Industrially benign one-pot process for preparation of substantially pure amitraz

Abstract

The present invention relates to an industrial one-pot process for the preparation of substantially pure Amitraz formula (I) in good yield and purity with lot-wise addition of trialkyl-orthoformate. The invention further relates to preparation of substantially pure crystal form-A of Amitraz using alcoholic solvent, or hydrocarbon solvent, or mixture thereof.

Description

[0001] INDUSTRIALLY BENIGN ONE-POT PROCESS FOR PREPARATION OF SUBSTANTIALLY PURE AMITRAZ

[0002] FIELD OF THE INVENTION

[0003] The present invention relates to an industrial one-pot process for the preparation of substantially pure Amitraz formula (I) in good yield and purity with lot-wise addition of trialkyl-orthoformate. The invention further relates to preparation of substantially pure crystal form-A of Amitraz using alcoholic solvent, or hydrocarbon solvent, or mixture thereof.

[0004] BACKGROUND OF THE INVENTION

[0005] Amitraz or Mitac® is an insecticide acaricide and a xenobiotic, an environmental contaminant and used primarily to control the pear psylla on Oregon pear crops. It is used to control whiteflies and mites on cotton and pear crops; livestock ticks, lice, and mange mites on beef and dairy cattle and swine; and ticks on dogs.

[0006] Amitraz, commercially available in different forms mainly drop, solution, emulsions and collar as a spray or wash-solution dosage forms and has an immediate effect against tick infestation as well as a preventive effect. In the process of acaricide development and application, delaying the drug resistance or cross resistance of harmful mites is a key factor for prolonging the service life of products, and the reasonable use of acaricides is particularly important for controlling the use time and the dosage which may be due to presence of impurities or low purity of Amitraz in final formulation.

[0007] A need arises for preparation method of substantially pure Amitraz, which does not contain any process impurities, and which is pharmaceutically acceptable and thermodynamically stable so that the problem of poor long-term storage stability can be solved, which may provide more choices for developing new formulations, and the requirements of the veterinary drug market. US3781355A, BR8203202A, BR8207373A, PL146200B, CN107778200A and CN110724070 disclose the preparation of Amitraz which involves numerous drawbacks for example: i) use of expensive reagents / catalyst; ii) use of multiple solvents; iii) multiple and tedious operations; iv) multiple purification processes; v) low overall process yield.

[0008] The research article J. Agric. Food Chem. 2004, 52, 7362- 7369 discloses that Amitraz exists in various crystalline polymorphic forms, three crystalline forms (A, B & C) and one metastable form (D). The article further disclosed that form A is the commercially available that crystallizes as monoclinic crystals having a melting point 86°C to 87°C.

[0009] The prior art documents involve expensive reagents, multiples solvents, tedious operations, and multiple purification processes with low yield. Moreover, the prior art document involves the addition of trialkyl orthoformate in one-lot which lead to formation of side product or impurities along with low purity. Thus, there is a need for an industrial one-pot process which selectively prepares substantially pure Amitraz which overcome all drawback cited in prior arts in an environment friendly and economically viable manner along with absence of non-pharmacopeial impurities. The inventors of instant application were motivated to develop an industrial, environmentally benign one-pot process which involve the lot-wise addition of trialkylorthoformate for preparation of substantially pure Amitraz in high yield, and greater purity with low effluent.

[0010] SUMMARY OF THE INVENTION

[0011] In one aspect the present invention provides an industrial one-pot process for the preparation of substantially pure Amitraz of formula (I) comprising the steps of: a) reacting 2,4 Xylidine, trialkyl-orthoformate and methylamine in presence of acid catalyst to obtain reaction mixture, wherein trialkyl-orthoformate is added in 1.0 to 2.0 molar equivalent; b) heating the reaction mixture of step (a) to obtain Amitraz; c) crystallizing Amitraz obtained in step (b) in solvent selected from alcohol or hydrocarbon or mixture thereof, to obtain substantially pure Amitraz of formula (I).

[0012] In another aspect the present invention provides an industrial one-pot process for the preparation of substantially pure Amitraz (I) comprising the step of: a) reacting 2,4 Xylidine (II) with 0.2 to 0.5 molar equivalent of trialkyl-orthoformate in presence of acid catalyst to obtain intermediate compound (III), wherein alkyl is C1-C4 b) adding 0.8 to 1.0 molar equivalent of trialkyl-ortho formate to the step (a) to obtain intermediate compound (IV), c) adding 0.1 to 0.2 molar equivalent of trialkyl-ortho formate, and monomethylamine gas to the step (b) to obtain intermediate compound (V), d) adding 0.1 to 0.2 molar equivalent of trialkyl-ortho formate to the step (c) to obtain

[0013] Amitraz (I), e) crystallizing Amitraz obtained in step (d) in a solvent selected from alcohol or hydrocarbon or mixture thereof to obtain substantially pure Amitraz of formula (I).

[0014] In yet another aspect the present invention provides an industrial process for the preparation of crystal form - A of Amitraz of formula (I); which comprising the step of:

[0015] 1) adding Amitraz in an alcoholic or hydrocarbon solvent,

[0016] 2) heating,

[0017] 3) cooling,

[0018] 4) optionally seeding with Amitraz form- A,

[0019] 5) filtering to obtain crystalline polymorphic form- A.

[0020] In yet another aspect the present invention provides an industrial process for the preparation of crystal form - A of Amitraz of formula (I); which comprising the step of:

[0021] 1) adding Amitraz in a mixture of alcoholic and hydrocarbon solvent,

[0022] 2) heating,

[0023] 3) cooling,

[0024] 4) optionally seeding with Amitraz form- A,

[0025] 5) filtering to obtain crystalline substantially pure crystal form- A. Brief Description of Drawings

[0026] Fig 1: is a characteristic powder X-ray diffraction (XRPD) pattern of Crystal form- A of Amitraz.

[0027] Fig 2: is a characteristic infra-red (IR) spectrum of Crystal form-A of Amitraz.

[0028] Fig 3: is a characteristic Differential Scanning Calorimetric (DSC) thermogram of Crystal form-A of Amitraz.

[0029] Fig 4: is a Thermogravimetric Analysis (TGA) of Crystal form-A of Amitraz.

[0030] Detailed Description of the Invention

[0031] The present invention now will be described more fully hereinafter. The invention may be embodied in many different forms and should not be construed as limited to the embodiments set forth herein; rather, these embodiments are provided so that this disclosure will satisfy applicable legal requirements. As used in the specification, and in the appended claims, the singular forms “a,” “an,” “the,” include plural referents unless the context clearly indicates otherwise.

[0032] The term solvent used herein, refers to the single solvent or mixture of solvents.

[0033] For the specification, the meaning of term “substantially pure” as used herein above refers to Amitraz of formula (I) with purity more than 99%; particularly more than 99.5%.

[0034] In an embodiment, the present invention provides a one-pot process for the preparation of substantially pure of Amitraz, starting from compound of formula (II) using commercially available, reusable, economical reagents, and solvents, thus the process is more economical, industrially benign, and environmentally friendly.

[0035] Furthermore, substantially pure Amitraz which is obtained by present process is stable at temperatures below 25°C without any additional stabilizers such as paraformaldehyde, specifically at temperatures 2°C to 8°C.

[0036] In another embodiment of the present invention, wherein the trialkyl-orthoformate in which alkyl is C1-C4 and selected from trimethyl-ortho formate, triethyl-ortho formate, tripropyl-orthoformate, tributyl-orthoformate and the like and used in 1 to 2 mole equivalents.

[0037] In another embodiment of the present invention, wherein the acid catalyst is Lewis’s acid, solid acid catalyst such as heteropoly acid (HP A), Zeolite and inorganic acid such as hydrochloric acid, sulfuric acid, acetic acid and the like.

[0038] In another embodiment of present invention, wherein alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol, iso-butanol, and the like and mixture thereof and used in 1 to 5 volumes.

[0039] In another embodiment of present invention, wherein hydrocarbon solvent is selected from cyclohexane, n-heptane, n-pentane, n-hexane and the like, and used in 1 to 5 volumes.

[0040] In another embodiment of present invention, wherein mixture of alcoholic and hydrocarbon solvent in a range of 1:1 to 1:5 Volume.

[0041] The reflux ratio cited in the present invention is a ratio between the boil up rate and the take-off rate of Tetramethyl orthoformate against Methanol which is generated in process.

[0042] In another embodiment of present invention, wherein temperature and reflux ratio are maintained in (3:1) during conversion of 2,4-Xylidine to Amitraz.

[0043] In another embodiment of present invention, wherein reaction temperature is 50°C to 150°C.

[0044] In another embodiment of present invention, wherein reaction step (a) is performed at temperature is 65°C to 85°C for 6-8 hrs.

[0045] In another embodiment of present invention, wherein reaction step (b) is performed at temperature is 85 °C to 115°C for 10-14 hrs.

[0046] In another embodiment of present invention, wherein reaction step (c) is performed at temperature is 55 °C to 65 °C for 1-2 hrs. In another embodiment of present invention, wherein reaction step (d) is performed at temperature is 135°C to 150°C for 11-14 hrs.

[0047] In another embodiment of present invention, wherein said crystallization step (e) is performed at temperature -10°C to 65 °C.

[0048] In another embodiment of the present invention, wherein crystallization step is performed by simple sequential step such as addition of solvent(s) or mixture of solvents, heating, cooling, seeding, filtering to obtain crystalline substantially pure Amitraz.

[0049] In another embodiment of the present invention, wherein seeding temperature is 40°C to 50°C.

[0050] In another embodiment of the present invention, wherein substantially pure Amitraz (I) obtained by the present process is Crystal form- A.

[0051] In another embodiment of the present invention, the resulting substantially pure Amitraz having purity greater than 99.5% comprising one or more impurities (A-D) as disclosed in British pharmacopeia as measured by GC.

[0052] In another embodiment of the present invention, wherein substantially pure Amitraz is resulted with purity at least 99.5% and comprising one or more pharmacopeial impurities selected from impurity A less than 0.1%, impurity B less than 0.2%, impurity C less than 0.1%, and impurity D less than 0.1% as measured by GC.

[0053] In another embodiment of the present invention, the substantially pure crystal form-A of Amitraz obtained by the process disclosed herein is characterized by a X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 7.356, 12.090, 14.084, 17.722 ± 0.2 degrees substantially in accordance with FIG. 1; an infrared (FT-IR) spectrum having main bands at about 1619.41, 1596.50, 1078.49, 803.27 ±2 cm-1substantially in accordance with FIG. 2; and a Differential Scanning Calorimetric (DSC) thermogram having a sharp endotherm peak at about 88°C substantially in accordance with FIG. 3, and a Thermogravimetric Analysis (TGA) having weight percentage loss up to 170°C in accordance with FIG. 4.

[0054] The process of present invention is illustrated in the following general synthetic scheme,

[0055] The inventor of the present invention developed a GC method for determination of Amitraz, key starting compounds / intermediates and impurities formed.

[0056] Analysis of Amitraz was performed by GC with following tests.

[0057] Instrument Parameter:

[0058] : Agilent GC-8890 system it h FID detector and autosampler or Equivalent.

[0059] Column Chrompack CP-Sil 5 CB (15 m X 0.53 mm X 1.5 pm)

[0060] Injector Split mode.

[0061] Injector temperature 230°C

[0062] Detector Flame ionization detector (FID)

[0063] Oxidant gas (Zero air) 400 mL / min

[0064] Fuel gas (Hydrogen) 40 mL / min

[0065] Make up gas (Nitrogen) 30 mL / min

[0066] Detector temperature 300°C

[0067] Carrier gas Helium

[0068] Carrier gas flow 12.00 mL / min

[0069] Purge flow 3.00 mL / min

[0070] Split ratio 1: 50

[0071] Injection volume 1.0 pL

[0072] Run time 49 min Table- 1: Column oven program:

[0073] Diluent: Methyl acetate.

[0074] Solution-C: Accurately transfer 2.0 mL Squalane in 100 mL volumetric flask and make up with Methyl acetate. (2 %v / v of Squalane)

[0075] Blank solution: Pipetted out 10 mL of solution -C in 30 mL volumetric flask and diluted up to mark with Methyl acetate.

[0076] Standard solution: Amitraz standard, impurities A-D is prepared as per standard.

[0077] Table-2: Retention Time (RT), and Relative Retention Time (RRT)

[0078] GC Method for identification of 2,4 xylidine and intermediates:

[0079] Instrument Parameter:

[0080] Instrument : Agilent 8890 GC System with 7693 A series Injector or equivalent.

[0081] Column : HP-5 (30-meter X 0.32 mm ID X 0.25 pm)

[0082] Injector : Split mode

[0083] Injector temperature : 250°C

[0084] Detector : FID

[0085]

[0086] Diluent: Dichloromethane (MDC)

[0087] Blank solution: Use diluent as a blank.

[0088] System suitability stock solution:

[0089] Weigh accurately about 25 mg of Trimethyl orthoformate standard and 25 mg of 2, 4- Xylidine (II) standard into a 100 mL volumetric flask and dilute to the volume with diluent (250 pg / mL of Trimethyl orthoformate and 250 pg / mL of 2, 4-Xylidine (II).

[0090] Sample solution:

[0091] Weigh accurately about 250 mg of sample into a 5 mL volumetric flask and dilute to the volume with diluent (50000 pg / mL of sample).

[0092] System suitability solution:

[0093] Weigh accurately about 175 mg of intermediate-III (Formamidine) standard into a 5 mL volumetric flask and add 1.0 mL of system suitability stock solution and dilute to the volume with diluent. (50 pg / mL (0.10% w / w) of Trimethyl orthoformate, 50 pg / mL (0.10% w / w) of 2, 4-Xylidine and 35000 pg / mL of intermediate-III (Formamidine).

[0094] System suitability stock solution:

[0095] Weigh accurately about 125 mg of intermediate-III (Formamidine) standard into a 5 mL volumetric flask and dilute to the volume with diluent (25000 pg / mL of intermediate-III (Formamidine).

[0096] System suitability solution:

[0097] Weigh accurately about 150 mg of intermediate-IV (Methyl Amidate) standard into a 5 mL volumetric flask and add 1.0 mL of system suitability stock solution and dilute to the volume with diluent (5000 pg / mL (10.0% w / w) of intermediate-III (Formamidine) and 30000 pg / mL of intermediate-IV (Methyl Amidate).

[0098] System suitability stock solution:

[0099] Weigh accurately about 125 mg of intermediate-IV (Methyl Amidate) standard into a 10 mL volumetric flask and dilute to the volume with diluent (12500 pg / mL of Compound- 1 (Methyl Amidate)).

[0100] System suitability solution:

[0101] Weigh accurately about 150 mg of intermediate- V (Methyl Amidine) standard into a 5 mL volumetric flask and add 1.0 mL of system suitability stock solution and dilute to the volume with diluent. (2500 pg / mL (5.0% w / w) of Compound-1 (Methyl Amidate) and 30000 pg / mL of Compound-3 (Methyl Amidine)).

[0102] Procedure:

[0103] Inject below sequence in chromatographic system after changing the glass wool followed by conditioning the column then report the result in an area percentage of the peaks corresponds to the sample, excluding the peaks arising due to diluent.

[0104] Table-4: Retention time (RT), relative retention time (RRT) & relative response factor (RRF):

[0105] EXPERIMENTAL:

[0106] 1) Preparation of substantially pure Amitraz formula (I).

[0107] In an RBF, 2,4-Xylidine (1.0 eq) and concentrated sulfuric acid (0.001 to 0.01 eq) was added at 20°C to 30°C. To the reaction mixture 1stlot of trimethyl orthoformate (0.2 to 0.5 eq) was added and gradually heated at 75°C to 85°C for 6-8 hrs with simultaneous removal of distillate. The reaction is monitored by GC. After completion a 2nd lot of trimethyl orthoformate (0.75 to 1.0 eq) was added and further heated gradually at 85°C to 115°C for 10-14 hrs with simultaneous removal of distillate. The reaction is monitored by GC. After completion the reaction mixture was cooled to 50°C to 55°C and 3rdlot of trimethyl ortho formate (0.1 to 0.2 eq) was added, estimated monomethylamine gas (1.0 to 1.2 eq) was purged and heated gradually at 55°C to 75°C for 2- 4 hrs with simultaneous removal of distillate. The reaction is monitored by GC. After completion the final 4thlot of trimethyl ortho formate (0.1 to 0.2 eq) was added and further heated at 135°C to 145°C for 1-2 hrs with simultaneous removal of distillate. The reaction is monitored by GC. After completion the reaction mixture was cooled to 50°C to 70°C. To this reaction mixture isopropyl alcohol (2-4 Vol) was added stirred for 1-2 hrs, and gradually cooled at -10°C to 10°C. The solid compound was filtered washed with cold isopropyl alcohol to obtain substantially pure Amitraz 99.8%, purity by GC).

[0108] 2) Preparation crystal form-A of Amitraz (I) using alcoholic solvent.

[0109] To the compound Amitraz (1.0 molar equivalent) isopropyl alcohol (1-5 Vol) was added and heated to get clear solution at 60°C to 75°C for 1 hr. The reaction mixture was cooled to 40°C to 50°C and seeded with crystal form-A. The reaction mixture was gradually cooled to -10°C to 10°C and maintained for 1-2 hrs. The precipitates were filtered, washed with isopropyl alcohol, dried to obtain substantially pure crystal form- A of Amitraz as an off-white to white solid (85-95% yield, GC purity >99.8%). 3) Preparation crystal form-A of Amitraz (I) using hydrocarbon solvent.

[0110] To the compound Amitraz (1.0 molar equivalent) n-heptane (1-5 Vol) was added and heated to get clear solution at 60°C to 75 °C for 1 hr. The reaction mixture was cooled to 40°C to 50°C and seeded with crystal form-A. The reaction mixture was gradually cooled to -10°C to 10°C and maintained for 1-2 hrs. The precipitates were filtered, washed with isopropyl alcohol, dried to obtain substantially pure crystal form-A of Amitraz as an off-white to white solid (85-95% yield, GC purity >99.8%).

[0111] 4) Preparation crystal form-A of Amitraz (I) using mixture of solvent.

[0112] To the compound Amitraz (1.0 molar equivalent) mixture of (1-5 Vol) isopropyl alcohol and n-heptane in the ratio of (1:0.5 to 1:1) was added and heated to get clear solution at 55°C to 65°C for 1 hr. The reaction mixture was cooled to 40°C to 50°C and seeded with crystal form-A. The reaction mixture was gradually cooled to -10°C to 10°C and maintained for 1-2 hrs. The precipitates were filtered, washed with isopropyl alcohol, dried to obtain substantially pure crystal form-A of Amitraz as an off-white to white solid (85-95% yield, GC purity >99.8%).

Claims

CLAIMS:

1. An industrial one-pot process for the preparation of substantially pure Amitraz of formula (I)comprising the step of: a) reacting 2,4 Xylidine (II) with 0.2 to 0.5 molar equivalent of trialkyl-orthoformate in presence of acid catalyst to obtain intermediate compound of formula (III),where alkyl is C1-C4 b) adding 0.8 to 1.0 molar equivalent of trialkyl-orthoformate to the step (a) to obtain intermediate compound of formula (IV),c) adding 0.1 to 0.2 molar equivalent of trialkyl-orthoformate, and monomethylamine gas to the step (b) to obtain intermediate compound of formula (V),d) adding 0.1 to 0.2 molar equivalent of trialkyl-orthoformate to the step (c) to obtain Amitraz of formula (I),e) crystallizing Amitraz obtained in step (d) in solvent selected from alcohol or hydrocarbon or their mixture to obtain substantially pure Amitraz of formula (I).

2. The process as claimed in claim 1, wherein substantially pure Amitraz is crystal form- A characterized by at least one of the following parameters: a) PXRD pattern having peaks value is 7.356, 12.090, 14.084, and 17.722 ±0.2 degrees of two-theta; b) DSC thermogram showing an endotherm at 88°C; c) TGA weight percentage loss up to 170°C; d) IR spectrum having absorption peaks at 1619. s 41, 1596.50, 1078.49, and 803.27 cm-1.

3. The substantially pure Amitraz as claimed in claim 1, wherein the purity is more than 99.5% by GC, comprising one or more pharmacopeial impurities selected from impurity A less than 0.1%, impurity B less than 0.2%, impurity C less than 0.1%, and impurity D less than 0.1% as measured by GC.

4. A process for preparation of substantially pure crystal form-A of Amitraz comprising the steps of:1) adding Amitraz in a solvent, wherein solvent is selected from alcohol or hydrocarbon or mixture of solvent,2) heating,3) cooling,4) optionally seeding with Amitraz Crystal form-A,5) filtering to obtain substantially pure crystal form-A.

5. The process as claimed in claim 1, wherein the trialkyl-ortho formate is selected from trimethyl-orthoformate, triethyl-orthoformate, tripropyl-orthoformate, and tributylorthoformate.

6. The process as claimed in claim 1, wherein an acid catalyst is Lewis’s acid, heteropoly acid (HP A), Zeolite, hydrochloric acid, sulfuric acid, and acetic acid.

7. The process as claimed in claim 1 and 4, wherein the alcoholic solvent is selected from methanol, ethanol, isopropanol, n-butanol, and iso-butanol, and the hydrocarbon solvent is selected from cyclohexane, n-heptane, n-pentane, and n-hexane.

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