A solid phase synthesis method of flurella

Abstract

The present invention discloses a solid phase synthesis method of flurana, which uses amino-protected glycine as a starting material, is connected to a solid phase resin to obtain resin 1, and then deamination protection is obtained to obtain resin 2; then solid phase reaction is carried out in sequence to obtain resin 3 and resin 4, and then a cutting liquid is added to separate the synthesized key structure from the solid phase resin to obtain a key intermediate F of flurana; the key intermediate F is condensed with 2,2,2-trifluoroethylamine to obtain flurana. The starting raw materials of this method are cheap and easy to obtain, and the technology of solid phase synthesis is applied. The process of synthesizing the key intermediate F saves tedious purification steps such as column chromatography or recrystallization. The method is novel, simple to operate, saves time, and has low yield loss, which meets the characteristics of an automated continuous production process. This method mainly relies on solid phase synthesis technology, can effectively improve product quality and yield, reduce operational difficulty, and enhance the continuity of the flurana synthesis process.

Description

Technical Field

[0001] The present invention relates to the technical field of drug synthesis, in particular to a solid phase synthesis method of flurellan. Background Art

[0002] Fluralaner belongs to the isoxazoline insecticide class, CAS number: 864731-61-3; molecular weight: 555.06; its chemical structure is shown below:

[0003] In the early days, Flurellan was mainly used to effectively control agricultural pests. Later, it was mostly used to control external parasites in dogs and cats. It was developed by Merck Animal Health (Merck Animal Health) as a veterinary anthelmintic and is marketed for the treatment of lice and fleas on cats and dogs. The trade name is BravectoTM (chewable tablets).

[0004] Flurellan works by interfering with chloride channels at the gamma-aminobutyric acid (GABA) and glutamate receptors in the invertebrate nervous system, leading to nervous system hyperexcitation and death. It has no activity against mammalian nervous system receptors, making it very safe for mammals and suitable for all dog breeds, including breeding, pregnant, and lactating dogs. Flurellan is virtually inert to animal degradation, with 90%-100% of the original molecule excreted in feces. No metabolites burden the animal body, and virtually no renal excretion is associated with an excellent safety profile, with no liver or kidney damage. Flurellan has no known resistance or incompatibilities with existing insecticides. After oral administration, the drug is evenly distributed across the body surface, taking effect within two hours and achieving at least 80% insecticide control within four hours. Protection lasts up to 12 weeks, and excellent deworming effectiveness is achieved even in repeat infestations. Protection covers the entire flea life cycle.

[0005] Due to the above advantages of flurellana, it has been favored by domestic and foreign veterinary drug researchers in recent years.

[0006]

[0007] Patents and literature on flurellan or its intermediates have been published in domestic and foreign journals.

[0008] Patent publication number CN102149695A discloses a method for producing an isoxazoline-substituted benzamide compound, which uses the corresponding para-aldehyde aromatic carboxylic acid as the raw material and undergoes esterification, hydroxylamine oximation, substitution & elimination (to obtain nitrile oxide) & cyclization, hydrolysis, and amide condensation to obtain the isoxazoline compound flurellanil.

[0009] Patent publication number CN101990530A discloses a method for preparing 3-trifluoromethyl chalcone, which uses 1-(3,5-dichloro)-2,2,2-trifluoroethanone (4) as a starting material, condenses with methyl 2-methyl-4-acetylbenzoate (5) under alkaline conditions to obtain chalcone (6), and then undergoes ring closure, hydrolysis, and acid-amine condensation to obtain Fluralaner.

[0010] The various technologies used to synthesize flurana indicate that existing methods for synthesizing flurana are all conducted in the liquid phase. Its structural characteristics clearly indicate the presence of chiral carbon atoms in the isoxazoline ring of flurana. Chiral compounds are much less stable in liquid than in solid form, thus increasing the risk of chiral isomer formation in liquid-phase reaction systems. Furthermore, both the trifluoromethyl group and the chlorine atoms on the benzene ring are at risk of hydrolysis at high temperatures in alkaline aqueous solutions. The trifluoromethyl group can hydrolyze into a carboxyl group, while the chlorine atoms on the benzene ring can also hydrolyze into a phenolic hydroxyl group.

[0011] Due to the existence of the above-mentioned risks, the synthesis and purification of flurana have become more difficult. The quality and yield are often low, and crystallization and purification are impossible, so industrial production is difficult. Summary of the Invention

[0012] The technical problem to be solved by the present invention is to provide a solid phase synthesis method of flurellanine with high product yield and good quality.

[0013] To solve the above technical problems, the technical solution adopted by the present invention is as follows: using amino-protected glycine as a starting material, connecting it to a solid-phase resin to obtain resin 1, and then deamino-protecting it to obtain resin 2; then, solid-phase reactions are sequentially performed to obtain resin 3 and resin 4; then, a cutting fluid is added to separate the synthesized key structure from the solid-phase resin to obtain a key intermediate F of flurellan; the key intermediate F is condensed with 2,2,2-trifluoroethylamine to obtain flurellan; the reaction route is:

[0014]

[0015] Further, the method comprises the following steps:

[0016] (1) Using glycine whose amino group is protected by a protecting group as a starting material, adding a condensing agent to react with a solid phase resin to obtain resin 1; the protecting group is tert-butyloxycarbonyl or fluorenylmethyloxycarbonyl; and the solid phase resin is dichlorotrityl resin;

[0017] (2) adding a deprotecting agent to the resin 1 to carry out a deamination protection reaction to obtain resin 2; when the protecting group in step (1) is tert-butyloxycarbonyl, the deprotecting agent is trifluoroacetic acid or hydrochloric acid; when the protecting group in step (1) is fluorenylmethyloxycarbonyl, the deprotecting agent is NaOH solution, or a dichloromethane solution of diethylamine, piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone or 1,8-diazabicycloundec-7-ene;

[0018] (3) adding a condensing agent to the resin 2 and reacting it with compound a in a solid phase to obtain resin 3; the compound a is [4-(hydroxyimino)methyl]-2-methylbenzoic acid or 4-acetyl-2-methylbenzoic acid;

[0019] (4) The resin 3 is reacted with the compound b in a solid phase reaction to obtain the resin 4; when the compound a in the step (3) is [4-(hydroxyimino)methyl]-2-methylbenzoic acid, the compound b is 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene; when the compound a in the step (3) is 4-acetyl-2-methylbenzoic acid, the compound b is 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone;

[0020] (5) adding a cutting liquid to the resin 4 to obtain the key intermediate F of Freilana after cutting;

[0021] (6) The key intermediate F is reacted with 2,2,2-trifluoroethylamine under the action of a condensing agent, and Frelane is obtained after extraction and crystallization.

[0022] Furthermore, in step (1), the condensing agent is HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) or TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate).

[0023] Furthermore, in step (3), the condensing agent is HBTU or TBTU.

[0024] Furthermore, in step (5), the cutting fluid is a mixture of trifluoroacetic acid, triisopropylsilane, 1,2-ethanedithiol and water, or a mixture of trifluoroacetic acid, triisopropylsilane and water.

[0025] Furthermore, in step (6), the condensing agent is any one of DPPA (diphenylphosphoryl azide), HBTU, CDI (N,N'-carbonyldiimidazole), DCC (N,N'-dicyclohexylcarbamide), and PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate).

[0026] The beneficial effects of the above technical solution are: the starting materials are inexpensive and readily available, and solid-phase synthesis technology is employed. The synthesis of the key intermediate F eliminates tedious purification steps such as column chromatography or recrystallization. The method is novel, simple to operate, saves time, and minimizes yield loss, thus meeting the requirements of an automated continuous production process. Relying primarily on solid-phase synthesis technology, the present invention can effectively improve product quality and yield, reduce operational complexity, and enhance the continuity of the flurellanine synthesis process. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments.

[0028] Figure 1 This is the HPLC spectrum of the flurellan product obtained in Example 1 of the present invention;

[0029] Figure 2 yes Figure 1 A local magnified view of the peak position. DETAILED DESCRIPTION

[0030] The present invention will be further described in detail below with reference to specific embodiments.

[0031] The solid phase synthesis method of benflurana comprises the following steps:

[0032] (1) Using glycine whose amino group is protected by a protecting group as a starting material, wherein the protecting group is tert-butyloxycarbonyl or fluorenylmethoxycarbonyl, i.e., using tert-butyloxycarbonylglycine or fluorenylmethoxycarbonylglycine as a starting material, preferably the protecting group is tert-butyloxycarbonyl; adding a condensing agent and a solid phase resin, and reacting to obtain resin 1; the solid phase resin is a dichlorotrityl resin; the condensing agent is HBTU (benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate) or TBTU (O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate), preferably HBTU. Preferably, the glycine whose amino group is protected by a protecting group is 1 molar equivalent, and the condensing agent is 2 to 5 molar equivalents.

[0033] (2) Adding a deprotecting agent to the resin 1 to carry out a deamination protection reaction to obtain resin 2; when the protecting group in step (1) is tert-butyloxycarbonyl, the deprotecting agent is trifluoroacetic acid or hydrochloric acid; when the protecting group in step (1) is fluorenylmethyloxycarbonyl, the deprotecting agent is a 2-4 mol / L NaOH aqueous solution, or a dichloromethane solution of diethylamine, piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone or 1,8-diazabicycloundec-7-ene, i.e., a solution prepared by dissolving diethylamine, piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone or 1,8-diazabicycloundec-7-ene in dichloromethane, wherein dichloromethane is a solvent at a concentration of 20-50% (volume); preferably, the deprotecting agent is a CH2Cl2 solution of 50 vol% piperidine. Preferably, the amount of the deprotecting agent added is 5-10 molar equivalents.

[0034] (3) A condensing agent is added to the resin 2 and reacted with compound a in a solid phase to obtain resin 3; the compound a is [4-(hydroxyimino)methyl]-2-methylbenzoic acid or 4-acetyl-2-methylbenzoic acid, preferably [4-(hydroxyimino)methyl]-2-methylbenzoic acid; the condensing agent is HBTU or TBTU, preferably HBTU. Preferably, the amount of the condensing agent added is 2 to 5 molar equivalents, and the amount of compound a added is 1.5 to 2 molar equivalents.

[0035] (4) The resin 3 reacts with compound b to obtain resin 4; preferably, compound b is 1.5 to 2 molar equivalents. When compound a in step (3) is [4-(hydroxyimino)methyl]-2-methylbenzoic acid, compound b is 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene; in this case, the synthesis process of resin 4 is as follows: the resin 3 reacts with NCS (N-chlorosuccinimide, C4H4ClNO2) to produce resin 3'; resin 3' reacts with Et3N (triethylamine) and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene to produce resin 4; preferably, NCS is 1 to 3 molar equivalents and Et3N is 3 to 5 molar equivalents; the synthesis process of resin 4 is as follows:

[0036]

[0037] When the compound a in step (3) is 4-acetyl-2-methylbenzoic acid, the compound b is 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone; preferably, the compound b is 1.5 to 2 molar equivalents; in this case, the synthesis process of resin 4 is as follows: the resin 3 reacts with 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone and a base to generate resin 3″; the base is preferably calcium hydroxide; the resin 3″ reacts with an aqueous sodium hydroxide solution of NH2OH·HCl (hydroxylamine hydrochloride) to generate resin 4; preferably, the hydroxylamine hydrochloride is 4 to 6 molar equivalents and the sodium hydroxide is 6 to 12 molar equivalents; the reaction process is as follows:

[0038]

[0039] (5) A cutting fluid is added to the resin 4 to obtain the key intermediate F of Frellana; the cutting fluid is a mixture of trifluoroacetic acid, triisopropylsilane, 1,2-ethanedithiol and H2O, and the volume ratio is: trifluoroacetic acid: triisopropylsilane: 1,2-ethanedithiol: H2O = (85-95%): (1-10%): (1-10%): (1-10%); or a mixture of trifluoroacetic acid, triisopropylsilane and water, and the volume ratio is: trifluoroacetic acid: triisopropylsilane: water = (90-95%): (1-10%): (1-10%), and the preferred ratio is trifluoroacetic acid: triisopropylsilane: water = 95:2.5:2.5.

[0040] (6) The key intermediate F reacts with 2,2,2-trifluoroethylamine under the action of a condensing agent, and triethylamine is added; after the reaction, extraction, crystallization, washing, and drying are performed to obtain Frelane; the condensing agent is any one of DPPA (diphenylphosphoryl azide), HBTU, CDI (N,N'-carbonyldiimidazole), DCC (N,N'-dicyclohexylcarbamide), and PyBop (benzotriazol-1-yl-oxytripyrrolidinophosphine hexafluorophosphate), preferably PyBop.

[0041] Example 1: The solid phase synthesis method of benflurana is described in detail as follows.

[0042] (1) Synthesis of Resin 1: 1 equivalent of fluorenylmethyloxycarbonylglycine and 2 equivalents of HBTU reagent were added to dichlorotrityl resin and reacted fully to obtain Resin 1; the reaction process is shown below:

[0043]

[0044] (2) Synthesis of Resin 2: 5 equivalents of a deprotection reagent (50% diethylamine CH2Cl2 solution) were added to Resin 1 and allowed to react fully to obtain Resin 2. The reaction process is shown below:

[0045]

[0046] (3) Synthesis of Resin 3: 1.5 equivalents of [4-(hydroxyimino)methyl]-2-methylbenzoic acid and 2 equivalents of HBTU were added to Resin 2 and reacted sufficiently to obtain Resin 3. The reaction process is shown below:

[0047]

[0048] (4) Synthesis of Resin 4: 2 equivalents of NCS were added to Resin 3 and reacted sufficiently to obtain an intermediate resin. Then, 3 equivalents of Et3N and 2 equivalents of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene were added and reacted sufficiently to obtain Resin 4. The reaction process is shown below:

[0049]

[0050] (5) Synthesis of key intermediate F: A cutting fluid was added to resin 4. The cutting fluid was trifluoroacetic acid: triisopropylsilane: water = 95:2.5:2.5. After sufficient reaction, key intermediate F was obtained with a yield of 96.26%. The reaction process is shown below:

[0051]

[0052] (6) Synthesis of Flurella: 1 equivalent of key intermediate F was reacted with 1.7 equivalents of 2,2,2-trifluoroethylamine, and 1.7 equivalents of triethylamine and 2 equivalents of DPPA condensing agent were added. After the reaction, the product was extracted, recrystallized, washed, and dried to obtain the Flurella product. The obtained Flurella product had an HPLC purity of 99.93%, a yield of 84.63%, and a total yield of 81.46%. The HPLC spectrum is shown in FIG. Figure 1 、 Figure 2 The reaction process is shown below:

[0053]

[0054] Example 2: The solid phase synthesis method of benflurana is described in detail as follows.

[0055] (1) Synthesis of Resin 1: 1 equivalent of tert-butyloxycarbonylglycine and 2 equivalents of TBTU reagent were added to dichlorotrityl resin and reacted fully to obtain Resin 1; the reaction process is shown below:

[0056]

[0057] (2) Synthesis of Resin 2: 5 equivalents of trifluoroacetic acid were added to Resin 1 and reacted sufficiently to obtain Resin 2. The reaction process is shown below:

[0058]

[0059] (3) Synthesis of Resin 3: 1.5 equivalents of 4-acetyl-2-methylbenzoic acid and 2.5 equivalents of TBTU were added to Resin 2 and reacted sufficiently to obtain Resin 3. The reaction process is shown below:

[0060]

[0061] (4) Synthesis of Resin 4: 1.7 equivalents of 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone and 1.9 equivalents of calcium hydroxide were added to Resin 3 and reacted sufficiently to obtain a chalcone structure intermediate resin. Then, an aqueous solution of 4 equivalents of hydroxylamine hydrochloride and 8 equivalents of sodium hydroxide was added and reacted sufficiently to obtain Resin 4. The reaction process is shown below:

[0062]

[0063] (5) Synthesis of key intermediate F: A cutting fluid was added to resin 4. The cutting fluid was trifluoroacetic acid: triisopropylsilane: 1,2-ethanedithiol: water = 94:1:2.5:2.5. After sufficient reaction, key intermediate F was obtained with a yield of 97.14%. The reaction process is shown below:

[0064]

[0065] (6) Synthesis of Flurella: One equivalent of the key intermediate F was reacted with 1.5 equivalents of 2,2,2-trifluoroethylamine, 1.5 equivalents of triethylamine, and 1 equivalent of PyBop condensing agent. After the reaction, the product was extracted, recrystallized, washed, and dried to obtain the Flurella product. The obtained Flurella product had an HPLC purity of 99.92%, a yield of 86.77%, and a total yield of 84.29%. The reaction process is shown below:

[0066]

[0067] Example 3: The solid phase synthesis method of benflurana is described in detail as follows.

[0068] (1) Synthesis of Resin 1: 1 equivalent of fluorenylmethoxycarbonylglycine and 3 equivalents of HBTU reagent were added to dichlorotrityl resin and reacted sufficiently to obtain Resin 1.

[0069] (2) Synthesis of Resin 2: 8 equivalents of a deprotection reagent was added to Resin 1. The deprotection reagent was a 50% piperidine CH2Cl2 solution. After sufficient reaction, Resin 2 was obtained.

[0070] (3) Synthesis of Resin 3: 1.8 equivalents of [4-(hydroxyimino)methyl]-2-methylbenzoic acid and 3 equivalents of HBTU were added to Resin 2 and reacted sufficiently to obtain Resin 3.

[0071] (4) Synthesis of resin 4: 1 equivalent of NCS was added to resin 3 and reacted sufficiently to obtain an intermediate resin; then 4 equivalents of Et3N and 1.8 equivalents of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene were added and reacted sufficiently to obtain resin 4.

[0072] (5) Synthesis of key intermediate F: Cutting fluid was added to resin 4. The cutting fluid was trifluoroacetic acid: triisopropylsilane: water = 95:2.5:2.5. After sufficient reaction, key intermediate F was obtained with a yield of 96.34%.

[0073] (6) Synthesis of Flurella: One equivalent of the key intermediate F was reacted with 1.8 equivalents of 2,2,2-trifluoroethylamine, 1.8 equivalents of triethylamine, and 1.2 equivalents of PyBop condensing agent. After the reaction, the product Flurella was extracted, recrystallized, washed, and dried to obtain the Flurella product. The obtained Flurella product had an HPLC purity of 99.94%, a yield of 84.67%, and a total yield of 81.57%.

[0074] Example 4: The solid phase synthesis method of benflurana is described in detail as follows.

[0075] (1) Synthesis of Resin 1: 1 equivalent of tert-butyloxycarbonyl and 5 equivalents of TBTU reagent were added to dichlorotrityl resin and the reaction was complete to obtain Resin 1.

[0076] (2) Synthesis of Resin 2: 10 equivalents of a deprotection reagent, hydrochloric acid, was added to Resin 1. After sufficient reaction, Resin 2 was obtained.

[0077] (3) Synthesis of Resin 3: 2 equivalents of [4-(hydroxyimino)methyl]-2-methylbenzoic acid and 5 equivalents of TBTU were added to Resin 2 and reacted sufficiently to obtain Resin 3.

[0078] (4) Synthesis of resin 4: 3 equivalents of NCS were added to resin 3 and reacted sufficiently to obtain an intermediate resin; then 5 equivalents of Et3N and 2 equivalents of 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene were added and reacted sufficiently to obtain resin 4.

[0079] (5) Synthesis of key intermediate F: A cutting fluid was added to resin 4. The cutting fluid was trifluoroacetic acid: triisopropylsilane: 1,2-ethanedithiol: H2O = 95:3:1:1. After sufficient reaction, key intermediate F was obtained with a yield of 96.25%.

[0080] (6) Synthesis of Flurella: One equivalent of the key intermediate F was reacted with 2,2,2-trifluoroethylamine, triethylamine, and HBTU. After the reaction, the product was extracted, recrystallized, washed, and dried to obtain the Flurella product. The obtained Flurella product had an HPLC purity of 99.91%, a yield of 84.63%, and a total yield of 81.45%.

[0081] Example 5: The solid phase synthesis method of benflurana is described in detail as follows.

[0082] (1) Synthesis of Resin 1: 1 equivalent of fluorenylmethyloxycarbonyl and 2.5 equivalents of HBTU reagent were added to dichlorotrityl resin and the mixture was allowed to react fully to obtain Resin 1.

[0083] (2) Synthesis of Resin 2: 6 equivalents of a deprotection reagent (a 20% morpholine CH2Cl2 solution) were added to Resin 1. After sufficient reaction, Resin 2 was obtained.

[0084] (3) Synthesis of Resin 3: 1.5 equivalents of 4-acetyl-2-methylbenzoic acid and 2 equivalents of TBTU were added to Resin 2 and reacted sufficiently to obtain Resin 3.

[0085] (4) Synthesis of Resin 4: 1.5 equivalents of 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone and 1.5 equivalents of calcium hydroxide were added to Resin 3. After sufficient reaction, a chalcone structure intermediate resin was obtained. Then, an aqueous solution of 5 equivalents of hydroxylamine hydrochloride and 6 equivalents of sodium hydroxide was added. After sufficient reaction, Resin 4 was obtained.

[0086] (5) Synthesis of key intermediate F: A cutting fluid was added to resin 4. The cutting fluid was trifluoroacetic acid: triisopropylsilane: 1,2-ethanedithiol: water = 85:5:5:5. After sufficient reaction, key intermediate F was obtained with a yield of 97.11%.

[0087] (6) Synthesis of Flurella: One equivalent of the key intermediate F was reacted with 1.5 equivalents of 2,2,2-trifluoroethylamine, 1.5 equivalents of triethylamine, and 1 equivalent of DCC condensing agent. After the reaction, the product Flurella was extracted, recrystallized, washed, and dried to obtain the Flurella product. The obtained Flurella product had an HPLC purity of 99.93%, a yield of 86.76%, and a total yield of 84.25%.

[0088] Example 6: The solid phase synthesis method of benflurana is described in detail as follows.

[0089] (1) Synthesis of Resin 1: To 1 equivalent of dichlorotrityl resin, 1 equivalent of tert-butyloxycarbonylglycine and 4 equivalents of TBTU reagent were added and reacted sufficiently to obtain Resin 1.

[0090] (2) Synthesis of Resin 2: 9 equivalents of trifluoroacetic acid were added to Resin 1 and the mixture was allowed to react sufficiently to obtain Resin 2.

[0091] (3) Synthesis of Resin 3: 2 equivalents of 4-acetyl-2-methylbenzoic acid and 4 equivalents of TBTU were added to Resin 2 and reacted sufficiently to obtain Resin 3.

[0092] (4) Synthesis of resin 4: 2 equivalents of 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone and 2 equivalents of calcium hydroxide were added to resin 3. After sufficient reaction, a chalcone structure intermediate resin was obtained. Then, an aqueous solution of 6 equivalents of hydroxylamine hydrochloride and 12 equivalents of sodium hydroxide was added. After sufficient reaction, resin 4 was obtained.

[0093] (5) Synthesis of key intermediate F: A cutting fluid was added to resin 4. The cutting fluid was trifluoroacetic acid: triisopropylsilane: water = 90:5:5. After sufficient reaction, key intermediate F was obtained with a yield of 97.13%.

[0094] (6) Synthesis of Flurella: One equivalent of the key intermediate F was reacted with two equivalents of 2,2,2-trifluoroethylamine, two equivalents of triethylamine, and one equivalent of CDI condensing agent. After the reaction, the product Flurella was extracted, recrystallized, washed, and dried to obtain the Flurella product. The obtained Flurella product had an HPLC purity of 99.91%, a yield of 86.73%, and a total yield of 84.24%.

[0095] Example 7: The solid phase synthesis method of benflurana is described in detail as follows.

[0096] The same procedures as in Example 1 were employed except that a 2 mol / L aqueous NaOH solution was used as the deprotection reagent in the synthesis of resin 2 in step (2); the yield of the key intermediate F was 96.25%; and the obtained flurellanine product had an HPLC purity of 99.94%, a yield of 84.65%, and a total yield of 81.48%.

[0097] Example 8: The solid phase synthesis method of benflurana is described in detail as follows.

[0098] The same procedures as in Example 1 were followed except that a 30% ethanolamine CH2Cl2 solution was used as the deprotection reagent in step (2) of the synthesis of resin 2. The yield of the key intermediate F was 96.23%. The obtained flurellanine product had an HPLC purity of 99.91%, a yield of 84.65%, and a total yield of 81.46%.

[0099] Example 9: The solid phase synthesis method of benflurana is described in detail as follows.

[0100] The same procedures as in Example 1 were followed except that a 40% cyclohexylamine CH2Cl2 solution was used as the deprotection reagent in step (2) of the synthesis of resin 2. The yield of the key intermediate F was 96.24%. The obtained flurellanine product had an HPLC purity of 99.95%, a yield of 84.57%, and a total yield of 81.39%.

[0101] Example 10: The solid phase synthesis method of benflurana is described in detail as follows.

[0102] The same procedures as in Example 1 were employed except that a 50% pyrrolidone CH2Cl2 solution was used as the deprotection reagent in step (2) the synthesis of resin 2. The yield of the key intermediate F was 96.25%. The obtained flurellanine product had an HPLC purity of 99.92%, a yield of 84.62%, and a total yield of 81.44%.

[0103] Example 11: The solid phase synthesis method of benflurana is described in detail as follows.

[0104] The same procedures as in Example 1 were employed except that a 45% solution of 1,8-diazabicycloundec-7-ene in CH2Cl2 was used as the deprotection reagent in the synthesis of resin 2 in step (2); the yield of the key intermediate F was 96.22%; and the obtained flurellanine product had an HPLC purity of 99.91%, a yield of 84.67%, and a total yield of 81.46%.

[0105] Comparative Example:

[0106] (1) Synthesis of 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester: [4-(hydroxyimino)methyl]-2-methylbenzoic acid methyl ester (1 equivalent), potassium iodide (5 equivalents) and potassium persulfate complex (5 equivalents) were added to a round-bottom flask, dissolved in water, and a methanol solution of [4-(hydroxyimino)methyl]-2-methylbenzoic acid methyl ester and 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene was added. The reaction was stirred at room temperature until the reaction was completed. The organic phase was extracted with ethyl acetate, washed with saturated sodium chloride solution, and dried over anhydrous magnesium sulfate. After vacuum distillation and column chromatography, 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester was obtained.

[0107] (2) Synthesis of 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid: 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid methyl ester was added into a 10% sodium hydroxide solution and stirred thoroughly. The mixture was acidified with 10% hydrochloric acid, crystallized, filtered, washed, and dried to obtain 4-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid.

[0108] (3) Synthesis of Flurella: 4-[5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-2-methyl-benzoic acid was added to a DMF solution of 2-amino-N-(2',2',2'-trifluoroethyl)acetamide, and triethylamine (2 equivalents) and DPPA condensing agent (1.5 equivalents) were added. After the reaction, the product was extracted, crystallized, filtered, washed, and dried to obtain Flurella. The HPLC purity was 99.74%, and the yield was 46.33%.

[0109] By comparison with the comparative examples, it can be seen that the present method has strong continuity, fewer intermediate purification processes, higher preparation purity, better yield, and is more suitable for industrial automated production.

Claims

1. A solid phase synthesis method of flurella, characterized in that: Glycine with protected amino groups is used as a starting material, which is connected to a solid-phase resin to obtain resin 1, and then deamino protection is performed to obtain resin 2. Solid-phase reactions are then performed in sequence to obtain resins 3 and 4. A cutting fluid is then added to detach the synthesized key structure from the solid-phase resin to obtain the key intermediate F of flurellan. The key intermediate F is condensed with 2,2,2-trifluoroethylamine to obtain flurellan. The reaction route is: The method comprises the following steps: (1) Using glycine whose amino group is protected by a protecting group as a starting material, adding a condensing agent to react with a solid phase resin to obtain resin 1; the protecting group is tert-butyloxycarbonyl or fluorenylmethyloxycarbonyl; and the solid phase resin is dichlorotrityl resin; (2) adding a deprotecting agent to the resin 1 to carry out a deamination protection reaction to obtain resin 2; when the protecting group in step (1) is tert-butyloxycarbonyl, the deprotecting agent is trifluoroacetic acid or hydrochloric acid; when the protecting group in step (1) is fluorenylmethyloxycarbonyl, the deprotecting agent is NaOH solution, or a dichloromethane solution of diethylamine, piperidine, ethanolamine, cyclohexylamine, morpholine, pyrrolidone or 1,8-diazabicycloundec-7-ene; (3) adding a condensing agent to the resin 2 and reacting it with compound a in a solid phase to obtain resin 3; the compound a is [4-(hydroxyimino)methyl]-2-methylbenzoic acid or 4-acetyl-2-methylbenzoic acid; (4) The resin 3 is reacted with the compound b in a solid phase reaction to obtain the resin 4; when the compound a in the step (3) is [4-(hydroxyimino)methyl]-2-methylbenzoic acid, the compound b is 1,3-dichloro-5-(1-trifluoromethyl-vinyl)benzene; when the compound a in the step (3) is 4-acetyl-2-methylbenzoic acid, the compound b is 1-(3,5-dichlorophenyl)-2,2,2,-trifluoroethanone; (5) adding a cutting fluid to the resin 4 and cutting to obtain the key intermediate F of Frellana; the cutting fluid is a mixture of trifluoroacetic acid, triisopropylsilane, 1,2-ethanedithiol and water, or a mixture of trifluoroacetic acid, triisopropylsilane and water; (6) The key intermediate F is reacted with 2,2,2-trifluoroethylamine under the action of a condensing agent, and Frelane is obtained after extraction and crystallization.

2. The solid phase synthesis method of flurella according to claim 1, characterized in that: In the steps (1) and (3), the condensing agent is benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate or O-benzotriazole-N,N,N',N'-tetramethyluronium tetrafluoroborate.

3. The solid phase synthesis method of flurella according to claim 1 or 2, characterized in that: In the step (6), the condensing agent is any one of diphenylphosphoryl azide, benzotriazole-N,N,N',N'-tetramethyluronium hexafluorophosphate, N,N'-carbonyldiimidazole, N,N'-dicyclohexylcarboximide, and benzotriazole-1-yl-oxytripyrrolidinophosphine hexafluorophosphate.

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