Improved chlorantraniliprole process using crystalline intermediates

Abstract

Ternary crystals containing a compound of formula II, a compound of formula III, and an amine base in an equimolar ratio (1:1:1) are disclosed. Also disclosed are methods for preparing ternary crystals containing a compound of formula II, a compound of formula III, and an amine base in an equimolar ratio (1:1:1). Furthermore, methods for preparing chlorantraniliprole using the ternary crystals of the present disclosure are disclosed. [Formula 1] TIFF2023537236000029.tif47170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Provisional Patent Application No. 63 / 055,446, filed July 23, 2020, which is incorporated by reference herein in its entirety.

[0002] The present disclosure relates to ternary crystals that include intermediates produced in the final step in the synthesis of chlorantraniliprole. The present disclosure also relates to methods of preparing chlorantraniliprole using the ternary crystals of the present disclosure. [Background technology]

[0003] 3-Bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylic acid (Formula II) and 2-amino-5-chloro-N,3-dimethylbenzamide (Formula III) [ka] is a compound of chlorantraniliprole (formula I) [ka] It is a key intermediate in the final step of the synthesis of

[0004] Conventional processes for producing highly pure compounds of formula II and III generally involve separate recrystallization steps for both intermediates, resulting in increased waste and reduced yields. New methods for producing highly pure compounds of formula II and III are needed. Summary of the Invention [Means for solving the problem]

[0005] The present disclosure provides: (a) a compound of formula II: [ka] (b) a compound of formula III; [ka] and (c) Amine base This relates to a ternary crystal containing these in an equimolar ratio (1:1:1).

[0006] The present disclosure further comprises: (a) a compound of formula II: [ka] (b) a compound of formula III; [ka] and (c) Amine base In a method for preparing a ternary crystal comprising: This method: (i) combining a compound of formula II, a compound of formula III, and an amine base in a polar aprotic solvent; and (ii) isolating the ternary crystals from the polar aprotic solvent. Includes:

[0007] The present disclosure further provides a compound of formula I [ka] 1. A method for preparing a medicament for the preparation of ... (a) (i) A compound of formula II: [ka] (ii) a compound of formula III; [ka] and (iii) Amine base reacting a suspension of ternary crystals containing the compounds in an equimolar ratio (1:1:1) in an aprotic polar solvent with an acid activator; (b) coupling of the acid-activated compounds of formula II and III to proceed to form the compound of formula I; Includes:

[0008] The present disclosure further provides a compound of formula I [ka] 1. A method for preparing a composition comprising: (a) a compound of formula II: [ka] Compound of formula III; [ka] and preparing a mixture comprising an amine base and a polar aprotic solvent; (b) gradually adding an acid activator to the mixture; and (c) coupling of the acid-activated compounds of formula II and III to proceed to form the compound of formula I; wherein the seeding material is a compound of formula I (i) is added when preparing the mixture of step (a); (ii) in step (b), added to the mixture before the acid activator is added; or (iii) In step (b), it is added during the addition of the activator. DETAILED DESCRIPTION OF THE INVENTION

[0009] As used herein, the terms "comprises," "comprising," "includes," "including," "has," "having," "contains," "containing," "characterized by," or any other variation thereof, are intended to cover a non-exclusive inclusion, subject to any limitations specified. For example, a composition, mixture, process, or method that includes a list of elements is not necessarily limited solely to those elements and may include other elements not expressly listed or inherent in such composition, mixture, process, or method.

[0010] The transitional phrase "consisting of" excludes any unspecified element, step, or ingredient. When recited in a claim, such a phrase limits the claim to the inclusion of materials other than those expressly recited, except for impurities ordinarily associated therewith. When the phrase "consisting of" appears in a clause in the body of a claim rather than immediately following the preamble, it limits only the elements specified in that clause; other elements are not excluded from the claim as a whole.

[0011] The transitional phrase "consisting essentially of" is used to define compositions or methods that include materials, steps, features, ingredients, or elements in addition to those literally disclosed, provided that these additional materials, steps, features, ingredients, or elements do not materially affect the basic and novel characteristics of the claim. The term "consisting essentially of" constitutes a compromise between "comprising" and "consisting of."

[0012] It should be readily understood that when applicants define an embodiment or portion thereof with open-ended terms such as "comprising," the description should be construed (unless otherwise indicated) as describing such embodiment using the terms "consisting essentially of" or "consisting of."

[0013] Furthermore, unless expressly stated to the contrary, "or" refers to an inclusive or and not an exclusive or. For example, condition A or B is satisfied by any one of the following: A is true (or exists) and B is false (or does not exist); A is false (or does not exist) and B is true (or exists); and both A and B are true (or exist).

[0014] Also, the indefinite articles "a" and "an" preceding an element or component of the present disclosure are intended to be open-ended regarding the number of instances (i.e., occurrences) of the element or component. Thus, "a" or "an" should be read to include one or at least one, and the singular form of an element or component also includes the plural unless the number clearly indicates singularity.

[0015] As used herein, "amine base" refers to organic bases and salts thereof, including primary, secondary, and tertiary amines. Examples include substituted amines, cyclic amines, and naturally occurring amines, such as pyridine bases (e.g., 3-picoline), N,N'-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, isopropylamine, morpholine, piperazine, piperidine, triethylamine, trimethylamine, tripropylamine, and tromethamine.

[0016] As used herein, the term "aprotic solvent" refers to any solvent that does not have the ability to donate a proton. Examples include, but are not limited to, acetonitrile, 2-methyltetrahydrofuran, tetrahydrofuran, ethyl acetate, propyl acetate (e.g., isopropyl acetate), acetone, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, hexamethylphosphoramide, and propylene carbonate.

[0017] As used herein, the term "polar aprotic solvent" refers to an aprotic solvent that is a polar solvent. Examples include, but are not limited to, acetonitrile, N,N-dimethylformamide, and the like.

[0018] As used herein, the term "acid-activating agent" refers to a reactant that promotes the coupling of a carboxylic acid compound with an anthranilamide. Examples include, but are not limited to, compounds of the general formula R 1 S(O)Cl compound (formula IV) 1 is a carbon-based group such as C1-C4 alkyl; C1-C2 haloalkyl; or phenyl optionally substituted with 1-3 substituents selected from the group consisting of halogen, C1-C3 alkyl, and nitro). Examples further include, but are not limited to, methanesulfonyl chloride (R 1 is CH3), propanesulfonyl chloride (R 1 is (CH2)2CH3), benzenesulfonyl chloride (R 1 is Ph) and p-toluenesulfonyl chloride (R 1 is 4-CH3-Ph).

[0019] As used herein, the term "approximately" refers to ±5%, ±2.5%, ±1%, ±0.5%, ±0.1%, or ±0.05% of a reference being referenced, such as, but not limited to, population %, w / w %, w / v %, v / v %, or particle size.

[0020] As used herein, the term "unit cell dimensions" refers to lattice parameters, and the unit cell is the simplest and smallest repeating unit, defined by three crystallographic axes, three vector lengths (a, b, c), and inter-axis angles (α, β, γ).

[0021] Embodiments of the present disclosure described in the Summary of the Invention include, but are not limited to, those described below.

[0022] Embodiment A. A ternary crystal comprising a compound of Formula II, a compound of Formula III, and an amine base in approximately an equimolar ratio (1:1:1) or equimolar ratio.

[0023] Embodiment A.1. The ternary crystal of embodiment A wherein the amine base is a pyridine base.

[0024] Embodiment A.2. The ternary crystal of embodiment A.1 wherein the pyridine base is 3-picoline.

[0025] Embodiment A.3. The ternary crystal of embodiment A.2 having unit cell dimensions of approximately 12.12 Å x 15.80 Å x 12.28 Å.

[0026] Embodiment B. A method for preparing a ternary crystal comprising a compound of Formula II, a compound of Formula III, and an amine base in an approximately equimolar ratio (1:1:1) or an equimolar ratio (1:1:1), comprising: (i) mixing the compound of Formula II, the compound of Formula III, and the amine base in approximately equimolar amounts in a polar aprotic solvent; and (ii) isolating the ternary crystal from the polar aprotic solvent.

[0027] Embodiment B.1. The method of Embodiment B wherein the aprotic polar solvent is acetonitrile.

[0028] Embodiment B.2. The method of Embodiment B or Embodiment B.1 wherein the amine base is a pyridine base.

[0029] Embodiment B.3. The method of Embodiment B.2 wherein the pyridine base is 3-picoline.

[0030] Embodiment C. A method for preparing a compound of Formula I, comprising: (a) reacting a suspension of ternary crystals comprising a compound of Formula II, a compound of Formula III, and an amine base in an approximately equimolar ratio (1:1:1) or equimolar ratio (1:1:1) in an aprotic polar solvent with an acid activating agent; and (b) coupling the acid-activated compounds of Formulas II and III to proceed to form the compound of Formula I.

[0031] Embodiment C.1. The method of Embodiment C wherein the aprotic polar solvent is acetonitrile.

[0032] Embodiment C.2. The method of Embodiment C or Embodiment C.1 wherein the acid activating agent is a sulfonyl chloride, such as methanesulfonyl chloride.

[0033] Embodiment C.3. The method of Embodiment C or Embodiments C.1-C.2 wherein the amine base is a pyridine base.

[0034] Embodiment C.4. The method of Embodiment C.3 wherein the pyridine base is 3-picoline.

[0035] Embodiment D. A method for preparing a compound of Formula I, comprising: (a) preparing a mixture comprising a compound of Formula II, a compound of Formula III, an amine base, and a polar aprotic solvent; (b) gradually adding an acid activating agent to the mixture; and (c) coupling the acid-activated compounds of Formula II and III to proceed with the formation of the compound of Formula I, wherein a seeding material of the compound of Formula I is (i) added during the preparation of the mixture of step (a); (ii) added to the mixture before the acid activating agent is added in step (b); or (iii) added during the addition of the activating agent in step (b).

[0036] Embodiment D.1. The method of Embodiment D wherein the amount of seeding material of the compound of Formula I is in the range of 0.5 to 15 mol-%.

[0037] Embodiment D.2. The method of Embodiment D or Embodiment D.1 wherein the mixture including the seeding material has a temperature within the range of about 30°C to reflux, or about 40°C to reflux, or about 45°C to about 70°C.

[0038] Embodiment D.3. The method of Embodiment D or Embodiments D.1-D.2 wherein a seeding material of a compound of Formula I is added when preparing the mixture of step (a) or prior to adding the activating agent in step (b).

[0039] Embodiment D.4. The method of Embodiment D.3 wherein the amount of seeding material of the compound of Formula I is in the range of about 5-15 mol-%.

[0040] Embodiment D.5. The method of Embodiment D or Embodiments D.1-D.2, wherein in step (b), a portion of the acid activator, such as at least about 5% of the acid activator, is added before the amount of seeding material of the compound of Formula I is added.

[0041] Embodiment D.6. The method of Embodiment D.5 wherein the amount of seeding material of the compound of Formula I is in the range of about 0.5-5 mol-%.

[0042] Embodiment D.7. The method of Embodiment D or any of Embodiments D.1-D.6, wherein the aprotic polar solvent is acetonitrile.

[0043] Embodiment D.8. The method of Embodiment D or any of Embodiments D.1-D.7 wherein the acid activating agent is a sulfonyl chloride, such as methanesulfonyl chloride.

[0044] Embodiment D.9. The method of Embodiment D or any of Embodiments D.1-D.8 wherein the amine base is a pyridine base such as 3-picoline.

[0045] Embodiment D.10. The method of Embodiment D or Embodiments D.1-D.9, wherein the seeding material of the compound of Formula I is in the form of purified crystalline material, centrifuged wet crystalline material, a suspension of solid material of Formula I in an organic solvent, or an unquenched slurry of crystalline material from the reaction described above.

[0046] It is noteworthy that the compositions of the present disclosure allow for the use of impure qualities of the compounds of Formulas II and III in the preparation of chlorantraniliprole. In some embodiments, the 1:1:1 crystals of Embodiments A-C can be filtered and / or isolated to remove any impurities in the mother liquor and then reacted to produce a pure chlorantraniliprole compound. In some embodiments, high purity can be achieved with only a single crystallization. In some embodiments, the 1:1:1 crystals can contain the exact stoichiometric amounts of each intermediate required for the reaction.

[0047] In some embodiments, producing the 1:1:1 crystals of Embodiments A-C may help ensure that the reaction is carried out in the correct ratio of compounds of Formula II and III required to produce chlorantraniliprole, and may also allow for better control of the process.

[0048] In some embodiments, the use of the 1:1:1 crystals of Embodiments A-C promotes the formation of smaller crystals of chlorantraniliprole. In some embodiments, the 1:1:1 crystals may act as a nucleation source during crystallization of the compound of Formula I. In some embodiments, the seeding material of Embodiment D may result in the formation of larger and more uniform crystals.

[0049] In various embodiments of embodiment D, in step (b), after addition of a portion of the acid activator, such as at least about 5% of the acid activator, or about 10% to about 20% of the activator, or about 15% to about 20% of the activator, an amount of seeding material of a compound of Formula I is added.

[0050] In various embodiments, suitable amine bases include tertiary amines (including optionally substituted pyridines) and mixtures thereof. In various embodiments, suitable amine bases may include 2-picoline, 3-picoline, 2,6-lutidine, pyridine, and mixtures of the foregoing.

[0051] In various embodiments, suitable solvents include nitriles (e.g., acetonitrile, propionitrile), esters (e.g., methyl acetate, ethyl acetate, butyl acetate), ketones (e.g., acetone, methyl ethyl ketone, methyl butyl ketone, haloalkanes (e.g., dichloromethane, trichloromethane), ethers (e.g., ethyl ether, methyl t-butyl ether, tetrahydrofuran, p-dioxane), aromatic hydrocarbons (e.g., benzene, toluene, chlorobenzene, dichlorobenzene), tertiary amines (e.g., trialkylamines, dialkylanilines, optionally substituted pyridines), and mixtures of the foregoing.

[0052] In various embodiments, an acid activating agent is used as a reactant to promote the coupling of compounds of Formula II and III. The nominal molar ratio of acid activating agent to compound of Formula II can be about 1.0 to 2.5 or 1.1 to 1.4. Suitable acid activating agents include sulfonyl chloride compounds such as methanesulfonyl chloride, propanesulfonyl chloride, benzenesulfonyl chloride, and 7-toluenesulfonyl chloride.

[0053] In various embodiments, the methods of the present disclosure can be carried out over a wide temperature range, but are typically carried out at temperatures ranging from −70° C. to +100° C., or from 30° C. to reflux, or from 40° C. to reflux, or from 45° C. to 70° C. In some embodiments of embodiment D, the reaction is carried out at a temperature of about 50° C.

[0054] In various embodiments, the amount of seeding material of the compound of formula I is in the range of 0.5-15 mol-%, or 0.5-5 mol-%, or 5-10 mol-%, or 5-15 mol-%.

[0055] In various embodiments, the 1:1:1 crystal of the present disclosure can include a ternary co-crystal containing an equimolar ratio of the compound of Formula II, the compound of Formula III, and 3-picoline. In some embodiments, the 3-picoline and the compound of Formula II can exist as salts in the crystal. In one embodiment, the 1:1:1 crystal has a monolithic structure, a 1.512-g / cm 3 and unit cell dimensions of 12.12 Å×15.80 Å×12.28 Å. In various embodiments, the 1:1:1 crystal may be characterized by a solubility of about 15-60 w / w% over a temperature range of 20-55° C.

[0056] The 1:1:1 crystals can be prepared by mixing 1-molar equivalent of the compound of formula II, 1-molar equivalent of the compound of formula III, and 1-molar equivalent of picoline in acetonitrile, and then adding 1:1:1 seed crystals to the resulting supersaturated solution to induce crystallization. Alternatively, crystallization can be performed without seed crystals using a reactor in which 1:1:1 crystals have already been produced. Cooling and / or the addition of an anti-solvent can be used to further promote the precipitation of the 1:1:1 crystals. The 1:1:1 crystals can then be recovered and subsequently used in a process to prepare chlorantraniliprole. Suitable recovery processes include filtration. The 1:1:1 crystals can also be immediately reacted with a standard amount of methanesulfonyl chloride and picoline to form chlorantraniliprole. [Example]

[0057] Comparative Example 1 Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide (chlorantraniliprole) Acetonitrile (54.5 g), 3-bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylic acid (46.6 g, 0.15 mol), 2-amino-5-chloro-N,3-dimethylbenzamide (32.1 g, 0.16 mol), and 3-picoline (37.3 g, 0.40 mol) were mixed together in a jacketed stirred vessel containing 1:1:1 seed crystals at 20°C. The resulting mixture formed a 1:1:1 crystal slurry in the vessel. Methanesulfonyl chloride (21.2 g, 0.19 mol) was then added slowly over 120 minutes, maintaining the temperature at approximately 32°C, and the reaction was then held for an additional hour. Water (46 g) was then added to the reactor over a 60-minute period, and the mixture was held for an additional hour. The resulting slurry was filtered and washed with a 5:1 mixture of acetonitrile and water. Chlorantraniliprole was produced in >90% yield. The median particle size obtained was 16.3 μm.

[0058] Example 2 Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide (chlorantraniliprole) 3-Bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylic acid (46.6 g, 0.15 mol), 2-amino-5-chloro-N,3-dimethylbenzamide (30.6 g, 0.15 mol), and 3-picoline (14.3 g, 0.15 mol) are mixed with a 1:1:1 crystal-saturated acetonitrile solution (58.6 g acetonitrile) in a jacketed stirred vessel containing 1:1:1 seed crystals at 20° C. The resulting slurry is filtered, and the 1:1:1 solids are washed with acetonitrile and dried.

[0059] 1:1:1 crystals (91.5 g), acetonitrile (54.5 g), and 3-picoline (23.0 g) were mixed in a jacketed stirred vessel at 20° C. Methanesulfonyl chloride (21.2 g, 0.19 mol) was then added slowly over 120 minutes, maintaining the temperature at approximately 32° C. The reaction was then held for an additional hour. Water (46 g) was then added to the reactor over a 60-minute period, and the mixture was held for an additional hour. The resulting slurry was filtered and washed with a 5:1 acetonitrile and water mixture. Chlorantraniliprole was produced in >90% yield.

[0060] Example 3 Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide (chlorantraniliprole) 3-Bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylic acid (583.0 g), 2-amino-5-chloro-N,3-dimethylbenzamide (406.5 g), chlorantraniliprole seeding material (94.5 g), and acetonitrile (684.9 g) were charged to a 3 L reactor equipped with a jacket controlled by a programmable heating / cooling unit, a thermometer, a mechanical stirrer (2 × 2 blade pitch-type), a reflux condenser (with nitrogen cover / nitrogen bubbler), and a syringe pump (programmable) inlet. The stirring was adjusted to 200 rpm. The mixture was heated to 50 °C. After the temperature reached 40 °C during heating, 3-picoline (469.4 g) was added to the stirred mixture. A 50 mL syringe was charged with MSCs and once the mixture reached 50°C, injection was initiated according to Table 1 below (262.6 g total).

[0061] [Table 1]

[0062] Once the injection of MSC was complete, the reaction was completed after an additional 1 hour post-reaction time. Water (577.5 g total) was injected according to Table 2 below.

[0063] [Table 2]

[0064] The mixture was cooled to 20°C over a period of 30 minutes. The suspension was transferred to a vacuum filter and vacuum was applied. After the filter cake solidified, suction was continued for an additional 5 minutes. The filter cake was washed with water (767.3 g) and the wet cake was allowed to stand on the filter under suction for an additional 30 minutes. The wet cake was dried at 50°C under vacuum overnight.

[0065] The dried chlorantraniliprole crystals were then weighed and a sample taken for HPLC and solids analysis.

[0066] Isolated yield: 95-98% (species-corrected, based on 3-bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylic acid) Average purity:+97% Crystal size distribution: D[4,3] values ​​were in the range of 90-200 μm, with very little fines. Bulk density: 0.62-0.70g / mL (without tapping); 0.75-0.80g / mL (after tapping) Complete dissolution of the 1:1:1 crystals was observed during the above reaction. The resulting chlorantraniliprole crystals appeared large and uniform, centrifuged very quickly, dried quickly, and produced a high bulk density product with minimal fines formation.

[0067] Example 4 Preparation of 3-bromo-N-[4-chloro-2-methyl-6-[(methylamino)carbonyl]phenyl]-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxamide (chlorantraniliprole) Chlorantraniliprole crystals were prepared in Experiments 1-12 using the parameters in Tables 3-5 below. As can be seen from Table 4, increasing the stirring speed results in a decrease in particle size and bulk density without tapping.

[0068] [Table 3]

[0069] [Table 4]

[0070] [Table 5]

Claims

1. (a) a compound of formula II: 【Chemistry 1】 (b) a compound of formula III; 【Chemistry 2】 and (c) an amine base; wherein the components are in an equimolar ratio of 1:1:

1.

2. 10. The ternary crystal of claim 1, wherein the amine is a pyridine base.

3. The ternary crystal of claim 2, wherein the pyridine base is 3-picoline.

4. A ternary crystal according to any one of claims 1 to 3 having unit cell dimensions of 12.12 Å x 15.80 Å x 12.28 Å.

5. (a) a compound of formula II: 【Transformation 3】 (b) a compound of formula III; 【Chemistry 4】 and (c) an amine base; 1. A method for preparing a ternary crystal comprising: (i) forming an admixture of the compound of formula II, the compound of formula III, and the amine base in equimolar amounts of 1:1:1 in an aprotic solvent; (ii) forming said ternary crystal therefrom; and (iii) isolating the ternary crystals from the aprotic solvent. A method comprising:

6. The method of claim 5 wherein the aprotic solvent is acetonitrile.

7. 7. The method of claim 5 or claim 6, wherein the amine base is a pyridine base.

8. The method of claim 7, wherein the pyridine base is 3-picoline.

9. Compounds of Formula I 【Transformation 5】 1. A method for preparing a compound comprising: (a) (i) A compound of formula II: 【Transformation 6】 (ii) a compound of formula III; 【Transformation 7】 and (iii) an amine base reacting a suspension of a ternary crystal comprising: (b) coupling the acid-activated compounds of formula II and III to proceed with the formation of the compound of formula I. A preparation method comprising:

10. 10. The method of claim 9, wherein the aprotic solvent is acetonitrile.

11. 11. The method of claim 9 or claim 10, wherein the acid activating agent is a sulfonyl chloride.

12. 12. The method of claim 11, wherein the sulfonyl chloride is methanesulfonyl chloride.

13. The method of any one of claims 9 to 11, wherein the amine base is a pyridine base.

14. The method of claim 13, wherein the pyridine base is 3-picoline.

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