Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1999-07-27
2001-09-25
Higel, Floyd D. (Department: 1613)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C548S333500, C548S334500, C514S397000, C514S398000
Reexamination Certificate
active
06294675
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a process for preparing eprosartan. This compound is described in U.S. Pat. No. 5,185,351 as being an angiotensin II receptor antagonist useful in the treatment of hypertension, congestive heart failure and renal failure.
BACKGROUND OF THE INVENTION
U.S. Pat. No. 5,185,351 describes processes for the preparation of imidazole compounds, in particular the preparation of eprosartan. Although the processes described in this patent produce the imidazoles claimed therein, there was a need to improve these processes when preparing compounds, such as eprosartan, on a commercial scale.
It has now been found that eprosartan can be prepared in three stages. These stages are: (Stage†1) the regioselective protection of 2-n-butyl4-formylimidazole; (Stage†2) the reaction between the product from Stage†1 and (2-thienyimethyl)-propanedioic acid, mono-C
1-4
alkyl ester; and (Stage†3) quaternary salt formation, followed by a basic work-up and an acidification. The efficiency of this synthetic sequence and the quality and yield of eprosartan are particularly important when preparing said product on a large scale for therapeutic use.
DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of eprosartan, which is (E)-&agr;-[[2-butyl- 1 -[(4carboxyphenyl)methyl]- 1H-imidazol-5-yl]methylenel]-2-thiophene propanoic acid, a compound of formula (I):
or a pharmaceutically acceptable salt thereof, which process comprises the steps of:
(i) treating a compound of formula (II):
with base, followed by reaction with a regioselective nitrogen-protecting reagent, such as a C
1-4
alkyl ester derivative of acrylic acid;
(ii) reacting the compound of formula (III):
wherein R1 is a nitrogen protecting group either consisting of (1) an ethylene bridge connecting the nitrogen to an electron-withdrawing group, such as an ester (COOR″, where R″=C
1-4
alkyl), acid, carbonyl, nitrile, sulfone, or sulfoxide, or (2) a methylene bridge connecting the nitrogen to a pivalate, 2-(trimethylsilyl)ethoxy, methoxy, tert-butoxy, or benzyloxy, with a compound of formula (IV):
wherein R′ is C
1-4
alkyl, in the presence of a catalyst; and
(iii) reacting the compound of formula (V):
wherein R′ and R1 are as defined above, with a compound of formula (VI):
wherein R″′ is C
1-4
alkyl and X is halo or OR*, in which R* is CH
3
SO
2
— or p—CH
3
C
6
H
4
SO
2
—, at elevated temperatures; and thereafter removing the N-3 protecting group and hydrolyzing the R′ and R″′ ester group, and optionally forming a pharmaceutically acceptable salt.
Acid addition salts of formula (I) are formed with the appropriate inorganic or organic acids by methods known in the art. Representative examples of suitable acids are maleic, fumaric, acetic, succinic, hydrochloric, hydrobromic, sulfuric, phosphoric or methanesulfonic. Preferably, the pharmaceutically acceptable acid addition salt for the formula (I) compound is the methanesulfonic acid addition salt.
Base addition salts of formula (I) are formed with the appropriate inorganic or organic bases by methods known in the art. Cationic salts are prepared by treating the parent compound with an excess of an alkaline reagent, such as hydroxide, carbonate or alkoxide, containing the appropriate cation; or with an appropriate organic amine. Representative examples of cations are Li
+
, Na
+
, K
+
, Ca
++
, Mg
++
and NH
4
+
.
As used herein, C
1-4
alkyl means an alkyl group of 1-4 carbons, branched or unbranched. C
1-4
alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl and t-butyl. The preferred R′ C
1-4
alkyl group is ethyl, the preferred R″ C
1-4
alkyl group is ethyl or methyl and the preferred R″′ C
1-4
alkyl group is ethyl or methyl.
Scheme I, below, summarizes the three stages of the novel synthetic pathway used to prepare eprosartan.
According to Scheme I, 2-n-butyl4-formylimnidazole is treated with a base, such as 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or 1,1,3,3-tetrarnethylguanidine, followed by reaction with a regioselective nitrogen-protecting reagent, such as methyl acrylate, ethyl acrylate, acetyl bromide, chloromethyl pivalate (POM-Cl) or di-tert-butyl dicarbonate, to give derivatization on the least hindered nitrogen atom of the imidazole ring. This reaction can be carried out in ethyl acetate, acetonitrile, toluene, DMF, THF or 1-methyl-2-pyrrolidinone (NMP). Preferably, this reaction is carried out using DBU and methyl acrylate or ethyl acetate in ethyl acetate at 50-60° C. Typically, the Scheme I-1 compound is then reacted with (2-thienylmethyl) propanedioic acid, mono-ethyl ester in a suitable solvent, such as toluene, acetonitrile, DMF, THF, NMP, or DMSO, in the presence of a catalyst, for example, in the presence of piperidine or piperidinium propionate in excess propionic acid, at a suitable temperature, such as a temperature of about 70° C. to about 100° C. Preferably, this reaction is carried out using piperidine in toluene at a reflux temperature of 65° C.-70° C.; this reflux temperature is obtained by placing the reaction mixture under reduced pressure. The quaternary salt of the Scheme I-2 compound is then prepared by reacting this compound with a benzyl halide, such as methyl or ethyl 4-(bromomethyl)benzoate, or a benzyl mesylate or tosylate at elevated temperatures, for example, at temperatures of 100-120° C., preferably at 105-110° C. The ester groups are hydrolyzed and the N-protecting group is removed using, for example, base, such as aqueous sodium or potassium hydroxide, to give eprosartan (Scheme I-3). Thereafter, pharmaceutically acceptable salts may be prepared as described above.
Alternately, eprosartan can be prepared as summarized in Scheme II, below.
According to Scheme II, the order of the first and second steps detailed in Scheme I have been reversed. In this synthetic sequence, 2-n-butyl4-formylimidazole is reacted with (2-thienylmethyl)propanedioic acid, mono-ethyl ester in the presence of a catalyst, and then the product from this reaction is regioselectively N-protected. Quatemization and basic work-up is carried out as detailed in Scheme I to give eprosartan.
Also included in the scope of the present invention are the novel intermediates used in the preparation of eprosartan. These intermediates are described hereinbefore.
REFERENCES:
patent: 5185351 (1993-02-01), Finkelstein et al.
patent: 5418250 (1995-05-01), Finkelstein et al.
patent: 5444080 (1995-08-01), Girard et al.
patent: 0 403 159 A2 (1990-06-01), None
patent: WO 92/10189 (1992-06-01), None
Keenan, et al., J. Med. Chem., 1993, vol. 36, pp. 1880-1892, abstract No. XP-002100935.
Keenan, et al., J. Med. Chem., 1992, vol. 35, pp. 3858-3872, abstract No. XP-002153508.
Shilcrat, et al., J. Med. Chem., 1997, vol. 62, pp. 8449-8454, abstract No. XP-002153509.
Liu Peng
Matsuoka Richard T.
Higel Floyd D.
Kinzig Charles M.
McCarthy Mary E.
SmithKline Beecham Corporation
Venetianer Stephen A.
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