WO2022016490A1 - Process for lotilaner intermediate - Google Patents

Process for lotilaner intermediate Download PDF

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Publication number
WO2022016490A1
WO2022016490A1 PCT/CN2020/104035 CN2020104035W WO2022016490A1 WO 2022016490 A1 WO2022016490 A1 WO 2022016490A1 CN 2020104035 W CN2020104035 W CN 2020104035W WO 2022016490 A1 WO2022016490 A1 WO 2022016490A1
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WO
WIPO (PCT)
Prior art keywords
methyl
trifluoromethyl
trichlorophenyl
isoxazol
thiophene
Prior art date
Application number
PCT/CN2020/104035
Other languages
French (fr)
Inventor
Jing Chen
Xin Zhang
Ping Huang
Original Assignee
Elanco Us Inc.
Elanco (Shanghai) Animal Health Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Elanco Us Inc., Elanco (Shanghai) Animal Health Co., Ltd. filed Critical Elanco Us Inc.
Priority to PCT/CN2020/104035 priority Critical patent/WO2022016490A1/en
Priority to US18/006,277 priority patent/US20230257370A1/en
Priority to EP21755236.3A priority patent/EP4185585A1/en
Priority to JP2023503451A priority patent/JP2023536070A/en
Priority to MX2023000936A priority patent/MX2023000936A/en
Priority to KR1020237005836A priority patent/KR20230043904A/en
Priority to AU2021311722A priority patent/AU2021311722A1/en
Priority to CN202180061376.1A priority patent/CN116194450A/en
Priority to CA3185969A priority patent/CA3185969A1/en
Priority to PCT/US2021/042769 priority patent/WO2022020585A1/en
Priority to TW110127208A priority patent/TW202212336A/en
Publication of WO2022016490A1 publication Critical patent/WO2022016490A1/en

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    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D413/00Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond

Definitions

  • Lotilaner inhibits insect and acarine gamma-aminobutyric acid (GABA) -gated chloride channels. This inhibition blocks the transfer of chloride ions across cell membranes, which results in the death of insects and acarines.
  • GABA gamma-aminobutyric acid
  • lotilaner is useful in the treatment of ectoparasites, such as flea infestations and the treatment and control of tick infestations in animals including humans, farm animals including fish, and domestic animals, especially in dogs.
  • Scheme 1 depicts coupling the compound of formula (5) with an appropriate amine to give lotilaner.
  • An appropriate amine refers to either 2-amino-2', 2', 2'-trifluoroethyl-acetamide or the sequential reaction of glycine optionally carboxyl protected, followed by coupling with 2, 2, 2-trifluorethylamine.
  • Such coupling reactions of carboxylic acids or activated carboxylic acid derivatives such as acid halides with amines to form amides are well known in the art.
  • the use of carboxyl protected glycine, deprotection, and an amide coupling with 2, 2, 2-trifluorethylamine is likewise readily accomplished. See WO 2010/070068 and WO 2014/090918.
  • the present invention provides a process for improving the enantiomeric purity of a compound of formula (5) , 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid, comprising: crystallization from a solvent (s) selected from the group consisting of C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone.
  • a solvent selected from the group consisting of C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone.
  • the enantiomeric purity of a compound of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid may be improved by crystallization under controlled conditions by crystallization from a solvent or a mixture of solvents.
  • C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone are useful solvents for such purification.
  • the present invention provides a process for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 2-5 alkyl cyanide.
  • the C 2-5 alkyl cyanide is acetonitrile.
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (the compound of formula (5) ) comprising: crystallization from a C 1-5 alcohol.
  • the C 1-5 alcohol is isopropanol.
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone.
  • the C 3-9 alkyl ketone is acetone.
  • the term “enantiomerically pure” refers to the (S) -enantiomer that is greater than 95%, that is, an 90%enantiomeric excess or 95% (S) -enantiomer and 5%(R) -enantiomer. In one embodiment, the term “enantiomerically pure” refers to the (S) -enantiomer that is present in greater than 94%and 6% (R) -enantiomer. In one embodiment, the term “enantiomerically pure” refers to the (S) -enantiomer that is present in greater than 96%and 4% (R) -enantiomer. In one embodiment, the term “enantiomerically pure” refers to the (S) -enantiomer that is present in greater than 98%and 2% (R) -enantiomer.
  • an anti-solvent refers to a solvent in which a compound of formula (5) is significantly less soluble relative to the selected solvent (s) .
  • an anti-solvent when used it is miscible with the selected solvent.
  • a solvent selected from the group consisting of C 1-5 alcohol, C 2-8 alkyl ether, C 2-8 alkyl acetate, and C 3-9 alkyl ketone, further comprising an anti-solvent.
  • a preferred anti-solvent is water.
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (the compound of formula (5) ) comprising: crystallization from a C 1-5 alcohol/water.
  • the ratio of C 1-5 alcohol to water is about 9: 1 (v/v) .
  • the C 1-5 alcohol is isopropanol.
  • the C 1-5 alcohol is isopropanol and ratio of isopropanol to water is 9: 1(v/v) .
  • the present invention provides a process for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 1-5 alcohol/water.
  • the ratio of C 1-5 alcohol to water is about 9: 1 (v/v) .
  • the C 1-5 alcohol is isopropanol.
  • the C 1-5 alcohol is isopropanol and ratio of isopropanol to water is 9: 1 (v/v) .
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone/water.
  • the ratio of C 3-9 alkyl ketone to water is about 9: 1 (v/v) .
  • the C 3-9 alkyl ketone is acetone.
  • the C 3-9 alkyl ketone is acetone and ratio of acetone to water is 9: 1 (v/v) .
  • the present invention provides a process for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone/water.
  • the ratio of C 3-9 alkyl ketone to water is about 9: 1 (v/v) .
  • the C 3-9 alkyl ketone is acetone.
  • the C 3-9 alkyl ketone is acetone and ratio of acetone to water is 9: 1 (v/v) .
  • Preferred anti-solvents are C 5-8 hydrocarbon.
  • preferred anti-solvents are selected from the group consisting of water, pentane, hexane, heptane, cyclohexane, and methylcyclohexane.
  • a particularly preferred anti-solvent is methylcyclohexane.
  • the ratio of selected solvent and anti-solvent is not critical and typically ranges from 2: 1 to 1: 6 (v/v) .
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 1-5 alcohol and a C 5-8 hydrocarbon.
  • the C 1-5 alcohol is selected from the group consisting of ethanol and isopropanol.
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 2-8 alkyl ether and a C 5-8 hydrocarbon.
  • the C 2-8 alkyl ether is selected from the group consisting of tetrahydrofuran and 2-methyltetrahydrofuran.
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 2-8 alkyl acetate and a C 5-8 hydrocarbon.
  • the C 2-8 alkyl acetate is selected from the group consisting of ethyl acetate and isopropyl acetate.
  • the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene- 2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone and a C 5-8 hydrocarbon.
  • the C 3-9 alkyl ketone is selected from the group consisting of acetone and methyl ethyl ketone.
  • an appropriate amine refers to either 2-amino-2', 2', 2'-trifluoroethyl-acetamide or the sequential reaction of glycine optionally carboxyl protected, followed by elaboration with 2, 2, 2-trifluorethylamine.
  • C 1-5 alcohol refers to a straight or branched alkanol having from one to five carbon atoms, for example methanol, ethanol, n-propanol, iso-propanol, 1-butanol, 1, 3-propanediol, and the like.
  • C 2-5 alkyl cyanide refers to straight or branched alkyl cyanides having a total of two to five carbon atoms, for example acetonitrile, proprionitrile, and butyronitrile.
  • C 3-9 alkyl ketone refers to a straight, branched, or cyclic alkyl group having an oxo group and having a total of from three to nine carbon atoms, for example acetone, methyl ethyl ketone, and cyclohexanone.
  • C 2-8 alkyl ether refers to a straight, branched, or cyclic alkyl ether having a total of from two to eight carbon atoms, for example diethyl ether, methyl t-butyl ether, THF, 2-methyl THF, dioxane, and the like.
  • C 3-8 alkyl acetate refers to straight or branched alkyl esters of acetic acid having a total of three to eight carbons, for example, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and the like.
  • C 5-8 hydrocarbon refers to a straight, branched, or cyclic saturated alkyl hydrocarbon, for example, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, methyl cyclohexane and the like.
  • reaction mixture was stirred at 30°C for 30 minutes and then cooled to the range of-20°C then slowly added a solution of hydroxylamine in water (50%, 40 mL, 313 mmol, 3.0 eq. ) and sodium hydroxide (34.5 mL, 345 mmol, 10 M, 3.3 eq. ) maintaining an internal temperature in the range of-15°C to-20°C.
  • aqueous hydrochloric acid (1N, 500 mL) was added and the reaction mixture was stirred at 15°C to 20°C then the stirring was stopped and after 30 minutes the phases were separated.
  • the organic layer was extracted with aqueous hydrochloric acid (1N, 75 mL) , the layers separated and the organic layer again extracted with aqueous hydrochloric acid (1N, 100 mL) .
  • the organic layer was separated and extracted with saturated aqueous sodium bicarbonate (75 mL) and the layers were separated and again the organic layer was extracted with saturated aqueous sodium bicarbonate (100 mL) .
  • the layers were separated and the organic layer was dried over sodium sulfate (10 g) .
  • the organic layer was filtered, the cake washed with ethyl t-butyl ether (50 mL) and then montmorillonite clay (50 g) was added and the mixture was stirred at 10°C to 20°C.
  • the reaction mixture was stirred at 0°C to 5°C for 2 hours and an 8%aqueous sodium chloride solution (601 g) was added dropwise at below 10°C, followed by addition of 37%aqueous HCl solution (92.5 g) at below 0°C.
  • the reaction mixture was stirred at 10°C to 15°C for 30 minutes then the stirring was stopped and after 30 minutes the phases were separated.
  • the organic layer was concentrated to about 370 mL under vacuum, followed by three iterations of THF (1850 mL) addition and concentration under vacuum to about 370 mL to 555 mL.
  • the crude product was dissolved in 50mL of EA and 100mL of heptane at 40°C. Additional 1000mL of heptane was charged dropwise into the mixture slowly. Then the mixture was stirred at 40°C for 15h. The mixture was filtered and the wet cake was obtained. The wet cake was slurried by acetone at 20°C. The mixture was filter and the wet cake was dried at 50°C under vacuum for 3h to afford 9.7g of product. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.
  • n-Heptane 1000 mL was added dropwise and the mixture was stirred at 55°C for three hours. The batch was gradually cooled to 35°C over three hours, then to 20°C over three hours. The batch was filtered and the cake was washed with n-heptane (200 mL) . 113 g of the title compound was obtained after drying at 50°C under vacuum for 12 hours.
  • a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a solvent selected from C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone.
  • Clause 4 The process of any one of clauses 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 98%or greater.
  • Clause 7 A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 98%or greater enantiomeric purity.
  • Clause 8 A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 99%or greater enantiomeric purity.
  • a composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 99.9%or greater enantiomeric purity.
  • Clause 10 The composition of any one of clauses 7-9, wherein the 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is crystalline.
  • Clause 11 A composition comprising lotilaner in 98%or greater enantiomeric purity.
  • Clause 13 A composition comprising lotilaner in 99.9%or greater enantiomeric purity.
  • Clause 14 A method of treating or preventing flea infestations, comprising administering a therapeutically effective amount to a patient in need thereof a composition comprising lotilaner in 98%or greater enantiomeric purity.
  • Clause 15 The method of clause 14, wherein the lotilaner is in 99%or greater enantiomeric purity.
  • Clause 16 The method of clause 14, wherein the lotilaner is in 99.9%or greater enantiomeric purity.
  • Clause 17 A method of treating or controlling tick infestations, comprising administering a therapeutically effective amount to a patient in need thereof a composition comprising lotilaner in 98%or greater enantiomeric purity.
  • Clause 18 The method of clause 17, wherein the lotilaner is in 99%or greater enantiomeric purity.
  • Clause 19 The method of clause 17, wherein the lotilaner is in 99.9%or greater enantiomeric purity.
  • Clause 20 The method of any one of clauses 14-19, wherein the patient is a dog.
  • Clause 21 The method of any one of clauses 14-19, wherein the patient is a cat.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

The present invention provides processes for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5-[(5S)-5-(3,4,5-trichlorophenyl)-5-(trifluoromethyl)-4H-isoxazol-3-yl]thiophene-2-carboxylic acid by crystallization.

Description

PROCESS FOR LOTILANER INTERMEDIATE
Lotilaner, 5- [ (5S) -4, 5-dihydro-5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -3-isoxazolyl] -3-methyl-N- [2-oxo-2- [ (2, 2, 2-trifluoroethyl) amino] ethyl] -2-thiophenecarboxamide, also known as (S) -5- [5- (3, 4, 5-trichloro-phenyl) -5-trifluoromethyl-4, 5-dihydro-isoxazol-3-yl] -3-methyl-thiophene-2-carboxylic acid [ (2, 2, 2-trifluoro-ethylcarbamoyl) -methyl] -amide, is the compound of formula (1) shown below:
Figure PCTCN2020104035-appb-000001
and is useful in pest control, in particular in the control of ectoparasites. Lotilaner inhibits insect and acarine gamma-aminobutyric acid (GABA) -gated chloride channels. This inhibition blocks the transfer of chloride ions across cell membranes, which results in the death of insects and acarines. In particular, lotilaner is useful in the treatment of ectoparasites, such as flea infestations and the treatment and control of tick infestations in animals including humans, farm animals including fish, and domestic animals, especially in dogs.
Manufacture of pure enantiomers is expensive and time-consuming. A method for the preparation of lotilaner is described in WO 2014/090918 in which the (S) -enantiomer is prepared by resolution of the carboxylic acid below:
Figure PCTCN2020104035-appb-000002
by crystallization of a diastereomeric salt followed by repeated cycles of racemization followed be further resolution by diastereomeric salt formation. The method of resolution and cycles of racemization and resolution is labor intensive and costly. Direct formation of the desired (S) -enantiomer is advantageous. Direct formation of enantiomers of certain  5-aryl-5-trifluoromethyl-4, 5-dihydro-isoxazoles are known in the art, including those described in US2014/0206633, US 2014/0350261, WO 2013/116236, WO 2014/081800, Angew, Chem. Int. Ed. 2010, 49, 5762-7566, and WO 2017/176948.
One method for preparing lotilaner is illustrated by Scheme 1.
Scheme 1
Figure PCTCN2020104035-appb-000003
Scheme 1 depicts coupling the compound of formula (5) with an appropriate amine to give lotilaner. An appropriate amine refers to either 2-amino-2', 2', 2'-trifluoroethyl-acetamide or the sequential reaction of glycine optionally carboxyl protected, followed by coupling with 2, 2, 2-trifluorethylamine. Such coupling reactions of carboxylic acids or activated carboxylic acid derivatives such as acid halides with amines to form amides are well known in the art. The use of carboxyl protected glycine, deprotection, and an amide coupling with 2, 2, 2-trifluorethylamine is likewise readily accomplished. See WO 2010/070068 and WO 2014/090918.
The present invention provides a process for improving the enantiomeric purity of a compound of formula (5) , 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid, comprising: crystallization from a solvent (s) selected from the group consisting of C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone.
The enantiomeric purity of a compound of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid may be improved by crystallization under controlled conditions by crystallization from a solvent or a mixture of solvents. In practice it has been found that C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone are useful solvents for such purification.
Thus, the present invention provides a process for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 2-5 alkyl cyanide. In a preferred embodiment the C 2-5 alkyl cyanide is acetonitrile.
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (the compound of formula (5) ) comprising: crystallization from a C 1-5 alcohol. In a preferred embodiment the C 1-5 alcohol is isopropanol.
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone. In a preferred embodiment the C 3-9 alkyl ketone is acetone.
As used herein, the term “enantiomerically pure” refers to the (S) -enantiomer that is greater than 95%, that is, an 90%enantiomeric excess or 95% (S) -enantiomer and 5%(R) -enantiomer. In one embodiment, the term “enantiomerically pure” refers to the (S) -enantiomer that is present in greater than 94%and 6% (R) -enantiomer. In one embodiment, the term “enantiomerically pure” refers to the (S) -enantiomer that is present in greater than 96%and 4% (R) -enantiomer. In one embodiment, the term “enantiomerically pure” refers to the (S) -enantiomer that is present in greater than 98%and 2% (R) -enantiomer.
The use of an anti-solvent may be advantageous. As used in this context an “anti-solvent” refers to a solvent in which a compound of formula (5) is significantly less soluble relative to the selected solvent (s) . Preferably, when an anti-solvent is used it is miscible with the selected solvent.
Also provided is a process for improving the enantiomeric purity of a compound of formula (5) , above, comprising: crystallization from a solvent (s) selected from the group consisting of C 1-5 alcohol, C 2-8 alkyl ether, C 2-8 alkyl acetate, and C 3-9 alkyl ketone, further comprising an anti-solvent. A preferred anti-solvent is water.
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (the compound of formula (5) ) comprising: crystallization from a C 1-5 alcohol/water. In a preferred embodiment the ratio of C 1-5 alcohol to water is about 9: 1 (v/v) . In a preferred embodiment the C 1-5 alcohol is isopropanol. In an even more preferred embodiment the C 1-5 alcohol is isopropanol and ratio of isopropanol to water is 9: 1(v/v) .
Thus, the present invention provides a process for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 1-5 alcohol/water. In a preferred embodiment the ratio of C 1-5 alcohol to water is about 9: 1 (v/v) . In a preferred embodiment the C 1-5 alcohol is isopropanol. In an even more preferred embodiment the C 1-5 alcohol is isopropanol and ratio of isopropanol to water is 9: 1 (v/v) .
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone/water. In a preferred embodiment the ratio of C 3-9 alkyl ketone to water is about 9: 1 (v/v) . In a preferred embodiment the C 3-9 alkyl ketone is acetone. In an even more preferred embodiment the C 3-9 alkyl ketone is acetone and ratio of acetone to water is 9: 1 (v/v) .
Thus, the present invention provides a process for making enatiomerically pure lotilaner characterized by improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid  comprising: crystallization from a C 3-9 alkyl ketone/water. In a preferred embodiment the ratio of C 3-9 alkyl ketone to water is about 9: 1 (v/v) . In a preferred embodiment the C 3-9 alkyl ketone is acetone. In an even more preferred embodiment the C 3-9 alkyl ketone is acetone and ratio of acetone to water is 9: 1 (v/v) .
Preferred anti-solvents are C 5-8 hydrocarbon. In particular, preferred anti-solvents are selected from the group consisting of water, pentane, hexane, heptane, cyclohexane, and methylcyclohexane. A particularly preferred anti-solvent is methylcyclohexane. The ratio of selected solvent and anti-solvent is not critical and typically ranges from 2: 1 to 1: 6 (v/v) .
Thus, the present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 1-5 alcohol and a C 5-8 hydrocarbon. In a preferred embodiment the C 1-5 alcohol is selected from the group consisting of ethanol and isopropanol.
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 2-8 alkyl ether and a C 5-8 hydrocarbon. In a preferred embodiment the C 2-8 alkyl ether is selected from the group consisting of tetrahydrofuran and 2-methyltetrahydrofuran.
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a C 2-8 alkyl acetate and a C 5-8 hydrocarbon. In a preferred embodiment the C 2-8 alkyl acetate is selected from the group consisting of ethyl acetate and isopropyl acetate.
The present invention provides a process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene- 2-carboxylic acid comprising: crystallization from a C 3-9 alkyl ketone and a C 5-8 hydrocarbon. In a preferred embodiment the C 3-9 alkyl ketone is selected from the group consisting of acetone and methyl ethyl ketone.
The term “an appropriate amine” refers to either 2-amino-2', 2', 2'-trifluoroethyl-acetamide or the sequential reaction of glycine optionally carboxyl protected, followed by elaboration with 2, 2, 2-trifluorethylamine.
The term “about” when used in connection with a measurable numerical variable, refers to the indicated value of the variable and to all values of the variable that are within the experimental error of the indicated value or within±10 percent of the indicated value, whichever is greater.
The term “C 1-5 alcohol” refers to a straight or branched alkanol having from one to five carbon atoms, for example methanol, ethanol, n-propanol, iso-propanol, 1-butanol, 1, 3-propanediol, and the like.
The term “C 2-5 alkyl cyanide” refers to straight or branched alkyl cyanides having a total of two to five carbon atoms, for example acetonitrile, proprionitrile, and butyronitrile.
The term “C 3-9 alkyl ketone” refers to a straight, branched, or cyclic alkyl group having an oxo group and having a total of from three to nine carbon atoms, for example acetone, methyl ethyl ketone, and cyclohexanone.
The term “C 2-8 alkyl ether” refers to a straight, branched, or cyclic alkyl ether having a total of from two to eight carbon atoms, for example diethyl ether, methyl t-butyl ether, THF, 2-methyl THF, dioxane, and the like.
The term “C 3-8 alkyl acetate” refers to straight or branched alkyl esters of acetic acid having a total of three to eight carbons, for example, methyl acetate, ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, and the like.
The term “C 5-8 hydrocarbon” refers to a straight, branched, or cyclic saturated alkyl hydrocarbon, for example, pentane, hexane, heptane, octane, cyclopentane, cyclohexane, methyl cyclohexane and the like.
It is understood that the terms “crystallize, ” “crystallizing, ” and “crystallization” refer to complete dissolution followed by precipitation and slurry processes that do not involve complete dissolution. Slurry processes include those that encompass continuation of stirring following precipitation after complete dissolution.
The invention is still further illustrated by the following examples. The examples are intended to be illustrative only and not intended to limit the invention in any way.
Example 1
(5S) -3- (5-Bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H- isoxazole
Figure PCTCN2020104035-appb-000004
Combined (Z/E) 1- (5-bromo-4-methyl-2-thienyl) -4, 4, 4-trifluoro-3- (3, 4, 5-trichlorophenyl) but-2-en-1-one (50.0 g, 104.5 mmol) and (R) - [ (2S) -1- [ [3, 5-bis (tert-butyl) phenyl] methyl] -5-vinyl-quinuclidin-1-ium-2-yl] - (6-methoxy-4-quinolyl) methanol bromide (0.11 eq. ) in dichloromethane (100 mL) and ethyl t-butyl ether (400 mL) . The reaction mixture was stirred at 30℃ for 30 minutes and then cooled to the range of-20℃ then slowly added a solution of hydroxylamine in water (50%, 40 mL, 313 mmol, 3.0 eq. ) and sodium hydroxide (34.5 mL, 345 mmol, 10 M, 3.3 eq. ) maintaining an internal temperature in the range of-15℃ to-20℃. After stirring 18 hours at-15℃ to-20℃ aqueous hydrochloric acid (1N, 500 mL) was added and the reaction mixture was stirred at 15℃ to 20℃ then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with aqueous hydrochloric acid (1N, 75 mL) ,  the layers separated and the organic layer again extracted with aqueous hydrochloric acid (1N, 100 mL) . The organic layer was separated and extracted with saturated aqueous sodium bicarbonate (75 mL) and the layers were separated and again the organic layer was extracted with saturated aqueous sodium bicarbonate (100 mL) . The layers were separated and the organic layer was dried over sodium sulfate (10 g) . The organic layer was filtered, the cake washed with ethyl t-butyl ether (50 mL) and then montmorillonite clay (50 g) was added and the mixture was stirred at 10℃ to 20℃. After 2 hours the reaction mixture was filtered, the cake rinsed with ethyl t-butyl ether (50 mL) and the filtrate was concentrated to about 100 mL, twice added THF and concentrated again to about 100 mL, and then added THF (150 mL) to obtain the title compound as a solution in THF. The solution was evaluated by chiral HPLC which indicated 96.5%S-isomer and 3.5%R-isomer.
Example 2
3-Methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3- yl] thiophene-2-carboxylic acid
Figure PCTCN2020104035-appb-000005
A 22%solution of (5S) -3- (5-bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazole (185.0 g, 374.8 mmol) in THF was cooled to 0℃ to 5℃. A solution of ethyl magnesium chloride in THF (2 M, 300 mL, 1.6 eq) was added dropwise maintaining an internal temperature below 10℃. The reaction mixture was stirred at 15℃ to 20℃ for 2 to 4 hours. Then carbon dioxide gas (58 g, 3.5 eq) was introduced subsurface at 0℃ to 5℃ after passing through concentrated sulfuric acid (50 mL) . The reaction mixture was stirred at 0℃ to 5℃ for 2 hours and an 8%aqueous sodium chloride solution (601 g) was added dropwise at below 10℃, followed by addition of 37%aqueous HCl solution (92.5 g) at below 0℃. The reaction mixture was stirred at 10℃ to 15℃ for 30 minutes then the stirring was stopped and after 30 minutes  the phases were separated. The organic layer was concentrated to about 370 mL under vacuum, followed by three iterations of THF (1850 mL) addition and concentration under vacuum to about 370 mL to 555 mL. After confirming the reaction mixture was dry, three cycles of acetonitrile (925 mL) addition followed by vacuum concentration to about 555 mL to 740 mL were performed. The reaction mixture was heated to 75℃ and gradually cooled to 50℃ over one hour. Product seeds (1.85 g) were added at 50℃ and the reaction mixture was stirred at 50℃ for 30 minutes. The batch was gradually cooled to-10℃ over three hours and kept at-10℃ for two hours. The batch was filtered and the cake was washed with cold acetonitrile (93 to 185 mL) . 110 g of the title compound was obtained after drying the wet cake at 50℃ under vacuum for 12 hours. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.
Above-referenced product seeds were prepared as follows. A solution of (5S) -3- (5-bromo-4-methyl-2-thienyl) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazole (48.93 g, 99.1 mmol) in 300mL of THF was cooled to 0℃ to 5℃. A solution of ethyl magnesium chloride in THF (2 M, 80 mL) was added dropwise maintaining an internal temperature below 10℃. The reaction mixture was stirred at 15℃ to 20℃ for 2 to 4 hours. Then carbon dioxide gas (25 g, 3.5 eq) was introduced subsurface at 0℃ to 5℃ after passing through concentrated sulfuric acid (50 mL) . The reaction mixture was stirred at 0℃ to 5℃ for 6 hours and an 5%aqueous sodium chloride solution (157 g) was added dropwise at below 10℃, followed by addition of 37%aqueous HCl solution (25 g) at below 0℃. The reaction mixture was stirred at 10℃ to 15℃ for 30 minutes then the stirring was stopped and after 30 minutes the phases were separated. The organic layer was concentrated to remove the solvent. 50ml of heptane was added into the mixture then removed the solvent. The crude product was dissolved in 50mL of EA and 100mL of heptane at 40℃. Additional 1000mL of heptane was charged dropwise into the mixture slowly. Then the mixture was stirred at 40℃ for 15h. The mixture was filtered and the wet cake was obtained. The wet cake was slurried by acetone at 20℃. The mixture was filter and the wet cake was dried at 50℃ under vacuum for 3h to afford 9.7g of product. The product was evaluated by chiral HPLC which indicated>99.9%S-isomer.
Example 3
3-Methyl-N- [2-oxo-2- (2, 2, 2-trifluoroethylamino) ethyl] -5- [ (5S) -5- (3, 4, 5-trichlorophenyl) - 5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxamide
Figure PCTCN2020104035-appb-000006
A solution of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid (101.5 g, 221.3 mmol) in DCM (1000 mL) was heated to 40℃. Thionyl chloride (50 g, 1.9 eq) was added dropwise and the reaction mixture was stirred at reflux for 2 to 4 hours. The reaction mixture was concentrated to 100 to 200 mL and DCM (500 mL) was added. Two more cycles of concentration followed by DCM addition were performed. In a separate vessel, a suspension of 2-amino-trifluoroethyl-acetamide HCl (50.26 g, 1.2 eq) in DCM (500 mL) was cooled to 0℃ to 5℃, triethylamine (70.15 g, 3.1 eq) was added, and the reaction mixture was stirred at 0℃ to 5℃ for 30 minutes. The acid chloride solution in DCM was then transferred to the reaction mixture containing 2-amino-trifluoroethyl-acetamide maintaining the internal temperature below 5℃. The reaction mixture was stirred at 0℃ to 5℃ for 2 to 4 hours. 1 N HCl (500 mL) was added dropwise and the reaction mixture was stirred at 15 to 25℃ for 30 minutes. The stirring was stopped and after 30 minutes the phases were separated. The organic layer was extracted with saturated sodium bicarbonate solution (1N, 1000 mL) , the layers separated and the organic layer extracted with water (1000 mL) . The layers were separated and the organic layer was concentrated under vacuum to 200 to 300 mL. Twice ethyl acetate (500 mL) was added and the batch was concentrated to 200 mL. The reaction mixture was heated to 55℃ and n-heptane (700 mL) was added dropwise at 55℃. Product seeds (1.0 g) was added and the reaction mixture was stirred at 55℃ for one hour. n-Heptane (1000 mL) was added dropwise and the mixture was stirred at 55℃ for three hours. The batch was gradually cooled to 35℃ over three hours, then to 20℃ over three hours. The batch was filtered and the cake was washed with n-heptane (200 mL) . 113 g of the title compound was obtained after drying at 50℃ under vacuum for 12 hours.
Above-referenced product seeds are prepared as follows. The crude product was dissolved in 7.9 wt-parts of cumene to obtain a solution at<150℃. Then 2.3 wt-parts of heptanes was added to the hot solution until slight haze was observed. The heating was turned off and the mixture was cooled to ambient temperature and stirred overnight. The desired polymorph G was obtained as powder after filtration and drying under vacuum, which was used as seeds to induce crystallization of polymorph G in future batches.
For reasons of completeness, various aspects of the disclosure are set out in the following numbered clauses.
Clause 1. A process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a solvent selected from C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone.
Clause 2. The process according to clause 1 wherein the solvent is C 2-5 alkyl cyanide.
Clause 3. The process according to clause 2 wherein the C 2-5 alkyl cyanide is acetonitrile.
Clause 4. The process of any one of clauses 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 98%or greater.
Clause 5. The process of any one of clauses 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 99%or greater.
Clause 6. The process of any one of clauses 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 99.9%or greater.
Clause 7. A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 98%or greater enantiomeric purity.
Clause 8. A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 99%or greater enantiomeric purity.
Clause 9. A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 99.9%or greater enantiomeric purity.
Clause 10. The composition of any one of clauses 7-9, wherein the 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is crystalline.
Clause 11. A composition comprising lotilaner in 98%or greater enantiomeric purity.
Clause 12. A composition comprising lotilaner in 99%or greater enantiomeric purity.
Clause 13. A composition comprising lotilaner in 99.9%or greater enantiomeric purity.
Clause 14. A method of treating or preventing flea infestations, comprising administering a therapeutically effective amount to a patient in need thereof a composition comprising lotilaner in 98%or greater enantiomeric purity.
Clause 15. The method of clause 14, wherein the lotilaner is in 99%or greater enantiomeric purity.
Clause 16. The method of clause 14, wherein the lotilaner is in 99.9%or greater enantiomeric purity.
Clause 17. A method of treating or controlling tick infestations, comprising administering a therapeutically effective amount to a patient in need thereof a composition comprising lotilaner in 98%or greater enantiomeric purity.
Clause 18. The method of clause 17, wherein the lotilaner is in 99%or greater enantiomeric purity.
Clause 19. The method of clause 17, wherein the lotilaner is in 99.9%or greater enantiomeric purity.
Clause 20. The method of any one of clauses 14-19, wherein the patient is a dog.
Clause 21. The method of any one of clauses 14-19, wherein the patient is a cat.

Claims (8)

  1. A process for improving the enantiomeric purity of 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid comprising: crystallization from a solvent selected from C 1-5 alcohol, C 2-5 alkyl cyanide, and C 3-9 alkyl ketone.
  2. The process according to claim 1 wherein the solvent is C 2-5 alkyl cyanide.
  3. The process according to claim 2 wherein the C 2-5 alkyl cyanide is acetonitrile.
  4. The process of any one of claims 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5 S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 98%or greater.
  5. The process of any one of claims 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5 S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 99%or greater.
  6. The process of any one of claims 1-3, wherein the enantiomeric purity of the crystallized 3-methyl-5- [ (5 S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid is 99.9%or greater.
  7. A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 99%or greater enantiomeric purity.
  8. A composition comprising 3-methyl-5- [ (5S) -5- (3, 4, 5-trichlorophenyl) -5- (trifluoromethyl) -4H-isoxazol-3-yl] thiophene-2-carboxylic acid in 99.9%or greater enantiomeric purity.
PCT/CN2020/104035 2020-07-24 2020-07-24 Process for lotilaner intermediate WO2022016490A1 (en)

Priority Applications (11)

Application Number Priority Date Filing Date Title
PCT/CN2020/104035 WO2022016490A1 (en) 2020-07-24 2020-07-24 Process for lotilaner intermediate
US18/006,277 US20230257370A1 (en) 2020-07-24 2021-07-22 Process for making an isoxazoline compound and intermediate thereof
EP21755236.3A EP4185585A1 (en) 2020-07-24 2021-07-22 Process for making an isoxazoline compound and intermediate thereof
JP2023503451A JP2023536070A (en) 2020-07-24 2021-07-22 Method for making isoxazoline compounds and intermediates thereof
MX2023000936A MX2023000936A (en) 2020-07-24 2021-07-22 Process for making an isoxazoline compound and intermediate thereof.
KR1020237005836A KR20230043904A (en) 2020-07-24 2021-07-22 Process for preparing isoxazoline compounds and intermediates thereof
AU2021311722A AU2021311722A1 (en) 2020-07-24 2021-07-22 Process for making an isoxazoline compound and intermediate thereof
CN202180061376.1A CN116194450A (en) 2020-07-24 2021-07-22 Process for preparing isoxazoline compounds and intermediates thereof
CA3185969A CA3185969A1 (en) 2020-07-24 2021-07-22 Process for making an isoxazoline compound and intermediate thereof
PCT/US2021/042769 WO2022020585A1 (en) 2020-07-24 2021-07-22 Process for making an isoxazoline compound and intermediate thereof
TW110127208A TW202212336A (en) 2020-07-24 2021-07-23 Process for making an isoxazoline compound and intermediate thereof

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014090918A1 (en) * 2012-12-13 2014-06-19 Novartis Ag Process for the enantiomeric enrichment of diaryloxazoline derivatives
CN107074835A (en) * 2014-11-10 2017-08-18 瑞士诺华动物保健有限公司 Diaryl isoxazole quinoline compound
CN109328017A (en) * 2016-05-10 2019-02-12 瑞士伊兰科动物保健有限公司 For controlling the dihydro-isoxazole compound of extra large lice
CN110028462A (en) * 2019-04-12 2019-07-19 丽珠集团新北江制药股份有限公司 A method of preparing isoxazoles intermediate and isoxazoline

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014090918A1 (en) * 2012-12-13 2014-06-19 Novartis Ag Process for the enantiomeric enrichment of diaryloxazoline derivatives
CN107074835A (en) * 2014-11-10 2017-08-18 瑞士诺华动物保健有限公司 Diaryl isoxazole quinoline compound
CN109328017A (en) * 2016-05-10 2019-02-12 瑞士伊兰科动物保健有限公司 For controlling the dihydro-isoxazole compound of extra large lice
CN110028462A (en) * 2019-04-12 2019-07-19 丽珠集团新北江制药股份有限公司 A method of preparing isoxazoles intermediate and isoxazoline

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