Title of Invention

PROCESS FOR MAKING PURE CRYSTALLINE FORM V OF "5-CHLORO-3-(4-METHANESULFONYLPHENYL)-6'-METHYL-[2,3']BIPYRIDINYL

Abstract

Abstract PROCESS FOR MAKING PURE CRYSTALLINE FORM V OF "5-CHLORO-3-(4- METHANESULFONYLPHENYL)-6'-METHYL-[2,3']BlPYRIDINYL The present invention relates to a process for making a Form V polymorph of structural Formula A Formula A comprising combining polymorph I, II, III or IV of Compound A with isopropyl acetate; heating to an elevated temperature less than about 75° C; and cooling to a low temperature to produce the Form V polymorph.

Full Text

The present invention relates to Form V polymorph of Compound A having the chemical structWe shown below; as well as a process for synthesizing the Form V polymorph. Compound A exists in five polymorphic forms (Forms IV), an amorphous form and two hydrated forms. The compound is a potent and selective cyclooxygenase2 (COX2) inhibitor, useful primarily in the treatment of inflammation, pain and fever as well as other COX2 mediated diseases, such as described in PCT Publication Nos. WO9610012 and W09616934. Compound A is described in U.S. Patent No. 5,861,419 granted on January 19, 1999 (Example 23), which is hereby incorporated by reference in its entirety. A process for making Compound A is described in U.S. Patent No. 6,040,319 granted on March 21, 2000, which is hereby incorporated by reference in its entirety. The present invention unexpectedly provides for a novel, robust process for making a Form V polymorph of compound A from any one of Forms I, II, III or IV or any mixture of polymorphs of compound A. SUMMARY OF THE INVENTION This invention encompasses the Form V polymorph of structural formula A: which is useful in the treatment of cyclooxygenase2 mediated diseases. The invention encompasses certain pharmaceutical compositions for the treatment of cyclooxygenase2 mediated diseases comprising the Form V polymorph of Compound A. The invention also encompasses a process for synthesizing the Form V polymorph of Compound A comprising: combining polymorph I, II, III or IV of Compound A with isopropyl acetate; heating to an elevated temperature less than about 75°C; and cooling to a low temperature to produce the Form V polymorph. BRIEF DESCRIPTION OF THE DRAWINGS The invention is described in connection with the appended drawings in which: Fig. 1 is the Xray powder diffraction (XRPD) pattern of Form V; Fig. 2 is the XRPD pattern of Form I; Fig. 3 is the XRPD pattern of Form II; Fig. 4 is the XRPD pattern of Form III; Fig. 5 is the XRPD pattern of Form IV; Fig. 6 is the XRPD pattern of the hemihydrate; and Fig. 7 is the XRPD pattern of the sesquihydrate. DETAILED DESCRIPTION having the following physical characteristics: DSC extrapolated onset melting temperature of 133.9°C, DSC peak melting temperature of 134.5°C and xray powder diffraction peak positions, Cu K alpha, of: 13.7, 7.2, 6.9, 6.7, 5.8, 5.7, 5.0, 4,9, 4.8, 4.7, 4.5, 4.2,4.0, 3.9, 3.8, 3.7, 3.6, 3.4, 3.3, 3.1, 3.0, 2.9 and 2.8 angstroms. An embodiment of the invention is the Form V polymorph of Compound A characterized as having an xray powder diffraction pattern peak position, Cu K alpha, at about 13.7 angstroms. Within this embodiment of the invention is the Form V polymorph of Compound A further characterized as having at least one xray powder diffraction pattern peak position, Cu K alpha, at about 7.2, 6.9, 6.7, 5.8, 5.7, 5.0, 4.9, 4,8, 4.7,4,5, 4,2, 4,0, 3.9, 3.8, 3.7, 3.6, 3.4, 3.3, 3.1, 3.0, 2.9 or 2.8 angstroms. An embodiment of the invention is the Form V polymorph of Compound A characterized as having a DSC extrapolated onset melting temperature of about 133.9°C. An embodiment of the invention is the Form V polymorph of Compound A characterized as having a DSC peak melting temperature of about 134.5°C. An embodiment of the invention is the Form V polymorph of Compound A having the aforesaid characteristics in substantially pure form. The invention also encompasses a pharmaceutical composition comprising a non¬toxic therapeutically effective amount of a Form V polymorph of Compoimd A and a pharmaceutically acceptable carrier. An embodiment of the invention encompasses a method of treating an inflammatory disease susceptible to treatment with an nonsteroidal antiinflammatory agent comprising administering to a patient in need of such treatment a nontoxic therapeutically effective amount of a Form V polymorph of Compound A. Another embodiment of the invention encompasses a method of treating a cyclooxygenase mediated disease advantageously treated by an active agent that selectively inhibits cyclooxygenase2 in preference to cyclooxygenase1 comprising administering to a patient in need of such treatment a nontoxic therapeutically effective amount of a Form V polymorph of Compound A. Another embodiment of the invention encompasses a method for treating an illness selected from the group consisting of: (a) rheumatic fever, (b) symptoms associated with influenza or other viral infections, common cold, (c) low back and neck pain, (d) dysmenorrhea, (e) headache, (f) toothache, (g) sprains and strains, (h) myositis, (i) neuralgia, (j) synovitis, (k) arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, (1) bursitis, (m) bums, (n) injuries, and (o) following surgical and dental procedures, comprising administering; to a patient in need of such treatment a nontoxic therapeutically effective amount of a Form V polymorph of Compound A. This invention also encompasses a novel process for making a Form V polymorph of structural formula Aomprising: combining polymorph 1, II, III or IV of Compound A with isopropyl acetate; heating to an elevated temperature less than about 75°C; and cooling to a low temierature to produce the Form V polymorph. For purposes of this Specification, the term elevated temperature means any temperature above room temperature but less than about 75°C, as high as about 35 70°C, preferably about SOeSC. Room temperature is about 20°C. The term low temperature means any temperature below the elevated temperature, as low as about 0 30°C, preferably as low as about 1020°C. Polymorphic forms of Compound A, for purposes of this invention, are identified as Form I (onset of melting m.p. 135.7 ± 0.2°C, peak m.p. 137.0 ± 0.2°C), Form II (onset of melting m.p 129.6°C, peak m.p. I31.S°C), Form III (onset of mating "m.p. 133.2°C, peak m.p, 134.4°C), Form IV (onset of melting m.p. 133.72 0.04C, peak m.p. 134,5 ± O.rC) and Form V (onset of melting, m.p. 133.9°C, peak m.p. 134.5°C). Forms I through V are anhydrous. An embodiment of the invention encompasses the ppcess for making the Form V polymorph of Compound A which further comprises isolating the Form V polymorph. A subset of this embodiment encompasses isolating the Form V polymorph by filtration. An embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the elevated temperature is about 4075°C. Another embodiment of the invention is the process ,for making a Form V polymorph of Compound A wherein the elevated temperatureis about 5065°C. An embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the elevated temperature is about 030°C. Another embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the low temperature is about 1020°C. Another embodiment of tl>e invention is the process for making a Form V _ polymorph of Compound A wheifein the elevated temperature is about 5065°C and the low temperature is about 1020°C. The invention will nolbe illustrated by the following nonlimiting examples: PREPARATIVE EXAMPLE A The starting material Compound A was made in accordance with U.S. Pat. No. 6,040,319. PREPARATIVE EXAMPLE B FORM II Form 11 was obtained by crystallizing Compound A obtained in accordance with Preparative Example A from ethyl acetate. Differential Scanning Caiorimetry showed an extrapolated onset of melting at about 130°C, and a peak melting point of about I31°C. PREPARATIVE EXAMPLE C FORM IV Form IV was prepared by mixing Preparative Example A (55.B.0g,.1.54 mol) and toluene (4.0L) and heating the mixture to 32.6°C to cause dissoiulibn. The solution was cooled to 16.5°C and Form IV crystallized. The mixture was ten cooled to 0°C over 1 hr. nHeptane (7.0L) was added over 2 hr and the mixture )as filtered. The cake was washed with 3:1 nheptanetoluene (3.0L) and dried to gjve the product {521.0 g) as a granular solid. PREPARATIVE EXMlPLE D HEMIHYDRATE A solution of preparative Example A* (65 g) in I L of water wet toluene was heated to 60°C and then cooled to ambient temperature. The hemihydrate form crystallized and was isolated by filtration The solids were dried at ambient temperature under vacuum to give 30 g of a colorless crystals. PREPRATIVE EXAMPLE E FORM in The hemihydrate of Preparative Example D was heated to 90°C in a vacuum oven for 12 hours and cooled down in the vacuum oven to give the Form III polymorph. REPARATIVE EXAMPLE G AMORPHOUS The amorphous foiin of compound A was obtained by heating the Form IV from Preparative Example cto above its melting temperature (above about ]35°C) under nitrogen, followed by Quench cooling to room temperature under a dry atmosphere. Another embodiment of the invention encompasses a method of treating a cyclooxygenase mediated disease advantageously treated by an active agent that selectively inhibits cyclooxygenase2 in preference to cyclooxygenase1 comprising administering to a patient in need of such treatment a nontoxic therapeutically effective amount of a Form V polymorph of Compound A. Another embodiment of the invention encompasses a method for treating an illness selected from the group consisting of: (a) rheumatic fever, (b) symptoms associated with influenza or other viral infections, common cold, (c) low back and neck pain, (d) dysmenorrhea, (e) headache, (f) toothache, (g) sprains and strains, (h) myositis, (i) neuralgia, (j) synovitis, (k) arthritis, including rheumatoid arthritis, degenerative joint diseases (osteoarthritis), gout and ankylosing spondylitis, (I) bursitis, (m) bums, (n) injuries, and (o) following surgical and dental procedures, comprising administering to a patient in need of such treatment a nontoxic therapeutically effective amount of a Form V polymorph of Compound A. This invention also encompasses a novel process for making a Form V polymorph of structural formula A comprising of combining polymorph I, U, 111 or IV of Compound A either substantially free of other polymorphs or as a mixture thereof viith isopropyl acetate; heating to an elevated temperature less than about TSC; cooling to a low temperature to produce the Form V polymorph; and isolating the Form V polymorph. Another embodiment of the invention encompasses a novel process for making a Form V polymorph of structural formula A wherein isolating the Form V polymorph is done by filtration. Another embodiment of the invention encompasses a novel process for making a Form V polymorph of structural formula A wherein the mixture of polymorph comprises one or more forms I, II, III and IV in any ratio so as to make the total weight hundred percent. Yet another embodiment of the invention encompasses a novel process for making a Form V polymorph of structural formula A wherein the ratio of polymorphs in the mixture is in the range of 0 to 100% by weight so as to make the total weight hundred percent. For purposes of this Specification, the term elevated temperature means any temperature above room temperature but less than about 75°C, as high as about 35 70°C, preferably about 5065C. Room temperature is about 20°C. The term low temperature means any temperature below the elevated temperature, as low as about 0 30°C, preferably as low as about 1020°C. Polymorphic forms of Compound A, for purposes of this invention, are identified as Form I (onset of melting m.p. 135.7 ± 0.2°C, peak m.p. 137.0 ± 0.2°C), Form II (onset of melting m.p 129.6°C, peak m.p. 131.5°C), Form III (onset of melting m.p. 133.2°C, peak m.p. 134.4°C), Form IV (onset of melting m.p. 133.72 0.04°C, peak m.p. 134.5 ± O.rC) and Form V (onset of melting, m.p. 133.9=C, peak m.p. 134.5°C). Forms I through V are anhydrous. An embodiment of the invention encompasses the process for making the Form V polymorph of Compound A which further comprises isolating the Form V polymorph. A subset of this embodiment encompasses isolating the Form V polymorph by filtration. An embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the elevated temperature is about 4075°C. Another embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the elevated temperature is about 5065°C. An embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the elevated temperature is about 030°C. Another embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the low temperature is about 1020°C. Another embodiment of the invention is the process for making a Form V polymorph of Compound A wherein the elevated temperature is about 5065°C and the low temperature is about 1020°C. The invention will not be illustrated by the following nonlimiting examples: PREPARATIVE EXAMPLE A The starting material Compound A was made in accordance with U.S. Pat. No. 6,040,319. PREPARATTVE EXAMPLE B FORM II Form 11 was obtained by crystallizing Compound A obtained in accordance with Preparative Example A from ethyl acetate. Differential Scanning Calorimetry showed an extrapolated onset of melting at about 130°C, and a peak melting point of about 131°C. PREPARATIVE EXAMPLE C FORM IV Fonn IV was prepared by mixing Preparative Example A (550.0g, 1.54 mol) and toluene (4.0L) and heating the mixture to 32.6°C to cause dissolution. The solution was cooled to 16.5°C and Form IV crystallized. The mixture was then cooled to 0°C over 1 hr. nHeptane (7.0L) was added over 2 hr and the mixture was filtered. The cake was washed with 3:1 nheptanetoluene (3.0L) and dried to give the product (521.0 g) as a granular solid. PREPARATIVE EXAMPLE D HEMIHYDRATE A solution of preparative Example A (65 g) in 1 L of water wet toluene was heated to 60°C and then cooled to ambient temperature. The hemihydrate form crystallized and was isolated by filtration. The solids were dried at ambient temperature under vacuum to give ~ 30 g of a colorless crystals. PREPARATIVE EXAMPLE E FORM III The hemihydrate of Preparative Example D was heated to 90°C in a vacuum oven for i 2 hours and cooled down in the vacuum oven to give the Form III polymorph. PREPARATIVE EXAMPLE G AMORPHOUS The amorphous form of compound A was obtained by heating the Form IV from Preparative Example C to above its melting temperature (above about 135°C) under nitrogen, followed by quench cooling to room temperature under a dry atmosphere. PREPARATIVE EXAMPLE H MIXTURE OF POLYMORPHS Compound I was synthesized in accordance with Preparative Example i of U.S. Pat. No. 6,040,319. Compound 2 was synthesized in accordance with Example 1 of U.S. Pat. No. 6,040,319. To a slurry of Compound 1 (1.10 kg) in tetrahydrofuran (THF) (2.5L) at 0°C was added potassium tertbutoxide (2.47 L). The resulting mixture was transferred to a slurry of Compound 2 (1.19 kg) in THF at ambient temperature. The slurry was transferred to a solution of acetic acid (1.5L) and trifluoroacetic acid (TFA) (0.23 L) in THF. Concentrated ammonium hydroxide (1.50 L) was added and the mixture to reflux. The reaction mixture was cooled and the phases were cut, The THF layer was concentrated and toluene was added. The toluene layer was washed with aqueous sodium hydroxide followed by water and then concentrated to 6L. Acetone was added and a solution of ptoluenesulfonic acid (pTSA) (0.73 kg) in acetone was added and batch was filtered. The filter cake was washed with tolueneacetone ana me soiia anea m vacuo to give 1.80 kg of Compound 3 in 90 % isolated yield as an off white solid. To a mixture of toluene, water and Compound 3 (1.80 kg) was added aqueous ammonia (1 equiv.). The phases were cut and the toluene layer was washed with water. The mixture was filtered through SOLKAFLOC and the filtrate was concentrated to a saturated solution and then cooled to ambient temperature and nheptane was added. The solid was isolated by filtration, washed with toiuenenheptane and then dried in vacuo to give Preparative Example H as an offwhite solid. EXAMPLE 1 FORM V OF 5CHLORO3(4METHANESULFONYLPHENYL)6METHYL [2,3]BIPYRID1NYL A mixture of Preparative Example H and isopropyl acetate (IPAC) was heated at 55°C. The suspension was cooled to ambient temperature and the solids were isolated by filtration. The solids were washed with IPAC and dried in vacuo to give the Form V polymorph (1.1 kg) as a colorless solid in 87 % yield. H NMR (400 MHz CDCb) 5 8.69 (d, IH, J=2.3 Hz), 8.36(3, IH, J=2.2 Hz), 7.88 (d, 2H, J=8.4 Hz), 7.72 (d, IH, J=2.3 Hz), 7.54 (dd, IH, J,=8.0 Hz, J2=2.3Hz), 7.38 (d, 2H, J=8.5 Hz), 7.07 (d, IH, J=8.0 Hz), 3.06 (S,3H), 2.51(S,3H), 2.51(8, 3H); C NMR (100 MHz, CDCb) 5 158.4, 152.2, 149.7, 148.3, 143.7, 140.1, 137.9, 137.2, 135.18, 131.1, 130.0, 130.3, 127.8, 122.7,44.4,24.1. CHARACTERIZATION OF POLYMORPHS The polymorphic forms of compound A were characterized using Che following procedures. Xrav Powder Diffraction Pattern Analysis The Xray patterns were collected using a Philips APD powder diffractometer utilizing copper Kalpha radiations. Table 1 below lists the XRPD peak locations for Forms I, II, 111, IV and V as well as the hemihydrate and sesquihydrate forms. The peak positions are expressed in angstroms in Table 1. The XPRD pattern for Form V is shown in Figure 1. XRPD patterns for Forms IIV are shown in Figures 25. XRPD patterns for the two hydrate forms are shown in Figures 6 and 7. The peak positions are expressed in degrees (2 theta) in the plots. Differential Scanning Calorimetry fPSC) DSC was carried out using a TA Instruments DSC 2910 instrument at heating rate of ICmin under a nitrogen atmosphere in an open pan. The extrapolated onset temperatures, To, and enthalpy of fusion, AH, observed for the melting endotherms are shown in Table 2 for Forms I, II, III, IV and V. We claim: ]. A process for making a Form V polymorph of structural formula A A comprising: combining polymorph I, II, III or IV of Compound A with isopropyl acetate; heating to an elevated temperature less than about 75° C; and cooling to a low temperature to produce the Form V polymorph. The process according to Claim I further comprising isolating the Form V polymorph. The process according to Claim 2 wherein isolating the Form V polymorph is by The process according to Claim 1 wherein the elevated temperature is about 35-70°C. The process according to Claim 4 wherein the elevated temperature is about 50-65°C. The process according to Claim 1 wherein the low temperature is about 0-30° C. The process according to Claim 6 wherein the low temperature is about 10-20°C. 8. The process according to Claim 1 wherein the elevated temperature is about 50- 65°C and the low temperature is about !0-20°C.

Documents:

2089.rtf

in-pct-2002-2089-che abstract duplicate.pdf

in-pct-2002-2089-che abstract.pdf

in-pct-2002-2089-che claims duplicate.pdf

in-pct-2002-2089-che claims.pdf

in-pct-2002-2089-che correspondence others.pdf

in-pct-2002-2089-che correspondence po.pdf

in-pct-2002-2089-che description (complete) duplicate.pdf

in-pct-2002-2089-che description (complete).pdf

in-pct-2002-2089-che drawings-duplicate.pdf

in-pct-2002-2089-che drawings.pdf

in-pct-2002-2089-che form-1.pdf

in-pct-2002-2089-che form-13.pdf

in-pct-2002-2089-che form-19.pdf

in-pct-2002-2089-che form-26.pdf

in-pct-2002-2089-che form-3.pdf

in-pct-2002-2089-che form-5.pdf

in-pct-2002-2089-che others.pdf

in-pct-2002-2089-che pct.pdf