Aminomethyl carbamate compounds and derivatives and methods of their making

Abstract

The present disclosure is directed to a process for preparation of a compound of Formula (I). Also disclosed are compounds of Formula (III) and Formula (V).

Description

AMINOMETHYL CARBAMATE COMPOUNDS AND DERIVATIVES AND METHODS OF THEIR MAKING

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Serial No. 63 / 681,984, filed August 12, 2024, which is hereby incorporated by reference in its entirety.FIELD

[0002] The present application relates to aminomethyl carbamate compounds and derivatives thereof and methods of their making.BACKGROUND

[0003] Aminomethyl carbamate compounds are generally prepared by treating an amine with chloromethyl chloroformate and the resulting chloromethyl derivative is coupled with another amine. This process does not work well when a free carboxyl group is present as the carboxyl group reacts with chloromethyl chloroformate. The preparation of aminomethyl carbamate compounds containing carboxylic acid functional groups require that the carboxylic acid be first protected as another functional group, such as a carboxylic ester, which is then isolated and purified. Next, the aminomethyl carbamate is synthesized, isolated, and purified. Subsequent removal of the protecting group followed by isolation and purification provides the desired aminomethyl carbamate compounds containing unprotected carboxylic acid. This strategy adds cost to synthetic endeavors, increases waste, and is generally inefficient. There is a need to identify methods that either eliminate the need for protecting groups, or allow in-situ protection of the carboxylic acid as part of the synthesis of the aminomethyl carbamate.

[0004] The present disclosure is directed to overcoming these and other deficiencies in the art.SUMMARY

[0005] One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):whereinR1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl;R4is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl;R5is selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of — OCi- C6alkyl, — C(O)OH, and — C(O)OCi-C6alkyl;R6is selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of — OCi- C6alkyl, — C(O)OH, and — C(O)OCi-C6alkyl;X is halogen, mesylate, tosylate, or triflate; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; p is 0, 1, 2, 3, or 4; or a solvate thereof. This process involves: providing a compound of Formula (II):or a salt thereof, wherein R2, R3, m, and n are as defined above for the Formula (I) compound; reacting the compound of Formula (II) or a salt thereof with an alkylating agent to produce the intermediate compound of Formula (III):or a salt thereof, wherein R1, R2, R3, m, and n are as defined above for the Formula (I) compound; reacting the intermediate compound of Formula (III) or a salt thereof with a compound of Formula (IV):whereinLG is a suitable leaving group; and Hal is halogen; to produce the intermediate compound of Formula (V):reacting the intermediate compound of Formula (V) with a compound of Formulato produce the compound of Formula (I).

[0006] Another aspect of the present disclosure relates to a compound of Formula (III):whereinR1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, 4, 5, or 6; andm is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; or a pharmaceutically acceptable salt thereof or a solvate thereof, with the proviso that when n is 1; R1is Me; m is 0; and p is 0, R2is not Ph.

[0007] Another aspect of the present disclosure relates to a compound of Formula (V):whereinHal is halogen;R1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; or a pharmaceutically acceptable salt thereof or a solvate thereof, with the proviso that when n is 1; R1is Me; m is 0; and p is 0, R2is not Ph.

[0008] The present disclosure involves preparation of aminomethyl carbamate compounds without having to isolate from the reaction mixture any amount of an intermediate compound of Formula (III).DETAILED DESCRIPTION

[0009] One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):whereinR1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl;R4is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl;R5is selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of — OCi- C6alkyl, — C(O)OH, and — C(O)OCi-C6alkyl;R6is selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of — OCi- C6alkyl, — C(O)OH, and — C(O)OCi-C6alkyl;X is halogen, mesylate, tosylate, or triflate; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; p is 0, 1, 2, 3, or 4; or a solvate thereof. This process involves: providing a compound of Formula (II):or a salt thereof, wherein R2, R3, m, and n are as defined above for the Formula (I) compound; reacting the compound of Formula (II) or a salt thereof with an alkylating agent to produce the intermediate compound of Formula (III):or a salt thereof, wherein R1, R2, R3, m, and n are as defined above for the Formula (I) compound; reacting the intermediate compound of Formula (III) or a salt thereof with a compound of Formula (IV):whereinLG is a suitable leaving group; and Hal is halogen; to produce the intermediate compound of Formula (V):reacting the intermediate compound of Formula (V) with a compound of Formula(VI):to produce the compound of Formula (I).

[0010] As used above, and throughout the description herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this technology belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0011] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise.

[0012] The terms “comprising,” “comprises,” and “comprised of’ as used herein are synonymous with “including,” “includes,” or “containing,” “contains,” and are inclusive or open- ended and do not exclude additional, non-recited members, elements, or method steps.

[0013] The terms “comprising,” “comprises,” and “comprised of’ also encompass the term “consisting of.” The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional,un-recited elements or method steps. By contrast, the transitional phrase “consisting of’ excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of’ limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel character! stic(s)” of the claimed subject matter. In some embodiments or claims where the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of’ or “consisting essentially of.”

[0014] Terms of degree such as “substantially,” “about,” and “approximately” and the symbol as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±0.1% (and up to ±1%, ±5%, or ±10%) of the modified term if this deviation would not negate the meaning of the word it modifies. Unless otherwise clear from context, all numerical values provided herein are modified by the term about. All numerical values provided herein that are modified by terms of degree set forth in this paragraphare also explicitly disclosed without the term of degree. For example, “about 1%” is also explicitly disclosed as “1%”.

[0015] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of’ or “one or more” of the listed items is used or present.

[0016] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third, and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member.

[0017] The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 10 carbon atoms in the chain. For example, straight or branched carbon chain could have 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl, or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, / / -propyl, z-propyl, / / -butyl, / -butyl, / / -pentyl, and 3 -pentyl.

[0018] The term “cycloalkyl” means a non-aromatic mono- or multicyclic ring system of about 3 to about 7 carbon atoms, about 3 to about 6 carbon atoms, preferably of about 5 to about7 carbon atoms. Exemplary monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the like.

[0019] The term “cycloalkylalkyl” means a cycloalkyl-alkyl-group in which the cycloalkyl and alkyl are as defined herein. Exemplary cycloalkylalkyl groups include cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclopropylethyl, cyclobutylethyl, and cyclopentylethyl. The alkyl radical and the cycloalkyl radical may be optionally substituted as defined herein.

[0020] The term “aryl” means an aromatic monocyclic or multi-cyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. Representative aryl groups include, without limitation, phenyl and naphthyl.

[0021] The term “heteroaryl” means an aromatic monocyclic or multi-cyclic ring system of about 5 to about 14 ring atoms, in which one or more of the atoms in the ring system is / are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In some embodiments, a “heteroaryl” is an aromatic monocyclic or multi-cyclic ring system of about 5 to about 10 ring atoms. In the case of multi-cyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “heteroaryl.” In some embodiments, exemplary heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include, without limitation, pyridyl, 2-oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2-oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotri azolyl, benzo[l,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[l,4]dioxinyl, benzofl, 2, 3]triazinyl, benzofl, 2, 4]triazinyl, 477-chromenyl, indolizinyl, quinolizinyl, 6a7 / -thieno[2,3-d]imidazolyl, 1H- pyrrolo[2,3-Z>]pyridinyl, imidazo[l,2-a]pyridinyl, pyrazolo[l,5-a]pyridinyl, [l,2,4]triazolo[4,3- a]pyridinyl, [l,2,4]triazolo[l,5-a]pyridinyl, thieno[2,3-Z>]furanyl, thieno[2,3-Z>]pyridinyl, thieno[3,2-Z>]pyridinyl, furo[2,3-Z>]pyridinyl, furo[3,2-Z>]pyridinyl, thieno[3,2-t ]pyrimidinyl, furo[3,2-t ]pyrimidinyl, thieno[2,3-Z>]pyrazinyl, imidazo[l,2-a]pyrazinyl, 5, 6,7,8- tetrahydroimidazo[l,2-a]pyrazinyl, 6,7-dihydro-4Z / -pyrazolo[5,l-c][l,4]oxazinyl, 2-oxo-2,3- dihydrobenzo[ ]oxazolyl, 3, 3-dimethyl -2-oxoindolinyl, 2-oxo-2,3-dihydro-l / / -pyrrolo[2,3- Z>]pyridinyl, benzo[c][l,2,5]oxadiazolyl, benzo[c][l,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[o] [ 1 ,4]oxazinyl, 5,6,7, 8-tetrahydro-[ 1 ,2,4]tnazolo[4,3 -a]pyrazinyl, [ 1 ,2,4]tnazolo[4,3 - a]pyrazinyl, 3-oxo-[l,2,4]triazolo[4,3-a]pyridin-2(3J7)-yl, and the like.

[0022] As used herein, “heterocyclyl” or “heterocycle” refers to a stable 3- to 18- membered ring (radical) which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. For purposes of this application, the heterocycle may be a monocyclic, or a polycyclic ring system, which may include fused, bridged, or spiro ring systems; and the nitrogen, carbon, or sulfur atoms in the heterocycle may be optionally oxidized; the nitrogen atom may be optionally quaternized; and the ring may be partially or fully saturated. Examples of such heterocycles include, without limitation, oxiranyl, azepinyl, azocanyl, pyranyl dioxanyl, dithianyl, 1,3-dioxolanyl, tetrahydrofuryl, dihydropyrrolidinyl, decahydroisoquinolyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2- oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, oxazolidinyl, oxiranyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, thiazolidinyl, tetrahydropyranyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. Further heterocycles and heteroaryls are described in Katritzky et al., eds., Comprehensive Heterocyclic Chemistry: The Structure, Reactions, Synthesis and Use of Heterocyclic Compounds, Vol. 1-8, Pergamon Press, N.Y. (1984), which is hereby incorporated by reference in its entirety.

[0023] The term “monocyclic” used herein indicates a molecular structure having one ring.

[0024] The term “polycyclic” or “multi-cyclic” used herein indicates a molecular structure having two or more rings, including, but not limited to, fused, bridged, or spiro rings.

[0025] The term “halo” or “halogen” means fluoro, chloro, bromo, or iodo.

[0026] The term “alkoxy” means groups of from 1 to 12 carbon atoms of a straight, branched, or cyclic configuration and combinations thereof attached to the parent structure through an oxygen. Examples include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like. Lower-alkoxy refers to groups containing one to four carbons. For the purposes of the present patent application, alkoxy also includes methylenedioxy and ethylenedioxy in which each oxygen atom is bonded to the atom, chain, or ring from which the methylenedioxy or ethylenedioxy group is pendant so as to form a ring. Thus, for example, phenyl substituted by alkoxy may be, for example,

[0027] The term “substituted” or “substitution” of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded.

[0028] The term “optionally substituted” is used to indicate that a group may have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom’s normal valency is not exceeded, and the identity of each substituent is independent of the others. Up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

[0029] “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =0), then two hydrogens on the atom are replaced.Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0030] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques.

[0031] In some embodiments, C3-C7 cycloalkyl is C3-C6 cycloalkyl.

[0032] In some embodiments, n is 0. In other embodiments, n is 1. In other embodiments, n is 2. In yet other embodiments, n is 3. In some other embodiments, n is 4. In other embodiments, n is 5. In other embodiments, n is 6.

[0033] In some embodiments, R1is methyl.

[0034] In some embodiments, R2is independently selected from the group consisting of Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy.

[0035] In some embodiments, R5is H.

[0036] In some embodiments, the compound of Formula (I) has the structure selected from the group consisting of

[0037] In some embodiments, the compound of Formula (I) has the following structure:

[0038] In some embodiments, the compound of Formula (I) has the following structure:

[0039] In some embodiments, the compound of Formula (II) has the structure selected from the group consisting of:

[0040] In some embodiments, the compound of Formula (II) is

[0041] According to the present disclosure, the alkylating agent in any of the above embodiments can be SOCI2 / C1-6 alkyl-OH (e.g., SOCh / MeOH, SOCh / EtOH, SOCh / PrOH, SOCh / i-PrOH, SOCh / BuOH, SOCh / i-BuOH, etc.). In some embodiments, the alkylating agent is SOCh / MeOH.

[0042] In some embodiments, the step of reacting the compound of Formula (II) or a salt thereof with the alkylating agent is carried out at a temperature of from about 25°C to about 60°C, from about 30°C to about 60°C, from about 35°C to about 60°C, from about 35°C to about 55°C, from about 35°C to about 50°C, or from about 40°C to about 50°C.

[0043] In some embodiments, the step of reacting the compound of Formula (II) or a salt thereof with the alkylating agent is carried out at a temperature of about 40°C, about 41 °C, about 42°C, about 43 °C, about 44°C, about 45 °C, about 46°C, about 47°C, about 48°C, about 49°C, or about 50°C.

[0044] In some embodiments, once the intermediate compound of Formula (III) or a salt thereof is produced, it is directly reacted with the compound of Formula (IV). In such embodiments, the compound of Formula (III) is not isolated e.g., in pure form) from the reaction mixture and the crude reaction mixture is directly used to carry out the reaction with the compound of Formula (IV).

[0045] In some embodiments, the compound of Formula (III) has the structure selected from the group consisting of:

[0046] In some embodiments, the compound of Formula (III) is

[0047] Suitable leaving groups (LG) that can be present in the compound of Formula (IV) include, but are not limited to, halogen, benzotri azolyl (Bt), and acyloxy.

[0048] In some embodiments, the compound of Formula (IV) is chloromethyl chloroformate.

[0049] In some embodiments, the step of reacting the compound of Formula (III) with the compound of Formula (IV) is carried out in the presence of a base. Suitable bases that can beused include, but are not limited to, 2,6-lutidine, N,N-dnsopropylethylamine, piperidine, morpholine, and triethylamine.

[0050] In some embodiments, the step of reacting the compound of Formula (III) with the compound of Formula (IV) can carried out at a temperature of from about 5°C to about 40°C, from about 5°C to about 35°C, from about 10°C to about 35°C, from about 15°C to about 35°C, from about 20°C to about 35°C, from about 25°C to about 35°C, or from about 28°C to about 32°C.

[0051] In some embodiments, the step of reacting the compound of Formula (III) with the compound of Formula (IV) can carried out at a temperature of about 25 °C, about 26°C, about 27°C, about 28°C, about 29°C, about 30°C, about 31°C, about 32°C, about 33°C, about 34°C, or about 35°C.

[0052] In some embodiments, the compound of Formula (V) is selected from the group consisting of:

[0053] In some embodiments, the compound of Formula (V) is

[0054] In some embodiments, the compound of Formula (VI) is selected from the group consisting of:

[0055] In some embodiments, the compound of Formula (VI) is

[0056] In some embodiments, the step of reacting the intermediate compound of Formula (V) with the compound of Formula (VI) is carried out at a temperature of from about 25°C to about 80°C, from about 30°C to about 75°C, from about 35°C to about 75°C, from about 40°C to about 75°C, from about 45°C to about 75°C, from about 45°C to about 70°C, from about 50°C to about 70°C, from about 55°C to about 70°C, or from about 55°C to about 65°C.

[0057] Another aspect of the present disclosure relates to a compound of Formula (III):whereinR1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; or a pharmaceutically acceptable salt thereof or a solvate thereof, with the proviso that when n is 1; R1is Me; m is 0; and p is 0, R2is not Ph.

[0058] Another aspect of the present disclosure relates to a compound of Formula (V):whereinHal is halogen;R1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; or a pharmaceutically acceptable salt thereof or a solvate thereof, with the proviso that when n is 1; R1is Me; m is 0; and p is 0, R2is not Ph.

[0059] The above disclosure is general. A more specific description is provided below in the following examples. The examples are described solely for the purpose of illustration and are not intended to limit the scope of the present application. Changes in form and substitution of equivalents are contemplated as circumstances suggest or render expedient. Although specific terms have been employed herein, such terms are intended in a descriptive sense and not for purposes of limitation.EXAMPLES

[0060] The following Examples are presented to illustrate various aspects of the present disclosure, but are not intended to limit the scope of the claimed application.Example 1 - Synthesis of Compound IVStep 1: Preparation of Compound I

[0061] D-Ritalonic acid hydrochloride (16 g, 1.0 eq, 62.5 mmol) was added to a 250 mL 4-necked round-bottom flask (RBF) at 25°C under N2. Methanol (76.96 mL, 4.81 vol) was added to RBF at 25°C under N2. Thionyl chloride (9.3 mL, 2.0 eq, 125 mmol) was slowly added at a rate that allowed the internal temperature to climb to 40°C once the addition was completed. The reaction mixture was then heated to 45 °C and aged for 16 hours. Gradual precipitation occurred resulting in a thin slurry. The reaction progress was monitored by HPLC. After completion, the reaction mixture was concentrated under reduced pressure to reduce the volume by approximately 60%. The flask was cooled to 5°C and deionized water (10 mL, 0.625 vol) was added before titrating the solution to a pH of around 8 with cold (5°C) 25% aqueous sodium hydroxide solution. Methyl tert-butyl ether (61.56 mL, 3.84 vol, cold 5°C) was added followedby 25% aqueous sodium hydroxide (cold 5°C) while stirring until no solids remained. Sodium chloride was added while stirring until saturation was achieved, and then the aqueous phase was separated. The organic layer was concentrated to an oil by vacuum distillation at < 45°C and then re-dissolved in methyl tert-butyl ether (162 mL). The resulting solution of compound (I) (freebase) in methyl tert-butyl ether was then filtered to remove any remaining salts. The filtered solution of compound (I) (freebase) in methyl tert-butyl ether was used in next step without further purification.Step 2: Preparation of Compound II

[0062] Crude solution of compound (I) (freebase) obtained from 16 g of D-ritalonic acid HC1 from step-1 (162.5 mL MTBE solution, Kf=0.15%) was added to a 4-necked flask at 25°C under N2. 2,6-Lutidine (11.07 mL, 1.52 eq, 95 mmol) was added to the reaction mixture using dropping funnel. The dropping funnel was subsequently rinsed with 13.42 mL of methyl tertbutyl ether and the rinse was added to the reaction mixture. Chloromethyl chloroformate (8.18 mL, 1.42 eq, 88 mmol.) was slowly added to the solution using dropping funnel while maintaining the internal temperature at below 30°C. The addition resulted in an extremely dense slurry (difficult to stir) that peaked in density after approximately 75% of the chloromethyl chloroformate was added. The slurry gradually thinned as the remainder was added and it was easily stirred once the addition was completed. The dropping funnel was rinsed with 13.42 mL of MTBE and the rinse was added to reaction mixture. The reaction mass was stirred at 30°C for 6-8 hours. The reaction was monitored by HPLC. After completion of the reaction, the reaction mixture was cooled to 20°C and quenched with water (46.4 mL). The resulting biphasic mixture was stirred overnight. The aqueous phase was separated and discarded. A solution of sodium bicarbonate (4.38 g) in deionized water (46.4 mL) was added to the reaction mixture and the resulting biphasic mixture was stirred for 2 hours. The aqueous phase was separated and discarded. Deionized water (46.4 mL) was added to the reaction mixture and the resulting biphasic mixture was stirred for 1 hour. The aqueous phase was separated and discarded.Organic layer was distilled under atmospheric pressure at 56°C. The residue was tested for residual water with a result of 0.11% (limit <0.2%). Compound II was obtained (19.5 g) as crude oil.Step 3: Preparation of Compound IV

[0063] Acetonitrile (78 mL, 4.0 vol) was added to the crude compound II (19.5 g, 1.0 eq., 59 mmol.) obtained from step 2 at 25°C under N2 in RBF. Acetonitrile was subsequently distilled at 100°C up to 1.5 vol. Reaction mixture was cooled to 40-45°C. Solution of compound (III) (15.43 g, 0.8 eq., 56 mmol.) in acetonitrile (19.5 mL, 1.0 vol) was added slowly to above solution at 40-45°C under N2. The reaction mixture was heated at 60°C and stirred for 35-40hours. Reaction was monitored by HPLC. After completion, the reaction mixture was cooled to 20°C. n-Heptane (355 mL, 18.2 vol) and methyl isobutyl ketone (176.86 mL, 9.01 vol) were added to a separate 1 lit RBF, followed by Compound IV seed crystal (0.04 g) and the contents were stirred at 20°C for 1 hour. The reaction mixture was added to the 1 lit RBF over 1 hour at 20°C, resulting in the formation of a slurry. Acetonitrile (1.5 mL) was used as a rinse. The slurry was stirred at 20°C for 8-10 hours. Suspension was filtered at 20°C under N2. The wet cake was washed with a cold solution of n-heptane (113 mL, 5.8 vol) and methyl isobutyl ketone (37 mL, 1.9 vol). The solid was dried under vacuum at 45°C for 12 hours. Compound IV was obtained (dry weight 28.5 g). Three step overall yield was 70.33% from D-Ritalonic acid hydrochloride. HPLC purity=99.7%.

[0064] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow.

Claims

WHAT IS CLAIMED:

1. A process for preparation of a compound of Formula (I):whereinR1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl;R4is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl;R5is selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of — OCi- C6alkyl, — C(O)OH, and — C(O)OCi-C6alkyl;R6is selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of — OCi- C6alkyl, — C(O)OH, and — C(O)OCi-C6alkyl;X is halogen, mesylate, tosylate, or tritiate; n is 0, 1, 2, 3, 4, 5, or 6; m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; p is 0, 1, 2, 3, or 4; or a solvate thereof, said process comprising:providing a compound of Formula (II):or a salt thereof, wherein R2, R3, m, and n are as defined above for the Formula (I) compound; reacting the compound of Formula (II) or a salt thereof with an alkylating agent to produce the intermediate compound of Formula (III):or a salt thereof, wherein R1, R2, R3, m, and n are as defined above for the Formula (I) compound; reacting the intermediate compound of Formula (III) or a salt thereof with a compound of Formula (IV):whereinLG is a suitable leaving group; and Hal is halogen; to produce the intermediate compound of Formula (V):reacting the intermediate compound of Formula (V) with a compound of Formula(VI):to produce the compound of Formula (I).

2. The process according to claim 1, wherein n is 0.

3. The process according to claim 1, wherein n is 1.

4. The process according to claim 1, wherein R1is methyl.

5. The process according to claim 1, wherein R5is H.

6. The process according to claim 1, wherein the compound of Formula (I) has the structure selected from the group consisting of7. The process according to claim 1, wherein the compound of Formula (I) has the following structure:

8. The process according to claim 7, wherein the compound of Formula (I) has the following structure:

9. The process according to claim 1, wherein the compound of Formula (II) is selected from the group consisting of:

10. The process according to claim 9, wherein the compound of Formula (II) is11. The process according to claim 1, wherein the alkylating agent is SOCh / Ci-6 alkyl-OH.

12. The process according to claim 1, wherein said reacting the compound of Formula (II) or a salt thereof with the alkylating agent is carried out at a temperature of from about 25°C to about 60°C.

13. The process according to claim 12, wherein said reacting the compound of Formula (II) or a salt thereof with the alkylating agent is carried out at a temperature of about 45°C.

14. The process according to claim 1, wherein the compound of Formula (III) is selected from the group consisting of:

15. The process according to claim 14, wherein the compound of Formula (III) is16. The process according to claim 1, wherein the compound of Formula (IV) is chloromethyl chloroformate.

17. The process according to claim 1, wherein said reacting the compound of Formula (III) with the compound of Formula (IV) is carried out at a temperature of from about 5°C to about 40°C.

18. The process according to claim 17, wherein said reacting the compound of Formula (III) with the compound of Formula (IV) is carried out at a temperature of about 30°C.

19. The process according to claim 1, wherein said reacting the compound of Formula (III) with the compound of Formula (IV) is carried out in the presence of a base.

20. The process according to claim 19, wherein the base is selected from the group consisting of 2,6-lutidine, N,N-diisopropylethylamine, and triethylamine.

21. The process according to claim 1, wherein the compound of Formula (V) has the structure selected from the group consisting of:

22. The process according to claim 21, wherein the compound of Formula (V) is23. The process according to claim 1, wherein the compound of Formula (VI) has the structure selected from the group consisting of :

24. The process according to claim 23, wherein the compound of Formula (VI) is25. The process according to claim 1, wherein said reacting the intermediate compound of Formula (V) with the compound of Formula (VI) is carried out at a temperature of from about 25°C to about 80°C.

26. The process according to claim 25, wherein said reacting the intermediate compound of Formula (V) with the compound of Formula (VI) is carried out at a temperature of from about 50°C to about 70°C.

27. The process according to claim 1, wherein once the intermediate compound of Formula (III) or a salt thereof is produced, said intermediate compound of Formula (III) is directly reacted with a compound of Formula (IV).

28. A compound of Formula (III):whereinR1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionallysubstituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; or a pharmaceutically acceptable salt thereof or a solvate thereof, with the proviso that when n is 1; R1is Me; m is 0; and p is 0, R2is not Ph.

29. A compound of Formula (V):whereinHal is halogen;R1is Ci-Ce alkyl;R2is independently selected from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl, wherein Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl can be optionally substituted from 1 to 3 times with a substituent selected independently at each occurrence from the group consisting of Ci-Ce alkyl, OH, halogen, and Ci-Ce alkoxy;R3is independently selected at each occurrence thereof from the group consisting of H, Ci-Ce alkyl, C3-C7 cycloalkyl, C4-C13 cycloalkylalkyl, heterocyclyl, aryl, and heteroaryl; n is 0, 1, 2, 3, 4, 5, or 6; and m is 0, 1, 2, 3, 4, 5, 6, 7, 8, or 9; or a pharmaceutically acceptable salt thereof or a solvate thereof, with the proviso that when n is 1; R1is Me; m is 0; and p is 0, R2is not Ph.

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