WO2012007758A2 - Pharmaceutical formulations - Google Patents

Pharmaceutical formulations Download PDF

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Publication number
WO2012007758A2
WO2012007758A2 PCT/GB2011/051322 GB2011051322W WO2012007758A2 WO 2012007758 A2 WO2012007758 A2 WO 2012007758A2 GB 2011051322 W GB2011051322 W GB 2011051322W WO 2012007758 A2 WO2012007758 A2 WO 2012007758A2
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WO
WIPO (PCT)
Prior art keywords
oxy
added
vols
ylcarbonyl
azetidin
Prior art date
Application number
PCT/GB2011/051322
Other languages
French (fr)
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WO2012007758A3 (en
Inventor
Lars-Erik Briggner
Lennart Lindfors
Craig Michael Smith
Original Assignee
Astrazeneca Ab
Astrazeneca Uk Limited
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Application filed by Astrazeneca Ab, Astrazeneca Uk Limited filed Critical Astrazeneca Ab
Publication of WO2012007758A2 publication Critical patent/WO2012007758A2/en
Publication of WO2012007758A3 publication Critical patent/WO2012007758A3/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates

Definitions

  • the present invention relates to novel pharmaceutical formulations of 3- ⁇ [5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5 - ⁇ [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N- (5-methylpyrazin-2-yl)benzamide.
  • the present invention relates to processes for reducing the particle size of this compound and to pharmaceutical compositions and pharmaceutical formulations prepared by these processes.
  • particle size of the active pharmaceutical ingredient may be advantageous or even necessary to ensure satisfactory dissolution behaviour of the drug. Proper dissolution is important to achieve acceptable bioavailability of the drug.
  • reducing the particle size of the active ingredient may be advisable in order to avoid segregation in the powder blend and thereby achieve content uniformity in the final formulation.
  • Micronisation in fluidized jet mill is a technique that is frequently used to reduce the particle size of an active pharmaceutical ingredient.
  • APIs described above may be successfully dry milled on a commercial production scale without significant build-up in the micronisation equipment by milling the API with one or more co -milling excipient(s).
  • a particular API that is suitable for use in the present invention is 3- ⁇ [5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5 - ⁇ [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5 - methylpyrazin-2-yl)benzamide ("the compound") illustrated in Formula (I) hereinafter, which is an activator of glucokinase (GLK or GK) as described in WO 2007/007041.
  • PCT/GB2010/050217 and PCT/GB2010/050216 disclose further crystalline forms of the compound of formula I and processes to prepare the compound of formula I, respectively.
  • PCT/GB2010/050217 discloses Form 6 of the compound of formula I.
  • the present invention provides a process for dry milling 3- ⁇ [5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5- methylpyrazin-2-yl)benzamide comprising dry milling 3- ⁇ [5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5- methylpyrazin-2-yl)benzamide with one or more co-milling excipients wherein the co- milling excipient has a primary particle size of mean diameter of at least 100 microns. Particularly the co-milling excipient is selected from lactose or mannitol. Optionally a surfactant is also used in the process.
  • the present invention provides a process for dry milling 3- ⁇ [5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5 - ⁇ [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N- (5-methylpyrazin-2-yl)benzamide comprising dry milling 3- ⁇ [5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5- methylpyrazin-2-yl)benzamide with one or more co-milling excipients and/or a surfactant wherein the co-milling excipient if present has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol.
  • the present invention provides a process for dry milling 3- ⁇ [5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5 - ⁇ [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N- (5-methylpyrazin-2-yl)benzamide comprising the steps of:
  • the present invention provides a process for dry milling 3- ⁇ [5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5 - ⁇ [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N- (5-methylpyrazin-2-yl)benzamide comprising the steps of:
  • the present invention provides a co-milled pharmaceutical composition
  • a co-milled pharmaceutical composition comprising a) 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [(15)-l- methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5-methylpyrazin-2-yl)benzamide and b) one or more co-milling excipients and/or a surfactant.
  • the present invention provides a co-milled pharmaceutical composition
  • a co-milled pharmaceutical composition comprising a) 93-98% by weight of 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5- ⁇ [(liS)-l -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5 -methylpyrazin-2-yl)benzamide and b) 2-7% by weight of a surfactant.
  • the present invention provides a co-milled pharmaceutical composition
  • a co-milled pharmaceutical composition comprising a) 45-50% by weight of 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5- ⁇ [(liS)-l -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5 -methylpyrazin-2-yl)benzamide and b) 40-50% by weight of one or more co-milling excipients and/or c) 2-8% by weight a surfactant.
  • the present invention provides a co-milled pharmaceutical composition
  • a co-milled pharmaceutical composition comprising a) 60-70% by weight of 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5- ⁇ [(liS)-l -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5 -methylpyrazin-2-yl)benzamide and b) 25-35%> by weight of one or more co-milling excipients and/or c) 2-8% by weight a surfactant.
  • the present invention provides a co-milled pharmaceutical composition
  • a co-milled pharmaceutical composition comprising a) 55-65% by weight of 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5- ⁇ [(liS)-l -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5 -methylpyrazin-2-yl)benzamide and b) 25-35% by weight of one or more co-milling excipients and/or c) 8-12% by weight a surfactant.
  • surfactant is sodium dodecyl sulphate also known as sodium lauryl sulphate.
  • the present invention provides a pharmaceutical formulation comprising a co-milled pharmaceutical composition as described in any one of the embodiments above and pharmaceutically acceptable excipients for a tablet formulation including, for example:
  • inert diluents such as lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, sodium carbonate, monobasic calcium phosphate, dibasic calcium phosphate (including dibasic calcium phosphate dihydrate and dibasic calcium phosphate anhydrate), tribasic calcium phosphate, calcium carbonate and the like;
  • disintegrants such as starch (such as potato, maize or corn), sodium starch glycolate, sodium carboxymethyl cellulose (NaCMC), low substituted
  • hydroxypropyl cellulose L-HPC
  • crosslinked polyvinyl pyrrolidone algenic acid and the like
  • binders such as starch (such as potato, maize or corn), polyvinyl pyrrolidone, microcrystalline cellulose, a polyethylene glycol (PEG), a polyethylene oxide (PEO), a hydroxypropylmethyl cellulose (HPMC) of a low molecular weight, a methyl cellulose (MC) of a low molecular weight, a hydroxypropyl cellulose (HPC) of a low molecular weight, a hydroxyethyl cellulose (HEC) of a low molecular weight, a sodium carboxymethyl cellulose of a low molecular weight and the like;
  • starch such as potato, maize or corn
  • PEG polyethylene glycol
  • PEO polyethylene oxide
  • HPMC hydroxypropylmethyl cellulose
  • MC methyl cellulose
  • HPC hydroxypropyl cellulose
  • HEC hydroxyethyl cellulose
  • one or more lubricants such as magnesium stearate, stearic acid, calcium stearate, stearyl alcohol, sodium stearyl fumarate;
  • a glidant such as talc or a colloidal silica
  • a surfactant such as, for example sodium dodecyl sulphate
  • Tablet formulations may be uncoated or coated using conventional coating agents and procedures well known in the art. It will be appreciated that some of the above mentioned excipients which may be present in a final oral (for example tablet) composition of the invention may have more than one of the above stated functions. Tablet formulations comprising API may, for example, be manufactured with the following strengths: 1 mg, 2.5 mg, 5 mg, lOmg, 20 mg, 25 mg, 45 mg, 50 mg, 75mg, 100 mg, 150 mg, 200mg, 250 mg and 500 mg.
  • filler 50 to 95%, such as 60-75% of mannitol plus 2.5 to 5.0% microcrystalline cellulose,
  • disintegrant 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate
  • lubricant 1 to 5% such as 1 to 3%, for example 2.3% magnesium stearate
  • surfactant 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
  • disintegrant 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate
  • lubricant 1 to 5% such as 1 to 3%, for example 2.3% magnesium stearate
  • surfactant 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
  • disintegrant 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate
  • lubricant 1 to 5% such as 1 to 3%, for example 2.3% magnesium stearate
  • surfactant 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
  • filler 30 to 75%, such as 2.5 to 5.0%> microcrystalline cellulose, for example 3.7 % or 3.8% or 4.3% or 4.8%
  • disintegrant 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate
  • lubricant 1 to 5% such as 1 to 3%, for example 1.1 % Or 1.3% or 2.3% magnesium stearate
  • e) surfactant 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
  • Tablets may be made by conventional means, including direct compression of the powder blend or by dry granulation, such as, for example, roller compaction.
  • a dry process, such as dry granulation, is likely to minimise any possible interchange of polymorphic form during the formulation process.
  • compositions for oral use may further be in the form of capsules in which the active ingredient is mixed with one or more inert diluent(s), as previously described.
  • a process for the manufacture of a pharmaceutical formulation which comprises:
  • a first blending step in which a co-milled pharmaceutical composition as described above is mixed with one or more filler(s), disintegrant(s) and surfactant(s) in a diffusion mixer
  • a second blending step in which a lubricant is added to the powder blend and the material is mixed in a diffusion mixer
  • the tablets according to the present invention have a dissolution profile such that 80% by weight of the 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [(15)-l- methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5-methylpyrazin-2-yl)benzamide is dissolved within 30 minutes.
  • the tablets according to the present invention have a dissolution profile such that 90% by weight of the 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [( 1 S)- 1 -methy l-2-(methyloxy)ethyl]oxy ⁇ -N-(5 -methylpyrazin-2-yl)benzamide is dissolved within 30 minutes.
  • the tablets according to the present invention have a dissolution profile such that 95% by weight of the 3- ⁇ [5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5- ⁇ [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5- methylpyrazin-2-yl)benzamide is dissolved within 30 minutes.
  • co-micronisation excipient examples include mannitol, particularly
  • the co-milling excipient has a primary particle size of mean diameter in the range of 100-200 microns, particularly 130-190 microns, more particularly 140-180 microns and especially 150-170 microns.
  • Crystalline mannitol having a primary particle size of mean diameter in the range of 100-200 microns, particularly 130- 190 microns, more particularly 140-180 microns, and especially 150-170 microns is particularly advantageous.
  • a particularly suitable form of mannitol is pearlitol® 160C which has a primary particle size of mean diameter of 160 microns and a particle size distribution as illustrated below.
  • Mastersizer The volume weighed distribution of particle size is described below by stating the measured particle diameter in microns corresponding to the percentile of the distribution given within brackets. Thus, the measured values given for d(0.1) show that 10% of the volume weighed distribution of particle diameters lies below approximately 19 microns.
  • the present invention provides the use of pearlitol® 160 C as the co-milling excipient and SDS as the surfactant. This particular combination appears to act in a synergistic manner to prevent hard build up of material in the milling equipment.
  • API is the 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5- ⁇ [(liS)-l -methyl-2-(methyloxy)ethyl]oxy ⁇ -N-(5 -methylpyrazin-2-yl)benzamide form 6.
  • API/SDS Co-micronisation 1
  • SDS sodium dodecyl sulphate
  • the internal surface of the jet mill was stainless steel.
  • the three components were separately fed into a spiral jet mill by three screw feeders and co-micronised.
  • the feed rates were; 0.9 kg/h for the SDS, 5.4 kg/h for the Mannitol and 11.7 kg/h for the API.
  • a first batch was made by feeding 9.04 kg of SDS, 54.21 kg of Mannitol and 117.46 kg of API into the jet mill and co-micronising the material at a grinding pressure of 6.0 bar, yielding 178.88 kg of co-micronised material. Dry cleaning of the milling chamber to remove the small amount of build up was performed after every four 55 L drums.
  • a second batch was made by feeding 7.58 kg of SDS, 45.45 kg of Mannitol and 98.48 kg of API into the jet mill and co-micronising the material at a grinding pressure of 6.0 bar, yielding 150.0 kg of co-micronised material. Dry cleaning of the milling chamber to remove the small amount of build up was performed after every four 55 L drums.
  • the internal surface of the jet mill was stainless steel. Examples of Pharmaceutical formulations
  • Magnesium stearate making up a total of 2931 g, into a Turbula mixer and was mixed for 10 minutes. 24 g of Magnesium stearate was sieved and added. The material was mixed a second time for 2 minutes. The powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 45 g of Magnesium stearate. The granulate was then compacted into tablets in a Korsch rotary tablet press.
  • API 44574 g was micronised in a spiral jet mill at a feed rate of 2 kg/h. The process could not be run continuously since hard build up of API in the mill chamber and the venturi tube forced the mill to be stopped and cleaned after approximately each 2 kg of API processed.
  • the internal surfaces of the mill were stainless steel.
  • 180 g of sodium starch glycolate was milled in a Comil mill.
  • 500 g of micronised API from micronisation 1 was charged together with approximately the same amount of mannitol and 30 g of sodium lauryl sulphate into a Pharmatech blender and was blended for 10 minutes at 25 rpm.
  • the resulting blend was charged together with 150 g of the milled sodium starch glycolate, the rest of the mannitol (2139 g mannitol altogether) and 113 g of microcrystalline cellulose into a Pharmatech blender and blended for 10 minutes at 16 rpm.
  • 24 g of Magnesium stearate was sieved and added. The material was blended in a third step for 2 minutes at 16 rpm.
  • the powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 45 g of Magnesium stearate.
  • the granulate was then compacted into tablets in a Piccola rotary tablet press. The dissolution is shown in Figure 2.
  • the dissolution of the API was analysed by a USP II (paddle) method. Each tablet was placed in 900 mL of 0.1M HC1 solution at 37°C and 50 rpm paddle speed, which was increased to 150 rpm after 60 minutes.
  • the dissolution of tablets from Examples 1-4 was measured using a SOT AX AT70 Smart automated dissolution system while the dissolution of the tablets from Examples 5 & 6 was measured using an optical fibre probe protruding into the dissolution vessel.
  • the data presented as dissolution curves in graphs 1 & 2 are each mean values of three measurements as described above.
  • Figure 1 shows the dissolution data for tablets produced according to Example 1 to 5 showing API dissolved (%) vs time.
  • Figure 2 shows dissolution data for tablets produced according to Example 6 showing API dissolved (%) vs time.
  • Figure 3 shows the build up in grams versus weight of API micronised
  • Figure 4 shows the XRPD pattern for Form 6 of 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N-(5 -methylpyrazin-2-yl)benzamide
  • N-methylmorpholine (5.0 eq) was added at 0°C, then 2,4,6-tripropyl-l, 3, 5, 2, 4, 6- trioxatriphosphinane 2,4,6-trioxide (supplied as 50% w/w in ethyl acetate) (2.5eq) was added in one portion via addition funnel over 45 minutes maintaining the reaction temperature at 0 - 5°C.
  • the addition funnel was washed with 2-methyltetrahydrofuran (0.5 vols), then the reaction mixture was boiled under reflux under nitrogen for at least 14 hours, before being cooled to 22°C. Water (4.0vols) was added to the reaction mixture in one portion, followed by 2-methyltetrahydrofuran (4.0vols).
  • the mixture was agitated for at least 30 minutes at 22 ⁇ 5°C the mixture was separated 5% w/w Sodium hydrogen carbonate (4.0 vols) solution was added the organic layer. The mixture was agitated for at least 30 minutes at 22 ⁇ 5°C then the mixture was separated. This process was repeated. Water (4.0 vols) was added to the organic layer, the mixture was agitated for at least 30 minutes at 22 ⁇ 5°C then the layers were separated. The organic layer was distilled under vacuum at 35°C collecting 19 vols of distillates. 2-Methyltetrahydrofuran (4 vols) was added, and the distillation was continued under vacuum at 35°C collecting 6 vols distillates.
  • N-Heptane (0.5 vols) was added to the mixture, and the temperature adjusted to 60°C, the mixture was cooled to 46°C, seeded, then cooled to 22°C and agitated for at least 12 hours. The mixture was filtered. The solid was washed with a mixture of methyl iso-butylketone (1.5 vols)/ heptane (0.16 vols). The solid was washed with heptane ( ⁇ 1.5 vols). The isolated solid was dried at 22°C under vacuum to afford the title compound as an off white solid. Corrected yield was 62%.
  • the reaction mixture was held for approximately 4 hours. Acetic acid (1.25eq) was added to the mixture at -10°C. The mixture was allowed to warm to 5°C. Acetic acid (2.37eq) was added to the mixture, the acetic acid line washed with water (3.5 vols) and the mixture allowed to warm to 22°C. The mixture was seeded, then water (5 vols) was added to the mixture. 2N hydrochloric acid (1.5eq) was added to the mixture until pH4 was reached. The reaction mixture was stirred for at least 14 hours, then cooled to 10°C, stirred for 1 hour at 10°C. The mixture was filtered. The solid was slurry washed with water (3 x 2.5 vol). The isolated solid was dried at 25°C under vacuum to afford the title compound as an off white solid.
  • the solid was charged to a flask, followed by ethyl acetate (27.2vols), and the mixture heated to reflux for at least 30 minutes.
  • the mixture was filtered hot and approximately 13 vols removed by vacuum distillation.
  • the mixture was cooled to 15°C, and agitated overnight at this temperature.
  • the mixture was filtered, and the (solid) washed with ethyl acetate (2.25 vols).
  • the isolated solid was dried at 25°C under vacuum to afford the title compound as an off white solid.
  • the corrected yield was 78%.
  • the mixture was agitated at 45°C for at least 14 hours then cooled to 22°C and iso-propylacetate (10 vols) added. Water (12 vols) was added over 25 minutes at 25°C, and the mixture was agitated for 15 minutes at 22°C. The organic layer was separated off, after which the aqueous layer was re-extracted with (2 x 5 vols) iso-propylacetate. The iso-propyl acetate layers were combined and water (8 vols) was added. The mixture was agitated at 22°C for 30 minutes. The aqueous layer was separated off and discarded. This process was repeated. The organic layer was distilled under vacuum to constant weight.
  • N,N-Dimethyl-1,3- propane-diamine (0.3eq) was added over 10 minutes at -5°C.
  • the mixture was agitated at - 5°C to 5°C for 30 minutes.
  • 2N hydrochloric acid (0.55eq) and 70ml water were added.
  • the mixture was agitated for 30 minutes at 22°C and the aqueous layer was separated off and discarded.
  • the mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash, the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to give the title compound as a dry light brown oil. Yield (corrected for assay) 93 - 97%.
  • Benzoyl chloride (1.0 eq) was added drop-wise in small portions over 1 - 2 hours, and sodium hydroxide was added concurrently drop-wise in small portions over the same time period to maintain the reaction in a pH range of pH 7.8 ⁇ 0.2 and at a reaction temperature of 20°C ⁇ 3°C.
  • the crude reaction mixture was agitated for a further 30 minutes, filtered, and then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05eq), and adjusted to pH7.5 with 10% w/w sodium hydroxide.
  • the crude solid was then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05eq), and adjusted to pH6.5 with 10%> w/w sodium hydroxide.
  • the crude solid was then disssolved in iso-propyl acetate (8 vols) and water (2 vols) and the mixture agitated for at least 30 minutes to ensure the solid had dissolved.
  • the mixture was filtered through a CUNOTM filter to remove a small amount of brown solid.
  • the aqueous layer was separated off. Water (2 vols) was added to the organic layer and the batch agitated for at least 30 minutes.
  • the aqueous layer was separated off and the organic layer was vacuum distilled, keeping the batch temperature below 40°C to reduce the volume to 5 - 6 vols.
  • Toluene was added then added (5 vols) and the mixture was vacuum distilled keeping the batch temperature below 40°C, reducing the volume to approximately 3.5 vols.
  • the mixture was cooled to 15°C ⁇ 3°C and agitated at this temperature for at least 30 minutes, then filtered, and the solid washed with toluene (1 vol).
  • the product was dried at 20°C - 40°C to give the desired product as a solid (corrected yield 40%> - 70%>).
  • the reaction mixture was agitated for 30 minutes and then the layers were separated.
  • the aqueous layer was re- extracted with a further charge of iso-propyl acetate (6 vols).
  • the batch was separated, and the combined organic layers were washed with saturated brine (6 vols), then with a solution of 0. IN hydrochloric acid/ brine.
  • the iso-propyl acetate was distilled to dryness on the rotary evaporator.
  • Iso-propyl acetate (6 vols) was added, and distilled to dryness on the rotary evaporator.
  • Toluene (6 vols) was added and distilled to dryness on the rotary evaporator.
  • Toluene (3.5 vols) was added and the reaction slurried for 30 minutes. The solid was filtered off and dried at 20°C - 40°C to give the desired product as a solid (corrected yield 72%).
  • the resulting suspension was agitated for further 60 minutes at 20- 22 °C and then filtered.
  • the filter cake was washed twice with water (2vol each) and pulled dry.
  • the crude product obtained was then dissolved in isopropyl acetate (8vol) before Diatomaceous earth was added and the slurry was stirred for lh.
  • the product is then solvent-swapped from isopropyl acetate into toluene (5vol) by vacuum distillation maintaining the internal temperature at or below 45 °C.
  • the resulting suspension was cooled to 15 °C, agitated for lh and then filtered. After washing the filter cake with 1 vol toluene the product was dried to constant weight yielding typically 75-80% of the title product at >98% purity.
  • the reaction mixture was stirred for 2 hours at 5°C, then water (5 vols) added at 5°C, then 5N hydrochloric acid (2 vols) was added slowly at 5°C.
  • the reaction mixture was warmed to 20°C, water (1 vol) was added followed by toluene (10 vols).
  • the reaction mixture was warmed to 30°C, then the aqueous layer separated off and discarded.
  • Water (5 vols) was added and the reaction mixture agitated for 30 minutes, then the water layer separated off and discarded.
  • 8% w/w Sodium carbonate (4 vols) was added, the reaction mixture agitated for 30 minutes, then the water layer separated off and discarded.
  • Water (5 vols) was added, the batch agitated for 30 minutes, then the water layer separated off and discarded.
  • the vessel was agitated for 15 minutes and then separated.
  • the aqueous layer was retained and the organic layer was treated with 0.5M sodium hydroxide (1.0 eq; added slowly keeping the batch temperature below 5°C).
  • the vessel was agitated for 15 minutes and then the layers were separated.
  • the aqueous layers were combined and toluene (3 vols) added slowly keeping the batch temperature below 5°C.
  • the vessel was agitated for 15 minutes and then separated.
  • the aqueous layer was warmed to 25 ⁇ 5°C, and 33% w/w sodium hydroxide added (0.5eq). After 2 hours stirring, 37% w/w hydrochloric acid (2.1 eq) was added to adjust the pH to pH ⁇ 2.
  • Methyl tert-butyl ether (3 vols) was added, the mixture was agitated for 15 minutes, then the layers separated. The organic layer was retained. The aqueous layer was re-extracted with MTBE (3 vols) and the combined organic layers were distilled under vacuum at 35°C to a pot volume of approximately 3 vols, collecting 3 vols distillates. Toluene (5vols) was added, and the batch temperature adjusted to 50°C. Water (1 vol) was added and the batch agitated for at least 15 minutes at this temperature then the layers were separated. The organic layer filtered through a filter then distilled at 35°C until the mixture became turbid.
  • the material was cooled to 20°C, seeded with 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid and agitated at this temperature for 3 hours.
  • the mixture was then distilled under vacuum at 25°C removing further MTBE, and then cooled to 5°C for at least 2 hours.
  • the mixture was filtered, and the solid was washed with toluene (1 vol) at 20°C.
  • the batch was dried with vacuum or under a stream of nitrogen until constant weight was attained at 20°C. After drying, the title compound was obtained as a solid (corrected yield typically 40 - 50%).
  • Diisopropyl azodicarboxylate (1.25 eq.) was added at a batch temperature of between 0 and 5 °C over ⁇ 2 h. The mixture was allowed to warm to room temperature and was stirred for further 30 min. at this temperature. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed and the filter cake was washed with toluene (1.5 vol).
  • Toluene (4 vol) and heptane (1 vol) were added and vacuum distillation was continued at a batch temperature of ⁇ 50 °C until no further MTBE was collected.
  • the batch was cooled to a temperature of ⁇ 40 °C, seeded and further cooled to a batch temperature of between 28 and 32 °C.
  • the resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10 °C. After 2h stirring at 5 to 10 °C the batch was filtered and washed with cold toluene (1 vol.).
  • salts of 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid e.g. sodium, calcium or magnesium salts
  • bases e.g. sodium hydroxide, magnesium hydroxide or calcium hydroxide or by salt exchange for example by using potassium acetate or potassium 2-ethyl hexanoate (in propan-2-ol) for the potassium salt or using calcium bis-(2-ethylhexanoate) for the calcium salt.
  • the layers were separated and the aqueous layer was treated again with iso-propylacetate in the same manner.
  • the layers were separated, the organic layer was discarded and 5N hydrochloric acid ( ⁇ 4.4eq) was added drop-wise over at least 30 minutes to the aqueous layer to a pH end-point of pH 3-0 - pH4.0 whilst maintaining the reaction temperature at 22 ⁇ 3°C.
  • Iso-propylacetate (10 vols) was then added and the mixture heated to 75°C.
  • the mixture was agitated at this temperature for at least 30 minutes, then the temperature was adjusted to 70°C and the layers were separated.
  • the organic layer was retained, and the aqueous layer treated with iso-propylacetate (10 vols) and the mixture heated to 75°C.
  • the mixture was agitated at this temperature for at least 30 minutes, then the temperature was adjusted to 70°C and the layers separated. The organic layer was retained, and the aqueous layer discarded. The combined organic layers from the previous 2 separations were reheated to reflux for dissolution. Water (5 vols) was added and the mixture stirred at 70 - 75°C for at least 15 minutes. The batch temperature was adjusted to 70°C and the aqueous layer separated off and discarded. This process was repeated twice with a further 5 vols of water at each time. The organic layer was set to distil at
  • the mixture was cooled to 60°C, and seeded with 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5-[(lS)-2-methoxy- l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide Form 1, agitated at 60°C for 1 hour, cooled to 50°C at 0.1°C, agitated at 50°C for 140 minutes, then cooled to 22°C at 0.1°C/ minute. The mixture was held at 22°C for at least 12 hours. Heptane (5.06 vols) was then added - drop-wise over at least 120 minutes maintaining the batch temperature at a temperature at 22 ⁇ 5°C.
  • the mixture was cooled to 0°C at 0.1 °C/ minute then held at 0°C for at least 12 hours and then filtered.
  • the isolated solid was washed with a mixture of methyl iso-butylketone (1.0 vols) and heptane (3.0vols) pre-chilled to 0°C.
  • the solid was dried at 40°C. After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid (corrected yield 85%.
  • the reaction mixture was heated at 60 - 65°C for at least 4 hours, then cooled to 40 - 45°C and distilled under vacuum, removing approximately 4.5 vol distillates, and distilling to a final volume of 3.2 vols.
  • Toluene (10.6vol) was added, and the mixture distilled under vacuum at 40 - 45°C, removing approximately 9.1 vol distillates, and distilling to a final volume of 4.7 vols.
  • the mixture was then cooled to 20 - 25°C, and dichloromethane (10.6 vols) added.
  • the mixture was cooled to 0 - 5°C. Meanwhile, to a second flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added azetidine hydrochloride (0.284eq),
  • the layers were separated and the organic layers was heated to reflux, and dichloromethane was removed by atmospheric distillation, distilling to a final volume of approximately 1 - 2 vols, collecting approximately 11.9 vols distillates.
  • the resulting mixture was cooled to 20 - 25°C, and heptane (10.5vols) added.
  • the mixture was heated to reflux for 60 minutes, and then cooled to 90 - 100°C.
  • the hot solution was filtered through a filter containing 10% w/w of activated charcoal into a clean dry vessel. The filter was washed with heptane (0.43vols) and the solution cooled to 20 - 25°C over at least 2 hours.
  • di-isopropylethylamine (1.5eq) under a nitrogen atmosphere.
  • the mixture was heated to 82°C, then diphenylphosphorylazide (l .Oeq) was added over a time period of 5 - 14 hours, maintaining the temperature of the reaction mixture at approximately 82°C.
  • the reaction mixture was stirred for at least 1.5 hours, and then cooled to approximately 60°C.
  • a solution of 4% w/w sodium hydroxide (1.75 eq) was added over a period of 2 hours.
  • the mixture was cooled to 15°C over at least 5 hours then held at 15°C for 3 hours.
  • the batch was then filtered, and the solid slurry washed with water (2vols).
  • the batch was again slurry washed with water (2 vols).
  • the mixture was heated at 70- 75°C for at least 4 hours, then cooled to 50 ⁇ 5°C.
  • Toluene (5.3vols) was added, and the mixture vacuum distilled at 50 ⁇ 5 °C (lOOmbar), removing approximately 5.3vol distillates, and distilling to a final volume of 5vols. This process was repeated.
  • the resulting mixture was then cooled to 20 - 25°C.
  • Toluene (8.93 vols) was added, and the batch agitated at 50 ⁇ 5 °C to give an acid chloride solution.
  • azetidine hydrochloride (1.05 eq)
  • toluene (6.07vols)
  • a solution of potassium carbonate (1.24eq) in water (6.07vols).
  • the resulting mixture was agitated at 20 ⁇ 5 °C for at least 15 minutes, then the layers were separated.
  • the aqueous layer was returned to the flask, and toluene (6.07vols) was added.
  • the mixture was agitated at 20 ⁇ 5 °C for at least 15 minutes, then the layers were separated.
  • the aqueous layer was returned to the flask, and potassium carbonate (1.24eq) and toluene (6.07vols) were added.
  • the mixture was agitated for at least 30 minutes
  • the acid chloride solution in the first flask was added to the mixture in the second flask in portions maintaining the reaction temperature at 20 ⁇ 5 °C over a time period of at least 20 - 60 minutes.
  • the reaction mixture was agitated for at least 30 minutes at 20 ⁇ 5 °C and then filtered, the filter was washed with toluene (0.17 vol) and then the layers were separated.
  • the lower aqueous phase was separated off and discarded.
  • Water (6.07vols) was added to the second flask and the mixture was agitated at 20 ⁇ 5 °C for approximately 15 minutes and then allowed to separate.
  • the lower aqueous phase was separated off and discarded.
  • diphenylphosphorylazide (l .OOeq) was added over a time period of 5 - 6 hours, maintaining the temperature of the reaction mixture at 15 ⁇ 2°C. The mixture was stirred for a further 1.5 hours. Meanwhile to a second flask was added benzyl alcohol (3.00eq) and toluene (1 lvols). The mixture was azeotropically dried to a volume of 10 vols. The contents of the second flask were sampled to ensure the water content was ⁇ 0.1% w/w, then heated to 85 - 90°C. The contents of the first flask were added slowly to the contents of the second flask over approximately 2 hours, maintaining the reaction temperature at approximately 85°C.
  • Activated charcoal (Norit SX Ultra) (5% wt charge) was added to the flask, the mixture was agitated for at least 30 minutes at 20 ⁇ 5°C, then filtered through a 0.45 micron filter. The filter was rinsed with methanol (lvol) then the mother liquors allowed to stir at 15°C under an atmosphere of 6% oxygen/ 94% nitrogen for up to 24 hours ( alternatively an atmosphere of 1% oxygen/ 99% nitrogen was used), then re-filtered through the 0.45 micron filter. The mother liquors were vacuum distilled at 45°C to a final volume of 1.5 vols. Toluene (1.5vols) was added and the mixture vacuum distilled at 45°C to a final volume of 1.5 vols.
  • the mixture was cooled to 45°C, and then seeded with 3- ⁇ [5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy ⁇ -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N-(5 -methylpyrazin-2-yl)benzamide) (form 6) (0.075% w/w).
  • the mixture was held at 45°C for 6 hours, then subjected to a stepped cooling profile.
  • the mixture was cooled to 40°C and held for 6 hours, then cooled to 35°C and held for 6 hours, then cooled to 30°C and held for 6 hours, then cooled to 20°C and held for 6 hours, then cooled to 10°C and held for 3 hours.
  • n-heptane was then added slowly over a period of 2 hours maintaining the mixture at 10°C, following the addition the mixture was held for a further 1 hour at 10°C.
  • the mixture was then cooled to 0°C and held for 6 hours before being filtered.
  • the solid was washed with (2 vols) methyl isobutyl ketone / n heptane mixture (9/1 volume ratio) pre-chilled to 0°C.
  • the solid was dried at 40°C until the solvent level was ⁇ 0.5% w/w. After drying in the vacuum oven at 40°C overnight, the title compound was obtained as a solid (corrected yield 85%).
  • the mixture was heated from 0°C to 30°C at 0.5°C/min, and held at 30°C for 2 hours and then cooled back to 0°C at 0.1°C/min and held at for 3 hours. This temperature cycle was repeated a further 3 times.
  • Potassium hydroxide liquor (662.0 mg of 50.4 %wt/wt, 5.95 mmol) was added dropwise to a solution of methyl 3,5-dihydroxybenzoate (1.00 g, 5.95 mmol) in undried dimethyl sulfoxide (6.61 g, 6 mL/g) so as to create a brown homogeneous solution.
  • 5-(Azetidin-l- ylcarbonyl)-2-chloropyrazine (1.18 g, 5.95 mmol) was added in one go and readily dissolved to leave a brown, homogeneous solution.
  • the vial was capped, placed in a preheated 50 °C stemblock and the solution stirred without inertion.
  • the vial was placed in a preheated 50 °C stemblock and left under these conditions. More potassium hydroxide liquor was added in 132.4 mg (1.19 mmol) portions after a reaction time of 66.5 h, 86.1 h and 95.8 h, before a final 66.2 mg (0.60 mmol) portion was added after 108.6 h. After a reaction time of 114.5 h, the vial was removed from the cooling block and allowed to cool to 21 °C. The solution was then pipetted into solution of concentrated hydrochloric acid (422.9 mg of 11.60 M, 4.16 mmol) that had been diluted with water to 20 mL. A gum formed.
  • concentrated hydrochloric acid 422.9 mg of 11.60 M, 4.16 mmol
  • Methyl 3 - ⁇ [5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5-[(l S)-2-methoxy- 1 - methylethoxy]benzoate was hydro lysed as previously described to give 3- ⁇ [5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5-[(15)-2-methoxy-l-methylethoxy]benzoic acid which was then reacted with 5-methylpyrazin-2-amine as previously described to give 3- ⁇ [5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy ⁇ -5 - ⁇ [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy ⁇ -N- (5-methylpyrazin-2-yl)benzamide.

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Abstract

The present invention relates to processes for reducing the particle size of active pharmaceutical ingredients and to pharmaceutical compositions and pharmaceutical formulations prepared by these processes.

Description

PHARMACEUTICAL FORMULATIONS
The present invention relates to novel pharmaceutical formulations of 3-{[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N- (5-methylpyrazin-2-yl)benzamide. In particular, the present invention relates to processes for reducing the particle size of this compound and to pharmaceutical compositions and pharmaceutical formulations prepared by these processes.
When formulating a compound for pharmaceutical use, it may be advisable to reduce the particle size of the active pharmaceutical ingredient (API) for several reasons. Depending on, inter alia, the solubility and the initial particle size distribution of the active ingredient and on the desired release profile of the formulated drug, particle size reduction of the active ingredient by a technique such as dry milling may be advantageous or even necessary to ensure satisfactory dissolution behaviour of the drug. Proper dissolution is important to achieve acceptable bioavailability of the drug. Furthermore, depending on the relative size of the API particles and that of the other components of the formulation, reducing the particle size of the active ingredient may be advisable in order to avoid segregation in the powder blend and thereby achieve content uniformity in the final formulation. Micronisation in fluidized jet mill is a technique that is frequently used to reduce the particle size of an active pharmaceutical ingredient.
During micronisation of certain compounds that have strong inherent cohesion and/or significant adhesion to stainless steel or titanium nitride it has been found that the material builds up on the surfaces of the milling equipment. This results in a loss of material and leads to a non-homogeneous product. It also diminishes the speed and efficiency of the process resulting in increased processing times and costs. In severe cases this may completely prevent such a process from being carried out on a scale needed for commercial production.
After various unsuccessful attempts to solve this problem it has now been found that such APIs described above may be successfully dry milled on a commercial production scale without significant build-up in the micronisation equipment by milling the API with one or more co -milling excipient(s).
A particular API that is suitable for use in the present invention is 3-{[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5 - methylpyrazin-2-yl)benzamide ("the compound") illustrated in Formula (I) hereinafter, which is an activator of glucokinase (GLK or GK) as described in WO 2007/007041.
Figure imgf000003_0001
(I)
Our co-pending applications PCT/GB2010/050217 and PCT/GB2010/050216 disclose further crystalline forms of the compound of formula I and processes to prepare the compound of formula I, respectively. PCT/GB2010/050217 discloses Form 6 of the compound of formula I.
Attempts to reduce the particle size of this compound have been unsuccessful due to build up of material in the particle size reduction equipment. A satisfactory method of reducing the particle size of this compound has now been found.
The present invention provides a process for dry milling 3- {[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide comprising dry milling 3- {[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide with one or more co-milling excipients wherein the co- milling excipient has a primary particle size of mean diameter of at least 100 microns. Particularly the co-milling excipient is selected from lactose or mannitol. Optionally a surfactant is also used in the process.
In a another aspect the present invention provides a process for dry milling 3- {[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N- (5-methylpyrazin-2-yl)benzamide comprising dry milling 3- {[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide with one or more co-milling excipients and/or a surfactant wherein the co-milling excipient if present has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol. In a further aspect the present invention provides a process for dry milling 3- {[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N- (5-methylpyrazin-2-yl)benzamide comprising the steps of:
1 ) preparing a mixture of 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5-{[(15)-l- methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide with one or more co-milling excipients and/or a surfactant wherein the co-milling excipient if present has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol and
2) dry milling the mixture prepared in 1) above.
In a further aspect the present invention provides a process for dry milling 3- {[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N- (5-methylpyrazin-2-yl)benzamide comprising the steps of:
1) preparing a mixture of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- {[(15)-l-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide with a co- milling excipient and a surfactant wherein the co-milling excipient has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol and
2) dry milling the mixture prepared in 1) above.
In another aspect the present invention provides a co-milled pharmaceutical composition comprising a) 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(15)-l- methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide and b) one or more co-milling excipients and/or a surfactant.
In one embodiment the present invention provides a co-milled pharmaceutical composition comprising a) 93-98% by weight of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5-{[(liS)-l -methyl-2-(methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide and b) 2-7% by weight of a surfactant.
In a second embodiment the present invention provides a co-milled pharmaceutical composition comprising a) 45-50% by weight of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5-{[(liS)-l -methyl-2-(methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide and b) 40-50% by weight of one or more co-milling excipients and/or c) 2-8% by weight a surfactant. In a third embodiment the present invention provides a co-milled pharmaceutical composition comprising a) 60-70% by weight of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5-{[(liS)-l -methyl-2-(methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide and b) 25-35%> by weight of one or more co-milling excipients and/or c) 2-8% by weight a surfactant.
In a fourth embodiment the present invention provides a co-milled pharmaceutical composition comprising a) 55-65% by weight of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5-{[(liS)-l -methyl-2-(methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide and b) 25-35% by weight of one or more co-milling excipients and/or c) 8-12% by weight a surfactant.
It will be understood by those skilled in the art that the percentage of each component of the co-milled pharmaceutical composition is selected to give a total composition of 100%.
Suitably of the surfactant is sodium dodecyl sulphate also known as sodium lauryl sulphate.
In a still further aspect the present invention provides a pharmaceutical formulation comprising a co-milled pharmaceutical composition as described in any one of the embodiments above and pharmaceutically acceptable excipients for a tablet formulation including, for example:
one or more inert diluents (which may also be termed "fillers") such as lactose, sucrose, glucose, mannitol, sorbitol, microcrystalline cellulose, silicified microcrystalline cellulose, sodium carbonate, monobasic calcium phosphate, dibasic calcium phosphate (including dibasic calcium phosphate dihydrate and dibasic calcium phosphate anhydrate), tribasic calcium phosphate, calcium carbonate and the like;
one or more disintegrants such as starch (such as potato, maize or corn), sodium starch glycolate, sodium carboxymethyl cellulose (NaCMC), low substituted
hydroxypropyl cellulose (L-HPC), crosslinked polyvinyl pyrrolidone , algenic acid and the like;
one or more binders such as starch (such as potato, maize or corn), polyvinyl pyrrolidone, microcrystalline cellulose, a polyethylene glycol (PEG), a polyethylene oxide (PEO), a hydroxypropylmethyl cellulose (HPMC) of a low molecular weight, a methyl cellulose (MC) of a low molecular weight, a hydroxypropyl cellulose (HPC) of a low molecular weight, a hydroxyethyl cellulose (HEC) of a low molecular weight, a sodium carboxymethyl cellulose of a low molecular weight and the like;
one or more lubricants such as magnesium stearate, stearic acid, calcium stearate, stearyl alcohol, sodium stearyl fumarate;
a glidant such as talc or a colloidal silica;
a surfactant such as, for example sodium dodecyl sulphate;
a colourant, a flavouring, a preservative;
and anti-oxidants.
Tablet formulations may be uncoated or coated using conventional coating agents and procedures well known in the art. It will be appreciated that some of the above mentioned excipients which may be present in a final oral (for example tablet) composition of the invention may have more than one of the above stated functions. Tablet formulations comprising API may, for example, be manufactured with the following strengths: 1 mg, 2.5 mg, 5 mg, lOmg, 20 mg, 25 mg, 45 mg, 50 mg, 75mg, 100 mg, 150 mg, 200mg, 250 mg and 500 mg.
In one aspect of the invention there is provided a tablet formulation (wherein % = % by weight of total tablet weight) comprising:
a) a co-milled pharmaceutical composition comprising
1 ) 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide: 15 to 30%, 2) 0.5-4% surfactant
b) filler: 50 to 95%, such as 60-75% of mannitol plus 2.5 to 5.0% microcrystalline cellulose,
c) disintegrant: 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate; d) lubricant: 1 to 5% such as 1 to 3%, for example 2.3% magnesium stearate; and e) surfactant: 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
In a further aspect of the invention there is provided a tablet formulation (wherein % = % by weight of total tablet weight) comprising:
a) a co-milled pharmaceutical composition comprising
1 ) 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 1 S)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide: 15 to 30% and 2) 5-25% of a co-milling excipient for example lactose or Pearlitol b) filler: 30 to 75%, such as 35-70%> of mannitol plus 2.5 to 5.0% microcrystalline cellulose,
c) disintegrant: 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate; d) lubricant: 1 to 5% such as 1 to 3%, for example 2.3% magnesium stearate; and e) surfactant: 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
In a further aspect of the invention there is provided a tablet formulation (wherein % = % by weight of total tablet weight) comprising:
a) a co-milled pharmaceutical composition comprising
1 ) 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 1 S)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide: 15 to 30%, 2) 5-25% of a co-milling excipient for example lactose or Pearlitol and 3) surfactant 0.5 to 4% b) filler: 30 to 75%, such as 35-70% of mannitol plus 2.5 to 5.0%> microcrystalline cellulose,
c) disintegrant: 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate; d) lubricant: 1 to 5% such as 1 to 3%, for example 2.3% magnesium stearate; and e) surfactant: 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
In a still further aspect of the invention there is provided a tablet formulation
(wherein % = % by weight of total tablet weight) comprising:
a) a co-milled pharmaceutical composition comprising
1 ) 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 1 S)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide: 1 to 10%, for example 1.7% or 6.7 % 2) 75-90% of a co-milling excipient for example lactose or Pearlitol for example 81.3% or 86.7% and 3) surfactant 0.5 to 4% for example 1%
b) filler: 30 to 75%, such as 2.5 to 5.0%> microcrystalline cellulose, for example 3.7 % or 3.8% or 4.3% or 4.8%
c) disintegrant: 2.5 to 7.5%, such as 3 to 7%, for example 5% sodium starch glycolate; d) lubricant: 1 to 5% such as 1 to 3%, for example 1.1 % Or 1.3% or 2.3% magnesium stearate; and
e) surfactant: 0.01 to 3%, such as 0.75 to 1.25%, for example 1% sodium dodecyl sulphate.
Tablets may be made by conventional means, including direct compression of the powder blend or by dry granulation, such as, for example, roller compaction. A dry process, such as dry granulation, is likely to minimise any possible interchange of polymorphic form during the formulation process.
Compositions for oral use may further be in the form of capsules in which the active ingredient is mixed with one or more inert diluent(s), as previously described.
In one aspect of the invention there is provided a process for the manufacture of a pharmaceutical formulation which comprises:
a first blending step, in which a co-milled pharmaceutical composition as described above is mixed with one or more filler(s), disintegrant(s) and surfactant(s) in a diffusion mixer, a second blending step, in which a lubricant is added to the powder blend and the material is mixed in a diffusion mixer,
dry granulation of the material by roller compaction,
final mixing, in which the granules are mixed with a lubricant in a diffusion mixer and tab letting by compaction of the granules.
Suitably the tablets according to the present invention have a dissolution profile such that 80% by weight of the 3- {[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- {[(15)-l- methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide is dissolved within 30 minutes. Particularly the tablets according to the present invention have a dissolution profile such that 90% by weight of the 3- {[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- { [( 1 S)- 1 -methy l-2-(methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide is dissolved within 30 minutes. More particularly the tablets according to the present invention have a dissolution profile such that 95% by weight of the 3- {[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide is dissolved within 30 minutes.
Examples of the co-micronisation excipient include mannitol, particularly
Pearlitol® 160 and lactose. Suitably the co-milling excipient has a primary particle size of mean diameter in the range of 100-200 microns, particularly 130-190 microns, more particularly 140-180 microns and especially 150-170 microns. Crystalline mannitol having a primary particle size of mean diameter in the range of 100-200 microns, particularly 130- 190 microns, more particularly 140-180 microns, and especially 150-170 microns is particularly advantageous. A particularly suitable form of mannitol is pearlitol® 160C which has a primary particle size of mean diameter of 160 microns and a particle size distribution as illustrated below.
Below are the measured values (two measurements) for Pearlitol® 160 in microns. The laser diffraction measurements were performed using a Malvern Instruments
Mastersizer. The volume weighed distribution of particle size is described below by stating the measured particle diameter in microns corresponding to the percentile of the distribution given within brackets. Thus, the measured values given for d(0.1) show that 10% of the volume weighed distribution of particle diameters lies below approximately 19 microns.
18.7
42.6
100.8
208.6
495.4
In a particular aspect the present invention provides the use of pearlitol® 160 C as the co-milling excipient and SDS as the surfactant. This particular combination appears to act in a synergistic manner to prevent hard build up of material in the milling equipment.
Particularly the 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 1 S)- 1 -methyl- 2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide used is 3- {[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide form 6.
Examples of pharmaceutical compositions
In the following examples the API is the 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5-{[(liS)-l -methyl-2-(methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide form 6. Co-micronisation 1 (API/SDS)
50 g of sodium dodecyl sulphate and 950 g of API were sieved separately through a 1 mm mesh and dispensed into the mixing vessel. After a first mixing with a Turbula mixer the blend was sieved through a 1 mm mesh and mixed a second time. 984.9 g of the material was charged into the spiral jet mill and micronised, yielding a particle size distribution with d(0.1)=1.5 micron, d(0.5)=2.5 micron and d(0.9)=4.4 micron. Build up of material in the equipment amounted to 2.5 g after 540.8 g of material processed and 3.1 g after 813.3 g of material processed. The internal surface of the jet mill was titanium nitride.
Co-micronisation 2 (API/mannitol/SDS)
100 g of sodium dodecyl sulphate, 900 g of mannitol pearlitol 160 and 1000 g of API were sieved separately through a 1 mm mesh and dispensed into the mixing vessel. After a first mixing with a Turbula mixer the blend was sieved through a 1 mm mesh and mixed a second time. 1993.4 g of the material was charged into the spiral jet mill and micronised, yielding a particle size distribution with d(0.1)=1.9 micron, d(0.5)=4.3 micron and d(0.9)=10.2 micron. Build up of material in the equipment amounted to 0.7 g after 563.4 g of material processed and 1.4 g after 1912.6 g of material processed. The internal surface of the jet mill was titanium nitride.
Co-micronisation 3: (API/Mannitol/SDS)
250 g of sodium dodecyl sulphate (SDS), 1500 g of Mannitol pearlitol 160 and 3250 g of API were sieved separately through a 1 mm mesh and dispensed into the mixing vessel. After a first mixing with a Turbula mixer for 15 minutes at 24 rpm the blend was sieved through a 1 mm mesh and mixed a second time for 15 minutes at 24 rpm yielding 4984,6 g of blended material.
A second lot of 250 g of sodium dodecyl sulphate (SDS), 1500 g of Mannitol pearlitol 160 and 3250 g of API was mixed similarly yielding 4993,2 g of blended material.
The two lots of blended material were fed into a spiral jet mill by a screw feeder and micronised. After having processed 3 kg of material the feed and nitrogen was stopped and a first lot of co-micronised material was taken out having a particle size distribution with d(0.1)=2,08 micron, d(0.5)=4,57 micron and d(0.9)=9,60 micron.
Visual inspection revealed that build up of material in the equipment was very low. After having processed another 3 kg of material the feed and nitrogen was stopped and a second lot of co-micronised material was taken out having a particle size distribution with d(0.1)=2,29 micron, d(0.5)=4,92 micron and d(0.9)=10,10 micron.
Visual inspection revealed that build up of material in the equipment was still very low.
After having processed yet another 3 kg of material the feed and nitrogen was stopped and a third lot of co-micronised material was taken out having a particle size distribution with d(0.1)=2,19 micron, d(0.5)=4,74 micron and d(0.9)=9,78 micron.
Visual inspection revealed that build up of material in the equipment was still low.
The internal surface of the jet mill was stainless steel.
Co-micronisation 4: (API/Mannitol/SDS)
37.98 kg of sodium dodecyl sulphate (SDS), 116.65 kg of Mannitol pearlitol 160 and 221.53 kg of API were sieved separately through a 1 mm mesh.
The three components were separately fed into a spiral jet mill by three screw feeders and co-micronised. The feed rates were; 0.9 kg/h for the SDS, 5.4 kg/h for the Mannitol and 11.7 kg/h for the API.
A first batch was made by feeding 9.04 kg of SDS, 54.21 kg of Mannitol and 117.46 kg of API into the jet mill and co-micronising the material at a grinding pressure of 6.0 bar, yielding 178.88 kg of co-micronised material. Dry cleaning of the milling chamber to remove the small amount of build up was performed after every four 55 L drums. The micronised material (composite sample from all drums) had a particle size distribution with d(0.1)= 1.02 micron , d(0.5)= 4.27 micron and d(0.9)= 14.56 micron .
A second batch was made by feeding 7.58 kg of SDS, 45.45 kg of Mannitol and 98.48 kg of API into the jet mill and co-micronising the material at a grinding pressure of 6.0 bar, yielding 150.0 kg of co-micronised material. Dry cleaning of the milling chamber to remove the small amount of build up was performed after every four 55 L drums. The micronised material (composite sample from all drums) had a particle size distribution with d(0.1)= 1.12 micron , d(0.5)= 4.96 micron and d(0.9)= 13.89 micron .
The internal surface of the jet mill was stainless steel. Examples of Pharmaceutical formulations
Example 1
528 g of co-micronised API and sodium dodecyl sulphate from co-micronisation 1 was charged together with the other components according to Table 1 , except for the
Magnesium stearate, making up a total of 2931 g, into a Turbula mixer and was mixed for 10 minutes. 24 g of Magnesium stearate was sieved and added. The material was mixed a second time for 2 minutes. The powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 45 g of Magnesium stearate. The granulate was then compacted into tablets in a Korsch rotary tablet press.
Example 2
1336 g of co-micronised API, mannitol Pearlitol 160 and sodium dodecyl sulphate from co-micronisation 2 was charged together with the other components according to Table 1 , except for the magnesium stearate, making up a total of 3908 g, into a Turbula mixer and was mixed for 10 minutes. 32 g of Magnesium stearate was sieved and added. The material was mixed a second time for 2 minutes. The powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 60 g of Magnesium stearate. The granulate was then compacted into tablets in a Korsch rotary tablet press.
Example 3
263 g of co-micronised API and sodium dodecyl sulphate from co-micronisation 1 was charged together with the other components according to Table 1 , except for the magnesium stearate, making up a total of 977 g, into a Turbula mixer and was mixed for 10 minutes. 8 g of Magnesium stearate was sieved and added. The material was mixed a second time for 2 minutes. The powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 15 g of Magnesium stearate. The granulate was then compacted into tablets in a Korsch rotary tablet press.
Example 4
500 g of co-micronised API, mannitol Pearlitol 160 and sodium dodecyl sulphate from co- micronisation 2 was charged together with the other components according to Table 1 , except for the magnesium stearate, making up a total of 977 g, into a Turbula mixer and was mixed for 10 minutes. 8 g of magnesium stearate was sieved and added. The material was mixed a second time for 2 minutes. The powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 15 g of magnesium stearate. The granulate was then compacted into tablets in a Korsch rotary tablet press.
Example 5
256.9 g of co-micronised API, mannitol and sodium dodecyl sulphate from co- micronisation 3 was charged together with the other components according to Table 1 , except for the magnesium stearate, making up a total of 977.0 g; the sodium starch glycolate was added by sieving it through a 500 μιη screen. The powder blend was mixed for 10 minutes in a Turbula mixer at 34 rpm. 8.03 g of magnesium stearate was sieved through a 500 μιη screen and added. The material was mixed a second time for 2 minutes in a Turbula mixer at 32 rpm. The powder blend was then compacted to ribbons, which were milled to granules, in an Alexanderwerk roller compactor. The resulting 862.7 g of granulate was final mixed with 13.1 g of magnesium stearate. The granulate was then compacted in a Korsch rotary tablet press
Figure imgf000013_0001
Table 1. Composition of tablets produced according to Examples 1 to 5.
Comparative Micronisation.
44574 g of API was micronised in a spiral jet mill at a feed rate of 2 kg/h. The process could not be run continuously since hard build up of API in the mill chamber and the venturi tube forced the mill to be stopped and cleaned after approximately each 2 kg of API processed. The micronised API had a particle size distribution with D(0.1)=1.40 microns, D(0.5)=4.35 microns and D(0.9)=16.47 microns. The internal surfaces of the mill were stainless steel.
Comparative Example 6.
180 g of sodium starch glycolate was milled in a Comil mill. 500 g of micronised API from micronisation 1 was charged together with approximately the same amount of mannitol and 30 g of sodium lauryl sulphate into a Pharmatech blender and was blended for 10 minutes at 25 rpm. The resulting blend was charged together with 150 g of the milled sodium starch glycolate, the rest of the mannitol (2139 g mannitol altogether) and 113 g of microcrystalline cellulose into a Pharmatech blender and blended for 10 minutes at 16 rpm. 24 g of Magnesium stearate was sieved and added. The material was blended in a third step for 2 minutes at 16 rpm. The powder blend was then compacted and milled to granules in a Alexanderwerk roller compactor and the resulting granulate was final mixed with 45 g of Magnesium stearate. The granulate was then compacted into tablets in a Piccola rotary tablet press. The dissolution is shown in Figure 2.
Table 2. Composition of tablets produced according to Example 6.
Component (%) Example 6
API micronised 16.7
Mannitol Parteck M200 71.3
Sodium dodecyl sulphate 1.0
Microcrystalline cellulose 3.8
Sodium starch glycolate 5.0
Magnesium stearate, intragranular 0.8
Magnesium stearate, extragranular 1.5 Tablet Strengths
Figure imgf000015_0001
Dissolution measurements:
The dissolution of the API was analysed by a USP II (paddle) method. Each tablet was placed in 900 mL of 0.1M HC1 solution at 37°C and 50 rpm paddle speed, which was increased to 150 rpm after 60 minutes. The dissolution of tablets from Examples 1-4 was measured using a SOT AX AT70 Smart automated dissolution system while the dissolution of the tablets from Examples 5 & 6 was measured using an optical fibre probe protruding into the dissolution vessel. The data presented as dissolution curves in graphs 1 & 2 are each mean values of three measurements as described above.
Description of the figures:
Figure 1 shows the dissolution data for tablets produced according to Example 1 to 5 showing API dissolved (%) vs time.
Figure 2 shows dissolution data for tablets produced according to Example 6 showing API dissolved (%) vs time.
Figure 3 shows the build up in grams versus weight of API micronised
Figure 4 shows the XRPD pattern for Form 6 of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N-(5 -methylpyrazin-2-yl)benzamide
The invention will now be particularly described by way of the following examples in which the following abbreviations may be used:
vols volume equivalents eq equivalents
w/w weight for weight
v/v volume for volume
DMSO dimethylsulfoxide
Ts tosylate (p-methylbenzenesulfonate)
TLC thin layer chromatography
NMR nuclear magnetic resonance spectroscopy
MTBE methyl tert-butyl ether
In the following non-limiting Examples, unless otherwise stated:
(i) operations were carried out at room temperature, that is in the range 18-25°C and under an atmosphere of an inert gas such as argon or nitrogen;
(ii) yields are given for illustration only and are not necessarily the maximum attainable;
(iii) the structures of the end-products of the Formula (I) were confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectral techniques; proton magnetic resonance chemical shift values were measured on the delta scale and peak multiplicities are shown as follows: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad; q, quartet; quin, quintet; sextet
(iv) purity of intermediates was assessed by NMR analysis;
Example 1: Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2- methoxy-l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide
Figure imgf000016_0001
To a flask was added 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy- l-methylethoxy]benzoic acid (l .Oeq), 5-methylpyrazin-2-amine (l .Oeq) and 2- methyltetrahydrofuran (3.5 vols) under a nitrogen atmosphere. The mixture was cooled to 0°C. N-methylmorpholine (5.0 eq) was added at 0°C, then 2,4,6-tripropyl-l, 3, 5, 2, 4, 6- trioxatriphosphinane 2,4,6-trioxide (supplied as 50% w/w in ethyl acetate) (2.5eq) was added in one portion via addition funnel over 45 minutes maintaining the reaction temperature at 0 - 5°C. The addition funnel was washed with 2-methyltetrahydrofuran (0.5 vols), then the reaction mixture was boiled under reflux under nitrogen for at least 14 hours, before being cooled to 22°C. Water (4.0vols) was added to the reaction mixture in one portion, followed by 2-methyltetrahydrofuran (4.0vols). After agitating for 30 minutes, the layers were separated. The upper organic layer was retained and the aqueous layer returned to the flask. 2-Methyltetrahydrofuran (4.0vols) was added to the flask, the mixture was agitated for 30 minutes, then the layers were separated. The organic layers were combined in the flask and further 2-methyltetrahydrofuran (6.0vols) was then added. The mixture was agitated, and 1.0N hydrochloric acid (4.0vols) was then added. The mixture was agitated for at least 30 minutes at 22 ± 5°C, and the layers were then separated. 1.0N Hydrochloric acid (4.0 vols) was added to the organic layer. The mixture was agitated for at least 30 minutes at 22 ± 5°C the mixture was separated 5% w/w Sodium hydrogen carbonate (4.0 vols) solution was added the organic layer. The mixture was agitated for at least 30 minutes at 22 ± 5°C then the mixture was separated. This process was repeated. Water (4.0 vols) was added to the organic layer, the mixture was agitated for at least 30 minutes at 22 ± 5°C then the layers were separated. The organic layer was distilled under vacuum at 35°C collecting 19 vols of distillates. 2-Methyltetrahydrofuran (4 vols) was added, and the distillation was continued under vacuum at 35°C collecting 6 vols distillates. Further 2-methyltetrahydrofuran (4 vols) was added and the reaction mixture sampled for water content. Further 2-methyltetrahydrofuran (4 vols) was added, and the reaction mixture was filtered through a CUNO™ filter then distilled until the pot volume was approximately 7 vols, then methyl iso-butylketone (11 vols) was added and the mixture vacuum distilled at 35°C to a pot volume of approximately 7 vols. Methyl iso- butylketone (11 vols) was added and the mixture vacuum distilled at 35°C to a pot volume of approximately 6 vols. N-Heptane (0.5 vols) was added to the mixture, and the temperature adjusted to 60°C, the mixture was cooled to 46°C, seeded, then cooled to 22°C and agitated for at least 12 hours. The mixture was filtered. The solid was washed with a mixture of methyl iso-butylketone (1.5 vols)/ heptane (0.16 vols). The solid was washed with heptane (~ 1.5 vols). The isolated solid was dried at 22°C under vacuum to afford the title compound as an off white solid. Corrected yield was 62%. 1H NMR δ (400 MHz DMSO) 11.04 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.57 (bs, 1H), 7.47 (bs, 1H), 7.13 (bs, 1H), 4.81 - 4.77 (m, 1H), 4.58 - 4.54 (t, 2H), 4.11 - 4.07 (t, 2H), 3.55 - 3.47 (m, 2H), 3.3 (s, 3H), 2.48 (s, 3H), 2.34 - 2.26 (m, 2H), 1.26 - 1.25 (d, 3H) Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy] benzoic acid
Figure imgf000018_0001
To a flask was added methyl 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2- methoxy-l-methylethoxy]benzoate (l .Oeq) and N-methylpyrrolidinone (7.6 vols). The contents of the flask were cooled to 10°C. Water (3.9 vols) was added, and the mixture then cooled to approximately -15°C. Sodium hydroxide (1.5eq) was dissolved in water (2.3 vols), and the sodium hydroxide solution added slowly to the flask over one hour, maintaining the reaction temperature below -10°C. The sodium hydroxide was line washed with water (0.5 vols). The reaction mixture was held for approximately 4 hours. Acetic acid (1.25eq) was added to the mixture at -10°C. The mixture was allowed to warm to 5°C. Acetic acid (2.37eq) was added to the mixture, the acetic acid line washed with water (3.5 vols) and the mixture allowed to warm to 22°C. The mixture was seeded, then water (5 vols) was added to the mixture. 2N hydrochloric acid (1.5eq) was added to the mixture until pH4 was reached. The reaction mixture was stirred for at least 14 hours, then cooled to 10°C, stirred for 1 hour at 10°C. The mixture was filtered. The solid was slurry washed with water (3 x 2.5 vol). The isolated solid was dried at 25°C under vacuum to afford the title compound as an off white solid.
The solid was charged to a flask, followed by ethyl acetate (27.2vols), and the mixture heated to reflux for at least 30 minutes. The mixture was filtered hot and approximately 13 vols removed by vacuum distillation. The mixture was cooled to 15°C, and agitated overnight at this temperature. The mixture was filtered, and the (solid) washed with ethyl acetate (2.25 vols). The isolated solid was dried at 25°C under vacuum to afford the title compound as an off white solid. The corrected yield was 78%.
1H NMR δ (400 MHz DMSO): 8.66 (s, 1H), 8.55 (s, 1H), 7.36 (s , 1H), 7.31 (s, 1H), 7.16 (s, 1H), 4.71 - 4.65 (m, 1H), 4.58 - 4.54 (t, 2H), 4.11 - 4.07 (t, 2H), 3.52 - 3.41 (m, 2H), 3.29 (s, 3H), 2.33 - 2.26 (m, 2H), 1.24 - 1.2 (d, 3).
Preparation of methyl (3-{[5-azetidinyl-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[lS)-l- methyl-2-(methyloxy)ethyl]oxy})benzoate
Figure imgf000019_0001
To a clean, dry, suitably serviced flask (flask A) fitted with overhead stirrer, thermometer, condenser, and nitrogen line was added methyl 3,5-dihydroxybenzoate (l .Oeq), 2- (azetidin-l-ylcarbonyl)-5-chloropyrazine (l .Oeq), cesium carbonate ( 3.5eq), and dimethylsulfoxide (9.4 vols) under a nitrogen atmosphere. The reaction vessel was heated to 45°C under a nitrogen atmosphere for at least 14 hours. (lR)-2-Methoxy-l-methylethyl 4-methylbenzenesulfonate (1.3eq) was added over 45 minutes. The mixture was agitated at 45°C for at least 14 hours then cooled to 22°C and iso-propylacetate (10 vols) added. Water (12 vols) was added over 25 minutes at 25°C, and the mixture was agitated for 15 minutes at 22°C. The organic layer was separated off, after which the aqueous layer was re-extracted with (2 x 5 vols) iso-propylacetate. The iso-propyl acetate layers were combined and water (8 vols) was added. The mixture was agitated at 22°C for 30 minutes. The aqueous layer was separated off and discarded. This process was repeated. The organic layer was distilled under vacuum to constant weight.
Meanwhile neutral alumina (18 weight eq) was mixed in a flask with iso-propyl acetate (4.5 vols) and heptane (11.2 vols). This mixture was added to a large chromatography column and the reaction mixture compressed on the column. The mobile organic layer was diluted with iso-propyl acetate (0.2 vols) and heptane (0.4 vols). The mobile organic layer was then added to the column and eluted sequentially with 1 :4 v/v iso-propyl acetate/ heptane (50 vols), 1 :3 v/v iso-propyl acetate/ heptane (20 vols) and 6:4 v/v iso-propyl acetate/ heptane (100 vols). Fractions were analysed by TLC, and fractions that contained clean product evaporated on the rotary evaporator to give the title compound as a thick oil in 59% corrected yield. 1H NMR (400 MHz, DMSO) : δ 8.62 (s, 1H), 8.50 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 4.68 - 4.64 (m, 1H), 4.54 - 4.50 (t, 2H), 4.07 - 4.03 (t, 2H), 3.81 (s, 3H), 3.49 - 3.41 (m, 2H), 3.25 (s, 3H), 2.29 - 2.21 (m, 2H), 1.20 - 1.18 (d, 3H) Preparation of (lR)-2-methoxy-l-methylethyl 4-methylbenzenesulfonate
(R)-(-
Figure imgf000020_0001
To a flask was added under a nitrogen atmosphere trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3eq) and toluene (5 vols) and the reaction mixture agitated to form an oily slurry. The slurry was cooled to -5°C. (2R)-l-Methoxypropan-2-ol(1.0eq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a wash followed by triethylamine (1.5eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature < 8°C. Further toluene (2.5 vols) was added as a wash and the reaction mixture held at -5°C to 5°C for 4.5 hours. N,N-Dimethyl-1,3- propane-diamine (0.3eq) was added over 10 minutes at -5°C. The mixture was agitated at - 5°C to 5°C for 30 minutes. Then 2N hydrochloric acid (0.55eq) and 70ml water were added. The mixture was agitated for 30 minutes at 22°C and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) and after separation of the aqueous wash, the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to give the title compound as a dry light brown oil. Yield (corrected for assay) 93 - 97%.
1H NMR (400 MHz CDC13): δ 7.78 - 7.75 (d, 2H), 7.45 - 7.43 (d, 2H), 4.66 - 1H), 3.35 - 3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13 - 1.11 (d , 3H) Preparation of methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate
Figure imgf000021_0001
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (l .Oeq), sodium phosphate mono-basic monohydrate (0.46eq) and water (10.5vols) under a nitrogen atmosphere. The temperature was adjusted to 20°C ± 3°C. 10% w/w Sodium hydroxide was added to adjust the pH to pH 7.8 ± 0.2. Benzoyl chloride (1.0 eq) was added drop-wise in small portions over 1 - 2 hours, and sodium hydroxide was added concurrently drop-wise in small portions over the same time period to maintain the reaction in a pH range of pH 7.8 ± 0.2 and at a reaction temperature of 20°C ± 3°C. The crude reaction mixture was agitated for a further 30 minutes, filtered, and then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05eq), and adjusted to pH7.5 with 10% w/w sodium hydroxide. The crude solid was then washed with 4 vols of a solution prepared from water (4 vols), sodium phosphate mono-basic monohydrate (0.05eq), and adjusted to pH6.5 with 10%> w/w sodium hydroxide. The crude solid was then disssolved in iso-propyl acetate (8 vols) and water (2 vols) and the mixture agitated for at least 30 minutes to ensure the solid had dissolved. The mixture was filtered through a CUNO™ filter to remove a small amount of brown solid. The aqueous layer was separated off. Water (2 vols) was added to the organic layer and the batch agitated for at least 30 minutes. The aqueous layer was separated off and the organic layer was vacuum distilled, keeping the batch temperature below 40°C to reduce the volume to 5 - 6 vols. Toluene was added then added (5 vols) and the mixture was vacuum distilled keeping the batch temperature below 40°C, reducing the volume to approximately 3.5 vols. The mixture was cooled to 15°C ± 3°C and agitated at this temperature for at least 30 minutes, then filtered, and the solid washed with toluene (1 vol). The product was dried at 20°C - 40°C to give the desired product as a solid (corrected yield 40%> - 70%>).
1H NMR δ (400 MHz; CDC13) : 8.21 - 8.18 (d, 2H), 7.67 - 7.63 (t, 1H), 7.54 - 7.49 (t, 2H), 7.44 (d, 2H), 6.98 - 6.96 (t, 1H), 6.7 (bs, 1H), 3.90 (s, 3H). Alternatively methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate may be made by the following process:
To a flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was added methyl-3,5-dihydroxybenzoate (l .Oeq), 325 mesh potassium carbonate (3.0eq) and dimethylformamide (DMF) (4 vols) under a nitrogen atmosphere. The mixture was heated to 47°C for 1 hour, then benzoyl chloride (l .Oeq) was added slowly drop-wise via syringe pump over approximately 2 hours. Further benzoyl chloride was added (0.1 eq) over 20 minutes via syringe pump. The reaction mixture was held for 1.5 hours, then water (lOvols) and iso-propyl acetate (6 vols) were added. The reaction mixture was agitated for 30 minutes and then the layers were separated. The aqueous layer was re- extracted with a further charge of iso-propyl acetate (6 vols). The batch was separated, and the combined organic layers were washed with saturated brine (6 vols), then with a solution of 0. IN hydrochloric acid/ brine. The iso-propyl acetate was distilled to dryness on the rotary evaporator. Iso-propyl acetate (6 vols) was added, and distilled to dryness on the rotary evaporator. Toluene (6 vols) was added and distilled to dryness on the rotary evaporator. Toluene (3.5 vols) was added and the reaction slurried for 30 minutes. The solid was filtered off and dried at 20°C - 40°C to give the desired product as a solid (corrected yield 72%).
Alternative Preparation of methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate
To an inerted flask fitted with thermometer, condenser, overhead stirrer, pH probe and nitrogen line was charged methyl 3,5-dihydroxy benzoate and suspended in lOvol water. The pH of the suspension was adjusted to 8.0 using an aqueous solution of 2.5% lithium hydroxide and 2.5% potassium carbonate. A solution of benzoyl chloride (1.0 eq.) in 2 vol toluene was added at such a rate that the internal temperature could be maintained between 20 and 22°C. The pH of the solution was maintained between 7.9 and 8.1 by simultaneous addition of an aqueous solution of 2.5% lithium hydroxide and 2.5% potassium carbonate (approximately 5 vol). The resulting suspension was agitated for further 60 minutes at 20- 22 °C and then filtered. The filter cake was washed twice with water (2vol each) and pulled dry. The crude product obtained was then dissolved in isopropyl acetate (8vol) before Diatomaceous earth was added and the slurry was stirred for lh. Following filtration of the suspension the product is then solvent-swapped from isopropyl acetate into toluene (5vol) by vacuum distillation maintaining the internal temperature at or below 45 °C. The resulting suspension was cooled to 15 °C, agitated for lh and then filtered. After washing the filter cake with 1 vol toluene the product was dried to constant weight yielding typically 75-80% of the title product at >98% purity.
Preparation of (lR)-2-methoxy-l-methylethyl 4-methylbenzenesulfonate
Figure imgf000023_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added trimethylamine hydrochloride (0.1 eq), tosyl chloride (1.3eq) and toluene (5 vols) under a nitrogen atmosphere and the reaction mixture agitated to form an oily slurry. The slurry was cooled to -5°C, then (2R)-l-methoxypropan-2-ol (l .Oeq) was added drop-wise over 30 minutes. Toluene (2.5 vols) was added as a line wash followed by triethylamine (1.5eq), which was added drop-wise via addition funnel over 30 minutes maintaining the reaction temperature < 8°C. Further toluene (2.5 vols) was added as a line wash and the reaction mixture held at -5°C to 5°C for 4.5 hours. N,N-dimethyl-l,3-propane-diamine, (0.3eq) was added over 10 minutes at -5°C. The reaction mixture was agitated at -5°C to 5°C for 30 minutes, then 2N hydrochloric acid (0.55eq) and 70ml water were added. The reaction mixture was agitated for 30 minutes at 22°C and the aqueous layer was separated off and discarded. The mixture was washed twice more with water (10 vols each wash) then the toluene layer was distilled to an oil on the rotary evaporator. Toluene (20 vols) was added to the oil and the solution evaporated to an oil to give the title compound as a dry light brown oil. Yield corrected for assay 93 - 97%. 1H NMR δ (400 MHz CDC13):7.78 - 7.75 (d, 2H), 7.45 - 7.43 (d, 2H), 4.66 - 4.62 (m, 1H), 3.35 - 3.26 (m, 2H), 3.16 (s, 3H), 2.4 (s, 3H), 1.13 - 1.11 (d, 3H).
Preparation of (lR)-2-methoxy-l-methylethyl 4-(trifluoromethyl)benzenesulfonate)
Figure imgf000023_0002
To a flask was added 4-trifluoromethylsulfonylchloride (1.3eq) and toluene (lOvols), the reaction mixture was cooled to 5°C, then (2R)-l-methoxypropan-2-ol (l .Oeq) was added at 5°C. Trimethylamine hydrochloride (O. leq) was added at 5°C, then triethylamine (1.5eq) added slowly drop-wise over 50 minutes maintaining the reaction temperature between 5 - 12°C. After holding for approximately 18 hours at 5°C, the reaction was quenched by the dropwise addition of 3-dimethylaminopropane (0.3eq) over minutes at 5°C. The reaction mixture was stirred for 2 hours at 5°C, then water (5 vols) added at 5°C, then 5N hydrochloric acid (2 vols) was added slowly at 5°C. The reaction mixture was warmed to 20°C, water (1 vol) was added followed by toluene (10 vols). The reaction mixture was warmed to 30°C, then the aqueous layer separated off and discarded. Water (5 vols) was added and the reaction mixture agitated for 30 minutes, then the water layer separated off and discarded. 8% w/w Sodium carbonate (4 vols) was added, the reaction mixture agitated for 30 minutes, then the water layer separated off and discarded. Water (5 vols) was added, the batch agitated for 30 minutes, then the water layer separated off and discarded. This water wash was repeated twice. The organic layer was evaporated to an oil on the rotary evaporator. Toluene was added and the organic layer was evaporated to an oil on the rotary evaporator. This process was repeated to give the desired product as a yellow oil (corrected yield 97%). 1H NMR δ (400 MHz CDC13) 8.07 - 8.05 (d, 2H), 7.82 - 7.80 (d, 2H), 4.84 - 4.80 (m, 1H), 3.44 - 3.35 (m, 1H), 3.19 (s, 3H), 1.35 - 1.33 (d, 3H). Preparation of 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid
Figure imgf000024_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate (l .Oeq), cesium carbonate (1.5eq) and dimethylsulfoxide (7.0vols) under a nitrogen atmosphere. The batch was heated to 40 - 45°C. (li?)-2-methoxy-l-methylethyl 4-methylbenzenesulfonate (1.3 eq) was added slowly dropwise over at least 90 minutes maintaining reaction temperature at 40 - 45°C. The reaction mixture was held for at least 8 hours and then was cooled to 15 ± 4°C. Iso-propyl acetate (4.0 vols) was added followed by water (5.0 vols), keeping the reaction temperature below 25°C. The reaction mixture was agitated for approximately 15 minutes and then the layers were separated. The organic phase was retained. The aqueous phase was re-extracted with further iso-propyl acetate (3 vols). The reaction mixture was agitated for approximately 15 minutes and then the layers separated. This process was repeated with further isopropyl acetate and the organic phases were combined and then washed with water (3 vols). After approximately 15 minutes agitation the layers were separated, and water (3 vols) was added to the organic layer. After approximately 15 minutes agitation the layers were separated and the organic layer was vacuum distilled at 40°C until no more solvent could be distilled. Methanol (7 vols) was added, then sulphuric acid (0.8eq) was added and the mixture was heated to reflux for at least 16 ± 4 hours. The reaction mixture was vacuum distilled at 40°C until a pot volume of 2.5 - 3 vols was achieved. Toluene (4 vols) was added to the flask, and vacuum distillation continued at 35°C until a pot volume of 4.0 vols was achieved. The mixture was cooled to 20 ± 5°C. Water (15 vols) was added to the reaction mixture and the mixture agitated at 20± 5°C for at least 15 minutes. The batch was separated and the organic layer was cooled to 0 - 5°C, before 0.5M sodium hydroxide (1.0 eq) was added slowly keeping the batch temperature below 5°C. The vessel was agitated for 15 minutes and then separated. The aqueous layer was retained and the organic layer was treated with 0.5M sodium hydroxide (1.0 eq; added slowly keeping the batch temperature below 5°C). The vessel was agitated for 15 minutes and then the layers were separated. The aqueous layers were combined and toluene (3 vols) added slowly keeping the batch temperature below 5°C. The vessel was agitated for 15 minutes and then separated. The aqueous layer was warmed to 25 ± 5°C, and 33% w/w sodium hydroxide added (0.5eq). After 2 hours stirring, 37% w/w hydrochloric acid (2.1 eq) was added to adjust the pH to pH <2. Methyl tert-butyl ether (3 vols) was added, the mixture was agitated for 15 minutes, then the layers separated. The organic layer was retained. The aqueous layer was re-extracted with MTBE (3 vols) and the combined organic layers were distilled under vacuum at 35°C to a pot volume of approximately 3 vols, collecting 3 vols distillates. Toluene (5vols) was added, and the batch temperature adjusted to 50°C. Water (1 vol) was added and the batch agitated for at least 15 minutes at this temperature then the layers were separated. The organic layer filtered through a filter then distilled at 35°C until the mixture became turbid. The material was cooled to 20°C, seeded with 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid and agitated at this temperature for 3 hours. The mixture was then distilled under vacuum at 25°C removing further MTBE, and then cooled to 5°C for at least 2 hours. The mixture was filtered, and the solid was washed with toluene (1 vol) at 20°C. The batch was dried with vacuum or under a stream of nitrogen until constant weight was attained at 20°C. After drying, the title compound was obtained as a solid (corrected yield typically 40 - 50%). 1H NMR δ (400 MHz DMSO): 12.82 (bs, 1H), 9.74 (bs, 1H), 6.95 (bs, 1H), 6.91 (bs, 1H), 6.56 - 6.55 (t, 1H), 4.59 - 4.52 (m, 1H), 3.5 - 3.41 (m, 2H), 3.28 (s, 3H), 1.21 - 1.19 (d, 3H).
Alternative Preparation of 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid
Methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate (1.0 eq.), (R)-l-methoxy-2-propanol (1.25 eq.) and triphenylphosphine (1.25 eq.) were suspended in toluene (10 vol).
Diisopropyl azodicarboxylate (1.25 eq.) was added at a batch temperature of between 0 and 5 °C over ~2 h. The mixture was allowed to warm to room temperature and was stirred for further 30 min. at this temperature. The resulting suspension was filtered to remove the bulk of the triphenylphosphine oxide formed and the filter cake was washed with toluene (1.5 vol). To the combined toluene fractions containing the resulting methyl 3-[(lS)-2- methoxy-l-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate was added sodium methylate (0.8 eq.) at a batch temperature of between 20 and 30 °C and the mixture was stirred to lh. The solution of the resulting methyl 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]- benzoate was then extracted twice with KOH 0.25 M (3.5 vol each) at a batch temperature of between 0 and 5 °C. KOH was then added (1 eq.) to hydrolyse the ester moiety and the batch was stirred for 1 h at a temperature of between 20 and 30 °C. The pH of the aqueous phase is then adjusted to 1.5 using cone, hydrochloric at a batch temperature of < 30 °C. Crude 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid was subsequently extracted into MTBE (2x 3vol) before activated charcoal was added. The batch was stirred for 10 minutes and then filtered. The batch was reduced to 3 pot volumes by distillation at a batch temperature of < 45 °C. Toluene (4 vol) and heptane (1 vol) were added and vacuum distillation was continued at a batch temperature of < 50 °C until no further MTBE was collected. The batch was cooled to a temperature of < 40 °C, seeded and further cooled to a batch temperature of between 28 and 32 °C. The resulting suspension was stirred for 1 h at this temperature before being further cooled to 5 to 10 °C. After 2h stirring at 5 to 10 °C the batch was filtered and washed with cold toluene (1 vol.). Drying at < 60 °C furnished 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid in >99% purity as colourless solid with a melting point of 95 °C in a typical yield between 65 and 70% from methyl 3-hydroxy-5-[(phenylcarbonyl)oxy]benzoate. Methyl 3- [(1 S)-2-methoxy- 1-methylethoxy] -5- [(phenylcarbonyl)oxy] benzoate
1H NMR (400 MHz, CDC13) δ 8.21 - 8.17 (d, 2H), 7.66 - 7.62 (t, 1H), 7.54 - 7.49 (m, 4H), 7.03 - 7.02 (t, 1H), 4.64 - 4.60 (m,lH), 3.9 (s, 3H), 3.61 - 3.49 (m, 2H), 3.45 (s, 3H), 1.35 - 1.33 (d , 3H)
13C NMR data (100.55 MHz, CDC13) δ 166.2, 164.91, 158.88, 151.79, 133.87, 132.25, 130.28, 129.28, 128.71, 115.6, 114.95, 114.27, 75.7, 73.83, 59.45, 52.44, 16.72.
Methyl 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoate
1H NMR (400 MHz, DMSO) δ 6.93 (s, 1H), 6.90 (s, 1H), 6.57 (bs, 1H), 4.55 - 4.51 (m, 1H), 3.79 (s, 3H), 3.47 - 3.41 (m, 2H), 3.26 (s, 3H), 1.18 - 1.17 (d, 3H)
Preparation of 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid (t- butylamine salt)
To a flask fitted with overhead stirrer was added 3-hydroxy-5-[(lS)-2-methoxy-l- methylethoxy]benzoic acid (l .Oeq) and acetonitrile (6 vols). Tert-butylamine (l .Oeq) was added at 22°C, followed by acetonitrile (3 vols). After stirring for at least 5 hours, the reaction mixture was filtered and dried in a vacuum oven to give the title compound as a crystalline white solid (73.6%). 1H NMR (400 MHz DMSO) δ: 6.90 (bs, 1H), 6.85 (s, 1H), 6.30 - 6.29 (t, 1H), 4.47 - 4.43 (m, 1H), 3.47 - 3.35 (m, 2H), 3.09 (s, 3H), 1.22 (s, 9H), 1.17 - 1.16 (d, 3H). Melting point by Differential Scanning Calorimetry (DSC) 154.7°C. Preparation of 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid (potassium salt)
KOH liquor (1.04 eq. of 50.4 wt %) was added to a stirred, nitrogen sparged solution of 3- hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid (1 eq.) in undried 1-propanol (4.87 vol.). At the end of the addition, water (0.33 vol.) and toluene (3.43 vol.) were separately added to the resulting slurry. The jacket temperature was raised to 67 °C before being subjected to the following cooling profile: 67 °C to 64 °C over 3 h, 64 to 57 °C over 3 h, 57 to 45 °C over 3 h, and 45 to 20 °C over 3 h. 6 h after the end of this ramp, the jacket temperature was lowered to 0 °C over 3 h, the jacket was foil wrapped and desupersaturation was allowed to complete overnight (> 6 h). The slurry was isolated by filtration through an 11 micron filter paper. The cake was sequentially washed twice with an equal weight of an ice-cold solution of toluene (41.79 wt %) in 1-propanol. The cake was dried in a 40 °C house vacuum oven to give 3-hydroxy-5-[(lS)-2-methoxy-l- methylethoxy]benzoic acid potassium salt as tri-hydrate in a typical yield of 93% of theoretical yield.
1H NMR (400 MHz, d6-DMSO) 9.05 (1H, br s), 6.86-6.83 (2H, m), 6.18 (1H, dd, J= 2.3, 2.3), 4.44 (1H, qdd, 6.2, 5.1, 5.1), 3.48-3.33 (8H, m), 3.28 (3H, s), 1.18 (3H, d, J= 2.3)
Other salts of 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid, e.g. sodium, calcium or magnesium salts, were formed in a similar way using appropriate bases, e.g. sodium hydroxide, magnesium hydroxide or calcium hydroxide or by salt exchange for example by using potassium acetate or potassium 2-ethyl hexanoate (in propan-2-ol) for the potassium salt or using calcium bis-(2-ethylhexanoate) for the calcium salt..
Process for enzymatic conversion of (methyl 3-[(lS)-2-methoxy-l-methylethoxy]-5- [(phenylcarbonyl)oxy]benzoate to methyl 3-hydroxy-5-[(lS)-2-methoxy-l- methylethoxy] benzoate
To a flask fitted with thermometer and magnetic stirrer was added (methyl 3-[(lS)-2- methoxy-l-methylethoxy]-5-[(phenylcarbonyl)oxy]benzoate) (l .Oeq), and tert-butanol (90 vols) followed by addition of either water (10 vols) or pH7 buffer (10 vols). Enzyme lwt eq (either AE 01 Lipase CI or Alphamerix AE-02) was added and the reaction agitated at 36°C for several days (such as 7 days) until the reaction was complete.
Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy] benzoic acid
Figure imgf000028_0001
To a clean dry flask fitted with thermometer, condenser, overhead stirrer and nitrogen line was added 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid* (l .Oeq), potassium carbonate (2.5eq), dimethylsulfoxide (3 vols) and water (1.0 vols) under a nitrogen atmosphere. The resulting mixture was heated to 45°C - 55°C for at least one hour. 2-(Azetidin-l-ylcarbonyl)-5-chloropyrazine (1.05eq) was dissolved in dimethylsulfoxide (5.0vols) at about 40°C - 50°C. The solution of 2-(azetidin-l- ylcarbonyl)-5-chloropyrazine in DMSO was added drop-wise via syringe pump to the above reaction mixture over 1 - 4 hours maintaining the reaction temperature at 45 °C - 55°C. The reaction was stirred for 16 hours at 45°C - 55°C. The bath was cooled to 22 ± 3°C. Water (8 vols) was added, followed by iso-propyl acetate (lOvols). The contents were agitated at 22°C for 15 minutes then the layers were separated The aqueous layers was treated with iso-propylacetate (10 vols) and the mixture agitated at 22 ± 3°C for at least 15 minutes. The layers were separated and the aqueous layer was treated again with iso-propylacetate in the same manner. The layers were separated, the organic layer was discarded and 5N hydrochloric acid (~4.4eq) was added drop-wise over at least 30 minutes to the aqueous layer to a pH end-point of pH 3-0 - pH4.0 whilst maintaining the reaction temperature at 22 ± 3°C. Iso-propylacetate (10 vols) was then added and the mixture heated to 75°C. The mixture was agitated at this temperature for at least 30 minutes, then the temperature was adjusted to 70°C and the layers were separated. The organic layer was retained, and the aqueous layer treated with iso-propylacetate (10 vols) and the mixture heated to 75°C. The mixture was agitated at this temperature for at least 30 minutes, then the temperature was adjusted to 70°C and the layers separated. The organic layer was retained, and the aqueous layer discarded. The combined organic layers from the previous 2 separations were reheated to reflux for dissolution. Water (5 vols) was added and the mixture stirred at 70 - 75°C for at least 15 minutes. The batch temperature was adjusted to 70°C and the aqueous layer separated off and discarded. This process was repeated twice with a further 5 vols of water at each time. The organic layer was set to distil at
atmospheric pressure to a pot volume of 4 vols. Iso-propyl acetate (8 vols) was added and the batch set to distil to a pot volume of approximately 4 vols. The batch was cooled to 22°C over 2 hours, the batch was agitated at 22°C for 3 hours, then cooled to 0°C, the mixture was held at 0°C for 5 hours, then filtered, and the solid washed with iso- propylacetate (20ml, 4 vols). After drying in the vacuum oven at 50°C overnight, the desired product was obtained as a solid (corrected yield 85 - 90%). 1H NMR δ (400 MHz DMSO): 8.66 (s, 1H), 8.55 (s, 1H), 7.36 (s, 1H), 7.31 (s, 1H), 7.16 (s, 1H), 4.71 - 4.65 (m, 1H), 4.58 - 4.54 (t, 2H), 4.11 - 4.07 (t, 2H), 3.52 - 3.41 (m, 2H), 3.29 (s, 3H), 2.33 - 2.26 (m, 2H), 1.24 - 1.19 (d , 3H) * Alternatively, salts of this acid may be used in this procedure, either directly or after transformation into the free acid by cracking the salt by appropriate method, eg:
acidification and extraction, adding NaOH then distilling, or any other process known in the art.
Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy] benzoic acid
Alternative Method
3-Hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoic acid (5.00g, 22.10 mmol) and tetra n-butyl phosphonium chloride (6.53 g, 22.1 mmol) were suspended in 2-methyl- tetrahydrofuran (25ml, 5 vol rel. to the benzoic acid) and 22mL water at ambient temperature under nitrogen. Solid potassium carbonate (27.98g, 202.4 mmol) was charged portionwise with vigorous mechanical stirring. At the end of addition KOH liquor (2.46g 50%wt/wt in water, 22.1 mmol) was added before the biphasic slurry was heated to 50°C. Once the temperature had stabilised, 2-(azetidin-l-ylcarbonyl)-5-chloropyrazine (4.586g, 23.21 mmol) was charged portionwise over 40 minutes and the mixtures was stirred over night under nitrogen at 50°C. The phases were split and the lower aqueous phase was run off. 25ml of toluene and 50mL water were added to the remaining dark red organic phase. The pH of the aqueous phase was then adjusted to 7.0 using cone, hydrochloric acid. The jacket temperature was adjusted to 20°C and the phases were separated again (the lower aqueous phase was run off and retained; the upper organic phase was discarded). The aqueous phase was washed with more toluene (25mL). After phase separation the toluene phase was removed again. The pH of the retained aqueous phase was adjusted to 2.1 using 5M hydrochloric acid solution (7.1mL). Isopropyl acetate (34.9g) was charged and the jacket temperature was raised to 80 °C. Equilibration was performed with the jacket temperature set to 80 °C. After phase split the lower aqueous phase was run off again and back-extracted with more isopropyl acetate (17.4g). The organic phases were combined and homogenised at 80 °C before being washed with water (10 mL). The organic phase was dried by azeotropic distillation under slight vacuum at constant batch volume (batch partially crystallised). The suspension was cooled to 0°C over 13.5h and the batch was isolated by filtration followed by a cake-wash with isopropyl acetate (17.4g). After drying at 40°C in a vacuum oven overnight 5.25g at 96% strength (59% corrected yield) of the desired product was obtained as white solid. 3-{[5-(Azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N- (5-methylpyrazin-2-yl)benzamide
A
Figure imgf000031_0001
To a flask fitted with overhead stirrer, thermometer, condenser, and nitrogen line was added 3 - {[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 - methylethoxy]benzoic acid (l .Oeq), 5-methylpyrazin-2-amine (1.12eq) and 2- methyltetrahydrofuran (4.4vols) under a nitrogen atmosphere. The mixture was cooled to 5°C, and then N-methylmorpholine (5.0eq) added drop-wise over at least 15 minutes maintaining the temperature at 5 ± 5°C. 1-Propanephosphonic acid cyclic anhydride (T3P) (as 50% w/w solution in ethyl acetate) (2.5eq) was added drop-wise over at least 15 minutes maintaining the temperature at 5 ± 5°C. The mixture was heated to reflux for at least 16 hours then cooled to 22 ± 5°C. Water (4.0vols) was added to the reaction mixture, followed by 2-methyltetrahydrofuran (4.0vols). After agitating for 30 minutes, the mixture was separated. The upper organic layer was retained and the aqueous layer treated with 2- methyltetrahydrofuran (4.0vols). After agitating for 30 minutes, this mixture was separated. The organic layers were combined and further 2-methyltetrahydrofuran
(6.0vols) was then added. The mixture was agitated, and 1.0N hydrochloric acid (4.0vols) was added. The mixture was agitated for at least 30 minutes at 22 ± 5°C, and the layers were then separated. The organic layer was treated with 1.0N hydrochloric acid (4.0 vols) then the mixture was agitated for at least 30 minutes at 22 ± 5°C, then the layers were separated. The organic layer was treated with 5% w/w sodium hydrogen carbonate (4.0 vols). The mixture was agitated for at least 30 minutes at 22 ± 5°C, the layers were separated. The organic layer was treated again with 5% w/w sodium hydrogen carbonate (4.0 vols) following the same procedure, and then with water (4.0 vols) following the same procedure. The organic layer was then distilled at atmospheric pressure to a pot volume of 4.7 vols. Methyl iso-butylketone (lOvols) was added, and the batch distilled at
atmospheric pressure to a pot volume of 4.68 vols. Methyl iso-butylketone (lOvols) was added, and the batch distilled at atmospheric pressure to a pot volume of 4.68 vols. The batch was cooled to 70°C, heptane (2.02vols) was added slowly drop-wise over at least 30 minutes maintaining the reaction temperature at 70 ± 5°C. The mixture was cooled to 60°C, and seeded with 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy- l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide Form 1, agitated at 60°C for 1 hour, cooled to 50°C at 0.1°C, agitated at 50°C for 140 minutes, then cooled to 22°C at 0.1°C/ minute. The mixture was held at 22°C for at least 12 hours. Heptane (5.06 vols) was then added - drop-wise over at least 120 minutes maintaining the batch temperature at a temperature at 22 ± 5°C. The mixture was cooled to 0°C at 0.1 °C/ minute then held at 0°C for at least 12 hours and then filtered. The isolated solid was washed with a mixture of methyl iso-butylketone (1.0 vols) and heptane (3.0vols) pre-chilled to 0°C. The solid was dried at 40°C. After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid (corrected yield 85%. 1H NMR δ (400MHz DMSO) 11.04 (s, 1H), 9.26 (s, 1H), 8.68 (s, 1H), 8.57 (s, 1H), 8.36 (s, 1H), 7.56 (s, 1H), 7.46 (s, 1H), 7.12 (s, 1H), 4.81 - 4.77 (m, 1H), 4.58 - 4.54 (t, 2H), 4.11 - 4.07 (t, 2H), 3.55 - 3.47 (m, 2H), 3.3 (s, 3H), 2.48 (s. 3H), 2.34 - 2.26 (m, 2H), 1.26 - 1.25 (d, 3H)
3-{[5-(Azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N-
(5-methylpyrazin-2-yl)benzamide
B
3- {[5-(Azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 -methylethoxy]- benzoic acid (l .Oeq), (1.00 mol eq), 5-methylpyrazin-2-amine (1.12 mol eq) and 2- methyltetrahydrofuran (2.00 rel vols) were charged to a vessel and stirred at 20°C. N- methylmorpholine (5.00 mol eq) was added followed by a line-wash with 2-methyl- tetrahydrofuran (0.50 rel vols). A 50wt% solution of 1-propanephosphonic acid cyclic anhydride (T3P) in 2-methyltetrahydrofuran (1.70 mol eq) was charged followed by a line wash with 2-methyltetrahydrofuran (0.50 rel vols). The resulting mixture was heated to 78°C over 30 minutes and the clear yellow solution was held at 78°C for roughly 22 hours, then checked for acceptable conversion. At the end of reaction the solution was further diluted with 2-methyltetrahydrofuran (7.00 rel vols) and the temperature was adjusted to 45°C. 5wt% aq. sodium bicarbonate solution (6.00 rel vols) was slowly added over 30mins to the stirring solution causing gas evolution. After 15 minutes stirring was turned off and the phases were allowed to separate over 30 minutes. The lower aqueous phase was drained off. 20wt% aq. phosphoric acid (3.30 rel vols) was charged to the stirring organic phase. After 15 minutes stirring the phases were allowed to separate and the lower aqueous phase was drained off again. A mixture of 20wt% aq. phosphoric acid (1.50 rel vols) and water (1.50 rel vols) was charged to the stirring organic phase. After 15 minutes, stirring was turned off and the mixture held overnight for phase separation. The lower (aqueous) phase was drained off again. 5Wt% aq. sodium bicarbonate (4.50 rel vols) was added over at least lOmins to the stirring solution. After phase separation the lower (aqueous) phase was run off again. The resulting solution was dried by azeotropic distillation to a concentration of approximately 241mg/g, collecting around 0.48 rel vols of the lower distillate phase. Heptane (1.60 rel vols) was added over lOmins to the dry solution at above 50°C before the batch was cooled to 40°C. The solution was seeded with 3-{[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N-(5-methylpyrazin-2- yl)benzamide (Form 1 Seed, 0.0010 rel wt) before an overnight temperature program was applied: held at 40°C for 2hrs; cooled to 35°C at O.rC/min (50 minutes); held for 2 hours; cooled to 30°C at O.rC/min (50 minutes); held for 2 hours; cooled to 0°C at O.rC/min (300 minutes); and held for at least 2 hours. After crystallisation overnight, further heptane (4.1 rel vols) was added over 2.0 hours to reduce losses to liquors to <4.0mg/mL. The suspension was then filtered followed by a line rinse with a pre-mixed solution of heptane (2.10 rel vols) and 2-methyltetrahydrofuran (0.90 rel vols) and transferred to a filtration apparatus. The filter cake was dried to constant weight at 40°C to furnish crude 3-{[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 -methylethoxy]-N-(5- methylpyrazin-2-yl)benzamide in 86-89% of theory as Form I.
Process for crystallisation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2- methoxy-l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide (as form 4) from 2- methyltetrahydrofuran/ isohexane
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added a solution of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide in 2-methyltetrahydrofuran under a nitrogen atmosphere. The solution was distilled at atmospheric pressure until a pot volume of 7 vols was obtained. Iso-hexane (3 vols) was added at 70°C, then cooled to 50°C for 1 hour. The mixture was seeded with 3- {[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- [(l S)-2-methoxy-l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide (form 1) (5% wt/wt). The mixture was cooled to 0°C at 0.1 °C/ minutes and left to agitate at 0°C for at least 48 hours. The mixture was filtered and dried and left to dry on standing at 22°C to give the title compound as an off white solid. Yield of isolated solid was 68% as form 4. Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide) (as form 6)
Figure imgf000034_0001
To a flask fitted with thermometer, condenser, overhead stirrer and nitrogen line was added 3- {[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 -methylethoxy]-N-(5- methylpyrazin-2-yl)benzamide (1.0 eq) and butyronitrile (5.4 vols) under a nitrogen atmosphere. The batch was heated to 50°C and filtered into another flask. The mixture was cooled to 45°C, and then seeded with 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}- 5-[(l S)-2-methoxy-l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide) (form 6) (0.075% w/w). The mixture was held at 45°C for 3 hours, then cooled to 15°C at 0.1 °CI minute and held at 15°C for at least 24 hours then filtered. The solid was washed with butyronitrile (2 vols) pre-chilled to 15°C. The solid was dried at 40°C until the solvent level was < 0.5% w/w. After drying in the vacuum oven at 40°C overnight, the title compound was obtained as a solid (corrected yield 85%>). Preparation of 5-Chloropyrazine-2-carboxylic acid
Figure imgf000035_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 5-chloropyrazine-2-carboxylate (l .Oeq) and tetrahydrofuran (4.92vols) under a nitrogen atmosphere. The reaction mixture was agitated until all the solid had dissolved, then filtered into a second flask. Water (8.65 vols) was added to the reaction mixture and the mixture agitated for approximately 15 minutes. Potassium carbonate (2.1eq) was added to the reaction mixture and the mixture agitated for 16 hours at 20 - 25°C. Then 32% w/w hydrochloric acid (3.76eq) was added over 3 hours in small portions, keeping the reaction temperature 20 - 25°C, to a pH end point of pH2.2. The resultant slurry was heated to approximately 35 - 40°C and then distilled under vacuum at this temperature distilling approximately 5.3 vols, to a final volume of approximately 9.3 vols. The mixture was then cooled to 20 - 25°C over at least 2 hours, agitated for 10 hours at this temperature and then filtered. The solid was washed with water (2.8vols), and the wet product produced dried at 35°C in a vacuum oven. The desired product was obtained as a solid (corrected yield 91%) 1H NMR δ (400 MHz CDC13): 7.20 (1H, bs), 8.72 (1H, s), 9.21 - 9.21 (1H, m); m/z 157 (M-H)+.
2-(Azetidin-l-ylcarbonyl)-5-chloropyrazine
Figure imgf000035_0002
dichloromethane
triethylamine
Azetidine HCI
Water
Heptane
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-chloropyrazine-2-carboxylic acid (l .Oeq), DMF (0.069eq) and toluene (5.52vols) under a nitrogen atmosphere. The mixture was heated to 60 - 65°C, and thionyl chloride (1.5eq) added drop-wise to the batch over approximately 2 hours. The thionyl chloride was washed into the flask with toluene (0.2 vols). The reaction mixture was heated at 60 - 65°C for at least 4 hours, then cooled to 40 - 45°C and distilled under vacuum, removing approximately 4.5 vol distillates, and distilling to a final volume of 3.2 vols. Toluene (10.6vol) was added, and the mixture distilled under vacuum at 40 - 45°C, removing approximately 9.1 vol distillates, and distilling to a final volume of 4.7 vols. The mixture was then cooled to 20 - 25°C, and dichloromethane (10.6 vols) added. The mixture was cooled to 0 - 5°C. Meanwhile, to a second flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added azetidine hydrochloride (0.284eq),
dichloromethane (5.2vols) under a nitrogen atmosphere. Triethylamine (2.57eq) was added over at least 15 minutes maintaining the reaction temperature from 20 -25°C, the triethylamine was washed into the flask with dichloromethane (0.13 vols), and the mixture cooled to -5°C to -10°C. The acid chloride solution in the first flask was added to the second flask in portions maintaining the reaction temperature at -5°C to -10°C over a time period of 2 - 5 hours. The pH was tested and adjusted to pH>7 after the acid chloride addition. The reaction mixture was agitated for at least 30 minutes at -5°C to -10°C. Water (10.6vols) was added to the second flask and the temperature was allowed to increase to 20 - 25°C. The mixture was agitated for approximately 25 minutes and then the layers were separated. A 3.17% w/w solution (1.46eq) of hydrochloric acid (prepared from 32% w/w hydrochloric acid and water) was added to the organic layer B keeping the batch temperature at 20 - 25°C. The mixture was agitated for 30 minutes at this temperature. The layers were separated, and the organic phase was treated with 26%> w/w sodium chloride solution (approximately 8.9vols) and the batch agitated at 20 -25°C for at least 15 minutes. The layers were separated and the organic layers was heated to reflux, and dichloromethane was removed by atmospheric distillation, distilling to a final volume of approximately 1 - 2 vols, collecting approximately 11.9 vols distillates. The resulting mixture was cooled to 20 - 25°C, and heptane (10.5vols) added. The mixture was heated to reflux for 60 minutes, and then cooled to 90 - 100°C. The hot solution was filtered through a filter containing 10% w/w of activated charcoal into a clean dry vessel. The filter was washed with heptane (0.43vols) and the solution cooled to 20 - 25°C over at least 2 hours. The resulting crystallised slurry was filtered, and the solid washed with pentane (0.94 vols). After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid (corrected yield 65 - 78%). 1H NMR δ (400MHz CDC13): 2.35 - 2.42 (2H, m), 4.26 (2H, t), 4.67 (2H, t), 8.52 (1H, d), 9.09 (1H, d); m/z 198 (M+H)+.
tert-Butyl (5-methylpyrazin-2-yl)carbamate
Figure imgf000037_0001
Water
sodium hydroxide
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-methylpyrazine-2-carboxylic acid (l .Oeq), tert-butanol (3.5vols) and
di-isopropylethylamine (1.5eq) under a nitrogen atmosphere. The mixture was heated to 82°C, then diphenylphosphorylazide (l .Oeq) was added over a time period of 5 - 14 hours, maintaining the temperature of the reaction mixture at approximately 82°C. The reaction mixture was stirred for at least 1.5 hours, and then cooled to approximately 60°C. A solution of 4% w/w sodium hydroxide (1.75 eq) was added over a period of 2 hours. The mixture was cooled to 15°C over at least 5 hours then held at 15°C for 3 hours. The batch was then filtered, and the solid slurry washed with water (2vols). The batch was again slurry washed with water (2 vols). After drying at 55 - 60°C overnight, the desired product was obtained as a solid (corrected yield 56 - 63%). 1H NMR δ (400 MHz CDC13): 9.18 (s, 1H), 8.17 (bs, 1H), 8.11 (s, 1H), 2.51 (s, 3H), 1.56 (s, 9H)
5-Meth lpyrazin-2-amine
Figure imgf000037_0002
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added tert-butyl (5-methylpyrazin-2-yl)carbamate (l .Oeq), and water (6.85vols). The mixture was heated to 70°C and trifluoroacetic acid (TFA) (1.2eq) was added slowly drop-wise over 90 - 120 minutes. Water (0.22 vols) was added to wash the TFA into the flask. The reaction mixture was heated at 65 - 75°C for at least 30 minutes, and then cooled to 15 - 25°C. Then 32% w/w sodium hydroxide (1.30 eq) was added drop-wise over 30 - 60 minutes maintaining the reaction temperature between 15 - 40°C. Water (0.22 vols) was added to wash the sodium hydroxide into the flask. N-Propylacetate (7.0vols) was added and the mixture agitated for 45 minutes at 20°C. The layers were separated, the organic layer was retained and the aqueous layer was returned to the flask. N-Propylacetate (7.0vols) was added and the mixture agitated for 45 minutes at 20°C. The layers were separated, the organic layer was retained and the aqueous layer was returned to the flask. This process was repeated twice. The combined organic layers were filtered through a filter containing silica (20% w/w) into a clean dry flask. The mixture was heated to 40°C and then vacuum distilled to a final volume of 1.0 - 1.33 vols. Toluene (3.0vols) was added, and the vacuum distillation continued at 40°C to a final volume of 1.0 - 1.33 vols. This process was repeated twice. The resulting mixture was cooled to 5°C, and agitated for 1 hour at this temperature then filtered, washed with toluene (0.3vols) at 0 - 5°C. The batch is slurry washed with toluene (1.0 vol) at 0 - 5°C. After drying at 45°C overnight, the desired product was obtained as a solid (corrected yield typically 75%). 1H NMR δ (400MHz CDCls): 7.92 (s, 1H), 7.87 (s, 1H), 4.6 (bs, 2H), 2.40 (s, 3H)
Preparation of methyl 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2- methoxy-l-methylethoxy]benzoate
Figure imgf000038_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added methyl 3-hydroxy-5-[(lS)-2-methoxy-l-methylethoxy]benzoate (l .Oeq), 2-(azetidin-l- ylcarbonyl)-5-chloropyrazine (1.05eq), cesium carbonate (1.5eq) and dimethylsulfoxide (lOvols) under a nitrogen atmosphere. The contents of the flask were heated to 45°C for 1.5 hours, then cooled to 22°C. Ethyl acetate (6vols) and water (6vols) were added to the flask, the mixture was agitated for 15 minutes, then the layers were separated. Water (3 vols) was added to the organic layer, the batch agitated for 15 minutes, then the layers were separated. This process was repeated with water (3 vols) then saturated brine (6 vols), then with water (6 vols). The organic layer was evaporated on the rotary evaporator to yield the title compound as an oil (93% yield corrected for assay). 1H NMR δ (400MHz) DMSO : 8.62 (s, 1H), 8.50 (s, 1H), 7.34 (s, 1H), 7.30 (s, 1H), 7.17 (s, 1H), 4.68 - 4.64 (m, 1H), 4.54 - 4.49 (t, 2H), 4.07 - 4.03 (t, 2H), 3.81 (s, 3H), 3.49 - 3.41 (m, 2H), 3.25 (s, 3H), 2.29 - 2.22 (m, 2H), 1.20 - 1.18 (d , 3H) .
3-{[5-(Azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l-methylethoxy]-N- ( -methylpyrazin-2-yl)benzamide
Figure imgf000039_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 3 - {[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 - methylethoxy]benzoic acid (l .Oeq), and acetonitrile (10 vols) followed by pyridine (3eq) under a nitrogen atmosphere. Thionyl chloride (1.2eq) as a solution in acetonitrile
(0.225vols) was added slowly, drop-wise via syringe pump over at least 2 hours. 5- Methylpyrazin-2-amine (1.2eq) was added to the mixture as a solid. After 2.5 hours the reaction was quenched by adding toluene (lOvols) and 1.0M sodium carbonate solution (2.5 eq). The layers were separated. The organic layer was retained in the flask, then 1.0M hydrochloric acid (1.94 eq) was added. The mixture was agitated for 15 minutes then separated. The organic layer was washed with two aliquots of water (5 vols) then the solvent was removed on the rotary evaporator. Toluene (5vols) was added to the residue, and warmed to 45°C. Isohexane (1.7vols) was added, the mixture was seeded, and allowed to cool to ambient temperature overnight. The mixture was cooled to 0°C for 4 hours, and then cooled to -10°C for 3 hours. The solid was isolated by filtration then washed with isohexane (2.5 vols). After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid (corrected yield 85%).
-(Azetidin-l-ylcarbonyl)-5-chloropyrazine
Figure imgf000039_0002
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-chloropyrazine-2-carboxylic acid (l .Oeq), tetrabutylammonium chloride (0.01 leq) and toluene (4vols) under a nitrogen atmosphere. The mixture was heated to 70-75°C, and thionyl chloride (1.35eq) added drop-wise over approximately 1 hours. The thionyl chloride was washed into the flask with toluene (1 vol). The mixture was heated at 70- 75°C for at least 4 hours, then cooled to 50 ± 5°C. Toluene (5.3vols) was added, and the mixture vacuum distilled at 50± 5 °C (lOOmbar), removing approximately 5.3vol distillates, and distilling to a final volume of 5vols. This process was repeated. The resulting mixture was then cooled to 20 - 25°C. Toluene (8.93 vols) was added, and the batch agitated at 50± 5 °C to give an acid chloride solution.
Meanwhile, to a second flask was added azetidine hydrochloride (1.05 eq), toluene (6.07vols), and a solution of potassium carbonate (1.24eq) in water (6.07vols). The resulting mixture was agitated at 20 ±5 °C for at least 15 minutes, then the layers were separated. The aqueous layer was returned to the flask, and toluene (6.07vols) was added. The mixture was agitated at 20 ±5 °C for at least 15 minutes, then the layers were separated. The aqueous layer was returned to the flask, and potassium carbonate (1.24eq) and toluene (6.07vols) were added. The mixture was agitated for at least 30 minutes The acid chloride solution in the first flask was added to the mixture in the second flask in portions maintaining the reaction temperature at 20 ±5 °C over a time period of at least 20 - 60 minutes. The reaction mixture was agitated for at least 30 minutes at 20 ±5 °C and then filtered, the filter was washed with toluene (0.17 vol) and then the layers were separated. The lower aqueous phase was separated off and discarded. Water (6.07vols) was added to the second flask and the mixture was agitated at 20 ±5 °C for approximately 15 minutes and then allowed to separate. The lower aqueous phase was separated off and discarded. A 5% w/w solution of hydrochloric acid (1.5eq) (prepared from 32% w/w hydrochloric acid and water was added to the organic layer keeping the batch temperature at 20 ±5 °C. The mixture was agitated for 15 minutes at this temperature then the layers were separated and the lower aqueous layer was discarded. 25% w/w Sodium chloride solution (approximately 6 vols) was added to the organic layer and the mixture agitated at 20 -25°C for at least 15 minutes. The layers were separated and the aqueous layer was discarded. The organic layer was heated to 50±5 °C, and vacuum distilled to a final volume of 4.5 vols, collecting 15.2vols distillate. Active charcoal (11% w/w) and heptane
(12.8vols) were added, and the mixture agitated at 90 -100°C for at least 1 hour. The mixture was filtered to clean dry vessel keeping the reaction temperature above 70°C. Heptane (1.16vols) was used to wash the mixture into the filter. The mixture was cooled to 55 - 60°C, seeded with 2-(azetidin-l-ylcarbonyl)-5-chloropyrazine and cooled to 15 - 20°C over at least 3 hours. The crystallised slurry was filtered, and the solid washed with 140— 155 petroleum ether (1.45vols). The solid was washed with 140 - 155 petroleum ether (1.45 vols). After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid corrected yield 65 - 78%).
B nzyl (5-methylpyrazin-2-yl)carbamate
Figure imgf000041_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-methylpyrazine-2-carboxylic acid (l .Oeq), toluene (2.5vols) and di-isopropylethylamine (1.50eq) under a nitrogen atmosphere. The mixture was vacuum distilled at a batch temperature of 50°C, distilling to a final volume of 2 vols. The batch was sampled to ensure the water content was < 0.1% w/w, then cooled to 15 ± 2°C, and
diphenylphosphorylazide (l .OOeq) was added over a time period of 5 - 6 hours, maintaining the temperature of the reaction mixture at 15 ± 2°C. The mixture was stirred for a further 1.5 hours. Meanwhile to a second flask was added benzyl alcohol (3.00eq) and toluene (1 lvols). The mixture was azeotropically dried to a volume of 10 vols. The contents of the second flask were sampled to ensure the water content was < 0.1% w/w, then heated to 85 - 90°C. The contents of the first flask were added slowly to the contents of the second flask over approximately 2 hours, maintaining the reaction temperature at approximately 85°C. The reaction mixture was stirred for 1 hour at 85°C, then cooled to 20°C. 5% w/w Sodium hydroxide solution (1.75eq) was added slowly over 1 hour, the mixture cooled to 5°C, agitated at 5°C for 1 hour, then filtered. The isolated solid was washed sequentially with water (2vols), then methanol (2vols). After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid (corrected yield 78 - 85%). 1H NMR (400 MHz, CDC13): 9.41 bs (1H), 9.24 s (1H), 7.87 s (1H), 7.39 - 7.41 m
(5H), 5.22 s (2H), 2.31 s (3H)
5-Meth lpyrazine-2-amine
Figure imgf000042_0001
To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added benzyl(5-methylpyrazin-2-yl)carbamate (l .Oeq), palladium on carbon catalyst El 96 (3% w/w palladium on dry basis)), sodium hydroxide (0.01 eq)-and methanol (5 vols) under a nitrogen pad. The reaction was de-gassed by pressurising and releasing under nitrogen, then charged with hydrogen to atmospheric pressure and the reaction agitated at 20 ± 5°C for at least 3 hours. Activated charcoal (Norit SX Ultra) (5% wt charge) was added to the flask, the mixture was agitated for at least 30 minutes at 20 ± 5°C, then filtered through a 0.45 micron filter. The filter was rinsed with methanol (lvol) then the mother liquors allowed to stir at 15°C under an atmosphere of 6% oxygen/ 94% nitrogen for up to 24 hours ( alternatively an atmosphere of 1% oxygen/ 99% nitrogen was used), then re-filtered through the 0.45 micron filter. The mother liquors were vacuum distilled at 45°C to a final volume of 1.5 vols. Toluene (1.5vols) was added and the mixture vacuum distilled at 45°C to a final volume of 1.5 vols. This process was repeated with further toluene (0.5vols) then the resulting mixture was cooled to 5°C and filtered. The solid was washed with toluene (1 vol). The solid was washed with toluene (1 vol). After drying in the vacuum oven at 40°C overnight, the desired product was obtained as a solid (corrected yield 65 - 78%).
Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide) (as form 6)
A
Figure imgf000043_0001
To a flask fitted with thermometer, condenser, overhead stirrer and nitrogen line was added 3- {[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 -methylethoxy]-N-(5- methylpyrazin-2-yl)benzamide (1.0 eq) and methyl isobutyl ketone (6.7 vols) under a nitrogen atmosphere. The batch was heated to 60°C and filtered into another flask. The mixture was cooled to 45°C, and then seeded with 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2- yl]oxy } -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N-(5 -methylpyrazin-2-yl)benzamide) (form 6) (0.075% w/w). The mixture was held at 45°C for 6 hours, then subjected to a stepped cooling profile. The mixture was cooled to 40°C and held for 6 hours, then cooled to 35°C and held for 6 hours, then cooled to 30°C and held for 6 hours, then cooled to 20°C and held for 6 hours, then cooled to 10°C and held for 3 hours. To the mixture n-heptane was then added slowly over a period of 2 hours maintaining the mixture at 10°C, following the addition the mixture was held for a further 1 hour at 10°C. The mixture was then cooled to 0°C and held for 6 hours before being filtered. The solid was washed with (2 vols) methyl isobutyl ketone / n heptane mixture (9/1 volume ratio) pre-chilled to 0°C. The solid was dried at 40°C until the solvent level was < 0.5% w/w. After drying in the vacuum oven at 40°C overnight, the title compound was obtained as a solid (corrected yield 85%).
Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide) (as form 6)
B
Crude 3 - {[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 -methyl- ethoxy]-N-(5-methylpyrazin-2-yl)benzamide) was suspended in 6.7 rel vol. of methyl isobutyl ketone (MIBK). The mixture was heated to 70°C to dissolve the solid. Once the solid has dissolved the mixture was filtered to generate a Pures envelope. The solution was then cooled to 45°C, seeded with 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-
2- methoxy-l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide) Form VI and held for 4 hours at 45°C. The mixture was then cooled using a stepped cooling profile (cooled to 40°C and held for 4 hours, cooled to 35°C and held for 6 hours, cooled to 30°C and held for 6 hours cooled to 20°C and held for 3 hours, cooled to 10°C and held for 3 hours and cooled to 0°C and held for 3 hours). The mixture was then subjected to a number of temperature cycles to break up the crystal agglomerates. The mixture was heated from 0°C to 30°C at 0.5°C/min, and held at 30°C for 2 hours and then cooled back to 0°C at 0.1°C/min and held at for 3 hours. This temperature cycle was repeated a further 3 times. After an in-process control to confirm the formation of the desired physical form, the mixture was filtered and washed with 50/50 v/v MIBK/n-heptane. The solid was dried under vacuum at 60°C until constant weight was attained. Yield = 75-82%. Washing may be also performed with mixtures of n-heptane and MIBK containing a higher or lower relative amount of MIBK.
Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide) (as form 6)
C
3- { [5 -(Azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - [( 1 S)-2-methoxy- 1 -methylethoxy] -N- (5-methylpyrazin-2-yl)benzamide was added to a mixture of MIBK, methanol and n- heptane (6 rel vols of MIBK, 0.5 rel vols of methanol and 7 rel vols of n-heptane) (of a ratio such as 6,0.5,7). The resulting slurry is heated to 65°C form a solution. The solution is cooled and seeded. The seeded solution is then further cooled to crystallise the batch. The solid is isolated, washed with a mixture of MIBK & n-heptane ( ratio such as 1 : 1 or
1 :3 alternatively n-heptane is used) and dried. Yield was 90% .
Formation of Form 6 from a slurry of Forms 1 and 4
An approximately 1 : 1 mixture of forms 1 and 4 (30 mg total) was slurried in 50-300 μΐ of IPA and held at elevated temperatures for a number of days. Substantially complete conversion into Form 6 (as identified by XRPD) was obtained as follows:
35°C: 8 days
40°C: 11 days (conversion not complete but sample was not kept moist all of the time and was at room temperature for 3 of the 11 days) 45°C: 11 days (not tested before this timepoint)
50°C: 11 days (not tested before this timepoint).
Alternative Preparation of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2- methoxy-l-methylethoxy]-N-(5-methylpyrazin-2-yl)benzamide)
This compound was also prepared by the method shown in Scheme A.
Figure imgf000045_0001
Scheme A
Methyl 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-hydroxybenzoate
Potassium hydroxide liquor (662.0 mg of 50.4 %wt/wt, 5.95 mmol) was added dropwise to a solution of methyl 3,5-dihydroxybenzoate (1.00 g, 5.95 mmol) in undried dimethyl sulfoxide (6.61 g, 6 mL/g) so as to create a brown homogeneous solution. 5-(Azetidin-l- ylcarbonyl)-2-chloropyrazine (1.18 g, 5.95 mmol) was added in one go and readily dissolved to leave a brown, homogeneous solution. The vial was capped, placed in a preheated 50 °C stemblock and the solution stirred without inertion.
The vial was placed in a preheated 50 °C stemblock and left under these conditions. More potassium hydroxide liquor was added in 132.4 mg (1.19 mmol) portions after a reaction time of 66.5 h, 86.1 h and 95.8 h, before a final 66.2 mg (0.60 mmol) portion was added after 108.6 h. After a reaction time of 114.5 h, the vial was removed from the cooling block and allowed to cool to 21 °C. The solution was then pipetted into solution of concentrated hydrochloric acid (422.9 mg of 11.60 M, 4.16 mmol) that had been diluted with water to 20 mL. A gum formed. The pH was adjusted to 2.50 through the dropwise addition of concentrated hydrochloric acid (11.60 M) and the mixture allowed to stirout so that the gum turned over to a freely-stirred solid. The slurry was filtered off (22 micron filter paper). The cake was washed with water (3 x 10 mL). The cake was dissolved in hot methanol, screened (0.45 micron) and allowed to cool down, whereupon methyl 3-{[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 -hydroxybenzoate crystallised. This was isolated and air dried (1.216 g at 91.8 % wt/wt, 57 % yield corrected for strength).
Methyl 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l- methylethoxy] benzoate
A slurry of methyl 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-hydroxybenzoate (510.4 mg, 1.55 mmol), triphenylphosphine (508 mg, 1.94 mmol) and (i?)-(-)-l-methoxy- 2-propanol (175 mg, 1.94 mmol) in dry toluene (4.45 g, 10 vol.) was prepared with an overhead nitrogen sweep. The slurry was chilled using an ice bath, prior to the addition of diisopropyl azodicarboxylate (395.3 mg, 1.94 mmol) by syringe pump over 60 min. At the end of the addition there was obtained a white solid suspended in light brown liquors. The flask was kept in the ice bath for a further 30 min., before being removed and being allowed to stir out overnight. The next morning, the reaction slurry was filtered (22 micron filter paper), washing through with toluene. The filter cake was discarded. The filtrate was concentrated to dryness before being diluted to 1000 mL with acetonitrile. The acetonitrile solution was concentrated to dryness. The residue was purified by flash column chromatography using 50 g silica and a dichloromethane-isopropanol gradient (0→5 %v/v isopropanol) as the eluent. This yielded methyl 3-{[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy}-5-[(lS)-2-methoxy-l-methylethoxy]benzoate, contaminated with triphenylphosphine oxide, as a viscous oil (864.1 mg, uncorrected for strength).
Methyl 3 - {[5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy} -5-[(l S)-2-methoxy- 1 - methylethoxy]benzoate was hydro lysed as previously described to give 3-{[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy}-5-[(15)-2-methoxy-l-methylethoxy]benzoic acid which was then reacted with 5-methylpyrazin-2-amine as previously described to give 3-{[5- (azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N- (5-methylpyrazin-2-yl)benzamide.

Claims

Claims
1. A process for dry milling 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(15)- 1 -methyl-2-(methyloxy)ethyl]oxy} -N-(5-methylpyrazin-2-yl)benzamide comprising dry milling 3 - {[5-(azetidin-l -ylcarbonyl)pyrazin-2-yl]oxy} -5- { [(15)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide with one or more co-milling excipients wherein the co-milling excipient has a primary particle size of mean diameter of at least 100 microns.
2. A process for dry milling 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(15)- 1 -methyl-2-(methyloxy)ethyl]oxy} -N-(5-methylpyrazin-2-yl)benzamide comprising dry milling 3 - {[5-(azetidin-l -ylcarbonyl)pyrazin-2-yl]oxy} -5- { [(15)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide with one or more co-milling excipients and/or a surfactant wherein the co-milling excipient if present has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol.
3. A process for dry milling 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(15)- 1 -methyl-2-(methyloxy)ethyl]oxy} -N-(5-methylpyrazin-2-yl)benzamide comprising the steps of:
1 ) preparing a mixture of 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5-{[(15)-l- methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide with one or more co-milling excipients and/or a surfactant wherein the co-milling excipient if present has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol and
2) dry milling the mixture prepared in 1) above.
4. A process for dry milling 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(15)- l-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide as claimed in claim 1 comprising the steps of:
1) preparing a mixture of 3-{[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- {[(15)-l-methyl-2-(methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide with a co- milling excipient and a surfactant wherein the co-milling excipient has a primary particle size of mean diameter of at least 100 microns and the co-milling excipient is selected from lactose or mannitol and
2) dry milling the mixture prepared in 1) above.
5. A co-milled pharmaceutical composition comprising a) 3- {[5-(azetidin-l- ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide and b) one or more co-milling excipients and/or a surfactant.
6. A co-milled pharmaceutical composition as claimed in claim 5 comprising a) 93- 98% by weight of 3- {[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- {[(15)-l-methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide and b) 2-7% by weight of a surfactant.
7. A co-milled pharmaceutical composition as claimed in claim 5 comprising a) 45- 50%) by weight of 3- {[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- {[(15)-l-methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide and b) 40-50% by weight of one or more co-milling excipients and/or c) 2-8% by weight of a surfactant.
8. A co-milled pharmaceutical composition as claimed in claim 5 comprising a) 60- 70%) by weight of 3- {[5-(azetidin-l-ylcarbonyl)pyrazin-2-yl]oxy}-5- {[(15)-l-methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide and b) 25-35% by weight of one or more co-milling excipients and/or c) 2-8% by weight of a surfactant.
9. A tablet formulation (wherein % = % by weight of total tablet weight) comprising: a) a co-milled pharmaceutical composition comprising
1 ) 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide: 15 to 30%, 2) 5-25% of a co- milling excipient and 3) surfactant 0.5 to 4% ;
b) filler: 30 to 75%,
c) disintegrant: 2.5 to 7.5%, d) lubricant: 1 to 5%; and
e) surfactant: 0.01 to 3%.
10. A tablet formulation (wherein % = % by weight of total tablet weight) comprising: a) a co-milled pharmaceutical composition comprising
1 ) 3 - { [5 -(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5 - { [( 15)- 1 -methyl-2- (methyloxy)ethyl]oxy}-N-(5-methylpyrazin-2-yl)benzamide: 15 to 30%, 2) 0.5-4% surfactant
b) filler: 50 to 95%,
c) disintegrant: 2.5 to 7.5%,
d) lubricant: 1 to 5% and
e) surfactant: 0.01 to 3%,
1 1. A process according to any one of claims 1 to 4 or a composition according to any one of claims 5 to 8 or a formulation according to either claim 9 or claim 10 wherein the 3- { [5-(azetidin- 1 -ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2- (methyloxy)ethyl]oxy } -N-(5 -methylpyrazin-2-yl)benzamide is 3 - { [5 -(azetidin- 1 - ylcarbonyl)pyrazin-2-yl]oxy } -5- { [( IS)- 1 -methyl-2-(methyloxy)ethyl]oxy } -N-(5- methylpyrazin-2-yl)benzamide form 6.
12. A process according to either claim 1 or claim 2 wherein a surfactant is also present.
13. A process according to any one of claims 1 to 4 or 12 a composition according to any one of claims 5 to 8 or a formulation according to either claim 9 or claim 10 wherein the surfactant is sodium dodecyl sulphate.
14. A process according to any one of claims 1 to 4 or claim 12 or a composition according to any one of claims 5 to 8 or a formulation according to either claim 9 or claim 10 wherein the co-micronisation excipient is mannitol having a primary particle size of mean diameter in the range of 100-200 microns.
15. A tablet formulation according to either claim 9 or claim 10 wherein the filler is 60-75% of mannitol plus 2.5 to 5.0% microcrystalline cellulose.
16. A tablet formulation according to either claim 9 or claim 10 wherein the disintegrant is sodium starch glycolate.
17. A tablet formulation according to either claim 9 or claim 10 wherein the lubricant is magnesium stearate.
PCT/GB2011/051322 2010-07-15 2011-07-14 Pharmaceutical formulations WO2012007758A2 (en)

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JP2020533346A (en) * 2017-09-14 2020-11-19 クイーン メアリー ユニバーシティ オブ ロンドン Drug
US11261198B2 (en) 2016-06-20 2022-03-01 Shionogi & Co., Ltd. Process for preparing substituted polycyclic pyridone derivative and crystal thereof
WO2023084313A2 (en) 2021-09-02 2023-05-19 Conduit Uk Management Ltd Therapeutic benzamide cocrystals

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Patent Citations (1)

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WO2007007041A1 (en) 2005-07-09 2007-01-18 Astrazeneca Ab Heteroaryl benzamide derivatives for use as glk activators in the treatment of diabetes

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11261198B2 (en) 2016-06-20 2022-03-01 Shionogi & Co., Ltd. Process for preparing substituted polycyclic pyridone derivative and crystal thereof
US11807648B2 (en) 2016-06-20 2023-11-07 Shionogi & Co., Ltd. Process for preparing substituted polycyclic pyridone derivative and crystal thereof
JP2020533346A (en) * 2017-09-14 2020-11-19 クイーン メアリー ユニバーシティ オブ ロンドン Drug
US11690841B2 (en) 2017-09-14 2023-07-04 Queen Mary University Of London Glycolysis-activating agents for treatment or prevention of disease
JP7387176B2 (en) 2017-09-14 2023-11-28 クイーン メアリー ユニバーシティ オブ ロンドン drug
WO2023084313A2 (en) 2021-09-02 2023-05-19 Conduit Uk Management Ltd Therapeutic benzamide cocrystals
WO2023084313A3 (en) * 2021-09-02 2023-07-13 Conduit Uk Management Ltd Therapeutic cocrystals of 3-{[5-(azetidine-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1 s)-1 -methyl-2- (methyloxy)ethyl]oxy)-n-(5-methylpyrazin-2-yl)benzamide

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