Organic compounds -- part of the class 532-570 series – Organic compounds – Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
2000-10-02
2002-06-25
Badio, Barbara P. (Department: 1616)
Organic compounds -- part of the class 532-570 series
Organic compounds
Cyclopentanohydrophenanthrene ring system containing
Reexamination Certificate
active
06410760
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The process of the present invention is a new way to produce androst-4-en-17-carboxylic acid.
2. Description of the Related Art
J. Am. Chem. Soc.,
82, 1709 (1960) discloses the monoethoxalylprogesterone or 21-methoxylalylprogesterone (III).
Tet. Lett.,
36(3) 833 (1995) and
J. Org. Chem.,
50, 1544 (1985) discloses that oxone is a known oxidizing agent. This and other documents discussing oxone's oxidizing properties teaches that oxone oxidation stops at the epoxide or diol stage and it does not cleave double bonds producing carboxylic acids. This includes oxidation of aldehydes to acids, amines to N-oxides, thioethers to sulfoxides or sulfones, alkenes to epoxides, cyclic ketones to lactams. There is no disclosure of the conversion of oxylates to acids.
International Publication WO90/00515 discloses the oxidation of 21-benzylidenepregn-4-ene-3,20-dione with ozone to give a seco steroid, 3,5-secoandrost-5-one-3,17&bgr;-dioic acid. The process of the present invention does not use ozone.
SUMMARY OF INVENTION
Disclosed is a process for the production of 17&bgr;-carboxyandrost-4-en-3-one (IV) or anion thereof, which comprises contacting a steroidal ketone (III) where R
1
is selected from the group consisting of:
(1) —OH,
(2) —OR
1-1
where R
1-1
is:
(a) C
1
-C
6
alkyl,
(b) trimethylsilyl,
(c) —CH
2
-&phgr;,
where R
2
is selected from the group consisting of:
(1) —H,
(2) —OR
2-1
where R
2-1
is:
(a) C
1
-C
6
alkyl,
(b) trimethylsilyl,
(c) &phgr;-,
(d) —CH
2
-&phgr;,
(3) —OH,
(4) C
1
-C
12
alkyl,
(5) C
3
-C
7
cycloalkyl,
(6) —CO—OR
2-3
where R
2-3
is:
(a) C
1
-C
6
alkyl,
(b) C
3
-C
7
cycloalkyl,
(c) -&phgr;,
(7) —CO—NHR
2-3
where R
2-3
is as defined above,
(8) —CO—NR
2-4
R
2-5
where R
2-4
and R
2-5
are the same or different and are C
1
-C
6
alkyl,
(9) -&phgr; optionally substituted with 1 or 2 —F, —Cl, —Br, —CH
3
, —NH
2
, —NO
2
, —OH, —OCH
3
,
(10) C
3
-C
7
cycloalkyl,
(11) C
1
-C
12
alkyl with K
2
SO
5
.KHSO
4
.K
2
SO
4
.
DETAILED DESCRIPTION OF THE INVENTION
The starting material for the process of the present invention is progesterone (I). The C
3
-ketone of progesterone (I) must be protected as is well known to those skilled in the art. It is preferred to protect the C
3
-ketone of progesterone (I) as an enol ether giving the C
3
-protected progesterone (II). The preferred enol ether is the methyl or ethyl enol ether; more preferred is the methyl enol ether.
The C
3
-protected progesterone (II) is then coverted to the corresponding steroidal ketone (i). The steroidal ketone (RD) can be of a number of different types depending on the nature of R
1
and R
2
. For example, when Ris —OH and R
2
is:
—CO—OR
2-3
, the steroidal ketone (III) is the acid derivative
STEROID-CO—CH
2
—CO—COOR
2-3
(IIIa)
alkyl, the steroidal ketone (III) is the ketone
STEROID-CO—CH
2
—CO—[C
1
-C
12
alkyl] (IIIb)
—H, the steroidal ketone (III) is the aldehyde
STEROID-CO—CH
2
—CO—H (IIIc)
-&phgr;, the steroidal ketone (III) is the phenyl derivative
STEROID-CO—CH
2
—CO-&phgr; (IIId)
—OR
2-1
, the steroidal ketone (III) is the ester
STEROID-CO—CH
2
—CO—OR
2-1
(IIIe)
It is readily apparent to those skilled in the art that the steroidal ketone (III) derivatives have corresponding tautomeric forms (III-t)
STEROID-CO—CH=C(OH)—COOR
2-3
(IIIa-t)
STEROID-CO—CH=C(OH)—[C
1
-C
6
alkyl] (IIIb-t)
STEROID-CO—CH=C(OH)—H (IIIc-t)
STEROID-CO—CH=C(OH)-&phgr; (IIId-t)
STEROID-CO—CH=C(OH)—OR
21
(IIIe-t)
The conversion of the C
3
-protected progesterone (II) to the steroidal ketone form (III), and corresponding tautomer form (III-t) is performed my methods well known to those skilled in the art. For example if it is desired to prepare the acid derivative (IIIa), the C
3
-protected progesterone (II) is contacted with a dialkyl oxylate and a basic system such as 25% methoxide/methanol in toluene followed by treatment with an acid such as hydrochloric acid. In fact, the preferred steroidal ketone, monoethoxalylprogesterone or 21-methoxylalylprogesterone (D) is known, see
J. Am. Chem. Soc.,
82, 1709 (1960).
The process of the present invention is performed by contacting the steroidal ketone (III), or tautomer thereof (III-t) with OXONE. OXONE is a trademark of the DuPont Company and refers to K
2
SO
5
.KHSO
4
.K
2
SO
4
; also known as potassium peroxymonosulfate also know as Karo's salt. The process of the present invention can be performed without any base but it is preferred to perform the process of the present invention in the presence of a weak base. The base may be either organic or inorganic. It is important that the base produce a mixture which has a pH of from about 1 to about 10; it is more preferred that the pH of the reaction mixture be from about 4 to about 9; more preferably from about 6 to about 8. Operable weak bases include bases selected from the group consisting of bicarbonate, carbonate, acetate, hydroxide, phosphate, pyridine, pyrrolidine, piperidine, piperazine, N,N-dimethylpiperazine, morpholine, N-methylmorpholine, N-methylpiperidine, dimethylaminopyridine, aniline and trialkylamines where the alkyl portion are the same or different and are C
1
-C
4
, It is preferred that the weak base is bicarbonate, carbonate, acetate and phosphate; it is more preferred that the weak base be aqueous bicarbonate. Operable solvents include water, ethyl acetate, ether, DMF, methylene chloride, THF, C
1
-C
4
methanol, ethanol, propanol, butanol, acetonitrile, acetone, methylisobutylketone, methyl-t-butyl ether and mixtures thereof; it is preferred that the solvent is water, acetonitrile and acetone. The process of the present invention proceeds between about −30° and about 60°; it is preferred that the reaction temperature be between about 0° and about 25°.
When the reaction is determined to be complete as determined by HPLC or TLC with regard to the steroidal ketone starting material (III or III-t), the solids are removed from the crude reaction mixture (preferably by filtration) and the waste cake is rinsed with solvent (preferably acetone). The filtrate is tested for peroxide with starch/iodide paper and quenched as necessary with sodium bisulfite. The pH of the mixture should be adjusted to a pH between 4 and 5 with strong acid (preferably sulfuric acid) and worked-up as is known to those skilled in the art to provide the desired product.
The product, 17&bgr;-carboxyandrost-4-en-3-one (II) also known as oxoetiocholenic acid, 3-oxo-4-etienic acid, androst-4-ene-17-carboxylic acid or 3-oxo-4-androstene-17-&bgr;-carboxylic acid, is known see, U.S. Pat. No. 5,650,526 and
Syn. Lett.,
6, 517-518 (1996).
DEFINITIONS
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
DEFINITIONS
All temperatures are in degrees Centigrade.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
CMR refers to C-13 magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from TMS.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from tetramethylsilane.
THF refers to tetrahydrofuran.
DMSO refers to dimethylsulfoxide.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight
Ashford Scott W.
Grega Kevin C.
Badio Barbara P.
Pharmacia & Upjohn Company
Stein Bruce
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