CN114456059B - Method for preparing aforana intermediate - Google Patents

Method for preparing aforana intermediate Download PDF

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CN114456059B
CN114456059B CN202210211730.0A CN202210211730A CN114456059B CN 114456059 B CN114456059 B CN 114456059B CN 202210211730 A CN202210211730 A CN 202210211730A CN 114456059 B CN114456059 B CN 114456059B
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reaction
solvent
aforana
carboxylic acid
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CN114456059A (en
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李冰冰
米俊儒
曾宝莹
姜桥
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Livzon New North River Pharmaceutical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/373—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of functional groups containing oxygen only in doubly bound form
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member

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Abstract

The invention belongs to the field of pharmacy, and discloses a method for preparing an aforana intermediate. The afrana intermediate is 4-formylnaphthalene-1-carboxylic acid, and the synthetic route isCompared with the prior art, will

Description

Method for preparing aforana intermediate
Technical Field
The invention belongs to the field of pharmacy, and particularly relates to a method for preparing an aforana intermediate.
Background
Aforana (afoxollan), trade name of nikoshi (NexGard), is the first line of market in china by the company bringeland, 8, 2017, for oral insect repellents for dogs against both parasites, ticks and fleas. The compound belongs to isoxazolines, and the action principle is that the death is caused by inhibiting GABA chloride ion channels of arthropods and then highly exciting nerves. The number of the current Chinese pet dogs exceeds 6200 ten thousand. Dogs are active, are susceptible to infection by a variety of parasites, and can be harmful to their health and the health of the feeding owners, thus requiring a series of measures to kill the parasites. Fleas cannot spawn because of killing fleas after taking afrana for two hours, environmental pollution is avoided, fleas can be effectively prevented from spawning after lasting five weeks, and meanwhile, 8 common cicada insects can be repelled and killed, and the effect lasts for more than 1 month.
4-formyl-naphthalene-1-carboxylic acid is a key intermediate for synthesizing aforana, and has a structural formula ofThere are few reports on the synthesis of this compound, and the specific route given in patent US6613942B1 (j. Med. Chem.2002,45, 5755-5775) is shown in (scheme 1):
the route takes 4- (bromomethyl) naphthalene-1-carboxylic acid as a starting material, and the target intermediate is obtained through 5 steps of bromination, hydrolysis, esterification, oxidation and ester hydrolysis. According to the yields reported in the patent literature, the esterification reaction yield is only 35% and the total yield is 24%.
Therefore, how to safely and efficiently prepare the oxazoline insecticide fluorine Lei Lana intermediate with low impurity content at low cost is a problem to be solved.
Disclosure of Invention
The invention aims to overcome at least one defect of the prior art and provides a method for preparing an aforana intermediate.
The technical scheme adopted by the invention is as follows:
in a first aspect of the invention, there is provided:
a method for preparing an aforana intermediate 4-formylnaphthalene-1-carboxylic acid comprises the following synthetic route:
the method comprises the following reactions:
halogenation reaction: dissolving the intermediate 3 in a solvent, adding a halogenating reagent to carry out halogenation reaction, and concentrating the solvent after the reaction is finished;
hydrolysis reaction: concentrating the halogenated reaction liquid, adding a solvent A for hydrolysis, and filtering after the reaction is finished to obtain an intermediate 4, namely 4-formylnaphthalene-1-carboxylic acid.
In some examples of the method, the solvent for the halogenation reaction is selected from at least one of methanol, ethanol, tetrahydrofuran, benzene, toluene, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, ethyl acetate.
In some examples of the method, the reaction temperature of the halogenation reaction is from 25 ℃ to reflux temperature.
In some examples of the method, the halogenating agent is selected from at least one of bromine, iodine, chlorine, N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 1, 3-dichloro-5, 5-dimethylhydantoin, 1, 3-dibromo-5, 5-dimethylhydantoin.
In some examples of the method, the solvent a is a mixture of water and at least one of methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, acetonitrile.
In some examples of the method, the volume percentage of water in the solvent a is 50 to 99%.
In some examples of the method, the temperature of the hydrolysis is 50 to 100 ℃.
In some examples of methods, the synthetic route for intermediate 3 is as follows:
the method comprises the following reactions:
acylation reaction: dissolving the initial material 1 in a solvent, adding an acylating agent for acylation, pouring the reaction solution into a hydrochloric acid solution after the reaction is finished, extracting by an organic solvent, and concentrating;
haloform reaction: reacting intermediate 2 with a hypohalite; after the reaction is completed, the water phase is washed by an organic solvent, the pH value of the water phase is regulated to separate out a product, and the intermediate 3 is obtained by filtering and washing.
In some examples of the method, the reaction temperature of the acylation reaction is 0 ℃ to 50 ℃.
In some examples of the method, the acylating reagent is selected from acetyl chloride, acetic anhydride, acetic acid.
In some examples of methods, the hypohalite is sodium hypochlorite.
In some examples of the process, the aqueous phase adjusts the pH to not exceed 7 to precipitate the product.
In a second aspect of the invention, there is provided:
a process for the preparation of aforana comprising preparing 4-formylnaphthalene-1-carboxylic acid according to the process of the first aspect of the present invention, followed by further preparing aforana.
The beneficial effects of the invention are as follows:
in contrast to the synthetic route of US6613942B1, the methods of some examples of the invention control the methyl halogenation process in a binary substitution stageX is Cl, br or I, then directly hydrolyzing to obtain aldehyde group, reducing oxidationThe reaction step is shortened from step 5 to step 2, the intermediate control step is simplified, and the alfosana intermediate product with qualified purity can be obtained, so that the product yield is improved, and the industrial production is easier.
Drawings
FIG. 1 is an HPLC chart of the preparation of 4-formyl-naphthalene-1-carboxylic acid (arvenna intermediate) prepared in example 1;
FIG. 2 is a preparation of 4-formyl-naphthalene-1-carboxylic acid prepared in example 1 (Alforanan intermediate) 1 H NMR spectrum.
Detailed Description
In a first aspect of the invention, there is provided:
a method for preparing an aforana intermediate 4-formylnaphthalene-1-carboxylic acid comprises the following synthetic route:
the method comprises the following reactions:
halogenation reaction: dissolving the intermediate 3 in a solvent, adding a halogenating reagent to carry out halogenation reaction, and concentrating the solvent after the reaction is finished;
hydrolysis reaction: concentrating the halogenated reaction liquid, adding a solvent A for hydrolysis, and filtering after the reaction is finished to obtain an intermediate 4, namely 4-formylnaphthalene-1-carboxylic acid.
The solvent for the halogenation reaction is not particularly required, and the intermediate 3 can be well dissolved, and the halogenation reaction is facilitated. In some examples of the method, the solvent for the halogenation reaction is selected from at least one of methanol, ethanol, tetrahydrofuran, benzene, toluene, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane, ethyl acetate. Preferably dichloromethane, acetonitrile or methanol.
In some examples of the method, the reaction temperature of the halogenation reaction is from 25 ℃ to reflux temperature.
In some examples of the method, the halogenating agent is selected from at least one of bromine, iodine, chlorine, N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 1, 3-dichloro-5, 5-dimethylhydantoin, 1, 3-dibromo-5, 5-dimethylhydantoin. Preferably NCS or NBS. In order to make the halogenating agent react more rapidly, a certain amount of initiator, such as the usual initiator of AIBN (azobisisobutyronitrile) or the like, may be added.
In order to remove impurities such as unreacted raw materials during the halogenation reaction, a certain amount of organic solvent may be added to the solvent A. The organic solvents are preferably those which have a low solubility or complete insolubility in 4-formylnaphthalene-1-carboxylic acid and a good solubility in impurities. In some examples of the method, the solvent a is a mixture of water and at least one of methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, acetonitrile.
The amount of the organic solvent may be adjusted as needed. In some examples of the method, the volume percentage of water in the solvent a is 50 to 99%.
In some examples of the method, the temperature of the hydrolysis is 50 to 100 ℃.
In some examples of methods, the synthetic route for intermediate 3 is as follows:
the method comprises the following reactions:
acylation reaction: dissolving the initial material 1 in a solvent, adding an acylating agent for acylation, pouring the reaction solution into a hydrochloric acid solution after the reaction is finished, extracting by an organic solvent, and concentrating;
haloform reaction: reacting intermediate 2 with a hypohalite; after the reaction is completed, the water phase is washed by an organic solvent, the pH value of the water phase is regulated to separate out a product, and the intermediate 3 is obtained by filtering and washing.
In some examples of the method, the reaction temperature of the acylation reaction is 0 ℃ to 50 ℃.
In some examples of the method, the acylating reagent is selected from acetyl chloride, acetic anhydride, acetic acid.
In some examples of methods, the hypohalite is sodium hypochlorite.
In some examples of the process, the aqueous phase adjusts the pH to not exceed 7 to precipitate the product.
In a second aspect of the invention, there is provided:
a process for the preparation of aforana comprising preparing 4-formylnaphthalene-1-carboxylic acid according to the process of the first aspect of the present invention, followed by further preparing aforana.
Example 1
Acylation reaction
Preparation of 4-methyl-1-naphthacenenone
1) 14.20g of 1-methylnaphthalene and 14.67g (1.1 eq) of aluminum trichloride were added to 142mL of methylene chloride and stirred to give a brownish black solution;
2) Mixing 8.64g of acetyl chloride with 20mL of dichloromethane, slowly dropwise adding the mixture into the solution under the protection of nitrogen, and reacting for 1h at 10-20 ℃ after the dropwise adding is finished;
3) After the reaction, slowly pouring the reaction solution into 115mL of 0.05mol/L hydrochloric acid solution which is pre-cooled to 10-20 ℃, stirring for 20min after pouring, separating the solution, extracting with dichloromethane, combining organic layers, and distilling the solution under reduced pressure at 45 ℃ to obtain 18.03g of oily matter, wherein the yield is 98%.
Haloform reaction
Preparation of 4-methyl-naphthalene-1-carboxylic acid
1) Adding 18.03g of 4-methyl-1-naphthacenedione into 110mL of water, and stirring to obtain a turbid liquid;
2) Heating the turbid liquid to 50-55 ℃, adding 135g of 10% sodium hypochlorite solution, and keeping the temperature of 50-55 ℃ for reaction for 2.5h;
3) The reaction solution was cooled to room temperature, washed twice with dichloromethane, sodium hydrogensulfite was added to the aqueous phase, the pH was adjusted to 4 or less with concentrated hydrochloric acid under stirring, a large amount of solids was precipitated, the obtained solid was filtered, washed with a small amount of water, and the solid was dried under reduced pressure at 50℃to obtain 16.22g of solid in 89% yield.
MS(m/z)：[M+H] + ＝187.07, 1 H NMR(500MHz,DMSO-d6)δ13.00(s,1H),8.95(dd,J＝7.9,2.0Hz,1H),8.12(dd,J＝7.7,2.0Hz,1H),8.06(d,J＝7.3Hz,1H),7.69-7.59(m,2H),7.45(d,J＝7.4Hz,1H),2.72(s,3H)。
Halogenation & hydrolysis
Preparation of 4-formyl-naphthalene-1-carboxylic acid (aforana intermediate)
1) 9.3g of 4-methyl-1-naphthoic acid, 20.45g (2.3 eq) of NBS and 0.53g (0.06 eq) of AIBN are added into 140mL of dichloromethane, and the mixture is stirred and heated to 70-75 ℃ for reaction for 1.5h;
2) Concentrating to remove dichloromethane after the reaction is finished;
3) 60mL of dioxane and 60mL of purified water are added into the concentrate, and the temperature is raised to 90 ℃ for reaction for 2.5h;
4) After the reaction, 60mL of purified water was added, the temperature of the reaction solution was slowly lowered to room temperature, the reaction solution was filtered, the filter cake was slurried with ethyl acetate, and the mixture was dried under reduced pressure at 50℃to obtain 9.40g of a white solid, with a yield of 94%.
The HPLC diagram of the white solid is shown in figure 1, 1 the H NMR spectrum is shown in FIG. 2.
1 H NMR(500MHz,DMSO)δ13.71(s,1H),10.51(s,1H),9.21(d,J＝8.0Hz,1H),8.75(d,J＝8.0Hz,1H),8.23(dd,J＝16.7,7.4Hz,2H),7.78(dtd,J＝16.6,6.9,1.2Hz,2H).
Example 2
Acylation reaction
Preparation of 4-methyl-1-naphthacenenone
1) 3.55g of 1-methylnaphthalene and 3.67g (1.1 eq) of aluminum trichloride were added to 35mL of acetonitrile and stirred to give a brownish black solution;
2) Mixing 2.16g of acetyl chloride with 5mL of acetonitrile, slowly dropwise adding the mixture into the solution under the protection of nitrogen, and reacting for 1h at 10-20 ℃ after the dropwise adding is finished;
3) After the reaction, slowly pouring the reaction solution into 30mL of 0.05mol/L hydrochloric acid solution which is pre-cooled to 10-20 ℃, stirring for 20min after pouring, separating the solution, extracting with dichloromethane, combining organic layers, and distilling the solution under reduced pressure at 45 ℃ to obtain 4.46g of oily matter, wherein the yield is 97%.
Haloform reaction
Preparation of 4-methyl-naphthalene-1-carboxylic acid
1) Adding 4.46g of 4-methyl-1-naphthacenedione into 30mL of water, and stirring to obtain a turbid liquid;
2) Heating the turbid liquid to 50-55 ℃, adding 33.42g of 10% sodium hypochlorite solution, and keeping the temperature of 50-55 ℃ for reaction for 2.5h;
3) The reaction solution was cooled to room temperature, washed twice with dichloromethane, sodium hydrogensulfite was added to the aqueous phase, the pH was adjusted to 3 or less with concentrated hydrochloric acid under stirring, a large amount of solids was precipitated, the obtained solid was filtered, washed with a small amount of water, and the solid was dried under reduced pressure at 50℃to obtain 4.06g of solid in 90% yield.
Halogenation & hydrolysis
Preparation of 4-formyl-naphthalene-1-carboxylic acid (aforana intermediate)
1) 6.2g of 4-methyl-1-naphthoic acid, 13.63g (2.3 eq) of NBS and 0.35g (0.06 eq) of AIBN are added into 90mL of acetonitrile, and the mixture is stirred and heated to 70-75 ℃ for reaction for 1.5h;
2) Concentrating to remove acetonitrile after the reaction is finished;
3) Adding 40mL of dioxane and 40mL of purified water into the concentrate, heating to 85 ℃ and reacting for 2.5h;
4) After the reaction, 40mL of purified water was added, the temperature of the reaction solution was slowly lowered to room temperature, the reaction solution was filtered, the filter cake was slurried with ethyl acetate, and the mixture was dried under reduced pressure at 50℃to obtain 6.07g of a white solid, the yield of which was 91%.
Example 3
Acylation reaction
Preparation of 4-methyl-1-naphthacenenone
1) 9.47g of 1-methylnaphthalene and 9.78g (1.1 eq) of aluminum trichloride were added to 90mL of methanol and stirred to give a brownish black solution;
2) Mixing 5.76g of acetyl chloride with 15mL of methanol, slowly dropwise adding the mixture into the solution under the protection of nitrogen, and reacting for 1h at 10-20 ℃ after the dropwise adding is finished;
3) After the reaction is finished, slowly pouring the reaction solution into 75mL of 0.05mol/L hydrochloric acid solution which is pre-cooled to 10-20 ℃, stirring for 20min after pouring, separating the solution, extracting with dichloromethane, combining organic layers, and distilling the solution under reduced pressure at 45 ℃ to obtain 11.77g of oily matter, wherein the yield is 96 percent
Haloform reaction
Preparation of 4-methyl-naphthalene-1-carboxylic acid
1) Adding 11.77g of 4-methyl-1-naphthacenedione into 70mL of water, and stirring to obtain a turbid liquid;
2) Heating the turbid liquid to 50-55 ℃, adding 87.66g of 10% sodium hypochlorite solution, and keeping the temperature of 50-55 ℃ for reaction for 2.5h;
3) The reaction solution was cooled to room temperature, washed twice with dichloromethane, sodium hydrogensulfite was added to the aqueous phase, the pH was adjusted to 5 or less with concentrated hydrochloric acid under stirring, a large amount of solids was precipitated, the obtained solid was filtered, washed with a small amount of water, and the solid was dried under reduced pressure at 50℃to obtain 10.47g of solid in 88% yield.
Halogenation & hydrolysis
Preparation of 4-formyl-naphthalene-1-carboxylic acid (aforana intermediate)
1) 7.15g of 4-methyl-1-naphthoic acid, 15.73g (2.3 eq) NBS and 0.41g (0.06 eq) AIBN are added into 100mL of methanol, and the mixture is stirred and heated to 70-75 ℃ for reaction for 1.5h;
2) Concentrating to remove dichloromethane after the reaction is finished;
3) 45mL of dioxane and 45mL of purified water are added into the concentrate, and the temperature is raised to 90 ℃ for reaction for 2.5h;
4) After the reaction, 45mL of purified water is added, the temperature of the reaction solution is slowly reduced to room temperature, the reaction solution is filtered, a filter cake is pulped and filtered by ethyl acetate, and the white solid is obtained by drying under reduced pressure at 50 ℃ to obtain 7.15g with the yield of 93%.
Comparative example 1: a process for the preparation of an aforamide intermediate disclosed in US6613942B1 (columns 373 to 374) or a process for the preparation of an aforamide intermediate disclosed in j.med.chem.2002,45,5755-5775 (column p 5772).
Comparative example 1 synthetic route and yield
The synthetic route and yield of the invention
Note that: the yield data of the synthetic route of the present invention were taken from: example 1.
Comparison of routes and yields:
the prior literature patent reports that the yield of 4-methyl-naphthalene-1-carboxylic acid to 4-formyl-naphthalene-1-carboxylic acid (aforamide intermediate) is only 24 percent (comparative example 1), the aforamide intermediate 4-formyl-naphthalene-1-carboxylic acid is obtained by the method according to the invention in 94 percent of yield (the method according to the invention, namely the compound 3 to the compound 4), the preparation yield is greatly improved, the steps are simplified, the product yield is improved, meanwhile, the synthetic route of the aforamide intermediate is enriched, the production cost is reduced, and the industrial production is easier.
The above description of the present invention is further illustrated in detail and should not be taken as limiting the practice of the present invention. It is within the scope of the present invention for those skilled in the art to make simple deductions or substitutions without departing from the concept of the present invention.

Claims (7)

1. A process for preparing an aforana intermediate, said intermediate being 4-formylnaphthalene-1-carboxylic acid, characterized in that: the synthetic route is as follows:
the method comprises the following reactions:
halogenation reaction: dissolving the intermediate 3 in a solvent, adding 2.3eq of halogenated reagent to carry out halogenated reaction at 25-reflux temperature, and concentrating the solvent after the reaction is finished;
hydrolysis reaction: concentrating the halogenated reaction liquid, adding a solvent A for hydrolysis, and filtering after the reaction is finished to obtain an intermediate 4, namely 4-formylnaphthalene-1-carboxylic acid;
the solvent for the halogenation reaction is at least one selected from methanol, ethanol, tetrahydrofuran, benzene, toluene, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide, acetonitrile, dichloromethane and ethyl acetate;
the halogenating reagent is at least one selected from bromine, iodine, chlorine, N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 1, 3-dichloro-5, 5-dimethyl hydantoin and 1, 3-dibromo-5, 5-dimethyl hydantoin.
2. The method according to claim 1, characterized in that: the solvent A is a mixed solution of water and at least one of methanol, ethanol, N-propanol, isopropanol, tetrahydrofuran, N-dimethylformamide, 1, 4-dioxane, dimethyl sulfoxide and acetonitrile.
3. The method according to claim 1 or 2, characterized in that: in the solvent A, the volume percentage of water is 50-99%.
4. The method according to claim 1, characterized in that: the temperature of the hydrolysis is 50-100 ℃.
5. The method according to claim 1, characterized in that: the synthetic route of intermediate 3 is as follows:
the method comprises the following reactions:
acylation reaction: dissolving the initial material 1 in a solvent, adding an acylating agent for acylation, pouring the reaction solution into a hydrochloric acid solution after the reaction is finished, extracting by an organic solvent, and concentrating;
haloform reaction: reacting intermediate 2 with a hypohalite; after the reaction is completed, the water phase is washed by an organic solvent, the pH value of the water phase is regulated to separate out a product, and the intermediate 3 is obtained by filtering and washing.
6. The method according to claim 5, wherein: the reaction temperature of the acylation reaction is 0-50 ℃; and/or
The acylating reagent is selected from acetyl chloride, acetic anhydride and acetic acid; and/or
The hypohalite is sodium hypochlorite; and/or
The pH value of the water phase is adjusted to be not more than 7 so that the product is separated out.
7. A process for the preparation of aforana comprising preparing 4-formylnaphthalene-1-carboxylic acid according to the process of any one of claims 1 to 6, followed by further preparing aforana.
CN202210211730.0A 2022-03-04 2022-03-04 Method for preparing aforana intermediate Active CN114456059B (en)

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