CN113512007A - Synthesis of flurarana - Google Patents
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- CN113512007A CN113512007A CN202110957670.2A CN202110957670A CN113512007A CN 113512007 A CN113512007 A CN 113512007A CN 202110957670 A CN202110957670 A CN 202110957670A CN 113512007 A CN113512007 A CN 113512007A
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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
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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Abstract
The invention relates to the synthesis of loratadine, the key steps of the synthesis are related to Zn (OTf)2The preparation of the flurarana is realized by the reaction of 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydro isoxazol-3-yl) -2-methyl-benzonitrile and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide under the action of hydroxylamine hydrochloride.
Description
Technical Field
The invention belongs to the field of chemical synthesis, and particularly relates to synthesis of frataxin.
Background
Flurania (English translation: Fluralanar) has been used as a pesticide veterinary drug (trade name Bravector) in 2014TM) The insecticide is sold in Germany, Spain, Italy, France, the Netherlands and the British and is mainly used for killing insects inside and outside animals; 2016 U.S. FDA approving Merck applications for 7 months
(topical solution of flurana) is used for the treatment of fleas and ticks on cats and dogs with a single administration effective period of up to 12 weeks. Research shows that the fraxidin is a very effective insecticidal active compound, and the fraxidin can kill the nervous system by interfering with the function of a gamma-aminobutyric acid (GABA) gate channel to cause over-excitation. As a novel high-efficiency GABA chlorine ion channel control interference agent, compared with phenylpyrazole, cyclopentadiene and macrolide insecticides, the loratadine has obvious differences in molecular structure, site of action, selectivity, cross resistance and the like. Among them, the cyclopentadiene insecticides dieldrin and Lindane (Lindane) are the first insecticides to be found and act on GABA-gated chloride channels, but both are prohibited in agricultural production in the global scope due to high residue, environmental pollution and harm to human health, and increase in resistance of agricultural pests.
The pharmaceutical ingredient of the fluranide is a mixture of R and S configuration, and the chemical name of the fluranide is 4- [5- (3, 5-dichlorophenyl group)) -4, 5-dihydro-5-trifluoromethyl-3-isoxazolyl]-2-methyl-aza- [ 2-oxo-2- [ (2,2, 2-trifluoroethyl) amino]Benzamide, the compound CAS No.: 864731-61-3; the chemical formula is as follows: c22H17C12F6N303(ii) a Relative molecular mass: 556.29. the compound has a pair of enantiomers, and the drug is marketed as a mixture of R and S, but further research results later indicate that the S configuration of fluralaner is the main insecticidal active ingredient. The current commercial preparation product is a racemic compound, and the chemical structure of the frairana is as follows:
the broad-spectrum insect repellent fluralaner of the isoxazoline type was successfully developed and synthesized by Nissan Chemical industries, Japan as early as 2004, and granted international patent in 2005, which was 2025 due to its expiration time. Scientists in japan Ozoe et al, 2010, also reported on the biological and electrophysiological activity properties of fluralaner. 2013 and 2014 scientists carried out related research on the action site and mechanism of fluralaner on GABA. Researchers at the German institute of Animal Health Innovation GMBH Germany performed a series of related experiments on dogs by using fluralaner, and verified the insecticidal activity of the insect repellent against ectoparasites of dogs, the toxicity to dogs, and the like.
At present, the synthesis of frairamide has been reported in a number of patents and literature. The patent WO2005085216/WO2009080250A describes the synthesis of frataxin. The preparation method comprises the steps of taking 2-methyl-4-formaldehyde oxime tert-butyl benzoate as a starting material, preparing an oxime chloride compound under the action of NCS, then carrying out 1, 3-dipolar cycloaddition reaction on the oxime chloride compound and 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) -benzene, and finally carrying out amidation reaction on the oxime chloride compound and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide under an alkaline condition to prepare the fluranine. The synthetic route is as follows:
patent CN109879826 describes an alternative synthetic route to flurarana. The patent advances the preparation of flurarana by condensation of a 2-amino-N- (2,2, 2-trifluoroethyl) acetamide group with benzoic acid and finally 1, 3-dichloro-5- (1-trifluoromethyl-vinyl) -benzene by 1, 3-dipolar cycloaddition. In the route, because the 2-amino-N- (2,2, 2-trifluoroethyl) acetamide group contains a plurality of active reaction sites, a large amount of side reactions are generated in the NCS chlorination and final 1, 3-dipolar cycloaddition reaction processes, so that the purification of the final product is difficult and the total yield is low. The synthetic route is as follows:
patent WO2009001942/EP2172462/WO2021038501 describes an alternative synthesis route for flurandrine. The route uses 1- (3, 5-dichlorophenyl) -2,2, 2-trifluoroethyl-1-one and 4-acetyl-2-methylbenzoic acid as starting materials and under the action of a base, the compound 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzoic acid triethylamine salt is obtained, and Ac is used as the auxiliary material2Removing a molecule of water under the O/DMAP condition to obtain an alpha, beta-unsaturated ketone compound; the alpha, beta-unsaturated ketone compound is subjected to isoxazole cyclization reaction under the action of hydroxylamine hydrochloride to obtain a corresponding carboxylic acid intermediate; the latter and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide are subjected to condensation reaction to realize the synthesis of the flurandrine. The synthesis steps of the route are long. The relevant synthetic route is as follows:
the U.S. Hoveyda group developed a route for the preparation of chiral flurandrine (nat. chem.,20168, 768-777). The synthetic route firstly prepares chiral (S) -2- (3, 5-dichlorophenyl) -1,1, 1-trifluoro-4-alkene-2-alcohol by a boron reagent, and then oxidizes a terminal double bond by ozone to obtain (S) -3- (3, 5-diChlorophenyl) -4,4, 4-trifluoro-3-hydroxybutanal; the obtained aldehyde compound and a product obtained after the reaction of the (4- (methoxycarbonyl) -3-methylphenyl) magnesium chloride lithium chloride complex are directly oxidized by Dess-Martin to obtain (S) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methyl benzoate; followed by reaction of methyl (S) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzoate with hydroxylamine hydrochloride and PhI (OH) OTs and P (OMe)3Under the action of ring closure, preparing (S) -4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl benzoate; finally, the condensation of methyl (S) -4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methylbenzoate with 2-amino-N- (2,2, 2-trifluoroethyl) acetamide enables the preparation of fluranide in S configuration. The relevant synthetic route is as follows:
by integrating the existing preparation method of the frailamide, the method is easily found to involve the step of preparing the 4, 5-dihydroisoxazole intermediate by ring closing, the existing ring closing precursor contains a plurality of active groups such as ester groups, amido groups, carboxyl groups and the like, the ring closing reagents are hydroxylamine hydrochloride, and the active groups are very easy to generate side reaction with the hydroxylamine hydrochloride, so that impurities are generated in the whole preparation process, and bottlenecks are brought to subsequent product purification and industrial production. Therefore, the development of a new preparation method of the flurarana is very important for the industrialization of the flurarana, the reduction of the industrialization cost and the improvement of the market competitiveness of the product.
Disclosure of Invention
The invention aims to provide a method for preparing the flurarana.
The research finds that the 1- (3, 5-dichlorophenyl) -2,2, 2-trifluoroethyl-1-ketone and 4-acetyl-2-methylbenzonitrile can realize the preparation of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile under the action of a solvent and alkali; 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile can be further converted into an alpha, beta-unsaturated ketone compound ((Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobut-2-enonyl) -2-methyl-benzonitrile) under the action of a solvent and a dehydrating reagent; the preparation of 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile can be achieved by reacting (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobut-2-enoyl) -2-methyl-benzonitrile with hydroxylamine hydrochloride; finally, 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide are subjected to a condensation reaction to prepare the flurandrine. The method has less side reaction in the reaction process because the nitrile group does not contain active hydrogen compared with ester group, amido group and carboxyl group and belongs to inert group. The relevant reaction scheme is as follows:
the solvent used in step 1 includes toluene, xylene, mesitylene, acetonitrile, 1, 4-dioxane, THF, 2-MeTHF and a mixed solvent of any combination of these solvents.
The base used in the step 1 comprises triethylamine, DIPEA, DABCO, DBU, DMAP, N-methylmorpholine and pyridine.
The solvent used in step 2 includes toluene, xylene, THF, 2-MeTHF, 1, 4-dioxane, acetonitrile and a mixed solvent of any combination of these solvents.
The reagent used in step 2 comprises SOCl2、Ac2O and a catalytic amount of DMAP.
The solvent used in step 3 includes THF, 2-MeTHF, 1, 4-dioxane, acetonitrile and a mixed solvent of any combination of these solvents.
The reagent used in the step 4 is Zn (OTf)2Hydroxylamine hydrochloride.
The solvent used in step 4 comprises 1, 4-dioxane and H2O, xylene, THF, 2-MeTHF, DMSO, and a mixed solvent of any combination of these solvents.
According to the preparation method of the flurarana, the last step is to perform condensation reaction on the relatively inert nitrile group and the 2-amino-N- (2,2, 2-trifluoroethyl) acetamide to realize the preparation of the flurarana, so that the side reaction in the whole synthesis process is less, and the preparation method is suitable for industrial scale-up production.
Detailed Description
The following exemplary embodiments are provided to illustrate the present invention, and simple replacement and modification of the present invention by those skilled in the art are within the technical scheme of the present invention.
EXAMPLE one preparation of 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile
Under the protection of nitrogen, 4-acetyl-2-methylbenzonitrile (40g,251.3mmol), 1- (3, 5-dichlorophenyl) -2,2, 2-trifluoroethyl-1-one (81.8g,336.6mmol), triethylamine (56.8g,561.3mmol) and anhydrous toluene (300mL) were added in this order to a four-necked flask. After the addition, the system was stirred at room temperature for 10 minutes until the system was clear. Then, the reaction system is slowly heated to reflux reaction until TLC tracking reaction is completed until 4-acetyl-2-methyl benzonitrile is basically reacted completely. Naturally cooling the system to room temperature, and then stirring for 2 hours under the condition of heat preservation; system addition of H2O (300mL), 2M hydrochloric acid is used for adjusting the pH value of the system to be weakly acidic, an organic phase is separated, and water phase toluene (200mL) is extracted once; the organic phases are combined, dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness and then added with toluene (200 mL); heating the system to be clear, then further slowly cooling the system to-5 ℃, and keeping the temperature and stirring overnight; the filtrate was filtered, and the filter cake was washed with toluene (40mL) cooled in advance to give a white solid, which was dried by air blow at 40 ℃ to constant weight to give 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile (white solid, 86.0g, 85.1%).
EXAMPLE two preparation of (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobut-2-enoyl) -2-methyl-benzonitrile
Under nitrogen protection, 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile (48.0g,119.3mmol), DMAP (1.1g,9.0mmol), acetic anhydride (19.0g,186.1mmol) and xylene (150mL) were added in this order to a three-necked flask. After the addition, the system was stirred at room temperature for 10 minutes, and then the system was slowly heated to 80 ℃ to react for 6 hours. The temperature of the system is reduced to 50 ℃, and the water solution of dilute sodium bicarbonate (with gas released) is slowly added to adjust the pH value to be neutral under the temperature. Then the system is layered at 50 ℃, an organic phase is collected, the temperature of the organic phase is reduced to room temperature, silica gel Pad is used for passing, the obtained organic phase is subjected to high vacuum and reduced pressure to remove the solvent to obtain (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-2-ketene) -2-methyl-benzonitrile (43.7g), and the product is directly used for the next reaction without further purification.
EXAMPLE three preparation of 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile
Under the protection of nitrogen, sodium hydroxide (13.1g,327.5mmol) and H were added in sequence to a reaction flask2O (150mL), hydroxylamine hydrochloride (22.7g,326.7mmol) and THF (120mL), and after the addition, the system is stirred for 20 minutes, and the system is cooled to 5 ℃; then, a solution of (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobut-2-enoyl) -2-methyl-benzonitrile (43.7g, product of example two) in THF (160mL) was added dropwise to the reaction system, and after the dropwise addition was completed, the system was slowly warmed to room temperature and stirred for 6 hours. Then removing the solvent in the system under high vacuum and reduced pressure, adding ethyl acetate (300mL) and water (300mL) into the residue, fully stirring, standing for layering, extracting the water phase for 1 time (100mL) with ethyl acetate, combining the organic phases, removing the solvent by organic phase under reduced pressure, adding ethyl acetate (200mL) into the residue, slowly dropwise adding n-heptane (500mL) after the system is heated and dissolved, slowly and naturally cooling the system to 0 ℃ after dropwise adding, stirring and crystallizing for 3 hours at 0 ℃, filtering by a Buchner funnel, leaching the filter cake with pre-cooled n-heptane (50mL), drying and drying the obtained solid for 8.0 hours in a blowing drying box at 50 ℃ to obtain 4- (5- (3, 5-)Dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile (light yellow solid, 37.8g, 79.4% (two-step combined yield)).
Example IV preparation of Fluralarana
Sequentially adding Zn (OTf) into a pressure-resistant reaction bottle2(1.82g,5.0mmol), hydroxylamine hydrochloride (350mg,5.04mmol), 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile (20.0g,50.1mmol), 2-amino-N- (2,2, 2-trifluoroethyl) acetamide (9.4g,60.2mmol), H2O (1.5g) and xylene (40mL), and the reaction system was sealed and heated to about 110 ℃ for 8 hours. The system is naturally cooled, the solvent is removed under high vacuum, the residue is dissolved by adding ethyl acetate (200mL), the solution is filtered, and the solvent is removed from the filtrate under reduced pressure. The residue was recrystallized by addition of ethyl acetate/heptane (50mL/150mL) to yield frataxin (pale yellow solid, 24.7g, 88.6%).
Claims (8)
1. A process for the preparation of flurarana. In particular to a method for preparing 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile from 1- (3, 5-dichlorophenyl) -2,2, 2-trifluoroethyl-1-ketone and 4-acetyl-2-methylbenzonitrile under the action of a solvent and alkali; preparing 4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluoro-3-hydroxybutyryl) -2-methylbenzonitrile under the action of a solvent and a dehydration reagent to obtain (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobutan-2-enoyl) -2-methyl-benzonitrile; (Z) -4- (3- (3, 5-dichlorophenyl) -4,4, 4-trifluorobut-2-enoyl) -2-methyl-benzonitrile is reacted with hydroxylamine hydrochloride to give 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile; 4- (5- (3, 5-dichlorophenyl) -5- (trifluoromethyl) -4, 5-dihydroisoxazol-3-yl) -2-methyl-benzonitrile and 2-amino-N- (2,2, 2-trifluoroethyl) acetamide react under the action of a reagent and a solvent to prepare the frataxin. The reaction formula is as follows:
2. the method of claim 1, wherein the solvent used in step 1 comprises toluene, xylene, mesitylene, acetonitrile, 1, 4-dioxane, THF, 2-MeTHF, or a mixture thereof.
3. The process of claim 1, wherein the base used in step 1 comprises triethylamine, DIPEA, DABCO, DBU, DMAP, N-methylmorpholine, pyridine.
4. The method of claim 1, wherein the solvent used in step 2 comprises toluene, xylene, THF, 2-MeTHF, 1, 4-dioxane, acetonitrile, or a mixture thereof.
5. The method of claim 1, wherein the reagent used in step 2 comprises SOCl2、Ac2O and a catalytic amount of DMAP.
6. The method of claim 1, wherein the solvent used in step 3 comprises THF, 2-MeTHF, 1, 4-dioxane, acetonitrile, or a mixture thereof.
7. The method of claim 1, wherein the reagent used in step 4 is Zn (OTf)2Hydroxylamine hydrochloride.
8. The method of claim 1, wherein the solvent used in step 4 comprises 1, 4-dioxane, H2O, xylene, THF, 2-MeTHF, DMSO, and a mixed solvent of any combination of these solvents.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114315748A (en) * | 2021-12-29 | 2022-04-12 | 江苏天和制药有限公司 | Synthesis method of flurarana |
| CN118047728A (en) * | 2024-04-15 | 2024-05-17 | 南京道尔医药研究院有限公司 | Preparation method of fluororalrana |
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| CN101827831A (en) * | 2007-10-16 | 2010-09-08 | 先正达参股股份有限公司 | Insecticidal compounds |
| US20110257011A1 (en) * | 2008-12-23 | 2011-10-20 | Basf Se | Substituted Amidine Compounds for Combating Animal Pests |
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| WO2021038501A1 (en) * | 2019-08-29 | 2021-03-04 | Pi Industries Ltd. | Isoxazoline compounds and their use as pest control agents |
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2021
- 2021-08-20 CN CN202110957670.2A patent/CN113512007A/en active Pending
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| US6376530B1 (en) * | 1999-05-10 | 2002-04-23 | Merck & Co., Inc. | Cyclic amidines useful as NMDA NR2B antagonists |
| EP2172462A1 (en) * | 2007-06-27 | 2010-04-07 | Nissan Chemical Industries, Ltd. | Method for production of 3-hydroxypropan-1-one compound, method for production of 2-propen-1-one compound, and method for production of isoxazoline compound |
| CN101827831A (en) * | 2007-10-16 | 2010-09-08 | 先正达参股股份有限公司 | Insecticidal compounds |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN114315748A (en) * | 2021-12-29 | 2022-04-12 | 江苏天和制药有限公司 | Synthesis method of flurarana |
| CN118047728A (en) * | 2024-04-15 | 2024-05-17 | 南京道尔医药研究院有限公司 | Preparation method of fluororalrana |
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