, 5g of ammonium acetate, 400mL of acetonitrile and 100mL of water was added to the reaction flask, and the mixture was stirred until the mixture was completely dissolved. Controlling the temperature at 25 ℃, adding 225g N-bromosuccinimide into the reaction flask, and reacting for 2 hours at 20 ℃ after the addition is finished. Then 450g of 25 percent by mass sodium hydroxide aqueous solution is added for cyclization reaction at 10 ℃ for 16h, then dichloromethane is added, and sodium thiosulfate aqueous solution is added for quenching reaction. The layers were separated and the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined, washed with water, dried over anhydrous magnesium sulfate and filtered to give a dichloromethane solution of compound C.
Examples 2 to 3:
a mixed solvent of 15g of Compound A, 0.15g of ammonium chloride, 100mL of acetonitrile and 20mL of water was added to the reaction flask, and the mixture was dissolved completely with stirring. Controlling the temperature at 25 ℃, adding 15.2g N-bromosuccinimide into a reaction flask, and reacting for 4 hours at 35 ℃ after the addition is finished. Then 40g of 25% by mass aqueous sodium hydroxide solution was added to carry out cyclization reaction at 25 ℃ for 16 hours, followed by addition of dichloromethane and addition of sodium thiosulfate to quench the reaction. The layers were separated and the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined, washed with water, dried over anhydrous magnesium sulfate and filtered to give a dichloromethane solution of compound C.
Examples 2 to 4:
to a reaction flask, 10g of compound A, 1g of ammonium acetate, 100mL of dichloromethane and 20mL of water were added and dissolved with stirring until completion. Controlling the temperature below 25 ℃, adding 14.2g N-iodosuccinimide into a reaction flask, and reacting for 0.5h at 20 ℃ after the addition is finished. Then 16g of sodium hydroxide aqueous solution with the mass fraction of 30% and 20g of potassium hydroxide aqueous solution with the mass fraction of 20% are added for cyclization reaction at 30 ℃ for 12h, after the reaction is finished, dichloromethane is added, and sodium thiosulfate is added for quenching reaction. The layers were separated and the aqueous layer was extracted with dichloromethane, the dichloromethane layers were combined, washed with water, dried over anhydrous magnesium sulfate and filtered to give a dichloromethane solution of compound C.
EXAMPLE 3-1 Synthesis of Compound D to 3-4
Example 3-1:
150mL of methylene chloride was added to the compound C obtained in example 2-1, the mixture was stirred and dissolved, the temperature was lowered to 10 ℃ and 0.2g of boron trifluoride diethyl etherate was added dropwise, and after the dropwise addition was completed, the temperature was raised to 30 DEG CThe reaction is carried out for 1 h. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and concentrated to give 6.4g of an oily liquid compound D in 83% yield and 95% purity. The nuclear magnetic resonance hydrogen spectrum detection shows that the structure is correct. The nuclear magnetic hydrogen spectrum is shown in FIG. 3, and the data is as follows:1H-NMR(CDCl3,400Hz)δppm:7.15(1H,d,J＝8.9Hz),6.76-6.78(2H,m),3.82(3H,s),3.50(1H,q,J＝7.0Hz),3.01-3.06(2H,m),2.58-2.66(1H,m),2.44-2.53(1H,m),1.48(3H,d,J＝7.0Hz)。
example 3-2:
the methylene chloride solution of the compound C of example 2-2 was cooled to 10 ℃ and 5g of boron trifluoride etherate solution was added dropwise, after the dropwise addition was completed, the temperature was raised to 30 ℃ to react for 3 hours. The reaction solution was washed with a saturated aqueous solution of sodium bicarbonate, concentrated to give an oily liquid, and distilled under reduced pressure to give a colorless liquid with a yield of 75%. The product was gradually solidified after standing, and turned into white solid 163.5g, purity 95%, through nuclear magnetic resonance hydrogen spectrum detection, showed that the structure is correct. The nuclear magnetic hydrogen spectrum data is as follows:1H-NMR(CDCl3,400Hz)δppm:7.15(1H,d,J＝8.9Hz),6.76-6.78(2H,m),3.82(3H,s),3.50(1H,q,J＝7.0Hz),3.01-3.06(2H,m),2.58-2.66(1H,m),2.44-2.53(1H,m),1.48(3H,d,J＝7.0Hz)。
examples 3 to 3:
the dichloromethane solution of the compound C of example 2-3 was cooled to 10 deg.C, 2g of concentrated HCl was added dropwise, after the addition was complete, the temperature was raised to 30 deg.C and the reaction was carried out for 12h until the starting material disappeared. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and concentrated to give 9.7g of Compound D, in 78% yield and 96% purity. Nuclear magnetic hydrogen spectrum data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.15(1H,d,J＝8.9Hz),6.76-6.78(2H,m),3.82(3H,s),3.50(1H,q,J＝7.0Hz),3.01-3.06(2H,m),2.58-2.66(1H,m),2.44-2.53(1H,m),1.48(3H,d,J＝7.0Hz)。
examples 3 to 4:
the dichloromethane solution of the compound C of example 2-4 was cooled to below 10 deg.C, 6.2g of p-toluenesulfonic acid was added, and then the temperature was raised to 30 deg.C and reflux reaction was carried out for 10h until the material disappeared. The reaction solution was washed with a saturated aqueous solution of sodium hydrogencarbonate and concentrated to give 7.1g of Compound D in 80% yield and 95% purity. Nuclear magnetic hydrogen spectrum data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.15(1H,d,J＝8.9Hz),6.76-6.78(2H,m),3.82(3H,s),3.50(1H,q,J＝7.0Hz),3.01-3.06(2H,m),2.58-2.66(1H,m),2.44-2.53(1H,m),1.48(3H,d,J＝7.0Hz)。
example 4-1 to 4-4 Synthesis of Compound E
Example 4-1:
300mL of toluene and 21.7g of 1, 5-dibromopentane were put into a reaction flask, the temperature was reduced to 10 ℃, 5g of a 30% aqueous solution of sodium hydroxide was added, 4.5g of a toluene solution of Compound D was added dropwise, and the reaction was carried out for 5 hours. Standing for layering, washing the organic phase with dilute hydrochloric acid and water in sequence, and concentrating to obtain yellow brown oil. And (3) separating and purifying by column chromatography to obtain a compound E3.6 g, wherein the structure is correct by nuclear magnetic resonance hydrogen spectrum detection. The nuclear magnetic hydrogen spectrum is shown in FIG. 4, and the detection data is as follows:1H-NMR(CDCl3,400Hz)δppm:7.09(1H,d,J＝8.3Hz),6.80(1H,d,J＝2,6Hz),6.75(1H,dd,J＝8.3,2.6Hz),3.82(3H,s),3.30(2H,t),2.96-3.00(2H,m),2.65-2.72(1H,m),2.53-2.60(1H,m),2.08-2.15(1H,m),1.71-1.78(2H,m),1.60-1.67(1H,m),1.39(3H,s),1.26-1.36(2H,m),1.92-1.02(2H,m)。
example 4-2:
50g of the compound D, 500mL of ethanol, 182g of 1, 5-dibromopentane and 1g of potassium iodide are added into a reaction bottle, the temperature is reduced to 0 ℃, 130g of 20% sodium ethoxide solution is added dropwise, and the reaction is carried out for 4h at 25 ℃. Adding dilute hydrochloric acid, adjusting pH to 6-7, and concentrating. Methyl tert-butyl ether and water were added to the concentrate, and after stirring, the layers were separated, and the organic layer was separated and concentrated to give compound E89 g. The nuclear magnetic detection data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.09(1H,d,J＝8.3Hz),6.80(1H,d,J＝2,6Hz),6.75(1H,dd,J＝8.3,2.6Hz),3.82(3H,s),3.30(2H,t),2.96-3.00(2H,m),2.65-2.72(1H,m),2.53-2.60(1H,m),2.08-2.15(1H,m),1.71-1.78(2H,m),1.60-1.67(1H,m),1.39(3H,s),1.26-1.36(2H,m),1.92-1.02(2H,m)。
examples 4 to 3:
1000mL of tetrahydrofuran, 102g of potassium tert-butoxide, 530g of 1, 5-dibromopentane and 0.5g of potassium iodide were added to a reaction flask, the temperature was lowered to 0 ℃ and 145g of a tetrahydrofuran solution of the compound D was added dropwise thereto, and the mixture was reacted at 30 ℃ for 2 hours. Adding intoAdjusting pH to 6-7 with dilute hydrochloric acid, and concentrating. Methyl tert-butyl ether and water were added to the concentrate, and after stirring, the layers were separated, the organic layer was separated, and the mixture was concentrated to give 256g of compound E. The nuclear magnetic detection data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.09(1H,d,J＝8.3Hz),6.80(1H,d,J＝2,6Hz),6.75(1H,dd,J＝8.3,2.6Hz),3.82(3H,s),3.30(2H,t),2.96-3.00(2H,m),2.65-2.72(1H,m),2.53-2.60(1H,m),2.08-2.15(1H,m),1.71-1.78(2H,m),1.60-1.67(1H,m),1.39(3H,s),1.26-1.36(2H,m),1.92-1.02(2H,m)。
examples 4 to 4:
600mL of t-amyl alcohol, 73g of sodium t-amyl alcohol and 2g of potassium iodide are added into a reaction bottle, the temperature is reduced to 5 ℃, a mixed solution of 100g of the compound D and 370g of 1, 5-dibromopentane in t-amyl alcohol is added dropwise, and after the addition, the mixture is reacted for 6 hours at 25 ℃. Adding dilute hydrochloric acid, adjusting pH to 7-8, and concentrating. Methyl tert-butyl ether and water were added to the concentrate, and after stirring, the layers were separated, the organic layer was separated, and concentrated to give 178g of compound E. The nuclear magnetic detection data are as follows:1H-NMR(CDCl3,400Hz)δppm:7.09(1H,d,J＝8.3Hz),6.80(1H,d,J＝2,6Hz),6.75(1H,dd,J＝8.3,2.6Hz),3.82(3H,s),3.30(2H,t),2.96-3.00(2H,m),2.65-2.72(1H,m),2.53-2.60(1H,m),2.08-2.15(1H,m),1.71-1.78(2H,m),1.60-1.67(1H,m),1.39(3H,s),1.26-1.36(2H,m),1.92-1.02(2H,m)。
example 5 Synthesis of 5-1 to 5-4 dezoxone
Example 5-1:
the compound E obtained in example 4-2 was dissolved in t-amyl alcohol, 37.5g of sodium t-amyl alcohol was added, the temperature was raised to 105 ℃ and the reaction was carried out for 3 hours, then the temperature was lowered to 40 ℃, and the PH was adjusted to about 7 with dilute hydrochloric acid. The layers were separated, the aqueous phase was discarded and the organic phase was concentrated to give 66g of crude dezoxone.
Example 5-2:
the compound E obtained in example 4-3 was dissolved in t-butanol, 102g of potassium t-butoxide was added and dissolved with stirring, the solution was transferred to a pressure vessel, the temperature was raised to 100 ℃ to react for 5 hours, then the temperature was lowered to 40 ℃, the reaction solution was taken out to a flask, and the PH was adjusted to about 7 with dilute hydrochloric acid. The organic layer was separated and concentrated to give 195g of crude dezoxone.
Examples 5 to 3:
dissolving the compound E obtained in example 4-4 in n-butanol, adding 35.7g of sodium ethoxide, stirring for dissolution, heating to 110 ℃ for reaction for 3 hours, cooling to 40 ℃, taking out the reaction solution to a flask, adjusting the pH to about 7 with dilute hydrochloric acid, standing, separating an organic layer, extracting an aqueous phase with methyl tert-ether, merging the aqueous phase into the organic layer, and concentrating to obtain 60g of crude dezoxone.
Examples 5 to 4:
the compound E obtained in example 4-4 was dissolved in n-butanol, 50g of potassium tert-butoxide and 50g of sodium tert-butoxide were added, the temperature was raised to 90 ℃ and the reaction was allowed to react for 8 hours, the temperature was lowered to 40 ℃, the reaction solution was transferred to a flask, the PH was adjusted to about 7 with dilute hydrochloric acid, an organic layer was separated after standing, the aqueous phase was extracted with methyl tert-ether and then incorporated into the organic layer, and crude dezoxone was obtained by concentration of 63 g.
Example 6 Synthesis of dezocanone Oxime
Example 6-1:
197g of hydroxylamine hydrochloride and 250g of anhydrous sodium acetate are added into 2000mL of anhydrous ethanol, then the crude dezocone ketone obtained in example 5-1 is added, reflux reaction is carried out at 110 ℃ for 8h, then water and ethyl acetate are added, standing and layering are carried out after stirring, the crude dezocone oxime is obtained after organic phase concentration, acetone is used for recrystallization, 20.8g of white solid is obtained, the purity is 99.7%, the total yield of three steps is 28.9% (the total reaction yield of three steps from the compound D to the dezocone oxime), and the purity is 99.5%. The product structure is confirmed by nuclear magnetic hydrogen spectrum detection, the nuclear magnetic hydrogen spectrum is shown in figure 5, and the data is as follows:1H-NMR(d6-DMSO,400Hz)δppm:7.04(1H,d,J＝8.2Hz),6.81(1H,d,J＝2.6Hz),6.72(1H,dd,J＝8.3,2.6Hz),3.73(3H,s),3.54-3.60(2H,m),2.90(1H,dd,J＝16.0,7.2Hz),2.75(1H,dd,J＝16,7.2Hz),2.20-2.26(1H,m),1.97-2.04(1H,m),1.44-1.58(10H,m),1.30-1.38(1H,m)。
example 6-2:
1kg of pyridine and 530g of hydroxylamine hydrochloride were added to the crude dezocinone obtained in example 5-2, and the mixture was reacted at 100 ℃ for 24 hours, then water and ethyl acetate were added, followed by stirring, standing for layering, and the organic phase was concentrated to obtain crude dezocinone, which was recrystallized from ethyl acetate to obtain 73.1g of white solid with a purity of 99.8% and a total yield of 35.0% in three steps (from compound D to dezocinone D)Total reaction yield of the three-step oxime reaction), and the purity is 99.6%. The product structure is confirmed by nuclear magnetic hydrogen spectrum detection, and the nuclear magnetic hydrogen spectrum data is as follows:1H-NMR(d6-DMSO,400Hz)δppm:7.04(1H,d,J＝8.2Hz),6.81(1H,d,J＝2.6Hz),6.72(1H,dd,J＝8.3,2.6Hz),3.73(3H,s),3.54-3.60(2H,m),2.90(1H,dd,J＝16.0,7.2Hz),2.75(1H,dd,J＝16,7.2Hz),2.20-2.26(1H,m),1.97-2.04(1H,m),1.44-1.58(10H,m),1.30-1.38(1H,m)。
examples 6 to 3:
1200mL of ethanol, 284g of acetone oxime and 15g of sulfuric acid are added into the crude dezocinone obtained in example 5-3, the mixture is heated to 60 ℃ to react for 20 hours, water and ethyl acetate are added, the mixture is stirred and then stands for layering, an organic phase is washed by saturated sodium bicarbonate, the crude dezocinone is obtained after concentration, and the crude dezocinone is recrystallized by ethyl acetate, so that 23.6g of white solid is obtained, the total yield of the three steps is 35.4% (the total package reaction yield of the three steps from the compound D to the dezocinone), and the purity is 99.8%. The product structure is confirmed by nuclear magnetic hydrogen spectrum detection, and the nuclear magnetic hydrogen spectrum data is as follows:1H-NMR(d6-DMSO,400Hz)δppm:7.04(1H,d,J＝8.2Hz),6.81(1H,d,J＝2.6Hz),6.72(1H,dd,J＝8.3,2.6Hz),3.73(3H,s),3.54-3.60(2H,m),2.90(1H,dd,J＝16.0,7.2Hz),2.75(1H,dd,J＝16,7.2Hz),2.20-2.26(1H,m),1.97-2.04(1H,m),1.44-1.58(10H,m),1.30-1.38(1H,m)。
examples 6 to 4:
600mL of isopropanol, 203g of acetoxime and 60g of p-toluenesulfonic acid are added into the crude dezocinone obtained in example 5-3, the mixture is heated to 50 ℃ to react for 48 hours, water and ethyl acetate are added, the mixture is stirred and then stands for layering, an organic phase is washed by saturated sodium bicarbonate, the crude dezocinone is obtained after concentration, and the crude dezocinone is recrystallized by ethyl acetate to obtain 20.3g of white solid with the total yield of 32.1% in three steps (the total reaction yield of the three steps from the compound D to the dezocinone), and the purity is 99.5%. The product structure is confirmed by nuclear magnetic hydrogen spectrum detection, and the nuclear magnetic hydrogen spectrum data is as follows:1H-NMR(d6-DMSO,400Hz)δppm:7.04(1H,d,J＝8.2Hz),6.81(1H,d,J＝2.6Hz),6.72(1H,dd,J＝8.3,2.6Hz),3.73(3H,s),3.54-3.60(2H,m),2.90(1H,dd,J＝16.0,7.2Hz),2.75(1H,dd,J＝16,7.2Hz),2.20-2.26(1H,m),1.97-2.04(1H,m),1.44-1.58(10H,m),1.30-1.38(1H,m)。
the applicant states that the present invention is illustrated by the above examples of the 1,2,3, 4-tetrahydronaphthalene derivatives of the present invention and the preparation method and application thereof, but the present invention is not limited to the above examples, i.e., it does not mean that the present invention must be implemented by the above examples. It should be understood by those skilled in the art that any modifications of the present invention, equivalent substitutions of the raw materials of the product of the present invention, and the addition of auxiliary components, selection of specific modes, etc., are within the scope and disclosure of the present invention.
The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.
It should be noted that the various technical features described in the above embodiments can be combined in any suitable manner without contradiction, and the invention is not described in any way for the possible combinations in order to avoid unnecessary repetition.
Claims (10)
1. A1, 2,3, 4-tetrahydronaphthalene derivative is characterized in that the structure of the 1,2,3, 4-tetrahydronaphthalene derivative is shown as a formula I:
wherein X is selected from any one of Cl, Br or I.
2. A method for preparing the 1,2,3, 4-tetrahydronaphthalene derivative according to claim 1, comprising the steps of: mixing and reacting a compound A1, 2-dihydro-6-methoxy-4-methylnaphthalene, a halogenating agent and a catalyst to obtain a compound B1,2,3, 4-tetrahydronaphthalene derivative, wherein the reaction formula is shown as a formula II:
wherein X is selected from any one of Cl, Br or I.
3. The method for producing a 1,2,3, 4-tetrahydronaphthalene derivative according to claim 2, wherein the catalyst is selected from any one or a combination of at least two of ammonium acetate, ammonium chloride, ammonium sulfate and a protonic acid;
preferably, the protic acid is selected from hydrochloric acid and/or acetic acid;
preferably, the halogenating agent is selected from N-halosuccinimide or N-halohydantoin;
preferably, the molar ratio of the 1, 2-dihydro-6-methoxy-4-methylnaphthalene to the halogenating agent is 1:0.9-1: 1.2;
preferably, the molar ratio of the 1, 2-dihydro-6-methoxy-4-methylnaphthalene to the catalyst is 1:0.05-1: 0.25;
preferably, the temperature of the reaction is 0-40 ℃;
preferably, the reaction time is 0.5 to 20 hours.
4. Use of the 1,2,3, 4-tetrahydronaphthalene derivative according to claim 1 for the preparation of dezocanone oxime.
5. The preparation method of dezoxime is characterized by comprising the following steps:
(1) reacting the compound B1, a 2,3, 4-tetrahydronaphthalene derivative with alkali to obtain a compound C;
(2) reacting the compound C obtained in the step (1) with boron trifluoride ethyl ether or protonic acid to obtain a compound D;
(3) reacting the compound D obtained in the step (2) with 1, 5-dibromopentane under the alkali condition to obtain a compound E;
(4) reacting the compound E obtained in the step (3) with alkali in an alcoholic solution to obtain dezoxone;
(5) reacting the dezoketone obtained in the step (4) to obtain dezoketoxime;
the reaction route is shown as formula III:
wherein X is selected from any one of Cl, Br or I.
6. The process for producing dezoketoxime according to claim 5, wherein the base in the step (1) is selected from any one of or a combination of at least two of sodium hydroxide, potassium hydroxide, ammonium acetate, ammonium chloride, lithium hydroxide and calcium hydroxide;
preferably, the molar ratio of the compound B to the base in the step (1) is 1:2-1: 4;
preferably, the temperature of the reaction of step (1) is 0-40 ℃;
preferably, the reaction time of the step (1) is 2-40 h;
preferably, the protic acid of step (2) is selected from p-toluenesulfonic acid or concentrated hydrochloric acid;
preferably, the alcohol solution in step (4) is selected from any one of tert-butyl alcohol, tert-amyl alcohol, n-butyl alcohol, cyclopentanol, n-amyl alcohol or cyclohexanol or a combination of at least two of the above;
preferably, the alkali in the step (4) is selected from sodium salt and/or potassium salt of any one of ethanol, tertiary butanol, tertiary amyl alcohol or methanol;
preferably, the temperature of the reaction in the step (4) is 90-110 ℃;
preferably, the reaction time of the step (4) is 2-24 h.
7. The process for producing dezoketoxime according to claim 5 or 6, wherein the reaction of step (5) comprises the steps of: reacting the dezoketone obtained in the step (4) with hydroxylamine hydrochloride and alkali to obtain dezoketone oxime;
preferably, the molar ratio of the dezoxone to the hydroxylamine hydrochloride is 1:8-1: 20;
preferably, the molar ratio of the dezoxone to the base is from 1:2 to 1: 20;
preferably, the base is selected from pyridine and/or sodium acetate;
preferably, the temperature of the reaction is 100-130 ℃;
preferably, the reaction time is 8-48 h.
8. The process for producing dezochytonoxime according to claim 5 or 6, characterized in that the reaction of step (5) comprises the steps of: reacting the dezoketone obtained in the step (4) with acetone oxime and acid to obtain the dezoketone oxime;
preferably, the molar ratio of dezoxone to acetoxime is from 1:1.5 to 1: 10;
preferably, the molar ratio of the dezoxone to the acid is from 1:0.1 to 1: 1;
preferably, the acid is selected from any one or a combination of at least two of p-toluenesulfonic acid, sulfuric acid, perchloric acid or periodic acid;
preferably, the temperature of the reaction is 50-70 ℃;
preferably, the reaction time is 16-48 h.
9. Process for the preparation of dezocanone oxime according to any one of claims 5 to 8, characterized in that it comprises the following steps:
(1) reacting a compound B1, a 2,3, 4-tetrahydronaphthalene derivative with alkali in a solvent and water at 0-40 ℃ for 2-40h to obtain a compound C;
(2) reacting the compound C obtained in the step (1) with boron trifluoride ethyl ether or protonic acid in a solvent to obtain a compound D;
(3) reacting the compound D obtained in the step (2) with 1, 5-dibromopentane under the alkali condition to obtain a compound E;
(4) reacting the compound E obtained in the step (3) with alkali in an alcohol solution at 90-110 ℃ for 2-24h to obtain dezozanone;
(5) and (3) carrying out reaction on the dezoketone obtained in the step (4) to obtain the dezoketoxime.
10. Use of the 1,2,3, 4-tetrahydronaphthalene derivative according to claim 1 for the preparation of dezocine.
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Citations (3)
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| CN102503840A (en) * | 2011-12-15 | 2012-06-20 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of dezocine |
| CN104910002A (en) * | 2015-05-28 | 2015-09-16 | 温州医科大学 | Dezocine key intermediate preparation method |
| WO2019007285A1 (en) * | 2017-07-03 | 2019-01-10 | 山东丹红制药有限公司 | Crystal form and amorphous form of dezocine analogue hydrochloride |
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| CN102503840A (en) * | 2011-12-15 | 2012-06-20 | 扬子江药业集团江苏海慈生物药业有限公司 | Preparation method of dezocine |
| CN104910002A (en) * | 2015-05-28 | 2015-09-16 | 温州医科大学 | Dezocine key intermediate preparation method |
| WO2019007285A1 (en) * | 2017-07-03 | 2019-01-10 | 山东丹红制药有限公司 | Crystal form and amorphous form of dezocine analogue hydrochloride |
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