Process for preparing tapinarof

Abstract

To provide processes for the preparation of (E)-2-chloro-2-isopropyl 5-styrylcyclohexane-1,3-dione (compound (Ila)) or a salt thereof.SOLUTION: The present invention provides processes for the preparation of a compound (IIa) or a salt thereof, comprising the step for halogenating a compound (III) or a salt thereof with a halogenating agent selected from 1,3-dichloro-5,5-dimethylhydantoin and the like.SELECTED DRAWING: Figure 1

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 584,192, entitled "PROCESS," filed November 10, 2017, the contents of which are incorporated herein by reference in their entirety. Summary of the Invention

[0002] Some embodiments of the present invention provide processes for the preparation of compounds of formula (I) or salts thereof, and novel intermediates used therein. [ka]

[0003] Some embodiments of the present invention include a compound of formula (IIa) or a salt thereof: [ka] and a process for preparing same is described.

[0004] Some embodiments of the present invention relate to a compound of formula (IVa) or a salt thereof: [ka] and a process for preparing same is described.

[0005] Some embodiments of the present invention include a compound of formula (V) or a salt thereof: [ka] and a process for preparing same is described.

[0006] Some embodiments of the present invention relate to a compound of formula (VI) or a salt thereof: [ka] and a process for preparing same is described.

[0007] Some embodiments of the present invention describe pharmaceutical compositions comprising a compound of formula (I) or a salt or solvate thereof prepared according to the process of the present invention, and a pharma- ceutically acceptable excipient. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the X-ray powder diffraction (XRPD) pattern of the compound of formula (I) in a crystalline solid form (Form 1). [Diagram 2] 1 shows the X-ray powder diffraction (XRPD) pattern of the acetic acid solvate of compound of formula (I) in crystalline solid form. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] 3,5-Dihydroxy-4-isopropyl-trans-stilbene of formula (I), also known as (E)-2-isopropyl-5-styrylbenzene-1,3-diol or tapinarof, is a natural product of bacterial origin. [ka]

[0010] The compounds have several potentially useful biological responses, including antibacterial, antioxidant, and anticancer activity. PCT patent application WO200142231 discloses polyhydroxystilbenes and oxidized stilbenes as antipsoriatic agents and protein kinase inhibitors.

[0011] Several routes to the synthesis of compounds of formula (I) are known in the art. Chinese Patent Application No. CN101648851 describes a synthetic route via the formation of (E)-olefins by Horner-Wadsworth-Emmons olefination. A route via the introduction of an isopropyl group into substituted resorcinol derivatives by Friedel-Crafts alkylation is also known.

[0012] An alternative synthetic approach similar to the known biosynthetic pathway was described by Kronenwerth et al. (Eur. J. Org. Chem. 2014, 8026-8028). However, this pathway has synthetic problems with low yields of intermediates and final products. There are also toxicity issues associated with incomplete removal of traces of mercury in isopropylstilbene, making this pathway unsuitable for large-scale pharmaceutical production.

[0013] Schamp et al. (Tetrahedron, 1973, 29, 3857-3859) disclose the synthesis of simple 2-substituted resorcinols such as 2-methyl-, 2-benzyl-, and 2-acetylresorcinol from the corresponding 1,3-cyclohexanedione. The conditions reported include chlorination of the 1,3-cyclohexanedione followed by elimination of HCl by heating with a 25% solution of dry hydrogen chloride in dimethylformamide.

[0014] There is a need for efficient and scalable routes for the large-scale production of compounds of formula (I), particularly high-yielding syntheses without potential toxicity issues.

[0015] The present invention provides several embodiments relating to the process summarized in Scheme 1 below. TIFF2024069233000008.tif99156

[0016] Preparation of Compounds of Formula (I)—Process A Some embodiments provide a process for the preparation of a compound of formula (I) or a salt or solvate thereof, comprising: [ka] comprising one or more of process steps (a), (b), and (c); (a) is a compound of formula (II) or a salt thereof [ka] Reaction of a compound of formula (III) or a salt thereof [ka] wherein X is Cl, Br, or I, and then (ii) converting the compound of formula (II) or a salt thereof to a compound of formula (I) or a salt or solvate thereof, (b) is a compound of formula (VI) or a salt thereof, [ka] conversion to a compound of formula (III) or a salt thereof; [ka] and then converting the compound of formula (III) or a salt thereof into a compound of formula (I) or a salt or solvate thereof, (c) is a compound of formula (IX) or a salt thereof, [ka] converting the compound of formula (VI) or a salt thereof into [ka] Thereafter, a process is described which comprises converting a compound of formula (VI) or a salt thereof into a compound of formula (I) or a salt or solvate thereof.

[0017] Some embodiments describe a process for making a compound of formula (I) or a salt or solvate thereof, comprising at least one of process steps (a)-(c). The process of the invention may comprise one, two, or all three of process steps (a), (b), and (c).

[0018] The products of each of process steps (a), (b) and (c) may optionally be crystallized.

[0019] In some embodiments, the compound of formula (I) prepared by process (a), (b) or (c) is in a crystalline solid form. In one embodiment, a compound of formula (I) is provided in a crystalline solid form (Form 1) having an X-ray powder diffraction pattern substantially as shown in Figure 1. In another embodiment, a compound of formula (I) is provided in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​±0.1° 2θ experimental error). In another embodiment, there is provided a compound of formula (I) in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern having at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​±0.1 degrees 2θ experimental error).

[0020] Process step (a) In some embodiments, X is Cl.

[0021] In some embodiments where X is Cl, the reaction is carried out using a chlorinating reagent selected from the group consisting of 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA).

[0022] In some embodiments, the chlorinating reagent is DCDMH.

[0023] In some embodiments, the conversion of a compound of formula (II) or a salt thereof to a compound of formula (I) or a salt thereof is carried out in a suitable solvent, optionally with an additive material.

[0024] It has been found that such a conversion can be achieved in good yields using several solvents. In some embodiments, the conversion of the compound of formula (II) or a salt thereof to obtain the compound of formula (I) or a salt thereof is carried out in a suitable solvent that is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU), dimethylacetamide (DMAC), and sulfolane.

[0025] Although the use of solvents such as DMF was operationally simple, its use in the manufacture of pharmaceuticals is of potential concern due to its reproductive toxicity. Therefore, there was a need for alternative solvents suitable for use in the large-scale manufacture of pharmaceuticals.

[0026] However, the conversion of a compound of formula (II) or a salt thereof (e.g., where X is Cl) to a compound of formula (I) or a salt thereof did not proceed satisfactorily in alternative solvents, including some commonly used solvents. In such situations, the use of an additive material such as benzylethylammonium chloride was found to facilitate this reaction in good yields, as shown in Table 1 below. [Table 1]

[0027] Therefore, further investigations were carried out into the use of a variety of different additive materials in the conversion of a compound of formula (II) or a salt thereof (X is Cl) to a compound of formula (I) or a salt or solvate thereof, the results of which are shown in Table 2 below. [Table 2]

[0028] In some embodiments, the conversion of the compound of formula (II) or its salt to the compound of formula (I) or its salt is carried out in the presence of an additive reagent that is a quaternary ammonium salt, such as a quaternary ammonium bromide salt or a quaternary ammonium chloride salt. In some embodiments, the quaternary ammonium bromide salt is tetrabutylammonium bromide. In some embodiments, the quaternary ammonium chloride salt is selected from the group consisting of benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride. In some embodiments, the quaternary ammonium chloride salt is tetraethylammonium chloride.

[0029] In some embodiments, the conversion of the compound of formula (II) or its salt to obtain the compound of formula (I) or its salt or solvate in the presence of an additive reagent is carried out in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran, isopropyl acetate, acetone, and methyl isobutyl ketone. It has been found that acetonitrile provides the best combination of solubility and high boiling point. In some embodiments, the conversion is carried out in a solvent that is acetonitrile.

[0030] An embodiment of the present disclosure describes a compound of formula (IIa) or a salt thereof: [ka]

[0031] The compound of formula (I) can be prepared in the form of its acetic acid solvate. Some embodiments of the present disclosure describe the compound of formula (I) in the form of its acetic acid solvate. It has been found that the formation of the acetic acid solvate of the compound of formula (I) provides the process of the present invention with impurity and color removal capabilities. The acetic acid solvate of the compound of formula (I) can then be converted to the compound of formula (I).

[0032] In some embodiments, an acetic acid solvate of the compound of formula (I) in a crystalline solid form is provided. In some embodiments, an acetic acid solvate of the compound of formula (I) in a crystalline solid form is provided having an X-ray powder diffraction pattern substantially as shown in Figure 2. In another embodiment, an acetic acid solvate of the compound of formula (I) in a crystalline solid state is provided, characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error). In another embodiment, there is provided an acetic acid solvate of compound of formula (I) in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (all 2θ values, ±0.1° 2θ experimental error).

[0033] In some embodiments, the process further comprises the step of recrystallization of the compound of formula (I) or a salt or solvate thereof. In some embodiments, the recrystallization is carried out using methanol and water.

[0034] Process step (b) In some embodiments, the conversion of a compound of formula (VI) or a salt thereof to a compound of formula (III) or a salt thereof comprises decarboxylation of the compound of formula (VI) or a salt thereof to form a compound of formula (V) or a salt thereof; [ka] followed by esterification of the compound of formula (V) or a salt thereof to form a compound of formula (IV) or a salt thereof; [ka] (Wherein R is C 1~4 alkyl), followed by cyclization of the compound of formula (IV) or a salt thereof to form a compound of formula (III) or a salt thereof.

[0035] In some embodiments, the conversion of a compound of formula (VI) or a salt thereof to a compound of formula (V) or a salt thereof comprises decarboxylation in the presence of a base. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In certain embodiments, the base is triethylamine.

[0036] In some embodiments, R is methyl, ethyl, propyl, or butyl. In some embodiments, R is t-butyl. In some embodiments, R is methyl.

[0037] In some embodiments, the esterification of a compound of formula (V) or a salt thereof to a compound of formula (IV) or a salt thereof is carried out using methanol, for example, the esterification is carried out using methanol and hydrochloric acid.

[0038] In some embodiments, the cyclization of a compound of formula (IV) or a salt thereof to a compound of formula (III) or a salt thereof is carried out using potassium tert-butoxide.

[0039] In some embodiments, the compound of formula (III) or a salt thereof is acidified and isolated by precipitation with methylcyclohexane.

[0040] In some embodiments, the conversion of a compound of formula (VI) or a salt thereof to a compound of formula (III) or a salt thereof is telescoped such that the compound of formula (V) or a salt thereof and the compound of formula (IV) or a salt thereof are not isolated.

[0041] Some embodiments describe a compound of formula (IVa) or a salt thereof: [ka]

[0042] The compound of formula (IVa), i.e. (E)-methyl 7-methyl-5-oxo-3-styryloctanoate, is characterized by the following data:

[0043] 1 H NMR(500MHz,DMSO)δ7.33(m,2H),7.29(m,2H),7.20(m,1H),6.37(d,1H,J=16.0Hz),6.15(dd,1H,J=8.1Hz,J=16.0Hz),3.56(s,3H),3.09(m ,1H),2.60(m,2H),2.50(dd,1H,6.1Hz,J=15.4Hz),2.42(dd,1H,J=8.1Hz,J=15.4Hz),2.29(d,2H,7.0Hz),2.00(m,1H),0.82(s,6H,6.7Hz).

[0044] 13 C NMR(125MHz,DMSO)δ208.7(C),171.8(C),136.8(C),131.9(CH),129.5(CH),128.5(CH),127.2(CH),125 .9(CH),51.4(CH2),51.2(CH3),46.7(CH2),38.5(CH2),34.4(CH),23.8(CH),22.29(CH3),22.26(CH3).

[0045] HRMS-APCI(m / z)[M+H] + C 18 H 25 Calculated value for O3: 289.1798; measured value: 289.1719.

[0046] In some embodiments, a compound of formula (V) or a salt thereof is provided: [ka]

[0047] The compound of formula (V), i.e. (E)-7-methyl-5-oxo-3-styryloctanoic acid, is characterized by the following data:

[0048] 1 H NMR(700MHz,DMSO)δ12.13(s,1H),7.33(m,2H),7.29(m,2H),7.20(m,1H),6.37(d,1H,J=16Hz),6.17(dd,1H,J=8.0Hz,J=16.0Hz),3.07(m,1 H),2.60(m,2H),2.46(dd,1H,J=6.2Hz,J=15.5Hz),2.33(dd,1H,J=8.0,J=15.5Hz),2.30(d,2H,J=7.1Hz),2.0(m,1H),0.82(d,6H,J=6.6Hz).

[0049] 13 C NMR(176MH,DMSO)δ208.8(C),172.9(C),136.9(C),132.2(CH),129.3(CH),128.5(CH),127.1(C H), 125.9(CH), 51.4(CH2), 46.8(CH2), 38.9(CH2), 34.4(CH), 23.8(CH), 22.3(CH3), 22.3(CH3).

[0050] HRMS-APCI(m / z)[M+H] + C 17 H 23 Calculated value for O3: 275.1642; measured value: 275.1635.

[0051] In some embodiments, there is provided a compound of formula (VI) or a salt thereof: [ka]

[0052] A compound of formula (III) or a salt thereof can be converted to a compound of formula (I) or a salt or solvate thereof by a method described herein (e.g., process step (a)) or a method known to one of skill in the art (e.g., by a method described in Kronenwerth, M. et al.). In some embodiments, a compound of formula (III) or a salt thereof can be converted to a compound of formula (I) or a salt or solvate thereof by process step (a).

[0053] Process Step (c) In some embodiments, the conversion of a compound of formula (IX) or a salt thereof to a compound of formula (VI) or a salt thereof comprises condensing a compound of formula (IX) or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] followed by the addition of a malonate ester (RO(O)C-CH2-C(O)OR2) to form a compound of formula (VII) or a salt thereof. [ka] (Wherein R1 and R2 are independently 1~4 alkyl), and then hydrolyzing the compound of formula (VII) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0054] In some embodiments, the condensation of a compound of formula (IX) or a salt thereof to a compound of formula (VIII) or a salt thereof is carried out using lithium hydroxide, potassium hydroxide, or sodium hydroxide, for example, the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol.

[0055] In some embodiments, the conversion of a compound of formula (VIII) or a salt thereof to a compound of formula (VII) or a salt thereof comprises the addition of a malonic acid ester that is di-tert-butyl malonate or diethyl malonate.

[0056] In some embodiments, the conversion of a compound of formula (IX), or a salt thereof, to a compound of formula (VI), or a salt thereof, is telescoped such that the compounds of formula (VII) and formula (VIII), or salts thereof, are not isolated.

[0057] In some embodiments, there is provided a compound of formula (VIIa) or a salt thereof: [ka]

[0058] The compound of formula (VIIa), namely (E)-diethyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate, is characterized by the following data:

[0059] 1 H NMR(700MHz,DMSO)δ7.30(m,2H),7.30(m,SH0,7.21(m,1H),6.39(d,1H)J=15.8Hz),6.14(dd ,1H,J=15.99Hz,J=8.9Hz),4.12(q,2H,J=7.13Hz),4.06(m,2H),3.68(d,1H,J=8.1Hz),3.33( m,1H),2.73(dd,1H,J=16.9Hz,J=9.0Hz),2.63(m,1H),2.28(d,2H,6.9Hz),1.98(m,1H,6.7Hz ),1.16(t,3H,J=7.1Hz),1.10(t,3H,J=7.0Hz),0.81(d,3H,J=6.6Hz),0.80(d,3H,J=6.7Hz).

[0060] 13 C NMR(176MHz,DMSO)δ208.1(C),167.7(C),167.6(C),136.6(C),131.4(CH),128.9(CH),127.4(CH),125.9(CH),61.0(CH 2),60.8(CH2),55.0(CH),51.3(CH2),44.8(CH2),37.7(CH),23.8(CH),22.3(CH3),22.2(CH3),13.9(CH3),13.9(CH3).

[0061] HRMS-APCI(m / z)[M+H] + C 22 H 31 Calculated value for O5: 375.2166; measured value: 375.2158.

[0062] A compound of formula (VI) or a salt thereof can be converted to a compound of formula (I) or a salt or solvate thereof by the methods described herein (e.g., process steps (a) and (b)) or by methods known to one of skill in the art (e.g., by the methods described in Kronenwerth, M. et al.). In some embodiments, a compound of formula (VI) or a salt thereof can be converted to a compound of formula (I) or a salt or solvate thereof by process steps (a) and (b).

[0063] Preparation of Compounds of Formula (I) - Process B Some embodiments herein provide a process for preparing a compound of formula (I) or a salt or solvate thereof, comprising: [ka] Aromatizing a compound of formula (II) or a salt thereof [ka] In some embodiments, the process further comprises purifying the compound of formula (I) or a salt or solvate thereof. In some embodiments, the purification comprises crystallizing the compound of formula (I) or a salt or solvate thereof. In some embodiments, the compound of formula (I) is in a crystalline form as described in any embodiment described herein. In some embodiments, the compound of formula (I) is in crystalline form 1. In some embodiments, the compound of formula (I) is anhydrous crystalline. In some embodiments, the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in FIG. 2. In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (all 2θ values, ±0.1° 2θ experimental error).In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from those at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error). In some embodiments, X is Cl. In some embodiments, the aromatization is carried out in a suitable solvent and, optionally, with an additive reagent. In some embodiments, the aromatization is carried out in a suitable solvent that is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodiments, the aromatization is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran, isopropyl acetate, acetone, and methyl isobutyl ketone. In some embodiments, the aromatization is carried out in acetonitrile in the presence of an additive reagent. In some embodiments, the additive reagent is a quaternary ammonium salt. In some embodiments, the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride. In some embodiments, the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments, the aromatization is carried out in acetonitrile with tetraethylammonium chloride.

[0064] In some embodiments, the process comprises reacting a compound of formula (III) or a salt thereof: [ka] The method further comprises halogenating with a halogenating agent to obtain a compound of formula (II) or a salt thereof. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH and the compound of formula (II) or a salt thereof is a compound of formula (IIa) or a salt thereof. [ka] In some embodiments, the halogenation is carried out in methanol. In some embodiments, the halogenating agent is DCDMH and the halogenation is carried out in methanol.

[0065] In some embodiments, the process comprises reacting a compound of formula (IV) or a salt thereof [ka] (Wherein R is C 1~4 In some embodiments, R is selected from the group consisting of methyl, ethyl, propyl, or butyl. In some embodiments, R is t-butyl. In some embodiments, R is methyl. In some embodiments, the cyclization comprises contacting the compound of formula (IV) or a salt thereof with a base. In some embodiments, the cyclization is carried out using potassium tert-butoxide. In some embodiments, the cyclization is carried out in 2-methyltetrahydrofuran. In some embodiments, the cyclization comprises treating the compound of formula (IV) or a salt thereof, such as the compound of formula (IVa) or a salt thereof, with potassium tert-butoxide in 2-methyltetrahydrofuran. In some embodiments, the compound of formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.

[0066] In some embodiments, the process comprises esterifying a compound of formula (V) or a salt thereof to [ka] The method further comprises obtaining a compound of formula (IV) or a salt thereof. In some embodiments, the esterification is carried out using methanol and hydrochloric acid to obtain compound (IV). In some embodiments, the esterification comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

[0067] In some embodiments, the process comprises decarboxylating a compound of formula (VI) or a salt thereof, [ka] The method further comprises obtaining a compound of formula (V) or a salt thereof. In some embodiments, the decarboxylation comprises the presence of a base. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base is trimethylamine. In some embodiments, the decarboxylation comprises heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0068] In some embodiments, the process comprises reacting a compound of formula (VII) or a salt thereof [ka] (wherein each of R1 and R2 is independently 1~4In some embodiments, each of R1 and R2 is ethyl (VIIa). In some embodiments, the hydrolysis comprises treating the compound of formula (VII) or a salt thereof with sodium hydroxide. In some embodiments, the hydrolysis comprises treating the compound of formula (VII) or a salt thereof with sodium hydroxide in ethanol. In some embodiments, the process comprises hydrolyzing the compound of formula (VIIa) or a salt thereof comprising treating the compound of formula (VIIa) or a salt thereof with sodium hydroxide in ethanol.

[0069] In some embodiments, the process comprises the step of preparing a dialkyl malonate ester (RO(O)C-CH-C(O)OR, where each R and R is independently 1~4 alkyl) to a compound of formula (VIII) or a salt thereof, [ka] The method further comprises obtaining a compound of formula (VII) or a salt thereof. In some embodiments, the dialkyl malonate is di-tert-butyl malonate or diethyl malonate. In some embodiments, the adding comprises contacting the dialkyl malonate with a compound of formula (VIII) or a salt thereof in the presence of lithium bromide / triethylamine.

[0070] In some embodiments, the process comprises reacting trans-cinnamaldehyde (a compound of formula (IX)) or a salt thereof with [ka] and methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof. In some embodiments, the condensation comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, for example, the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.

[0071] Preparation of Compounds of Formula (I) - Process C In some embodiments, a process for preparing a compound of formula (I) or a salt or solvate thereof, comprising: [ka] a) decarboxylating a compound of formula (VI) or a salt thereof, [ka] forming a compound of formula (V) or a salt thereof; [ka] b) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IV) or a salt thereof; [ka] (Wherein R is C 1~4 alkyl), c) cyclizing the compound of formula (IV) or a salt thereof to form a compound of formula (III) or a salt thereof; [ka] d) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (II) or a salt thereof; [ka] wherein X is selected from Br, Cl, and I; e) aromatizing a compound of formula (II) or a salt thereof to form a compound of formula (I) or a salt thereof.

[0072] In some embodiments, the process further comprises isolating the compound of formula (III) or a salt thereof in step c). In some embodiments, the process further comprises isolating the compound of formula (II) or a salt thereof in step d). In some embodiments, the process further comprises purifying the compound of formula (I) or a salt or solvate thereof obtained from step e). In some embodiments, the purification comprises crystallizing the compound of formula (I) or a salt or solvate thereof. In some embodiments, the compound of formula (I) is in a crystalline form described in any embodiment described herein. In some embodiments, the compound of formula (I) is in crystalline form 1. In some embodiments, the compound of formula (I) is anhydrous crystalline. In some embodiments, the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in Figure 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (all 2θ values, ±0.1° 2θ experimental error).

[0073] In some embodiments, the decarboxylation of the compound of formula (VI) or a salt thereof in step a) comprises the presence of a base. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base is trimethylamine. In some embodiments, the decarboxylation comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0074] In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is selected from the group consisting of methyl, ethyl, propyl, or butyl. In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is t-butyl. In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is methyl. In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step b) is carried out using methanol and hydrochloric acid to obtain compound (IV) or a salt or solvate thereof. In some embodiments, the esterification comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

[0075] In some embodiments, the cyclization comprises contacting the compound of formula (IV) or a salt thereof with a base. In some embodiments, the cyclization is carried out using potassium tert-butoxide. In some embodiments, the cyclization is carried out in 2-methyltetrahydrofuran. In some embodiments, the cyclization comprises treating the compound of formula (IV) or a salt thereof, such as the compound of formula (IVa) or a salt thereof, with potassium tert-butoxide in 2-methyltetrahydrofuran. In some embodiments, the compound of formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.

[0076] In some embodiments, X of the compound of formula (II) or salt thereof in step d) is Cl, Br, or I. In some embodiments, X of the compound of formula (II) or salt thereof in step d) is Cl. In some embodiments, the halogenation comprises treating the compound of formula (III) or salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH and the compound of formula (II) or salt thereof is a compound of formula (IIa) or salt thereof.

[0077] In some embodiments, the aromatization in step e) is carried out in a suitable solvent and optionally with an additive reagent. In some embodiments, the aromatization in step e) is carried out in a suitable solvent that is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodiments, the aromatization in step e) is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran, isopropyl acetate, acetone, and methyl isobutyl ketone. In some embodiments, the aromatization is carried out in acetonitrile in the presence of an additive reagent. In some embodiments, the additive reagent is a quaternary ammonium salt. In some embodiments, the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride. In some embodiments, the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments, the aromatization is carried out in acetonitrile with tetraethylammonium chloride.

[0078] In some embodiments, R in step b) is methyl and X in step d) is chloro.

[0079] In some embodiments, the compound of formula (VI) or salt thereof in step a) is i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. Dialkyl malonate esters of formula RO(O)C-CH-C(O)OR, where each of R and R is independently 1~4alkyl) to a compound of formula (VIII) or a salt thereof to form a compound of formula (VII) or a salt thereof; [ka] wherein each R1 and R2 is as defined for the dialkyl malonate; iii. hydrolyzing a compound of formula (VII) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0080] In some embodiments, the condensation in step i. comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, for example, the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step i. comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.

[0081] In some embodiments, R in step ii. 1 and R 2 is ethyl. In some embodiments, the dialkyl malonate in step ii. is di-tert-butyl malonate or diethyl malonate. In some embodiments, the adding in step ii. comprises contacting the malonate with the compound of formula (VIII) or a salt thereof in the presence of lithium bromide / triethylamine.

[0082] Preparation of Compounds of Formula (I) - Process D Some embodiments herein provide a process for preparing a compound of formula (I) or a salt or solvate thereof, comprising: [ka] a) reacting a compound of formula (VI) [ka] heating with catalytic triethylamine to form a compound of formula (V); [ka] b) heating a compound of formula (V) with methanol and aqueous hydrochloric acid to form a compound of formula (IVa); [ka] c) treating a cooled solution of a compound of formula (IVa) with potassium tert-butoxide to form a compound of formula (III); [ka] d) heating the compound of formula (III) with 1,3-dichloro-5,5-dimethylhydantoin to form a compound of formula (IIa); [ka] e) heating a compound of formula (IIa) with tetraethylammonium chloride to form a compound of formula (I), a salt or a solvate thereof.

[0083] In some embodiments, the process further comprises purifying the compound of formula (I) from step e) by crystallization. In some embodiments, the process further comprises isolating the compound of formula (III) after step c), step ci). In some embodiments, the process further comprises isolating the compound of formula (IIa) after step d), step di). In some embodiments, the process further comprises purifying the compound of formula (I) obtained from step e). In some embodiments, the purification comprises crystallization of formula (I). In some embodiments, the compound of formula (I) is in a crystalline form as described in any embodiment described herein. In some embodiments, the compound of formula (I) is in crystalline form 1. In some embodiments, the compound of formula (I) is anhydrous crystalline. In some embodiments, the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in FIG.In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error). In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern with at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from the peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).

[0084] In some embodiments, the compound of formula (VI) in step a) is i. treating methyl isobutyl ketone with trans-cinnamaldehyde in the presence of methanolic sodium hydroxide to form a compound of formula (VIII); [ka] ii. treating the compound of formula (VIII) with diethyl malonate in the presence of lithium bromide and triethylamine to form a compound of formula (VIIa); [ka] iii. hydrolyzing a compound of formula (VIIa) with sodium hydroxide and ethanol to obtain a compound of formula (VI).

[0085] Preparation of Compounds of Formula (I) - Process E Some embodiments are shown in Scheme 2 below, which illustrates the process of certain embodiments of the invention, and are described in detail in the Examples. TIFF2024069233000053.tif126161

[0086] Process for the preparation of compounds of formula (VI) Some embodiments herein provide a process for preparing a compound of formula (VI) or a salt thereof: [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolysing the compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0087] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine.

[0088] Process for the preparation of compounds of formula (V) Some embodiments herein provide a process for preparing a compound of formula (V) or a salt thereof, comprising: [ka] A compound of formula (VI) or a salt thereof [ka] Described herein is a process that includes decarboxylating in the presence of a base to form a compound of formula (V) or a salt thereof. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base is trimethylamine. In some embodiments, the decarboxylation includes heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, a compound of formula (VI) or a salt thereof is prepared by any process described herein. In some embodiments, a compound of formula (VI) or a salt thereof is a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0089] Some embodiments herein provide a process for preparing a compound of formula (V) or a salt thereof, comprising: [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof; [ka] d) decarboxylating a compound of formula (VI) or a salt thereof in the presence of a base to form a compound of formula (V) or a salt thereof.

[0090] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine. In some embodiments, the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base in step d) is trimethylamine. In some embodiments, the decarboxylation in step d) comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0091] Process for the preparation of compounds of formula (IVa) Some embodiments herein provide a process for preparing a compound of formula (IVa) or a salt thereof, comprising: [ka] Esterifying a compound of formula (V) or a salt thereof [ka] A process is described that includes forming a compound of formula (IVa) or a salt thereof. In some embodiments, esterification of a compound of formula (V) or a salt thereof is carried out using methanol and hydrochloric acid to obtain compound (IVa). In some embodiments, the esterification includes treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments, a compound of formula (V) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (V) or a salt thereof is prepared by reacting a compound of formula (VI) or a salt thereof with: [ka] In some embodiments, the compound of formula (VI) or a salt thereof is prepared by a process comprising decarboxylation in the presence of a base to form a compound of formula (V) or a salt thereof. In some embodiments, the compound of formula (VI) or a salt thereof is prepared by any process described herein. In some embodiments, the compound of formula (VI) or a salt thereof is prepared by i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] iii. hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0092] Some embodiments herein provide a process for preparing a compound of formula (IVa) or a salt thereof, comprising: [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof; [ka] d) decarboxylating the compound of formula (VI) or a salt thereof in the presence of a base to form a compound of formula (V) or a salt thereof; [ka] e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof.

[0093] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine. In some embodiments, the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base in step d) is trimethylamine. In some embodiments, the decarboxylation in step d) comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (IVa). In some embodiments, the esterification in step e) comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

[0094] Process for the preparation of compounds of formula (IIa) Some embodiments herein provide a process for preparing a compound of formula (IIa) or a salt thereof, comprising: [ka] Halogenating a compound of formula (III) or a salt thereof [ka] A process is described that includes forming a compound of formula (IIa) or a salt thereof. In some embodiments, the halogenation includes treating a compound of formula (III) or a salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH. In some embodiments, the compound of formula (III) or a salt thereof is prepared by any process described herein. In some embodiments, the compound of formula (III) or a salt thereof is prepared by cyclizing a compound of formula (IVa) or a salt thereof, [ka] The compound of formula (III) or a salt thereof is prepared by a process comprising forming the compound of formula (III) or a salt thereof. In some embodiments, the compound of formula (IVa) or a salt thereof is prepared by any process described herein. In some embodiments, the compound of formula (IVa) or a salt thereof is prepared by a process comprising esterifying the compound of formula (V) or a salt thereof. [ka] In some embodiments, the compound of formula (V) or a salt thereof is prepared by any process described herein. In some embodiments, the compound of formula (V) or a salt thereof is prepared by reacting a compound of formula (VI) or a salt thereof with: [ka] In some embodiments, the compound of formula (VI) or a salt thereof is prepared by a process comprising decarboxylation in the presence of a base to form a compound of formula (V) or a salt thereof. In some embodiments, the compound of formula (VI) or a salt thereof is prepared by any process described herein. In some embodiments, the compound of formula (VI) or a salt thereof is prepared by i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] iii. hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0095] Some embodiments herein provide a process for preparing a compound of formula (IIa) or a salt thereof, comprising: [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof; [ka] d) decarboxylating the compound of formula (VI) or a salt thereof in the presence of a base to form a compound of formula (V) or a salt thereof. [ka] e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof; [ka] f) cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (III) or a salt thereof; [ka] g) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (IIa) or a salt thereof.

[0096] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine. In some embodiments, the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base in step d) is trimethylamine. In some embodiments, the decarboxylation in step d) comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (IVa). In some embodiments, the esterification in step e) comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments, the halogenation in step g) comprises treating the compound of formula (III) or a salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH.

[0097] Compound of formula (I) prepared by process A Some embodiments herein include [ka] a) decarboxylating a compound of formula (VI) or a salt thereof, [ka] forming a compound of formula (V) or a salt thereof; [ka] b) esterifying said compound of formula (V) or a salt thereof to form a compound of formula (IV) or a salt thereof; [ka] (Wherein R is C 1~4 alkyl), c) cyclizing the compound of formula (IV) or a salt thereof to form a compound of formula (III) or a salt thereof; [ka] d) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (II) or a salt thereof; [ka] wherein X is selected from Br, Cl, and I; e) aromatizing a compound of formula (II) or a salt thereof to form a compound of formula (I) or a salt thereof.

[0098] Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises isolating a compound of formula (III) or a salt thereof. Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises isolating a compound of formula (II) or a salt thereof. Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises purifying the compound of formula I obtained from step e). In some embodiments, the purification comprises crystallization of formula (I). In some embodiments, the compound of formula (I) is in crystalline form 1. In some embodiments, the compound of formula (I) is anhydrous crystalline. In some embodiments, the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in Figure 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (all 2θ values, ±0.1° 2θ experimental error).

[0099] In some embodiments, the decarboxylation of the compound of formula (VI) or a salt thereof in step a) comprises the presence of a base. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base is trimethylamine. In some embodiments, the decarboxylation comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0100] In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is selected from the group consisting of methyl, ethyl, propyl, or butyl. In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is t-butyl. In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is methyl. In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step b) is carried out using methanol and hydrochloric acid to obtain compound (IV). In some embodiments, the esterification comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

[0101] In some embodiments, the cyclization in step c) comprises contacting the compound of formula (IV) or a salt thereof with a base. In some embodiments, the cyclization is carried out using potassium tert-butoxide. In some embodiments, the cyclization is carried out in 2-methyltetrahydrofuran. In some embodiments, the cyclization comprises treating the compound of formula (IV) or a salt thereof, such as the compound of (IVa) or a salt thereof, with potassium tert-butoxide in 2-methyltetrahydrofuran. In some embodiments, the compound of formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.

[0102] In some embodiments, X of the compound of formula (II) or salt thereof in step d) is Cl, Br, or I. In some embodiments, X of the compound of formula (II) or salt thereof in step d) is Cl. In some embodiments, the halogenation comprises treating the compound of formula (III) or salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH and the compound of formula (II) or salt thereof is a compound of formula (IIa) or salt thereof.

[0103] In some embodiments, the aromatization in step e) is carried out in a suitable solvent and optionally with an additive reagent. In some embodiments, the aromatization in step e) is carried out in a suitable solvent that is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodiments, the aromatization in step e) is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran, isopropyl acetate, acetone, and methyl isobutyl ketone. In some embodiments, the aromatization is carried out in acetonitrile in the presence of an additive reagent. In some embodiments, the additive reagent is a quaternary ammonium salt. In some embodiments, the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride. In some embodiments, the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments, the aromatization is carried out in acetonitrile with tetraethylammonium chloride.

[0104] In some embodiments, R in step b) is methyl and X in step d) is chloro.

[0105] Some embodiments describe a compound of formula (I), or a salt thereof, wherein the compound of formula (VI), or a salt thereof, is prepared by any process described herein. Some embodiments describe a compound of formula (VI), or a salt thereof, wherein the compound of formula (VI), or a salt thereof, is i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. Dialkyl malonate esters of formula RO(O)C-CH-C(O)OR, where each of R and R is independently 1~4 alkyl) to a compound of formula (VIII) or a salt thereof to form a compound of formula (VII) or a salt thereof; [ka] wherein each R1 and R2 is as defined for the dialkyl malonate; iii. hydrolyzing said compound of formula (VII) or salt thereof to form said compound of formula (VI) or salt thereof.

[0106] In some embodiments, the condensation in step i. comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, for example, the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step i. comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.

[0107] In some embodiments, R in step ii. 1 and R 2 is ethyl. In some embodiments, the dialkyl malonate in step ii. is di-tert-butyl malonate or diethyl malonate. In some embodiments, the adding in step ii. comprises contacting the malonate with the compound of formula (VIII) or a salt thereof in the presence of lithium bromide / triethylamine.

[0108] Compounds of formula (I) prepared by process B Some embodiments herein include [ka] a) decarboxylating a compound of formula (VI) or a salt thereof, [ka] forming a compound of formula (V) or a salt thereof; [ka] b) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof; [ka] c) cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (III) or a salt thereof; [ka] d) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (IIa) or a salt thereof; [ka] e) aromatizing a compound of formula (IIa) or a salt thereof to form a compound of formula (I) or a salt thereof.

[0109] Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises isolating a compound of formula (III) or a salt thereof. Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises isolating a compound of formula (IIa) or a salt thereof. Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises purifying the compound of formula (I) obtained from step e). In some embodiments, the purification comprises crystallization of formula (I). In some embodiments, the compound of formula (I) is in crystalline form 1. In some embodiments, the compound of formula (I) is anhydrous crystalline. In some embodiments, the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in Figure 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (all 2θ values, ±0.1° 2θ experimental error).

[0110] In some embodiments, the decarboxylation of the compound of formula (VI) or a salt thereof in step a) comprises the presence of a base. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base is trimethylamine. In some embodiments, the decarboxylation comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0111] In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step b) is carried out using methanol and hydrochloric acid to obtain a compound of formula (IVa). In some embodiments, the esterification comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

[0112] In some embodiments, the cyclization in step c) comprises contacting the compound of formula (IVa) or a salt thereof with a base. In some embodiments, the cyclization is carried out using potassium tert-butoxide. In some embodiments, the cyclization is carried out in 2-methyltetrahydrofuran. In some embodiments, the cyclization comprises treating the compound of formula (IVa) or a salt thereof with potassium tert-butoxide in 2-methyltetrahydrofuran. In some embodiments, the compound of formula (III) or a salt thereof is further acidified and isolated by precipitation with methylcyclohexane.

[0113] In some embodiments, the halogenation in step d) comprises treating the compound of formula (III) or a salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH.

[0114] In some embodiments, the aromatization in step e) is carried out in a suitable solvent and optionally with an additive reagent. In some embodiments, the aromatization in step e) is carried out in a suitable solvent that is a polar aprotic solvent selected from the group consisting of dimethylformamide (DMF), 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone. In some embodiments, the aromatization in step e) is carried out in the presence of an additive reagent in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran, isopropyl acetate, acetone, and methyl isobutyl ketone. In some embodiments, the aromatization is carried out in acetonitrile in the presence of an additive reagent. In some embodiments, the additive reagent is a quaternary ammonium salt. In some embodiments, the quaternary ammonium salt is selected from the group consisting of tetrabutylammonium bromide, benzyltriethylammonium chloride, tetrabutylammonium chloride, tetraethylammonium chloride, and tetramethylammonium chloride. In some embodiments, the quaternary ammonium salt is tetraethylammonium chloride. In some embodiments, the aromatization is carried out in acetonitrile with tetraethylammonium chloride.

[0115] Some embodiments describe a compound of formula (I), or a salt thereof, wherein the compound of formula (VI), or a salt thereof, is prepared by any process described herein. Some embodiments describe a compound of formula (VI), or a salt thereof, wherein the compound of formula (VI), or a salt thereof, is i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] iii. hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0116] In some embodiments, the condensation in step i. comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, for example, the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step i. comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol.

[0117] In some embodiments, the adding in step ii. comprises contacting diethyl malonate with the compound of formula (VIII) or a salt thereof in the presence of lithium bromide / triethylamine.

[0118] Compounds of formula (I) prepared by process C Some embodiments include [ka] a) reacting a compound of formula (VI) [ka] heating with catalytic triethylamine to form a compound of formula (V); [ka] b) heating a compound of formula (V) with methanol and aqueous hydrochloric acid to form a compound of formula (IVa); [ka] c) treating the compound of formula (IVa) with potassium tert-butoxide to form a compound of formula (III); [ka] d) chlorinating the compound of formula (III) with 1,3-dichloro-5,5-dimethylhydantoin to form a compound of formula (IIa); [ka] e) heating a compound of formula (IIa) with tetraethylammonium chloride to form the compound of formula (I), salt or solvate thereof.

[0119] Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises isolating a compound of formula (III). Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises isolating a compound of formula (IIa). Some embodiments describe a compound of formula (I) or a salt or solvate thereof, wherein the process further comprises purifying the compound of formula (I) obtained from step e). In some embodiments, the purification comprises crystallization of formula (I). In some embodiments, the compound of formula (I) is in crystalline form 1. In some embodiments, the compound of formula (I) is anhydrous crystalline. In some embodiments, the compound of formula (I) has an X-ray powder diffraction pattern substantially as shown in FIG. 1. In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​± 0.1 ° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in Figure 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in a crystalline solid state characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error).In another embodiment, the compound of formula (I) is a crystalline solid state acetic acid solvate characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least three specific peaks selected from peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (all 2θ values, ±0.1° 2θ experimental error).

[0120] Some embodiments describe a compound of formula (I), or a salt thereof, wherein the compound of formula (VI), or a salt thereof, is prepared by any process described herein. Some embodiments describe a compound of formula (VI), or a salt thereof, wherein the compound of formula (VI) is i. treating methyl isobutyl ketone with trans-cinnamaldehyde in the presence of methanolic sodium hydroxide to form a compound of formula (VIII); [ka] ii. treating the compound of formula (VIII) with diethyl malonate in the presence of lithium bromide and triethylamine to form a compound of formula (VIIa); [ka] iii. hydrolyzing a compound of formula (VIIa) with sodium hydroxide and ethanol to form a compound of formula (VI).

[0121] Compound of formula (VI) prepared by the process Some embodiments herein include [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0122] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine.

[0123] Compound of formula (V) prepared by the process Some embodiments herein include [ka] A compound of formula (VI) or a salt thereof [ka] The present invention describes a compound of formula (V) or a salt thereof prepared by a process comprising decarboxylation in the presence of a base to form a compound of formula (V) or a salt thereof. In some embodiments, the base is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base is trimethylamine. In some embodiments, the decarboxylation comprises heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the compound of formula (VI) or a salt thereof is prepared by any process described herein. In some embodiments, the compound of formula (VI) or a salt thereof is i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] iii. hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0124] Some embodiments herein include [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof; [ka] and d) decarboxylating a compound of formula (VI) or a salt thereof in the presence of a base to form a compound of formula (V) or a salt thereof.

[0125] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine. In some embodiments, the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base in step d) is trimethylamine. In some embodiments, the decarboxylation in step d) comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0126] Compound of formula (IVa) prepared by the process Some embodiments herein include [ka] Esterifying a compound of formula (V) or a salt thereof [ka] Some embodiments describe a compound of formula (IVa) or a salt thereof prepared by a process comprising forming a compound of formula (IVa) or a salt thereof. In some embodiments, esterification of the compound of formula (V) or a salt thereof is carried out using methanol and hydrochloric acid to obtain compound (IVa) or a salt thereof. In some embodiments, the esterification comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. Some embodiments describe a compound of formula (IVa) or a salt thereof prepared by any process described herein. Some embodiments describe a compound of formula (V) or a salt thereof prepared by forming a compound of formula (VI) or a salt thereof with [ka] Described herein is a compound of formula (IVa) or a salt thereof, prepared by a process comprising decarboxylation in the presence of a base to form a compound of formula (V) or a salt thereof. Some embodiments describe a compound of formula (IVa) or a salt thereof, prepared by any process described herein. Some embodiments describe a compound of formula (V) or a salt thereof, prepared by reacting a compound of formula (VI) or a salt thereof with a compound of formula (VI) or a salt thereof, [ka] Described herein is a compound of formula (IVa) or a salt thereof, prepared by a process comprising decarboxylation in the presence of a base to form a compound of formula (V) or a salt thereof. Some embodiments describe a compound of formula (IVa) or a salt thereof, prepared by any process described herein, wherein the compound of formula (VI) or a salt thereof is prepared by any process described herein. Some embodiments describe a compound of formula (VI) or a salt thereof, prepared by any process described herein, wherein the compound of formula (VI) or a salt thereof is prepared by any process described herein. i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] iii. hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0127] Some embodiments herein include [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof; [ka] d) decarboxylating the compound of formula (VI) or a salt thereof in the presence of a base to form a compound of formula (V) or a salt thereof; [ka] e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof.

[0128] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine. In some embodiments, the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base in step d) is trimethylamine. In some embodiments, the decarboxylation in step d) comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (IVa). In some embodiments, the esterification in step e) comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

[0129] Compound of formula (IIa) prepared by the process Some embodiments herein include [ka] Halogenating a compound of formula (III) or a salt thereof [ka]

[0023] Some embodiments describe a compound of formula (IIa) or a salt thereof prepared by a process comprising forming a compound of formula (IIa) or a salt thereof. In some embodiments, the halogenation comprises treating a compound of formula (III) or a salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). Some embodiments describe a compound of formula (IIa) or a salt thereof prepared by any process described herein. Some embodiments describe a compound of formula (III) or a salt thereof prepared by cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (IVa) or a salt thereof. [ka] Described herein is a compound of formula (IIa) or a salt thereof, prepared by a process comprising forming a compound of formula (III) or a salt thereof. Some embodiments describe a compound of formula (IIa) or a salt thereof, prepared by any process described herein. Some embodiments describe a compound of formula (IIa) or a salt thereof, prepared by a process comprising esterifying a compound of formula (V) or a salt thereof. [ka] Some embodiments describe a compound of formula (IIa) or a salt thereof, wherein the compound of formula (V) or a salt thereof is prepared by any process described herein. Some embodiments describe a compound of formula (V) or a salt thereof, wherein the compound of formula (IIa) or a salt thereof is prepared by any process described herein. Some embodiments describe a compound of formula (V) or a salt thereof, wherein the compound of formula (VI) or a salt thereof is prepared by [ka] Described herein is a compound of formula (IIa) or a salt thereof, prepared by a process comprising decarboxylation in the presence of a base to form a compound of formula (V) or a salt thereof. Some embodiments describe a compound of formula (IIa) or a salt thereof, prepared by any process described herein, wherein the compound of formula (VI) or a salt thereof is prepared by any process described herein. Some embodiments describe a compound of formula (VI) or a salt thereof, prepared by any process described herein, wherein the compound of formula (VI) or a salt thereof is i. condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] ii. adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] iii. hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0130] Some embodiments herein include [ka] a) condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof; [ka] b) adding diethyl malonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof; [ka] c) hydrolyzing a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof; [ka] d) decarboxylating the compound of formula (VI) or a salt thereof in the presence of a base to form a compound of formula (V) or a salt thereof; [ka] e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof; [ka] f) cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (III) or a salt thereof; [ka] g) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (IIa) or a salt thereof.

[0131] In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of lithium hydroxide, potassium hydroxide, or sodium hydroxide, e.g., the condensation is carried out using potassium hydroxide or sodium hydroxide in methanol. In some embodiments, the condensation in step a) comprises treating methyl isobutyl ketone with trans-cinnamaldehyde or a salt thereof in the presence of sodium hydroxide in methanol. In some embodiments, the addition in step b) comprises contacting diethyl malonate with the compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide / triethylamine. In some embodiments, the base in step d) is selected from imidazole, pyridine, and lutidine (2,6-dimethylpyridine). In some embodiments, the base in step d) is trimethylamine. In some embodiments, the decarboxylation in step d) comprises heating the compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of the compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to obtain compound (IVa). In some embodiments, the esterification in step e) comprises treating the compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments, the halogenation in step g) comprises treating the compound of formula (III) or a salt thereof with a halogenating agent. In some embodiments, the halogenating agent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating agent is DCDMH.

[0132] compound Some embodiments describe a compound of Formula (I) in a crystalline solid form (Form 1) having an X-ray powder diffraction pattern substantially as shown in Figure 1. In some embodiments, the compound of Formula (I) in Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​±0.1 degrees 2-theta experimental error). In another embodiment, the compound of formula (I) in Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern with at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees (all values ​​±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is at least 80% Form 1. In some embodiments, the compound of formula (I) is at least 85% Form 1. In some embodiments, the compound of formula (I) is at least 90% Form 1. In some embodiments, the compound of formula (I) is at least 95% Form 1. In some embodiments, the compound of formula (I) is at least 99% Form 1. In some embodiments, the compound of formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Form 1.

[0133] Some embodiments describe an acetic acid solvate of the compound of formula (I). In some embodiments, the acetic acid solvate of the compound of formula (I) is a crystalline solid form having an X-ray powder diffraction pattern substantially as shown in FIG. 2. In another embodiment, the acetic acid solvate of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error). In another embodiment, the acetic acid solvate of the compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from the peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees (all 2θ values, ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is at least 80% acetate solvate of formula (I). In some embodiments, the compound of formula (I) is at least 85% acetate solvate of formula (I). In some embodiments, the compound of formula (I) is at least 90% acetate solvate of formula (I). In some embodiments, the compound of formula (I) is at least 95% acetate solvate of formula (I). In some embodiments, the compound of formula (I) is at least 99% acetate solvate of formula (I). In some embodiments, the compound of formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% acetate solvate of formula (I).

[0134] It will be understood by those skilled in the art that the percentage of a particular form of the compound of formula (I) is expressed with respect to all forms of formula (I) present in a sample. For example, the phrase "the compound of formula (I) is at least 95% form 1" is meant to convey that at least 95% of all forms of the compound of formula (I) present are form 1. Similarly, the phrase "the compound of formula (I) is at least 80% acetic acid solvate of formula (I)" means that at least 80% of the sample of the compound of formula (I) is in the form of acetic acid solvate.

[0135] Some embodiments describe a compound of formula (IIa) or a salt thereof: [ka]

[0136] Some embodiments describe a compound of formula (IVa) or a salt thereof: [ka]

[0137] Some embodiments describe a compound of formula (V) or a salt thereof: [ka]

[0138] Some embodiments describe a compound of formula (VI) or a salt thereof: [ka]

[0139] Pharmaceutical Compositions Embodiments herein describe pharmaceutical compositions comprising a compound of formula (I) or a salt or solvate thereof, prepared according to any embodiment described herein, and a pharma- ceutically acceptable excipient.

[0140] Some embodiments describe pharmaceutical compositions comprising a therapeutically effective amount of a compound of Formula (I) in Form 1 and a pharma- ceutically acceptable excipient. In some embodiments, the compound of Formula (I) in Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern with particular peaks at 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees 2θ (±0.1° 2θ). In some embodiments, the compound of formula (I) in Form 1 is characterized by an X-ray powder diffraction (XRPD) pattern having at least 9, or at least 8, or at least 7, or at least 6, or at least 5, or at least 4, or at least 3 specific peaks selected from 15.0, 17.8, 19.1, 20.2, 21.5, 22.4, 23.3, 24.5, 26.2, and 27.9 degrees 2θ (±0.1° 2θ). In some embodiments, the compound of formula (I) is at least 80% Form 1. In some embodiments, the compound of formula (I) is at least 85% Form 1. In some embodiments, the compound of formula (I) is at least 90% Form 1. In some embodiments, the compound of formula (I) is at least 95% Form 1. In some embodiments, the compound of formula (I) is at least 99% Form 1. In some embodiments, the compound of formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% Form 1.

[0141] Some embodiments describe pharmaceutical compositions comprising a therapeutically effective amount of an acetic acid solvate of a compound of formula (I) and a pharma- ceutically acceptable excipient. In some embodiments, the acetic acid solvate of a compound of formula (I) is a crystalline solid form having an X-ray powder diffraction with specific peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (±0.1° 2θ). In some embodiments, the acetic acid solvate of a compound of formula (I) is characterized by an X-ray powder diffraction (XRPD) pattern with at least six, or at least five, or at least four, or at least three specific peaks selected from the peaks at 6.7, 10.2, 11.1, 15.4, 16.9, 17.2, and 24.8 degrees 2θ (±0.1° 2θ). In some embodiments, the compound of formula (I) is at least 80% acetic acid solvate of formula (I). In some embodiments, the compound of formula (I) is at least 85% acetic acid solvate of formula (I). In some embodiments, the compound of formula (I) is at least 90% acetic acid solvate of formula (I). In some embodiments, the compound of formula (I) is at least 95% acetic acid solvate of formula (I). In some embodiments, the compound of formula (I) is at least 99% acetic acid solvate of formula (I). In some embodiments, the compound of formula (I) is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% acetic acid solvate of formula (I).

[0142] Some embodiments describe pharmaceutical compositions comprising a compound of Formula (IIa) and a pharma- ceutically acceptable excipient.

[0143] Some embodiments describe pharmaceutical compositions comprising a compound of Formula (IVa) and a pharma- ceutically acceptable excipient.

[0144] Some embodiments describe pharmaceutical compositions comprising a compound of formula (V) and a pharma- ceutically acceptable excipient.

[0145] Some embodiments describe pharmaceutical compositions comprising a compound of formula (VI) and a pharma- ceutically acceptable excipient.

[0146] In any of the foregoing pharmaceutical compositions, the compound of formula (I) is present in a therapeutically effective amount.

[0147] Remington:The Science and Practice of Pharmacy,21 st Methods for preparing pharmaceutical compositions of the compounds of formula (I) and their salts and solvates as described in the 2006 Edition are known to those skilled in the art.

[0148] In some embodiments, the compound of formula (I) or its salt or solvate prepared by any process described herein is at least 80% pure by weight. In some embodiments, the compound of formula (I) or its salt or solvate prepared by any process described herein is at least 85% pure by weight. In some embodiments, the compound of formula (I) or its salt or solvate prepared by any process described herein is at least 90% pure by weight. In some embodiments, the compound of formula (I) or its salt or solvate prepared by any process described herein is at least 95% pure by weight. In some embodiments, the compound of formula (I) or its salt or solvate prepared by any process described herein is at least 99% pure by weight. In some embodiments, the compound of formula (I) or its salt or solvate prepared by any process described herein is about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99% pure by weight.

[0149] definition "C 1~4 The term "alkyl" means a straight or branched chain alkyl containing at least 1 and at most 4 carbon atoms. 1~4Examples of "alkyl" include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and t-butyl.

[0150] References herein to a compound of a particular formula and "salts thereof" encompass the compound as a free base or as a salt thereof, e.g., as a pharma- ceutically acceptable salt thereof. For a review of suitable pharma-ceutically acceptable salts, see Berge et al., J. Pharm. Sci., 66:1-19 (1977).

[0151] "Solvates" of a compound of a particular formula may be formed when solvent molecules are incorporated into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropyl alcohol, N,N-dimethylsulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or solvates may include water as the solvent incorporated into the crystal lattice.

[0152] As used herein, "a pharma- ceutically acceptable excipient" refers to one or more pharma- ceutically acceptable materials, compositions, or vehicles involved in giving a pharmaceutical composition a form or consistency. Each excipient must be compatible with the other components of the pharmaceutical composition when mixed such that interactions substantially reduce the efficacy of the compound of formula (I) or its pharma- ceutically acceptable salt when administered to a patient.

[0153] As used herein, an X-ray powder diffraction pattern "substantially as shown in FIG. 1" or "substantially as shown in FIG. 2" refers to an X-ray powder diffraction pattern that is believed by one of skill in the art to represent a compound having the same crystalline form as the compound that provided the XRPD pattern in FIG. 1 or FIG. 2. It is well known and understood by those of skill in the art that the equipment used, humidity, temperature, powder crystal orientation, and other parameters involved in obtaining an X-ray powder diffraction pattern may cause some variability in the appearance, intensity, and position of the lines of the diffraction pattern. Thus, an X-ray powder diffraction pattern "substantially as shown in FIG. 1" or "substantially as shown in FIG. 2" may not necessarily show every line of any one of the diffraction patterns presented herein and / or may show slight variations in the appearance, intensity, or position of such lines resulting from differences in the conditions involved in obtaining the data. One of skill in the art can determine whether a sample of a crystalline compound has the same or different morphology as disclosed herein by comparison of their XRPD patterns (e.g., by overlaying).

[0154] Throughout the following description and claims, unless the context requires otherwise, the word "comprise" and variations such as "comprises" and "comprising" are understood to imply the inclusion of a stated integer or step or group of integers, but not to exclude any other integer or step or group of integers or steps.

[0155] A "therapeutically effective amount" of a compound, its pharma- ceutically acceptable salt or solvate, or pharmaceutical composition according to any embodiment described herein is an amount sufficient to produce a selected effect on at least one symptom or parameter of a particular disease or disorder. The therapeutic effect may be objective (i.e., measurable by some test or marker) or subjective (i.e., the subject shows or feels signs of an effect, or the physician observes a change). The effects contemplated herein include both medical and / or prophylactic treatments, as appropriate. The particular dose of a compound administered in accordance with the present disclosure to obtain a therapeutic and / or prophylactic effect is determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration, the co-administration of other active ingredients, the condition being treated, the activity of the particular compound used, the particular composition used, the age, weight, general health, sex, and diet of the patient; the time of administration, the route of administration, and the excretion rate of the particular compound used, as well as the duration of treatment. The therapeutically effective amount administered will be determined by the physician, taking into account the relevant circumstances described above and the exercise of sound medical judgment. A therapeutically effective amount of a compound according to any embodiment described herein is typically an amount that is sufficient to achieve an effective systemic or local concentration in a tissue when administered in a physiologically acceptable excipient composition.

[0156] Although the present invention has been described in some detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and preferred versions contained herein. Various embodiments of the present invention are illustrated with reference to the following non-limiting examples. The following examples are for illustrative purposes only and should not be construed as limiting the present invention in any manner.

[0157] As used herein, the symbols and rules used in these processes, schemes and examples are consistent with those used in modern scientific literature, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry.Unless otherwise stated, all starting materials were obtained from commercial suppliers and used without further purification.Specifically, the following abbreviations may be used in the examples and throughout the specification: TIFF2024069233000153.tif237159 EXAMPLES

[0158] General Experimental Procedures All reactions were carried out under positive nitrogen pressure in a jacketed laboratory reactor equipped with overhead stirring and fitted with a Teflon septum.

[0159] Materials: Commercially available solvents and reagents were used as received.

[0160] Equipment: Unless otherwise stated, proton nuclear magnetic resonance spectra ( 1 H NMR (H NMR) were recorded at 400 MHz at 25 °C. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to residual protons in the NMR solvent. Data are expressed as follows: chemical shift, multiplicity (s = singlet, d = doublet, sep = septet, m = multiplet and / or multiple resonances, br = broad), integral, coupling constant in Hertz, and assignment. Proton decoupled carbon nuclear magnetic resonance spectra ( 13 C NMR was recorded at 100 MHz at 25 °C. Chemical shifts are expressed in parts per million (ppm, δ scale) downfield from tetramethylsilane and are referenced to the carbon resonance of the solvent. High-resolution mass spectra (HRMS) were obtained using an Orbitrap mass spectrometer.

[0161] X-ray powder diffraction (XRPD) data were acquired on a PANalytical X′Pert Pro powder diffractometer, model PW3050 / 60, using an X′Celerator detector. Acquisition conditions were as follows: radiation: Cu Kα, generator tension: 45 kV, generator current: 40 mA, step size: 0.017°2θ, time per step: 500 s, divergence slit type: fixed, divergence slit size: 0.4354°, measurement temperature: 20-25 °C, goniometer radius: 240 mm. Samples were prepared by packing the sample into a 0.9 mm capillary or silicone sample holder with zero background. Peak positions were acquired using PANalytical X′Pert Highscore Plus software. Error bars are approximately ±0.1°2θ for each of the peak assignments.

[0162] Example 1 Synthesis of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (compound of formula (VIII)) [ka] A solution of sodium hydroxide (11.4 g, 284 mmol, 1.5 equiv.) in methanol (100 mL) was added dropwise over 1 h to a stirred solution of cinnamaldehyde (compound of formula (IX)) (25 g, 189 mmol, 1 equiv.) and methyl isobutyl ketone (75 mL, 602 mmol, 3.2 equiv.) at −5° C. Once the addition was complete, the reaction mixture was stirred at 0° C. for 2 h. Toluene (250 mL) and water (125 mL) were then added directly to the reactor at 0° C. and the stirred biphasic mixture was allowed to warm to 20° C. The aqueous layer was removed and the organic layer was washed with water (2×75 mL). The washed organic layer was then dried by azeotropic distillation under vacuum to a final solution volume of 75 mL or until analysis by Karl Fischer titration revealed a water content of less than 0.2%. The crude material was utilized in the next transformation without further treatment.

[0163] Example 2 Synthesis of (E)-di-tert-butyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula VII where R1+R2=tBu) [ka] The concentrated solution obtained in the previous step (Example 1) was diluted with toluene to a total volume of the solution of 175 mL. Then, to a solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (compound of formula (VIII)) in toluene at 20° C., di-tert-butyl malonate (40.3 mL, 180 mmol, 0.95 equiv.), triethylamine (13.1 mL, 94.5 mmol, 0.5 equiv.), and powdered lithium bromide (3.28 g, 37.8 mmol, 0.2 equiv.) were added. The heterogeneous reaction mixture was stirred at 20° C. for 2 hours. Then, water (200 mL) was charged directly to the stirred reaction mixture. The layers were allowed to separate and the aqueous layer was discarded. The resulting product solution was utilized for the next transformation without further treatment. Alternatively, the di-tert-butyl malonate addition product (E)-di-tert-butyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VII)) can also be isolated by concentration of a toluene solution and crystallization from isopropyl alcohol / water (3:2) to yield (E)-di-tert-butyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VII)) as a pale yellow solid.

[0164] 1H NMR(400MHz,DMSO)δ7.32-7.29(m,4H),7.24-7.18(m,1H),6.38(d,1H,J=16Hz),6 .12(dd,1H,J=16,8.4Hz),3.39(d,1H,J=8.4Hz),3.27-3.20(m,1H),2.70(dd,1H,J =16.8,9.2Hz),2.58(dd,1H,J=16.8,4.4Hz),2.28(d,2H,J=7.2Hz),1.98(sep,1H, J=6.8Hz),1.39(s,9H),1.33(S,9H),0.81(d,3H,J=6.4Hz),0.80(d,3H,J=6.4Hz).

[0165] 13 C NMR(100MHz,DMSO)δ208.2(C),167.0(C),166.8(C),136.7(C),131.2(CH),129.1(CH),128.6(CH),127.3(CH),125.9(CH), 81.2(C),80.9(C),56.8(CH),51.4(CH2),45.0(CH2),37.7(CH),27.5(CH3),27.4(CH3),23.9(CH),22.3(CH3),22.2(CH3).

[0166] HRMS-APCI(m / z)[M+H] + C 26 H 39 Calculated value for O5: 431.2792; measured value: 431.2754.

[0167] Example 3 Synthesis of (E)-Diethyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula VIIa) [ka] The concentrated solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (approximately 7.6 moles) is diluted with toluene. Then, to the solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (compound of formula (VIII)) in toluene at 20°C, diethyl malonate (1.83 kg, 1.73 L, 1.5 equiv.), triethylamine (1.15 kg, 1.58 L, 1.5 equiv.), and powdered lithium bromide (131 g, 0.2 equiv.) are added. The heterogeneous reaction mixture is stirred at 35-40°C for at least 8 hours. Then, water (8 L, 8 vol.) is charged directly to the stirred reaction mixture and stirred at 35°C for 15-30 minutes. The layers are allowed to separate and the aqueous layer is discarded. The resulting product solution is utilized for the next transformation without further treatment. Alternatively, the diethyl malonate addition product (E)-diethyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VIIa)) can also be isolated by concentration and crystallization of a toluene solution to yield (E)-diethyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VIIa)).

[0168] 1 H NMR(700MHz,DMSO)δ7.30(m,2H),7.30(m,SH0,7.21(m,1H),6.39(d,1H)J=15.8Hz),6.14(dd ,1H,J=15.99Hz,J=8.9Hz),4.12(q,2H,J=7.13Hz),4.06(m,2H),3.68(d,1H,J=8.1Hz),3.33( m,1H),2.73(dd,1H,J=16.9Hz,J=9.0Hz),2.63(m,1H),2.28(d,2H,6.9Hz),1.98(m,1H,6.7Hz ),1.16(t,3H,J=7.1Hz),1.10(t,3H,J=7.0Hz),0.81(d,3H,J=6.6Hz),0.80(d,3H,J=6.7Hz).

[0169] 13C NMR(176MHz,DMSO)δ208.1(C),167.7(C),167.6(C),136.6(C),131.4(CH),128.9(CH),127.4(CH),125.9(CH),61.0(CH 2),60.8(CH2),55.0(CH),51.3(CH2),44.8(CH2),37.7(CH),23.8(CH),22.3(CH3),22.2(CH3),13.9(CH3),13.9(CH3).

[0170] HRMS-APCI(m / z)[M+H] + C 22 H 31 Calculated value for O5: 375.2166; measured value: 375.2158.

[0171] Example 4 Synthesis of (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula VI) [ka] Method A The toluene solution of (E)-di-tert-butyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VII)) obtained in the previous step was diluted with acetic acid (50 mL) and added dropwise to a stirred solution of acetic acid (100 mL) and concentrated aqueous hydrochloric acid (75 mL) at 60° C. over 1 h. Once the addition was complete, the resulting solution was stirred at 60° C. for 4 h. The product mixture was cooled to 20° C. over 30 min and water (200 mL) was added. The two layers were stirred vigorously at 20° C. and then allowed to settle. The aqueous layer was then discarded and the toluene layer was concentrated to dryness. Toluene (250 mL) was added to the resulting oil and the solution was heated to 60° C. with stirring. The warm toluene solution was then slowly cooled to 20° C. over 1 hour, at which point (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula (VI)) precipitated from solution. The solid was then filtered and the wet cake was washed with toluene (100 mL). The wet cake was then dried under vacuum at 30° C. for 12 hours to provide (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula (VI)) as a white crystalline solid (37.3 g, 62% from cinnamaldehyde (compound of formula (IX)).

[0172] Method B To a toluene solution of (E)-diethyl 2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (approximately 7.6 moles, compound of formula (VIIa)) from Example 3 at 20-30° C., was charged 6 M aqueous sodium hydroxide (5.05 L, 4 equivalents), toluene (0.5 L or 0.5 volume), and 200 proof ethanol (2 volumes), and the contents were diluted with T J= 20 °C for at least 4 hours. Once complete, the temperature was adjusted to 35-50 °C and stirred for at least 30 minutes, after which stirring was stopped and the layers separated. The aqueous layer was cooled to 0-5 °C, while maintaining the temperature below 10 °C during the addition, and the pH was adjusted to 0-1 with concentrated hydrochloric acid (required 2.9 L or 4.7 equiv). Once the desired pH was reached, the vessel was charged with TBME (3 L, 3 vol) and the biphasic mixture was warmed to 20-25 °C. The mixture was stirred for 15-30 minutes and the layers separated. Toluene (7 L, 7 vol) and water (6 L, 6 vol) were added to the organic layer and the mixture was stirred for 15-30 minutes. The layers were separated and toluene was added to achieve a charge of 16-18 volumes (3 L, 3 vol). The mixture was distilled to approximately 9-9.5 volumes using vacuum distillation, the temperature was adjusted to 40-45 °C, and the mixture was seeded with 5 g of compound VI (0.2% w / w relative to theoretical yield). The mixture was stirred at 40-45 °C for 30-60 min. Once nucleation was observed, the mixture was diluted to 12 volumes with toluene and held at 40-45 °C for at least 1 h. The slurry was cooled to 10-20 °C at 0.5 °C / min and held at 10-20 °C for at least 1 h. The solid was isolated by filtration and the filter cake was washed with toluene (2 × 7 volumes). The solid was dried overnight in a vacuum oven at 25-35 °C to obtain (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula (VI)).

[0173] 1 H NMR(400MHz,DMSO)δ12.78(br s,2H),7.32-7.27(m,4H),7.23-7.19(m,1H),6.39(d,1H,J=16Hz),6.17 (dd,1H,J=16,8.4Hz),3.43(d,1H,J=8.4Hz),3.31-3.24(m,1H),2.72(d d,1H,J=16.8,8.8Hz),2.63(dd,1H,J=16.4,4Hz),2.28(d,2H,J=7.2Hz),1.98(sep,1H,J=6.8Hz),0.81(d,3H,J=6.4Hz),0.80(d,3H,J=6.4Hz).

[0174] 13C NMR(100MHz,DMSO)δ208.4(C),169.6(C),169.5(C),136.8(C),130.9(CH),129.6(CH),128.5(CH),12 7.3(CH), 126.0(CH), 55.7(CH), 51.4(CH2), 45.1(CH2), 37.6(CH), 23.9(CH), 22.3(CH3), 22.2(CH3).

[0175] HRMS-APCI(m / z)[M+H] + C 18 H 23 Calculated value for O5: 319.1540; measured value: 319.1528.

[0176] Example 5 Synthesis of (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III)) [ka] Triethylamine (4.4 mL, 31.4 mmol, 0.25 equiv.) was charged to a stirred slurry of (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula (VI)) (40.0 g, 126 mmol, 1 equiv.) in toluene (210 mL). The resulting mixture was heated to 110° C. and stirred for 2 hours. The reaction mixture containing the unisolated intermediate (E)-7-methyl-5-oxo-3-styryloctanoic acid (compound of formula V) was then cooled to 20° C. and charged with methanol (120 mL) and concentrated aqueous hydrochloric acid (10.5 mL). The resulting solution was stirred at 60° C. for 4 hours. The resulting mixture containing the unisolated intermediate (E)-methyl 7-methyl-5-oxo-3-styryloctanoate (compound of formula (IVa)) was cooled to 20° C. and washed with water (200 mL). The washed organic layer was then dried by vacuum distillation to a final solution volume of 120 mL. The solution of the methyl ester (E)-methyl 7-methyl-5-oxo-3-styryloctanoate (compound of formula (IVa)) was then cooled to 0° C. A solution of potassium tert-butoxide (19.7 g, 176 mmol, 1.4 equiv.) in 2-methyltetrahydrofuran (80 mL) was then added dropwise over 1 h to the cooled solution of (E)-methyl 7-methyl-5-oxo-3-styryloctanoate (compound of formula (IVa)). Once the addition was complete, the reaction mixture was allowed to warm to 20° C. over 30 min. The warmed solution was stirred at 20° C. for 1 h. The resulting product mixture was then charged with 1.0 M aqueous hydrochloric acid (180 mL) and the biphasic mixture was stirred for 10 minutes. The aqueous layer was then discarded and the organic layer was washed with 10% aqueous sodium chloride (2×160 mL). Methylcyclohexane (400 mL) was then added dropwise to the solution of (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III)) over 1 hour, at which point the product began to precipitate. The slurry was then filtered and the wet cake was washed with methylcyclohexane (120 mL).The wet cake was then dried under vacuum at 30° C. for 12 hours to give (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III)) as a white crystalline solid (25.3 g, 79% from (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid, (compound of formula (VI)).

[0177] 1 H NMR(400MHz,DMSO)δ10.33(br s,1H,OH),7.39-7.37(m,2H),7.34-7.29(m,2H),7.24-7.20(m,1H),6.43(d,1H,J=16Hz),6.27(dd, 1H,J=16,7.2Hz),3.08(sep,1H,J=7.2Hz),2.87-2.78(m,1H),2.40(br,4H),1.08(d,6H,J=7.2Hz).

[0178] 13 C NMR (100 MHz, DMSO) δ 136.8 (C), 132.5 (CH), 128.9 (CH), 128.6 (CH), 127.3 (CH), 126.0 (CH), 119.2 (C), 36.1 (CH), 22.6 (CH), 20.4 (CH); other carbons undergo enol tautomerization.

[0179] HRMS-APCI(m / z)[M+H] + C 17 H 21 Calculated value for O2: 257.1536; measured value: 257.1519.

[0180] Example 6 Synthesis of (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)) [ka] A 1-L jacketed laboratory reactor was charged with (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III)) (55 g, 215 mmol, 1 equiv.) and methanol (495 mL), resulting in a heterogeneous suspension. The mixture was heated to an internal temperature of approximately 45-50 °C, at which point a homogeneous solution was obtained. To this solution was sequentially charged solid 1,3-dichloro-5,5-dimethylhydantoin (23.3 g, 118 mmol, 0.55 equiv.) in five equal portions. The product solution was then cooled to 40 °C over 10 min and seeded with 146 mg of (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)). The mixture was aged for 30 min and then cooled to 23 °C over 60 min. Water (330 mL) was then added dropwise to the slurry over 1 hour, and the mixture was stirred at 20° C. for 30 minutes. The slurry was then filtered, and the wet cake was washed with 1:1 methanol / water (2×110 mL). The wet cake was then dried under vacuum at 45° C. for 12 hours to provide (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)) as a white crystalline solid (60.0 grams, 96%), present as an approximately 2:1 mixture of diastereomers.

[0181] Isomer 1: 1 H NMR(400MHz,DMSO)δ7.41-7.39(m,2H),7.36-7.32(m,2H),7.23-7.22(m,1H),6.54(d,1H,J=16Hz),6.32(dd,1H, J=16,7.2Hz),3.20-3.14(m,3H),2.84-2.77(m,1H),2.73-2.72(m,1H),2.70-2.69(m,1H),0.82(d,6H,J=6.8Hz).

[0182] 13C NMR (100MHz, DMSO) δ198.5(C),136.5(C),130.4(CH),129.9(CH),128.6(CH),127.5(CH),126.1(CH),94.6(C),43.4(CH2),35.0(CH),32.8(CH),16.7(CH3).

[0183] Isomer 2: 1 H NMR(400MHz,DMSO)δ7.33-7.28(m,4H),7.25-7.21(m,2H),6.35(dd,1H,J=16,2Hz),6.03(dd,1H,J=16,5.6Hz),3.48( dd,1H,J=14.8,6Hz),3.24-3.18(m,1H),3.10(sep,1H,J=6.4Hz),2.86(dd,1H,J=14.8,3.6Hz),0.83(d,6H,J=6.4Hz).

[0184] 13 C NMR (100MHz, DMSO) δ199.6(C),136.1(C),130.3(CH),130.1(CH),128.6(CH),127.7(CH),126.1(CH),94.5(C),42.2(CH2),34.7(CH),30.9(CH),16.9(CH3).

[0185] HRMS-APCI(m / z)[M+H] + C 17 H 20 Calculated for ClO2, 291.1146; found, 291.1132.

[0186] Example 7 Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (compound of formula (I)) [ka] A jacketed laboratory reactor was charged with (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)) (407 g, 1.4 mol, 1 equiv.), tetraethylammonium chloride (464 g, 2.8 mol, 2 equiv.), and acetonitrile (1.2 L). The mixture was heated to 75-80 °C for 6 h. The product mixture was then cooled to 20 °C over 30 min and diluted with tert-butyl methyl ether (3.26 L). The resulting solution was washed four times with water (2 L each wash). The resulting solution was concentrated to a volume of approximately 610 mL. Acetic acid (815 mL) was charged and the solution was concentrated under reduced pressure to a volume of approximately 1.3 L. The resulting slurry was heated to 55 °C until homogeneous and then slowly cooled to 35 °C over 1 h, during which time the product began to precipitate. Methylcyclohexane (6.5 L) was added to the slurry over 2 h. Once the addition was complete, the mixture was further cooled to about 23° C. over 1 hour. The solid was filtered and washed twice with 6:1 methylcyclohexane / AcOH. The isolated solid was then dried under vacuum at 80° C. for 24 hours to give (E)-2-isopropyl-5-styrylbenzene-1,3-diol (compound of formula (I)) as a white crystalline solid (305 g, 86%).

[0187] 1 H NMR(400MHz,DMSO)δ9.05(s,2H,OH),7.58-7.55(m,2H),7.37-7.33(m,2H),7.27-7.22(m,1H),7.00(d ,1H,J=16.4Hz),6.87(d,1H,J=16.4Hz),6.47(s,2H),3.43(sep,1H,J=7.2Hz),1.24(d,6H,J=7.2Hz).

[0188] 13 C NMR(100MHz,DMSO)δ156.4(C),137.0(C),134.7(C),128.9(CH),128.7(CH),12 7.4 (CH), 126.7 (CH), 126.3 (CH), 120.1 (C), 105.1 (CH), 23.7 (CH), 20.6 (CH3).

[0189] HRMS-APCI(m / z)[M+H] + C 17 H 19 Calculated value for O2: 255.1380; measured value: 255.1376.

Claims

1. A process for preparing a compound of formula (IIa) or a salt thereof, The process involves a compound of formula (III) or a salt thereof. A process comprising the step of halogenating with a halogenating agent selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH), N-chlorosuccinimide (NCS), and trichloroisocyanuric acid (TCCA) to form a compound of formula (IIa) or a salt thereof.

2. In the process according to Claim 1, the compound of formula (III) or a salt thereof is the compound of formula (IVa) or a salt thereof. A process that includes the step of cyclizing to form a compound of formula (III) or a salt thereof.

3. In the process according to Claim 2, the compound of formula (IVa) or a salt thereof is the compound of formula (V) or a salt thereof. A process that includes the step of esterifying to form a compound of formula (IVa) or a salt thereof.

4. In the process according to claim 3, the compound of formula (V) or a salt thereof is the compound of formula (VI) or a salt thereof. A process that includes the step of decarboxylating in the presence of a base to form a compound of formula (V) or a salt thereof.

5. In the process according to claim 4, the compound of formula (VI) or a salt thereof is i) Condensing trans-cinnamaldehyde or a salt thereof with methyl isobutyl ketone to obtain the compound of formula (VIII) or a salt thereof The process of forming, ii) Adding diethyl malonate to the compound of formula (VIII) or a salt thereof to obtain the compound of formula (VIIa) or a salt thereof The process of forming, and iii) A step of hydrolyzing the compound of formula (VIIa) or a salt thereof to form the compound of formula (VI) or a salt thereof, A process that is prepared by a process that includes [a specific element].

6. An isolated compound of formula (IIa) or a salt thereof.

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