WO2007081895A2

WO2007081895A2 - Preparation of substituted 2-hydroxygibba-1(10a), 2, 4, 4b-tetraen-6-ones

Info

Publication number: WO2007081895A2
Application number: PCT/US2007/000431
Authority: WO
Inventors: Sarah Elizabeth Brewer; Steven Fraser Oliver; Jeremy Peter Scott; Gavin William Stewart; Narayan Variankaval; Debra Jane Wallace
Original assignee: Merck & Co., Inc.; Merck Sharp & Dohme Limited
Priority date: 2006-01-09
Filing date: 2007-01-05
Publication date: 2007-07-19
Also published as: WO2007081895A3

Abstract

The instant invention describes processes for synthesizing substituted 2-hydroxygibba-1(10a),2,4,4b-tetraen-6-ones.

Description

TITLE OF THE INVENTION

PREPARATION OF SUBSTITUTED 2-HYDROXYGIBBA-I (IOA), 2, 4, 4B-TETRAEN-6-ONES

BACKGROUND OF THE INVENTION This invention describes processes for the preparation of substituted 2-hydroxygibba-l-

(10A), 2, 4, 4B-tetraen-6-ones. A selective chlorination of 5-methoxyindan-l-one described herein allows for preferential chlorination at the 5-position over the reactive 2- and 7-positions. The invention further allows for the preparation of highly enantiomerically enriched substituted 2-hydroxygibba-l- (10A), 2, 4, 4B-tetraen-6-ones by providing for an upgrade of enantiomeric excess without chromatography. The process described herein further provides for a selective chlorination in the final step which chlorinates at the 4-position without competing chlorination of the aromatic ring.

SUMMARY OF THE INVENTION

By this invention, there are provided processes for the preparation of compounds of structural formula I:

I. BRIEF DESCRIPTION OF THE DRAWINGS

FIGURE 1 is a characteristic X-ray diffraction pattern of the crystalline free acid Form A of (7β-9aβ)-l ,4-Dichloro-2-hydroxygibba-l (10a),2,4,4b-tetraen-6-one.

FIGURE 2 is a carbon-13 cross-polarization magic-angle spinning (CPMAS) nuclear magnetic resonance (NMR) spectrum of the crystalline free acid Form A of (7j3-9a/3)-l,4-Dichloro-2- hydroxygibba-l(10a),2,4,4b-tetraen-6-one.

FIGURE 3 is a typical differential scanning calorimetry (DSC) curve of the crystalline free acid Form A of (lβ-9aβ)-l ,4-Dichloro-2-hydroxygibba-l (10a),2,4,4b-tetraen-6-one.

DETAILED DESCRIPTION OF THE INVENTION

wherein Rl is Ci -4 alkyl, comprising a) chlorinating an indanone of formula II to yield a chloroindanone of formula HI;

π m b) alkylating the chloroindanone of formula HI to yield a monoalkylated indanone of formula IV;

rv c) asymmetrically adding the monoalkylated indanone of formula IV to methyl vinyl ketone with a chiral phase transfer catalyst to yield a dialkylated indanone of formula V;

V d) cyclizing the dialkylated indanone of formula V to yield a tetrahydrofluorenone of formula VI;

VI e) cyclizing the tetrahydrofluorenone of formula VI to yield a gibbatetraenone of formula VII;

vπ f) chlorinating the gibbatetraenone of formula VII to yield the compound of formula I.

In an embodiment of the invention, the indanone in step a) is chlorinated with NaOCl, Cl2, t-butylhypochlorite, N-chlorosuccinimide or l,2,-dichloro-5,5-dimethylhydantoin. In a class of the invention, the chlorinating agent in step a) is NaOCl. In an embodiment of the invention, the chiral phase transfer catalyst is N-2- napthylmethyl cinchoninium bromide, N-(3,4-dichlorobenzyl) cinchoninium bromide, N-(4- trifiuoromethylbenzyl) cinchoninium bromide, N-(2-fluoro-4-trifluoromethylbenzyl) cinchoninium bromide, N-(3-fluoro-4-trifluoromethylbenzyl) cinchoninium bromide, N-(l-napthylmethyl) cinchoninium bromide, N-benzyl cinchoninium bromide, N-(3,4-difluorobenzyl) cinchoninium bromide, N-(9-anthracenylmethyl) cinchoninium bromide, N-2-napthylmethyl cinchoninium chloride, N-(3,4- dichlorobenzyl) cinchoninium chloride, N-(4-trifluoromethylbenzyl) cinchoninium chloride, N-(2-fluoro- 4-trifluoromethylbenzyl) cinchoninium chloride, N-(3-fluoro-4-trifluoromethylbenzyl) cinchoninium chloride, N-(l-napthylmethyl) cinchoninium chloride, N-benzyl cinchoninium chloride, N-(3,4- difluorobenzyl) cinchoninium chloride or N-(9-anthracenylmethyl) cinchoninium chloride. In a class of the invention, the chiral phase transfer catalyst is N-2-napthylmethyl cinchoninium bromide.

In an embodiment of the invention, the gibbatetraenone of formula VH is cyclized by heating in a polar solvent, wherein the polar solvent is ethanol, methanol, isopropanol or DMF. In a class of the invention, the polar solvent is isopropanol.

Li an embodiment of the invention, Rl is methyl. In an embodiment of the invention, the compound of formula I is crystalline (7/3-9a/3)-

1 ,4-dichloro-2-hydroxygibba- 1(10a),2,4,4b-tetraen-6-one. As used herein, "alkyl" is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having one to ten carbon atoms unless otherwise specified. For example, C 1-4, as in "C 1-4 alkyl" is defined to include groups having 1, 2, 3 or 4 carbons in a linear, branched, or cyclic arrangement. For example, "C1-4 alkyl" specifically includes methyl, ethyl, propyl, butyl, and so on.

The crystalline free acid of (7/3-9ajS)-l,4-dichloro-2-hydroxygibba-l(10a),2,4,4b-tetraen- 6-one, also known as "Form A" or "novel polymorphic Form A," is characterized by an X-ray powder diffraction (XRPD) pattern, collected using copper Ka radiation, corresponding to d-spacings of 4.67, 6.81 and 3.93 angstroms. The pattern is further characterized by d-spacings of 5.57, 6.42 and 3.22 angstroms. The pattern is further characterized by d-spacings of 3.87, 3.65 and 3.36 angstroms. The X- ray diffraction patterns were measured using a Panalytical XTert Pro with a Cu LFF source (Cu K-alpha - wavelength = 1.54187) at a generator power of 4OkV and 50 mA from 2-40 degrees 2-theta.

In addition to the X-ray powder diffraction patterns described above, novel polymorphic Form A is further characterized by solid-state carbon- 13 nuclear magnetic resonance (NMR) spectra. Novel polymorphic Form A of (7β-9aβ)- 1 ,4-dichloro-2-hydroxygibba- 1(10a),2,4,4b-tetraen-6-one is characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals at 55.6, 127.8, 26.8, and 158.1 p.p.m. The spectrum is further characterized by signals at 38.2, 42.5, 151.5, and 170.3 p.p.m. The solid-state carbon-13 NMR spectra were obtained on a Bruker DSX 500WB NMR system using a Bruker 4 mm H/X/Y CPMAS probe. The carbon_r13 NMR spectra utilized proton/carbon-13 cross-polarization magic-angle spinning with variable-amplitude cross polarization, total sideband suppression, and SPINAL decoupling at 100kHz. The samples were spun at 10.0 kHz, and a total of 256 scans were collected with a recycle delay of 10 seconds. A line broadening of 10 Hz was applied to the spectra before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference. In addition to the X-ray powder diffraction patterns and carbon-13 CPMAS nuclear magnetic resonance spectrum described above, the crystalline free acid of (7j3-9aβ)-l,4-dichloro-2- hydroxygibba-l(10a),2,4,4b-tetraen-6-one is characterized by melting onset at 231.4°C.

The imwitor solvate of (70-9a/3)-l,4-dichloro-2-hydroxygibba-l(10a),2,4,4b-tetraen-6- one, also referred to as "the imwitor solvate," is characterized by an X-ray powder diffraction (XRPD) pattern, collected using copper Ka radiation, corresponding to d-spacings of 43.686, 36.404, 17.249, 12.301, 11.41, 8.707, 8.098, 6.197, 5.839, 5.748, 4.849, 4.138 and 3.841 angstroms. The X-ray diffraction patterns were measured using a Panalytical XTert Pro with a Cu LFF source (Cu K-alpha - wavelength = 1.54187) at a generator power of 4OkV and 50 mA from 2-40 degrees 2-theta.

In addition to the X-ray powder diffraction patterns described above, the imwitor solvate is further characterized by solid-state carbon-13 nuclear magnetic resonance (NMR) spectra. The crystalline imwitor solvate of (7j3-9a/3)-l,4-dichloro-2-hydroxygibba-l(10a),2,4,4b-tetraen-6-one is characterized by a solid-state carbon-13 CPMAS nuclear magnetic resonance spectrum showing signals at 14.1, 51.6, 149.4 and 197.5 p.p.m. The spectrum is further characterized by signals at 26.1, 36.3, 126.8 and 156.3 p.p.m. The spectrum is further characterized by signals at 25.1, 29.4 and 155.5 p.p.m. The solid-state carbon- 13 NMR spectra were obtained on a Bruker DSX 500WB NMR system using a Bruker 4 mm H/X/Y CPMAS probe. The carbon-13 NMR spectra utilized proton/carbon- 13 cross- polarization magic-angle spinning with variable-amplitude cross polarization, total sideband suppression, and SPINAL decoupling at lOOkHz. The samples were spun at 10.0 kHz, and a total of 256 scans were collected with a recycle delay of 10 seconds. A line broadening of 10 Hz was applied to the spectra before FT was performed. Chemical shifts are reported on the TMS scale using the carbonyl carbon of glycine (176.03 p.p.m.) as a secondary reference.

In the following schemes and examples below, various reagent symbols and abbreviations have the following meanings:

AcOH: Acetic acid

BBr 3: Boron tribromide

CH2CI2: Methylene chloride

CH3CN: Acetonitrile

HCl: Hydrochloric acid

IPA: Isopropanol

DPAc: Isopropyl acetate

Me2NNH2: 1 , 1 -Dimethy lhydrazine

NaOCl: Sodium hypochlorite

NaOH: Sodium hydroxide

NCS: N-chlorosuccinimide

N-HexLi: n-Hexyl lithium

PhMe: Toluene

THF: Tetrahydrofuran

The compounds of the present invention can be prepared according to the following general scheme, using appropriate materials, and are further exemplified by the subsequent specific examples. The compounds illustrated in the examples are not, however, to be construed as forming the only genus that is considered as the invention. Those skilled in the art will readily understand that known variations of the conditions and processes of the following preparative procedures can be used to prepare these compounds. All temperatures are degrees Celsius unless otherwise noted. SCHEME

The scheme depicts the selective chlorination of 5-methoxyindanone, followed by monoalkylation with beta-bromophenetole by way of the dimethylhydrazone derivative. Asymmetric addition to methyl vinyl ketone under phase transfer conditions and dehydrative cyclization affords the tetrahydrofluorenone skeleton in enantiomerically enriched form. The enantiopurity is upgraded by crystallisation at this stage. Conversion of the phenoxy substituent to a bromide leaving group is accompanied by cleavage of the phenolic methoxy ether under the reaction conditions. A final selective chlorination allows for preparation of the desired substituted 2-hydroxygibba-l(10A), 2, 4, 4B-tetraen-6- one.

EXAMPLE l PREPARATION OF 4-CHLORO-5-METHOXYTNDAN-1 -OlSfE

5-Methoxyindan-l-one (17.5 kg, 108 mol) was dissolved in AcOH (147 kg) and cooled to +14°C. Sodium hypochlorite 10/11% aqueous solution (87 kg, 136 mol) was added such that the internal temperature was maintained below 17°C (2.5 h addition time). After a 20 min age at <10°C, the batch was cooled to 0-2⁰C and aged for 30 min. Water (50 L) was then added to crystallised and the batch. The batch was filtered and the cake washed with 5: 1 water/AcOH (18 L) followed by water (2 x 20 L). Drying at 40⁰C under a N₂ sweep afforded 15.57 kg of 4-chloro-5-methoxyindan-l-one as an off- white solid in 74% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.66 (IH, d, J= 8.4 Hz), 7.00 (IH, d, J= 8.4 Hz), 4.00 (3H, s), 3.09 (2H, t, J= 6.0 Hz), 2.71. (2H, d, J= 6.0 Hz); ¹³C NMR (100 MHz, CDCl₃) δ 204.8, 160.0, 154.7, 131.4, 123.3, 119.7, 111.5, 56.7, 36.3, 24.9.

EXAMPLE 2

PREPARATION OF 4-CHLORO-5-METHOXY-2-(2-PHENOXYETHYL)INDAN-l-ONE 4-Chloro-5-methoxyindan-l-one (14.0 kg, 71.2 mol) (Example 1) was slurried in n- heptane (154 L). Glacial acetic acid (2.14 kg, 35.6 mol) was then added followed by 1,1- dimethylhydrazine (6.42 kg, 106.8 mol) such that the temperature remained <40°C. The batch was then heated to 90⁰C for 3 h. The batch was cooled to 60⁰C, treated with THF (28 L) then concentrated to 40 L by distillation under atmospheric pressure. The resulting concentrate was cooled to 50⁰C and diluted with THF (182 L). The THF solution was held overnight at <15°C. The batch was cooled to -50⁰C by direct injection of liquid N₂, then n-hexyllithium (2.39 M in hexane, 21.2 kg, 71.2 mol) was added over 1.5 h, maintaining the internal temperature <-25°C. The resulting slurry was aged between -30 and -20⁰C for 30 min then a solution of β-bromophenetole (14.4 kg) in THF (14 L) was added over 5 min, maintaining the internal temperature <-25°C. The batch was then aged at -5⁰C for 30 min. 6 N HCl (30 kg 37% HCl + 30 kg H₂O) was charged to the mixture which was then aged at 50⁰C until complete hydrolysis of the intermediate hydrazone was confirmed by HPLC (1.5 h). After cooling the batch to 20⁰C, isopropyl acetate (56 L) was added and the aqueous layer was discarded. The organic phase was washed with water (75 L) then concentrated to 40 L using vacuum distillation at 4O⁰C. n-Heptane (40 L) was added and after aging for 30 min at 40⁰C, 0.2% seed of the product ketone was added. The mixture was stirred for 1 h to allow a seed bed to develop, then a further 80 L of n-heptane was charged over 1 h at 40⁰C. The resulting slurry was allowed to cool to 20⁰C overnight then cooled to 5°C over 1 h before filtering. The filter cake was washed with 4:1 heptanerisopropyl acetate (25 L), then sucked dry under a stream OfN₂ for 3 h. The solid was dried in a vacuum oven at 45°C for 48 h affording 20.2 kg of product as an off white solid in 88% yield. ¹H NMR (400 MHz, CDCl₃) δ 7.70 (IH, d, J = 8.4 Hz), 7.35-7.25 (2H, m), 7.04-6.88 (4H, m), 4.25-4.15 (2H, m), 4.00 (3H, s), 3.46-3.35 (IH, m)_> 2.98-2.87 (2H, m), 2.54- 2.41 (IH, m), 2.03-1.89 (IH, m); ¹³C NMR (IOO MHz, CDCl₃) δ 206J, 160.2, 158.8, 153.2, 130.8, 129.5, 123.6, 120.8, 119.7, 1 14.5, 111.6, 65.9, 56.8, 45.0, 32.2 <>31.0.

EXAMPLE 3 PREPARATION OF (9AS)-8-CHLORO-7-METHOXY-9A-(2-PHENOXYETHYL)-l ,2,9,9A-

TETRAJHYDRO-3H-FLUOREN-3-ONE

N-(2-napthylmethylcinchoninium bromide (3.38 kg, 6.56 mol) and 4-chloro-5-methoxy- 2-(2-phenoxyethyl)indan-l-one (13.8 kg, 43.6 mol)(Example 2) were slurried in toluene (208.9 kg). Sodium hydroxide (50%, 51.5 kg) was then charged and the batch aged for 14 h at 20-25⁰C. A solution of methyl vinyl ketone (2.75 kg, 39.2 mol) in toluene (26.4 kg) was added at 20⁰C over 30 min at T

<27°C. After a further 15 min aging, a further charge of methyl vinyl ketone (366 g, 5.2 mol) in toluene (3.0 kg) was then made such that HPLC assay indicated <0.5 A% unconverted indanone. Water (67.0 kg) was added over 40 min such that T <30°C. After allowing the batch to settle, around 90% by weight of the lower aqueous layer was cut. The remaining batch was filtered and washed through with additional toluene (2 x 12.5 kg). The batch was settled and the remaining aqueous cut away. The toluene layer was washed successively with 2M HCl (prepared from c. HCl 17.7 kg and water 72.2 kg) containing methanol (5.76 kg) followed by water (87.3 kg). The batch was distilled at 45°C to a volume of ca. 167 L and held overnight. AcOH (2.62 kg, 43.6 mol) and pyrrolidine (3.11 kg, 43.6 mol) were then added and the batch aged at 85°C for 4 h. Water (130.9 kg) was charged at 85°C and the batch mixed for 10 min prior to settling. The lower aqueous was cut away and the organic washed with further water (130.9 kg). The aqueous was cut and the organics distilled to a volume of ca. 57 L at 45°C. On cooling to 39°C, the batch crystallised and after formation of a seedbed, heptane (58.5 kg) was added over 20 min. After aging a minimum of 1 h, filtration, washing with heptane (14.9 kg) and drying in vacuo at 45°C for 16 h afforded 13.83 kg of (9aS)-8-Chloro-7-methoxy-9a-(2-phenoxyethyl)-l, 2,9,9a- tetrahydro-3H-fluoren~3-one as a tan solid in 85% yield with 52% ee. ¹H NMR (400 MHz, CDCl₃) δ

7.45 (IH, d, J= 8.4 Hz), 7.30-7.21 (2H, m), 6.95-6.83 (2H, m), 6.80-6.76 (IH, m), 6.21 (IH, s), 4.03-3.91 (5H, m), 3.39-3.35 (IH₃ d, J= 17.2 Hz), 2.83-2.68 (2H, m), 2.53 (IH, dd, J=14.8, 4.8 Hz), 2.40 (IH, dd, /= 3.2, 13.2 Hz), 2.21-1.98 (3H, m); ¹³C NMR (100 MHz, CDCl₃) δ 198.7, 171.2, 158.3, 157.9, 146.7, 131.5, 129.4, 122.1, 120.9, 119.6, 116.7, 114.2, 111.6, 64.6, 56.6, 46.0, 43.0, 36.6, 34.0, 32.5.

EXAMPLE 4 ENANTIOPURTTY UPGRADE FOR (9AS)-8-CHLORO-7-METHOXY-9A-(2-PHENOXYETHYL)-

1 ,2,9,9A-TETRAHYDRO-3H-FLUOREN-3-ONE

(9a5)-8-Chloro-7-methoxy-9a-(2-phenoxyethyl)-l,2,9,9a-tetrahydro-3H-fluoren-3-one (27.4 kg, 74.3 mol)(Example 3) was suspended in isopropyl acetate (358.0 kg) and the mixture degassed (3 x) and placed under nitrogen. The mixture was heated to 76°C to dissolve the batch and then cooled to 20⁰C over >1 h and aged at 20⁰C for at least 1 h. The crystallised racemic material was then filtered off and the solid washed with cold (4°C) isopropyl acetate (23.9 kg). HPLC assay of the combined filtrates gave 96.3% ee, 14.7 kg. The filtrates were distilled under vacuum to a volume of 4.5 mL/g based on the previous assay (approx. 222 mg/mL) and then heated to 65°C to redissolve the crystallised solids. The batch was allowed to cool to 60⁰C and then seed was added (1 wt%) based on assay. After formation of a seedbed, the batch was allowed to cool to ambient and then cooled to -5 to 0⁰C, aging for >1 h. HPLC indicated the ML assayed was 22.9 mg/mL. Filtration and washing with cold (4°C) isopropyl acetate and drying in vacuo at 45⁰C for 16 h afforded 12.84 kg of (9aS)-8-Chloro-7-methoxy- 9a-(2-ρhenoxyethyl)-l,2,9,9a-tetrahydro-3H-fluoren-3-one in 93% yield and 97% ee.

EXAMPLE 5 PREPARATION OF (7β-9Aβ)-l-CHLORO-2-HYDROXYGlBBA-l(10A),2,4,4B-TETRAEN-6-ONE

Boron tribromide (IM in dichloromethane, 97.4 kg, 66.4 mol) was cooled to 1°C. A solution of(9a5)-8-Chloro-7-methoxy-9a-(2-phenoxyethyl)-l,2,9,9a-tetrahydro-3H-fluoren-3-one (7.0 kg, 19.0 mol)(Example 4) in dichloromethane (31.0 kg) was added over 10 min such that T <15°C. The solution was aged at 12-14⁰C for 16-22 hours. The solution was cooled to I⁰C and methanol (8.51 kg.) was added over 1 h, T <15°C. After a 1 h age, water (21 kg) was added, followed by dichloromethane (23.2 kg) and the slurry stirred for 20 min at ambient. The batch was then filtered and the solid washed with dichloromethane (2 x 18.6 kg). The filtrate and washes were combined and further water (28 kg) added. The batch was agitated for 10 min, left to settle and the layers cut. The organic layer was washed with 5 wt % sodium bicarbonate (47.3 L, prepared from 45.0 kg water and 2.36 kg sodium hydrogen carbonate). The organic layer was switched to isopropanol at a final volume of 56 L (8 mL/g) by concentrating to around 40 L and then charging isopropanol (76.9 kg). Further distillation was performed to reach the target volume of 56 L. This isopropanol solution was heated at 80⁰C for 12-15 hours to effect cyclisation. A volume of 7 L of isopropanol (3 mL/g) was removed by distillation (giving a 35 L/5 mL/g solution) and the solution cooled to 45°C and seeded (0.1 - 0.2 w/t%). After a seedbed had formed, water (70 L) was added dropwise over 1 h. The slurry was allowed to cool to ambient, aged for 1 h and filtered, washing with 5% isopropanol/water (21 L) and water (14 kg). Drying in vacuo at 50⁰C under a nitrogen stream for 16 h afforded 4.53 kg of (7β-9aβ)-l^chloro-2-hydroxygibba- l(10a),2,4,4b-tetraen-6-one as a pink solid in 91% yield. ¹H NMR (400 MHz, d₆-DMSO) δ 10.90 (IH, s), 7.53 (IH, d, J= 8.4 Hz)₃ 6.97 (IH, d, J = 8.4 Hz), 6.03 (IH, s), 3.18-3.02 (2H, m), 2.82-2.78 (IH, m), 2.26-2.15 (IH, m), 1.98-1.85 (3H, m), 1.72-1.63 (lH, m), 1.50-1.40 (IH, m); ¹³C NMR (IOO MHz₃ d₆-

DMSO) δ 202.4, 173.9, 157.0, 148.9, 128.6, 123.7, 117.2, 116.9, 112.8, 52.7, 50.9, 43.2, 39.4, 36.8, 26.1.

EXAMPLE 6

PREPARATION OF (7β-9Aβ)-l,4-DICHLORO-2-HYDROXYGIBBA-l(10A),2,4,4B-TETRAEN-6- ONE

A suspension of (7β-9aβ)-l-chloro-2-hydroxygibba-l(10a),2,4,4b-tetraen-6-one (4.1 kg, 13.9 mol)(Example 5) in acetonitrile (29.0 kg) was heated to 71-75°C. N-Chlorosuccinimide (2.23 kg, 14.7 mol) was dissolved in acetonitrile (12.9 kg) and added over 20 min followed by a line rinse of acetonitrile (2.0 kg). The batch was aged at 71-75°C for 1.5 h and then cooled to 20⁰C and water (92.0 kg) added over 1.5 h to crystallise the batch. After aging 12-16 h, the batch was filtered, the solids washed with 2:1 water: acetonitrile (16.4 L) and dried at 40⁰C in vacuo for 22 h. A total of 4.08 kg of (7β-9aβ)-l,4-dichloro-2-hydroxygibba-l(10a),2,4,4b-tetraen-6-one was obtained as a brown/green solid in 87% yield. ¹H NMR (400 MHz, d₆-DMSO) δ 11.20 (IH, s), 8.04 (IH, d, J= 8.4 Hz), 7.06 (IH, d, J= 8.4 Hz), 3.24 (IH, d, J= 18.0 Hz), 3.12-3.04 (2H, m), 2.30-2.21 (IH, m), 2.05-1.90 (3H, m), 1.80-1.69 (IH, m), 1.55-1.45 (IH, m); ¹³C NMR (IOO MHz, d₆-DMSO) δ 195.0, 166.2, 157.4, 150.3, 127.6, 127.4, 118.3, 117.3, 116.7, 55.6, 50.7, 42.7, 39.8, 36.8, 25.9.

EXAMPLE 7

PREPARATION OF (7β-9Aβ)-l,4-DICHLORO-2-HYDROXYGIBB A-I(10A),2,4,4B-TETRAEN-6-

ONE ΓMWΠΌR SOLVATE

To about 6 g of liquid Imwitor 742 (Imwitor 742 is semi-solid at 25°C but free-flowing at 30⁰C) in a 20 ml scintillation glass vial, add about 250 mg of anhydrous Form A of (7β-9aβ)-l ,4- dichloro-2-hydroxygibba-l(10a),2,4,4b-tetraen-6-one. Stir continuously at 30⁰C using a magnetic stir bar. Form A converts to the imwitor solvate over a period of about 10 days. This conversion can be monitored by XRPD. To obtain a sample for XRPD, a small quantity of the slurry is centrifuged. The solid at the bottom of the centrifuge tube is submitted to XRPD using a zero-background Si-substrate. Solubility of (7β-9aβ)-l,4-dichloro-2-hydroxygibba-l(10a),2,4,4b-tetaen-6-one in Imwitor 742 is 9.6 mg/g; solid-form conversion to the imwitor solvate will occur as long as excess (7β-9aβ)-l,4-dichloro-2- hydroxygibba-l(10a),2,4,4b-tetaen-6-one is added to Imwitor 742.

Claims

WHAT IS CLAIMED IS:

1. A process for preparing a compound of formula I:

wherein Rl is C 1-4 alkyl, comprising a) chlorinating an indanone of formula II to yield a chloroindanone of formula IH;

IV c) asymmetrically adding the monoalkylated indanone of formula IV to methyl vinyl ketone with a chiral phase transfer catalyst to yield a dialkylated indanone of formula V;

d) cyclizing the dialkylated indanone of formula V to yield a tetrahydrofluorenone of formula VI;

VI e) cyclizing the tetrahydroflourenone of formula VI to yield a gibbatetraenone of formula VH;

2. The process of Claim 1 wherein the indanone in step a) is chlorinated with NaOCl, CI2, t-butylhypochlorite, N-chlorosuccinimide or l,2,-dichloro-5,5-dirnethylhydantoin.

3. The process of Claim 2 wherein the chiral phase transfer catalyst isN-2- napthylmethyl cinchoninium bromide, N-(3,4-dichlorobenzyl) cinchoninium bromide, N-(4- trifluoromethylbenzyl) cinchoninium bromide, N-(2-fluoro-4-trifluoromethylbenzyl) cinchoninium bromide, N-(3-fluoro-4-trifluoromethylbenzyl) cinchoninium bromide, N-(l-napthylmethyl) cinchoninium bromide, N-benzyl cinchoninium bromide, N-(3,4-difiuorobenzyl) cinchoninium bromide, N-(9-anthracenylmethyl) cinchoninium bromide, N-2-napthylmethyl cinchoninium chloride, N-(3,4- dichlorobenzyl) cinchoninium chloride, N-(4-trifiuoromethylbenzyl) cinchoninium chloride, N-(2-fluoro- 4-trifluoromethylbenzyl) cinchoninium chloride, N-(3-fluoro-4-trifluoromethylbenzyl) cinchoninium chloride, N-(l-napthylmethyl) cinchoninium chloride, N-benzyl cinchoninium chloride, N-(3,4- difluorobenzyl) cinchoninium chloride or N-(9-anthracenylmethyl) cinchoninium chloride.

4. The process of Claim 3 wherein the gibbatetraenone of formula VII is cyclized by heating in a polar solvent, wherein said polar solvent is ethanol, methanol, isopropanol or DMF.

5. Crystalline (7/5-9a/3)-l,4-dichloro-2-hydroxygibba-l(10a),2,4,4b-tetraen-6-one.

6. A novel polymorphic Form A of (7/3-9a/3)- 1 ,4-dichloro-2-hydroxygϊbba- l(10a),2,4,4b-tetraen-6-one which is characterized by an x-ray powder diffraction pattern, collected using copper Ka radiation, corresponding to d-spacings of 4.67, 6.81 and 3.93 angstroms.

7. The x-ray powder diffraction pattern of Claim 6 which is further characterized by d-spacings of 5.57, 6.42 and 3.22 angstroms.

8. The x-ray powder diffraction pattern of Claim 7 which is further characterized by d-spacings of 3.87, 3.65 and 3.36 angstroms.

9. A novel polymorphic Form A of (7/3-9a(8)-l,4-dichloro-2-hydroxygibba- l(10a),2,4,4b-tetraen-6-one which is characterized by a solid-state carbon- 13 CPMAS nuclear magnetic resonance spectrum showing signals at 55.6, 127.8, 26.8, and 158.1 p.p.m.

10. The novel polymorphic Form A of Claim 9 which is further characterized by signals at 38.2, 42.5, 151.5, and 170.3 p.p.m.

11. A novel polymorphic Form A of (7/3-9a/ϊ)-l ,4-dichloro-2-hydroxygibba- l(10a),2,4,4b-tetraen-6-one characterized by melting onset at 231.4°C.