CN114456059A - Method for preparing Aforana intermediate - Google Patents

Method for preparing Aforana intermediate Download PDF

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CN114456059A
CN114456059A CN202210211730.0A CN202210211730A CN114456059A CN 114456059 A CN114456059 A CN 114456059A CN 202210211730 A CN202210211730 A CN 202210211730A CN 114456059 A CN114456059 A CN 114456059A
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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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    • 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
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    • 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
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    • C07—ORGANIC CHEMISTRY
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    • 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
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Abstract

The invention belongs to the field of pharmacy, and discloses a method for preparing an Aforana intermediate. The Aforana intermediate is 4-formyl naphthalene-1-carboxylic acid, and the synthetic route is
Figure DDA0003532567770000011
Compared with the prior art, the method has the advantages that

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
Aforala (Afoxolaner), tradename nixie (NexGard), is the first oral anthelmintic for dogs to target both ticks and fleas in china marketed by blinge invargham in 2017 at 8 months. The compound belongs to an isoxazoline compound, and has the action principle that the nerve hyperexcitability is caused to die by inhibiting the GABA chloride channel of arthropods. At present, the number of Chinese pet dogs exceeds 6200 ten thousand. Canines are sexually active, are susceptible to various parasites, and may pose a hazard to both themselves and the health of the breeder, thus requiring a series of measures to kill the parasites. After the aforaline is taken for two hours, fleas are killed to cause the fleas to be incapable of laying eggs, the environmental pollution is avoided, the fleas can be effectively prevented from laying eggs for five weeks, 8 common cicadas can be killed, and the effect lasts for more than 1 month.
4-formyl-naphthalene-1-carboxylic acid is a key intermediate for synthesizing alfilana and has a structural formula
Figure BDA0003532567750000011
The synthesis of this compound is reported in a few cases, and the specific route given in U.S. Pat. No. 8, 6613942B1(J.Med. chem.2002,45,5755-5775) is shown in (route 1):
Figure BDA0003532567750000012
the method takes 4- (bromomethyl) naphthalene-1-carboxylic acid as an initiator, and a target intermediate is obtained by 5 steps of reactions of bromination, hydrolysis, esterification, oxidation and ester hydrolysis. According to the yield reported in the patent literature, the esterification yield is only 35%, and the total yield is 24%.
Therefore, how to prepare the oxazoline insecticide fralazine intermediate with low impurity content safely, with low cost and high efficiency is a problem to be solved.
Disclosure of Invention
The present invention aims to overcome at least one of the disadvantages of the prior art and to provide a process for the preparation of an alfilana intermediate.
The technical scheme adopted by the invention is as follows:
in a first aspect of the present invention, there is provided:
a method for preparing an Aforana intermediate 4-formylnaphthalene-1-carboxylic acid comprises the following synthetic route:
Figure BDA0003532567750000021
comprises the following reactions:
and (3) halogenation reaction: dissolving the intermediate 3 in a solvent, adding a halogenating reagent for halogenating reaction, and concentrating the solvent after the reaction is finished;
and (3) hydrolysis reaction: and (3) 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, and ethyl acetate.
In some process examples, the reaction temperature of the halogenation reaction ranges 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, and acetonitrile.
In some examples of the method, the solvent A contains 50 to 99% by volume of water.
In some examples of the method, the temperature of the hydrolysis is 50 to 100 ℃.
In some example methods, the synthetic route for intermediate 3 is as follows:
Figure BDA0003532567750000022
comprises the following reactions:
acylation reaction: dissolving the initiator 1 in a solvent, adding an acylating agent for acylation, pouring a reaction solution into a hydrochloric acid solution after the reaction is finished, extracting by using an organic solvent, and concentrating;
carrying out halogen imitation reaction: reacting intermediate 2 with a hypohalite; and (3) after the reaction is finished, washing a water phase by using an organic solvent, regulating the pH value of the water phase to separate out a product, and filtering and washing to obtain an intermediate 3.
In some examples of the process, the reaction temperature for the acylation reaction is from 0 ℃ to 50 ℃.
In some examples of the method, the acylating agent is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid.
In some process examples, the hypohalite is sodium hypochlorite.
In some process embodiments, the aqueous phase is adjusted to a pH of no more than 7 to precipitate the product.
In a second aspect of the present invention, there is provided:
a process for the preparation of alfilana which comprises preparing 4-formylnaphthalene-1-carboxylic acid according to the process of the first aspect of the present invention and then further preparing alfilana.
The invention has the beneficial effects that:
in contrast to the synthetic route of US6613942B1, the process of some embodiments of the present invention controls the methyl halogenation process to a binary substitution stage
Figure BDA0003532567750000031
X is Cl, Br or I, then is directly hydrolyzed to obtain aldehyde group, and the oxidation step is reduced, so that
Figure BDA0003532567750000032
The reaction steps are shortened from 5 steps to 2 steps, so that the intermediate control step is simplified, and meanwhile, an Aforana intermediate product with qualified purity can be obtained, the product yield is improved, and the industrialized production is facilitated.
Drawings
FIG. 1 is an HPLC chromatogram for the preparation of 4-formyl-naphthalene-1-carboxylic acid (Aforana intermediate) prepared in example 1;
FIG. 2 is a diagram showing the preparation of 4-formyl-naphthalene-1-carboxylic acid (Aforana intermediate) obtained in example 11H NMR spectrum.
Detailed Description
In a first aspect of the present invention, there is provided:
a method for preparing an Aforana intermediate 4-formylnaphthalene-1-carboxylic acid comprises the following synthetic route:
Figure BDA0003532567750000041
comprises the following reactions:
and (3) halogenation reaction: dissolving the intermediate 3 in a solvent, adding a halogenating reagent for halogenating reaction, and concentrating the solvent after the reaction is finished;
and (3) hydrolysis reaction: and (3) 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 has no special requirement, as long as 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, and ethyl acetate. Preferably dichloromethane, acetonitrile or methanol.
In some process examples, the reaction temperature of the halogenation reaction ranges 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 reaction of the halogenating agent more rapid, a certain amount of initiator, such as the conventional initiator of AIBN (azobisisobutyronitrile), may be added.
In order to remove impurities such as unreacted raw materials in the halogenation reaction more effectively, a certain amount of an organic solvent may be added to the solvent A. The organic solvent is preferably one which has low solubility or is completely insoluble in 4-formylnaphthalene-1-carboxylic acid and has good solubility for 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, and acetonitrile.
The amount of the organic solvent of the solvent A can be adjusted correspondingly according to the needs. In some examples of the method, the solvent A contains 50 to 99% by volume of water.
In some examples of the method, the temperature of the hydrolysis is 50 to 100 ℃.
In some example methods, the synthetic route for intermediate 3 is as follows:
Figure BDA0003532567750000051
comprises the following reactions:
acylation reaction: dissolving the initiator 1 in a solvent, adding an acylating agent for acylation, pouring a reaction solution into a hydrochloric acid solution after the reaction is finished, extracting by using an organic solvent, and concentrating;
carrying out halogen imitation reaction: reacting intermediate 2 with a hypohalite; and (3) after the reaction is finished, washing a water phase by using an organic solvent, regulating the pH value of the water phase to separate out a product, and filtering and washing to obtain an intermediate 3.
In some examples of the process, the reaction temperature for the acylation reaction is from 0 ℃ to 50 ℃.
In some examples of the method, the acylating agent is selected from the group consisting of acetyl chloride, acetic anhydride, acetic acid.
In some process examples, the hypohalite is sodium hypochlorite.
In some process embodiments, the aqueous phase is adjusted to a pH of no more than 7 to precipitate the product.
In a second aspect of the present invention, there is provided:
a process for the preparation of alfilana which comprises preparing 4-formylnaphthalene-1-carboxylic acid according to the process of the first aspect of the present invention and then further preparing alfilana.
Example 1
Acylation reaction
Preparation of 4-methyl-1-acetonaphthone
Figure BDA0003532567750000052
1) Adding 14.20g of 1-methylnaphthalene and 14.67g (1.1eq) of aluminum trichloride into 142mL of dichloromethane, and stirring to obtain a brown black solution;
2) mixing 8.64g of acetyl chloride and 20mL of dichloromethane, slowly dripping the mixture into the solution under the protection of nitrogen, and reacting for 1h at 10-20 ℃ after dripping is finished;
3) after the reaction is finished, 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 liquid, extracting with dichloromethane, combining organic layers, and distilling the solution at 45 ℃ under reduced pressure to obtain 18.03g of oily matter with the yield of 98%.
Haloform reaction
Preparation of 4-methyl-naphthalene-1-carboxylic acid
Figure BDA0003532567750000061
1) Adding 18.03g of 4-methyl-1-acetonaphthone into 110mL of water, and stirring to obtain a turbid liquid;
2) heating the turbid solution to 50-55 ℃, adding 135g of 10% sodium hypochlorite solution, and reacting for 2.5h at 50-55 ℃;
3) cooling the reaction solution to room temperature, washing twice with dichloromethane, adding sodium bisulfite into the water phase, adjusting the pH value to be less than or equal to 4 with concentrated hydrochloric acid while stirring, separating out a large amount of solid, filtering, washing the obtained solid with a small amount of water, and drying the solid at 50 ℃ under reduced pressure to obtain 16.22g of solid with the yield of 89%.
MS(m/z)：[M+H]+＝187.07,1H 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 reactions
Preparation of 4-formyl-naphthalene-1-carboxylic acid (Aforana intermediate)
Figure BDA0003532567750000062
1) Adding 9.3g of 4-methyl-1-naphthoic acid, 20.45g (2.3eq) of NBS and 0.53g (0.06eq) of AIBN into 140mL of dichloromethane, and heating to 70-75 ℃ under stirring for reaction for 1.5 h;
2) after the reaction is finished, concentrating to remove dichloromethane;
3) adding 60mL of dioxane and 60mL of purified water into the concentrate, and heating to 90 ℃ to react for 2.5 h;
4) after the reaction, 60mL of purified water was added, the temperature of the reaction solution was slowly cooled to room temperature and filtered, the filter cake was slurried with ethyl acetate and filtered, and the white solid was dried at 50 ℃ under reduced pressure to give 9.40g, 94% yield.
The HPLC profile of the white solid is shown in figure 1,1the H NMR spectrum is shown in FIG. 2.
1H 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-acetonaphthone
Figure BDA0003532567750000071
1) Adding 3.55g of 1-methylnaphthalene and 3.67g (1.1eq) of aluminum trichloride into 35mL of acetonitrile, and stirring to obtain a brown black solution;
2) mixing 2.16g of acetyl chloride and 5mL of acetonitrile, slowly dripping into the solution under the protection of nitrogen, and reacting for 1h at 10-20 ℃ after dripping is finished;
3) after the reaction is finished, 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 liquid, extracting with dichloromethane, combining organic layers, and distilling the solution at 45 ℃ under reduced pressure to obtain 4.46g of oily matter with the yield of 97%.
Haloform reaction
Preparation of 4-methyl-naphthalene-1-carboxylic acid
Figure BDA0003532567750000072
1) Adding 4.46g of 4-methyl-1-acetonaphthone into 30mL of water, and stirring to obtain a turbid liquid;
2) heating the turbid solution to 50-55 ℃, adding 33.42g of 10% sodium hypochlorite solution, and reacting for 2.5h at 50-55 ℃;
3) cooling the reaction solution to room temperature, washing twice with dichloromethane, adding sodium bisulfite into the water phase, adjusting the pH value to be less than or equal to 3 with concentrated hydrochloric acid while stirring, separating out a large amount of solid, filtering, washing the obtained solid with a small amount of water, and drying the solid at 50 ℃ under reduced pressure to obtain 4.06g of solid with the yield of 90%.
Halogenation & hydrolysis reactions
Preparation of 4-formyl-naphthalene-1-carboxylic acid (Aforana intermediate)
Figure BDA0003532567750000073
1) Adding 6.2g of 4-methyl-1-naphthoic acid, 13.63g (2.3eq) of NBS and 0.35g (0.06eq) of AIBN into 90mL of acetonitrile, heating to 70-75 ℃ under stirring, and reacting for 1.5 h;
2) after the reaction is finished, concentrating to remove acetonitrile;
3) adding 40mL of dioxane and 40mL of purified water into the concentrate, and heating to 85 ℃ to react for 2.5 h;
4) after the reaction, 40mL of purified water was added, the temperature of the reaction solution was slowly cooled to room temperature and filtered, the filter cake was slurried with ethyl acetate and filtered, and dried at 50 ℃ under reduced pressure to obtain 6.07g of a white solid with a yield of 91%.
Example 3
Acylation reaction
Preparation of 4-methyl-1-acetonaphthone
Figure BDA0003532567750000081
1) Adding 9.47g of 1-methylnaphthalene and 9.78g (1.1eq) of aluminum trichloride into 90mL of methanol, and stirring to obtain a brown black solution;
2) mixing 5.76g of acetyl chloride and 15mL of methanol, slowly dripping the mixture into the solution under the protection of nitrogen, and reacting for 1h at 10-20 ℃ after dripping 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 liquid, extracting with dichloromethane, combining organic layers, distilling the solution at 45 ℃ under reduced pressure to obtain 11.77g of oily matter with the yield of 96 percent
Haloform reaction
Preparation of 4-methyl-naphthalene-1-carboxylic acid
Figure BDA0003532567750000082
1) Adding 11.77g of 4-methyl-1-acetonaphthone into 70mL of water, and stirring to obtain a turbid liquid;
2) heating the turbid solution to 50-55 ℃, adding 87.66g of 10% sodium hypochlorite solution, and reacting for 2.5h at 50-55 ℃;
3) cooling the reaction solution to room temperature, washing twice with dichloromethane, adding sodium bisulfite into the water phase, adjusting the pH value to be less than or equal to 5 with concentrated hydrochloric acid while stirring, separating out a large amount of solid, filtering, washing the obtained solid with a small amount of water, and drying the solid at 50 ℃ under reduced pressure to obtain 10.47g of solid with the yield of 88%.
Halogenation & hydrolysis reactions
Preparation of 4-formyl-naphthalene-1-carboxylic acid (Aforana intermediate)
Figure BDA0003532567750000083
1) Adding 7.15g of 4-methyl-1-naphthoic acid, 15.73g (2.3eq) of NBS and 0.41g (0.06eq) of AIBN into 100mL of methanol, and heating to 70-75 ℃ under stirring for reaction for 1.5 h;
2) after the reaction is finished, concentrating to remove dichloromethane;
3) adding 45mL of dioxane and 45mL of purified water into the concentrate, and heating to 90 ℃ to react for 2.5 h;
4) after the reaction, 45mL of purified water was added, the temperature of the reaction solution was slowly cooled to room temperature and filtered, the filter cake was slurried with ethyl acetate and filtered, and dried at 50 ℃ under reduced pressure to obtain 7.15g of a white solid with a yield of 93%.
Comparative example 1: the preparation method of the Aforana intermediate disclosed in U.S. Pat. No. 4, 6613942, 1 (column 373-374) or the preparation method of the Aforana intermediate disclosed in J.Med.chem.2002,45,5755-.
Comparative example 1 synthetic route and yield
Figure BDA0003532567750000091
The synthetic route and the yield of the invention
Figure BDA0003532567750000092
Note: the yield data for the synthetic route of the invention are taken from: example 1.
According to the route and the yield comparison:
the existing patent reports that the yield from 4-methyl-naphthalene-1-carboxylic acid to 4-formyl-naphthalene-1-carboxylic acid (alfilana intermediate) is only 24% (comparative example 1), and the alfilana intermediate 4-formyl-naphthalene-1-carboxylic acid is obtained by the method with the yield of 94% (the compound 3 to the compound 4 in the method), so that the preparation yield is greatly improved, the steps are simplified, the product yield is improved, the synthetic route of the alfilana intermediate is enriched, the production cost is reduced, and the method is easier for industrial production.
The foregoing is a more detailed description of the invention and is not to be taken in a limiting sense. It will be apparent to those skilled in the art that various modifications, additions and substitutions can be made without departing from the spirit and scope of the invention.

Claims (10)

1. A process for preparing an afuram intermediate which is a 4-formylnaphthalene-1-carboxylic acid, characterized by: the synthetic route is as follows:
Figure FDA0003532567740000011
comprises the following reactions:
and (3) halogenation reaction: dissolving the intermediate 3 in a solvent, adding a halogenating reagent for halogenating reaction, and concentrating the solvent after the reaction is finished; and (3) hydrolysis reaction: and (3) 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.
2. The method of claim 1, wherein: 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.
3. The method of claim 1, wherein: the reaction temperature of the halogenation reaction is 25 ℃ to reflux temperature.
4. The method of claim 1, wherein: the halogenating reagent is at least one selected from bromine, iodine, chlorine, N-chlorosuccinimide NCS, N-bromosuccinimide NBS, 1, 3-dichloro-5, 5-dimethylhydantoin and 1, 3-dibromo-5, 5-dimethylhydantoin.
5. The method of claim 1, wherein: 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.
6. The method of claim 5, wherein: in the solvent A, the volume percentage of water is 50-99%.
7. The method of claim 1, wherein: the hydrolysis temperature is 50-100 ℃.
8. The method of claim 1, wherein: the synthetic route of the intermediate 3 is as follows:
Figure FDA0003532567740000012
comprises the following reactions:
acylation reaction: dissolving the initiator 1 in a solvent, adding an acylating agent for acylation, pouring a reaction solution into a hydrochloric acid solution after the reaction is finished, extracting by using an organic solvent, and concentrating;
carrying out halogen imitation reaction: reacting intermediate 2 with a hypohalite; and (3) after the reaction is finished, washing a water phase by using an organic solvent, regulating the pH value of the water phase to separate out a product, and filtering and washing to obtain an intermediate 3.
9. The method of claim 8, wherein: the reaction temperature of the acylation reaction is 0-50 ℃; and/or
The acylating agent 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 as to separate out the product.
10. A process for the preparation of alfilana which comprises preparing 4-formylnaphthalene-1-carboxylic acid by a process as claimed in any one of claims 1 to 9 and then further preparing alfilana.
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CN116253658A (en) * 2022-11-25 2023-06-13 济南久隆医药科技有限公司 Synthesis method of aforana intermediate
CN116253658B (en) * 2022-11-25 2023-08-11 济南久隆医药科技有限公司 Synthesis method of aforana intermediate
CN117384028A (en) * 2023-10-20 2024-01-12 济南久隆医药科技有限公司 Synthesis method of 4-acetyl-1-naphthoic acid

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