Cross-Reference to Related Applications

[0001] This application claims the benefit of U.S. Provisional Patent Application Serial No. 63/288,802 filed on December 13, 2021, which is incorporated by reference herein in its entirety.

Technical Field

[0002] The present invention relates generally to a simplified process for the preparation of dimethyl alpha-propargyl homoterephthalate via a three step process mechanism which, among other things, is an intermediate in the production of pralatrexate which has proven effective in treatment of people with relapsed or refractory peripheral T- cell lymphoma,

Background Art

[0003] Pralatrexate is a dihydrofolate reductase inhibitor which has been found to be effective in the treatment of relapsed or refractory' peripheral T-cell lymphoma (PTCL), an aggressive type of non-Hodgkins lymphoma. When pralatrexate was approved for medical use in the United States in September 2009, it was the first treatment approved treatment for PTCL, and it is currently sold under the brand name FOLOTYN® by Acrotech Biopharma, LLC. More recently, pralatrexate is being considered as a potential treatment of persons infected with the novel coronavirus, COVID-19.

[0004] Unfortunately, as with many cutting edge pharmaceuticals, the cost of treatment with pralatrexate is very' expensive. Treatment has been reported to cost in the range of about $30,000 per month, and well over $100,000 over the entire course of a treatment regimen. As will be appreciated, this is simply cost prohibitive to many people who could benefit from treatment with this potentially life saving drug.

[0005] One factor believed to drive up the cost of manufacturing pralatrexate is the rather complicated process to obtain an essential intermediate compound, namely, dimethyl alpha-propargyl homoterephthalate. Specifically, the current process for the production of dimethyl alpha-propargyl homoterephthalate is complex and, thus, expensive. The current process for obtaining dimethyl alpha-propargyl homoterephthalate first requires the formation of a paracarboxyphenyl acetic acid. Once the acid intermediate is obtained, which is a complex and costly process in and of itself, an esterification step is required followed by alkylation with excess propargyl bromide which produces a final mixture of mono alkyl, dialkyl and other diesters. To avoid performing a tedious separation of the mixture of esters, which contains only about 60-65% of the desired monopropargyl intermediate, the mixture is treated with 2,4-di amino-6-bromomethyl-pteridine. Only the monopropargyl diester reacts with the bromomethyl reagent. The desired product is readily obtained, but the yield is diminished accordingly by about 35-40%.

[0006] The combination of the need to form an acetic acid intermediate and the subsequent separation of a low' yield final product is believed to considerably impact the cost of manufacturing pralatrexate, and thus, the overall cost to those whose lives may be saved but for the cost of treatment with pralatrexate.

[0007] Accordingly, there is an established need for a simpler and more cost effective process for producing a potentially life saving pharmaceutical.

Summary of the Invention

[0008] The present invention is directed generally to a simplified and more cost effective process for the preparation of dimethyl alpha-propargyl homoterephthalate via a three step process mechanism w'hich, among other things, is an intermediate in the production of pralatrexate w-hich has proven effective in treatment of people with relapsed or refractory peripheral T-cell lymphoma.

[0009] In a first implementation of the invention, a process for the preparation of dimethyl alpha-propargyl homo terephthalate may comprise: a first process step including arylation of a diester to form a first intermediate compound; a second process step comprising alkylation of the first intermediate compound to form a second intermediate compound; and, a third process step including decarbomethoxylation of the second intermediate compound resulting in formation of the dimethyl alpha-propargyl homoterephthalate.

[0010] In a second aspect, the process for the preparation of dimethyl alpha-propargyl homoterephthalate can include a first process step comprising arylation of a diester of a malonic acid.

[0011] In another aspect, the process for the preparation of dimethyl alpha-propargyl homoterephthalate may have a first process step comprising arylation of dimethyl malonate.

[0012] In a further aspect, the process for the preparation of dimethyl alpha-propargyl homoterephthalate can include a first process step comprising' arylation of dimethyl malonate with methyl 4-iodobenzoate to form a first intermediate compound.

[0013] In one other aspect, the process for the preparation of dimethyl alpha-propargyl homoterephthalate may have a first intermediate compound comprising dimethyl 4- carbomethoxy phenyl malonate.

[0014] In yet another aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate can include a second process step comprising alkylation of a first intermediate compound with propargyl bromide to form a second intermediate compound.

[0015] In still one further aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate may have a second process step comprising alkylation of dimethyl 4-carbomethoxy phenyl malonate with propargyl bromide to form a second intermediate compound.

[0016] In yet one other aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate can include a second intermediate compound comprising dimethyl propargyl 4-methoxycarbonyl phenyl malonate.

[0017] In still another aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate may have a third process step comprising decarbomethoxylation of a second intermediate compound. [0018] In yet one further aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate can include a third process step comprising decarbomethoxylation of a second intermediate compound, wherein the second intermediate compound comprises a propargyl malonate compound,

[0019] In still one other aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate may have a third process step comprising decarbomethoxylation of dimethyl propargyl 4-methoxy carbonyl phenyl malonate.

[0020] In yet another aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate can include a third process step comprising decarbomethoxylation of a second intermediate compound with lithium chloride and dimethyl sulfoxide.

[0021] In still one further aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate may have a third process step comprising decarbomethoxylation of a second intermediate compound with lithium chloride and dimethyl sulfoxide, wherein the second intermediate compound comprises a propargyl malonate compound.

[0022] In yet one other aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate can include a third process step comprising decarbomethoxylation of a second intermediate compound with lithium chloride and dimethyl sulfoxide, wherein the second intermediate compound comprises dimethyl propargyl 4-methoxy carbonyl phenyl malonate.

[0023] In still another aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate may comprise: a first process step including arylation of a diester of a malonic acid with methyl 4-iodobenzoate to form a first intermediate compound; a second process step comprising alkylation of the first intermediate compound with propargyl bromide to form a second intermediate compound; and, a third process step including decarbomethoxylation of the second intermediate compound with lithium chloride and dimethyl sulfoxide resulting in formation of dimethyl alpha-propargyl homoterephthalate. [0024] In yet one further aspect, the process for the preparation of dimethyl alphapropargyl homoterephthalate can include: a first process step including arylation of dimethyl malonate with methyl 4-iodobenzoate to form dimethyl 4-carbomethoxy phenyl malonate; a second process step comprising alkylation of dimethyl 4-carbomethoxy phenyl malonate with propargyl bromide to form dimethyl propargyl 4-methoxy carbonyl phenyl malonate; and, a third process step including decarbomethoxylation of dimethyl propargyl 4-methoxycarbonyl phenyl malonate with lithium chloride and dimethyl sulfoxide resulting in formation of dimethyl alpha-propargy l homoterephthalate.

[0025] These and other objects, features, and advantages of the present invention will become more readily apparent from the attached drawings and the detailed description of the embodiments, which follow'.

Description of Embodiments

[0026] The following detailed description is merely exemplars' in nature and is not intended to limit the described embodiments or the application and uses of the described embodiments. As used herein, the word “exemplary” or ‘illustrative” means “serving as an example, instance, or illustration.” Any implementation described herein as “exemplary” or “illustrative” is not necessarily to be construed as preferred or advantageous over other implementations. All of the implementations described below' are exemplary implementations provided to enable persons skilled in the art to make or use the embodiments of the disclosure and are not intended to limit the scope of the disclosure, which is defined by the claims. Furthermore, there is no intention to be bound by any expressed or implied theory' presented in the preceding technical field, background, brief summary' or the following detailed description. It is also to be understood that the specific devices and processes illustrated in the atached drawings, and described in the following specification, are simply exemplary embodiments of the inventive concepts defined in the appended claims. Hence, specific dimensions and other physical characteristics relating to the embodiments disclosed herein are not to be considered as limiting, unless the claims expressly state otherwise.

[0027] As before, the present invention is directed to a simplified and more cost effective process for the preparation of dimethyl alpha-propargyl homoterephthalate via a three step process mechanism which, among other things, is an intermediate in the production of pralatrexate which has proven effective in treatment of people with relapsed or refractory peripheral T-cell lymphoma.

[0028] More in particular, in one embodiment, the present process for the preparation of dimethyl alpha-propargyl homoterephthalate comprises a three step process mechanism. The first step in the process mechanism is the arylation of a diester. In at least one embodiment, the first step in the preparation of dimethyl alpha-propargyl homoterephthalate in accordance with the present invention comprises arylation of a di ester of a malonic acid, for example, dimethyl malonate.

[0029] In yet one further embodiment, the present process for the preparation of dimethyl alpha-propargyl homoterephthalate begins with the arylation of dimethyl malonate with methyl 4-iodobenzoate to form a first intermediate compound. The result of this first step in the process mechanism in at least one embodiment is the formation of a first intermediate compound, specifically, the formation of dimethyl 4-carbomethoxy phenyl malonate, which is utilized as the starting point in the second step of the process mechanism as described in more detail hereinafter.

[0030] The second step in the process mechanism for the preparation of dimethyl alpha-propargyl homoterephthalate in accordance with the present invention comprises alkylation of a diester. In one embodiment, the second step of the process mechanism includes alkylation of a first intermediate diester compound. More in particular, the present process for the preparation of dimethyl alpha-propargyl homoterephthalate in at least one embodiment comprises alkylation of dimethyl 4-carbomethoxy phenyl malonate to form a second intermediate compound.

[0031] The result of the second step in the process mechanism in at least one embodiment is the formation of a second intermediate compound, specifically, the formation of dimethyl propargyl 4-methoxycarbonyl phenyl malonate, which is utilized as a starting point in the third step of the process mechanism as described in more detail hereinafter. [0032] The third and final step in the process mechanism for the preparation of dimethyl alpha-propargyl homoterephthalate in accordance with at least one embodiment of the present invention comprises decarbomethoxylation of a propargyl malonate compound. In one embodiment, the third and final step of the process mechanism includes decarbomethoxylation of a second intermediate propargyl malonate compound. More in particular, the third step in the process mechanism of present process, in at least one embodiment, comprises the decarbomethoxylation of dimethyl propargyl 4- methoxy carbonyl phenyl malonate to form dimethyl alpha-propargyl homoterephthalate.

EXAMPLE

[0033] The following is an illustrative example of one embodiment of the present process for the preparation of dimethyl alpha-propargyl homoterephthalate via a three step process mechanism, such as is described hereinabove.

PROCESS MECHANISM - FIRST STEP

[0034] The first step in the preparation of dimethyl alpha-propargyl homoterephthalate in accordance with at least one embodiment of the present invention begins with the acylation of dimethyl malonate with methyl 4-iodobenzoate to form a first intermediate compound, namely dimethyl 4-carbomethoxy phenyl malonate, as is represented by Reaction Equation 1 presented below:

* The substituents on the benzene rings in each of the reaction equations presented herein are at the 1,4- (para-) position, however, due to the limitations of word processing they are not able to be precisely presented herein. [0035] In one example, an amount of about 4.6 milliliters of dimethyl malonate, which is equivalent to about 5.3 grams or 0.04 moles, is added dropwise to a stirred suspension of 1.6 grams of 60% sodium hydride in oil, also equivalent to about 0.04 moles. The sodium hydride mixture is in about 50 milliliters of dry dioxane which is cooled in an ice bath to a temperature of about 0° Celsius to about 5° Celsius. Following the addition of the dimethyl malonate the mixture is removed from the ice bath and stirred until gas evolution has ceased.

[0036] At this point, an amount of about 7.6 grams of cuprous iodide, also equivalent to about 0.04 moles, is added to the mixture followed by about 5.2 grams of methyl 4- iodobenzoate, which is equivalent to about 0.02 moles. This mixture is stirred under reflux for about 6 hours, after which it is cooled, and the pH is adjusted to about 5 with acetic acid, and the mixture is evaporated in vacuo. A molar ratio of about 2 to 1 cuprous iodide to methy l 4-iodo benzoate is utilized to obtain the desired product.

[0037] About 50 milliliters each of water and ether are added to the vacuum dried mixture. The solution is thoroughly stirred and is allowed to stand and separate into layers after mixing, and a first ether layer is decanted and saved. A second extraction in about 25 milliliters of ether is conducted, and a second ether layer is decanted and added to the first ether layer. This first combined ether extract is washed with 15 milliliters of saturated sodium bicarbonate followed by about 20 milliliters of water. The washed combined ether extract is dried over magnesium sulfate resulting in about 6.2 grams of a white semisolid. The resultant white semisolid is washed with about 25 milliliters of hexane to remove oil, after which, about 4.9 grams of dried residue remains.

[0038] The dried residue is treated with about 10 milliliters of ether and placed in a freezer for about 24 hours at a temperature of about -20° Celsius. The ether is decanted and saved leaving a solid w'hite cry stalline material w-hich is washed with another 10 milliliters of ether, which is also decanted and combined with the first. The white crystalline solid is dried to leave about 1.2 grams of 4-iodobenzoate.

[0039] The second combined ether extract is evaporated and the remaining residue is treated with about 20 milliliters of 10% methanol and the mixture is allowed to stand for about 1 hour at room temperature. The aqueous portion is decanted from the remaining solid material and discarded. Lastly, the remaining solid material is dried resulting in about 2.3 grams of dimethyl 4-carbomethoxy phenyl malonate, which is referenced herein as the first intermediate compound. The yield of the first intermediate compound from dimethyl malonate in accordance with the first step of the process mechanism disclosed above is about 43%.

[0040] Upon testing the first intermediate compound prepared via the first step of the process mechanism as presented hereinabove via infrared spectroscopy, it is determined to be equivalent to dimethyl 4-carbomethoxy phenyl malonate prepared by decarbonylation of 2-methoxalyl dimethyl homoterephalate, as represented in Reaction Equation 2 below:

PROCESS MECHANISM - SECOND STEP

[0041] The process mechanism of at least one embodiment of the present process for the preparation of dimethyl alpha-propargyl homoterephthalate continues with a second step, the alkylation of a first intermediate compound, namely, the alkylation of dimethyl 4- carbomethoxy phenyl malonate to produce dimethyl propargyl 4-methoxycarbonyl phenyl malonate, as is represented below in Reaction Equation 3:

[0042] To begin, about 50 milliliters of dry tetrahydrofuran is added to a suspension containing about 2.0 grams of 60% sodium hydride in oil, about 0.05 moles, at a temperature of about 0° Celsius to about 5° Celsius. This initial mixture is stirred for about 10 minutes after which a solution of about 12.7 grams of the first intermediate compound, i.e., about 12.7 grains of dimethyl 4-carbomethoxy phenyl malonate, which is equivalent to about 0.048 moles, in about 40 milliliters of tetrahydrofuran is added dropwise over a period of about 15 minutes under continuous stirring, until gas evolution ceases.

[0043] A solution of about 7.9 grams of 80% by weight of propargyl bromide in toluene, equivalent to about 0.06 moles, is added dropwise to the initial solution while stirring, and the subsequent solution is stirred for about 15 hours at room temperature. The resultant white mixture has a pH of about 7 and is evaporated in vacuo.

[0044] The dried residue is partitioned between about 150 milliliters of ether and about 75 milliliters of water. The ether solution is decanted and dried over magnesium sulfate, and then evaporated leaving about 11.8 grams of a clear oil. The clear oil is washed with about 10 milliliters of hexane which was extracted with about 10 milliliters of 10% methanol. The methanol extract is combined with the washed clear oil product and evaporated in vacuo leaving about 10.9 grams of a second intermediate compound, namely, dimethyl propargyl 4-methoxycarbonyl phenyl malonate. The yield of dimethyl propargyl 4-methoxycarbonyl phenyl malonate from dimethyl 4-carbomethoxy phenyl malonate in Step 2 disclosed hereinabove is about 86%.

[0045] A second intermediate compound obtained via the foregoing second step of the process mechanism in accordance with the present invention, i.e., dimethyl propargyl 4- methoxycarbonyl phenyl malonate, was analyzed via infrared spectroscopy and a strong peak for the propargyl group is observed at about 3295 cm' ^! .

PROCESS MECHANISM - THIRD STEP

[0046] Finally, the present process for the preparation of dimethyl alpha-propargyl homoterephthalate concludes with the third step of the process mechanism which is the decarbomethoxylation of the second intermediate compound. More in particular, the third step in the process mechanism in accordance with the present invention comprises decarbomethoxylation of dimethyl propargyl 4-methoxycarbonyl phenyl malonate, to produce dimethyl alpha-propargyl homoterephthalate, as represented below in Reaction Equation 4:

[0047] Specifically, the third and final step of the process mechanism of the present process for the preparation of dimethyl alpha-propargyl homoterephthalate begins with heating a mixture of about 2.6 grams of dimethyl propargyl 4-methoxycarbonyl phenyl malonate, once again, the second intermediate compound, about 0.66 grams of lithium chloride, about 20 milliliters of dimethyl sulfoxide, and about 0.25 milliliters of water to a temperature of about 150° Celsius to about 155° Celsius for about 1.5 hours. Carbon dioxide gas begins forming at about 145° Celsius and is released from the solution. After cooling to room temperature, the resultant solution is diluted with about 150 milliliters of water, and this aqueous solution is extracted, first with about 30 milliliters of chloroform, and twice again with amounts of about 20 milliliters cloroform each. Each of the three chloroform extracts are combined and washed twice with about 20 milliliters of water each, and then dried over magnesium sulfate.

[0048] The washed and dried extract is evaporated in vacuo followed by high vacuum evaporation yielding about 2.1 grams of an oil consisting essentially of dimethyl alphapropargyl homoterephthalate. As will be appreciated, this represents a yield of about 81% dimethyl alpha-propargyl homoterephthalate from the amount of dimethyl propargyl 4- methoxycarbonyl phenyl malonate, i.e,, the second intermediate compound, utilized in the third step of the present process as disclosed hereinabove.

[0049] As will be appreciated, the present process for the preparation of high yield, estimated to be 1.5 to 2.0 times greater than currently utilized processes, and high purity dimethyl alpha-propargyl homoterephthalate is simpler, safer, and more cost effective than any currently brown processes which will allow for more efficient and cost effective production of pralatrexate, such that this potentially life saving drug will be more affordable so that a greater percentage of the population in need can reap the benefits it offers. The infrared spectrum of the decarbomethoxylation product obtained by the foregoing process is equivalent to the spectrum for the pure compound as described in the literature for the initial synthesis of pralatrexate.

[0050] In addition to its role in the manufacture of pralatrexate, the first intermediate compound, i.e., dimethyl 4-carbomethoxy phenyl malonate, can be subjected to direct decarbomethoxylation by lithium chloride in dimethyl sulfoxide, or DMSO, at 150° Celsius to produce dimethyl homoterephthalate, which may be saponified to form homoterephthalic acid. Both the diacid and diester of homoterephthalate are useful in polymer production. It is understood that esters other than methyl may be utilized, such as those with lower alkyl chain lengths in the foregoing processes. In addition, 4- iodobenzonitrile could be utilized as a starting material in the overall process, particularly for the synthesis of homoterephthalic acid and esters therefrom.

[0051] Since many modifications, variations, and changes in detail can be made to the described embodiments of the invention, it is intended that all matters in the foregoing description and shown in the accompanying drawings be interpreted as illustrative and not in a limiting sense. Furthermore, it is understood that any of the features presented in the embodiments may be integrated into any of the other embodiments unless explicitly stated otherwise. The scope of the invention should be determined by the appended claims and their legal equivalents.