AP403A - N-t-butyl-androst-3,5-diene-17b-carboxyamide-3-carboxylic acid polymorph A. - Google Patents
N-t-butyl-androst-3,5-diene-17b-carboxyamide-3-carboxylic acid polymorph A. Download PDFInfo
- Publication number
- AP403A AP403A APAP/P/1993/000497A AP9300497A AP403A AP 403 A AP403 A AP 403A AP 9300497 A AP9300497 A AP 9300497A AP 403 A AP403 A AP 403A
- Authority
- AP
- ARIPO
- Prior art keywords
- polymorph
- diene
- androst
- carboxylic acid
- carboxamide
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0066—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 the 17-beta position being substituted by a carbon atom forming part of an amide group
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Steroid Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Polymorph
Description
N-T-BU2XL-ANDRQST-3.5-DIENE-17a-CARBQXAMIDE-3-CARBOXYT.IC
ACID POLYMORPH A
The present invention relates to a novel polymorphic form of N-t-butyl-androst-3,5-diene-17flcarboxamide-3-carboxylic acid.
Brief Description of the Drawings
Figure I is an Infra-red Spectrum of N-t-butylandrost-3, 5-diene-17fl-carboxylic acid polymorph A.
Figure II is an enhanced FT-IR spectra of the 33993501 cm-1 region of Polymorph A disclosing the characteristic N-H stretch of Polymorph A.
Detailed Description of the Invention
N-t-butyl-androst-3,5-diene-17fl-carboxamide-3carboxylic acid is a compound which is disclosed and claimed as being useful in the treatment of benign prostatic hypertrophy in U.S. Patent No. 5,017,568, the entire disclosure of which is incorporated by reference.
Said compound can be prepared by methods such as described in U.S. Patent No. 5,017,568. The isolation
BAD ORIGINAL ffl
APO00403
- 2 and identification of the polymorphic forms of said compound is advantageous in identifying desirable physical characteristics of the different crystal forms of said compound.
It has now been found that a polymorphic form (hereinafter Polymorph A) of the compound N-t-butylandrost-3,5-diene-17B-carboxamide-3-carboxylic acid can be obtained in a high state of polymorphic purity by triturating, by crystallizing or by precipitating said compound from a solvent consisting of or primarily consisting of ethyl acetate or from a solvent consisting of or primarily consisting of t-butyl methyl ether. The substantially pure polymorphic A form of said compound can also obtain by trituration, by crystallization or by precipitation from N-butyl acetate and isopropyl acetate. Contemplated herein is the process of obtaining substantially pure polymorph A from a solvent consisting of or primarily consisting of an organic solvent or a combination of organic solvents which contain an acetate substituent.Also, contemplated herein is the process of obtaining substantially pure polymorph A by trituration, by crystallizing or by precipitating said compound from a solvent consisting of or primarily consisting of an organic solvent which contains an acetate group, preferably ethyl acetate, and t-butyl methyl ether. Typically, a slurry of crude N-t-butylandrost-3,5-diene-17B-carboxamide-3-carboxylic acid is stirred at above ambient temperature in a solvent consisting primarily of ethyl acetate. Preferably a 1240% by weight slurry of N-t-butyl-androst-3,5-diene-17Bcarboxamide-3-carboxylic acid in ethyl acetate is warmed above ambient temperature, preferably in the range of 65-70°C, and stirred, preferably for about an hour, followed by filtration which is typically conducted below ambient temperature, preferably in the range of 05°C. Most preferably said slurry is a 14-20% slurry.
bad original $
Presently, N-t-butyl-androst-3,5-diene-17Bcarboxamide-3-carboxylic acid is known to assume only two polymorphic forms, A and B.
Polymorph A and Polymorph B were individually 5 subjected to intense grinding in a mortar with a pestle for a period of approximately five minutes. Infra-red spectral absorbencies of the post-grinding Polymorph B compound indicated that approximately 5-10% of said polymorph had converted to the Polymorph A form. Infra10 red spectral absorbencies of the post-grinding Polymorph A compound indicated retention of polymorphic identity and purity. The above findings indicate that the polymorphic A form of N-t-butyl-androst-3, 5-diene-17ficarboxamide-3-carboxylic acid is thermodynamically more stable than the polymorphic B form. The themodynamically more stable polymorphic form of a compound is advantageous for maintaining crystal integrity during manufacture, storing, shipping and handling of solid compositions of said compound. Since, as described above, the polymorphic B form of N-t-butylandrost-3, 5-diene-17B-carboxamide-3-carboxylic acid does not retain its crystal integrity upon grinding and the polymorphic A form retains crystal integrity, Polymorph
C A is particularly advantageous in the manufacture of tableted forms of N-t-butyl-androst-3,5-diene-17Bcarboxamide-3-carboxylic acid.
By the term crude as used herein is meant that the isolated N-t-butyl-androst-3,5-diene-17Bcarboxamide-3-carboxylic acid starting material exist as an amorphous solid, in an undesired polymorphic form or as a plurality of polymorphic forms.
By the term N-t-butyl-androst-3,5-diene-17Bcarboxamide-3-carboxylic acid as used herein is meant a
APOOO 40 3
N-t-butyl-androst-3,5-diene-17fi-carboxamide-3carobxylic acid polymorph A (prepared by crystallization from ethyl acetate) was analyzed by an X-ray powder diffraction (X-ray diffractometry (XRD) obtained from Micron Incorporated of Wilmington, Delaware) . The characteristic d-spacings, intensities, and 2-theta values for the diffraction pattern of Polymorph A are listed in Table 1 below.
Table 1
X-Ray diffraction pattern listing of N-t-butyl-androst3, 5-diene-17S-carboxamide-3-carboxylic acid Polymorph A.
| D | I/IMAX | 2Theta | PK WIDTH | |
| 1 | 19.12558 | 76.46 | 4.620 | 0.00 |
| 2 | 10.64122 | 2.44 | 8.309 | 0.00 |
| 3 | 9.42222 | 6.60 | 9.386 | 0.00 |
| 4 | 8.72598 | 2.26 | 10.137 | 0.00 |
| 5 | 7.47791 | 12.67 | 11.835 | 0.00 |
| 6 | 6.80494 | 19.00 | 13.010 | 0.00 |
| 7 | 6.14523 | 27.60 | 14.413 | 0.00 |
| 8 | 5.95738 | 47.09 | 14.871 | 0.00 |
| 9 | 5.49032 | 35.12 | 16.144 | 0.00 |
| 10 | 4.91804 | 34.76 | 18.037 | 0.00 |
| 11 | 4.44050 | 25.31 | 19.996 | 0.00 |
| 12 | 4.28147 | 14.11 | 20.746 | 0.00 |
| 13 | 4.09672 | 14.41 | 21.693 | 0.00 |
| 14 | 4.01321 | 19.43 | 22.150 | 0.00 |
| 15 | 3.71622 | 6.71 | 23.946 | 0.00 |
| 16 | 3.47394 | 6.11 | 25.643 | 0.00 |
| 17 | 3.30066 | 4.51 | 27.014 | 0.00 |
| 18 | 3.23171 | 4 .04 | 27.602 | 0.00 |
| 19 | 2.75384 | 1.93 | 32.514 | 0.00 |
| 20 | 2.67300 | 2.36 | 33.526 | 0.00 |
| 21 | 2.51415 | 1.96 | 35.713 | 0.00 |
| 22 | 2.20969 | 2.68 | 40.838 | 0.00 |
The following example illustrates preparation of Nt-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylie acid polymorph A. The example is not intended to limit the scope of the invention as defined hereinabove and as claimed below.
Example 1
N-t-butyl-androst-3,5-dlene-17fi-carboxamide-3-carboxylic acid. Polymorph A
6.4 g of crude N-t-butyl-androst-3,5-diene-17Bcarboxamide-3-carboxylic acid was added to 38.4 ml of ethyl acetate. The resulting slurry was warmed, with stirring, at about 65-70°C for about two hours. The resulting slurry was cooled to about 0-5°C for 1 hour, and was filtered and washed with 5-10 ml of cold ethyl acetate. The product was filtered dried under vacuum at about 50°C to afford 5 grams of substantially pure N-tbutyl-androst-3, 5-diene-176-carboxamide-3-carboxylie acid in its polymorph form. The infra-red spectrum of the product is shown in Figures 1 and 2.
Infra-red spectral absorbancies of N-t-butylandrost-3, 5-diene-17fi-carboxamide-3-carboxylic acid polymorph A (prepared by crystallization from ethyl acetate) were obtained. (spectrum obtained from Nujol
AP Ο Ο Ο 4 Ο 3
- 6 (mineral oil) on sodium chloride plates, (apparatus, Nicolet 6000 FT-IR using a mercury cadmium telluride detector, analysis time 7.6 minutes (800 scans), Enhancement Program Nicolet 1RDCON) .
Characteristic polymorph A form bands occur at 3441 cm-1 (N-H stretch); 1678 cm-1 (acid C=O stretch); and 1662 cm”l (amide C=O stretch). An FT-IR spectra of polymorph A is shown in Figure 1 below. The resolution enhanced FT-IR spectra of the 3399-3501 cm“l region disclosing said characteristic N-H stretch of polymorph A is shown in Figure 2 below.
ιη'·Υ oesrs-p:
' C ν“< Λ· \ , t , > ·5
Η Ί ' ·' » Mr ,;.·.
♦ο βε '-''’W ΡΛ»Τι,-.„λ, Οβε Ρ£«ΑΟ«Μ£Ο. VWE DEClIrc~ '
- 7 - ν 6 DECLARE THAI ν.( .<,
| What is claimed is: | ||
| 1. A compound of | the st | ructure |
| 11 JM HO-C^ | NCHXXCH,), H |
Claims (8)
- - 7 - ν 6 DECLARE THAI ν.( .<,
What is claimed is: 1. A compound of the st ructure 11 JM HO-C^ NCHXXCH,), H substantially in the polymorph A form. - 2. A compound according to claim 1 having the infra-red spectrum as shown in Figure 1 and the x-ray diffraction pattern listing shown in Table 1.
- 3. A compound according to claim 1 having the infra-red spectrum as shown in Figure 2 and the x-ray diffraction pattern listing shown in Table 1.
- 4. A process for preparing a compound of the structure substantially in the polymorph A form, which comprises triturating, crystallizing or precipitating crude N-tbutyl-androst-3,
- 5-diene-17B-carboxamide-3-carboxylie acid from a solvent consisting of or primarily consisting of ethyl acetate or from a solvent consisting of or primarily consisting of t-butyl methyl ether with subsequent isolation of said polymorph.BAD ORIGINAL &APOOO403- β 5. A process according to claim 4 which comprises stirring a slurry of crude N-t-butyl-androst-3,5-diene17S-carboxamide-3-carboxylic acid in a solvent, consisting primarily of ethyl acetate, at above ambient temperature with subsequent isolation of said polymorph.
- 6. A process according to claim 5 which comprises stirring a 12-40% by weight slurry of the crude N-tbutyl-androst-3, 5-diene-17B-carboxamide-3-carboxylie acid in ethyl acetate for about an hour at a temperature above 60°C, then stirring said slurry at a temperature from about 0-5°C with subsequent isolation of said polymorph .
- 7. A process according to claim 6 which comprises stirring a 14-20% by weight slurry of the crude N-tbutyl-androst-3, 5-diene-17fi-carboxamide-3-carboxylic acid in ethyl acetate for over an hour at a temperature above 60°C, then stirring said slurry at a temperature from about 0-5°C with subsequent isolation of said polymorph.
- 8. A process for perparing a compound of the structure substantially in the polymorph A form, which comprises triturating, crystallizing or precipitating crude N-tbutyl-androst-3, 5-diene-17fi-carboxamide-3-carboxylic acid from a solvent consisting of or primarilyBAD ORIGINAL ft consisting of ethyl acetate and t-butyl methyl ethyl with subsequent isolation of said polymorph.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB929206413A GB9206413D0 (en) | 1992-03-24 | 1992-03-24 | N-t-butyl-androst-3,5-diene-17b-carboxamide-3-carboxylic acid polymorph a |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| AP9300497A0 AP9300497A0 (en) | 1993-04-30 |
| AP403A true AP403A (en) | 1995-08-24 |
Family
ID=10712749
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| APAP/P/1993/000497A AP403A (en) | 1992-03-24 | 1993-03-18 | N-t-butyl-androst-3,5-diene-17b-carboxyamide-3-carboxylic acid polymorph A. |
Country Status (29)
| Country | Link |
|---|---|
| EP (1) | EP0633892B1 (en) |
| JP (1) | JP2736169B2 (en) |
| CN (1) | CN1078723A (en) |
| AP (1) | AP403A (en) |
| AT (1) | ATE180490T1 (en) |
| AU (1) | AU669522B2 (en) |
| BG (1) | BG99062A (en) |
| BR (1) | BR9306139A (en) |
| CA (1) | CA2132535A1 (en) |
| CZ (1) | CZ286266B6 (en) |
| DE (1) | DE69325094T2 (en) |
| DK (1) | DK0633892T3 (en) |
| ES (1) | ES2134260T3 (en) |
| FI (1) | FI114709B (en) |
| GB (1) | GB9206413D0 (en) |
| GR (1) | GR3030779T3 (en) |
| HU (1) | HUT68120A (en) |
| IL (1) | IL105102A (en) |
| MA (1) | MA22841A1 (en) |
| MX (1) | MX9301656A (en) |
| NO (1) | NO943547D0 (en) |
| NZ (1) | NZ252008A (en) |
| OA (1) | OA10100A (en) |
| PL (1) | PL172523B1 (en) |
| RU (1) | RU94041839A (en) |
| SI (1) | SI9300140A (en) |
| SK (1) | SK113894A3 (en) |
| WO (1) | WO1993019081A1 (en) |
| ZA (1) | ZA932014B (en) |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4910226A (en) * | 1987-04-29 | 1990-03-20 | Smithkline Beckman Corporation | Steroid 5-alpha-reductase inhibitors |
| IL104602A (en) * | 1992-02-07 | 1997-07-13 | Smithkline Beecham Corp | Process for the preparation of 3-carbonylandrostadiene- 17-carboxamides and intermediates for this process |
-
1992
- 1992-03-24 GB GB929206413A patent/GB9206413D0/en active Pending
-
1993
- 1993-03-18 IL IL10510293A patent/IL105102A/en not_active IP Right Cessation
- 1993-03-18 AP APAP/P/1993/000497A patent/AP403A/en active
- 1993-03-22 ZA ZA932014A patent/ZA932014B/en unknown
- 1993-03-23 MA MA23136A patent/MA22841A1/en unknown
- 1993-03-23 SI SI19939300140A patent/SI9300140A/en unknown
- 1993-03-24 CN CN 93103518 patent/CN1078723A/en active Pending
- 1993-03-24 PL PL93305206A patent/PL172523B1/en unknown
- 1993-03-24 NZ NZ252008A patent/NZ252008A/en unknown
- 1993-03-24 RU RU94041839/04A patent/RU94041839A/en unknown
- 1993-03-24 AU AU40448/93A patent/AU669522B2/en not_active Ceased
- 1993-03-24 DK DK93911567T patent/DK0633892T3/en active
- 1993-03-24 WO PCT/US1993/002974 patent/WO1993019081A1/en active IP Right Grant
- 1993-03-24 HU HU9402740A patent/HUT68120A/en unknown
- 1993-03-24 SK SK1138-94A patent/SK113894A3/en unknown
- 1993-03-24 EP EP93911567A patent/EP0633892B1/en not_active Expired - Lifetime
- 1993-03-24 CA CA002132535A patent/CA2132535A1/en not_active Abandoned
- 1993-03-24 ES ES93911567T patent/ES2134260T3/en not_active Expired - Lifetime
- 1993-03-24 BR BR9306139A patent/BR9306139A/en not_active Application Discontinuation
- 1993-03-24 JP JP5516858A patent/JP2736169B2/en not_active Expired - Fee Related
- 1993-03-24 MX MX9301656A patent/MX9301656A/en unknown
- 1993-03-24 DE DE69325094T patent/DE69325094T2/en not_active Expired - Fee Related
- 1993-03-24 AT AT93911567T patent/ATE180490T1/en not_active IP Right Cessation
- 1993-03-24 CZ CZ19942319A patent/CZ286266B6/en not_active IP Right Cessation
-
1994
- 1994-09-20 OA OA60561A patent/OA10100A/en unknown
- 1994-09-23 NO NO943547A patent/NO943547D0/en unknown
- 1994-09-23 FI FI944414A patent/FI114709B/en active
- 1994-09-26 BG BG99062A patent/BG99062A/en unknown
-
1999
- 1999-07-14 GR GR990401866T patent/GR3030779T3/en unknown
Non-Patent Citations (2)
| Title |
|---|
| Bioorganic Chemistry, 1989, METCALF et al. pp. 372-376 * |
| Journal of Steroid Biochemistry, 1989, LEVY et al. pp. 571-575 * |
Also Published As
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CA2634811C (en) | Novel modifications to 2-amino-4-(4-fluorobenzylamino) -1- ethoxycarbonyl-aminobenzene and processes for preparing said compound | |
| SK6298A3 (en) | Crystalline [r-(r*,r*)]-2-(4-fluorophenyl)-beta,delta-dihydroxy- -5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1h-pyrrole- -1-heptanoic acid hemi calcium salt (atorvastatin) | |
| KR20000019206A (en) | Preparing process of crystal form ii of clarithromycin | |
| DE112012004944T5 (en) | Crystalline forms of cabazitaxel and their method of preparation | |
| AP403A (en) | N-t-butyl-androst-3,5-diene-17b-carboxyamide-3-carboxylic acid polymorph A. | |
| WO2005123721A2 (en) | Amorphous and polymorphic forms of candesartan cilexetil | |
| DE2153813A1 (en) | Phenylalanine amides | |
| US5504207A (en) | Process and intermediate for the preparation of terazosin hydrochloride dihydrate | |
| US5596109A (en) | N-t-butyl-androst-3,5-diene-17β-carboxamide-3-carboxylic acid polymorph A | |
| US5859266A (en) | "N-T-butyl-androst-3-5-diene-17 β-carboxamide-3-carboxylic" acid polymorph A | |
| CA2187128A1 (en) | New and useful polymorph of anhydrous paroxetine hydrochloride | |
| US9981985B2 (en) | Pharmaceutical formulations containing 3-(4-cinnamyl-l-piperazinyl) amino derivatives of 3-formylrifamycin SV and 3-formylrifamycin S and a process of their preparation | |
| CN108440626A (en) | The crystal form and preparation method thereof of 5 '-O-L- valinate hydrochlorides of cytarabine | |
| US7393964B2 (en) | Process for the preparation of norelgestromin | |
| US20070167477A1 (en) | Processes to prepare finasteride polymorphs | |
| JP4307594B2 (en) | Method for isolating 1- [N2-((S-ethoxycarbonyl) -3-phenylpropyl) -N6-trifluoroacetyl] -L-lysyl-L-proline and isolated product thereof | |
| EP0643722A1 (en) | N-T-BUTYL-ANDROST-3,5-DIENE-17$g(b)-CARBOXAMIDE-3-CARBOXYLIC ACID POLYMORPH B | |
| AT227688B (en) | Process for the preparation of new derivatives of 1,2,3,4-tetrahydronaphthyl-2-amine and their salts | |
| Evans | Synthesis and properties of N-Phenyl derivatives of 4, 4'-Diaminobenzophenone | |
| JPH07103115B2 (en) | Method for crystallizing 2- (10,11-dihydro-10-oxodibenzo [b, f] thiepin-2-yl) propionic acid | |
| PL216883B1 (en) | Method for manufacturing crystalline form Ó of additive salt of metanesulphonic acid and 4-(4-methylpiperazin-1-yl methyl)-N-[4-methyl-3-[(4-pyridin-3-yl)pyrimidin-2-yl amine] phenyl] benzamide | |
| JPS5821661A (en) | Sulfonate derivative and its preparation |