Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
2002-04-15
2003-01-28
Killos, Paul J. (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C564S191000, C549S330000, C549S434000, C549S439000
Reexamination Certificate
active
06512140
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to novel processes and intermediates for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid.
BACKGROUND OF THE INVENTION
The compound 1-(mercaptomethyl)-cyclopropaneacetic acid and its derivatives are important intermediates for the synthesis of leukotriene antagonists, which are useful in the treatment of asthma and other conditions mediated by leukotrienes, such as inflammation and allergies. A number of leukotriene antagonists are described in European Patent Nos. 480,717 and 604,114, and U.S. Pat. No. 5,270,324. Among the compounds disclosed in these patents are those which include a thiomethylcyclopropaneacetic acid moiety. This moiety is introduced using derivatives of 1-(mercaptomethyl)-cyclopropaneacetic acid.
A number of methods for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid are known, for example in U.S. Pat. Nos. 5,523,477 and 5,534,651. Most known syntheses for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid use either thiolacetic acid or hydrogen sulfide derivatives to introduce the mercapto function. Due to their strong disagreeable odour, the manipulation of these reagents and the corresponding synthetic intermediates is technically demanding. Further, essentially all the key intermediates in these syntheses are liquids or oils, which require either vacuum distillation or column chromatography for purification. In addition, the final step of each of these syntheses involves a hot basic hydrolysis in which the temperature may range from 80° C. to aqueous reflux. Since 1-(mercaptomethyl)-cyclopropaneacetic acid is sensitive to oxidation, the use of such harsh reaction conditions may lead to reduced yields and/or product of unacceptable purity.
Therefore, the need exists for an improved process for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides a novel process for the preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid which avoids the above-described disadvantages of known processes. In the process of the present invention, 1-(mercaptomethyl)-cyclopropaneacetic acid is prepared from 1-(hydroxymethyl)-cyclopropaneacetonitrile, which is commercially available or can be prepared by known methods from readily available reagents.
The process of the present invention essentially comprises four steps, the first step being the conversion of 1-(hydroxymethyl)-cyclopropaneacetonitrile to 5-oxa-spiro[2.4]hept-6-ylideneamine (also referred to herein as the “imino ester”) and acid addition salts thereof, which may be partially or totally converted to 1-(halomethyl)-cyclopropaneacetamide (also referred to herein as the “halo-amide”) under the reaction conditions.
The imino ester and halo-amide intermediates are preferably not isolated, but are reacted in situ with thiourea in the second step of the process to give the novel intermediate 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide, which is preferably isolated in the form of a solid acid addition salt, and optionally purified prior to further reaction.
In the third step of the process, 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide, or a salt thereof, is subjected to basic hydrolysis followed by oxidation in situ to form the disulfide of 1-(mercaptomethyl)-cyclopropaneacetic acid, a solid, which is preferably isolated and purified.
In the fourth and final step, the disulfide is reduced to 1-(mercaptomethyl)-cyclopropaneacetic acid.
Thus, the novel process for synthesizing 1-(mercaptomethyl)-cyclopropaneacetic acid provided by the present invention avoids the use of malodorous reagents such as thiolacetic acid and hydrogen sulfide derivatives, proceeds via solid intermediates which can be isolated and purified prior to further reaction, and avoids the use of a base hydrolysis as the final step in the process. The process according to the invention is therefore capable of producing 1-(mercaptomethyl)-cyclopropaneacetic acid of higher purity than known processes while using simpler techniques for handling reagents and for handling and purifying intermediates.
In another aspect, the present invention provides the novel intermediates 5-oxa-spiro[2.4]hept-6-ylideneamine and acid addition salts thereof and the corresponding 1-(halomethyl)-cyclopropaneacetamide, and a novel process for preparing these intermediates which essentially comprises the first step of the above-described process for preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid.
In yet another aspect, the present invention provides the novel intermediate 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide and acid addition salts thereof, and a novel process for preparing this intermediate which essentially comprises the first two steps of the above-described synthesis for preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid.
In yet another aspect, the present invention provides a novel process for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid disulfide which essentially comprises the first three steps of the above-described synthesis for preparation of 1-(mercaptomethyl)-cyclopropaneacetic acid.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
The following is a detailed description of preferred processes according to the invention for preparing 1-(mercaptomethyl)-cyclopropaneacetic acid.
As mentioned above, the starting material in the process of the present invention is 1-(hydroxymethyl)-cyclopropaneacetonitrile, which is known in the art and may be readily prepared according to known processes. For example, U.S. Pat. No. 5,523,477 discloses a method for preparing 1-(hydroxymethyl)-cyclopropaneacetonitrile from 1,1-cyclopropanedimethanol.
In the first step of the process of the invention, shown below, 1-(hydroxymethyl)-cyclopropaneacetonitrile (I) is treated with an acid to form the corresponding imino ester salt (II), which is partially or completely converted to the corresponding halo-amide (III) under the reaction conditions.
The reaction depicted above is an example of a Pinner Synthesis, generally described in Pinner et al., Ber. 10, 1889 (1877); 11, 4, 11475 (1878); 16, 352, 1643 (1883).
Preferred acids for the reaction with 1-(hydroxymethyl)-cyclopropaneacetonitrile include those selected from the group comprising HBr, HCl, LiBr/H
2
SO
4
, NaBr/ H
2
SO
4
, KBr/H
2
SO
4
, KCl/H
2
SO
4
, NaCl/H
2
SO
4
or LiCl/H
2
SO
4
. It is preferred that about 0.5 to 2 molar equivalents of the acid are used.
The reaction is preferably conducted in an inert solvent or a mixture of solvents, with preferred inert solvents being selected from the group comprising ethyl acetate, isopropyl acetate, acetone, methyl ethtone, methyl isobutyl ketone, propanol, butanol, isopropanol and t-butanol. The reaction temperature preferably ranges from about −10° C. to about 25° C.
In a particularly preferred embodiment of the invention, the acid comprises LiBr(1-1.2 eq)/H
2
SO
4
(0.5-0.65 eq) and the inert solvent comprises isopropyl acetate. This combination produces the bromide salt of the above imino ester intermediate (II) and the bromo amide intermediate (III).
Preferably the intermediates (II) and (III) are not isolated prior to further reaction. Isolation is unnecessary since both species react in a similar manner in the second step of the process, now described below.
The second step of the preferred process, depicted below, comprises reaction of the intermediates (II) and (III) with thiourea to give a salt of 1-(carbamimidoylsulfanylmethyl)-cyclopropaneacetamide (IV), also referred to herein as the “amide-isothiuronium salt”.
Preferably, the second step of the process comprises addition of from about 1 to about 1.5 molar equivalents of thiourea to the reaction mixture of step 1 containing the imidate salt (II) and/or the halo amide (III). The reaction is preferably carried out in an inert solvent or a mixture of inert solvents, with preferred solvents including those selected from the group comprising acetone, ethyl acetate, isopropyl acetate, isopropanol, ethanol and toluene. The
Bydlinski Gregory
Harper Sylvain
Liu Lu Wei
Marrugo Hérika
Quan David D. C.
Delmar Chemicals Inc.
Kirkpatrick & Lockhart LLP
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