Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/32—One oxygen, sulfur or nitrogen atom
  • C07D239/42—One nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
  • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
  • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
  • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
  • C07D239/30—Halogen atoms or nitro radicals

Definitions

• Compound (I) is disclosed in U.S. Patent No. 8,148,526 as an HDAC inhibitor.
• Example 2 of U.S. Patent Application Publication No. 2015/0099744 discloses a synthesis of compound (I). As detailed herein in Example 3, this synthesis procedure resulted in the formation of significant amounts of de-chlorination and chlorine-migration side products. These impurities have solubilities that are similar to the solubilities of the desired
• the improved method entirely avoids the formation of de-chlorination and chlorine- migration impurities. Moreover, the improved method results in a higher (e.g., over double) yield of compound (I) (e.g., 15.7% overall yield by the method of Example 2, versus 40% overall yield by the improved method). Also provided are compounds useful as intermediates in the synthesis of compound (la) and compositions comprising said compounds.
• X is selected from fluorine, chlorine, bromine and iodine
• Z is selected from the group consisting of -CN and -C0 2 R; and R is Ci-C 6 alkyl; and
• compound 1 la is prepared by a method comprising the step of: converting compo nd la into compound 11a:
• X is selected from fluorine, chlorine, bromine and iodine
• step of converting compound 3a into compound (la) comprises the steps of:
• step of converting compound 4a into compound (la) comprises the steps of:
• X is selected from fluorine, chlorine, bromine and iodine
• R' is Ci-C 6 alkyl
• X is selected from fluorine, chlorine, bromine and iodine.
• X is chlorine.
• Z is C0 2 Et (i.e., R is ethyl).
• R is methyl.
• Z is selected from the group consisting of -CN and -C0 2 R; and wherein R Ci-C 6 alkyl;
• compound 1 lb is prepared by a method comprising the step of: converting compound lb into compound l ib:
• Z is selected from the group consisting of -CN and -C0 2 R; and wherein R is Ci-C 6 alkyl.
• step of converting compound 3b into compound (I) comprises the steps of: converting compound 3b into compound 4:
• the step of converting compound 4 into compound (I) comprises the steps of: converting compound 4 into compound 5b:
• R' is Ci-C 6 alkyl
• Z is C0 2 Et (i.e., R is ethyl). In another particular embodiment, R' is methyl.
• the step of converting compound lb into compound 1 lb comprises reacting compound 1 with 2-chloroaniline to obtain compound 11 :
• the step of converting compound 1 lb into compound 3b comprises reacting compound 11 with iodobenzene to obtain compound 3:
• the step of converting compound 4 into compound 5b comprises reacting compound 4 with methyl 7-aminoheptanoate to obtain compound 5:
• the step of converting compound 5b into compound (I) comprises reacting compound 5 with hydroxylamine, or a salt thereof, to obtain compound (I), or a salt thereof.
• Z is selected from the group consisting of -CN and -C0 2 R; and wherein R is Ci-C 6 alkyl.
• Z is -C0 2 R.
• Z is -C0 2 R and R is ethyl.
• compound 1 lb is compound 11.
• composition comprising lb and 1 lb, wherein lb and 1 lb are defined above.
• lb is compound 1
• l ib is compound 11.
• composition comprising 1 lb and 3b, wherein 1 lb and 3b are defined above.
• 1 lb is compound 11 and 3b is compound 3.
• composition comprising the compound 1 lb. In one embodiment, the composition further comprises compound 3.
• composition comprising compound 3, wherein the composition is free from compounds de-Cl-3 and m-Cl-3:
• composition comprising compound 4, wherein the composition is free from compounds de-Cl-4 and m-Cl-4:
• composition comprising compound 5, wherein the composition is free from compounds de-Cl-5 and m-Cl-5:
• Figure 1 depicts a generic synthesis of compound (I) according to the improved method described herein.
• Figure 2 depicts a specific synthesis of compound (I) according to the improved method described herein.
• FIG. 3 depicts 1 HNMR data for compound 11.
• Figure 4 depicts 1 HNMR data for compound 4.
• Figure 5 depicts 1 HNMR data for compound 5.
• Figure 6 depicts 1 HNMR data for compound (I).
• Figure 7 depicts the correlation of 1 HNMR data to the structure of compound (I).
• Figure 8 depicts the XRPD pattern (Pattern A) of compound (I), Form I.
• Figure 9 depicts the DSC graph of compound (I), Form I.
• Figure 10 depicts the TGA thermogram of compound (I), Form I.
• Figure 11 depicts the XRPD pattern (Pattern D) of compound (I), Form IV.
• X is selected from fluorine, chlorine, bromine and iodine
• Z is selected from the group consisting of -CN and -C0 2 R;
• R is Ci-C 6 alkyl
• compound 11a is prepared by a method comprising the step of: converting compound la into compound 11a:
• X is selected from fluorine, chlorine, bromine and iodine
• Z is selected from the group consisting of -CN and -C0 2 R;
• R is Ci-Ce alkyl.
• step of converting compound 3a into compound (la) comprises the steps of:
• step of converting compound 4a into compound (la) comprises the steps of:
• X is selected from fluorine, chlorine, bromine and iodine; and R' is Ci-C 6 alkyl; and
• X is selected from fluorine, chlorine, bromine and iodine.
• X is chlorine.
• Z is C0 2 Et (i.e., R is ethyl).
• R is methyl.
• R is Ci-C 6 alkyl
• R is Ci-C 6 alkyl
• R is ethyl
• R is methyl
• the method comprises the step of converting compound lb to compound 1 lb, i.e., Step (1).
• Step (1) comprises reacting compound lb with 2-chloroaniline to obtain compound 1 lb.
• the method comprises the step of converting compound 1 lb to compound 3b, i.e., Step (2).
• Step (2) comprises reacting compound 1 lb with iodobenzene to obtain compound 3b.
• the method comprises Steps (l)-(2), and the step of converting compound 3b to compound 4, i.e., Step (3).
• Step (3) comprises forming a mixture of the product of Step (2) (i.e., the reaction mixture comprising compound 3b) and water, and heating the mixture.
• the method comprises Steps (l)-(3), and the step of converting compound 4 to compound 5b, i.e., Step (4).
• Step (4) comprises reacting compound 4 with an ester of 7-aminoheptanoic acid to obtain compound 5b.
• the method comprises Steps (l)-(4), and the step of converting compound 5b to compound (I), i.e., Step (5).
• Step (5) comprises reacting compound 5b with hydroxylamine, or a salt thereof, to obtain compound (I), or a salt thereof.
• the method comprises Steps (l)-(5).
• the method comprises Steps (l)-(2), with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• Steps (l)-(2) with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• the method comprises Steps (l)-(3) with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• the method comprises Steps (l)-(4) with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• a method of making compound (I) comprises the step of converting compound 1 to compound 11, i.e., Step (1).
• Step (1) comprises reacting ethyl 2- chloropyrimidine-5-carboxylate with 2-chloroaniline.
• Step (1) comprises the use of an alcohol solvent (particularly, e.g., ethanol).
• Step (1) comprises the use of elevated temperatures (particularly, e.g., about 78 °C).
• Step (1) comprises the conditions disclosed in Example 4.
• Step (1) comprises the conditions disclosed in Example 5.
• Step (1) produces compound 11 in at least about 81% yield (e.g., in about 81% yield).
• the method comprises the step of converting compound 11 to compound 3, i.e., Step (2).
• Step (2) comprises the use of a polar aprotic solvent (particularly, e.g., dimethylsulfoxide).
• Step (2) comprises the use of elevated temperatures (particularly, e.g., about 120 ⁇ 5 °C).
• Step (2) comprises reacting compound 11 with iodobenzene.
• Step (2) comprises reacting compound 11 with iodobenzene in presence of copper.
• Step (2) comprises reacting compound 11 with iodobenzene in presence of copper and potassium carbonate.
• Step (2) comprises the conditions disclosed in Example 4.
• Step (2) comprises the conditions disclosed in Example 5.
• the method comprises Steps (l)-(2), and the step of converting compound 3 to compound 4, i.e., Step (3).
• Step (3) comprises forming a mixture of the product of Step (2) (i.e., the reaction mixture comprising compound 3) and water.
• Step (3) comprises the use of elevated temperatures (particularly, e.g., about 90-100 °C).
• Step (3) comprises the conditions disclosed in Example 4.
• Step (3) comprises the conditions disclosed in Example 5.
• Steps (2)-(3) produce compound 4 from compound 11 in at least about 65% yield (e.g., in about 65% yield).
• Steps (2)-(3) produce compound 4 from compound 11 in at least about 81% yield (e.g., in about 81% yield).
• the method comprises Steps (l)-(3), and the step of converting compound 4 to compound 5, i.e., Step (4).
• Step (3) comprises the use of a polar aprotic solvent (particularly, e.g., dimethylformamide).
• Step (4) comprises the use of dimethylformamide and dichloromethane.
• Step (4) comprises reacting compound 4 with methyl 7-aminoheptanoate, or a salt thereof.
• Step (4) comprises converting compound 4 to an activated acid derivative, then reacting the activated acid derivative with methyl 7-aminoheptanoate.
• the activated acid derivative is an acid chloride.
• Step (4) comprises the conditions disclosed in Example 4.
• Step (4) comprises the conditions disclosed in Example 5.
• the method comprises Steps (l)-(4), and the step of converting compound 5 to compound (I), i.e., Step (5).
• Step (5) comprises the use of lowered temperatures (particularly, e.g., about 0-5 °C, or about 0-10 °C, or about 0 ⁇ 5 °C).
• Step (5) comprises reacting compound 5 with hydroxylamine, or a salt thereof.
• Step (5) comprises the use of an alkoxide base in an alcohol solvent (particularly, e.g., sodium methoxide in methanol).
• Step (5) comprises crystallizing crude compound (I) from a solvent comprising a Ci-C 6 alcohol to obtain Form I.
• the solvent is isopropanol. In another particular embodiment, the solvent is 1 -propanol/water. In another particular embodiment, Step (5) comprises the conditions disclosed in Example 4. In another particular embodiment, Step (5) comprises the conditions disclosed in Example 5.
• the method comprises Steps (l)-(5).
• the method comprises Steps (l)-(2), with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• Steps (l)-(2) with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• the method comprises Steps (l)-(3) with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• the method comprises Steps (l)-(4) with subsequent steps known in the art, such that compound (I), or a salt thereof, is formed.
• the methods of making compound (I) are superior to previous methods, at least for the following reasons.
• the claimed methods involve introduction of the chlorine atom in Step (1). This step does not involve conditions under which the aryl chloride is reactive. Accordingly, the chloride moiety is not subject to copper-mediated migration and/or dechlorination.
• Analysis of Step (1) by high performance liquid chromatography (UPLC) reveals the reaction mixture is free from such migration and/or dechlorination side products.
• compound (I) provided herein are compounds useful as intermediates in the synthesis of compound (I).
• Z is selected from the group consisting of -CN and -C0 2 R, and wherein R is Ci-C 6 alkyl.
• Z is -C0 2 R.
• Z is -C0 2 Et.
• a composition comprising compounds lb and 1 lb, wherein Z is defined according to the embodiments above.
• Z is -C0 2 R.
• Z is -C0 2 Et.
• the composition further comprises 2-chloroaniline.
• composition comprising compounds 1 and 11.
• the composition further comprises 2-chloroaniline.
• the composition further comprises reagents specified in Example 4.
• composition comprising compounds 1 lb and 3b, wherein Z is defined according to the embodiments above.
• Z is -C0 2 R.
• Z is -C0 2 Et.
• the composition further comprises compound 1 lb.
• the composition further comprises iodobenzene.
• the composition is free from dechlorination and chlorin -migration impurities, such as de-Cl-3b and m-Cl-3b:
• composition further comprises compound 4, or a salt thereof, and is free from
• dechlorination and chlorine-migration impurities such as de-Cl-4 and m-Cl-4, or salts thereof:
• composition comprising compounds 11 and 3.
• the composition further comprises iodobenzene.
• the composition is free from dechlorination and chlorine-migration impurities, such as de-Cl- 3 and m-Cl-3:
• the composition further comprises compound 4, or a salt thereof, and is free from dechlorination and chlorine-migration impurities, such as de-Cl-4 and m-Cl-4, or salts thereof.
• composition comprising compound 4 and one or more compounds selected from lb, 1 lb and 3b, wherein Z is defined according to the embodiments above.
• Z is -C0 2 R.
• Z is -C0 2 Et.
• composition comprising compound 4 and one or more compounds selected from compounds 1, 11 and 3.
• composition comprising compound 5b and less than about 1% (combined area percentage as measured by HPLC) of compounds de-Cl-5b and m- l-5b:
• composition is free from de-Cl-5b and m-Cl-5b.
• composition comprising compound 5 and less than about 1% (combined area percentage as measured by HPLC) of compounds de-Cl-5 and m-Cl-5:
• the composition is free from de-Cl-5 and m-CI-5.
• composition comprising compound 5, compound (I) and less than about 1% (combined area percentage as measured by HPLC) of compounds de-Cl-(I) and m-Cl-(I):
• the composition is free from de-Cl-(I) and m-Cl-(I).
• Acids and bases useful in the methods herein are known in the art.
• Acid catalysts are any acidic chemical, which can be inorganic (e.g., hydrochloric, sulfuric, nitric acids, aluminum trichloride) or organic (e.g., camphorsulfonic acid, p-toluenesulfonic acid, acetic acid, ytterbium triflate) in nature. Acids are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
• Bases are any basic chemical, which can be inorganic (e.g., sodium bicarbonate, potassium hydroxide) or organic (e.g., triethylamine, pyridine) in nature. Bases are useful in either catalytic or stoichiometric amounts to facilitate chemical reactions.
• alkyl refers to a fully saturated branched or unbranched hydrocarbon moiety.
• the alkyl comprises 1 to 6 carbon atoms (i.e., Ci-C 6 alkyl).
• react refers to the formation of a bond between two or more reactant compounds to produce a product compound.
• a first compound and a second compound may react to form a product compound, wherein the product compound comprises a portion of the first compound and a portion of the second compound, wherein the two portions are joined by a covalent bond.
• reacting does not refer to the interaction of solvents, catalysts, ligands, or other components that may serve to promote the occurrence of the reaction between the compounds.
• salt thereof may refer to acid addition salts, metal salts, or ammonium salts. Such salts can be formed by procedures well known and described in the art. Acid addition salts may be formed from inorganic acids, e.g.
• hydrochloric, hydrobromic, sulphuric or phosphoric acids and organic acids, e.g. succinic, malaeic, tartaric, acetic, oxalic or fumaric acid.
• addition salts include, without limitation, the hydrochloride derived from hydrochloric acid, the hydrobromide derived from hydrobromic acid, the nitrate derived from nitric acid, the perchlorate derived from perchloric acid, the phosphate derived from phosphoric acid, the sulphate derived from sulphuric acid, the formate derived from formic acid, the acetate derived from acetic acid, the aconate derived from aconitic acid, the ascorbate derived from ascorbic acid, the benzenesulphonate derived from benzensulphonic acid, the benzoate derived from benzoic acid, the cinnamate derived from cinnamic acid, the citrate derived from cit
• copper can refer to Cu(0), Cu(I) or Cu(II).
• Non-limiting examples of copper include Cu(0) powder, copper-bronze, cupric oxide, cupric chloride, cupric iodide, cuprous chloride, cuprous iodide and other forms or salts of copper that are known by those of skill in the art.
• activated acid derivative refers to a derivative of a carboxylic acid that is susceptible to nucleophilic acyl substitution, for example, by virtue of having a leaving group on the carbonyl carbon.
• activated acid derivatives include acyl halides (also referred to as acid chlorides), carboxylic acid anhydrides (including, for example, mixed carboxylic acid anhydrides), acyl imidazoles (prepared, for example, by reaction of a carboxylic acid with carbonyl diimidazole), and O- acyl isoureas (prepared, for example, by reaction of a carboxylic acid with a carbodiimide reagent such as EDC or DCC).
• acyl halides also referred to as acid chlorides
• carboxylic acid anhydrides including, for example, mixed carboxylic acid anhydrides
• acyl imidazoles prepared, for example, by reaction of a carboxylic acid with carbonyl diimidazole
• O- acyl isoureas prepared
• compositions and mixtures that are "free from” a particular solute or substance may comprise less than 5% (e.g., less than 4%, less than 3%, less than 2%, less than 1%, less than 0.1% or less than 0.01%) by weight of the solute or substance.
• compositions and mixtures that are "free from” a particular solute or substance comprise an amount of the solute or substance that is below the limit of detection of the analytical instrumentation described herein.
• DSC Differential Scanning Calorimetry
• TGA Thermal Gravimetric Analysis
• Dynamic Vapor Soprtion (DVS) analysis was performed using an Aquadyne DVS-2 gravimetric water sorption analyzer. The relative humidity was adjusted between 2-95% and the weight of the sample was continuously monitored and recorded with respect to the relative humidity and time.
• the dichloromethane was then vacuumdistilled at ⁇ 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that ⁇ 1 mol% DCM was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (6.4 Kgs). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 2.2 Kgs (77% yield) was isolated in 95.9% AUC purity (method TM-113.953) and 99.9 wt %. See 1 HNMR data in Figure 5.
• the reaction was stirred until the reaction was complete (method TM-113.964, compound 5 ⁇ 2%).
• the mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate.
• the pH was adjusted to 8 - 9 using 6N HC1 then stirred for up to 3 hours before filtering.
• the filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight.
• the crude solid compound (I) was determined to be Form IV/ Pattern D.
• the mixture was filtered and water (280 g) and ethyl acetate (890 g) were added to the filtrate.
• the pH was adjusted to 8 - 9 using HC1 then stirred for up to 3 hours before filtering.
• the filter cake was washed with cold water (2570 g), then dried under reduced pressure to constant weight to yield 980 g crude solid in 83% yield.
• the crude solid compound (I) was determined to be Form IV/ Pattern D.
• the crude solid (980 g) was suspended in 1-propanol (400 g) and purified water (220 g). The suspension was heated to 40°C. The batch was then cooled to 38°C over 30 minutes. The solution was seeded with crystals of Compund (I) (Form I/Pattern A, 2-5 wt %). The batch was kept at 37-38°C for 2-4 hours, then was gradually cooled to 20 ⁇ 2°C. Water (950 g) was charged over 3 -5 hours. The batch was cooled to 12°C and was stirred for 2 hrs at this temperature. The batch was filtered and washed with cold 1-propanol/water, then dried at 50 ⁇ 5°C to constant weight to yield 910 g purified compound (I) in 93% yield and 99.8% AUC purity.
• Compund (I) Form I/Pattern A, 2-5 wt %
• Form I 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5- carboxamide (i.e., compound (I)) may exist in crystal Form I (referred to herein as "Form I").
• Form I can be characterized using X-ray powder diffraction (XRPD).
• XRPD X-ray powder diffraction
• Form I can also be characterized by differential scanning calorimetry (DSC) and thermal gravimetric analysis (TGA) (see Figures 8 and 9, respectively).
• DSC differential scanning calorimetry
• TGA thermal gravimetric analysis
• the dynamic vapor sorption (DVS) experiment revealed less than 0.2 % of moisture uptake by Compound (I), Form V Pattern A, when subjected to relative humidity between 0-95 percent and no change in the crystalline form was observed.
• DSC analysis also indicated an endothermic thermal event (melting point) at around 173 °C, followed by an exothermic event (possible decomposition).
• TGA analysis revealed that there is less than 0.1% weight loss in the sampl from 35 to 150 °C.
• Karl Fischer (KF) titration also revealed less than ⁇ 1 % of water content.
• Form I of compound (I) can be prepared from amorphous compound (I), or from another crystalline form of compound (I), by stirring for 8-16 hours (e.g., overnight) in a slurry of ethanol.
• Form IV 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5 carboxamide (i.e., compound (I)) may exist in crystal Form IV (referred to herein as "Form IV").
• Form IV can be characterized using X-ray powder diffraction (XRPD).
• XRPD X-ray powder diffraction

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