WO2022072650A1 - Polymorphs of compounds having pesticidal activity - Google Patents

Polymorphs of compounds having pesticidal activity Download PDF

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Publication number
WO2022072650A1
WO2022072650A1 PCT/US2021/052900 US2021052900W WO2022072650A1 WO 2022072650 A1 WO2022072650 A1 WO 2022072650A1 US 2021052900 W US2021052900 W US 2021052900W WO 2022072650 A1 WO2022072650 A1 WO 2022072650A1
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ppm
polymorph form
crystalline polymorph
peaks
powder
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PCT/US2021/052900
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English (en)
French (fr)
Inventor
Pablo CABRERA VENTURA
Ricky Hunter
Paul Larsen
Jeffrey Nissen
Martin Walsh
Honglu Zhang
Tay ROSENTHAL
Abraham Schuitman
Zheyu JIANG
Fangzheng LI
Nakyen Choy
Gregory T. Whiteker
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Corteva Agriscience Llc
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Publication of WO2022072650A1 publication Critical patent/WO2022072650A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/42—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N53/00—Biocides, pest repellants or attractants, or plant growth regulators containing cyclopropane carboxylic acids or derivatives thereof
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P5/00—Nematocides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P7/00—Arthropodicides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01P—BIOCIDAL, PEST REPELLANT, PEST ATTRACTANT OR PLANT GROWTH REGULATORY ACTIVITY OF CHEMICAL COMPOUNDS OR PREPARATIONS
    • A01P9/00—Molluscicides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • This disclosure relates to polymorphic forms of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide, or a solvate or hydrate thereof, that are useful in the control of pests in Phyla Arthropoda, Mollusca, and Nematoda, processes to produce such polymorphic forms, intermediates used in such processes, pesticidal compositions containing such polymorphic forms, and processes of using such pesticidal compositions against such pests.
  • These pesticidal compositions may be used, for example, as acaricides, insecticides, miticides, molluscicides, and nematicides.
  • Plant parasitic nematodes are among the most widespread pests, and are frequently one of the most insidious and costly. It has been estimated that losses attributable to nematodes are from about 9% in developed countries to about 15% in undeveloped countries. However, in the United States of America a survey of 35 States on various crops indicated nematode-derived losses of up to 25% (Nicol et al.).
  • gastropods are pests of less economic importance than other arthropods or nematodes, but in certain places, they may reduce yields substantially, severely affecting the quality of harvested products, as well as transmitting human, animal, and plant diseases. While only a few dozen species of gastropods are serious regional pests, a handful of species are important pests on a worldwide scale. In particular, gastropods affect a wide variety of agricultural and horticultural crops, such as arable, scenic, and fiber crops; vegetables; bush and tree fruits; herbs; and ornamentals (Speiser).
  • [0010] is a potent small-molecule showing activity against a variety of pests.
  • Compounds related to Compound 1 are disclosed in International Patent Publication No. WO 2018/071327 Al and United States Patent No. 10,258,045, which are incorporated herein by reference in their entirety.
  • Compound 1 has found application as a pesticide, it is advantageous to have polymorphic forms having improved properties, such as improved crystallinity, dissolution properties, decreased hygroscopicity, and/or ease of formulation in commercially viable compositions for application in the field, while maintaining chemical and enantiomeric stability properties.
  • active ingredient means a material having activity useful in controlling pests, and/or that is useful in helping other materials have better activity in controlling pests; examples of such materials include, but are not limited to, acaricides, algicides, antifeedants, avicides, bactericides, bird repellents, chemosterilants, fungicides, herbicide safeners, herbicides, insect attractants, insect repellents, insecticides, mammal repellents, mating disrupters, molluscicides, nematicides, plant activators, plant growth regulators, rodenticides, synergists, and virucides (see alanwood.net).
  • biopesticide means a microbial biological pest control agent that, in general, is applied in a similar manner to chemical pesticides. Commonly they are bacterial, but there are also examples of fungal control agents, including Trichoderma spp. and Ampelomyces quisqualis.
  • biopesticide example is Bacillus species, a bacterial disease of Lepidoptera, Coleoptera, and Diptera.
  • Biopesticides include products based on entomopathogenic fungi (e.g. Metarhizium anisopliae), entomopathogenic nematodes (e.g. Steinernemafeltiae)' , and entomopathogenic viruses (e.g.
  • Cydia pomonella granulovirus Cydia pomonella granulovirus
  • Other examples of entomopathogenic organisms include, but are not limited to, baculoviruses, protozoa, and Microsporidia.
  • biopesticides are also referred to as active ingredients.
  • locus means a habitat, breeding ground, plant, seed, soil, material, or environment, in which a pest is growing, may grow, or may traverse.
  • a locus includes but is not limited to, areas where crops, trees, fruits, cereals, fodder species, vines, turf, and/or ornamental plants, are growing; where domesticated animals are residing; the interior or exterior surfaces of buildings (such as places where grains are stored); in and around materials of construction used in buildings (such as impregnated wood); and the soil around buildings.
  • MoA Material means an active ingredient having a mode of action (“MoA") as indicated in IRAC MoA Classification v. 7,4, located at irac-online.org.
  • the phrase "pesticidally effective amount” means the amount of a pesticide needed to achieve an observable effect on a pest, for example, the effects of necrosis, death, retardation, prevention, removal, destruction, or otherwise diminishing the occurrence and/or activity of a pest in a locus. This effect may come about when pest populations are repulsed from a locus, pests are incapacitated in, or around, a locus, and/or pests are exterminated in, or around, a locus. Of course, a combination of these effects can occur.
  • pest populations, activity, or both are desirably reduced more than fifty percent, preferably more than 90 percent, and most preferably more than 99 percent,
  • a pesticidally effective amount, for agricultural purposes is from about 0.0001 grams per hectare to about 5000 grams per hectare, preferably from about 0.0001 grams per hectare to about 500 grams per hectare, and it is even more preferably from about 0.0001 grams per hectare to about 50 grams per hectare.
  • the present disclosure provides one or more crystalline forms of 5- ((lR,3R)-3-(3,5-bis(trifhioromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2- chloro-A-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (Compound 1) represented by the formula
  • the one or more crystalline forms of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide is a solvate or hydrate.
  • the one or more crystalline forms of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-A-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide are a crystalline polymorph form of a solvate or hydrate.
  • the one or more crystalline forms of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-A-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide are anhydrous and solvent-free crystalline polymorph forms.
  • the one or more crystalline forms are crystalline polymorph forms I- VII, X, or XI (individually referred to herein as polymorph form I, polymorph form II, polymorph form III, polymorph form IV, polymorph form V, polymorph form VI, polymorph form VII, polymorph form X, and polymorph form XI) of Compound 1. It is noted that solvate polymorph forms VIII and IX, not suitable for use, were also identified , and are not described herein.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 16.8 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 15.6 + 0.2 and 16.8 + 0.2. In a further embodiment, the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 15.6 + 0.2, and 16.8 + 0.2. In a further embodiment, the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 15.6 + 0.2, 16.8 + 0.2, and 17.9 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, and 17.9 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, and 17.9 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, and 18.6 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, and 18.6 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, and
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.1 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 15.6 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 20.8 + 0.2, and 28.3 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 20.8 + 0.2, and 28.3 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 20.8 + 0.2, and 28.3 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 20.8 + 0.2, 24.2 + 0.2, and 28.3 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 20.8 + 0.2, 24.2 + 0.2, 25.5 + 0.2, and
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 24.2 + 0.2, 25.5 + 0.2, and 28.3 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X- ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 24.2 + 0.2, 25.5 + 0.2, and 28.3 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 11.6 + 0.2, 12.4 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 20.8 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 24.2 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 22.9 + 0.2, 24.2 + 0.2, 25.5 + 0.2, 28.3 + 0.2, and 31.0 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X- ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 22.9 + 0.2, 24.2 + 0.2, 25.0 + 0.2, 25.5 + 0.2, 28.3 + 0.2, and 31.0 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 22.9 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 22.9 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.6 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.1 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 19.7 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 22.9 + 0.2, 23.5 + 0.2, 24.2 + 0.2, 25.0 + 0.2, 25.5 + 0.2, 28.3 + 0.2, 29.6 + 0.2, and 31.0 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 11.1 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 19.7 + 0.2, 20.8 + 0.2, 21.5 + 0.2, 22.4 + 0.2, 22.9 + 0.2, 23.5 + 0.2, 24.2 + 0.2, 25.0 + 0.2, 25.5 + 0.2, 26.7 + 0.2, 28.3 + 0.2, 29.6 + 0.2, and 31.0 + 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.1 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2, 18.6 + 0.2, 19.7 + 0.2, 20.8 + 0.2, 21.5 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.1 + 0.2, 11.6 + 0.2, 12.4 + 0.2, 14.5 + 0.2, 15.6 + 0.2, 16.8 + 0.2, 17.9 + 0.2,
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 1.
  • the crystalline polymorph form I of Compound 1 has a Differential Scanning Calorimetry (DSC) thermogram comprising an endothermal peak having a peak temperature of about 146.7 °C.
  • the crystalline polymorph form I of Compound 1 has a DSC thermogram substantially the same as FIG. 6.
  • the crystalline polymorph form I of Compound 1 has a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 17 cm 1 , about 60 cm 1 , about 102 cm 1 , about 130 cm 1 , about 152 cm 1 , about 186 cm 1 , about 201 cm 1 , about 226 cm 1 , about 242 cm 1 , about 271 cm 1 , about 283 cm 1 , and about 301 cm 1 .
  • the crystalline polymorph form I of Compound 1 has a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 11.
  • the crystalline polymorph form I of Compound 1 has a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -58.7 ⁇ 0.2 ppm, -60.6 ⁇ 0.2 ppm, -61.8 ⁇ 0.2 ppm, -63.0 ⁇ 0.2 ppm, -124.9 ⁇ 0.2 ppm, and -128.7 ⁇ 0.2 ppm.
  • the crystalline polymorph form I of Compound 1 has a ssNMR ( 19 F) spectrum the same as shown in FIG. 16 or FIG. 17.
  • the crystalline polymorph form I further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 146.7 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers about 17 cm 1 , about 60 cm 1 , about 102 cm 1 , about 130 cm 1 , about 152 cm 1 , about 186 cm 1 , about 201 cm 1 , about 226 cm 1 , about 242 cm 1 , about 271 cm 1 , about 283 cm 1 , and about 301 cm' 1 and/or a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -58.7 ⁇ 0.2 ppm, -60.6 ⁇ 0.2 ppm, -61.8 ⁇ 0.2 ppm, -63.0 ⁇ 0.2 ppm, -124.9 ⁇ 0.2
  • the crystalline polymorph form I further comprises a DSC thermogram substantially the same as FIG. 6 and/or a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 11 and/or a ssNMR ( 19 F) spectrum the same as shown in FIG. 16 or FIG. 17.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 13.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2 and 16.8 ⁇ 0.2. In a further embodiment, the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 15.5 ⁇ 0.2, and 16.8 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, and 16.8 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, and 18.4 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.4 ⁇ 0.2, and 18.4 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, and 19.3 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, and 19.3 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, and 19.3 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.8 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, and 19.3 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 16.8 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 18.4 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 22.3 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, and 26.9 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2,
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2,
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 26.9 ⁇ 0.2, and 31.1 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, and 31.1 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 13.9 ⁇ 0.2,
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, and 31.1 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, and 31.1 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 12.6 ⁇ 0.2,
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 17.9 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 25.3 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, and 31.1 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 10.7 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 17.9 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 25.3 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, and 31.1 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 10.7 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 17.9 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 25.3 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, 31.1 ⁇ 0.2, and 32.4 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 10.7 ⁇ 0.2,
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 10.7 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 17.9 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 25.3 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, 29.7 ⁇ 0.2, 31.1 ⁇ 0.2, and 32.4 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 7.0 ⁇ 0.2, 8.9 ⁇ 0.2,
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 2.
  • the crystalline polymorph form II of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 189.3 °C.
  • the crystalline polymorph form II of Compound 1 has a DSC thermogram substantially the same as FIG. 7.
  • the crystalline polymorph form II of Compound 1 has a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 9 cm 1 , about 16 cm 1 , about 54 cm 1 , about 104 cm 1 , about 155 cm 1 , about 194 cm 1 , about 217 cm 1 , about 233 cm 1 , about 274 cm 1 , and about 309 cm 1 .
  • the crystalline polymorph form II of Compound 1 has a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 12.
  • the crystalline polymorph form II of Compound 1 has a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -61.8 ⁇ 0.2, -63.7 ⁇ 0.2, -65.8 ⁇ 0.2, -66.6 ⁇ 0.2, -67.4 ⁇ 0.2, -68.2 ⁇ 0.2, -120.6 ⁇ 0.2, -122.5 ⁇ 0.2, and -128.7 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a ssNMR ( 19 F) spectrum the same as shown in FIG. 18 or FIG. 19.
  • the crystalline polymorph form II further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 189.3 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 9 cm 1 , about 16 cm 1 , about 54 cm 1 , about 104 cm 1 , about 155 cm 1 , about 194 cm 1 , about 217 cm 1 , about 233 cm 1 , about 274 cm 1 , and about 309 cm' 1 and/or a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -61.8 ⁇ 0.2, -63.7 ⁇ 0.2, -65.8 ⁇ 0.2, -66.6 ⁇ 0.2, -67.4 ⁇ 0.2, -68.2 ⁇ 0.2, -120.6 ⁇ 0.2, -122.5
  • the crystalline polymorph form II further comprises a DSC thermogram substantially the same as FIG. 7 and/or a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 12 and/or a ssNMR ( 19 F) spectrum the same as shown in FIG. 18 or FIG. 19.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 16.7 ⁇ 0.2. In a further embodiment, the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 16.7 ⁇ 0.2 and 19.1 ⁇ 0.2. In a further embodiment, the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, and 19.1 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2 ,and 19.7 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, and 19.7 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, and 19.7 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 11.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, and 19.7 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 11.3 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, and 19.7 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 11.3 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 13.6 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 12.2 + 0.2, 13.2 + 0.2, 13.6 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 8.4 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 12.2 + 0.2, 13.2 + 0.2, 13.6 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 8.4 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 12.2 + 0.2, 12.6 + 0.2, 13.2 + 0.2, 13.6 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, and 19.7 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 16.7 + 0.2, 19.1 + 0.2, and 21.2 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 16.7 + 0.2, 19.1 + 0.2, and 21.2 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 21.2 ⁇ 0.2, and 25.4 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, and 26.8 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, and 26.8 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, and 26.8 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2,
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 11.3 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 11.3 ⁇ 0.2,
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 11.3 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2,
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 11.3 + 0.2, 14.7 + 0.2,
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 25.4 + 0.2, 26.3 + 0.2, 26.8 + 0.2, 27.3 + 0.2, 28.4 + 0.2, and 29.6 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 23.5 + 0.2, 25.4 + 0.2, 26.3 + 0.2, 26.8 + 0.2, 27.3 + 0.2, 28.4 + 0.2, and 29.6 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 23.5 + 0.2, 25.4 + 0.2, 26.3 + 0.2, 26.8 + 0.2, 27.3 + 0.2, 28.4 + 0.2, and 29.6 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 23.5 + 0.2, 25.4 + 0.2, 26.3 + 0.2, 26.8 + 0.2, 27.3 + 0.2, 28.4 + 0.2, and 29.6 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 23.5 + 0.2, 25.4 + 0.2, 26.3 + 0.2, 26.8 + 0.2, 27.3 + 0.2, 28.4 + 0.2, and 29.6 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 13.2 + 0.2, 13.6 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 23.5 + 0.2, 25.4 + 0.2, 26.3 + 0.2, 26.8 + 0.2, 27.3 + 0.2, 28.4 + 0.2, and 29.6 + 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 + 0.2, 5.6 + 0.2, 9.5 + 0.2, 10.5 + 0.2, 11.3 + 0.2, 12.2 + 0.2, 13.2 + 0.2, 13.6 + 0.2, 14.0 + 0.2, 14.7 + 0.2, 15.4 + 0.2, 16.7 + 0.2, 17.8 + 0.2, 19.1 + 0.2, 19.7 + 0.2, 21.2 + 0.2, 22.6 + 0.2, 23.5 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 8.4 ⁇ 0.2, 9.5 ⁇ 0.2, 10.5 ⁇ 0.2, 11.3 ⁇ 0.2, 12.2 ⁇ 0.2, 13.2 ⁇ 0.2, 13.6 ⁇ 0.2, 14.0 ⁇ 0.2, 14.7 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 22.6 ⁇ 0.2, 23.5 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 8.4 ⁇ 0.2, 9.5 ⁇ 0.2, 10.5 ⁇ 0.2, 11.3 ⁇ 0.2, 12.2 ⁇ 0.2, 12.6 ⁇ 0.2, 13.2 ⁇ 0.2, 13.6 ⁇ 0.2, 14.0 ⁇ 0.2, 14.7 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 21.2 ⁇ 0.2, 22.6 ⁇ 0.2, 23.5 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 2.8 ⁇ 0.2, 5.6 ⁇ 0.2, 8.4 ⁇ 0.2, 9.5 ⁇ 0.2, 10.5 ⁇ 0.2, 11.3 ⁇ 0.2, 12.2 ⁇ 0.2, 12.6 ⁇ 0.2, 13.2 ⁇ 0.2, 13.6 ⁇ 0.2, 14.0 ⁇ 0.2, 14.7 ⁇ 0.2, 15.4 ⁇ 0.2, 16.7 ⁇ 0.2, 17.8 ⁇ 0.2, 19.1 ⁇ 0.2, 19.7 ⁇ 0.2, 20.3 ⁇ 0.2, 21.2 ⁇ 0.2, 22.6 ⁇ 0.2, 23.5 ⁇ 0.2, 25.4 ⁇ 0.2, 26.3 ⁇ 0.2, 26.8 ⁇ 0.2, 27.3 ⁇ 0.2, 28.4 ⁇ 0.2, and 29.6 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 3.
  • the crystalline polymorph form III of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 171.9 °C.
  • the crystalline polymorph form III of Compound 1 has a DSC thermogram substantially the same as FIG. 8.
  • the crystalline polymorph form III of Compound 1 has a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 13 cm 1 , about 56 cm 1 , about 83 cm 1 , about 112 cm 1 , about 149 cm 1 , about 194 cm 1 , about 221 cm 1 , about 240 cm 1 , and about 300 cm 1 .
  • the crystalline polymorph form III of Compound 1 has a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 13.
  • the crystalline polymorph form III of Compound 1 has a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -61.9 ⁇ 0.2, -65.5 ⁇ 0.2, -120.0 ⁇ 0.2, -123.7 ⁇ 0.2, -123.8 ⁇ 0.2, and -128.1 ⁇ 0.2.
  • the crystalline polymorph form III of Compound 1 has a ssNMR ( 19 F) spectrum the same as shown in FIG. 20 or FIG. 21.
  • the crystalline polymorph form III further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 171.9 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 13 cm 1 , about 56 cm 1 , about 83 cm 1 , about 112 cm 1 , about 149 cm 1 , about 194 cm 1 , about 221 cm 1 , about 240 cm 1 , and about 300 cm' 1 and/or a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -61.9 ⁇ 0.2, -65.5 ⁇ 0.2, -120.0 ⁇ 0.2, -123.7 ⁇ 0.2, -123.8 ⁇ 0.2, and -128.1 ⁇ 0.2.
  • a DSC thermogram comprising an endothermal peak having a peak temperature of about 171.9 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 13 cm 1 , about 56 cm 1
  • the crystalline polymorph form III further comprises a DSC thermogram substantially the same as FIG. 8 and/or a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 13 and/or a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 12 and/or a ssNMR ( 19 F) spectrum the same as shown in FIG. 20 or FIG. 21.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 15.6 ⁇ 0.2. In a further embodiment, the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 12.2 ⁇ 0.2 and 15.6 ⁇ 0.2. In a further embodiment, the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, and 23.4 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.8 ⁇ 0.2, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, and 23.4 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.8 ⁇ 0.2, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, 23.4 ⁇ 0.2, and 27.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.8 ⁇ 0.2, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, 23.4 ⁇ 0.2, 27.5 ⁇ 0.2, and 31.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.8 ⁇ 0.2, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, 18.4 ⁇ 0.2, 23.4 ⁇ 0.2, 27.5 ⁇ 0.2, and 31.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 6.1 ⁇ 0.2, 7.8 ⁇ 0.2, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, 18.4 ⁇ 0.2, 23.4 ⁇ 0.2, 27.5 ⁇ 0.2, and 31.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 6.1 ⁇ 0.2, 7.8 ⁇ 0.2, 10.1 ⁇ 0.3, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, 18.4 ⁇ 0.2, 23.4 ⁇ 0.2, 27.5 ⁇ 0.2, and 31.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 4.
  • the crystalline polymorph form IV of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 183.7 °C.
  • the crystalline polymorph form IV of Compound 1 has a DSC thermogram substantially the same as FIG. 9.
  • the crystalline polymorph form IV of Compound 1 has a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 14 cm 1 , about 46 cm 1 , about 83 cm 1 , about 105 cm 1 , about 155 cm 1 , about 196 cm 1 , about 215 cm 1 , about 283 cm 1 , and about 302 cm 1 .
  • the crystalline polymorph form IV of Compound 1 has a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 14.
  • the crystalline polymorph form IV of Compound 1 has a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -63.4 ⁇ 0.2, -67.6 ⁇ 0.2, -118.6 ⁇ 0.3, and -124.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a ssNMR ( 19 F) spectrum the same as shown in FIG. 22 or FIG. 23.
  • the crystalline polymorph form IV further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 183.7 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 14 cm 1 , about 46 cm 1 , about 83 cm 1 , about 105 cm 1 , about 155 cm 1 , about 196 cm 1 , about 215 cm 1 , about 283 cm 1 , and about 302 cm 1 and/or a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -63.4 ⁇ 0.2, -67.6 ⁇ 0.2, -118.6 ⁇ 0.3, and -124.5 ⁇ 0.2.
  • a DSC thermogram comprising an endothermal peak having a peak temperature of about 183.7 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 14 cm 1 , about 46 cm 1 , about 83 cm 1 , about 105 cm
  • the crystalline polymorph form IV further comprises a DSC thermogram substantially the same as FIG. 9 and/or a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 14 and/or a ssNMR ( 19 F) spectrum the same as shown in FIG. 22 or FIG. 23.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 16.7 ⁇ 0.2. In a further embodiment, the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 16.7 + 0.2 and 26.3 + 0.2. In a further embodiment, the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 16.1 + 0.2, 16.7 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 20.8 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 20.8 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 20.8 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 19.3 + 0.2, 20.8 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 19.3 + 0.2, 20.8 + 0.2, 22.1 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 19.3 + 0.2, 20.8 + 0.2, 22.1 + 0.2, 23.6 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 5.6 + 0.2, 11.2 + 0.2, 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 19.3 + 0.2, 20.8 + 0.2, 22.1 + 0.2, 23.6 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 5.
  • the crystalline polymorph form V of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 155.3 °C. In a further embodiment, the crystalline polymorph form V of Compound 1 has a DSC thermogram substantially the same as FIG. 10.
  • the crystalline polymorph form V of Compound 1 has a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 13 cm 1 , about 21 cm 1 , about 56 cm 1 , about 83 cm 1 , about 102 cm 1 , about 147 cm 1 , about 182 cm 1 , about 193 cm 1 , about 219 cm 1 , about 240 cm 1 , about 253 cm 1 , about 283 cm 1 , and about 303 cm 1 .
  • the crystalline polymorph form V of Compound 1 has a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 15.
  • the crystalline polymorph form V of Compound 1 has a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -61.6 ⁇ 0.2, -62.7 ⁇ 0.3, -120.2 ⁇ 0.3, -125.4 ⁇ 0.3, and -128.3 ⁇ 0.2.
  • the crystalline polymorph form V of Compound 1 has a ssNMR ( 19 F) spectrum the same as shown in FIG. 24 or FIG. 25.
  • the crystalline polymorph form V further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 155.3 °C and/or a low frequency Raman spectrum comprising one or more peaks at wavenumbers of about 13 cm 1 , about 21 cm 1 , about 56 cm 1 , about 83 cm 1 , about 102 cm 1 , about 147 cm 1 , about 182 cm 1 , about 193 cm 1 , about 219 cm 1 , about 240 cm 1 , about 253 cm 1 , about 283 cm 1 , and about 303 cm 1 and/or a ssNMR ( 19 F) spectrum comprising one or more resonance signals [ppm] at -61.6 ⁇ 0.2, -62.7 ⁇ 0.3, -120.2 ⁇ 0.3, -125.4 ⁇ 0.3, and -128.3 ⁇ 0.2.
  • the crystalline polymorph form V further comprises a DSC thermogram substantially the same as FIG. 10 and/or a low frequency Raman spectrum comprising peaks at wavenumbers essentially the same as shown in FIG. 15 and/or a ssNMR ( 19 F) spectrum the same as shown in FIG. 24 or FIG. 25.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 15.5 ⁇ 0.2. In a further embodiment, the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 15.5 ⁇ 0.2 and 23.7 ⁇ 0.2. In a further embodiment, the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, and 23.7 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 23.7 ⁇ 0.2, and 27.0 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, and 27.0 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, and 27.0 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, 27.0 ⁇ 0.2, and 27.4 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.9 ⁇ 0.2, 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, 27.0 ⁇ 0.2, and 27.4 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.9 ⁇ 0.2, 7.6 ⁇ 0.2, 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, 27.0 ⁇ 0.2, and 27.4 ⁇ 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 26.
  • the crystalline polymorph form VI of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 181.0 °C. In a further embodiment, the crystalline polymorph form VI of Compound 1 has a DSC thermogram substantially the same as FIG. 30.
  • the crystalline polymorph form VI further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 181.0 °C.
  • the crystalline polymorph form VI of Compound 1 has a thermogravimetry analysis (TGA) spectrum as shown in FIG. 34.
  • the crystalline polymorph form VI further comprises a thermogravimetry analysis (TGA) spectrum as shown in FIG. 34.
  • TGA thermogravimetry analysis
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 20.1 ⁇ 0.2. In a further embodiment, the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 20.1 ⁇ 0.2 and 22.2 ⁇ 0.2. In a further embodiment, the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 18.2 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 16.5 ⁇ 0.2, 18.2 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 14.3 ⁇ 0.2, 16.5 ⁇ 0.2, 18.2 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 27.
  • the crystalline polymorph form VII of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 188.5 °C. In a further embodiment, the crystalline polymorph form VII of Compound 1 has a DSC thermogram substantially the same as FIG. 31.
  • the crystalline polymorph form VII further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 188.5 °C.
  • the crystalline polymorph form VII of Compound 1 has a thermogravimetry analysis (TGA) spectrum as shown in FIG. 35.
  • the crystalline polymorph form VII further comprises a thermogravimetry analysis (TGA) spectrum as shown in FIG. 35.
  • TGA thermogravimetry analysis
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 4.8 ⁇ 0.3.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.3 and 25.0 ⁇ 0.3.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.3, 18.6 ⁇ 0.3, and 25.0 ⁇ 0.3.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.3, 18.6 ⁇ 0.3, 19.6 ⁇ 0.3, and 25.0 ⁇ 0.3.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.3, 7.2 ⁇ 0.3, 18.6 ⁇ 0.3, 19.6 ⁇ 0.3, and 25.0 ⁇ 0.3.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 4.8 ⁇ 0.2.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.2 and 25.0 ⁇ 0.2.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.2, 18.6 ⁇ 0.2, and 25.0 ⁇ 0.2.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2 and 25.0 ⁇ 0.2.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.2, 7.2 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2, and 25.0 ⁇ 0.2.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 28.
  • the crystalline polymorph form X of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 136.5 °C. In a further embodiment, the crystalline polymorph form X of Compound 1 has a DSC thermogram substantially the same as FIG. 32.
  • the crystalline polymorph form X further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 136.5 °C.
  • the crystalline polymorph form X of Compound 1 has a thermogravimetry analysis (TGA) spectrum as shown in FIG. 36.
  • the crystalline polymorph form X further comprises a thermogravimetry analysis (TGA) spectrum as shown in FIG. 36.
  • TGA thermogravimetry analysis
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising a peak at diffraction angle (20) of 15.6 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 15.6 ⁇ 0.3 and 19.5 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, and 19.5 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, and 19.5 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 7.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, 19.5 ⁇ 0.3, and 20.4 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.3 ⁇ 0.3, 7.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, 19.5 ⁇ 0.3, and 20.4 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.3 ⁇ 0.3, 7.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, 17.9 ⁇ 0.3, 19.5 ⁇ 0.3, and 20.4 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.3 ⁇ 0.3, 6.2 ⁇ 0.3, 7.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, 17.9 ⁇ 0.3, 19.5 ⁇ 0.3, and 20.4 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.3 ⁇ 0.3, 6.2 ⁇ 0.3, 7.9 ⁇ 0.3, 12.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, 17.9 ⁇ 0.3, 19.5 ⁇ 0.3, and 20.4 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) essentially the same as shown in FIG. 29.
  • the crystalline polymorph form XI of Compound 1 has a DSC thermogram comprising an endothermal peak having a peak temperature of about 177.0 °C.
  • the crystalline polymorph form XI of Compound 1 has a DSC thermogram substantially the same as FIG. 33.
  • the crystalline polymorph form XI further comprises a DSC thermogram comprising an endothermal peak having a peak temperature of about 177.0 °C.
  • the crystalline polymorph form XI of Compound 1 has a thermogravimetry analysis (TGA) spectrum as shown in FIG. 37.
  • the crystalline polymorph form XI further comprises a thermogravimetry analysis (TGA) spectrum as shown in FIG. 37.
  • TGA thermogravimetry analysis
  • the present disclosure further provides a composition comprising one or more of polymorph forms I- VII, X, or XI of Compound 1.
  • the disclosure provides a process to control a pest said process comprising applying to a locus, a pesticidally effective amount of one or more of polymorph forms I- VII, X, or XI of 5-((17?,37?)-3-(3,5-bis(trifhioromethyl)phenyl)-2,2- dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide, as described herein, or a composition comprising one or more of polymorph forms I- VII, X, or XI of 5-((17?,37?)-3-(3,5-bis(trifhioromethyl)phenyl)-2,2- dichlorocyclopropane-l-car
  • said pest is selected from the group consisting of ants, aphids, bed bugs, beetles, bristletails, caterpillars, cockroaches, crickets, earwigs, fleas, flies, grasshoppers, grubs, leafhoppers, lice, locusts, maggots, mites, nematodes, planthoppers, psyllids, sawflies, scales, silverfish, slugs, snails, spiders, springtails, stink bugs, symphylans, termites, thrips, ticks, wasps, whiteflies, and wireworms.
  • said pest is selected from the group consisting of Adelges spp., Aulacaspis spp., Aphrophora spp., Aphis spp., Bemisia spp., Ceroplastes spp., Chionaspis spp., Chrysomphalus spp., Coccus spp., Empoasca spp., Euschistus spp., Lepidosaphes spp., Lagynotomus spp., Lygus spp., Macrosiphum spp., Nephotettix spp., Nezara spp., Nilaparvata spp., Philaenus spp., Phytocoris spp., Piezodorus spp., Pianococcus spp., Pseudococcus spp., Rhopalosiphum spp., Saisseti
  • pest is selected from the group consisting of Acrosternum hilare, Acyrthosiphon pisum, Aleyrodes proletella, Aleurodicus dispersus, Aleurothrixus floccosus, Amrasca biguttula biguttula, Aonidiella aurantii, Aphis f abac, Aphis gossypii, Aphis glycines, Aphis pomi, Aulacorthum solani, Bactericera cockerelli, Bagrada hilaris, Bemisia argentifolii, Bemisia tabaci, Blissus leucopterus, Boisea trivittata, Brachycorynella asparagi, Brevennia rehi, Brevicoryne brassicae, Cacopsylla pyri, Cacopsylla pyricola, Calocoris norvegicus, Ceroplastes
  • said pest is selected from the group consisting of Adoxophyes spp., Agrotis spp., Argyrotaenia spp., Cacoecia spp., Caloptilia spp., Chilo spp., Chrysodeixis spp., Colias spp., Crambus spp., Diaphania spp., Diatraea spp., Earias spp., Ephestia spp., Epimecis spp., Feltia spp., Gortyna spp., Helicoverpa spp., Heliothis spp., Indarbela spp., Lithocolletis spp., Loxagrotis spp., Malacosoma spp., Nemapogon spp., Peridroma spp., Phyllonorycter spp.
  • said pest is selected from the group consisting of Achaea janata, Adoxophyes orana, Agrotis ipsilon, Alabama argillacea, Amorbia cuneana, Amyelois transitella, Anacamptodes defectaria, Anarsia lineatella, Anomis sabulifera, Anticarsia gemmatalis, Archips argyrospila, Archips rosana, Argyrotaenia citrana, Autographa gamma, Bonagota cranaodes, Borbo cinnara, Bucculatrix thurberiella, Capua reticulana, Carposina niponensis, Chlumetia transversa, Choristoneura rosaceana, Cnaphalocrocis medinalis, Conopomorpha cramerella, Corcyra cephalonica, Cossus cossus,
  • polymorph forms described herein are unexpectedly and surprisingly much more active than the racemic compound Fl 802 over a variety of pests that cause agricultural damage around the world.
  • the disclosure provides a process for the preparation of a compound of the formula 1
  • the disclosure provides a process for the preparation of a compound of the formula 1
  • 74 The crystalline polymorph form of any one of embodiments 65 to 73, wherein the crystalline polymorph form has a powder X-ray diffraction pattern comprising one or more peaks essentially the same as shown in FIG. 4.
  • 75 The crystalline polymorph form of any one of embodiments 65 to 74, having a Raman spectrum comprising one or more peaks at wavenumbers of about 14 cm 1 , about 46 cnr about 83 cm 1 , about 105 cm 1 , about 155 cm 1 , about 196 cm 1 , about 215 cm 1 , about 283 cm' and about 302 cm 1 .
  • 105 The crystalline polymorph form of any one of embodiments 101 to 104, wherein the crystalline polymorph form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, and 27.0 ⁇ 0.2.
  • 106 The crystalline polymorph form of any one of embodiments 101 to 105, wherein the crystalline polymorph form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, and 27.0 ⁇ 0.2.
  • thermogravimetric analysis substantially the same as FIG. 34.
  • 129 The crystalline polymorph form of any one of embodiments 125 to 128, wherein the crystalline polymorph form has a powder X-ray diffraction pattern comprising peaks at diffraction angles (20) of 4.8 ⁇ 0.3, 7.2 ⁇ 0.3, 18.6 ⁇ 0.3, 19.6 ⁇ 0.3, and 25.0 ⁇ 0.3.
  • thermogravimetric analysis TGA
  • a composition comprising a crystalline form according to embodiment 1 or a crystalline polymorph form according to any one of embodiments 2 to 146.
  • a suspension composition comprising a crystalline form according to embodiment 1 or a crystalline polymorph form according to any one of embodiments 2 to 146, water, and optionally one or more dispersants, wetting agents, emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners.
  • the suspension composition of embodiments 148 comprising water, a dispersant, a wetting agent, and optionally one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners.
  • 150 A process for preparing a suspension composition comprising
  • step of contacting comprises the crystalline form according to embodiment 1 or the crystalline polymorph form according to any one of embodiments 2 to 146, water, a dispersant, a wetting agent, and optionally one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners.
  • a process to control a pest comprising applying to a locus, a pesticidally effective amount of a crystalline form according to embodiment 1 , a crystalline polymorph form according to any one of embodiments 2 to 146, or a composition according to embodiment 147, or a suspension composition of embodiment 148 or 149.
  • a process to control a pest comprising applying to a locus, a pesticidally effective amount of a suspension composition prepared by a process comprising i. contacting a crystalline form according to embodiment 1 or a crystalline polymorph form according to any one of embodiments 2 to 146 with water and optionally one or more dispersants, wetting agents, emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners to provide a suspension mixture, and ii. agitating the suspension mixture to provide the suspension composition.
  • TBTU 1.1.3.3-tetramethyluronium tetrafluoroborate
  • HBTU 2-(6-chloro- 1 H-benzotriazol- 1-yl)- A,A,A’,A’-tetramethylaminium hexafluorophosphate
  • HCTU 2-chloro-4,6-dimethoxy-l,3,5- triazine
  • CDMT 2-[(5-chloro-3-oxido- IH-benzo triazol- l-yl)-4-morpholinylmethylene]-A- methylmethanaminium hexafluorophosphate
  • HDMC methylmethanaminium hexafluorophosphate
  • HDMC (l-cyano-2-ethoxy-2- oxoethylidenaminooxy)
  • FIG. 1 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( l /?,3/?)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form I.
  • FIG. 2 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( l /?,3/?)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form II.
  • FIG. 3 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( l /?,3/?)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form III.
  • FIG. 4 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( l /?,3/?)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form IV.
  • FIG. 5 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( l /?,3/?)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form V.
  • FIG. 6 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifhioromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form I.
  • DSC differential scanning calorimetry
  • FIG. 7 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifhioromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form II.
  • DSC differential scanning calorimetry
  • DSC differential scanning calorimetry
  • FIG. 9 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form IV.
  • DSC differential scanning calorimetry
  • FIG. 10 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form V.
  • DSC differential scanning calorimetry
  • FIG. 11 shows a Raman spectrum of the crystalline form of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form I.
  • FIG. 12 shows a Raman spectrum of the crystalline form of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form II.
  • FIG. 13 shows a Raman spectrum of the crystalline form of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form III.
  • FIG. 14 shows a Raman spectrum of the crystalline form of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form IV.
  • FIG. 15 shows a Raman spectrum of the crystalline form of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form V.
  • FIG. 16 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form I, obtained using the 19 F DP/TOSS method described herein.
  • FIG. 17 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifhioromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form I, obtained using the 19 F DP method described herein.
  • FIG. 18 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-N-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form II, obtained using the 19 F DP/TOSS method described herein.
  • FIG. 19 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-N-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form II, obtained using the 19 F DP method described herein.
  • FIG. 20 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-N-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form III, obtained using the 19 F DP/TOSS method described herein.
  • FIG. 21 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-N-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form III, obtained using the 19 F DP method described herein.
  • FIG. 22 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-N-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form IV, obtained using the 19 F DP/TOSS method described herein.
  • FIG. 23 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-N-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form IV, obtained using the 19 F DP method described herein.
  • FIG. 24 shows a solid-state 19 F NMR spectrum of the crystalline form of 5-((lR,3R)-3- (3,5-bis(trifhioromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form V, obtained using the 19 F DP/TOSS method described herein. [0321] FIG.
  • FIG. 26 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( I /?,3/?)- 3-(3,5-bis(trifhioromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3- (2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form VI.
  • FIG. 27 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( I /?,3/?)- 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3- (2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form VII.
  • FIG. 28 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( I /?,3/?)- 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3- (2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form X.
  • FIG. 29 shows a powder X-ray diffraction pattern of the crystalline form of 5-(( I /?,3/?)- 3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3- (2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form XI.
  • FIG. 30 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((17?,37?)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form VI.
  • DSC differential scanning calorimetry
  • FIG. 31 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((17?,37?)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form VII.
  • DSC differential scanning calorimetry
  • FIG. 32 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((17?,37?)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form X.
  • DSC differential scanning calorimetry
  • FIG. 33 shows a differential scanning calorimetry (DSC) thermogram of the crystalline form of 5-((17?,37?)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l- carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide, polymorph form XI.
  • DSC differential scanning calorimetry
  • FIG. 34 shows a Thermogravimetry Analysis (TGA) spectrum of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2- chloro-A-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form VI.
  • TGA Thermogravimetry Analysis
  • FIG. 35 shows a Thermogravimetry Analysis (TGA) spectrum of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2- chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form VII.
  • TGA Thermogravimetry Analysis
  • FIG. 36 shows a Thermogravimetry Analysis (TGA) spectrum of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2- chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form X.
  • TGA Thermogravimetry Analysis
  • FIG. 37 shows a Thermogravimetry Analysis (TGA) spectrum of the crystalline form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2- chloro-V-(3-(2,2-difluoroacetamido)-2,4-difluorophenyl)benzamide (solvent-free and anhydrous), polymorph form XI.
  • TGA Thermogravimetry Analysis
  • the carboxylic acid starting material can be reacted with a chlorinating agent in the presence of a solvent, and an optional catalyst.
  • the chlorinating agent can be any such reagent known in the art for converting a carboxylic acid to an acyl chloride under conditions suitable for such conversion.
  • the chlorinating agent can be thionyl chloride (SOCh), phosphorous trichloride (PCh), phosphorous pentachloride (PCI5), oxalyl chloride, 2,4,6-trichloro-l,3,5-triazine (cyanuric chloride), and the like (See for example Org. Process Res. Dev. 2016, 20. 140).
  • the chlorinating agent is oxalyl chloride. In some embodiments, it can be advantageous to use the chlorinating agent in about an equimolar amount compared to the carboxylic acid starting material. In some embodiments, it can be advantageous to use the chlorinating agent in excess compared to the carboxylic acid starting material. In some embodiments, the chlorinating agent is used in about a 1.05-fold to about a 5-fold molar excess. In some embodiments, the chlorinating agent is used in about an equimolar to about a 2-fold molar excess. In some embodiments, the chlorinating agent is used in about a 2-fold to about a 3-fold molar excess.
  • the chlorinating agent is used in about a 3-fold to about a 4-fold molar excess. In some embodiments, the chlorinating agent is used in about a 4-fold to about a 5-fold molar excess. In some embodiments, the chlorinating agent is used in about a 2-fold molar excess. In some embodiments, the chlorinating agent is used in about a 3-fold molar excess. In some embodiments, the chlorinating agent is used in about a 4-fold excess. In some embodiments, the chlorinating agent is used in about a 5-fold molar excess.
  • the carboxylic acid starting material in excess compared to the chlorinating agent.
  • the carboxylic acid is used in about a 2-fold to about a 5-fold molar excess.
  • the carboxylic acid is used in about a 2-fold to about a 3-fold molar excess.
  • the carboxylic acid is used in about a 3-fold to about a 4-fold molar excess.
  • the carboxylic acid is used in about a 4-fold to about a 5 -fold molar excess.
  • the carboxylic acid is used in about a 2-fold molar excess.
  • the carboxylic acid is used in about a 3-fold molar excess. In some embodiments, the carboxylic acid is used in about a 4-fold molar excess. In some embodiments, the carboxylic acid is used in about a 5-fold molar excess.
  • Step (a) of Scheme 1 can optionally be carried out in the presence of a catalyst that is known in the art as useful in the conversion of a carboxylic acid to an acyl chloride, such as a Lewis base catalyst.
  • Suitable catalysts include, but are not limited to, formamide catalysts, such as AfA i methyl formamide (DMF), N- formyl piperidine (piperidine- 1-carbaldehy de), A'- formyl pyrrolidine, 4-formylmorpholine, or other catalysts, such as pyridine, 4-dimethylaminepyridine (DMAP) and the like.
  • the catalyst can be used in an amount of about 1 mole percent (mol%) to about 50 mol% compared to the carboxylic acid starting material. In some embodiments, the catalyst can be used in an amount equal to about 1 mol% to about 10 mol% compared to the carboxylic acid starting material. In some embodiments, the catalyst can be used in an amount equal to about 10 mol% to about 20 mol% compared to the carboxylic acid starting material. In some embodiments, the catalyst can be used in an amount equal to about 20 mol% to about 30 mol% compared to the carboxylic acid starting material. In some embodiments, the catalyst can be used in an amount equal to about 30 mol% to about 40 mol% compared to the carboxylic acid starting material.
  • Step (a) of Scheme 1 can be carried out in the presence of a solvent or a mixture of solvents.
  • the solvent can be or the mixture of solvents can include an aprotic solvent such as dimethyl sulfoxide (DMSO), acetone, hexamethylphosphoric triamide (HMPT), acetonitrile (CH3CN), methyl acetate, ethyl acetate (EtOAc), n-propyl acetate (n- PrOAc), isopropyl acetate (z-PrOAc), n-butyl acetate (n-BuOAc), isobutyl acetate (z-BuOAc), isoamyl acetate, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2- methylTHF), toluene, benzene, hexane, pentane, heptanes, cyclo
  • Step (a) it can be advantageous to carry out the reaction of Step (a) at below room temperature or an elevated temperature.
  • the reaction is carried out at a temperature between about 0 °C to about 25 °C. In some embodiments, the reaction is carried out at a temperature between about 25 °C and about 100 °C. In some embodiments, the reaction is carried out at a temperature between about 30 °C and about 50 °C. In some embodiments, the reaction is carried out at a temperature between about 40 °C and about 70 °C.
  • Step (b) of Scheme 1 the acyl chloride starting material can be reacted with the amine starting material and a base in the presence of a solvent.
  • the base in Step (b) can be an inorganic base or an organic base.
  • Exemplary suitable bases for use in connection with Step (b) include, but are not limited to, sodium bicarbonate (NaHCCh), sodium carbonate (Na2CO ), calcium carbonate (CaCCh), cesium carbonate (CS2CO3), cesium bicarbonate (CsHCCh), lithium carbonate (Li2CC>3), potassium carbonate (K2CO3), potassium bicarbonate (KHCO3), lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), cesium hydroxide (CsOH), calcium hydroxide (Ca(OH)2), sodium diphosphate dibasic (Na2HPO4), potassium phosphate (K3PO4), sodium phosphate (Na3PO4), and the like.
  • NaHCCh sodium bicarbonate
  • Na2CO sodium carbonate
  • CaCCh calcium carbonate
  • CaCCh cesium carbonate
  • CsHCCh cesium bicarbonate
  • Li2CC>3 lithium carbonate
  • K2CO3 potassium bicarbon
  • the base is NaHCOs.
  • the base can be an organic base, such as an amine base.
  • Suitable amine bases include, but are not limited to, N,N- diisopropylethylamine (DIPEA or Hiinig’s base), triethyl amine (TEA), tributylamine, 2,6- lutidine, 2,2,6,6-tetramethylguanidine, N-methyl morpholine, pyridine, 1 ,8- Diazabicyclo[5.4.0]undec-7-ene (DBU), and the like.
  • DIPEA or Hiinig’s base N,N- diisopropylethylamine
  • TEA triethyl amine
  • tributylamine 2,6- lutidine
  • 2,2,6,6-tetramethylguanidine N-methyl morpholine
  • pyridine 1 ,8- Diazabicyclo[5.4.0]undec-7-ene
  • DBU Diazabi
  • the base is used in about a 0.5-fold to about a 5-fold molar excess. In some embodiments, the base is used in about a 2-fold to about a 3 -fold molar excess. In some embodiments, the base is used in about a 2-fold molar excess.
  • Step (b) of Scheme 1 can be carried out in the presence of a solvent or a mixture of solvents.
  • the solvent can be or the mixture of solvents can include an aprotic solvent such as dimethyl sulfoxide (DMSO), acetone, hexamethylphosphoric triamide (HMPT), acetonitrile (CH3CN), ethyl acetate (EtOAc), dichloromethane (DCM), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-methylTHF), isopropyl acetate, N,N- dimethylformadmide (DMF), anisole, and the like.
  • the solvent is EtOAc.
  • the solvent in step (b) can be or the mixture of solvents can include an aprotic solvent such as dimethyl sulfoxide (DMSO), acetone, hexamethylphosphoric triamide (HMPT), acetonitrile (CH3CN), methyl acetate, ethyl acetate (EtOAc), n-propyl acetate (n- PrOAc), isopropyl acetate (z-PrOAc), n-butyl acetate (n-BuOAc), isobutyl acetate (z-BuOAc), isoamyl acetate, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2- methylTHF), toluene, benzene, hexane, pentane, heptanes, cyclohexane, Me-cyclohexane, isopar C, D-limonene
  • the solvent in step (b) can be the same as the solvent in step (a). In some embodiments, it can be advantageous to carry out the reaction of Step (b) at below room temperature or at about room temperature. In some embodiments, the reaction is carried out at a temperature between about 0 °C to about 100 °C. In some embodiments, the reaction is carried out at a temperature between about 25 °C and about 30 °C.
  • the carboxylic acid starting material can be reacted with the amine starting material, a base, and a coupling agent in the presence of a solvent.
  • the base can be an inorganic base, such as potassium phosphate (K3PO4) or potassium carbonate (K2CO3), or an organic base, such as an amine base.
  • Suitable amine bases include, but are not limited to, A,A-diisopropylethylamine (DIPEA or Hiinig’s base), triethyl amine (TEA), tributylamine, 2,6-lutidine, 2,2,6,6-tetramethylguanidine, N-methyl morpholine, pyridine, and the like.
  • the base is used in about a 1-fold to about a 5-fold molar excess. In some embodiments, the base is used in about a 2-fold to about a 3-fold molar excess. In some embodiments, the base is used in about a 3-fold to about a 4-fold molar excess. In some embodiments, the base is used in about a 4-fold to about a 5-fold molar excess. In some embodiments, the base is used in about a 2-fold molar excess. In some embodiments, the base is used in about a 3-fold molar excess. In some embodiments, the base is used in about a 4-fold molar excess. In some embodiments, the base is used in about a 5-fold molar excess.
  • the coupling agent can be any coupling agent known in the art used in connection with carboxylic acid-amine coupling reactions.
  • Suitable coupling agent include, but are not limited to, benzotriazol- l-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (BOP), (1H- benzotriazol-l-yl-oxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-aza- benzotriazol-l-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), [ethyl cyano(hydroxyimino)acelalo-tT
  • the coupling agent in excess compared to the carboxylic acid or amine starting material.
  • the coupling agent is used in about a 1-fold to about a 5-fold molar excess.
  • the coupling agent is used in about a 1-fold to about a 3-fold molar excess.
  • the coupling agent is used in about a 3-fold to about a 4-fold molar excess.
  • the coupling agent is used in about a 4-fold to about a 5-fold molar excess.
  • the coupling agent is used in about a 1-fold molar excess.
  • the coupling agent is used in about a 2-fold molar excess.
  • the coupling agent is used in about a 3-fold molar excess. In some embodiments, the coupling agent is used in about a 4-fold molar excess. In some embodiments, the coupling agent is used in about a 5 -fold molar excess.
  • the reaction in Scheme 2 can be carried out in the presence of a solvent or a mixture of solvents.
  • the solvent can be or the mixture of solvents can include an aprotic solvent such as dimethyl sulfoxide (DMSO), acetone, hexamethylphosphoric triamide (HMPT), acetonitrile (CH3CN), methyl acetate, ethyl acetate (EtOAc), n-propyl acetate (n-PrOAc), isopropyl acetate (z-PrOAc), n-butyl acetate (n-BuOAc), isobutyl acetate (z-BuOAc), isoamyl acetate, dichloromethane (DCM), tetrahydrofuran (THF), 2-methyl tetrahydrofuran (2-methylTHF), toluene, benzene, hexane, pentane, heptanes, cyclohex
  • the solvent is EtOAc.
  • the reaction is carried out at a temperature between about 0 °C to about 25 °C. In some embodiments, the reaction is carried out at a temperature between about 25 °C and about 50 °C.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 11.2 ⁇ 0.1, 11.6 ⁇ 0.2, 12.4 ⁇ 0.2, 14.5 ⁇ 0.2, 15.6 ⁇ 0.2, 16.8 ⁇ 0.2, 17.9 ⁇ 0.2, 18.6 ⁇ 0.2, 19.7 ⁇ 0.2, 20.8 ⁇ 0.2, 21.5 ⁇ 0.2, 22.4 ⁇ 0.2, 22.9 ⁇ 0.2, 23.5 ⁇ 0.2, 24.2 ⁇ 0.2, 25.0 ⁇ 0.2, 25.5 ⁇ 0.2, 26.0 ⁇ 0.2, 26.7 ⁇ 0.2, 27.4 ⁇ 0.2, 28.3 ⁇ 0.2, 29.6 ⁇ 0.2, and 31.0 ⁇ 0.2.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 ⁇ 0.1, 11.1 ⁇ 0.1, 11.6 ⁇ 0.1, 12.4 ⁇ 0.1, 14.5 ⁇ 0.1, 15.6 ⁇ 0.1, 16.8 ⁇ 0.1, 17.9 ⁇ 0.1, 18.6 ⁇ 0.1, 19.7 ⁇ 0.1, 20.8 ⁇ 0.1, 21.5 ⁇ 0.1, 22.4 ⁇ 0.1, 22.9 ⁇ 0.1, 23.5 ⁇ 0.1, 24.2 ⁇ 0.1, 25.0 ⁇ 0.1, 25.5 ⁇ 0.1, 26.0 ⁇ 0.1, 26.7 ⁇ 0.1, 27.4 ⁇ 0.1, 28.3 ⁇ 0.1, 29.6 ⁇ 0.1, and 31.0 ⁇ 0.1.
  • the crystalline polymorph form I of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 1 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • the DSC thermogram for crystalline polymorph form I is shown in FIG. 6. It has been determined that during the DSC method as described in Example 14, polymorph form I melted at about 146.7 °C, as shown in FIG. 6, recrystallized at a temperature of about 172 °C, forming crystalline polymorph form II, which then melted at a temperature of about 187 °C. [0352] The Raman spectrum for crystalline polymorph form I is shown in FIG. 11.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 7.0 ⁇ 0.2, 8.9 ⁇ 0.2, 10.7 ⁇ 0.2, 11.6 ⁇ 0.2, 12.6 ⁇ 0.2, 13.9 ⁇ 0.2, 14.4 ⁇ 0.2, 15.5 ⁇ 0.2, 16.9 ⁇ 0.2, 17.4 ⁇ 0.2, 17.9 ⁇ 0.2, 18.4 ⁇ 0.2, 19.3 ⁇ 0.2, 20.2 ⁇ 0.2, 21.0 ⁇ 0.2, 22.3 ⁇ 0.2, 23.0 ⁇ 0.2, 25.3 ⁇ 0.2, 26.1 ⁇ 0.2, 26.9 ⁇ 0.2, 28.6 ⁇ 0.2, 29.7 ⁇ 0.2, 31.1 ⁇ 0.2, and 32.4 ⁇ 0.2.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 ⁇ 0.1, 7.0 ⁇ 0.1, 8.9 ⁇ 0.1, 10.7 ⁇ 0.1, 11.6 ⁇ 0.1, 12.6 ⁇ 0.1, 13.9 ⁇ 0.1, 14.4 ⁇ 0.1, 15.5 ⁇ 0.1, 16.9 ⁇ 0.1, 17.4 ⁇ 0.1, 17.9 ⁇ 0.1, 18.4 ⁇ 0.1, 19.3 ⁇ 0.1, 20.2 ⁇ 0.1, 21.0 ⁇ 0.1, 22.3 ⁇ 0.1, 23.0 ⁇ 0.1, 25.3 ⁇ 0.1, 26.1 ⁇ 0.1, 26.9 ⁇ 0.1, 28.6 ⁇ 0.1, 29.7 ⁇ 0.1, 31.1 ⁇ 0.1, and 32.4 ⁇ 0.1.
  • the crystalline polymorph form II of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 2 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 2.8 ⁇ 0.2,
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 2.8 ⁇ 0.1, 5.6 ⁇ 0.1, 8.4 ⁇ 0.1, 9.5 ⁇ 0.1, 10.5 ⁇ 0.1, 11.3 ⁇ 0.1, 12.2 ⁇ 0.1, 12.6 ⁇ 0.1, 13.2 ⁇ 0.1,
  • the crystalline polymorph form III of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 3 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • the DSC thermogram for crystalline polymorph form III is shown in FIG. 8.
  • the Raman spectrum for crystalline polymorph form III is shown in FIG. 13.
  • the solid-state NMR ( 19 F) spectra for crystalline polymorph form III are shown in FIG. 20 and FIG. 21.
  • a unique physical form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2- dichlorocyclopropane-l-carboxamido)-2-chloro-A-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide , polymorph form IV has been prepared according to the methods described herein.
  • An exemplary powder X-ray diffraction (PXRD) pattern of polymorph form IV is shown in FIG. 4.
  • Tabulated data for polymorph form IV is shown in Table 4. The data provided in Table 4 is averaged data obtained from PXRD experiments of five unique samples of polymorph form IV prepared according to the methods described herein.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.1 ⁇ 0.3, 7.8 ⁇ 0.3, 10.1 ⁇ 0.3, 12.2 ⁇ 0.3, 15.6 ⁇ 0.3, 18.4 ⁇ 0.3, 23.4 ⁇ 0.3, 27.5 ⁇ 0.3, and 31.5 ⁇ 0.3.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.1 ⁇ 0.2, 7.8 ⁇ 0.2, 10.1 ⁇ 0.2, 12.2 ⁇ 0.2, 15.6 ⁇ 0.2, 18.4 ⁇ 0.2, 23.4 ⁇ 0.2, 27.5 ⁇ 0.2, and 31.5 ⁇ 0.2.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 6.1 ⁇ 0.1, 7.8 ⁇ 0.1, 10.1 ⁇ 0.1, 12.2 ⁇ 0.1, 15.6 ⁇ 0.1, 18.4 ⁇ 0.1, 23.4 ⁇ 0.1, 27.5 ⁇ 0.1, and 31.5 ⁇ 0.1.
  • the crystalline polymorph form IV of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 4 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • the DSC thermogram for crystalline polymorph form IV is shown in FIG. 9.
  • the Raman spectrum for crystalline polymorph form IV is shown in FIG. 14.
  • the solid-state NMR ( 19 F) spectra for crystalline polymorph form IV are shown in FIG. 22 and FIG. 23.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 + 0.3,
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 ⁇ 0.2, 11.2 + 0.2, 11.9 + 0.2, 16.1 + 0.2, 16.7 + 0.2, 18.5 + 0.2, 19.3 + 0.2, 20.8 + 0.2, 22.1 + 0.2, 23.6 + 0.2, and 26.3 + 0.2.
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 5.6 + 0.1, 11.2 + 0.1, 11.9 + 0.1, 16.1 + 0.1, 16.7 + 0.1, 18.5 + 0.1,
  • the crystalline polymorph form V of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 5 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • the DSC thermogram for crystalline polymorph form V is shown in FIG. 10.
  • the Raman spectrum for crystalline polymorph form V is shown in FIG. 15.
  • the solid-state NMR ( 19 F) spectra for crystalline polymorph form V are shown in FIG. 22 and FIG. 25.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.9 + 0.2, 7.6 + 0.2, 11.8 + 0.2, 15.5 + 0.2, 19.4 + 0.2, 19.9 + 0.2, 23.7 + 0.2, 27.0 + 0.2, and 27.4 + 0.2.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.9 + 0.1, 7.6 + 0.1, 11.8 + 0.1, 15.5 + 0.1, 19.4 + 0.1, 19.9 + 0.1, 23.7 + 0.1, 27.0 + 0.1, and 27.4 + 0.1.
  • the crystalline polymorph form VI of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 6 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • TGA Thermogravimetry Analysis
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 14.3 ⁇ 0.3, 16.5 ⁇ 0.3, 18.2 ⁇ 0.3, 19.3 ⁇ 0.3, 20.1 ⁇ 0.3, 22.2 ⁇ 0.3, and 23.1 ⁇ 0.3.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 14.3 ⁇ 0.2, 16.5 ⁇ 0.2, 18.2 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, and 23.1 ⁇ 0.2.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 14.3 ⁇ 0.1, 16.5 ⁇ 0.1, 18.2 ⁇ 0.1, 19.3 ⁇ 0.1, 20.1 ⁇ 0.1, 22.2 ⁇ 0.1, and 23.1 ⁇ 0.1.
  • the crystalline polymorph form VII of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 7 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • TGA Thermogravimetry Analysis
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8 ⁇ 0.3, 7.2 ⁇ 0.3, 18.6 ⁇ 0.3, 19.6 ⁇ 0.3, and 25.0 ⁇ 0.3.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8 ⁇ 0.2, 7.2 ⁇ 0.2, 18.6 ⁇ 0.2, 19.6 ⁇ 0.2, and 25.0 ⁇ 0.2.
  • the crystalline polymorph form X of Compound 1 has a powder X- ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.8 ⁇ 0.1, 7.2 ⁇ 0.1, 18.6 ⁇ 0.1, 19.6 ⁇ 0.1, and 25.0 ⁇ 0.1.
  • the crystalline polymorph form X of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 8 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • TGA Thermogravimetry Analysis
  • a unique physical form of 5-((lR,3R)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2- dichlorocyclopropane-l-carboxamido)-2-chloro-A-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide, polymorph form XI has been prepared according to the methods described herein.
  • An exemplary powder X-ray diffraction (PXRD) pattern of polymorph form XI is shown in FIG. 29.
  • Tabulated data for polymorph form XI is shown in Table 9. The data provided in Table 9 is averaged data obtained from PXRD experiments of three unique samples of polymorph form XI prepared according to the methods described herein.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.3 ⁇ 0.3, 6.2 ⁇ 0.3, 7.9 ⁇ 0.3, 12.9 ⁇ 0.3, 14.9 ⁇ 0.3, 15.6 ⁇ 0.3, 17.9 ⁇ 0.3, 19.5 ⁇ 0.3, and 20.4 ⁇ 0.3.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.3 ⁇ 0.2, 6.2 ⁇ 0.2, 7.9 ⁇ 0.2, 12.9 ⁇ 0.2, 14.9 ⁇ 0.2, 15.6 ⁇ 0.2, 17.9 ⁇ 0.2, 19.5 ⁇ 0.2, and 20.4 ⁇ 0.2.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising one or more peaks at diffraction angles (20) of 4.3 ⁇ 0.1, 6.2 ⁇ 0.1, 7.9 ⁇ 0.1, 12.9 ⁇ 0.1, 14.9 ⁇ 0.1, 15.6 ⁇ 0.1, 17.9 ⁇ 0.1, 19.5 ⁇ 0.1, and 20.4 ⁇ 0.1.
  • the crystalline polymorph form XI of Compound 1 has a powder X-ray diffraction pattern comprising a combination of two or more peaks at diffraction angles (20) as provided in the above embodiments. It will be appreciated that the diffraction angles (20) provided in Table 9 are within the experimental error of the values provided above and also referred to in the present disclosure.
  • TGA Thermogravimetry Analysis
  • 2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide having a powder X-ray diffraction pattern comprising one or more peaks at diffraction angle (20) of 4.9 ⁇ 0.2, 7.6 ⁇ 0.2, 11.8 ⁇ 0.2, 15.5 ⁇ 0.2, 19.4 ⁇ 0.2, 19.9 ⁇ 0.2, 23.7 ⁇ 0.2, 27.0 ⁇ 0.2, or 27.4 ⁇ 0.2; or essentially the same as shown in FIG. 26.
  • 2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide having a powder X-ray diffraction pattern comprising one or more peaks at diffraction angle (20) of 14.3 ⁇ 0.2, 16.5 ⁇ 0.2, 18.2 ⁇ 0.2, 19.3 ⁇ 0.2, 20.1 ⁇ 0.2, 22.2 ⁇ 0.2, or 23.1 ⁇ 0.2; or essentially the same as shown in FIG. 27.
  • 2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide having a powder X-ray diffraction pattern comprising one or more peaks at diffraction angle (20) of 4.8 ⁇ 0.3, 7.2 ⁇ 0.3, 18.6 ⁇ 0.3, 19.6 ⁇ 0.3, or 25.0 ⁇ 0.3; or essentially the same as shown in FIG. 28.
  • a suspension composition comprising a crystalline form according to embodiment 1 or a crystalline polymorph form according to any one of embodiments 2 to 38, water, and optionally one or more dispersants, wetting agents, emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners.
  • the suspension composition of embodiment 40 comprising water, a dispersant, a wetting agent, and optionally one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners.
  • step of contacting comprises the crystalline form according to embodiment 1 or the crystalline polymorph form according to any one of embodiments 2 to 38, water, a dispersant, a wetting agent, and optionally one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners.
  • a process to control a pest comprising applying to a locus, a pesticidally effective amount of a crystalline form according to embodiment 1 , a crystalline polymorph form according to any one of embodiments 2 to 38, or a composition according to embodiment 39, or a suspension composition of embodiment 40 or 41.
  • a process to control a pest comprising applying to a locus, a pesticidally effective amount of a suspension composition prepared by a process comprising i. contacting a crystalline form according to embodiment 1 or a crystalline polymorph form according to any one of embodiments 2 to 38 with water and optionally one or more dispersants, wetting agents, emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners to provide a suspension mixture, and ii. agitating the suspension mixture to provide the suspension composition.
  • any one of polymorph forms I- VII, X, or XI of Compound 1 may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more active ingredients.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more active ingredients each having an insecticidal mode of action (MoA) that is the same as, similar to, but more likely different from, the MoA of any one or more of polymorph forms I- VII, X, or XI of Compound 1.
  • MoA insecticidal mode of action
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more molecules having acaricidal, algicidal, avicidal, bactericidal, fungicidal, herbicidal, insecticidal, molluscicidal, nematicidal, rodenticidal, and/or virucidal properties.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be used in combination (such as, in a compositional mixture, or a simultaneous or sequential application) with one or more molecules that are antifeedants, bird repellents, chemosterilants, herbicide safeners, insect attractants, insect repellents, mammal repellents, mating disrupters, plant activators, plant growth regulators, and/or synergists.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may also be used in combination (such as in a compositional mixture, or a simultaneous or sequential application) with one or more biopesticides.
  • a pesticidal composition in a pesticidal composition combination of any one or more of polymorph forms I- VII, X, or XI of Compound 1 and an active ingredient may be used in a wide variety of weight ratios.
  • weight ratios in a two-component mixture, the weight ratio of any one or more of polymorph forms I- VII, X, or XI of Compound 1 to an active ingredient, various ratios may be used. However, in general, weight ratios less than about 10:1 to about 1:10 are preferred. It is also preferred sometimes to use a three, four, five, six, seven, or more, component mixture comprising any one or more of polymorph forms I- VII, X, or XI of Compound 1 and an additional two or more active ingredients.
  • Weight ratios of any one or more of polymorph forms I- VII, X, or XI of Compound 1 to an active ingredient may also be depicted as X:Y; wherein X is the parts by weight of any one or more of polymorph forms I- VII, X, or XI of Compound 1 and Y is the parts by weight of active ingredient.
  • the numerical range of the parts by weight for X is 0 ⁇ X ⁇ 100 and the parts by weight for Y is 0 ⁇ Y ⁇ 100.
  • the weight ratio of any one or more of polymorph forms I- VII, X, or XI of Compound 1 to an active ingredient may be 20:1.
  • a pesticide is many times not suitable for application in its pure form. It is usually necessary to add other substances so that the pesticide may be used at the required concentration and in an appropriate form, permitting ease of application, handling, transportation, storage, and maximum pesticide activity.
  • pesticides are formulated into, for example, baits, concentrated emulsions, dusts, emulsifiable concentrates, fumigants, gels, granules, microencapsulations, seed treatments, suspension concentrates, suspoemulsions, tablets, water-soluble liquids, water-dispersible granules or dry flowables, wettable powders, and ultra-low volume solutions.
  • Pesticides are applied most often as aqueous suspensions or emulsions prepared from concentrated formulations of such pesticides.
  • Such water-soluble, water-suspendable, or emulsifiable formulations are either solids, usually known as wettable powders, water- dispersible granules, liquids usually known as emulsifiable concentrates, or aqueous suspensions.
  • Wettable powders which may be compacted to form water-dispersible granules, comprise an intimate mixture of the pesticide, a carrier, and surfactants.
  • the concentration of the pesticide is usually from about 10% to about 90% by weight.
  • the carrier is usually selected from among the attapulgite clays, the montmorillonite clays, the diatomaceous earths, or the purified silicates.
  • Effective surfactants comprising from about 0.5% to about 10% of the wettable powder, are found among sulfonated lignins, condensed naphthalenesulfonates, naphthalenesulfonates, alkylbenzenesulfonates, alkyl sulfates, and non-ionic surfactants such as ethylene oxide adducts of alkyl phenols.
  • SC pesticidal formulations are formulations that have generally insoluble solid active ingredients suspended in water with the aid of dispersants and wetting agents.
  • ingredients may have additional ingredients such as one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners, in order to make better products for use in agriculture and other uses, and for in a variety of environments (such as, field, laboratory, and different climate conditions).
  • emulsifiers such as one or more emulsifiers, antifreeze agents, biocides, antifoaming agents, and thickeners
  • Such ingredients are known in the art and used in a variety of combinations and amounts in an SC formulation.
  • WO 2000/008931; WO 2009/007344; WO 2014/047934; WO 2017/125010; WO 2017/202684; WO 2019/072602; WO2019076744; WO 2019/123186; WO 2019/197634; and WO 2021/127126 The method of the preparation of suspension concentrate formulations is known in the art and can be produced by known methods familiar to those skilled in the art.
  • Emulsifiable concentrates of pesticides comprise a convenient concentration of a pesticide, such as from about 50 to about 500 grams per liter (g/E) of liquid dissolved in a carrier that is either a water-miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers.
  • a carrier that is either a water-miscible solvent or a mixture of water-immiscible organic solvent and emulsifiers.
  • Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha.
  • Other organic solvents may also be used, such as the terpenic solvents including rosin derivatives, aliphatic ketones such as cyclohexanone, and complex alcohols such as 2-ethoxyethanol.
  • Suitable emulsifiers for emulsifiable concentrates are selected from conventional
  • Aqueous suspensions comprise suspensions of water-insoluble pesticides dispersed in an aqueous carrier at a concentration in the range from about 5% to about 50% by weight.
  • Suspensions are prepared by finely grinding the pesticide and vigorously mixing it into a carrier comprised of water and surfactants.
  • Ingredients, such as inorganic salts and synthetic or natural gums, may also be added to increase the density and viscosity of the aqueous carrier. It is often most effective to grind and mix the pesticide at the same time by preparing the aqueous mixture and homogenizing it in an implement such as a sand mill, ball mill, or piston-type homogenizer.
  • the pesticide in suspension might be microencapsulated in plastic polymer.
  • Oil dispersions comprise suspensions of organic solvent-insoluble pesticides finely dispersed in a mixture of organic solvent and emulsifiers at a concentration in the range from about 2% to about 50% by weight.
  • One or more pesticide might be dissolved in the organic solvent.
  • Useful organic solvents include aromatics, especially xylenes and petroleum fractions, especially the high-boiling naphthalenic and olefinic portions of petroleum such as heavy aromatic naphtha.
  • Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.
  • Suitable emulsifiers for oil dispersions are selected from conventional anionic and non-ionic surfactants. Thickeners or gelling agents are added in the formulation of oil dispersions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets.
  • Pesticides may also be applied as granular compositions that are particularly useful for applications to the soil.
  • Granular compositions usually contain from about 0.5% to about 10% by weight of the pesticide, dispersed in a carrier that comprises clay or a similar substance.
  • Such compositions are usually prepared by dissolving the pesticide in a suitable solvent and applying it to a granular carrier, which has been pre-formed to the appropriate particle size, in the range of from about 0.5 millimeters (mm) to about 3 mm.
  • Such compositions may also be formulated by making a dough or paste of the carrier and molecule, and then crushing and drying to obtain the desired granular particle size.
  • Another form of granules is a water- emulsifiable granule (EG).
  • Dusts containing a pesticide are prepared by intimately mixing the pesticide in powdered form with a suitable dusty agricultural carrier, such as kaolin clay, ground volcanic rock, and the like. Dusts can suitably contain from about 1% to about 10% of the pesticide.
  • Dusts may be applied as a seed dressing or as a foliage application with a dust blower machine.
  • a pesticide in the form of a solution in an appropriate organic solvent, usually petroleum oil, such as the spray oils, which are widely used in agricultural chemistry.
  • Pesticides can also be applied in the form of an aerosol composition.
  • the pesticide is dissolved or dispersed in a carrier, which is a pressure-generating propellant mixture.
  • the aerosol composition is packaged in a container from which the mixture is dispensed through an atomizing valve.
  • Pesticide baits are formed when the pesticide is mixed with food or an attractant or both. When the pests eat the bait, they also consume the pesticide. Baits may take the form of granules, gels, flowable powders, liquids, or solids. Baits may be used in pest harborages.
  • Fumigants are pesticides that have a relatively high vapor pressure and hence can exist as a gas in sufficient concentrations to kill pests in soil or enclosed spaces. The toxicity of the fumigant is proportional to its concentration and the exposure time. They are characterized by a good capacity for diffusion and act by penetrating the pest's respiratory system or being absorbed through the pest's cuticle. Fumigants are applied to control stored product pests under gas proof sheets, in gas sealed rooms or buildings, or in special chambers.
  • Pesticides may be microencapsulated by suspending the pesticide particles or droplets in plastic polymers of various types. By altering, the chemistry of the polymer or by changing factors in the processing, microcapsules may be formed of various sizes, solubility, wall thicknesses, and degrees of penetrability. These factors govern the speed with which the active ingredient within is released, which in turn, affects the residual performance, speed of action, and odor of the product.
  • the microcapsules might be formulated as suspension concentrates or water dispersible granules.
  • Oil solution concentrates are made by dissolving pesticide in a solvent that will hold the pesticide in solution
  • oil solutions of a pesticide usually provide faster knockdown and kill of pests than other formulations due to the solvents themselves having pesticidal action and the dissolution of the waxy covering of the integument increasing the speed of uptake of the pesticide.
  • Other advantages of oil solutions include better storage stability, better penetration of crevices, and better adhesion to greasy surfaces.
  • Another embodiment is an oil-in-water emulsion, wherein the emulsion comprises oily globules which are each provided with a lamellar liquid crystal coating and are dispersed in an aqueous phase, wherein each oily globule comprises at least one molecule which is agriculturally active, and is individually coated with a monolamellar or oligolamellar layer comprising: (1) at least one non- ionic lipophilic surface- active agent, (2) at least one non- ionic hydrophilic surface-active agent, and (3) at least one ionic surface-active agent, wherein the globules having a mean particle diameter of less than 800 nanometers.
  • such formulation can also contain other components.
  • these components include, but are not limited to, (this is a non-exhaustive and non-mutually exclusive list) wetters, spreaders, stickers, penetrants, buffers, sequestering agents, drift reduction agents, compatibility agents, anti-foam agents, cleaning agents, and emulsifiers. A few components are described forthwith.
  • a wetting agent is a substance that when added to a liquid increases the spreading or penetration power of the liquid by reducing the interfacial tension between the liquid and the surface on which it is spreading.
  • Wetting agents are used for two main functions in agrochemical formulations: during processing and manufacture to increase the rate of wetting of powders in water to make concentrates for soluble liquids or suspension concentrates; and during mixing of a product with water in a spray tank to reduce the wetting time of wettable powders and to improve the penetration of water into water-dispersible granules.
  • wetting agents used in wettable powder, suspension concentrate, and water-dispersible granule formulations are: sodium lauryl sulfate, sodium dioctyl sulfosuccinate, alkyl phenol ethoxylates, and aliphatic alcohol ethoxylates.
  • a dispersing agent is a substance that adsorbs onto the surface of particles, helps to preserve the state of dispersion of the particles, and prevents them from reaggregating.
  • Dispersing agents are added to agrochemical formulations to facilitate dispersion and suspension during manufacture, and to ensure the particles redisperse into water in a spray tank. They are widely used in wettable powders, suspension concentrates, and water-dispersible granules.
  • Surfactants that are used as dispersing agents have the ability to adsorb strongly onto a particle surface and provide a charged or steric barrier to reaggregation of particles. The most commonly used surfactants are anionic, non-ionic, or mixtures of the two types.
  • the most common dispersing agents are sodium lignosulfonates.
  • suspension concentrates very good adsorption and stabilization are obtained using poly electrolytes, such as sodium-naphthalene-sulfonate-formaldehyde-condensates.
  • Tristyrylphenol ethoxylate phosphate esters are also used.
  • Non-ionics such as alkylarylethylene oxide condensates and EO-PO block copolymers are sometimes combined with anionics as dispersing agents for suspension concentrates.
  • anionics as dispersing agents for suspension concentrates.
  • new types of very high molecular weight polymeric surfactants have been developed as dispersing agents. These have very long hydrophobic 'backbones' and a large number of ethylene oxide chains forming the 'teeth' of a 'comb' surfactant. These high molecular weight polymers can give very good long-term stability to suspension concentrates because the hydrophobic backbones have many anchoring points onto the particle surfaces.
  • dispersing agents used in agrochemical formulations are: sodium lignosulfonates, sodium naphthalene sulfonate formaldehyde condensates, tristritylphenol- ethoxylate-phosphate-esters, aliphatic alcohol ethoxylates, alkyl ethoxylates, EO-PO block copolymers, and graft copolymers.
  • An emulsifying agent is a substance that stabilizes a suspension of droplets of one liquid phase in another liquid phase. Without the emulsifying agent, the two liquids would separate into two immiscible liquid phases.
  • the most commonly used emulsifier blends contain an alkylphenol or an aliphatic alcohol with twelve or more ethylene oxide units and the oil- soluble calcium salt of dodecyl benzenesulfonic acid.
  • a range of hydrophile-lipophite balance (“HLB”) values from about 8 to about 18 will normally provide good stable emulsions. Emulsion stability can sometimes be improved by the addition of a small amount of an EO-PO block copolymer surfactant.
  • a solubilizing agent is a surfactant that will form micelles in water at concentrations above the critical micelle concentration. The micelles are then able to dissolve or solubilize water-insoluble materials inside the hydrophobic part of the micelle.
  • the types of surfactants usually used for solubilization are non-ionics, sorbitan monooleates, sorbitan monooleate ethoxylates, and methyl oleate esters.
  • Surfactants are sometimes used, either alone or with other additives such as mineral or vegetable oils as adjuvants to spray-tank mixes to improve the biological performance of the pesticide on the target.
  • the types of surfactants used for bioenhancement depend generally on the nature and mode of action of the pesticide. However, they are often non-ionics such as: alkyl ethoxylates, linear aliphatic alcohol ethoxylates, and aliphatic amine ethoxylates.
  • a carrier or diluent in an agricultural formulation is a material added to the pesticide to give a product of the required strength.
  • Carriers are usually materials with high absorptive capacities, while diluents are usually materials with low absorptive capacities.
  • Carriers and diluents are used in the formulation of dusts, wettable powders, granules, and water-dispersible granules.
  • Organic solvents are used mainly in the formulation of emulsifiable concentrates, oil-in- water emulsions, suspoemulsions, oil dispersions, and ultra-low volume formulations, and to a lesser extent, granular formulations. Sometimes mixtures of solvents are used.
  • the first main groups of solvents are aliphatic paraffinic oils such as kerosene or refined paraffins.
  • the second main group (and the most common) comprises the aromatic solvents such as xylene and higher molecular weight fractions of C9 and C10 aromatic solvents.
  • Chlorinated hydrocarbons are useful as cosolvents to prevent crystallization of pesticides when the formulation is emulsified into water. Alcohols are sometimes used as cosolvents to increase solvent power.
  • Other solvents may include vegetable oils, seed oils, and esters of vegetable and seed oils.
  • Thickeners or gelling agents are used mainly in the formulation of suspension concentrates, oil dispersions, emulsions and suspoemulsions to modify the rheology or flow properties of the liquid and to prevent separation and settling of the dispersed particles or droplets.
  • Thickening, gelling, and anti-settling agents generally fall into two categories, namely water-insoluble particulates and water-soluble polymers. It is possible to produce suspension concentrate and oil dispersion formulations using clays and silicas. Examples of these types of materials, include, but are not limited to, montmorillonite, bentonite, magnesium aluminum silicate, and attapulgite.
  • Water-soluble polysaccharides in water-based suspension concentrates have been used as thickening-gelling agents for many years, the types of polysaccharides most commonly used are natural extracts of seeds and seaweeds or are synthetic derivatives of cellulose. Examples of these types of materials include, but are not limited to, guar gum, locust bean gum, carrageenan, alginates, methyl cellulose, sodium carboxymethyl cellulose (SCMC), and hydroxy ethyl cellulose (HEC).
  • Other types of anti-settling agents are based on modified starches, polyacrylates, polyvinyl alcohol, and polyethylene oxide. Another good anti-settling agent is xanthan gum.
  • Microorganisms can cause spoilage of formulated products. Therefore, preservation agents are used to eliminate or reduce their effect. Examples of such agents include, but are not limited to: propionic acid and its sodium salt, sorbic acid and its sodium or potassium salts, benzoic acid and its sodium salt, p-hydroxybenzoic acid sodium salt, methyl p- hydroxybenzoate, and l,2-benzisothiazolin-3-one (BIT).
  • anti-foam agents are often added either during the production stage or before filling into bottles.
  • anti-foam agents there are two types of anti-foam agents, namely silicones and non-silicones. Silicones are usually aqueous emulsions of dimethyl polysiloxane, while the nonsilicone anti-foam agents are water- insoluble oils, such as octanol and nonanol, or silica. In both cases, the function of the anti-foam agent is to displace the surfactant from the air- water interface.
  • Green agents can reduce the overall environmental footprint of crop protection formulations.
  • Green agents are biodegradable and generally derived from natural and/or sustainable sources, e.g. plant and animal sources. Specific examples are: vegetable oils, seed oils, and esters thereof
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied to any locus.
  • loci to apply such molecules include loci where alfalfa, almonds, apples, barley, beans, canola, com, cotton, crucifers, flowers, fodder species (Rye Grass, Sudan Grass, Tall Fescue, Kentucky Blue Grass, and Clover), fruits, lettuce, oats, oil seed crops, oranges, peanuts, pears, peppers, potatoes, rice, sorghum, soybeans, strawberries, sugarcane, sugarbeets, sunflowers, tobacco, tomatoes, wheat (for example, Hard Red Winter Wheat, Soft Red Winter Wheat, White Winter Wheat, Hard Red Spring Wheat, and Durum Spring Wheat), and other valuable crops are growing or the seeds thereof are going to be planted.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may also be applied where plants, such as crops, are growing and where there are low levels (even no actual presence) of pests that can commercially damage such plants. Applying such molecules in such locus is to benefit the plants being grown in such locus.
  • Such benefits may include, but are not limited to: helping the plant grow a better root system; helping the plant better withstand stressful growing conditions; improving the health of a plant; improving the yield of a plant (e.g. increased biomass and/or increased content of valuable ingredients); improving the vigor of a plant (e.g. improved plant growth and/or greener leaves); improving the quality of a plant (e.g. improved content or composition of certain ingredients); and improving the tolerance to abiotic and/or biotic stress of the plant.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied with ammonium sulfate when growing various plants as this may provide additional benefits.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied on, in, or around plants genetically modified to express specialized traits, such as Bacillus thuringiensis (for example, CrylAb, CrylAc, CrylFa, CrylA.105, Cry2Ab, Vip3A, mCry3A, Cry3Ab, Cry3Bb, Cry34Abl/Cry35Abl), other insecticidal toxins, or those expressing herbicide tolerance, or those with "stacked" foreign genes expressing insecticidal toxins, herbicide tolerance, nutrition-enhancement, or any other beneficial traits.
  • Bacillus thuringiensis for example, CrylAb, CrylAc, CrylFa, CrylA.105, Cry2Ab, Vip
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied to the foliar and/or fruiting portions of plants to control pests. Either such polymorph of Compound 1 will come in direct contact with the pest, or the pest will consume such polymorph of Compound 1 when eating the plant or while extracting sap or other nutrients from the plant.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may also be applied to the soil, and when applied in this manner, root and stem feeding pests may be controlled. The roots may absorb such molecules thereby taking it up into the foliar portions of the plant to control above ground chewing and sap feeding pests.
  • Systemic movement of pesticides in plants may be utilized to control pests on one portion of the plant by applying (for example by spraying a locus) any one or more of polymorph forms I- VII, X, or XI of Compound 1 to a different portion of the plant.
  • control of foliar-feeding insects may be achieved by drip irrigation or furrow application, by treating the soil with for example pre- or post-planting soil drench, or by treating the seeds of a plant before planting.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be used with baits.
  • the baits are placed in the ground where, for example, termites can come into contact with, and/or be attracted to the bait.
  • Baits can also be applied to a surface of a building, (horizontal, vertical, or slant surface) where, for example, ants, termites, cockroaches, and flies can come into contact with, and/or be attracted to, the bait.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be encapsulated inside, or placed on the surface of a capsule.
  • the size of the capsules can range from nanometer size (about 100-900 nanometers in diameter) to micrometer size (about 10-900 microns in diameter).
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied to eggs of pests. Because of the unique ability of the eggs of some pests to resist certain pesticides, repeated applications of such molecules may be desirable to control newly emerged larvae.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied as seed treatments. Seed treatments may be applied to all types of seeds, including those from which plants genetically modified to express specialized traits will germinate. Representative examples include those expressing proteins toxic to invertebrate pests, such as Bacillus thuringiensis or other insecticidal toxins, those expressing herbicide tolerance, such as "Roundup Ready” seed, or those with "stacked” foreign genes expressing insecticidal toxins, herbicide tolerance, nutrition-enhancement, drought tolerance, or any other beneficial traits, Furthermore, such seed treatments with any one or more of polymorph forms I- VII, X, or XI of Compound 1 may further enhance the ability of a plant to withstand stressful growing conditions better.
  • any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be applied with one or more active ingredients in a soil amendment.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may be used for controlling endoparasites and ectoparasites in the veterinary medicine sector or in the field of non-human- animal keeping.
  • Such molecules may be applied by oral administration in the form of, for example, tablets, capsules, drinks, and granules; by dermal application in the form of, for example, dipping, spraying, pouring on, spotting on, and dusting; and by parenteral administration in the form of, for example, an injection.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may also be employed advantageously in livestock keeping, for example, cattle, chickens, geese, goats, pigs, sheep, and turkeys. They may also be employed advantageously in pets such as, horses, dogs, and cats. Particular pests to control would be flies, fleas, and ticks that are bothersome to such animals. Suitable formulations are administered orally to the animals with the drinking water or feed. The dosages and formulations that are suitable depend on the species.
  • Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may also be used for controlling parasitic worms, especially of the intestine, in the animals listed above. Any one or more of polymorph forms I- VII, X, or XI of Compound 1 may also be employed in therapeutic methods for human health care, such methods include, but are not limited to, oral administration in the form of, for example, tablets, capsules, drinks, and granules, and by dermal application.
  • Polymorph forms I- VII, X, or XI of Compound 1 may also be applied to invasive pests. Pests around the world have been migrating to new environments (for such pest) and thereafter becoming a new invasive species in such new environment. Such polymorphs may also be used on such new invasive species to control them in such new environments.
  • Step 1 In a 100 milliliter (mL) one-neck round bottom flask were added ( l /?,3/?)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l -carboxylic acid prepared according to the methods described in USPN 10258045 or 9,781,935 (1-1; 2.02 grams (g), 5.5 millimoles (mmol)) and toluene (5 mL). To this suspension was added thionyl chloride (1.19 g, 10 mmol) and DMF (3 drops). The suspension was heated to 40 °C and held there for 15 hours (h).
  • Step 2 To a 500 mL one-neck flask were added 5-amino-2-chloro-jV-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (1-3 prepared according to the methods described in USPN 10258045; 1.88 g, 5 mmol), ethyl acetate (EtOAc; 50 mL) and sodium bicarbonate (NaHCCh; 1.26 g, 15 mmol). The suspension was stirred under a nitrogen (N2) atmosphere and cooled to 5 °C (ice bath). To this suspension was added a solution of acid chloride, as prepared in Step 1, dropwise maintaining the temperature below 10 °C.
  • N2 nitrogen
  • Step 1 In a 250-mL jacketed reactor equipped with an overhead stirrer, internal temperature probe, N2-inlet, and vent tubing were added (lR,3R)-3-(3 ,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l -carboxylic acid prepared according to the methods described in USPN 10258045 (1-1; 5 g, 13.62 mmol), A-formylpiperidine (0.077 g, 0.681 mmol) and ethyl acetate (25 mL) at 21 °C. Oxalyl chloride (1.312 mL, 14.98 mmol) was added dropwise over 30 minutes at 21-25 °C.
  • step 2 (coupling reaction) without further purification or isolation.
  • Step 2 In a 250-mL jacketed reactor equipped with an overhead stirrer, internal temperature probe, and N2-inlet were added 5-amino-2-chloro-A , -(3-(2,2-dil’luoroacetamido)- 2,4-difluorophenyl)benzamide (1-3 prepared according to the methods described in USPN 10258045; 4.61 g, 12.26 mmol) and sodium bicarbonate (2.289 g, 27.2 mmol) in ethyl acetate (40 mL). The mixture was cooled to 10-15 °C. At this temperature, the acid chloride solution was added dropwise over 30 minutes.
  • the solution was transferred to a separatory funnel and was washed with a solution of sodium dihydrogen phosphate (43.0 g, 359 mmol) and sodium phosphate dibasic (50.9 g, 359 mmol) in water (1 L) (2 x 500 mL), then with brine (1 x 200 mL).
  • the EtOAc portion was collected, dried (Na2SO4) and concentrated.
  • the residue was diluted in MeCN (300 mL) and re-concentrated to a foam.
  • the oil was taken up in DCM (-800 mL) and transferred to a 4-neck round-bottom flask equipped with an overhead stirred, reflux condenser, N2-inlet and temperature probe.
  • Example 7A Polymorph form II (without seed material):
  • Example 7B Polymorph form II (with seed material):
  • Example 7C Polymorph form II (Mixed solvent):
  • the mixture was kept shaking at 8 °C for 24 h.
  • the off-white suspension was centrifuged and the residue was subjected to two-stage drying. It was first dried under vacuum (700 mm of Hg) at room temperature for 24 h, then dried under vacuum (700 mm of Hg) at 40 °C for 24 h. The same was performed for both of the solvent systems. In each case, crystalline polymorph form II was obtained.
  • Example 8A Polymorph form III (without seed material)
  • Example 8B Polymorph form III (with seed material)
  • Example 8C Polymorph III Scale-up Procedure:
  • the off-white solid thus formed was centrifuged and subjected to two-stage drying. First dried under vacuum (700 mm of Hg) at room temperature for 24 h, then dried under vacuum (700 mm of Hg) at 40 °C for 24 h. The same process followed for both the solvent systems.
  • Example 9A Crystallization of 5-((17?,37?)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2- dichlorocyclopropane-l-carboxamido)-2-chloro-jV-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide (1) as polymorph form IV.
  • step 2 The organic phase from Example 4, step 2 was concentrated to about 15 mL of ethyl acetate. The mixture was heated to 40 °C and n-heptane (45 mL) was added slowly over 30 minutes. The mixture was slowly cooled to 21 °C upon which time a slurry formed. The slurry was filtered at 21 °C to give an off-white solid that was dried in vacuo to afford desired product (8.09 g, 82%). Analysis by PXRD and DSC showed desired product as polymorph form IV.
  • Example 9B Alternative crystallization of 5-((lR,3R)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (1) as polymorph form IV.
  • the filtrate was transferred to the 20-L reactor and rinsed with ethyl acetate (0.125) at 25-30 °C.
  • the reaction mass was heated to 40-45 °C and stirred for 15-20 minutes.
  • Heptane (5 L) was added slowly to the reaction mass over 2-3 h at 40-45 °C.
  • the reaction mass was seeded with desired form IV at 40-45 °C.
  • the reaction mass was stirred for 1.0-2.5 h at 40-45 °C.
  • Heptane (3.5 L) was added slowly to the reaction mass over 1-2 h at 40-45 °C.
  • the reaction mass was stirred for 2 h at 40-45 °C. Polymorph interconversion was monitored by DSC.
  • reaction mass Upon formation of desired form IV, the reaction mass was cooled to 25-30 °C and stirred for 2-3 h. The slurry was filtered under vacuum at 25-30 °C. The wet cake was washed with heptane (I L) and dried under vacuum for 2-4 h. The wet solid was dried at 50-55 °C for 8-10 h in a vacuum tray drier. The vacuum was released, and the sample was cooled to 25-30 °C. The material was removed from the oven and analysed indicating formation of desired product form IV (440 g, 88%).
  • Example 9C Alternative recrystallization of 5-(( l /?,3/?)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (1) as polymorph form IV.
  • Hexanes (7 L) was added to the reactor continuously over 1.5 hr using a peristaltic pump.
  • the solution was seed with slurry of polymorph form IV of Compound 1 (4.7 g) in 4:1 v/v hexanes/ethyl acetate (150 mL). Additional hexanes (7 L) was added to the reactor continuously over 3 hr using a peristaltic pump.
  • the resulting slurry was stirred at 45 °C for 18hr.
  • the slurry was cooled to 20 °C and stirred for 2 hours.
  • the slurry was filtered through a fritted funnel and the cake was washed with hexanes (8 L).
  • the wet cake was dried at 45 °C under vacuum to obtain polymorph form IV of Compound 1 (1288 g, 92% recovery).
  • Example 9D Alternative crystallization of 5-((17?,37?)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (1) as polymorph form IV.
  • Heptane (135 mL) was then added slowly to the reaction mass over 20-30 minutes at 40-45 °C.
  • the reaction mass was seeded at 40-45 °C with a wet slurry containing the desired polymorph form IV.
  • heptane 300 mL was then added slowly to reaction mass over 0.5-1 h at 50-55 °C.
  • the reaction mass was linearly cooled to 20 °C over 3-4 h and stirred for 1-2 h.
  • the slurry was filtered under vacuum at room temperature.
  • the wet cake was then washed with heptane (100 mL).
  • the wet solid was dried at 50 °C for 8-10 h in vacuum tray drier. The vacuum is released, and the sample is cooled to 25-30 °C.
  • the material was unloaded from oven and analyzed confirming formation of polymorph form IV (22 g, 91%).
  • Example 9E Alternative crystallization of 5-((17?,37?)-3-(3,5- bis(trifluoromethyl)phenyl)-2,2-dichlorocyclopropane-l-carboxamido)-2-chloro-V-(3-(2,2- difluoroacetamido)-2,4-difluorophenyl)benzamide (1) as polymorph form IV.
  • the product was filtered, washed with heptane and dried.
  • the solids were dissolved in acetonitrile (800 mL).
  • the acetonitrile solution was slowly concentrated to dryness via rotary evaporator to provide polymorph form V.
  • Heptanes 150mL were added using a peristaltic pump over 90 minutes. The mixture was seeded with a slurry of polymorph form IV (100 mg) in ethyl acetate/hexanes (3:1 v/v). Additional heptanes (150mL) were added using a peristaltic pump over 90 minutes. The slurry was stirred at 45 °C for 48 hours. The slurry was cooled to 20 °C and stirred for 2 hours.
  • Example 15 [0563] Powder X-ray Diffraction (PXRD) of crystalline polymorph forms I, II, III, and IV of Compound 1.
  • the Rigaku Smart- Lab X-ray diffraction system was configured for reflection Bragg- Brentano geometry using a line source X-ray beam.
  • the x-ray source is a Cu Long Fine Focus tube that was operated at 40 kV and 44 mA. That source provides an incident beam profile at the sample that changes from a narrow line at high angles to a broad rectangle at low angles. Beam conditioning slits are used on the line X-ray source to ensure that the maximum beam size is less than 10 mm both along the line and normal to the line.
  • the Bragg-Brentano geometry is a para-focusing geometry controlled by passive divergence and receiving slits with the sample itself acting as the focusing component for the optics.
  • the inherent resolution of Bragg-Brentano geometry is governed in part by the diffractometer radius and the width of the receiving slit used. Typically, the Rigaku Smart-Lab is operated to give peak widths of 0.1 °20 or less.
  • the axial divergence of the X-ray beam is controlled by 5.0-degree Seller slits in both the incident and diffracted beam paths.
  • Powder samples were prepared in a low background Si holder using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder. Each sample was analyzed from 2 to 40 °20using a continuous scan of 6 °20per minute with an effective step size of 0.02 °20. High resolution samples were analyzed using a continuous scan of 1 °20per minute and the sample were rotated at 50 rpm (one revolution per 0.02 °20step).
  • the PXRD data provided in Table 4 are averaged data from PXRD experiments of five unique samples of polymorph form IV.
  • FIG. 4 is a representative PXRD spectrum of polymorph form IV.
  • Three of the samples used in the averaged data of Table 4 were obtained using Example 9D.
  • One of the samples used in the averaged data of Table 4 was obtained using Example 9D except that the experiment was seeded with polymorph form II instead of polymorph form IV, and polymorph form IV was obtained from the experiment instead of polymorph form II.
  • One sample was prepared as described in Example 9E.
  • Samples were analyzed using a Rigaku Miniflex II Benchtop X-ray diffractometer.
  • the X-ray source is a Cu Normal Focus tube operated at 30 kV and 15 mA. Additional operating parameters are provided in Table 14.
  • Powder samples were prepared by adding at least 20 mg to a glass sample holder and using light manual pressure to keep the sample surfaces flat and level with the reference surface of the sample holder. The glass holder was placed on top of an aluminum support. Each sample was analyzed from 3 to 40 °2 fusing a continuous scan of 5 °20per minute with an effective step size of 0.02 °2ft High resolution samples were analyzed using a continuous scan of 0.2 °20 per minute and an effective step size of 0.01 °20.
  • DSC Differential Scanning Calorimetry
  • DSC analyses were carried out using a TA Instruments Q2500 Discovery Series instrument. The instrument temperature calibration was performed using indium. The DSC cell was kept under a nitrogen purge of ⁇ 50 mL per minute during each analysis. The sample was placed in a standard, crimped, aluminum pan and was heated from approximately 25 °C to 350 °C at a rate of 10 °C per minute.
  • DSC analyses were carried out using a TA Instruments DSC Q2000 instrument.
  • the DSC cell was kept under a nitrogen purge of ⁇ 50 mL per minute during each analysis.
  • the sample was placed in a standard, crimped, aluminum pan and was heated from approximately 25 °C to 200 °C at a rate of 10 °C per minute.
  • DSC Differential Scanning Calorimetry
  • Each sample was packed into the 4 mm (thick wall GFT) rotor, and then spun at 10 - 15 kHz using the Doty probe at room temperature.
  • Various spinning speeds (10 - 15 kHz) were measured, in order to identify isotropic 19 F chemical shifts of each polymorph and also to obtain the best resolved spectra.
  • the spectra are provided in FIGs. 16-25.
  • Spinning sidebands (SSBs) in 19 F DP spectra and residual SSBs in 19 F DP/TOSS spectra are represented by single asterisks in FIGs. 16-25.
  • a double asterisk in FIGs. 16-25 indicates SSBs overlapped with background 19 F signals from the probe.
  • Table 18 represents the reference peak for chemical shifts reported as “shift from reference”
  • Table 19 represents the reference peak for chemical shifts reported as “shift from reference”
  • Table 20 represents the reference peak for chemical shifts reported as “shift from reference”
  • Table 21 represents the reference peak for chemical shifts reported as “shift from reference”
  • ssNMR spectra for polymorph form V are shown in FIGs. 24 and 25, and the results are provided in Table 22.
  • the tabulated results show chemical shifts using a 19 F DP experimental method and a 19 F DP/TOSS experimental method.
  • Table 22 represents the reference peak for chemical shifts reported as “shift from reference”
  • Powder samples were loaded into a platinum pan and heated from 25 °C to 225 °C at a rate of 10 °C/minute using a TA Instruments TGA Q50 instrument with a balance nitrogen purge of 40 mL/min and a sample nitrogen purge of 85 mL/min. The results are shown in FIGs. 34-37.
  • Fl 802 has an (R,R) enantiomer which is described by the following formula.
  • the (R,R) enantiomer is named 5-((17?,37?)-3-(3,5-bis(trifluoromethyl)phenyl)-2,2- dichlorocyclopropane-l-carboxamido)-2-chloro-jV-(3-(2,2-difluoroacetamido)-2,4- difluorophenyl)benzamide (a.k.a. “Fl 802 (7?,7?)-enantiomer”).
  • Fl 802 (7?,7?)-enantiomer As disclosed above in this application polymorph forms of Fl 802 (7?,7?)-enantiomer have been discovered.
  • polymorph form IV of F1802 (a.k.a. polymorph form IV of Compound 1), as prepared herein, was used.
  • F1802 as prepared according to the methods described in WO2018/071327, was used.
  • Example 22b- 1 Foliar Spray Method for Evaluating Lepidopteran Species
  • Test materials were formulated as suspension concentrates (SC, see Table A). Test solutions were prepared by weighing the appropriate amount of formulated material (adjusted for active ingredient purity) and then adding the appropriate amount of diluent containing purified water with Tween- 20 at 0.125% v/v (volume per volume). Subsequent two-fold serial dilutions were prepared and the resulting test concentrations included 5, 2.5, 1.25, 0.625, 0.3125, 0.156, 0.078 and 0.039 grams of active ingredient per hectare (gai/h).
  • Brassica oleracea capitata (Early Jersey Wakefield cabbage), was grown to the 2-3 true leaf stage (5-7 cm). Two cabbage plants (containing 4 true leaves/treatment) were setup in staging trays to ensure uniform application coverage. Test solutions were applied to the cabbage using an overhead boom with single hollow-cone nozzle calibrated to 200 liters per hectare (L/h) spray volume. After spray application, leaves were allowed to dry in a ventilated area for one hour before excising treated leaves. One excised leaf was placed in a test container containing a bed of 2% solidified agar to maintain moisture in the test chamber. Each treatment was replicated four times. Two larval stage 2 (L2) insects were placed on each treated leaf (8 larvae per dose).
  • L2 larval stage 2
  • Example 22b-2 Cotton Leaf-Dip Method for Evaluating Western Flower Thrips (Frankliniella occidentalism
  • Test materials used were formulated as suspension concentrates (SC, see Table A). Test solutions were prepared by weighing the appropriate amount of formulated material (adjusted for active ingredient purity) and then adding the appropriate amount of diluent containing purified water with Tween- 20 at 0.025% v/v. Test solutions were calculated in parts of the active ingredient per million (ppm, e.g., 20 mg of SC formulation added to 10 mL of diluent solution achieved the 200-ppm stock solution). Subsequent two-fold serial dilutions were prepared and the resulting test concentrations included 6.25, 3.125, 1.562, 0.781, 0.390, 0.195, 0.097, 0.048, 0.024 ppm.
  • Leaf disks were trimmed from the true leaves of cotton plants (2.7 centimeter (cm) diameter). Leaf disks were dipped into test solution and agitated for 5 seconds and then removed and placed adaxial-side up in a petri dish lined with filter paper to dry. Leaf disks were dried for 30 minutes before infesting. Once leaves were dry, 150 microliters (pL) of distilled water was applied to the filter paper to create a moist holding environment over the three-day holding period. Each treatment was replicated two times. Western flower thrips (WFT) larvae were collected via aspiration and transferred to the treated leaf disc using a fine paintbrush (5 larvae per leaf disc). After infestation, the petri dish was capped immediately to prevent insect escape. Tests were held for three days at 26 °C, 16-hour light: 8-hour dark photoperiod. The number of live WFT larvae per treated leaf disc was recorded three days after treatment and infestation. Each LC50 was determined using probit analysis.
  • WFT Western flower thrips
  • Example 22b-3 Bean-Dip Method for Evaluating Lygus hesperus (Western Tarnished Plant Bug) and Stink bug (Euschistus heros)
  • test solutions were evaluated using a dip assay on green bean segments (3-4 cm in length).
  • Test materials were formulated as suspension concentrates (SC, see Table A).
  • Test solutions were prepared by weighing the appropriate amount of formulated material (adjusted for active ingredient purity) and then adding the appropriate amount of diluent containing purified water with Tween-20 at 0.025% v/v. Test solutions were calculated in ppm. Subsequent four-fold serial dilutions were prepared and the resulting test concentrations included 200, 50, 1.25, and 3.125 ppm. Additional lower doses were prepared as needed.
  • Green bean segments were prepared and were placed in vials containing test solutions. The vials were capped and agitated to ensure uniform coverage. Bean segments were allowed to soak for 15 minutes after agitation. After soaking, one bean segment was placed in a test chamber containing filter paper at the bottom and air-dried for 30 minutes. A negative control was included and consisted of beans soaked in Millipore water diluent with no compound. Each treatment was replicated four times. Each treated green bean was infested with either three WTPB or five SB nymphs. After infestation, the test chambers were sealed with adhesive perforated lids to allow air exchange and prevent insect escape.
  • Test containers were held at 25 °C, 16-hour light: 8-hour dark photoperiod and held for 3 days after infestation for WTPB and 4 days after infestation for SB. Upon completion of the test, the number of dead nymphs were recorded and probit analysis was used to determine each LC50.

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WO2023208447A1 (en) 2022-04-25 2023-11-02 Basf Se An emulsifiable concentrate having a (substituted) benzaldehyde-based solvent system
EP4342885A1 (en) 2022-09-20 2024-03-27 Basf Se N-(3-(aminomethyl)-phenyl)-5-(4-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine derivatives and similar compounds as pesticides
EP4389210A1 (en) 2022-12-21 2024-06-26 Basf Se Heteroaryl compounds for the control of invertebrate pests

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023208447A1 (en) 2022-04-25 2023-11-02 Basf Se An emulsifiable concentrate having a (substituted) benzaldehyde-based solvent system
EP4342885A1 (en) 2022-09-20 2024-03-27 Basf Se N-(3-(aminomethyl)-phenyl)-5-(4-phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazol-3-amine derivatives and similar compounds as pesticides
EP4389210A1 (en) 2022-12-21 2024-06-26 Basf Se Heteroaryl compounds for the control of invertebrate pests

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