Shrinkage process method for preparing fluralana

Abstract

The invention discloses a shrinkage process method for preparing fluralan, which comprises the following steps: taking 2-methyl-4-acetylbenzoic acid as an initial raw material, carrying out aldol condensation reaction on the initial raw material and 1-(3, 5-dichlorophenyl)-2, 2, 2-trifluoroethanone, and then sequentially carrying out elimination reaction, cyclization reaction and amide condensation reaction to obtain the fluralan. According to the method, the synthesis time of the fluralana can be effectively shortened, the generation of mixed anhydride impurities and oxime impurities can be effectively controlled, and the purity and yield of the fluralana are improved.

Description

Technical Field

[0001] The invention relates to the technical field of chemical drug synthesis, and in particular to a telescoping process for preparing flurellan. Background Art

[0002] Fluerana is a broad-spectrum isoxazoline anthelmintic. It is an early discovered active compound in the category of isoxazoline drugs and is widely used to treat external parasites such as fleas, ticks, lice, etc. infecting dogs, cats and other pets. The CAS number of Fluerana is 864731-61-3, and the CAS name is 4-[5-(3,5-dichlorophenyl)-4,5-dihydro-5-(trifluoromethyl)-3-isoxazolyl]-2-methyl-nitrogen-[2-oxo-2-[(2,2,2-trifluoroethyl)amino]benzamide, and the molecular formula is: C 22 H 17 Cl2F6N3O3, molecular weight: 556.29, chemical structure is as follows:

[0003]

[0004] At present, there are many methods for the synthesis of flurana. For example, CN202111644720.8 discloses a method for the synthesis of flurana. This method first uses 4-bromo-2-methyl-benzoic acid to obtain 2-methyl-4-acetylbenzoic acid through a Suzuki coupling reaction, and then uses 2-methyl-4-acetylbenzoic acid as a starting material to synthesize flurana. The synthesis route is as follows: Figure 1 As shown, the following steps are included:

[0005] Step 1: With triethylamine as a base, 2-methyl-4-acetylbenzoic acid and 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone undergo an aldol condensation reaction, followed by column chromatography to generate 4-(3-(3-chloro-5-(trifluoromethyl)phenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid (Intermediate 3);

[0006] Step 2: Intermediate 3 reacts with acetic anhydride under the catalytic effect of 4-dimethylaminopyridine to generate 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-2-methylbenzoic acid (Intermediate 2) through elimination reaction;

[0007] Step 3: Intermediate 2 undergoes a cyclization reaction with hydroxylamine hydrochloride under the conditions of using tetrabutylammonium bromide as a surfactant and sodium hydroxide as a base to promote the formation of the key isoxazole ring, and column chromatography is performed to obtain 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (Intermediate 1);

[0008] Step 4: Intermediate 1 first reacts with thionyl chloride to generate an acyl chloride, and then undergoes an amidation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide to finally synthesize flurellan.

[0009] This synthesis method has the following problems:

[0010] (1) Although the intermediate 2 obtained in step 2 of the method does not need to be purified by column chromatography, and the continuous addition of steps 2 to 3 can be achieved, column chromatography purification is still required in step 1 to obtain intermediate 3 and step 3 to obtain intermediate 1, and the continuous addition of the entire synthesis process cannot be achieved, which will greatly prolong the reaction time of the overall process and increase the production cost;

[0011] (2) In step 2, 4-dimethylaminopyridine (DMAP) is used as a catalyst and acetic anhydride is used as a dehydrating agent. DMAP is a super-strong nucleophilic acylation catalyst. The resonance between the electron-donating dimethylamino group and the parent ring (pyridine ring) in its molecular structure can catalyze acetic anhydride in the reaction system to generate acetic acid and react with intermediate 2 to generate mixed anhydride impurities. The chemical structure of the mixed anhydride impurities is as follows:

[0012]

[0013] The use of DMAP and acetic anhydride not only generates and introduces mixed anhydride impurities, reducing the yield and purity of the product; in order to remove acetic anhydride, an additional heating and hydrolysis step is required, which increases the complexity of the operation and increases the consumption of equipment and energy; it also reduces the catalytic efficiency of DMAP, making the reaction time reach 6 hours, greatly increasing the synthesis time of flurellan.

[0014] (3) In step 3, tetrabutylammonium bromide is used as a surfactant and sodium hydroxide is used as a base. During the reaction, hydroxylamine hydrochloride reacts with intermediate 2 to generate an oxime impurity. The chemical structure of the oxime impurity is as follows:

[0015]

[0016] Since the activation energy of the Michael addition ring-closure reaction within the molecule is high, and neither tetrabutylammonium bromide nor sodium hydroxide can reduce the reaction activation energy, the oxime cannot be smoothly ring-closed to convert into the intermediate 1, and conventional heating cannot achieve ring closure, so oxime impurities are generated in step three, so that the prepared intermediate 1 needs to be purified by column chromatography for refining and impurity removal; the oxime impurities will not only reduce the purity of the intermediate 1, affecting the product yield and purity, but also increase the steps of purification, refining and impurity removal, thereby extending the preparation time of flurellana.

[0017] In summary, there is an urgent need to provide a green, environmentally friendly, simple and easy-to-operate flurellanine synthesis process that can effectively control the generation of mixed anhydride impurities and oxime impurities. Summary of the invention

[0018] The technical problem to be solved by the present invention is to overcome the deficiencies of the prior art and provide a telescoping process method for preparing flurana, which can effectively shorten the synthesis time of flurana, and can also effectively control the generation of mixed anhydride impurities and oxime impurities, thereby improving the purity and yield of flurana.

[0019] The technical solution adopted by the present invention to solve the technical problem is: a telescopic process method for preparing flurana, comprising the following steps: 1) synthesizing intermediate 3; 2) synthesizing intermediate 2; 3) synthesizing intermediate 1; 4) synthesizing flurana;

[0020] In the step 1), intermediate 3 is synthesized by using 2-methyl-4-acetylbenzoic acid as a starting material and reacting it with 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone to generate intermediate 3. The structural formula of intermediate 3 is shown in Formula I:

[0021]

[0022] In the step 2), intermediate 2 is synthesized, and intermediate 3 is heated under the conditions of 4-dimethylaminopyridine N-oxide as a catalyst and di-tert-butyl dicarbonate as a dehydrating agent to undergo an elimination reaction to obtain intermediate 2. The structural formula of intermediate 2 is shown in formula II:

[0023]

[0024] In the step 3), intermediate 1 is synthesized, and intermediate 2 is subjected to a cyclization reaction with hydroxylamine salt in the presence of an organic phosphoric acid catalyst under heating and water separation conditions to obtain intermediate 1. The structural formula of intermediate 1 is shown in formula III:

[0025]

[0026]

[0027] In the step 4), flurellanine is synthesized. Intermediate 1 undergoes an amide condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide under a condensing agent and alkaline conditions to obtain flurellanine. The structural formula of flurellanine is shown in Formula IV:

[0028]

[0029] Furthermore, in the step 1), the molar ratio of 2-methyl-4-acetylbenzoic acid to 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone is 1:1.05-1.2, the reaction temperature is 50°C-70°C, the solvent used in the reaction is a non-polar solvent, and the mass ratio of the solvent to 2-methyl-4-acetylbenzoic acid is 1:3-8.

[0030] Furthermore, the base used in the aldol condensation reaction in step 1) is an organic base or an inorganic base.

[0031] Furthermore, the organic base is triethylamine, N,N-diisopropylethylamine or 1,8-diazobispiro[5.4.0]undec-7-ene, and the inorganic base is potassium carbonate or sodium carbonate.

[0032] Furthermore, in the step 1), the residual amount of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone is detected after the aldol condensation reaction is carried out for 24 hours, and the reaction is stopped when the residual amount is less than 0.5%.

[0033] Furthermore, in the step 2), the molar ratio of the intermediate 3 to 4-dimethylaminopyridine N-oxide is 1:0.05-0.15, and the molar ratio of the intermediate 3 to di-tert-butyl dicarbonate is 1:1.50-2.50.

[0034] Furthermore, the reaction temperature of the elimination reaction in step 2) is 50° C. to 70° C., and the reaction time is 2-3 hours.

[0035] Furthermore, in step 3), the organic phosphoric acid catalyst has a structure of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6 or Formula 7,

[0036]

[0037] Furthermore, in the step 3), the molar ratio of intermediate 2 to the organic phosphoric acid catalyst is 1:0.10-0.50, the molar ratio of intermediate 2 to the hydroxylamine salt is 1:1.00-2.00, the reaction temperature of the cyclization reaction is 80°C-125°C, and the residual amount of intermediate 2 is detected after the cyclization reaction is carried out for 2 hours, and the reaction is stopped when the residual amount is less than 0.5%.

[0038] Furthermore, the hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate.

[0039] Furthermore, the condensing agent in the step 4) is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole, the molar ratio of intermediate 1 to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is 1:1.00-2.50, the molar ratio of intermediate 1 to 1-hydroxybenzotriazole is 1:0.50-1.50, the base used is triethylamine, the molar ratio of intermediate 1 to triethylamine is 1:2.0-5.0, the molar ratio of intermediate 1 to 2-amino-N-(2,2,2-trifluoroethyl)acetamide is 1:1.0-1.5, the reaction temperature of the amide condensation reaction is 25-35°C; and the reaction time is 6h-18h.

[0040] Furthermore, the step 4) further comprises refining flurella, and the specific steps are: adding methanol to the flurella obtained in step 4), stirring at 60°C and then cooling to grow crystals, stirring again and filtering to obtain pure flurella.

[0041] Beneficial effects of the telescopic process for preparing fluororana of the present invention:

[0042] (1) The process of the present invention is simple and highly operable. Steps 1) to 4) thereof adopt a continuous feeding process. No impurities (such as mixed anhydride impurities and oxime impurities) are generated during the entire preparation process, so that the intermediates obtained in each step do not need to be subjected to any refining and purification treatment process such as column chromatography purification. This can not only effectively shorten the reaction time of the overall process, reduce the time spent in the subsequent treatment stage, and reduce the production cost of flurella, but also effectively improve the yield of flurella;

[0043] (2) The present invention uses 4-dimethylaminopyridine N-oxide as a catalyst and di-tert-butyl dicarbonate as a dehydrating agent during the elimination reaction in step 2), which can inhibit the generation of impurity mixed anhydride, not only improving the yield and purity of flurellane, but also shortening the elimination reaction time from 6 hours to 2 hours, greatly shortening the process time for preparing flurellane;

[0044] (3) The present invention uses an organic phosphoric acid catalyst during the cyclization reaction in step 3). The organic phosphoric acid catalyst can reduce the activation energy of the cyclization reaction, so that the oxime can be smoothly cyclized and converted into the intermediate 1, effectively inhibiting the generation of oxime impurities, thereby improving the yield and purity of flurellana. BRIEF DESCRIPTION OF THE DRAWINGS

[0045] Figure 1 — is a synthetic route map of flurellana in the prior art;

[0046] Figure 2 - A synthetic route for preparing Flurellana according to the present invention;

[0047] Figure 3- Chromatogram of the reaction solution containing intermediate 2 obtained in step 2) of Example 1;

[0048] Figure 4 - Chromatogram of the oily intermediate 1 obtained in step 3) of Example 1;

[0049] Figure 5 - Chromatogram of the viscous oily flurellana obtained in step 4) of Example 1;

[0050] Figure 6 - Chromatogram of the pure flurellana obtained in Example 8;

[0051] Figure 7 - Chromatogram of the reaction solution containing intermediate 2 obtained in step 2) of Comparative Example 3;

[0052] Figure 8 —Chromatogram of the oily intermediate 1 obtained in step 3) of Comparative Example 3. DETAILED DESCRIPTION

[0053] The present invention is further described below in conjunction with the accompanying drawings and examples, but these specific implementation schemes do not limit the protection scope of the present invention in any way.

[0054] Example 1

[0055] A telescopic process for preparing fluororana, the synthesis route is as follows Figure 2 As shown, the method comprises the following steps:

[0056] 1) Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-3-hydroxybutyryl)-2-methylbenzoic acid (Intermediate 3): 2-methyl-4-acetylbenzoic acid as a starting material undergoes an aldol condensation reaction with 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone to generate Intermediate 3. The reaction formula is:

[0057]

[0058] The specific operation steps are as follows: 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one (1000 g, 1.00 eq), 4-acetyl-2-methylbenzoic acid (806.6 g, 1.10 eq), chlorobenzene (5000 g, 5.00 w) and triethylamine (TEA, 657.9 g, 1.58 eq) are added to a reaction vessel with a thermometer in sequence, the temperature is raised to 65°C, and samples are taken for inspection after reacting for 24 hours. The reaction is stopped when the residual amount of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethane-1-one is less than 0.5%; the temperature in the reaction vessel is lowered to 25°C; the mixture is directly used for the next step reaction without purification; according to the external standard method, 1700 g of intermediate 3 is contained, the yield is 98%, and the mass fraction is 22.85%;

[0059] 2) Synthesis of 4-(3-(3,5-dichlorophenyl)-4,4,4-trifluorobut-2-enoyl)-2-methylbenzoic acid (intermediate 2): Intermediate 3 is heated under the conditions of 4-dimethylaminopyridine N-oxide (DMAPO) as a catalyst and di-tert-butyl dicarbonate as a dehydrating agent to undergo an elimination reaction to obtain intermediate 2. The reaction formula is:

[0060]

[0061] The specific operation steps are as follows: take 437g of the reaction solution obtained in step 1) (containing 100g of intermediate 3), add DMAPO (2.97g, 0.09eq) and di-tert-butyl dicarbonate (Boc2O, 114g, 2.20eq) to the reaction solution, heat to 55°C, react for 2h before stopping the reaction, cool to 25°C; use it directly in the next step without purification. According to the external standard method, it contains 91g of intermediate 2, with a yield of 95% and a mass fraction of 18.31%; the chromatogram of the reaction solution containing intermediate 2 obtained in this step is as follows Figure 3 As shown in the figure, it can be seen that the reaction liquid does not contain mixed anhydride impurities generated by the reaction with di-tert-butyl dicarbonate, and the peak area (purity) corresponding to the intermediate 2 is 97.9%;

[0062] In this step, 4-dimethylaminopyridine N-oxide (DMAPO) is used as a catalyst and di-tert-butyl dicarbonate is used as a dehydrating agent. During the reaction, the generation of mixed anhydride impurities can be effectively suppressed, thereby improving the yield and purity of flurellana. Since 4-dimethylaminopyridine N-oxide does not catalyze the formation of mixed anhydride impurities between di-tert-butyl dicarbonate and the intermediate, the catalytic efficiency is higher, and the active lipid reaction activity formed by 4-dimethylaminopyridine N-oxide and di-tert-butyl dicarbonate is higher, which is more conducive to the dehydration reaction, thereby shortening the reaction time to 2 hours.

[0063] 3) Synthesis of 4-(5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-yl)-2-methylbenzoic acid (Intermediate 1):

[0064] The intermediate 2 is subjected to a cyclization reaction with hydroxylamine hydrochloride in the presence of an organic phosphoric acid catalyst under heating and water separation conditions to obtain the intermediate 1. The reaction formula is:

[0065]

[0066] The specific operation steps are as follows: take 273g of the reaction solution obtained in step 2) (containing 50g of intermediate 2), add organic phosphonic acid binaphthol phosphate (8.64g, 0.2eq) and hydroxylamine hydrochloride (10.88g, 1.3eq) of formula 1 to the reaction solution under stirring, heat to 95°C, and use a water separation device to timely separate the water generated in the system, take samples after reacting for 2h to detect the residual amount of intermediate 2, and stop the reaction when the residual amount of intermediate 2 is less than 0.5%; then add 125g of water to the reaction solution to obtain an emulsion, and add concentrated hydrochloric acid to adjust the pH to 2-3, collect the chlorobenzene layer after separation, and then repeat this step once, and combine the chlorobenzene solutions obtained by each separation; finally, the chlorobenzene solution is concentrated under reduced pressure to obtain 51.34g of viscous oily intermediate 1, and the yield is 99%; the chromatogram of the oily intermediate 1 obtained in this step is as shown Figure 4 As shown in the figure, it can be seen that the oxime impurity generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine is not found in the oily intermediate 1, and the peak area (purity) corresponding to intermediate 1 is 95.84%;

[0067] In this step, organophosphonic acid binaphthol phosphate is used as a catalyst. Since there are hydrogen bond donors and hydrogen bond acceptors in the organophosphonic acid, hydrogen bonds are formed with hydroxylamine hydrochloride and intermediate 2, respectively, thereby reducing the activation energy of the reaction, so that the oxime impurity can be smoothly ring-closed and converted into intermediate 1, effectively inhibiting the generation of oxime impurities, thereby improving the yield and purity of flurellana;

[0068] 4) Synthesis of Flurellana:

[0069] Intermediate 1 undergoes an amide condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide in the presence of a condensing agent and alkaline conditions to obtain flurellanine. The reaction formula is:

[0070]

[0071] The specific operation steps are as follows: add chlorobenzene (250 g, 5.00 w) to the intermediate 1 and stir, cool to 25 ° C after the intermediate 1 is completely dissolved, then add TEA (triethylamine, 49.36 g, 4.0 eq), HOBt (1-hydroxybenzotriazole, 16.48 g, 1.0 eq) and EDCI (1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, 35.07 g, 1.5 eq) in sequence, stir for 1 h, then add 2-amino-N-(2,2,2-trifluoromethyl)-1-nitropropene ethyl)acetamide (22.85g, 1.2eq), react at 25°C for 16h, sample and detect the residual amount of intermediate 1, when the residual amount of intermediate 1 is less than 1.0%, stop the reaction; add water (250g, 5.00w) to the reaction solution, and adjust the pH to 5-6, stir for 0.5h, separate and collect the chlorobenzene layer, then repeat the operation twice, combine the chlorobenzene solution obtained by each separation; after reducing the pressure and concentrating the chlorobenzene solution, 66.48g of viscous oily flurellana was obtained, and its chromatogram is as shown Figure 5 As shown, the yield was 98% and the purity was 97%.

[0072] Example 2

[0073] The difference between this embodiment and embodiment 1 is that: the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 is an organic phosphoric acid of formula 2, and 49.25 g of viscous oily intermediate 1 is obtained in this step, with a yield of 95% and a purity of 96%, and no oxime impurities generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine are found.

[0074] Example 3

[0075] The difference between this embodiment and embodiment 1 is that: the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 is an organic phosphoric acid of formula 3, and 49.77 g of viscous oily intermediate 1 is obtained in this step, with a yield of 96% and a purity of 96%, and no oxime impurities generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine are found.

[0076] Example 4

[0077] The difference between this embodiment and embodiment 1 is that: the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 is an organic phosphoric acid of formula 4, and 50.29 g of viscous oily intermediate 1 is obtained in this step, with a yield of 97% and a purity of 96%, and no oxime impurities generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine are found.

[0078] Example 5

[0079] The difference between this embodiment and embodiment 1 is that: the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 is an organic phosphoric acid of formula 5, and 48.63 g of viscous oily intermediate 1 is obtained in this step, with a yield of 94% and a purity of 96%, and no oxime impurities generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine are found.

[0080] Example 6

[0081] The difference between this embodiment and embodiment 1 is that: the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 is an organic phosphoric acid of formula 6, and 48.69 g of viscous oily intermediate 1 is obtained in this step, with a yield of 94% and a purity of 95%, and no oxime impurities generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine are found.

[0082] Example 7

[0083] The difference between this embodiment and embodiment 1 is that: the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 is an organic phosphoric acid of formula 7, and 49.36 g of viscous oily intermediate 1 is obtained in this step, with a yield of 95% and a purity of 95%, and no oxime impurities generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine are found.

[0084] Example 8

[0085] The difference between this embodiment and embodiment 1 is that: step 4) further includes the purification of flurellana. The operation of this step is as follows: methanol (332 g, 5.00 w) is added to the viscous oily flurellana obtained in step 4), and then the temperature is raised to 60°C and stirred until it is completely dissolved. After stirring for 2 hours, the temperature is lowered to 40°C for crystal growth for 2 hours, and then the temperature is lowered to 25°C and stirred for 1 hour. Finally, the obtained suspension is filtered to obtain 56.5 g of pure white solid flurellana, and the yield is 85%. The chromatogram of the pure flurellana obtained in this step is as shown in FIG. Figure 6 As shown in the figure, it can be seen that no mixed anhydride impurities and oxime impurities were found in the pure product of flurellana, and the peak area (purity) corresponding to flurellana was 99.18%.

[0086] Comparative Example 1

[0087] The difference between this comparative example and Example 1 is that: in step 2), 4-dimethylaminopyridine is used as a catalyst and acetic anhydride is used as a dehydrating agent in the synthesis of intermediate 2. The operation steps are as follows: 437g of the reaction solution obtained in step 1) (containing 100g of intermediate 3) is taken, 4-dimethylaminopyridine (2.97g, 0.09eq) and acetic anhydride (114g, 2.20eq) are added to the reaction solution, the temperature is raised to 55°C, the reaction is stopped after 2h, and the temperature is lowered to 25°C; it is directly used for the next step reaction without purification; the reaction solution obtained in this step contains 68g of intermediate 2, the yield is 71%, the mass fraction is 12%, and the largest single impurity is found in the reaction solution, which is a mixed anhydride impurity generated by the reaction with di-tert-butyl dicarbonate, and the peak area corresponding to the mixed anhydride impurity reaches 24.16% (that is, the generated mixed anhydride impurity accounts for 24.16%), and the peak area (purity) corresponding to intermediate 2 is only 71.73%.

[0088] Comparative Example 2

[0089] The difference between this comparative example and Example 1 is that: in step 3), no organic phosphoric acid catalyst is used in the synthesis of intermediate 1, tetrabutylammonium bromide is used as a surfactant, and sodium hydroxide is used as a base; the operation steps are:

[0090] Take 273 g of the reaction solution obtained in step 2) (containing 50 g of intermediate 2), add NaOH (39.68 g, 8.00 eq) and TBAB (tetrabutylammonium bromide, 31.98 g, 0.80 eq) to the reaction solution under stirring, and dissolve hydroxylamine hydrochloride (10.88 g, 1.30 eq) in 108 g of water to prepare a solution, and slowly add it dropwise to the reaction solution, maintaining the temperature in the reaction container at 5°C. After the dropwise addition, the reaction was continued for 2 hours and then a sample was taken for control. The reaction was stopped when the residual amount of intermediate 2 was less than 0.5%. 125 g of water was added to the reaction solution to obtain an emulsion, and concentrated hydrochloric acid was added to adjust the pH to 2-3. The chlorobenzene layer was collected after separation, and then the step was repeated once, and the chlorobenzene solutions obtained from each separation were combined. Finally, the chlorobenzene solution was concentrated under reduced pressure to obtain 49.35 g of viscous oily intermediate 1, with a yield of 94% and a purity of 91%. The largest single impurity found in the oily intermediate 1 was an oxime impurity generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine, and the oxime impurity accounted for 12%.

[0091] Comparative Example 3

[0092] The difference between this comparative example and Example 1 is that:

[0093] Step 2) 4-dimethylaminopyridine is used as a catalyst and acetic anhydride is used as a dehydrating agent in the synthesis of intermediate 2. The operation steps are as follows: 437 g of the reaction solution obtained in step 1) (containing 100 g of intermediate 3) is taken, 4-dimethylaminopyridine (2.97 g, 0.09 eq) and acetic anhydride (114 g, 2.20 eq) are added to the reaction solution, the temperature is raised to 55° C., the reaction is stopped after 2 h, and the temperature is lowered to 25° C.; it is directly used for the next step without purification; according to the external standard method, it contains 68 g of intermediate 2, the yield is 71%, and the mass fraction is 12%; the chromatogram of the reaction solution containing intermediate 2 obtained in this step is as shown Figure 7 As shown in the figure, it can be seen that the largest single impurity found in the reaction solution is the mixed anhydride impurity generated by the reaction with di-tert-butyl dicarbonate, and the peak area corresponding to the mixed anhydride impurity reaches 24.16% (that is, the generated mixed anhydride impurity accounts for 24.16%), and the peak area (purity) corresponding to the intermediate 2 is only 71.73%, indicating that the use of 4-dimethylaminopyridine as a catalyst and acetic anhydride as a dehydrating agent will produce mixed anhydride impurities.

[0094] Step 3) In the synthesis of intermediate 1, no organic phosphoric acid catalyst is used, tetrabutylammonium bromide is used as a surfactant, and sodium hydroxide is used as a base; the operation steps are as follows: take 416g of the reaction solution obtained in step 2) (containing 50g of intermediate 2), add NaOH (39.68g, 8.00eq) and TBAB (31.98g, 0.80eq) to the reaction solution under stirring, and dissolve hydroxylamine hydrochloride (10.88g, 1.30eq) in 108g of water to prepare a solution, and slowly drip it into the reaction solution, during which the temperature in the reaction container is maintained at 5°C. After the dripping is completed, continue the reaction for 2h and then take a sample for central control. When the residual amount of intermediate 2 is less than 0.5%, stop the reaction;

[0095] 125 g of water was then added to the reaction solution to obtain an emulsion, and concentrated hydrochloric acid was added to adjust the pH to 2-3. After separation, the chlorobenzene layer was collected, and then the step was repeated once, and the chlorobenzene solutions obtained from each separation were combined; finally, the chlorobenzene solution was concentrated under reduced pressure to obtain 49.35 g of viscous oily intermediate 1, with a yield of 95%. The chromatogram of the oily intermediate 1 obtained in this step is shown as follows: Figure 8 As shown;

[0096] Depend on Figure 8 It can be seen that the largest single impurity found in the oily intermediate 1 is the oxime impurity generated by the reaction of the carbonyl group of the intermediate 2 with hydroxylamine, and the peak area corresponding to the oxime impurity reaches 12% (corresponding to the peak times of 10.565 and 11.314), and the peak area (purity) corresponding to the intermediate 1 is only 83.71%, indicating that the use of tetrabutylammonium bromide as a surfactant and sodium hydroxide as a base will produce oxime impurities.

[0097] Comparative Example 4

[0098] The difference between this comparative example and Example 1 is that: in step 2), 4-dimethylaminopyridine N-oxide is used as a catalyst and acetic anhydride is used as a dehydrating agent in the synthesis of intermediate 2. The operation steps are as follows: 437g of the reaction solution obtained in step 1) (containing 100g of intermediate 3) is taken, 4-dimethylaminopyridine N-oxide (2.97g, 0.09eq) and acetic anhydride (114g, 2.20eq) are added to the reaction solution, the temperature is raised to 55°C, the reaction is stopped after 2h, and the temperature is lowered to 25°C; it is directly used for the next step without purification; the reaction solution obtained in this step contains 79.7g of intermediate 2, the yield is 83%, the mass fraction is 14%, and the largest single impurity is found in the reaction solution, which is a mixed anhydride impurity generated by the reaction with di-tert-butyl dicarbonate, and the mixed anhydride impurity accounts for 13%, and the peak area (purity) corresponding to intermediate 2 is only 83%.

[0099] Comparative Example 5

[0100] The difference between this comparative example and Example 1 is that: in step 2), 4-dimethylaminopyridine is used as a catalyst and di-tert-butyl dicarbonate is used as a dehydrating agent in synthesizing intermediate 2. The operation steps are as follows: 437g of the reaction solution obtained in step 1) (containing 100g of intermediate 3) is taken, 4-dimethylaminopyridine (2.97g, 0.09eq) and di-tert-butyl dicarbonate (114g, 2.20eq) are added to the reaction solution, the temperature is raised to 55°C, the reaction is stopped after 2h, and the temperature is lowered to 25°C; it is directly used for the next step reaction without purification; the reaction solution obtained in this step contains 68.15g of intermediate 2, the yield is 71%, the mass fraction is 12%, and the largest single impurity in the reaction solution is a mixed anhydride impurity generated by the reaction with di-tert-butyl dicarbonate, and the mixed anhydride impurity accounts for 24%, and the peak area (purity) corresponding to intermediate 2 is only 83%.

[0101] Comparative Example 6

[0102] The difference between this comparative example and Example 1 is that the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 has a structural formula of Formula 8. This step 3) can obtain 47.30 g of viscous oily intermediate 1, with a yield of 91% and a purity of 91%, wherein the largest single impurity is an oxime impurity generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine, accounting for 7%.

[0103]

[0104] Comparative Example 7

[0105] The difference between this comparative example and Example 1 is that the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 has a structural formula of Formula 9. This step 3) can obtain 46.57 g of viscous oily intermediate 1, with a yield of 90% and a purity of 88%, wherein the largest single impurity is the oxime impurity generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine, accounting for 9%.

[0106]

[0107] Comparative Example 8

[0108] The difference between this comparative example and Example 1 is that the organic phosphoric acid catalyst used in step 3) for synthesizing intermediate 1 has a structural formula of Formula 10. This step 3) can obtain 46.05 g of viscous oily intermediate 1, with a yield of 89% and a purity of 86%, wherein the largest single impurity is the oxime impurity generated by the reaction of the carbonyl group of intermediate 2 with hydroxylamine, accounting for 10%.

[0109]

[0110] The similarities and differences between the steps of preparing flurana in Example 1 and Comparative Examples 1-8 are shown in Table 1:

[0111] Table 1. Similarities and differences between the steps of preparing flurellana in Example 1 and Comparative Examples 1-8

[0112]

[0113] The present invention adopts the method of Examples 1-7 and Comparative Examples 1-8 to prepare flurellane, and the yield and purity of the prepared flurellane and the mass percentage of the mixed anhydride impurities and oxime impurities obtained in step 2) and step 3) are measured. The results are shown in Table 2:

[0114] Among them, the detection of flurellana, mixed anhydride impurities and oxime impurities adopts high performance liquid chromatography. The instrument used in this method and the actual and chromatographic parameters are as follows:

[0115] Experimental instrument: Shimadzu high performance liquid chromatography HPLC (LC-2050).

[0116] Experimental reagents: acetonitrile (CINC, chromatography grade); phosphoric acid (Kermel, chromatography grade).

[0117] Chromatographic column: Shimadzu, Shim-pack GWS C18, 4.6×250mm, 5μm.

[0118] Experimental methods:

[0119] Mobile phase A: 0.1% phosphoric acid aqueous solution; Mobile phase B: acetonitrile;

[0120] Diluent 1: acetonitrile; Diluent 2: 50% acetonitrile;

[0121] Column temperature: 35°C; detection wavelength: 220nm; flow rate: 1ml / min; injection volume: 10μL;

[0122] The elution gradient is as follows:

[0123]

[0124] Table 2 Yield, purity and mass percentage of impurities obtained in step 2) and step 3) of flurellan prepared in Examples 1-7 and Comparative Examples 1-8

[0125]

[0126]

[0127] As shown in Table 2, the yield of flurana prepared by the method of the present invention (Examples 1-7) reached more than 93%, and the purity reached more than 95%, while the yield and purity of flurana prepared by Comparative Examples 1-7 were both lower than 90%, indicating that the present invention uses 4-dimethylaminopyridine N-oxide as a catalyst and di-tert-butyl dicarbonate as a dehydrating agent in step 2) when synthesizing intermediate 2, and uses organic phosphoric acid as a catalyst in step 3) when synthesizing intermediate 1, which can effectively inhibit the generation of mixed anhydride impurities and oxime impurities, not only can the purity and yield of flurana be effectively improved, but also the intermediate obtained in each step does not need to be subjected to column chromatography, water washing and other refining and purification treatments, thereby realizing the continuous investment of the entire process, simplifying the preparation process of flurana, shortening the preparation time of flurana, reducing the preparation cost of flurana, and improving its preparation efficiency.

[0128] Comparative Example 3 is a catalyst and a dehydrating agent used in the synthesis of intermediate 2 in step 2 and intermediate 1 in step 3 in the background technology to prepare flurana. The preparation process does not use a static purification treatment step, but mixed anhydride impurities and oxime impurities are generated, so that the yield of the prepared flurana is only 72% and the purity is only 80%. The corresponding yield and purity are significantly lower than those in Example 1, indicating that the generation of mixed anhydride impurities and oxime impurities will have a significant impact on the yield and purity of flurana.

[0129] Moreover, in Comparative Example 1 and Comparative Example 2, the catalyst and dehydrating agent corresponding to step 2) and step 3) were respectively replaced on the basis of Example 1, and the corresponding yield and purity of flurana were still significantly lower than those of Example 1, indicating that only when the catalyst and dehydrating agent of the present invention are used in both steps 2 and 3 to synthesize intermediate 2 and intermediate 1, can the effect of better controlling impurities be achieved, thereby achieving a better effect of improving the yield and purity of flurana;

[0130] Comparative Examples 4 and 5 respectively replaced the dehydrating agent and the catalyst in step 2 on the basis of Example 1. The results showed that after replacing the dehydrating agent or the catalyst in step 2, mixed anhydride impurities would still be produced, indicating that only when the elimination reaction is carried out under the conditions of 4-dimethylaminopyridine N-oxide (DMAPO) as a catalyst and di-tert-butyl dicarbonate as a dehydrating agent can the formation of mixed anhydride impurities be effectively suppressed, thereby improving the yield and purity of flurana.

[0131] Comparative Examples 6-8 respectively use organic phosphoric acids of formula 8-10 in step 3 to synthesize intermediate 1 on the basis of Example 1. Compared with Comparative Example 3, although the formation of oxime impurities can be greatly inhibited, the degree of inhibition of the formation of oxime impurities is still lower than that of the organic phosphoric acid used in Examples 1-7, resulting in the yield and purity of flurellan prepared by them being lower than those of Examples 1-7, indicating that the organic phosphoric acid with the structural formula of formula 1-7 as a catalyst for the cyclization reaction has a better effect of improving the yield and purity of flurellan.

[0132] Based on the above analysis, it is found that the inhibitory effects of different combinations of catalysts and dehydrating agents on mixed anhydride impurities and oxime impurities in step 2) synthesizing intermediate 2 and step 3) synthesizing intermediate 1 are different. The catalysts and dehydrating agents interact with each other to jointly control the impurities and further affect the purity and yield of flurana. Only when 4-dimethylaminopyridine N-oxide is used as a catalyst and di-tert-butyl dicarbonate is used as a dehydrating agent in step 2) synthesizing intermediate 2 and organic phosphoric acid is used as a catalyst in step 3) synthesizing intermediate 1 can the generation of mixed anhydride impurities and oxime impurities be effectively inhibited, and the purity and yield of flurana can be significantly improved, so that the purity and yield of flurana reach more than 95% and 93%, respectively.

[0133] Experimental Example 1 Step 3) Investigation of reaction temperature of synthesis of intermediate 1

[0134] In this experimental example, flurana was prepared by referring to the method of Example 1, and in step 3), when synthesizing intermediate 1, organic phosphonic acid binaphthol phosphate (8.64 g, 0.2 eq) of formula 1 and hydroxylamine hydrochloride (10.88 g, 1.3 eq) were added, and then the temperature was raised to different reaction temperatures (40°C, 65°C, 80°C, 95°C, 110°C, 125°C, 140°C), respectively, to study the effects of different reaction temperatures on the mass percentage of oxime impurities in the obtained intermediate 1 and the yield and purity of flurana. The results are shown in the following table:

[0135] Table 3 Effect of different reaction temperatures on the mass percentage of oxime impurities and the yield and purity of flurellana

[0136]

[0137] As can be seen from the above table, the mass percentage of oxime impurities shows a trend of first decreasing and then increasing with the increase of temperature, and no oxime impurities are detected in intermediate 1 at a temperature of 80-125°C, and when the temperature continues to rise to 140°C, the content of oxime impurities increases to 7%, which may be due to the hydrolysis of the organophosphorus catalyst caused by the higher reaction temperature. It shows that when the cyclization reaction uses organophosphoric acid as a catalyst to prepare intermediate 1, the reaction temperature will affect the generation of oxime impurities, which will in turn affect the yield and purity of flurellana, so the reaction temperature of step 3) is preferably 80-125°C.

[0138] The above description is only a preferred embodiment of the present invention and does not limit the present invention in any form. Although the present invention has been disclosed as a preferred embodiment as above, it is not used to limit the present invention. Any technician familiar with this profession can make some changes or modifications to equivalent embodiments of equivalent changes using the technical contents disclosed above without departing from the scope of the technical solution of the present invention. However, any simple modification, equivalent change and modification made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solution of the present invention still fall within the scope of the technical solution of the present invention.

Claims

1. A telescopic process for preparing fluororana, comprising the following steps: 1) Synthetic intermediate 3; 2) Synthetic intermediate 2; 3) Synthetic intermediate 1; 4) Synthetic flurellana; characterized in that, In the step 1), intermediate 3 is synthesized by using 2-methyl-4-acetylbenzoic acid as a starting material and reacting it with 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone to generate intermediate 3. The structural formula of intermediate 3 is shown in Formula I: In the step 2), intermediate 2 is synthesized, and intermediate 3 is heated under the conditions of 4-dimethylaminopyridine N-oxide as a catalyst and di-tert-butyl dicarbonate as a dehydrating agent to undergo an elimination reaction to obtain intermediate 2. The structural formula of intermediate 2 is shown in formula II: In the step 3), intermediate 1 is synthesized, and intermediate 2 is subjected to a cyclization reaction with hydroxylamine salt in the presence of an organic phosphoric acid catalyst under heating and water separation conditions to obtain intermediate 1. The structural formula of intermediate 1 is shown in formula III: In the step 4), flurellanine is synthesized. Intermediate 1 undergoes an amide condensation reaction with 2-amino-N-(2,2,2-trifluoroethyl)acetamide under a condensing agent and alkaline conditions to obtain flurellanine. The structural formula of flurellanine is shown in Formula IV:

2. A telescopic process for preparing fluororana according to claim 1, characterized in that: In the step 1), the molar ratio of 2-methyl-4-acetylbenzoic acid to 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone is 1:1.05-1.2, the reaction temperature is 50°C-70°C, the solvent used in the reaction is a non-polar solvent, and the mass ratio of the solvent to 2-methyl-4-acetylbenzoic acid is 1:3-8.

3. A telescopic process for preparing fluororana according to claim 1, characterized in that: After the aldol condensation reaction in step 1) is carried out for 24 hours, the residual amount of 1-(3,5-dichlorophenyl)-2,2,2-trifluoroethanone is detected, and the reaction is stopped when the residual amount is less than 0.5%.

4. A telescopic process for preparing fluororana according to claim 1, characterized in that: In the step 2), the molar ratio of the intermediate 3 to 4-dimethylaminopyridine N-oxide is 1:0.05-0.15, and the molar ratio of the intermediate 3 to di-tert-butyl dicarbonate is 1:1.50-2.

50.

5. A telescopic process for preparing fluororana according to claim 1, characterized in that: The reaction temperature of the elimination reaction in step 2) is 50° C. to 70° C., and the reaction time is 2 hours.

6. A telescopic process for preparing fluororana according to claim 1, characterized in that: In step 3), the organic phosphoric acid catalyst has a structure of Formula 1, Formula 2, Formula 3, Formula 4, Formula 5, Formula 6 or Formula 7, 7. A telescopic process for preparing fluororana according to claim 1, characterized in that: In the step 3), the molar ratio of intermediate 2 to the organic phosphoric acid catalyst is 1:0.10-0.50, the molar ratio of intermediate 2 to the hydroxylamine salt is 1:1.00-2.00, the reaction temperature of the cyclization reaction is 80°C-125°C, and the residual amount of intermediate 2 is detected after the cyclization reaction is carried out for 2 hours, and the reaction is stopped when the residual amount is less than 0.5%.

8. A telescopic process for preparing fluororana according to claim 7, characterized in that: The hydroxylamine salt is hydroxylamine hydrochloride or hydroxylamine sulfate.

9. A telescopic process for preparing fluororana according to claim 1, characterized in that: The condensing agent in the step 4) is 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide and 1-hydroxybenzotriazole, the molar ratio of intermediate 1 to 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide is 1:1.00-2.50, the molar ratio of intermediate 1 to 1-hydroxybenzotriazole is 1:0.50-1.50, the base used is triethylamine, the molar ratio of intermediate 1 to triethylamine is 1:2.0-5.0, the molar ratio of intermediate 1 to 2-amino-N-(2,2,2-trifluoroethyl)acetamide is 1:1.0-1.5, the reaction temperature of the amide condensation reaction is 25-35°C; and the reaction time is 6h-18h.

10. The telescopic process for preparing fluororana according to any one of claims 1 to 9, characterized in that: The step 4) further comprises refining flurella, which specifically comprises the following steps: adding methanol to the flurella obtained in step 4), stirring at 60° C. and then cooling to grow crystals, stirring again and filtering to obtain pure flurella.

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