Source: https://patents.justia.com/patent/8309594
Timestamp: 2020-07-05 21:22:00
Document Index: 442462199

Matched Legal Cases: ['Application No. 60', 'Application No. 2007', 'Application No. 2005237520', 'Application No. 200580013278', 'Application No. 2984', 'Application No. 2', 'Application No. 2', 'Application No. 2005237520', 'Application No. 2007', 'Application No. 2984']

US Patent for Purification of progesterone receptor modulators Patent (Patent # 8,309,594 issued November 13, 2012) - Justia Patents Search
Justia Patents Spiro Ring SystemUS Patent for Purification of progesterone receptor modulators Patent (Patent # 8,309,594)
Feb 12, 2009 - Wyeth LLC
Methods for purifying a compound of formula I are provided, wherein A, B, X, Q, and R1 are defined herein. The methods include mixing the compound of formula I and a solvent; adding a base to the solvent; and precipitating purified compound of formula I.
This application is a divisional of U.S. patent application Ser. No. 11/113,730, filed Apr. 25, 2005, which claims the benefit under 35 USC 119(e) of prior U.S. Provisional Patent Application No. 60/565,659, filed Apr. 27, 2004, now expired.
The term “heterocyclic” as used herein refers to a stable 4- to 10-membered monocyclic or multicyclic heterocyclic ring which is saturated, partially unsaturated, or wholly unsaturated. The heterocyclic ring has carbon atoms and one or more heteroatoms including nitrogen, oxygen, and sulfur atoms. In one embodiment, the heterocyclic ring has 1 to about 4 heteroatoms in the backbone of the ring. When the heterocyclic ring contains nitrogen or sulfur atoms in the backbone of the ring, the nitrogen or sulfur atoms can be oxidized. The term “heterocyclic” also refers to multicyclic rings in which a heterocyclic ring is fused to an aryl ring, e.g. of 6 to 14 carbon atoms. The heterocyclic ring can be attached to the aryl ring through a heteroatom or carbon atom provided the resultant heterocyclic ring structure is chemically stable.
A variety of heterocyclic groups are known in the art and include, without limitation, oxygen-containing rings, nitrogen-containing rings, sulfur-containing rings, mixed heteroatom-containing rings, fused heteroatom containing rings, and combinations thereof. Oxygen-containing rings include, but are not limited to, furyl, tetrahydrofuranyl, pyranyl, pyronyl, and dioxinyl rings. Nitrogen-containing rings include, without limitation, pyrrolyl, pyrazolyl, imidazolyl, triazolyl, pyridyl, piperidinyl, 2-oxopiperidinyl, pyridazinyl, pyrimidinyl, pyrazinyl, piperazinyl, azepinyl, triazinyl, pyrrolidinyl, azepinyl, and carbazolyl rings. Sulfur-containing rings include, without limitation, thienyl and dithiolyl rings. Mixed heteroatom containing rings include, but are not limited to, oxathiolyl, oxazolyl, thiazolyl, oxadiazolyl, oxatriazolyl, dioxazolyl, oxathiazolyl, oxathiolyl, oxazinyl, oxathiazinyl, morpholinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, oxepinyl, thiepinyl, and diazepinyl rings. Fused heteroatom containing rings include, but are not limited to, benzofuranyl, thionapthene, indolyl, benazazolyl, purindinyl, pyranopyrrolyl, isoindazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzopyranyl, quinolinyl, isoquinolinyl, benzodiazonyl, napthylridinyl, benzothienyl, pyridopyridinyl, benzoxazinyl, xanthenyl, acridinyl, and purinyl rings.
The term “electron withdrawing group” as used herein is meant to describe a chemical substituent that withdraws electrons from the chemical group to which it is attached. Examples of electron withdrawing groups include, without limitation, CN, SO3H, CO2H, CO2R, CHO, COR, NO2, NR3+, CF3, or CCl3. In one embodiment, the electron withdrawing group is CN.
RI is located at any position on the ring. In one embodiment, R1 is halogen. In another embodiment, the halogen is bromine. In still another embodiment, R1 is selected from among a substituted benzene ring containing the substituents X, Y and Z as shown below:
The compounds of the invention are treated with a base in the presence of a purifying solvent to form a basic salt. One of skill in the art would readily be able to select a suitable base according to its basicity and the compound being purified. A number of bases can be used according to the present invention and include hydroxides, alkoxides, amines, amidines, ketones, and amino acids such as arginine, lysine, and betaine, among others. Hydroxides can include, without limitation, 2-hydroxy-N,N,N-trimethylethaminium hydroxide(choline hydroxide), sodium hydroxide, potassium hydroxide, lithium hydroxide, zinc hydroxide, calcium hydroxide, and magnesium hydroxide. Alkoxides can include, without limitation, potassium, sodium, and lithium alkoxides such as potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium methoxide, sodium ethoxide, sodium tert-pentoxide, and potassium tert-pentoxide. Amines can include dimethylamine, diethylamine, piperidine, ethylenediamine, ethanolamine, diethanolamine, triethanolamine, lysine, arginine, morpholine, and tris(hydroxymethyl)aminomethane, among others. In one embodiment, the amine is diethylamine. Amidines can include tetramethylguanidine, diazabicycloundecene, or diazabicyclononene, among others. Ketones can include lower ketones, e.g., of 2 to 7 carbon atoms such as acetone and methyl ethyl ketone.
wherein, X is selected from the group consisting of H, halogen, CN, C1 to C3 alkyl, substituted C1 to C3 alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 thioalkoxy, substituted C1 to C3 thioalkoxy, amino, C1 to C3 aminoalkyl, substituted C1 to C3 aminoalkyl, NO2, C1 to C3 perfluoroalkyl, 5 or 6 membered heterocyclic ring containing in its backbone 1 to 3 heteroatoms, SO2NH2, CORC, OCORC, and NRDCORC. RC is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl. RD is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl. Y and Z are independently selected from the group consisting of H, halogen, CN, NO2, amino, aminoalkyl, C1 to C3 alkoxy, C1 to C3 alkyl, and C1 to C3 thioalkoxy. In another embodiment, R1 is a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO2, amino, C, to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, SO2NH2, CORE, and NRFCORE. RE is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl. RF is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl. R2 is H, absent, O, or C1 to C4 alkyl. The method includes mixing the compound of formula I and a solvent; adding a base to the solvent; and precipitating purified compound of formula I using an agent selected from the group consisting of an acid, water, or heat.
Example 2 Purification of 5-(4,4-Dimethyl-2-Thioxo-1,4-Dihydro-2H-3,1-Benzoxazin-6-Yl)-1H-Methyl-1H-Pyrrole-2-Carbonitrile
Crude 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile (10.0 g), containing 16% of an impurity, was suspended in MeOH (25 mL) followed by addition of potassium tert-butoxide (4.48 g). The suspension was stirred at 65° C. until a clear solution was obtained. Upon cooling to about 5° C., a 4M HCl solution in dioxane (12 mL) was added dropwise. The yellow precipitate was filtered and washed with a 1:1 acetone:water mixture. Recrystallization from an acetone:water mixture yielded 5.4 g of the product containing only 0.5% of the impurity.
Example 8 Preparation of 5′-(5-Cyano-1-Methyl-1H-Pyrrol-2-Yl)Spiro[Cyclohexane-1,3′-[3H]Indol]-2′-Ylindenecy Anamide Choline Salt
X Ha Hb Hc Hd He H 7.02 6.33 7.71 7.41 7.17 choline 6.98 6.22 7.41 7.14 6.89
Example 9 Purification of 5-(2′-Thioxospiro[Cyclohexane-1,3′-[3H]Indol]-5′-Yl)-1-Methyl-1H-Pyrrole-2-Carbonitrile
5′-(5-Cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2-ylidenecyanamide (0.96 g) in ethanol (20 mL) was reacted with the bases set forth in Table 2 to form, upon cooling, filtering and drying, 5′-(5-cyano-1-methyl-1H-pyrrol-2-yl)spiro[cyclohexane-1,3′-[3H]indol]-2′-ylidenecyanamide salt as a solid. The 1H-NMR spectra (DMSO-d6) of the purified compound (X═H) and isolated salts (X═Na, K, choline, and Et2NH·H) were obtained and the data compiled in Table 2.
base X Ha Hb Hc Hd He — H 7.02 6.33 7.71 7.41 7.17 sodium Na 6.98 6.21 7.41 7.13 6.89 hydroxide potassium K 6.97 6.21 7.42 7.14 6.93 hydroxide choline choline 6.98 6.22 7.41 7.14 6.89 hydroxide Et2NH•H 7.00 6.27 7.58 7.21 7.05
Example 11 Preparation of 5-(2′-Thixoxspiro[Cyclohexane-1,3′-[3H]Indol]-5′-Yl)-1-Methyl-1H-Pyrrole-2-Carbonitrile Sodium Salt
Example 12 Preparation of 5-(2′-Thixoxspiro[Cyclohexane-1,3′-[3H]Indol]5′-Yl)-1-Methyl-1H-Pyrrole-2-Carbonitrile Choline Salt
1. A method for purifying a compound of formula I: wherein: wherein:
(vi) a five or six membered ring having in its backbone 1, 2, or 3 heteroatoms selected from the group consisting of O, S, SO, SO2 and NR2 and containing one or two substituents independently selected from the group consisting of H, halogen, CN, NO2, amino, C1 to C3 alkyl, C1 to C3 alkoxy, C1 to C3 aminoalkyl, SO2NH2, CORE, and NRFCORE; RE is H, C1 to C3 alkyl, substituted C1 to C3 alkyl, aryl, substituted aryl, C1 to C3 alkoxy, substituted C1 to C3 alkoxy, C1 to C3 aminoalkyl, or substituted C1 to C3 aminoalkyl; RF is H, C1 to C3 alkyl, or substituted C1 to C3 alkyl;
R4 is C1 to C6 alkyl, substituted C1 to C6 alkyl, aryl, or substituted aryl; wherein said method comprises: (a) treating a crude form of a compound of formula I with a base in the presence of a solvent to form a basic salt; and (b) converting said basic salt to a purified form of a compound of formula I.
5. The method according to claim 1, wherein said basic salt is soluble in said solvent.
6. The method according to claim 1, wherein said basic salt is insoluble in said solvent.
7. The method according to claim 1, further comprising isolating said basic salt.
8. The method according to claim 7, wherein said isolated basic salt is dissolved in a solubilizing solvent.
9. The method according to claim 8, wherein said solubilizing solvent is acetone or aqueous acetone.
10. The method according to claim 1, further comprising filtering the product of step (a).
11. The method according to claim 1, wherein said purified compound of formula I is precipitated.
12. The method according to claim 11, wherein said precipitation is performed using an acid.
13. The method according to claim 12, wherein said acid is an organic acid or a mineral acid.
14. The method according to claim 11, wherein said precipitation is performed using water.
15. The method according to claim 11, wherein said precipitation is performed using heat.
16. The method according to claim 1, wherein said step (b) comprises treating said basic salt with an agent that converts said basic salt to said purified compound of formula I.
17. The method according to claim 16, wherein said agent is selected from the group consisting of water, an acid, and heat.
18. The method according to claim 1, further comprising isolating said purified compound of formula I.
19. The method according to claim 1, further comprising recrystallizing said purified compound of formula I.
20. The method according to claim 1, wherein said compound of formula I is selected from the group consisting of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin)-1-methyl-1H-pyrrole-2-carbonitrile, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin)-3-chloro-benzonitrile, 5-(4,4-dimethyl-2-thioxo-1,4-dihydro-benzoxazin)-1-methyl-1H-pyrrole-2-carbonitrile, 6-bromo-4,4-dimethyl-1,4-dihydro-benzoxazin-2-one, 5-(4,4-dimethyl-2-oxo-1,4-dihydro-benzoxazin)-3-fluoro-benzonitrile, and 5-(4,4-diethyl-2-oxo-1,4-dihydro-benzoxazin)-3-chloro-4-fluoro-benzonitrile.
21. The method according to claim 1, wherein said basic salt is selected from the group consisting of 5-(4,4-dimethyl-2-oxo-1,4-dihydro-2H-3,1-benzoxazin-6-yl)-1-methyl-1H-pyrrole-2-carbonitrile sodium salt, 6-bromo-4,4-dimethyl-benzoxazin-2-one sodium salt, and 6-bromo-4,4-dimethyl-benzoxazin-2-one lithium salt.
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Patent Publication Number: 20090143577
Inventors: Bogdan Kazimierz Wilk (New City, NY), Arkadiy Zinoviy Rubezhov (West Nyack, NY), Anthony Francis Hadfield (Ruskin, FL), Jean Louise Helom (Hillsdale, NJ)
Application Number: 12/369,775
Current U.S. Class: Spiro Ring System (514/409); Additional Hetero Ring Which Is Not Part Of The Bicyclo Ring System (514/414); Chalcogen Bonded Directly To Ring Carbon Of The Five-membered Hetero Ring (e.g., Adrenochrome, Etc.) (514/421)
International Classification: A01N 43/318 (20060101); A61K 31/40 (20060101);