CN114276243A - Synthetic method of loxoprofen and analogs thereof - Google Patents

Synthetic method of loxoprofen and analogs thereof Download PDF

Info

Publication number
CN114276243A
CN114276243A CN202111513343.4A CN202111513343A CN114276243A CN 114276243 A CN114276243 A CN 114276243A CN 202111513343 A CN202111513343 A CN 202111513343A CN 114276243 A CN114276243 A CN 114276243A
Authority
CN
China
Prior art keywords
acid
compound
analogues
organic
reaction
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202111513343.4A
Other languages
Chinese (zh)
Inventor
梅义将
李洁平
李永刚
于帅
胡剀
王长发
汪路峰
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zhejiang Jiuzhou Pharmaceutical Co Ltd
Original Assignee
Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Zhejiang Jiuzhou Pharmaceutical Co Ltd filed Critical Zhejiang Jiuzhou Pharmaceutical Co Ltd
Priority to CN202111513343.4A priority Critical patent/CN114276243A/en
Priority to PCT/CN2021/139085 priority patent/WO2023108601A1/en
Publication of CN114276243A publication Critical patent/CN114276243A/en
Pending legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/01—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms
    • C07C255/32—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring
    • C07C255/40—Carboxylic acid nitriles having cyano groups bound to acyclic carbon atoms having cyano groups bound to acyclic carbon atoms of a carbon skeleton containing at least one six-membered aromatic ring the carbon skeleton being further substituted by doubly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/317—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C67/32—Decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
    • C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
    • C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids

Abstract

The invention relates to the field of drug synthesis, in particular to a method for synthesizing loxoprofen and analogues thereof, which has the following reaction formula:

Description

Synthetic method of loxoprofen and analogs thereof
Technical Field
The invention relates to the field of drug synthesis, in particular to a synthetic method of loxoprofen and analogues thereof.
Background
The finished medicine is formed from its sodium salt, i.e. loxoprofen sodium, and is a precursor medicine, and can be absorbed by digestive tract, and converted into active metabolite, and its active metabolite can inhibit synthesis of prostaglandin so as to attain the goal of relieving pain, resisting inflammation and clearing away heat.
The existing loxoprofen synthesis process has one-step hydrolysis decarboxylation reaction, a hydrochloric acid-acetic acid system or a dilute sulfuric acid-acetic acid system is usually adopted for hydrolysis, and mixed acid is not effectively recovered in the post-treatment process, so that a large amount of acid water is wasted and the environment is polluted.
For example, in WO2014167509a2, a mixed (acetic acid-concentrated hydrochloric acid) system of a large excess amount of organic acid and inorganic acid is selected for hydrolysis, and the mixed acid is not effectively recovered in the post-treatment process, so that a large amount of acid water is wasted and the environment is polluted, and even if the mixed acid is recovered, the resource needs to be invested, and the treatment cost is increased.
Disclosure of Invention
The invention provides a method for synthesizing loxoprofen and analogues thereof, which avoids the use of a large amount of acid solution.
The invention adopts the following technical scheme:
a method for synthesizing loxoprofen and analogues thereof is disclosed, wherein the reaction formula is as follows:
Figure 100002_DEST_PATH_IMAGE002
。
the compound I reacts under the catalysis of a catalyst to generate a compound II.
In the above-mentioned technical means, the catalyst is preferably one or a mixture of plural kinds of inorganic metal salts of halogen such as fluorine, chlorine, bromine, iodine, etc., organic ammonium salts, organic phosphonium salts (tetramethylphosphonium bromide, tetraphenylphosphonium bromide, etc.), organic amines (including alkylamine and nitrogen-containing heterocycle), hydrochlorides, hydrobromides, hydroiodides of organic phosphines.
Preferably, the reaction temperature is 100 to 200 ℃.
Preferably, the reaction is carried out in the absence of a solvent or in a solvent having a boiling point above 100 ℃.
The reaction temperature of the reaction in the invention is generally required to reach 100 ℃, and therefore a solvent-free reaction or a solvent having a boiling point exceeding 100 ℃ is selected. The reaction substrate may act as a solvent in a liquid state at high temperature. Dipolar solvent, oxygen-containing solvent, and a small amount of water can effectively increase the solubility of the catalyst so as to accelerate the reaction. In a nonpolar solvent such as toluene, the solubility of the catalyst is lowered, and the reaction rate is relatively slow.
In the above aspect, the solvent having a boiling point of more than 100 ℃ is preferably one or more selected from DMF (N, N-dimethylformamide), DMAC (N, N-dimethylacetamide), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), toluene, xylene, chlorobenzene, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, and the like.
When organic acid such as oxalic acid, acetic acid, propionic acid, butyric acid, malonic acid, malic acid, citric acid and the like or acidic organic matter such as phenol, p-nitrophenol and the like are added into a reaction system in an equivalent or excessive amount, the catalyst can be recycled and reused. Or when an equivalent or excess amount of a metal salt of an organic acid such as an organic amine (including an alkylamine and a nitrogen-containing heterocycle), an organic phosphine, sodium oxalate, sodium acetate, sodium propionate, sodium butyrate, disodium malonate, sodium malate, or sodium citrate, or a basic compound such as a metal salt of a phenol compound such as phenol or p-nitrophenol is added to the reaction system, the catalyst can be recovered and used.
Preferably, a small amount of water is added to the reaction system to facilitate the reaction.
Through the implementation of the technical scheme, compared with the prior art, the invention has the following advantages:
the invention avoids the use of a large amount of acid solution.
The invention can be carried out under the condition of no solvent, and is more green and environment-friendly.
The catalyst used by the method can be recycled, the recovery rate of the catalyst reaches 98 percent, and the three-waste discharge and the environmental pollution are greatly reduced.
Detailed Description
The implementation procedures and the resulting advantages described in detail below by specific examples are intended to help the reader to better understand the essence and features of the present invention, and are not intended to limit the implementable scope of the present invention.
Example 1
Figure DEST_PATH_IMAGE004
Adding 0.5 mol of the compound A into a 500mL four-neck flask, adding 0.5 mol of NaBr, adding 200g of DMF, replacing with nitrogen, heating to the internal temperature of 130-150 ℃, keeping the temperature for reacting for 8-9 h, then completely reacting, cooling to 60-80 ℃, and distilling 160-180 g of DMF under reduced pressure. After the distillation, cooling to the internal temperature of 10-20 ℃, adding 200g of water and 600g of ethyl acetate, stirring and extracting, and separating a lower water phase. Adding 100g of water into the organic phase, stirring and separating the lower-layer water phase, and concentrating the organic phase under reduced pressure at the temperature of 30-50 ℃ in a water bath to obtain 125.4g of brown oil-like compound B, wherein the yield is 96.3%, and the purity is 97.2% by HPLC (high performance liquid chromatography).
Example 2
Figure DEST_PATH_IMAGE006
Adding 0.5 mol of the compound A into a 500mL four-neck flask, adding 0.5 mol of NaBr, adding 200g of DMF, adding 0.5 mol of water, replacing with nitrogen, heating to an internal temperature of 130-150 ℃, keeping the temperature for reaction for 7-8 h, then completely reacting, cooling to an internal temperature of 60-80 ℃, and distilling 160-180 g of DMF under reduced pressure. After the distillation, cooling to the internal temperature of 10-20 ℃, adding 200g of water and 600g of ethyl acetate, stirring and extracting, and separating a lower water phase. Adding 100g of water into the organic phase, stirring and separating the lower-layer water phase, and concentrating the upper-layer organic phase in a water bath at 30-50 ℃ under reduced pressure to obtain 123.3g of brown oil-like compound B, wherein the yield is 94.7%, and the purity is 96.6% by HPLC (high performance liquid chromatography).
Example 3
Figure DEST_PATH_IMAGE008
In a 500mL four-necked flask, 0.5 mol of Compound A and 0.25 mol of NiBr were added2Adding 200g of DMSO (dimethyl sulfoxide), replacing with nitrogen, heating to the internal temperature of 140-160 ℃, keeping the temperature for reaction for 12-13 h, completely reacting, cooling to the internal temperature of 60-80 ℃, and distilling 160-180 g of DMF under reduced pressure. After the distillation, cooling to the internal temperature of 10-20 ℃, adding 200g of water and 600g of ethyl acetate, stirring and extracting, and separating a lower water phase. Adding 100g of water into the organic phase, stirring and separating the lower aqueous phase, and concentrating the upper organic phase in a water bath at 30-50 ℃ under reduced pressure to obtain 121.1g of brown oil-like compound B, wherein the yield is 93.0%, and the purity is 96.8% by HPLC (high performance liquid chromatography).
Example 4
Figure DEST_PATH_IMAGE010
Adding 0.5 mol of the compound A into a 500mL four-neck flask, adding 0.5 mol of tetrabutylammonium bromide, adding 200g of DMF, replacing with nitrogen, heating to an internal temperature of 130-150 ℃, keeping the temperature for reaction for 5-6 h, then completely reacting, cooling to an internal temperature of 60-80 ℃, and distilling 160-180 g of DMF under reduced pressure. Cooling to an internal temperature of 10-20 ℃ after the steaming, and adding 200g of water and
600g of ethyl acetate are extracted with stirring, and the lower aqueous phase is separated off. Adding 100g of water into the organic phase, stirring and separating the lower-layer water phase, and concentrating the upper-layer organic phase under reduced pressure at 30-50 ℃ in a water bath to obtain 115.3 g of brown oily compound B, wherein the yield is 88.6%, and the purity is 97.4% by HPLC (high performance liquid chromatography).
Example 5
Figure DEST_PATH_IMAGE012
Adding 0.5 mol of the compound A into a 500mL four-neck flask, adding 0.5 mol of tetraethylammonium bromide, adding 200g of NMP, replacing with nitrogen, heating to an internal temperature of 130-150 ℃, keeping the temperature for reaction for 5-6 h, then completely reacting, cooling to an internal temperature of 60-80 ℃, and distilling 160-180 g of DMF under reduced pressure. Cooling to an internal temperature of 10-20 ℃ after the steaming, and adding 200g of water and
600g of ethyl acetate are extracted with stirring, and the lower aqueous phase is separated off. Adding 100g of water into the organic phase, stirring and separating the lower-layer water phase, and concentrating the upper-layer organic phase under reduced pressure at 30-50 ℃ in a water bath to obtain 117.7 g of brown oily compound B, wherein the yield is 90.4%, and the purity is 98.1% by HPLC (high performance liquid chromatography).
Example 6
Figure DEST_PATH_IMAGE014
Adding 0.5 mol of compound C into a 500mL four-neck flask, adding 0.5 mol of 1-butyl-3-methylimidazolium bromide, adding 300g of toluene, replacing with nitrogen, heating to reflux, keeping the temperature for reaction for 24-30 h, then completely reacting, cooling to the internal temperature of 10-20 ℃, adding 200g of water, stirring and extracting, and removing the lower-layer water phase. Adding 100g of water into the organic phase, stirring and separating the lower aqueous phase, and concentrating the upper organic phase under reduced pressure at 40-60 ℃ in a water bath to obtain 126.1g of brown oil-like compound D, wherein the yield is 91.9%, and the purity is 98.3% by HPLC (high performance liquid chromatography).
Example 7
Figure DEST_PATH_IMAGE016
Adding 0.5 mol of compound C into a 500mL four-necked bottle, adding 0.5 mol of 1-butyl-3-methylimidazolium bromide, adding 300g of ethylene glycol diethyl ether, replacing with nitrogen, heating to reflux, keeping the temperature for reaction for 24-30 h, reacting completely, cooling to an internal temperature of 60-80 ℃, and distilling 260-280 g of ethylene glycol diethyl ether under reduced pressure. After the distillation, cooling to the internal temperature of 10-20 ℃, adding 200g of water and 600g of ethyl acetate, stirring and extracting, and separating a lower water phase. Adding 100g of water into the organic phase, stirring and separating the lower-layer water phase, and concentrating the upper-layer organic phase under reduced pressure at 30-50 ℃ in a water bath to obtain 123.7 g of brown oily compound D, wherein the yield is 90.2%, and the purity is 98.4% by HPLC (high performance liquid chromatography).
Example 8
Figure DEST_PATH_IMAGE018
Adding 0.5 mol of compound C into a 500mL four-neck flask, adding 0.1 mol of 1-butyl-3-methylimidazolium chloride, adding 300g of ethylene glycol diethyl ether, adding 0.55mol of acetic acid, heating to reflux after nitrogen replacement, separating the methyl acetate evaporated in the reaction process by a water separator, reacting completely after heat preservation for 24-30 h, cooling to the internal temperature of 50-70 ℃, and evaporating 260-280 g of ethylene glycol diethyl ether under reduced pressure. After the distillation is finished, cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 17.2 g of recovered 1-butyl-3-methylimidazole hydrochloride, wherein the recovery rate is 98.5%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 125.2 g brown oily compound D, with yield of 91.3% and purity of 98.5% as detected by HPLC.
Example 9
Figure DEST_PATH_IMAGE020
Adding 0.5 mol of compound C into a 500mL four-neck flask, adding 0.5 mol of tetrabutylammonium bromide, adding 300g of chlorobenzene, adding 0.3mol of malonic acid, replacing with nitrogen, heating to reflux, and reacting for 10-12 h under heat preservation to complete the reaction. And cooling to the internal temperature of 10-20 ℃, filtering, leaching a filter cake with 100g of chlorobenzene, transferring the filter cake to a vacuum oven at 40-50 ℃, and drying for 12-16 h to obtain 158.4 g of recovered tetrabutylammonium bromide, wherein the recovery rate is 98.3%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 40-60 deg.c and decompression to obtain brown oily compound D in the yield of 93.7% and HPLC purity of 98.7%.
Example 10
Figure DEST_PATH_IMAGE022
Adding 0.5 mol of the compound E into a 500mL four-neck flask, adding 0.2mol of triethylmethylammonium bromide, adding 300g of diethylene glycol dimethyl ether, adding 0.55mol of propionic acid, replacing with nitrogen, heating to reflux, separating the methyl propionate evaporated in the reaction process by a water separator, keeping the temperature for reaction for 24-30 h, completely reacting, cooling to the internal temperature of 50-70 ℃, and evaporating 260-280 g of diethylene glycol dimethyl ether under reduced pressure. After the distillation is finished, cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 38.3 g of recovered triethyl methyl ammonium bromide, wherein the recovery rate is 98.2%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 128.2 g brown oily compound D with yield of 93.5% and purity of 97.3% by HPLC.
Example 11
Figure DEST_PATH_IMAGE024
Adding 0.5 mol of the compound E into a 500mL four-mouth bottle, adding 0.1 mol of hexadecyl trimethyl ammonium bromide, adding 0.55mol of butyric acid, replacing with nitrogen, heating to the internal temperature of 160-165 ℃, and keeping the temperature to react for 6-8 h to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 33.1g of recovered hexadecyl trimethyl ammonium bromide, wherein the recovery rate is 98.4%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. And concentrating the upper organic phase in a water bath at 30-50 ℃ under reduced pressure to obtain 129.2 g of brown oily compound D, wherein the yield is 94.2%, and the purity is 98.3% by HPLC (high performance liquid chromatography).
Example 12
Figure DEST_PATH_IMAGE026
Adding 0.5 mol of compound C into a 500mL four-neck flask, adding 0.1 mol of triethylamine hydrochloride, adding 300g of DMSO, replacing with nitrogen, heating to the internal temperature of 160-170 ℃, keeping the temperature for reacting for 16-18 h, then completely reacting, cooling to the internal temperature of 60-80 ℃, and distilling 260-280 g of DMSO under reduced pressure. After the distillation is finished, cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 19.2 g of recovered triethyl hexyl ammonium chloride, wherein the recovery rate is 98.5%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 119.2 g brown oily compound D with yield of 87.0% and purity of 96.1% by HPLC.
Example 13
Figure DEST_PATH_IMAGE028
Adding 0.5 mol of the compound F into a 500mL four-neck flask, adding 0.1 mol of pyridine hydrobromide, adding 0.2mol of malic acid, adding 300g of DMF, replacing with nitrogen, heating to the internal temperature of 135-145 ℃, keeping the temperature, reacting for 6-8 h, and then completely reacting. Cooling to an internal temperature of 50-70 ℃, and distilling 260-280 g of DMF under reduced pressure. After the distillation is finished, cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 18.5g of recovered N-ethylpyridine bromide, wherein the recovery rate is 98.4%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 133.1G brown oily compound G with yield of 92.4% and purity of 96.7% by HPLC.
Example 14
Figure DEST_PATH_IMAGE030
Adding 0.5 mol of compound H, 0.1 mol of tetramethyl phosphonium bromide and 0.55mol of propionic acid into a 500mL four-necked bottle, heating to the internal temperature of 140-150 ℃ after nitrogen replacement, separating the methyl propionate evaporated in the reaction process by a water separator, and reacting for 16-18H under the condition of heat preservation to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 16.8 g of recovered tetramethyl phosphonium bromide, wherein the recovery rate is 98.2%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 138.4 g brown oily compound J with yield of 91.5% and purity of 97.9% by HPLC.
Example 15
Figure DEST_PATH_IMAGE032
Adding 0.5 mol of compound K, 0.06 mol of tetraphenyl phosphine bromide and 0.55mol of acetic acid into a 500mL four-necked bottle, heating to the internal temperature of 130-140 ℃ after nitrogen replacement, connecting a water separator to separate the methyl acetate evaporated in the reaction process, and keeping the temperature to react for 6-8 h to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 24.8g of recovered tetraphenyl phosphonium bromide, wherein the recovery rate is 96.3%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 152.3 g brown oily compound L with yield of 92.2% and purity of 97.9% by HPLC.
Example 16
Figure DEST_PATH_IMAGE034
Adding 0.5 mol of the compound A into a 500mL four-neck flask, adding 0.1 mol of tetrabutylammonium bromide, adding 0.55mol of sodium propionate, replacing with nitrogen, heating to the internal temperature of 140-150 ℃, separating the methyl propionate evaporated in the reaction process by a water separator, and reacting for 16-18 h under the condition of heat preservation to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 31.0 g of recovered tetrabutylammonium bromide, wherein the recovery rate is 96.2%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 122.3 g brown oily compound B with yield of 94.0% and purity of 97.6% by HPLC.
Example 17
Figure DEST_PATH_IMAGE036
Adding 0.5 mol of the compound A into a 500mL four-neck flask, adding 0.1 mol of tetrabutylammonium bromide, adding 0.55mol of n-propylamine, replacing with nitrogen, heating to the internal temperature of 130-140 ℃, and keeping the temperature to react for 12-14 h to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven at 40-50 ℃, drying for 12-16 h to obtain 27.8g of recovered tetrabutylammonium bromide and tri-n-propylmethylammonium bromide compounds, and recovering 86.2%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 120.1 g brown oily compound B with yield of 92.3% and purity of 95.8% by HPLC.
Example 18
Figure DEST_PATH_IMAGE038
Adding 0.5 mol of compound M into a 500mL four-neck flask, adding 0.1 mol of tetraethylammonium bromide, adding 0.55mol of propionic acid, replacing with nitrogen, heating to the internal temperature of 140-150 ℃, separating the methyl propionate evaporated in the reaction process by a water separator, and reacting for 16-18 h under the condition of heat preservation to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 19.8 g of recovered tetraethylammonium bromide, wherein the recovery rate is 94.2%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.c and decompression to obtain brown oily compound N in the yield of 96.6% and HPLC purity of 95.4%.
Example 19
Figure DEST_PATH_IMAGE040
Adding 0.5 mol of compound P, 0.1 mol of tetrabutylammonium bromide and 0.55mol of pyridine into a 500mL four-neck flask, replacing with nitrogen, heating to the internal temperature of 130-140 ℃, and keeping the temperature for reaction for 10-12 h to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven at 40-50 ℃, drying for 12-16 h to obtain 28.8g of recovered tetrabutylammonium bromide and N-methylpyridine bromide, and recovering 89.4%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 110.6 g brown oily compound Q with yield of 97.3% and purity of 94.3% by HPLC.
Example 20
Figure DEST_PATH_IMAGE042
Adding 0.5 mol of compound M into a 500mL four-neck flask, adding 21.0g of recovered tetraethylammonium bromide, adding 0.55mol of propionic acid, replacing with nitrogen, heating to the internal temperature of 140-150 ℃, connecting a water separator to separate the methyl propionate evaporated in the reaction process, and keeping the temperature for reacting for 16-18 h to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven for drying at 40-50 ℃ for 12-16 h to obtain 20.1 g of recovered tetraethylammonium bromide, wherein the recovery rate is 95.7%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 108.4 g brown oily compound N with yield of 95.4% and purity of 96.7% by HPLC.
Example 21
Figure DEST_PATH_IMAGE044
Adding 0.5 mol of the compound P into a 500mL four-neck flask, adding 32.2g of recovered tetrabutylammonium bromide, adding 0.55mol of pyridine, replacing with nitrogen, heating to the internal temperature of 130-140 ℃, and keeping the temperature for reaction for 10-12 h to complete the reaction. Cooling to the internal temperature of 10-20 ℃, adding 500 g of ethyl acetate, stirring, pulping and filtering, leaching a filter cake with 100g of ethyl acetate, transferring the filter cake to a vacuum oven at 40-50 ℃, drying for 12-16 h to obtain 27.4g of a recovered tetrabutylammonium bromide and N-methylpyridine bromide salt mixture, and recovering 85.1%. 100g of water was added to the filtrate, and the mixture was extracted with stirring to separate the lower aqueous phase. Concentrating the upper organic phase in water bath at 30-50 deg.C under reduced pressure to obtain 110.6 g brown oily compound Q with yield of 97.3% and purity of 94.3% by HPLC.

Claims (10)

1. A method for synthesizing loxoprofen and analogues thereof is characterized in that the reaction formula is as follows:
Figure DEST_PATH_IMAGE002
and reacting the compound I under the catalysis of a catalyst to generate a compound II.
2. The method for synthesizing loxoprofen and the analogues thereof according to claim 1, wherein the catalyst is one or more of halogen, inorganic metal salt, organic ammonium salt, organic phosphonium salt, organic amine, organic phosphine hydrochloride, hydrobromide or hydroiodide.
3. The method for synthesizing loxoprofen and analogues thereof according to claim 1, wherein the reaction temperature is 100-200 ℃.
4. The method for synthesizing loxoprofen and its analogues according to claim 1, wherein the reaction is carried out in the absence of a solvent or in a solvent having a boiling point exceeding 100 ℃.
5. The method as claimed in claim 4, wherein the solvent with boiling point over 100 ℃ is one or more of DMF (N, N-dimethylformamide), DMAC (N, N-dimethylacetamide), NMP (N-methylpyrrolidone), DMSO (dimethyl sulfoxide), toluene, xylene, chlorobenzene, ethylene glycol diethyl ether, and diethylene glycol dimethyl ether.
6. The method for synthesizing loxoprofen and analogues thereof according to claim 2, wherein said catalyst is recovered by using an acidic organic substance or a metal salt of an organic acid or a basic compound.
7. The method as claimed in claim 6, wherein the acidic organic substance is oxalic acid, acetic acid, propionic acid, butyric acid, malonic acid, malic acid, citric acid, phenol or p-nitrophenol.
8. The method for synthesizing loxoprofen and analogues thereof according to claim 6, wherein said metal salt of organic acid is organic amine, organic phosphine, sodium oxalate, sodium acetate, sodium propionate, sodium butyrate, disodium malonate, sodium malate or sodium citrate.
9. The method for synthesizing loxoprofen and analogues thereof as claimed in claim 6, wherein said basic compound is a metal salt of phenolic compound.
10. The method for synthesizing loxoprofen and analogues thereof according to claim 1, wherein water is added to the reaction system.
CN202111513343.4A 2021-12-13 2021-12-13 Synthetic method of loxoprofen and analogs thereof Pending CN114276243A (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
CN202111513343.4A CN114276243A (en) 2021-12-13 2021-12-13 Synthetic method of loxoprofen and analogs thereof
PCT/CN2021/139085 WO2023108601A1 (en) 2021-12-13 2021-12-17 Synthesis method for loxoprofen and analogues thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN202111513343.4A CN114276243A (en) 2021-12-13 2021-12-13 Synthetic method of loxoprofen and analogs thereof

Publications (1)

Publication Number Publication Date
CN114276243A true CN114276243A (en) 2022-04-05

Family

ID=80872007

Family Applications (1)

Application Number Title Priority Date Filing Date
CN202111513343.4A Pending CN114276243A (en) 2021-12-13 2021-12-13 Synthetic method of loxoprofen and analogs thereof

Country Status (2)

Country Link
CN (1) CN114276243A (en)
WO (1) WO2023108601A1 (en)

Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001081066A (en) * 1999-09-10 2001-03-27 Nippon Petrochem Co Ltd Substituted styrene derivative
JP4074341B2 (en) * 1995-12-29 2008-04-09 日本ゼオン株式会社 Method for producing carbonyl group-containing compound
CN101412670A (en) * 2007-10-19 2009-04-22 浙江普洛医药科技有限公司 Method for synthesizing loxoprofen sodium
CN103189337A (en) * 2010-08-13 2013-07-03 Abbvie德国有限责任两合公司 Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
CN103449946A (en) * 2013-09-04 2013-12-18 黄山学院 Preparation method of alpha-monochlorinated ketone compound
CN104591989A (en) * 2015-01-05 2015-05-06 上海华谊（集团）公司 Method for preparing 5-[(4-chlorophenyl)methyl]-2,2-dimethyl-cyclopentanone
WO2015075981A1 (en) * 2013-11-22 2015-05-28 株式会社クレハ Method for producing carbonyl compound
CN104684881A (en) * 2012-11-27 2015-06-03 株式会社吴羽 Production method for carbonyl compound
CN108083967A (en) * 2017-12-27 2018-05-29 安徽金善化工科技有限公司 A kind of distillation recovery method of toluene
CN108440274A (en) * 2018-03-06 2018-08-24 大桐制药（中国）有限责任公司 A kind of synthetic method of high-purity nonsteroidal anti-inflammatory drug loxoprofen sodium

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104326903A (en) * 2014-10-14 2015-02-04 合肥远志医药科技开发有限公司 Industrial production method of high purity loxoprofen sodium dehydrate
CN104710309A (en) * 2015-02-05 2015-06-17 浙江普洛医药科技有限公司 Synthetic methods of loxoprofen sodium and intermediate thereof

Patent Citations (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4074341B2 (en) * 1995-12-29 2008-04-09 日本ゼオン株式会社 Method for producing carbonyl group-containing compound
JP2001081066A (en) * 1999-09-10 2001-03-27 Nippon Petrochem Co Ltd Substituted styrene derivative
CN101412670A (en) * 2007-10-19 2009-04-22 浙江普洛医药科技有限公司 Method for synthesizing loxoprofen sodium
CN103189337A (en) * 2010-08-13 2013-07-03 Abbvie德国有限责任两合公司 Aminoindane derivatives, pharmaceutical compositions containing them, and their use in therapy
CN104684881A (en) * 2012-11-27 2015-06-03 株式会社吴羽 Production method for carbonyl compound
CN103449946A (en) * 2013-09-04 2013-12-18 黄山学院 Preparation method of alpha-monochlorinated ketone compound
WO2015075981A1 (en) * 2013-11-22 2015-05-28 株式会社クレハ Method for producing carbonyl compound
CN104591989A (en) * 2015-01-05 2015-05-06 上海华谊（集团）公司 Method for preparing 5-[(4-chlorophenyl)methyl]-2,2-dimethyl-cyclopentanone
CN108083967A (en) * 2017-12-27 2018-05-29 安徽金善化工科技有限公司 A kind of distillation recovery method of toluene
CN108440274A (en) * 2018-03-06 2018-08-24 大桐制药（中国）有限责任公司 A kind of synthetic method of high-purity nonsteroidal anti-inflammatory drug loxoprofen sodium

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
ATUL GUPTA ET AL.: "Simple and Efficient Synthesis of Steroidal Hybrids of Estrogen and Vitamin D3", 《SYNTHETIC COMMUNICATIONS》, vol. 39, pages 61 - 69 *

Also Published As

Publication number Publication date
WO2023108601A1 (en) 2023-06-22

Similar Documents

Publication Publication Date Title
CN107915586B (en) Phenol compound and preparation method thereof
FI63927C (en) FOERFARANDE FOER FRAMSTAELLNING AV DI-N-PROPYL-AETTIKSSYRA OCHDESS SALTER
CN103724261A (en) Novel industrial production method for hydroxychloroquine sulfate
KR102233455B1 (en) Method for preparation of intermediate of 4-methoxypyrrole derivative
CN111303018A (en) Synthetic method of omeprazole intermediate
CN102731349B (en) Aromatic sulfinic acid compound preparation method
KR102233456B1 (en) Method for preparation of intermediate of 4-methoxypyrrole derivative
CN114276243A (en) Synthetic method of loxoprofen and analogs thereof
CN109503513B (en) One-pot synthesis method of febuxostat intermediate
KR101705210B1 (en) Method of preparing composition of chlorohydrins and method of preparing epichlorohydrin using composition of chlorohydrins prepared by the same
KR101705206B1 (en) Method of preparing chlorohydrins and method of preparing epichlorohydrin using chlorohydrins prepared by the same
CN111253276B (en) Preparation method of oseltamivir phosphate
US7741518B2 (en) Method for producing trifluoromethanesulfonic anhydride
WO2012002650A2 (en) Method for preparing chlorohydrins composition and method for preparing epichlorohydrin using chlorohydrins composition prepared thereby
CN108467410B (en) Preparation method, product and application of TAF intermediate
KR101705209B1 (en) Method of preparing composition of chlorohydrins and method of preparing epichlorohydrin using composition of chlorohydrins prepared by the same
CN115093339A (en) Synthetic method of L-glufosinate-ammonium intermediate
CN109824687B (en) Novel synthetic method of xylofuranose derivative
CN109053800B (en) Quaternary phosphonium salt supported chiral amino-thiourea and preparation method and application thereof
KR101705207B1 (en) Method of preparing chlorohydrins and method of preparing epichlorohydrin using chlorohydrins prepared by the same
CN111646907B (en) Preparation method of 2, 3-dichloro-6-nitroaniline
JP2001515496A (en) Method for producing 5-aminomethyl-chloropyridines
CN111440079A (en) Synthesis method of D L-threo-p-chlorophenylserine
CN101665427B (en) Process for preparing 5-bromo-n-valeryl bromide
CN113105419B (en) Method for preparing S-citalopram from R-diol

Legal Events

Date Code Title Description
PB01 Publication
PB01 Publication
SE01 Entry into force of request for substantive examination
SE01 Entry into force of request for substantive examination
RJ01 Rejection of invention patent application after publication

Application publication date: 20220405

RJ01 Rejection of invention patent application after publication