AU760075B2 - Process for the crystallization of a reverse transcriptase inhibitor using an anti-solvent - Google Patents

Description

I I S&F Ref: 470975D1

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

0 0 0 0 0 00 l Name and Address of Applicant: Actual Inventor(s): Address for Service: Invention Title: Merck Co., Inc.

126 East Lincoln Avenue Rahway New Jersey 07065 United States of America William Clarke, Louis S. Crocker, Joseph L. Kukura II, Andrew S. Thompson Spruson Ferguson St Martins Tower,Level 31 Market Street Sydney NSW 2000 (CCN 3710000177) Process for the Crystallization of a Reverse Transcriptase Inhibitor Using an Anti-solvent The following statement is a full description of this invention, including the best method of performing it known to me/us:- 5845c TITLE OF THE INVENTION PROCESS FOR THE CRYSTALLIZATION OF A REVERSE TRANSCRIPTASE INHIBITOR USING AN ANTI-SOLVENT BACKGROUND OF THE INVENTION The synthesis of the reverse transcriptase inhibitor (RTI), 6 -chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro-2H- 3,1-benzoxazin-2-one, also known as DMP-266 has been described in US Patent 5,519,021 issued on May 21, 1996 and the corresponding PCT International Patent Application WO 95/20389, which published on August 3, 1995. Additionally, the asymmetric synthesis of an enantiomeric benzoxazinone by a highly enantioselective acetylide addition and cyclization sequence has been described by Thompson, et al., Tetrahedron Letters 1995, 36, 937-940, as well as the PCT 15 publication, WO 96/37457, which published on November 28, 1996.

S* The compound was previously crystallized from a heptanetetrahydrofuran (THF) solvent system. The crystallization procedure required the use of high temperatures (about 90°C) to dissolve the final product. Crystals formed by nucleation during the cooling process.

The crystals which were produced were Form II and are converted to the desired Form I while drying under vacuum at 90 0 C. This crystallization provided minimal purification and produced material with inconsistent physical properties. The final product slurry was .extremely difficult to mix and handle due to its high viscosity and S 25 heterogeneous nature.

The instant invention describes a method for crystallizing 6 -chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro-2H- 3,1 -benzoxazin-2-one from a solvent and anti-solvent solvent system and producing the crystalline product. The desired final crystal form, Form I, can be produced when using methanol or ethanol. Form II is isolated from 2-propanol and can be converted to the desired crystal form at low drying temperatures, as low at 40 0

C.

Summary of the Invention A process for the crystallisation of a compound of the structural formula

F

3 C

CI

0

H

comprising the use of a solvent to effect the dissolution of the compound following by the addition of an anti-solvent to initiate the crystallisation.

The principal embodiments of the invention, the subject of this application are as follows: Form I of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1benzoxazin-2-one, characterised by crystallographic D-spacings of 14.5, 8.5 and 7.2 10 Angstroms; Form II of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-l,4-dihydro-2H-3,1benzoxazin-2-one, characterised by crystallographic D-spacings of 24.3, 6.9 and SAngstroms; and SForm III of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H-3,1- 15 benzoxazin-2-one, characterised by crystallographic D-spacings of 12.2, 6.1 and 4.3 Angstroms.

Brief Description of the Figures Figure 1.

Flowsheet of the controlled anti-solvent addition crystallisation method.

Figure 2.

Flowsheet of the heel crystallisation method.

Figure 3.

X-ray powder diffraction pattern for Form I of (-)-6-chloro-4-cyclopropylethynyl-4trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one.

Figure 4.

X-ray powder diffraction pattern for Form II of (-)-6-chloro-4-cyclopropylethynyl- 4-trifluoromethyl- 1,4-dihydro-2H-3,1 -benzoxazin-2-one.

[I:\DayLib\LIBAA]07013.doc:ACR Figure X-ray powder diffraction pattern for Form III of (-)-6-chloro-4-cyclopropylethynyl- 4-trifluoromethyl- 1 ,4-dihydro-2H-3, 1 -benzoxazin-2-one.

0 [I:\DayLib\LIBAA]07013ldo:ACR -3- Figure 6.

DSC curve for Form III of (-)-6-chloro-4-cyclopropylethynyl-4trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one.

Figure 7.

TG analysis for Form III of (-)-6-chloro-4-cyclopropylethynyl-4trifluoromethyl-1,4-dihydro-2H-3,1 -benzoxazin-2-one.

DETAILED DESCRIPTION OF THE INVENTION A process for the crystallization of a compound of the structural formula

F

3

C

CI 0

H

comprising the use of a solvent to effect the dissolution of the compound followed by the addition of an anti-solvent to initiate crystallization.

A process for the crystallization of a compound of the structural formula comprising the steps of: 1. dissolving the compound in a solvent in a ratio of about 3.0ml to about 10.0ml of solvent to 1 gram of the compound; 2. filtering the solution of the compound to remove any particulate matter; 3. adding the anti-solvent to the stirring solution at room temperature over a period of about 30 minutes to about an hour to reach the saturation point of the solution containing the compound; 4. adding to the solution a solid seed charge of the compound in the amount of about 2 to about 10 percent by weight to form a slurry; milling the slurry to reduce the thickness of the slurry; 6. adding the remaining anti-solvent to reach the desired solvent composition of about 30 to about 50 percent and milling the slurry as needed during the addition; 7. slowly cooling the slurry to about 5°C to about 8. aging for about 2 to about 16 hours until the supernatant concentration reaches equilibrium; *15 9. milling the slurry, as needed, to reduce the thickness of the slurry; filtering the milled slurry to isolate a wetcake of the crystalline compound; 11. washing the wetcake once with about 1 to about 2 bed volumes of the final crystallisation solvent composition and then twice with water using about 5-10ml water S per gram of compound; and 12. drying the washed wetcake at about 40°C to about 90°C under vacuum for .i about 1 hour to about 3 days, or until the loss on dryness is less that 0.5 weight percent.

•The controlled anti-solvent crystallisation process as recited above wherein the solvent is defined as alcohol, wherein alcohol is a straight or branched chain (C 1

-C

6 alkanol. A preferred embodiment of the solvents useful in the controlled anti-solvent crystallisation crystallisation [I:\DayLib\LlBAA]07013.doc:ACR process is (C1-C6)-alkanol, such as, methanol, ethanol, and 2-propanol.

The preferred alcohol is 2-propanol.

The preferred alcohol is 2-propanol for reasons relating to obtaining consistent crystal forms. Although methanol and ethanol solvent systems have been shown to be capable of producing the desired Form I crystal structure, a slight contamination of Form II crystals in a crystallization slurry in these systems can convert the entire slurry to containing exclusively Form II crystals, which are relatively difficult to convert to the desired Form I structure. Any known crystal structure of 10 this compound placed in an about 25 to 35 2-propanol water solvent system has been shown to quickly convert to the Form II crystal structure, which can readily convert to the desired Form I crystal structure during drying.

The anti-solvent as recited above is defined as a solvent in which the compound has limited solubility. In the instant process, the preferred anti-solvent is water.

The temperature of the solution during the anti-solvent addition (Step 3) was about 20°C to about 25 0 C. The temperature of the slurry being about 5°C to about 20 0 C, and preferrably at about 10 0

C.

20 The temperature used during the drying of the washed wetcake (Step 12) is about 40 0 C to about 90 0 C, and preferrably about 40 0 C to about 60 0

C.

The solvent system (solvent plus anti-solvent) used ranged from about 30% to about 50% solvent volume to anti-solvent volume ratio. The total volume of the solvent system ranging from about 12 to about 20 ml of the solvent system per gram of the compound. The solvent volume to anti-solvent volume ratio for selected solvent systems is as follows: 1) an ethanol-water solvent system is about 30% to about ethanol to water v/v ratio; 2) a methanol-water solvent system is about 40% to about 50% methanol to water v/v ratio; and 3) an 2propanol-water solvent system is about 25% to about 35% 2-propanol to water v/v ratio. The perferred solvent system is 2-propanol-water used in about a 30% volume to volume ratio and a total solvent system volume of about 15 ml per gram of the compound.

-6- A process for the crystallization of a compound of the structural formula

F

3

C

CI

XNXO

H

comprising the steps of: i 5 mixing about 10% to about 20% by weight of the final amount of (-)-6-chloro-4-cyclopropylethynyl-4- S" trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one in Sthe desired v/v ratio of solvent to anti-solvent at about to form the heel or retaining a final slurry from a previous 10 batch; adding the solution of solvent and (-)-6-chloro-4cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro-2H-3,1benzoxazin-2-one, and anti-sovent to the heel simultaneuosly at constant rates over about 6 hours 15 maintaining the v/v ratio of solvent to anti-solvent; milling the slurry during the addition to reduce the thickness of the slurry; cooling the slurry to about 10 0 C over about 3 hours and aging slurry until the supematant concentration reaches equilibrium; filtering the milled slurry to isolate a wet cake of the crystalline compound; washing the wetcake once with about 1 to about 2 bed volumes of the final crystallization solvent composition and then twice with water using about 5 ml to about 10 ml water per gram of compound; and 7. drying the washed wetcake at about 40 0 C to about 90 0 C under vacuum for about 1 hour to about 3 days, or until the loss on dryness is less than 0.5 weight percent.

The heel crystallisation process as recited above wherein the solvent is defined as acetonitrile, dimethyl acetamide, dimethyl formamide or alcohol. A preferred embodiment of the solvents useful in the controlled anti-solvent crystallisation process is alcohol, wherein alcohol is defined as (Ci-C 6 )-alkanol, such as, methanol, ethanol, and 2propanol. The prefered alcohol is 2-propanol.

The anti-solvent as recited above is defined as a solvent in which the compound has limited solubility. In the heel crystallisation process the preferred anti-solvent is water.

The process as recited above wherein the temperature of the solution during the anti-solvent addition is about 5°C to about 20 0

C.

The temperature used during the drying of the washed wetcake is about 40 0 C to about 90 0 C, and preferably about 40 0 C to about 60 0

C.

The solvent system (solvent plus anti-solvent) used ranges from about 30 to about 15 50 percent solvent volume to anti-solvent volume ratio. The total volume of the solvent system ranging from about 12 to about 20 ml of the solvent system per gram of the compound. The solvent to anti-solvent volume to volume ratio for selected solvent systems is as follows: 1. an ethanol-water solvent system is about 30% to about 40% ethanol to water 20 v/v ratio; 2. a methanol-water solvent system is about 40% to about 50% methanol to water v/v ratio; and 3. a 2-propanol-water solvent system is about 25% to about 35% 2-propanol to water v/v ratio.

25 The preferred solvent system is 2-propanol-water used in about a 30% volume to volume ratio and a total solvent system volume of about 15ml per gram of the compound.

As previously stated the prinicpal embodiments of the invention the subject of this application are as follows: Form I of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H- 3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 14.5, and 7.2 Angstroms; Form II of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro-2H- 3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 24.3, 6.9 and 5.5 Angstroms; and [I:\DayLib\LBAA]07013.doc:ACR 0 Form III of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-.1 ,4-dihydro- 2H-3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 12.2, 6.1 and 4.3 Angstroms.

The disclosure of the invention also includes the following: Form I of 6 -chloro-4-cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2H-3,1-benzoxazin-2-one which is characterised by an X-ray powder diffraction pattern as exhibited in Figure 3.

0 Form I of 6 -chloro-4-cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2H-3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 14.5, 8.5 and 7.2 Angstroms.

Form I of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2H-3, 1-benzoxazin-2-one characterised by crystallographic D-spacings of 14.5, 8.5, 7.2, 6.7, 6.2, 5.2, 4.6, 4.4, 4.2, and 3.6 Angstroms.

Form 11 of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2H-3,1-benzoxazin-2-one which is characterised by an X-ray powder diffraction pattern :as exhibited in Figure 4.

0 Form 11 of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2H-3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 24.3, 6.9 and Angstroms.

20 Form 11 of 6 -chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro- 2H-3, 1-benzoxazin-2-one characterised by crystallographic D-spacings of 24.3, 13.9, 9:00 6.9, 6.6, 5.5, 4.6, 4.5, 4.3, 4.2, 3.9, 3.6, 3.4, 3.3 and 3.2 Angstroms.

Form III of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-.1 ,4-dihydro- 2H-3, 1-benzoxazin-2-one which is characterised by an X-ray powder diffraction pattern as exhibited in Figure Form III of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl.1 ,4-dihydro- 2H-3,1-benzoxazin.2-one as recited in claim 29, which is further characterised by a DSC curve as exhibited in Figure 6.

*Formn III of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2 H-3,1-benzoxazin-2-one as recited in claim 41, which is further characterised by a TG analysis as exhibited in Figure 7.

Form III of 6 -chloro- 4 -cyclopropylethynyl-4-trifluoromethyl-1 ,4-dihydro- 2 H-3,1--benzoxazin-2-one, characterised by crystallographic D-spacings of 12.2, 6.1 and 41_ RA~z.3Angstroms.

[RA\LB)XX]03277.doc~aak 0 Form III of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1,4-dihydro- 2H-3,1-benzoxazin-2-one characterised by crystallogenic D-spacings of 12.2, 8.1, 6.4, 6.1, 4.7, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2 and 3.0 Angstroms.

Figures 3, 4 and 5 are the X-ray powder diffraction (XRPD) patterns for Forms 1, 11 and 111, respectively. These XRPD patterns were recorded using an automated X-ray diffractometer APD 3720 with copper K alpha radiation. The crystal forms I and II of 6-chloro-4-cyclopropylethynyl-4-trifluoromethyl- 1 ,4-dihydro-2H-3, 1- 0000* 0* 0 *.00 0.00* *00.

0 0 [R \LBXX]03277.doc aak -8benzoxazin-2-one which are characterized by the noted X-ray powder diffraction patterns have the following key diffraction peaks (20) with intensities (IImax, of 10 or greater: Form I Form II Form III 6.0800 3.6375 7.2150 6.3900 6.3325 10.9675 10.3950 11.0725 13.7275 10.9875 12.7750 14.5325 12.2850 13.3275 16.7275 13.1900 14.2925 19.0675 14.1700 16.1200 19.6550 15.1925 16.8975 20.8250 16.9000 18.5025 21.7450 18.4375 19.1975 22.2825 19.2275 19.6025 22.8475 20.0925 20.6650 23.1750 21.2100 21.3250 23.8850 22.3600 22.6150 24.4900 23.0725 23.1775 24.9075 24.8900 24.4075 25.8200 25.9500 24.9650 27.0325 26.3575 26.0100 27.6050 27.2550 26.8550 29.2975 28.1150 27.6400 30.2600 28.5850 28.3675 30.7300 29.1325 29.1725 31.3125 29.5625 29.63.25 33.3975 30.6850 30.5650 38.4325 32.3725 31.8950 39.2100 38.3125 33.8225 -9- Additionally, these crystal forms are characterized by peaks with varying D-spacings. Form I is characterized by peaks with Dspacings of: 14.5, 8.5, 8.0, 7.2, 6.7, 6.2, 5.2, 4.6, 4.4, 4.2, and 3.6 angstroms. Form II is characterized by peaks with D-spacings of: 24.3, 13.9, 8.0, 6.9, 6.6, 5.5, 4.6, 4.5, 4.3, 4.2, 3.9, 3.6, 3.4, 3.3, and 3.2 angstroms. Form III is characterized by peaks with D-spacings of: 12.2, 8.1, 6.4, 6.1, 4.7, 4.3, 4.1, 4.0, 3.9, 3.8, 3.7, 3.6, 3.3, 3.2, and angstroms.

Thermogravimetric analysis results of Form III (Figure 7) indicated there was no significant weight loss observed from 43 0 C to about 137°C. This result is indicative of an anhydrous or unsolvated crystal form.

The differential scanning calorimetry (DSC) results obtained for Form I show an endotherm with an extrapolated onset 15 temperature of 117°C, a peak temperature of 118 0 C, and an enthalpy of 34 J/g, this is followed by an exotherm with a peak temperature of 120°C and an enthalpy of 23J/g. A second endotherm with an extrapolated onset temperature of 138 0 C, a peak temperature of 139 0

C,

and an enthalpy of 55 J/g is also observed. The first endotherm is associated with the melting of Form II, which subsequently crystallizes to Form I during the exothermic event. The second endothermic event is associated with the melting of Form I.

A process for isolating (-)-6-chloro-4-cyclopropylethynyl- 4-trifluoromethyl-1,4-dihydro-2H-3,1-benzoxazin-2-one, the final 25 product from solutions containing an organic solvent and water has been developed. In this process water serves as an anti-solvent to produce a solid product from material dissolved in organic solvent. The final solvent composition is chosen to balance yield loss, purification, and slurry handling properties.

For methanol solvent systems about 40% to about volume to volume solvent to anti-solvent (water) has been present in the final slurry. Ethanol solvent systems have contained about to about 40% v/v solvent to anti-solvent, and 2-propanol solvent systems have used about 25% to about 35% solvent to anti-solvent. The total amount of liquid (alcohol and water) ranges from 12 20 ml/(g solid). The crystallizations are typically performed between 20 251C, and some slurries have been cooled to 5 10 0 C before being filtered.

Following the filtration, the wetcake is washed with approximately one bed volume (the approximate volume of the wetcake) of the final crystallization solvent composition. The wetcake is then washed with at least 2 bed volumes of deionized (DI) water.

The rate at which the product is precipitated is controlled by either slowly adding the water to a saturated system following a seed charge (anti-solvent addition) or simultaneously adding the product in alcohol and water at controlled rates to an existing product slurry (heel crystallization).

For the anti-solvent process (Figure enough water is first added to the organic solvent solution containing the product over i" 15 0.5 2 hours to saturate the system in final product. A solid charge of final product is then added to the system as seed (2 10 of the initial amount of product). The seed should be Form I (the crystal form associated with dry final product) for ethanol and methanol systems, and Form II seed (the crystal form generated from a THF/heptane crystallization) is used for 2-propanol systems. The resultant slurry is aged for 0.5 2 hours to establish a seed bed. The remaining water is then added over 2 4 hours in a controlled manner. The slurry is then aged for 2 20 hours and cooled to the desired finaltemperature during the age, allowing the supemrnatant to reach equilibrium.

25 For the heel process (Figure a slurry at the desired final solvent composition is mixed while adding the product dissolved in alcohol and water at controlled relative rates to maintain a constant solvent ratio. The slurry (the crystalline compound in the final desired solvent system) is often 10-20% of the product from a prior run. The total charge is typically performed over 4 6 hours at 20 25°C. The slurry is then aged for several hours at the desired final temperature before being filtered to allow the supemrnatant to reach equilibrium.

Following the filtration, the wetcake is washed with approximately one bed volume of a clean alcohol/water mixture matching the final 11crystallization conditions. The wetcake is then washed with at least 2 bed volumes of DI water.

Further control of the crystal size and slurry viscosity is achieved by using a wet-mill on slurries with excessively long particles and/or extremely thick consistencies. The product typically forms rod shaped crystals which grow much faster in the axial direction than the radial direction. It is understood that the reference to 'thickness' will refer to the crystal size and consistency of the slurry. The mill has been shown to reduce the length of the long crystals and produce a thin slurry from a thick slurry which contains many agglomerates of crystals. On the laboratory scale, the entire slurry can be milled batch-wise when desired. At larger scales, the wet-mill can be used on a recycle loop circulating around the crystallization vessel. An in-line particle size measurement and viscosity measurements could be coordinated to 15 control the mill. Varying the temperature of the slurry through a range of 5°C to 50'C cycles has also been shown to be a useful way of modifying the crystal size and shape.

The solvents useful in this method include alcohol, acetonitrile (heel process only), dimethyl formamide (heel process only), and dimethyl acetamide (heel process only), The preferred solvent is an alcohol selected form methanol, ethanol or 2-propanol.

•This crystallization process is advantageous over the prior method. The instant method allows one to isolate a crystalline product with consistent physical properties namely the ability to produce the 25 desired crystal form of the product or convert to Form I with mild drying conditions (heating to about 40 to 60'C). The alcohol-water crystallizations have also been shown to reject some impurities carried forward from the chemical synthesis. The final product slurry is less viscous and more homogenous with the instant process and is thus easier to mix and.handle.

The following examples are meant to be illustrative of the present invention. These examples are presented to exemplify the invention and are not to be construed as limiting the scope of the invention.

-12- EXAMPLE 1 Controlled Anti-Solvent Addition Crystallization Process 400 g of DMP-266 starting material is dissolved in 2.400 L of ethanol. See Figure 1. The solution is filtered to remove extraneous matter. 2.088 L of deionized (DI) water is added to the solution over to 60 minutes. 20 g of DMP-266 seed is added to the solution. The seed bed is aged for 1 hour. The use of Intermig agitators is preferred to mix the slurry. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet-milled for 15 60 seconds.

1.512 L of DI water is added to the slurry over 4 to 6 hours. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet-milled for 15 to about 60 seconds during the addition.

The slurry is aged for 1 to 3 hours before being cooled to 10C over 3 hours. The slurry is aged for 2 to 16 hours until the product concentration in the supernatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 40 ethanol in water and then twice with 2 L of DI water each. The washed wet cake is dried under vacuum at EXAMPLE 2 Semi-Continuous Heel Crystallization Process :i 25 400 g of DMP-266 starting material is dissolved in 2.400 L of ethanol. See Figure 2. A heel slurry is produced by mixing 20 g of DMP-266 in 0.3 L of 40 ethanol in water. The dissolved batch and 3.6 L of DI water are simultaneously charged to the heel slurry at constant rates over 6 hours to maintain a constant solvent composition in the crystallizer. Use of Intermig agitators during the crystallization is preferred. During this addition the slurry is wet-milled when the crystal lengths become excessively long or the slurry becomes too thick.

The slurry is cooled to about 10°C over 3 hours. The slurry is aged for 2 to 16 hours until the product concentration in the supemrnatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The 13 *000 *0**0 0 wet cake is washed with 1 to 2 bed volumes of 40 ethanol in water and then twice with 2 L of DI water each. The washed wet cake is dried under vacuum at 50 0

C.

EXAMPLES 3-8 Following the crystallization procedures described in Examples 1 and 2 above using the solvents noted in the table below in the amounts recited DMP-266 can be crystallized.

Ex Solvent ml solvent per ml H20 per g. Anti-solvent Heel g. DMP-266* DMP-266* Process Process EX. 3: Acetonitrile 3.6 8.0 7.2 14 X EX. 4: Dimethyl acetamide 3.6 8.0 7.2 14 X EX. 5: Dimethyl formamide 3.6 8.0 7.2 14 X EX. 6: Ethanol 3.6 8.0 7.2 14 X X EX. 7: Methanol 4.8- 10 5.4- 12 X X EX. 8: 2-Propanol 3.0 7.0 7.8 15 X X The sum of the amounts of solvent and water should be at least 12 ml/g. The currently preferred concentration is 15 ml/g.

method did not work.

X method worked.

EXAMPLE 9 Crystallization of DMP-266 from 30% 2-Propanol in Water using a ratio of 15 ml solvent per gram DMP-266 Using Controlled Anti- Solvent Addition on a 400 g Scale 400 g. of DMP-266 starting material is dissolved in 1.8 L of 2-propanol. The solution is filtered to remove extraneous matter.

1.95 L of deionized (DI) water is added to the solution over 30 to minutes. 10 g. to 20 g. of DMP-266 seed (Form I wetcake) is added to the solution. The seed bed is aged for 1 hour. The use of Intermig 14agitators is preferred to mix the slurry. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet-milled for 60 seconds. 2.25 L of DI water is added to the slurry over 4 to 6 hours. If required (by the presence of extremely long crystals or a thick slurry), the slurry is wet-milled for 15 60 seconds during the addition. The slurry is aged for 2 to 16 hours until the product concentration in the supernatant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 30 2-propanol in water and then twice with 1 bed volume of DI water each. The washed wet cake is dried under vacuum at 50 *C.

EXAMPLE Crystallization of DMP-266 from 30% 2-Propanol in Water using a 15 ratio of 15 ml solvent per gram DMP-266 Using a Semi-Continuous ""Process on a 400 g Scale 400 g. of DMP-266 starting material is dissolved in 1.8 L "of 2-propanol. A heel slurry is produced by mixing 20 g. of Form II DMP-266 in 0.3 L of 30 2-propanol in water or retaining part of a slurry froma previous crystallization in the crystallizer. The I dissolved batch and 4.2 L of DI water are simultaneously charged to the heel slurry at constant rates over 6 hours to maintain a constant solvent 2 composition in the crystallizer. Use of Intermig agitators during the crystallization is preferred. During this addition the slurry is wetmilled when the crystal lengths become excessively long or the slurry becomes too thick. The slurry is aged for 2 to 16 hours until the product concentration in the supematant remains constant. The slurry is filtered to isolate a crystalline wet cake. The wet cake is washed with 1 to 2 bed volumes of 30 2-propanol in water and then twice with 1 bed volume of DI water each. The washed wet cake is dried under vacuum at 50 °C.

Claims (4)

1. Form I of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro- 2H-3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 14.5, 8.5 and

7.2 Angstroms. 2. Form I according to claim 1, characterised by crystallographic D-spacings of

14.5, 8.5, 7.2, 6.2, 4.4 and 4.2 Angstroms. 3. Form I according to claim 2, characterised by crystallographic D-spacings of 14.5, 8.5, 8.0, 7.2, 6.7, 6.2, 4.4 and 4.2 Angstroms. 4. Form I according to any one of claims 1 to 3, having no detectable peaks for Form II or Form III in its X-ray powder diffraction pattern. Form II of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro- 2H-3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 24.3, 6.9 and Angstroms. 6. Form II according to claim 5, characterised by crystallographic D-spacings of

24.3, 13.9, 6.9, 6.6, 5.5 and 4.3 Angstroms. 7. Form II according to claim 6, characterised by crystallographic D-spacings of 24.3, 13.9, 8.0. 6.9, 6.6, 5.5, 4.5, 4.3 and 3.6 Angstroms. S8. Form II according to any one of claims 5 to 7, having no detectable peaks for Form I or Form III in its X-ray powder diffraction pattern. 9. Form III of (-)-6-chloro-4-cyclopropylethynyl-4-trifluoromethyl-1,4-dihydro- 2H-3,1-benzoxazin-2-one, characterised by crystallographic D-spacings of 12.2, 6.1 and 4.3 Angstroms. Form III according to claim 9, characterised by crystallographic D-spacings of 12.2, 8.1, 6.1, 4.7, 4.3 and 4.1 Angstroms. 11. Form III according to claim 10, characterised by crystallographic D-spacings se of 12.2, 8.1, 6.4, 6.1, 4.7, 4.3, 4.1, 3.7 and 3.6 Angstroms. .oo 12. Form III according to any one of claims 9 to 11, having no detectable peaks for Form I or Form II in its X-ray powder diffraction pattern. 13. Form III according to any one of claims 9 to 12, which is further characterised by a DSC curve with a peak temperature of 118 0 C of an enthalpy of 34 J/g. 14. Form III according to any one of claims 9 to 13, which is further characterised by a thermogravimetric analysis indicating no significant weight loss from 43°C to 137 0 C. Dated 12 April, 2002 Merck Co., Inc. RPatent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [R:\LIBXX]03277.doc:ak