RU2795144C2 - Method of obtaining tapinarof - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to variants of the method for obtaining the compounds of formula (I)

, which has several potentially useful biological reactions, including antibacterial, antioxidant, and anticancer activity, or a salt or solvate thereof, to processes for preparing intermediates, as well as to intermediates for preparing a compound of formula I. One embodiment of a process for preparing a compound of formula I involves aromatization compounds of formula (II)

, where X represents Cl, Br or I.

EFFECT: technical result is the development of a highly productive synthesis of the compound of formula I without any potential problems with toxicity.

28 cl, 2 dwg, 2 tbl, 7 ex

Description

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This application claims the benefit and priority of U.S. Provisional Application No. 62/584192, entitled "PROCESS", filed November 10, 2017, the contents of which are incorporated herein in their entirety by reference.

SUMMARY OF THE INVENTION

[0002] In some embodiments, this invention provides methods for preparing a compound of formula (I) or a salt thereof, as well as new intermediates used therewith.

[0003] In some embodiments, this invention describes a compound of formula (IIa) or a salt thereof

and how to get them.

[0004] In some embodiments, this invention describes a compound of formula (IVa) or a salt thereof

and how to get them.

In some embodiments, this invention describes a compound of formula (V) or a salt thereof

and how to get them.

[0005] In some embodiments, this invention describes a compound of formula (VI) or a salt thereof

and how to get them.

[0006] In some embodiments, this invention describes a pharmaceutical composition that contains a compound of formula (I), or a salt or solvate thereof, obtained in accordance with the methods of this invention, and a pharmaceutically acceptable excipient.

BRIEF DESCRIPTION OF GRAPHICS

[0007] In FIG. 1 illustrates an X-ray powder diffraction (XRPD) pattern of a compound of formula (I) in crystalline solid form (Form 1).

[0008] In FIG. 2 illustrates an X-ray powder diffraction (XRPD) pattern of an acetic acid solvate of a compound of formula (I) in crystalline solid form.

DETAILED DESCRIPTION OF THE INVENTION

[0009] 3,5-Dihydroxy-4-isopropyl-trans-stilbene, also known as (E)-2-isopropyl-5-styrylbenzene-1,3-diol, of formula (I), is a product of natural origin derived from bacteria

[0010] This compound has several potentially beneficial biological reactions, including antibacterial, antioxidant, and anticancer activity. PCT patent application WO 200142231 discloses polyhydroxystilbenes and stilbene oxides as antipsoriasis agents and protein kinase inhibitors.

[0011] There are several routes known in the art for synthesizing a compound of formula (I). Chinese Patent Application CN 101648851 describes a synthesis route through the formation of an (E)-olefin via Horner-Wadsworth-Emmons olefination. Ways are also known that are carried out by introducing an isopropyl group into a substituted resorcinol derivative via Friedel-Crafts alkylation.

[0012] An alternative synthetic approach similar to the known biosynthetic pathway has been described by Kronenwerth et al. (Eur. J. Org. Chem. 2014, 8026-8028). However, problems arise along this path in the synthesis process with low yields of intermediate compounds and the final product. There is also a toxicity problem associated with the incomplete removal of trace amounts of mercury in isopropylstilbene, making this route unsuitable for large-scale drug production.

[0013] Schamp et al. (Tetrahedron, 1973, 29, 3857-3859) discloses the synthesis of simple 2-substituted resorcinols, for example 2-methyl-, 2-benzyl- and 2-acetylresorcinol from the corresponding 1,3-cyclohexanediones. These conditions include chlorination of 1,3-cyclohexanediones followed by removal of HCl by heating with 25% dry hydrogen chloride in dimethylformamide.

[0014] There is a need for an efficient and scalable method for the large-scale production of a compound of formula (I), in particular a high-yield synthesis without potential toxicity problems.

[0015] The present invention proposes a number of embodiments of the invention relating to the method shown in Scheme 1 below:

Preparation of the compound of formula (I) - method A

[0016] In some embodiments, a process for preparing a compound of formula (I) or a salt or solvate thereof is described.

including one or more steps (a), (b) and (c) of the method, wherein:

step (a) involves the chemical reaction of a compound of formula (III) or a salt thereof

to form a compound of formula (II) or a salt thereof

where X represents Cl, Br or I, and then (ii) the conversion of the compounds of formula (II) or its salts in the compound of formula (I) or its salt or solvate;

step (b) comprises the conversion of a compound of formula (VI) or a salt thereof

to a compound of formula (III) or a salt thereof

and thereafter converting a compound of formula (III) or a salt thereof into a compound of formula (I) or a salt or solvate thereof; And

step (c) comprises converting a compound of formula (IX) or a salt thereof

to a compound of formula (VI) or a salt thereof

and thereafter converting a compound of formula (VI) or a salt thereof into a compound of formula (I) or a salt or solvate thereof.

[0017] In some embodiments, methods for preparing compounds of formula (I) or a salt or solvate thereof are described, comprising at least one of process steps (a)-(c). The methods of this invention may include one, two or all three steps (a), (b) and (c) of the method.

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

[0019] In some embodiments of the invention, the compound of formula (I) obtained by method (a), (b) or (c) is in crystalline solid form. In one embodiment, the invention provides a compound of formula (I) in crystalline solid form (Form 1) which has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In another embodiment, the invention provides a compound of formula (I) in crystalline solid form, 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, the invention provides a compound of formula (I) in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least nine, or at least eight, or at least seven, or at least six, or at least at least five, or at least four, or at least three 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).

Process step (a)

[0020] In some embodiments, X is Cl.

[0021] In some embodiments of the invention, where X is Cl, the chemical reaction is carried out using a chlorination 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 chlorination 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 and optionally with an additive.

[0024] Good conversion yields have been found to be achieved using a range of solvents. In some embodiments, the conversion of a compound of formula (II) or a salt thereof to give a compound of formula (I) or a salt thereof is carried out in a suitable solvent which 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 a solvent, such as DMF, was the most practical from a practical point of view, its use in the manufacture of a drug raises potential concerns due to its reproductive toxicity. Therefore, an alternative solvent was found that would be suitable for use in large-scale drug production.

[0026] However, it has been found that the conversion of a compound of formula (II) or a salt thereof, for example where X is Cl, to a compound of formula (I) or a salt thereof did not proceed well with alternative solvents, including some commonly used solvents. Under such circumstances, it has been found that the use of an additive, for example benzylethylammonium chloride, facilitates this reaction in good yields. This is demonstrated in Table 1 below.

[0027] Therefore, further research was carried out on the use of a number of different additives in the conversion of a compound of formula (II) or a salt thereof, where X is Cl, to a compound of formula (I) or a salt or solvate thereof. These results are presented in Table 2 below.

[0028] 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 the presence of an additional reagent that is a quaternary ammonium salt, for example, 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 of the invention, the conversion of a compound of formula (II) or a salt thereof to obtain a compound of formula (I) or a salt or solvate thereof in the presence of an additional reagent is carried out in a solvent selected from the group consisting of acetonitrile, toluene, 2-methyltetrahydrofuran , isopropyl acetate, acetone and methyl isobutyl ketone. Acetonitrile has been found to provide the best combination of solubility and high boiling point. In some embodiments of the invention, this transformation is carried out in a solvent, which is acetonitrile.

[0030] Embodiments of this invention describe a compound of formula (IIa) or a salt thereof

[0031] The compound of formula (I) can be obtained in the form of its solvate with acetic acid. In some embodiments, this invention describes the compound of formula (I) in the form of its solvate with acetic acid. It has been found that the formation of an acetic acid solvate of the compound of formula (I) allows the purification of impurities and dyes for the process of the invention. An acetic acid solvate of a compound of formula (I) may then be converted to a compound of formula (I).

[0032] In some embodiments, an acetic acid solvate of a compound of formula (I) is provided in crystalline solid form. In some embodiments, an acetic acid solvate of the compound of formula (I) in crystalline solid form is provided which has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the invention provides an acetic acid solvate of the compound of formula (I) in crystalline solid form, 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, experimental error ± 0.1° 2θ). In another embodiment, the invention provides an acetic acid solvate of a compound of formula (I) in crystalline solid form, 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 (all 2θ values, experimental error ± 0.1° 2θ) .

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

Step (b) of the process

[0034] In some embodiments, converting a compound of formula (VI) or a salt thereof to a compound of formula (III) or a salt thereof comprises decarboxylation of a compound of formula (VI) or a salt thereof to form a compound of formula (V) or a salt thereof

followed by esterification of a compound of formula (V) or a salt thereof to form a compound of formula (IV) or a salt thereof

where R represents C _1-4 alkyl; and thereafter cyclizing a compound of formula (IV) or a salt thereof to form a compound of formula (III) or a salt thereof.

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

[0036] In some embodiments, R is methyl, ethyl, propyl, or butyl. In some embodiments, R is tert-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 of the invention, the compound of formula (III) or its salt 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 accelerated such that the compounds of formula (V) or a salt thereof and formula (IV) or a salt thereof are not isolated into pure form.

[0041] In some embodiments, the invention describes a compound of formula (IVa) or a salt thereof

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

[0043] ¹ H NMR (500 MHz, DMSO) δ 7.33 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 6.37 (d, 1H, J=16, 0 Hz), 6.15 (dd, 1H, J=8.1 Hz, J=16.0 Hz), 3.56 (s, 3H), 3.09 (m, 1H), 2.60 (m , 2H), 2.50 (dd, 1H, 6.1 Hz, J=15.4 Hz), 2.42 (dd, 1H, J=8.1 Hz, J=15.4 Hz), 2, 29 (d, 2H, 7.0 Hz), 2.00 (m, 1H), 0.82 (s, 6H, 6.7 Hz).

[0044] ¹³ C NMR (125 MHz, DMSO) δ 208.7 (C), 171.8 (C), 136.8 (C), 131.9 (CH), 129.5 (CH), 128, 5 (CH), 127.2 (CH), 125.9 (CH), 51.4 (CH ₂ ), 51.2 (CH ₃ ), 46.7 (CH ₂ ), 38.5 (CH ₂ ) , 34.4 (CH), 23.8 (CH), 22.29 (CH ₃ ), 22.26 (CH ₃ ).

[0045] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₁₈ H ₂₅ O ₃ , 289.1798; found 289,1719.

[0046] In some embodiments, the invention provides a compound of formula (V) or a salt thereof

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

[0048] ¹ H NMR (700 MHz, DMSO) δ 12.13 (s, 1H), 7.33 (m, 2H), 7.29 (m, 2H), 7.20 (m, 1H), 6 .37 (d, 1H, J=16 Hz), 6.17 (dd, 1H, J=8.0 Hz, J=16.0 Hz), 3.07 (m, 1H), 2.60 (m , 2H), 2.46 (dd, 1H, J=6.2 Hz, J=15.5 Hz), 2.33 (dd, 1H, J=8.0, J=15.5 Hz), 2 .30 (d, 2H, J=7.1 Hz), 2.0 (m, 1H), 0.82 (d, 6H, J=6.6 Hz).

[0049] ¹³ C NMR (176 MH, DMSO) δ 208.8 (C), 172.9 (C), 136.9 (C), 132.2 (CH), 129.3 (CH), 128, 5 (CH), 127.1 (CH), 125.9 (CH), 51.4 (CH ₂ ), 46.8 (CH ₂ ), 38.9 (CH ₂ ), 34.4 (CH), 23.8 (CH), 22.3 (CH ₃ ), 22.3 (CH ₃ ).

[0050] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₁₇ H ₂₃ O ₃ , 275.1642; found 275.1635.

[0051] In some embodiments, the invention provides a compound of formula (VI) or a salt thereof.

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

Process step (c)

[0053] In some embodiments, converting 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

followed by addition of a malonic acid ester (R ₁ O(O)C-CH ₂ -C(O)OR ₂ ) to form a compound of formula (VII) or a salt thereof

where R ₁ and R ₂ independently represent C _1-4 alkyl;

and thereafter 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, converting a compound of formula (VIII) or a salt thereof to a compound of formula (VII) or a salt thereof comprises adding a malonic acid ester that is di-t-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 scaled up such that the compounds of formula (VII) and formula (VIII) or salts thereof are not isolated in pure form.

[0057] In some embodiments, the invention provides a compound of formula (VIIa) or a salt thereof.

[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 (700 MHz, DMSO) δ 7.30 (m, 2H), 7.30 (m, SH0, 7.21 (m, 1H), 6.39 (d, 1H) J=15 .8 Hz), 6.14 (dd, 1H, J=15.99 Hz, J=8.9 Hz), 4.12 (kv, 2H, J=7.13 Hz), 4.06 (m, 2H), 3.68 (d, 1H, J=8.1 Hz), 3.33 (m, 1H), 2.73 (dd, 1H, J=16.9 Hz, J=9.0 Hz) , 2.63 (m, 1H), 2.28 (d, 2H, 6.9 Hz), 1.98 (m, 1H, 6.7 Hz), 1.16 (t, 3H, J=7, 1 Hz), 1.10 (t, 3H, J=7.0 Hz), 0.81 (d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.7 Hz ).

[0060] ¹³ C NMR (176 MHz, DMSO) δ 208.1 (C), 167.7 (C), 167.6 (C), 136.6 (C), 131.4 (CH), 128, 9 (CH), 127.4 (CH), 125.9 (CH), 61.0 (CH2), 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] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₂₂ H ₃₁ O ₅ , 375.2166; found 375,2158.

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

Preparation of Compound of Formula (I) - Method B

[0063] In some embodiments, this document describes a process for preparing a compound of formula (I), or a salt or solvate thereof.

comprising aromatization of a compound of formula (II) or a salt thereof

where X is Cl, Br or I; to obtain a compound of formula (I). In some embodiments, said method further comprises purifying a compound of formula (I) or a salt or solvate thereof. In some embodiments, purification includes crystallization of a compound of formula (I) or a salt or solvate thereof. In some embodiments, the compound of formula (I) is the crystalline form described in any of the embodiments of the invention described herein. In some embodiments, the compound of formula (I) is a crystalline Form 1. In some embodiments, the compound of formula (I) is an anhydrous crystal. In some embodiments, a compound of formula (I) has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) is in crystalline solid form, characterized by powder x-ray diffraction (XRPD) 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 crystalline solid form, characterized by an x-ray powder diffraction pattern (XRPD) having at least nine, or at least eight, or at least seven, or at least six, or at at least five, or at least four, or at least three 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 crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, 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 values 2θ, experimental error ± 0.1° 2θ). In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least 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 (all 2θ values, experimental error ± 0.1° 2θ ). In some embodiments, X is Cl. In some embodiments of the invention, the aromatization is carried out in a suitable solvent and, optionally, with an additional reagent. In some embodiments, the aromatization is carried out in a suitable solvent, which 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-methyl-tetrahydrofuran, isopropyl acetate, acetone, and methyl isobutyl ketone. In some embodiments of the invention, the aromatization is carried out in acetonitrile in the presence of an additional 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, said method further comprises halogenating a compound of formula (III) or a salt thereof

with a halogenating reagent to give a compound of formula (II) or a salt thereof. In some embodiments, the halogenation reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating reagent is DCDMH and the compound of formula (II) or a salt thereof is a compound of formula (IIa) or a salt thereof:

In some embodiments of the invention, the halogenation is carried out in methanol. In some embodiments, the halogenation reagent is DCDMH and the halogenation is carried out in methanol.

[0065] In some embodiments, said method further comprises cyclizing a compound of formula (IV) or a salt thereof

where R is C _1-4 alkyl to give a compound of formula (III) or a salt thereof. In some embodiments, R is selected from the group consisting of methyl, ethyl, propyl, or butyl. In some embodiments, R is tert-butyl. In some embodiments, R is methyl. In some embodiments of the invention, cyclization includes bringing into contact a compound of formula (IV) or a salt thereof with a base. In some embodiments of the invention, the cyclization is carried out using potassium tert-butoxide. In some embodiments of the invention, the cyclization is carried out in 2-methyltetrahydrofuran. In some embodiments, the cyclization comprises treating a compound of formula (IV) or a salt thereof, eg compound (IVa) or a salt thereof, with potassium tert-butoxide in 2-methyltetrahydrofuran. In some embodiments of the invention, the compound of formula (III) or its salt is further acidified and isolated by precipitation with methylcyclohexane.

[0066] In some embodiments, said method further comprises esterifying a compound of formula (V) or a salt thereof

to obtain a compound of formula (IV) or a salt thereof. In some embodiments of the invention, 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, said method further comprises decarboxylation of a compound of formula (VI) or a salt thereof

to obtain a compound of formula (V) or a salt thereof. In some embodiments of the invention, decarboxylation includes 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, decarboxylation comprises heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0068] In some embodiments, said method further comprises hydrolyzing a compound of formula (VII) or a salt thereof

where each R ₁ and R ₂ independently represents C _1-4 alkyl; to obtain a compound of formula (VI) or a salt thereof. In some embodiments of the invention, each of R ₁ and R ₂ represents ethyl (VIIa). In some embodiments, the hydrolysis comprises treating a compound of formula (VII) or a salt thereof with sodium hydroxide. In some embodiments, the hydrolysis comprises treating a compound of formula (VII) or a salt thereof with sodium hydroxide in ethanol. In some embodiments, said method comprises hydrolyzing a 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, said method further comprises adding a dialkylmalonic ether (R ₁ O(O)C-CH ₂ -C(O)OR ₂ , where each R ₁ and R ₂ is independently C _1-4 alkyl) to a compound of formula (VIII) or a salt thereof

to obtain a compound of formula (VII) or a salt thereof. In some embodiments, the dialkylmalonic ester is di-tert-butylmalonate or diethylmalonate. In some embodiments, the addition comprises contacting a dialkylmalonic ether with a compound of formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.

[0070] In some embodiments of the invention, this method further includes the condensation of trans-cinnamic aldehyde (compound of formula (IX)) or its salt

with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof. In some embodiments, the condensation comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 the methyl isobutyl ketone with trans-cinnamic aldehyde or a salt thereof in the presence of sodium hydroxide in methanol.

Preparation of Compound of Formula (I) - Method C

[0071] In some embodiments, this document describes a process for preparing a compound of formula (I), or a salt or solvate thereof.

including:

a) decarboxylation of a compound of formula (VI) or a salt thereof

to form a compound of formula (V) or a salt thereof

b) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IV) or a salt thereof

где R представляет собой С_1-4 алкил;

where R represents C _1-4 alkyl;

c) cyclization of a compound of formula (IV) or a salt thereof to form a compound of formula (III) or a salt thereof,

d) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (II) or a salt thereof,

where X is selected from Br, Cl and I; And

e) aromatizing a compound of formula (II) or a salt thereof to form a compound of formula (I) or a salt or solvate thereof.

[0072] In some embodiments, said method further comprises isolating a compound of formula (III) or a salt thereof in step c). In some embodiments, said method comprises isolating a compound of formula (II) or a salt thereof in step d). In some embodiments, said method further comprises purifying a compound of formula (I) or a salt or solvate thereof obtained in step e). In some embodiments, purification includes crystallization of a compound of formula (I) or a salt or solvate thereof. In some embodiments, the compound of formula (I) is the crystalline form described in any of the embodiments of the invention described herein. In some embodiments, the compound of formula (I) is a crystalline Form 1. In some embodiments, the compound of formula (I) is an anhydrous crystal. In some embodiments, a compound of formula (I) has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) is in crystalline solid form, characterized by powder x-ray diffraction (XRPD) 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 crystalline solid form, characterized by an x-ray powder diffraction pattern (XRPD) having at least nine, or at least eight, or at least seven, or at least six, or at at least five or at least four or at least three 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 crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, 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 values 2θ, experimental error ± 0.1° 2θ). In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least 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 (all 2θ values, experimental error ± 0.1° 2θ ).

[0073] In some embodiments, the decarboxylation of a compound of formula (VI) or a salt thereof in step a) involves 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, decarboxylation comprises heating a 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 tert-butyl. In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is methyl. In some embodiments of the invention, the esterification of the compound of formula (V) or its salt in stage b) is carried out using methanol and hydrochloric acid to obtain the compound (IV) or its salt or solvate. In some embodiments, the esterification comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

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

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

[0077] In some embodiments, the aromatization in step e) is carried out in a suitable solvent and, optionally, with an additional reagent. In some embodiments, the aromatization in step e) is carried out in a suitable solvent which 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 of the invention, the aromatization is carried out in acetonitrile in the presence of an additional 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 chlorine.

[0079] In some embodiments, the compound of formula (VI) or a salt thereof in step a) is prepared by a process including:

i. condensation of a trans-cinnamic aldehyde or salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding a dialkylmalonic ester of formula R ₁ O(O)C-CH ₂ -C(O)OR ₂ , where R ₁ and R ₂ are each independently C _1-4 alkyl, to a compound of formula (VIII) or a salt thereof to form a compound of formula (VII) or a salt thereof

where each R ₁ and R ₂ have the meanings defined for dialkylmalonic ether;

iii. hydrolysis of a compound of formula (VII) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0080] In some embodiments of the invention, the condensation in step i. involves treating methyl isobutyl ketone with trans-cinnamic aldehyde or its salt 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 of the invention, the condensation in step i. involves treating methyl isobutyl ketone with trans-cinnamic aldehyde or its salt in the presence of sodium hydroxide in methanol.

[0081] In some embodiments of the invention, each of R ¹ and R ² in stage ii. is ethyl. In some embodiments, the dialkylmalonic ether in step ii. is di-tert-butylmalonate or diethylmalonate. In some embodiments of the invention, the addition in step ii. involves contacting a malonic ester with a compound of formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.

Preparation of a Compound of Formula (I)—Method D

[0082] In some embodiments, this document describes a process for preparing a compound of formula (I), or a salt or solvate thereof.

including:

a) heating the compound of formula (VI)

with catalytic triethylamine to form a compound of formula (V)

b) heating a compound of formula (V) with methanol and aqueous hydrochloric acid to form a compound of formula (IVa)

c) treating the cooled solution of a compound of formula (IVa) with potassium tert-butoxide to form a compound of formula (III)

d) heating a compound of formula (III) with 1,3-dichloro-5,5-dimethylhydantoin to form a compound of formula (IIa)

e) heating a compound of formula (IIa) with tetraethylammonium chloride to form a compound of formula (I), a salt or solvate thereof.

[0083] In some embodiments, said method further comprises purifying the compound of formula (I) from step e) by crystallization. In some embodiments of the invention, said method further comprises, after step c), step ci), isolating the compound of formula (III). In some embodiments of the invention, said method further comprises, after step d) step di) isolating the compound of formula (IIa). In some embodiments, said method further comprises purifying the compound of formula (I) obtained in step e). In some embodiments of the invention, purification includes crystallization of the compound of formula (I). In some embodiments, the compound of formula (I) is the crystalline form described in any of the embodiments of the invention described herein. In some embodiments, the compound of formula (I) is a crystalline Form 1. In some embodiments, the compound of formula (I) is an anhydrous crystal. In some embodiments, a compound of formula (I) has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) is in crystalline solid form, characterized by powder x-ray diffraction (XRPD) 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 crystalline solid form, characterized by an x-ray powder diffraction pattern (XRPD) having at least nine, or at least eight, or at least seven, or at least six, or at at least five or at least four or at least three 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 crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, 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, experimental error ± 0.1° 2θ). In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least 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 (all 2θ values, experimental error ± 0.1° 2θ ).

[0084] In some embodiments, the compound of formula (VI) in step a) is prepared by a method including:

i. treatment of methyl isobutyl ketone with trans-cinnamic aldehyde in the presence of methanolic sodium hydroxide to form a compound of formula (VIII)

ii. treating a compound of formula (VIII) with diethyl malonate in the presence of lithium bromide and triethylamine to form a compound of formula (VIIa)

iii. hydrolysis of a compound of formula (VIIa) with sodium hydroxide and ethanol to give a compound of formula (VI).

Preparation of a Compound of Formula (I)—Method E

[0085] In some embodiments of the invention, a method is described for a specific embodiment of the invention according to this invention, shown in Scheme 2 below and described in detail in the examples.

Process for the preparation of a compound of formula (VI)

[0086] In some embodiments, this document describes a process for preparing a compound of formula (VI) or a salt thereof.

including:

a) condensation of trans-cinnamic aldehyde or its salt with methyl isobutyl ketone to form a compound of formula (VIII) or its salt

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

c) hydrolysis of a 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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide/triethylamine.

Process for preparing a compound of formula (V)

[0088] In some embodiments, this document describes a process for preparing a compound of formula (V) or a salt thereof.

comprising decarboxylation of 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. 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, decarboxylation comprises heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments of the invention, the compound of formula (VI) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (VI), or a salt thereof, is prepared by a process including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0089] In some embodiments, this document describes a process for preparing a compound of formula (V) or a salt thereof.

including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof

d) decarboxylation of 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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a 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 a compound of formula (VI) or a salt thereof in the presence of trimethylamine.

Process for preparing a compound of formula (IVa)

[0091] In some embodiments, this document describes a process for preparing a compound of formula (IVa) or a salt thereof.

comprising the esterification of a compound of formula (V) or a salt thereof

to form a compound of formula (IVa) or a salt thereof. In some embodiments, the esterification of a compound of formula (V) or a salt thereof is carried out using methanol and hydrochloric acid to give compound (IVa). In some embodiments, the esterification comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments of the invention, the compound of formula (V) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (V) or a salt thereof is prepared by a process comprising decarboxylation of 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. In some embodiments of the invention, the compound of formula (VI) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (VI), or a salt thereof, is prepared by a process including:

i. condensation of a trans-cinnamic aldehyde or salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding diethylmalonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof

iii. hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0092] In some embodiments, this document describes a process for preparing a compound of formula (IVa) or a salt thereof.

including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof

d) decarboxylation of 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

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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a 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 a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of a compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to give compound (IVa). In some embodiments, the esterification in step e) comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

Process for the preparation of a compound of formula (IIa)

[0094] In some embodiments, this document describes a process for preparing a compound of formula (IIa) or a salt thereof.

including halogenation of a compound of formula (III) or a salt thereof

to form 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 reagent. In some embodiments, the halogenation reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating reagent is DCDMH. In some embodiments of the invention, the compound of formula (III) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (III) or a salt thereof is prepared by a process comprising cyclization of a compound of formula (IVa) or a salt thereof

to form a compound of formula (III) or a salt thereof. In some embodiments of the invention, the compound of formula (IVa) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (IVa) or a salt thereof is prepared by a process comprising esterification of a compound of formula (V) or a salt thereof

In some embodiments of the invention, the compound of formula (V) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (V) or a salt thereof is prepared by a process comprising decarboxylation of 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. In some embodiments of the invention, the compound of formula (VI) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (VI), or a salt thereof, is prepared by a process including:

i. condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding diethylmalonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof

и

And

iii. hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0095] In some embodiments, this document describes a process for preparing a compound of formula (IIa) or a salt thereof.

including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof

d) decarboxylation of 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

e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof

f) cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (III) or a salt thereof

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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a 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 a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of a compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to give compound (IVa). In some embodiments, the esterification in step e) comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments, the halogenation in step g) comprises treating a compound of formula (III) or a salt thereof with a halogenating reagent. In some embodiments, the halogenation reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating reagent is DCDMH.

The compound of formula (I) obtained by method A

[0097] In some embodiments, this document describes a compound of formula (I), or a salt or solvate thereof.

obtained by a method including:

a) decarboxylation of a compound of formula (VI) or a salt thereof

to form a compound of formula (V) or a salt thereof

b) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IV) or a salt thereof

, где R представляет собой С_1-4 алкил;

, where R represents C _1-4 alkyl;

c) cyclizing a compound of formula (IV) or a salt thereof to form a compound of formula (III) or a salt thereof

d) halogenating a compound of formula (III) or a salt thereof to form
compounds of formula (II) or salts thereof

where X is selected from Br, Cl and I; And

e) aromatizing a compound of formula (II) or a salt thereof to form a compound of formula (I) or a salt or solvate thereof.

[0098] In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method further comprising isolating a compound of formula (III), or a salt thereof. In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method comprising isolating a compound of formula (II), or a salt thereof. In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method further comprising purifying the compound of formula I obtained in step e). In some embodiments of the invention, purification includes crystallization of the compound of formula (I). In some embodiments, the compound of formula (I) is a crystalline form I. In some embodiments, the compound of formula (I) is an anhydrous crystal. In some embodiments, a compound of formula (I) has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) is in crystalline solid form, characterized by powder x-ray diffraction (XRPD) 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 are ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is in crystalline solid form, characterized by an x-ray powder diffraction pattern (XRPD) having at least nine, or at least eight, or at least seven, or at least six, or at at least five or at least four or at least three 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 are ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, 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 values 2θ, experimental error ±0.1° 2θ). In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least 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 (all 2θ values, experimental error ±0.1° 2θ ).

[0099] In some embodiments, the decarboxylation of a compound of formula (VI) or a salt thereof in step a) involves 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, decarboxylation comprises heating a 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 tert-butyl. In some embodiments, R of the compound of formula (IV) or a salt thereof in step b) is methyl. In some embodiments of the invention, the esterification of the compound of formula (V) or its salt in stage b) 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.

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

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

[0103] In some embodiments of the invention, the aromatization at stage e) is carried out in a suitable solvent and, optionally, with an additional reagent. In some embodiments, the aromatization in step e) is carried out in a suitable solvent which 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 of the invention, the aromatization is carried out in acetonitrile in the presence of an additional 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, 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 chlorine.

[0105] In some embodiments, a compound of formula (I) or a salt thereof is described, wherein a compound of formula (VI) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, wherein the compound of formula (VI), or a salt thereof, is prepared by a method including:

i. condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding a dialkylmalonic ester of formula R ₁ O(O)C-CH ₂ -C(O)OR ₂ , where R ₁ and R ₂ are each independently C _1-4 alkyl, to a compound of formula (VIII) or a salt thereof to form a compound of formula (VII) or a salt thereof

where each R ₁ and R ₂ have the meanings defined for dialkylmalonic ether;

iii. hydrolysis of a compound of formula (VII) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0106] In some embodiments of the invention, the condensation in step i. involves treating methyl isobutyl ketone with trans-cinnamic aldehyde or its salt 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 of the invention, the condensation in step i. involves the treatment of methyl isobutyl ketone with trans-cinnamic aldehyde or its salt in the presence of sodium hydroxide in methanol.

[0107] In some embodiments, each of R ¹ and R ² in step ii. is ethyl. In some embodiments, the dialkylmalonic ether in step ii. is di-tert-butylmalonate or diethylmalonate. In some embodiments of the invention, the addition in step ii. involves contacting a malonic ester with a compound of formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.

The compound of formula (I) obtained by method B

[0108] In some embodiments, this document describes a compound of formula (I), or a salt or solvate thereof.

obtained by a method including:

a) decarboxylation of a compound of formula (VI) or a salt thereof

to form a compound of formula (V) or a salt thereof

b) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof

c) cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (III) or a salt thereof

d) halogenating a compound of formula (III) or a salt thereof to form a compound of formula (IIa) or a salt thereof

и

And

e) aromatizing a compound of formula (IIa) or a salt thereof to form a compound of formula (I) or a salt or solvate thereof.

[0109] In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method further comprising isolating a compound of formula (III), or a salt thereof. In some embodiments, a compound of formula (I) or a salt or solvate thereof is described, said method comprising isolating a compound of formula (IIa) or a salt thereof. In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method further comprising purifying the compound of formula (I) obtained in step e). In some embodiments of the invention, purification includes crystallization of the compound of formula (I). In some embodiments, the compound of formula (I) is a crystalline Form 1. In some embodiments, the compound of formula (I) is an anhydrous crystal. In some embodiments, a compound of formula (I) has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) is in crystalline solid form, characterized by powder x-ray diffraction (XRPD) 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 are ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is in crystalline solid form, characterized by an x-ray powder diffraction pattern (XRPD) having at least nine, or at least eight, or at least seven, or at least six, or at at least five or at least four or at least three 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 are ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, 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 values 2θ, experimental error ±0.1° 2θ). In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least 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 (all 2θ values, experimental error ±0.1° 2θ ).

[0110] In some embodiments, the decarboxylation of a compound of formula (VI) or a salt thereof in step a) involves 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, decarboxylation comprises heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine.

[0111] In some embodiments of the invention, the esterification of a 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 a 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 a compound of formula (IVa) or a salt thereof with a base. In some embodiments of the invention, the cyclization is carried out using potassium tert-butoxide. In some embodiments of the invention, the cyclization is carried out in 2-methyltetrahydrofuran. In some embodiments, the cyclization comprises treating a compound of formula (IVa) or a salt thereof with potassium tert-butoxide in 2-methyltetrahydrofuran. In some embodiments of the invention, the compound of formula (III) or its salt is further acidified and isolated by precipitation with methylcyclohexane.

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

[0114] In some embodiments of the invention, the aromatization at stage e) is carried out in a suitable solvent and, optionally, with an additional reagent. In some embodiments, the aromatization in step e) is carried out in a suitable solvent which 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 of the invention, the aromatization is carried out in acetonitrile in the presence of an additional 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, aromatization is carried out in acetonitrile with tetraethylammonium chloride.

[0115] In some embodiments, a compound of formula (I) or a salt thereof is described, wherein a compound of formula (VI) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (I) or a salt thereof is described, wherein the compound of formula (VI) or a salt thereof is prepared by a method including:

i. condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding diethylmalonic ether to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof

и

And

iii. hydrolysis of 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. involves treating methyl isobutyl ketone with trans-cinnamic aldehyde or its salt 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 of the invention, the condensation in step i. involves treating methyl isobutyl ketone with trans-cinnamic aldehyde or its salt in the presence of sodium hydroxide in methanol.

[0117] In some embodiments of the invention, the addition in step ii. involves contacting diethylmalonic ether with a compound of formula (VIII) or a salt thereof in the presence of lithium bromide/triethylamine.

The compound of formula (I) obtained by method C

[0118] In some embodiments, a compound of formula (I) or a salt or solvate thereof is described.

obtained by a method including:

a) heating the compound of formula (VI)

with catalytic triethylamine to form a compound of formula (V)

b) heating a compound of formula (V) with methanol and aqueous hydrochloric acid to form a compound of formula (IVa)

c) treating a compound of formula (IVa) with potassium tert-butoxide c
the formation of a compound of formula (III)

d) chlorination of a compound of formula (III) with 1,3-dichloro-5,5-dimethylhydantoin to form a compound of formula (IIa)

e) heating a compound of formula (IIa) in acetonitrile with tetraethylammonium chloride to form a compound of formula (I) or a salt or solvate thereof.

[0119] In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method further comprising isolating a compound of formula (III). In some embodiments, a compound of formula (I) is described, said method comprising isolating a compound of formula (IIa). In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, said method further comprising purifying the compound of formula (I) obtained in step e). In some embodiments of the invention, purification includes crystallization of the compound of formula (I). In some embodiments, the compound of formula (I) is a crystalline Form 1. In some embodiments, the compound of formula (I) is an anhydrous crystal. In some embodiments, a compound of formula (I) has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) is in crystalline solid form, characterized by powder x-ray diffraction (XRPD) 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 are ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is in crystalline solid form, characterized by an x-ray powder diffraction pattern (XRPD) having at least nine, or at least eight, or at least seven, or at least six, or at at least five or at least four or at least three 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 are ±0.1° 2θ experimental error). In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form. In some embodiments, the compound of formula (I) is an acetic acid solvate in crystalline solid form that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 2. In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, 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 values 2θ, experimental error ±0.1° 2θ). In another embodiment, the compound of formula (I) is an acetic acid solvate in crystalline solid form, characterized by an X-ray powder diffraction (XRPD) pattern having at least six, or at least five, or at least four, or at least 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 (all 2θ values, experimental error ±0.1° 2θ ).

[0120] In some embodiments, a compound of formula (I) or a salt thereof is described, wherein a compound of formula (VI) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (I), or a salt or solvate thereof, is described, wherein the compound of formula (VI) is prepared by a method including:

i. treatment of methyl isobutyl ketone with trans-cinnamic aldehyde in the presence of methanolic sodium hydroxide to form a compound of formula (VIII)

ii. treating a compound of formula (VIII) with diethyl malonate in the presence of lithium bromide and triethylamine to form a compound of formula (VIIa)

iii. hydrolysis of a compound of formula (VIIa) with sodium hydroxide and ethanol to form a compound of formula (VI).

The compound of formula (VI) obtained by the method according to the invention

[0121] In some embodiments, this document describes a compound of formula (VI) or a salt thereof

obtained by a method including:

a) condensation of trans-cinnamic aldehyde or its salt with methyl isobutyl ketone to form a compound of formula (VIII) or its salt

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

c) hydrolysis of 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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a compound of formula (VIIIa) or a salt thereof in the presence of lithium bromide/triethylamine.

The compound of formula (V) obtained by the method according to the invention

[0123] In some embodiments, this document describes a compound of formula (V) or a salt thereof

obtained by a process comprising decarboxylation of 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. 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, decarboxylation comprises heating a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments of the invention, the compound of formula (VI) or its salt is obtained by any method described in this document. In some embodiments, a compound of formula (V) or a salt thereof is described, wherein the compound of formula (VI) or a salt thereof is prepared by a method including:

i. condensation of a trans-cinnamic aldehyde or salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding diethylmalonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof

и

And

iii. hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0124] In some embodiments, this document describes a compound of formula (V) or a salt thereof

obtained by a method including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof

d) decarboxylation of 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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a 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 a compound of formula (VI) or a salt thereof in the presence of trimethylamine.

The compound of formula (IVa) obtained by the method according to the invention

[0126] In some embodiments, this document describes a compound of formula (IVa) or a salt thereof

obtained by a process comprising the esterification of a compound of formula (V)
or its salt

to form a compound of formula (IVa) or a salt thereof. In some embodiments of the invention, the esterification of the compound of formula (V) or its salt is carried out using methanol and hydrochloric acid to obtain the compound (IVa) or its salt. In some embodiments, the esterification comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments, a compound of formula (IVa) or a salt thereof is described, wherein the compound of formula (V) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (IVa) or a salt thereof is described, wherein the compound of formula (V) or a salt thereof is prepared by a process comprising decarboxylation of 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. In some embodiments, a compound of formula (IVa) or a salt thereof is described, wherein the compound of formula (V) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (IVa) or a salt thereof is described, wherein the compound of formula (V) or a salt thereof is prepared by a process comprising decarboxylation of 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. In some embodiments, a compound of formula (IVa) or a salt thereof is described, wherein a compound of formula (VI) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (IVa) or a salt thereof is described, wherein the compound of formula (VI) or a salt thereof is prepared by a method including:

i. condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding diethylmalonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof

iii. hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0127] In some embodiments, this document describes a compound of formula (IVa) or a salt thereof

obtained by a method including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof

d) decarboxylation of 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

и

And

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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a 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 a compound of formula VI or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of a compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to give compound (IVa). In some embodiments, the esterification in step e) comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol.

The compound of formula (IIa) obtained by the method according to the invention

[0129] In some embodiments, this document describes a compound of formula (IIa) or a salt thereof

obtained by a process comprising halogenation of a compound of formula (III)
or its salt

to form 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 reagent. In some embodiments, the halogenation reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein the compound of formula (III) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein the compound of formula (III) or a salt thereof is prepared by a process comprising cyclization of a compound of formula (IVa) or a salt thereof

to form a compound of formula (III) or a salt thereof. In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein a compound of formula (IVa) or a salt thereof is prepared by any method described herein. In some embodiments, the invention describes a compound of formula (IIa) or a salt thereof, while the compound of formula (IVa) or its

the salt is prepared by a process comprising the esterification of a compound of formula (V) or a salt thereof

In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein the compound of formula (V) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein the compound of formula (V) or a salt thereof is prepared by a process comprising decarboxylation of 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. In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein a compound of formula (VI) or a salt thereof is prepared by any method described herein. In some embodiments, a compound of formula (IIa) or a salt thereof is described, wherein the compound of formula (VI) or a salt thereof is prepared by a method including:

i. condensation of a trans-cinnamic aldehyde or salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

ii. adding diethylmalonate to a compound of formula (VIII) or a salt thereof to form a compound of formula (VIIa) or a salt thereof

и

And

iii. hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof.

[0130] In some embodiments, this document describes a compound of formula (IIa) or a salt thereof

obtained by a method including:

a) condensation of trans-cinnamic aldehyde or a salt thereof with methyl isobutyl ketone to form a compound of formula (VIII) or a salt thereof

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

c) hydrolysis of a compound of formula (VIIa) or a salt thereof to form a compound of formula (VI) or a salt thereof

d) decarboxylation of 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

e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa) or a salt thereof

f) cyclizing a compound of formula (IVa) or a salt thereof to form a compound of formula (III) or a salt thereof

и

And

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 the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a) comprises treating the methyl isobutyl ketone with trans-cinnamic aldehyde 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 a 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 a compound of formula (VI) or a salt thereof in the presence of trimethylamine. In some embodiments, the esterification of a compound of formula (V) or a salt thereof in step e) is carried out using methanol and hydrochloric acid to give compound (IVa). In some embodiments, the esterification in step e) comprises treating a compound of formula (V) or a salt thereof with aqueous hydrochloric acid in methanol. In some embodiments, the halogenation in step g) comprises treating a compound of formula (III) or a salt thereof with a halogenating reagent. In some embodiments, the halogenation reagent is selected from 1,3-dichloro-5,5-dimethylhydantoin (DCDMH); N-chlorosuccinimide (NCS); and trichloroisocyanuric acid (TCCA). In some embodiments, the halogenating reagent is DCDMH.

Connections

[0132] In some embodiments, a compound of formula (I) in crystalline solid form (Form 1) is described that has an X-ray powder diffraction pattern substantially as illustrated in FIG. 1. In some embodiments of the invention, the compound of formula (I) in form 1 is characterized by powder x-ray diffraction (XRPD) 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 are ±0.1° 2θ experimental error). In another embodiment, the compound of formula (I) in form 1 is characterized by an X-ray powder diffraction (XRPD) pattern having at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four or at least three 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 are ±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 Form 1 about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%

[0133] In some embodiments, an acetic acid solvate of a compound of formula (I) is described. In some embodiments, the acetic acid solvate of the compound of formula (I), which is in crystalline solid form, has an X-ray powder diffraction pattern substantially as illustrated 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 values 29, experimental error ±0.1° 2θ). In another embodiment, the acetic acid solvate of the compound of formula (I) is 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 (all values 29, experimental error ±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 an acetic acid solvate of formula (I) at about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, by about 96%, by about 97%, by about 98%, or by about 99%.

[0134] One skilled in the art will appreciate that the percentage of a particular form of a compound of formula (I) is expressed relative to all forms of formula (I) present in a sample. For example, the phrase "a compound of formula (I) is at least 95% Form 1 is intended to mean that at least 95% of all forms of a compound of formula (I) are in Form 1. Similarly, the phrase "a compound of formula (I ) is at least 80% acetic acid solvate of formula (I) means that at least 80% of a sample of the compound of formula (I) is in the form of an acetic acid solvate.

[0135] In some embodiments, the invention describes a compound of formula (IIa) or a salt thereof

[0136] In some embodiments, the invention describes a compound of formula (IVa) or a salt thereof

[0137] In some embodiments, the invention describes a compound of formula (V) or a salt thereof

[0138] In some embodiments, the invention describes a compound of formula (VI) or a salt thereof

Pharmaceutical compositions

[0139] Embodiments herein describe a pharmaceutical composition comprising a compound of formula (I), or a salt or solvate thereof, prepared in accordance with any embodiment of the invention described herein, and a pharmaceutically acceptable excipient.

[0140] In some embodiments, the invention describes a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I) Form 1 and a pharmaceutically acceptable excipient. In some embodiments of the invention, the composition of formula (I) form 1 is characterized by powder x-ray diffraction (XRPD) 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 2θ (±0.1° 2θ). In some embodiments, the compound of formula (I) form 1 is characterized by an X-ray powder diffraction (XRPD) pattern having at least nine, or at least eight, or at least seven, or at least six, or at least five, or at least four, or at least three 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 Form 1 about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, or about 99%.

[0141] In some embodiments, a pharmaceutical composition is described comprising a therapeutically effective amount of an acetic acid solvate of a compound of formula (I) and a pharmaceutically acceptable excipient. In some embodiments, an acetic acid solvate of a compound of formula (I), which is in crystalline solid form, has 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 (±0.1° 2θ). In some embodiments, an acetic acid solvate of a compound of formula (I) is 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 (±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 an acetic acid solvate of formula (I) about 90%, about 91%, about 92%, about 93%), about 94%, about 95% , by about 96%, by about 97%, by about 98%, or by about 99%.

[0142] In some embodiments, the invention describes a pharmaceutical composition containing a compound of formula (IIa) and a pharmaceutically acceptable excipient.

[0143] In some embodiments, the invention describes a pharmaceutical composition containing a compound of formula (IVa) and a pharmaceutically acceptable excipient.

[0144] In some embodiments, the invention describes a pharmaceutical composition containing a compound of formula (V) and a pharmaceutically acceptable excipient.

[0145] In some embodiments, the invention describes a pharmaceutical composition containing a compound of formula (VI) and a pharmaceutically acceptable excipient.

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

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

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

DEFINITIONS

[0149] The term "C _1-4 alkyl" means straight or branched chain alkyl containing at least one and at most four carbon atoms. Examples of "C _1-4 alkyl" used herein include, but are not limited to: methyl, ethyl, n-propyl, n-butyl, isobutyl, isopropyl, and tert-butyl.

[0150] References herein to compounds of the indicated formulas and "their salts" encompass the compounds in the form of free bases or in the form of their salts, for example, in the form of their pharmaceutically acceptable salts. For a review of suitable pharmaceutically acceptable salts, see Berge et ah, J. Pharm. Sci. 66:1-19 (1977).

[0151] "Solvates" of compounds of the indicated formulas can be formed in which solvent molecules are introduced into the crystal lattice during crystallization. Solvates may include non-aqueous solvents such as ethanol, isopropyl alcohol, N,N-dimethyl sulfoxide (DMSO), acetic acid, ethanolamine, and ethyl acetate, or they may include water as a solvent that is introduced into the crystal lattice.

[0152] As used herein, the term "pharmaceutically acceptable excipient" refers to one or more pharmaceutically acceptable substances, compositions, or carriers involved in imparting shape or consistency to a pharmaceutical composition. Each excipient must be compatible with the other ingredients of the pharmaceutical composition when mixed in such a way as to avoid interactions which would substantially impair the efficacy of the compound of formula (I) or a pharmaceutically acceptable salt thereof when administered to a patient.

[0153] As used herein, an X-ray powder diffraction pattern that is "substantially as illustrated in FIG. 1" or "substantially as illustrated in FIG. 2" refers to an X-ray powder diffraction pattern, which should be considered by a person skilled in the art to represent a compound having the same crystal form as the compound that provided the X-ray powder diffraction pattern in FIG. 1 or Fig. 2. It is well known and understood by those skilled in the art that the device used, humidity, temperature, powder crystal orientation, and other parameters involved in producing an X-ray powder diffraction pattern can cause some variability in the appearance, intensities, and positions of the lines in the diffraction pattern. Thus, an X-ray powder diffraction pattern that is "essentially as illustrated in FIG. 1" or "substantially as illustrated in FIG. 2" may optionally show each of the lines of any of the diffraction patterns provided herein, and/or may show a slight change in appearance, intensity, or shift in the position of said lines as a result of differences in data acquisition conditions. One skilled in the art is able to determine (eg, by superposition) whether a sample of a crystalline compound has the same shape or a different shape than the shape disclosed herein by comparing their X-ray powder diffraction patterns.

[0154] Throughout the description and claims below, unless the context otherwise requires, the word "comprise" and variations such as "comprises" and "comprising" are intended to include the specified integer, or pitch, or groups of integers, but not excluding any other integer, or step, or group of integers or steps.

[0155] A "therapeutically effective amount" of a compound, a pharmaceutically acceptable salt or solvate thereof, or a pharmaceutical composition according to any embodiment of the invention described herein, is an amount sufficient to have the selected effect on at least one a symptom or parameter of a particular disease or disorder. The therapeutic effect may be objective (ie, measurable using some test or marker) or subjective (ie, the subject gives an indication or feels an effect, or the clinician observes a change). The effect considered in this document includes both medicinal therapeutic and/or prophylactic treatment, depending on the situation. The specific dosage of a compound administered according to this disclosure to obtain therapeutic and/or prophylactic effects is determined by the particular circumstances associated with the case, including, for example, compound administered, route of administration, co-administration of other active ingredients, condition being treated, activity the specific compound used, the specific composition used, age, body weight, general health, sex and diet of the patient; the time of administration, the route of administration and the rate of elimination of the particular compound used, and the duration of treatment. The therapeutically effective amount to be administered will be determined by the physician in light of the foregoing relevant circumstances and an informed medical judgment. A therapeutically effective amount of a compound according to any embodiment of the invention described herein is generally such an amount that, when administered in a physiologically tolerable vehicle composition, is sufficient to achieve an effective systemic or local tissue concentration.

[0156] While the invention has been described in some detail with reference to some of its preferred embodiments, other variations are possible. Therefore, the spirit and scope of the appended claims should not be limited by the description and preferred versions contained in this specification. Various embodiments of the present invention will be illustrated with reference to the following non-limiting examples. The following examples are provided for illustration only and should not be construed as limiting the invention in any way.

[0157] As used herein, the symbols and conventions used in these methods, schemes, and examples are consistent with those used in current scientific literature, such as in the Journal of the American Chemical Society or the Journal of Biological Chemistry. Unless otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. In particular, the following abbreviations may be used in the examples and in the description:

ABBREVIATIONS

AcOH - acetic acid

APCI - Atmospheric Pressure Chemical Ionization

aq. - water

CH ₃ CN - acetonitrile

CH ₃ COOH - acetic acid

CH ₃ OH - methanol

DCDMH - 1,3-dichloro-5,5-dimethylhydantoin

DMAC - dimethylacetamide

DMF - N,N-dimethylformamide

DMPU - 1,3-dimethyltetrahydropyrimidin-2(1Н)-one

DMCO - dimethyl sulfoxide

Et - ethyl

EtOH - ethanol

equiv. - equivalents

HCl - hydrochloric acid

HRMS - high resolution mass spectrometry

iPr - isopropyl

KOH - potassium hydroxide

KOtbutoxide - potassium tert-butoxide

LiBr - lithium bromide

Me - methyl

2-MeTHF - 2-methyl tetrahydrofuran

EXAMPLES

[0158] General experimental procedures. All reactions were carried out under a positive pressure nitrogen atmosphere in a jacketed laboratory reactor equipped with overhead agitation and Teflon baffles.

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

[0160] Toolkit:

[0161] Unless otherwise indicated, proton nuclear magnetic resonance spectra ( ¹ H NMR) were recorded at 400 MHz and 25°C. Chemical shifts are expressed in parts per million (ppm, δ scale) below tetramethylsilane and refer to the residual proton in the NMR solvent. Data are presented as follows: chemical shift, multiplicity (s=singlet, d=doublet, sept=septet, m=multiplet and/or multiple resonances, broad=broad), integration, coupling constant in hertz, and assignment. Spectra of carbon nuclear magnetic resonance with split proton signals ( ¹³ C NMR) were recorded at 100 MHz and 25°C. Chemical shifts are expressed in parts per million (ppm, δ scale) below tetramethylsilane and refer to solvent carbon resonances. High resolution mass spectrometry (HRMS) was obtained using an Orbitrap mass analyzer.

[0162] X-ray powder diffraction (XRPD) data were obtained on a PANalytical X'Pert Pro powder diffractometer, model PW3050/60, using an X'Celerator detector. Recording conditions were as follows: radiation: Cu Kα, generator voltage: 45 kV, generator current: 40 mA, step size: 0.017° 2θ, time per step: 500 seconds, divergence slit type: fixed, divergence slit size: 0, 4354°, measurement temperature: 20-25°C, goniometer radius: 240 mm. The sample was prepared by packing the sample into a 0.9 mm capillary or silicon zero background sample holder. Peak positions were obtained using the PANalytical X'Pert Highscore Plus software. The margin of error is approximately ±0.1° 2θ for each of the peak distributions.

Example 1

Synthesis of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (compound of formula (VIII))

[0163] A solution of sodium hydroxide (11.4 g, 284 mmol, 1.5 eq.) in methanol (100 ml) was added dropwise over 1 hour at -5°C to a stirred solution of cinnamaldehyde (compound of formula (IX) ) (25 g, 189 mmol, 1 eq.) and methyl isobutyl ketone (75 ml, 602 mmol, 3.2 eq.). Upon completion of the addition, the reaction mixture was stirred for 2 hours at 0°C. 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 in vacuo to a final solution volume of 75 ml or until analysis by Karl Fischer titration indicated a water content of less than 0.2%. The crude material was used in the next transformation without any further processing.

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 R ₁ +R ₂ =tBu)

[0164] The concentrated solution obtained in the previous step (Example 1) was diluted with toluene so that the total volume of the solution was 175 ml. To a solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (compound of formula (VIII)) in toluene at 20°C was then added di-tert-butylmalonate (40.3 ml , 180 mmol, 0.95 eq.), triethylamine (13.1 ml, 94.5 mmol, 0.5 eq.) and powdered lithium bromide (3.28 g, 37.8 mmol, 0.2 eq. .). The heterogeneous reaction mixture was stirred for 2 hours at 20°C. Water (200 ml) was then charged directly to the stirred reaction mixture. The layers were allowed to separate and the aqueous layer was removed. The resulting product solution was used in the next transformation without any further processing. Alternatively, the addition product of di-tert-butylmalonate (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 concentrating a toluene solution and crystallizing from isopropyl alcohol/water (3:2) to give (E)-di-tert-butyl 2-(7-methyl-5-oxo-1-phenyloct-1-ene -3-yl)malonate (compound of formula (VII)) as a light yellow solid.

[0165] ¹ H NMR (400 MHz, DMSO) δ 7.32-7.29 (m, 4H), 7.24-7.18 (m, 1H), 6.38 (d, 1H, J=16 Hz), 6.12 (dd, 1H, J=16, 8.4 Hz), 3.39 (d, 1H, J=8.4 Hz), 3.27-3.20 (m, 1H), 2.70 (dd, 1H, J=16.8, 9.2 Hz), 2.58 (dd, 1H, J=16.8, 4.4 Hz), 2.28 (d, 2H, J= 7.2 Hz), 1.98 (sept, 1H, J=6.8 Hz), 1.39 (s, 9H), 1.33 (s, 9H), 0.81 (d, 3H, J= 6.4 Hz), 0.80 (d, 3H, J=6.4 Hz).

[0166] ¹³ C NMR (100 MHz, DMSO) δ 208.2 (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 (CH ₂ ), 45.0 (CH ₂ ), 37.7 (CH), 27.5 (CH ₃ ), 27.4 (CH ₃ ), 23.9 (CH ), 22.3 (CH ₃ ) , 22.2 (CH ₃ ).

[0167] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₂₆ H ₃₉ O ₅ , 431.2792; found 431,2754.

Example 3

Synthesis of (E)-diethyl-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula VIIa)

[0168] A concentrated solution of (5E,7E)-2-methyl-8-phenylocta-5,7-dien-4-one (about 7.6 mol) was diluted with toluene. Diethylmalonate (1.83 kg, 1.73 l, 1.5 eq.), triethylamine (1.15 kg, 1.58 l, 1.5 eq.), and powdered lithium bromide (131 g, 0.2 eq.). The heterogeneous reaction mixture was stirred at 35-40° C. for at least 8 hours. Then water (8 l, 8 vol.) was loaded directly into the stirred reaction mixture and stirred at 35°C for 15-30 minutes. The layers were allowed to separate and the aqueous layer was removed. The resulting product solution was used in the next transformation without any further processing. Alternatively, the addition product of diethyl malonate (E)-diethyl-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VIIa)) can also be isolated by concentration toluene solution and crystallization to give (E)-diethyl-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate (compound of formula (VIIa)).

[0169] ¹ H NMR (700 MHz, DMSO) δ 7.30 (m, 2H), 7.30 (m, SH0, 7.21 (m, 1H), 6.39 (d, 1H) J=15 .8 Hz), 6.14 (dd, 1H, J=15.99 Hz, J=8.9 Hz), 4.12 (kv, 2H, J=7.13 Hz), 4.06 (m, 2H), 3.68 (d, 1H, J=8.1 Hz), 3.33 (m, 1H), 2.73 (dd, 1H, J=16.9 Hz, J=9.0 Hz) , 2.63 (m, 1H,), 2.28 (d, 2H, 6.9 Hz), 1.98 (m, 1H, 6.7 Hz), 1.16 (t, 3H, J=7 .1 Hz), 1.10 (t, 3H, J=7.0 Hz), 0.81 (d, 3H, J=6.6 Hz), 0.80 (d, 3H, J=6.7 Hz).

[0170] ¹³ C NMR (176 MHz, DMSO) δ 208.1 (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 (CH ₂ ), 55.0 (CH), 51.3 (CH ₂ ), 44.8 (CH ₂ ), 37.7 (CH), 23.8 (CH), 22.3 (CH ₃ ), 22.2 (CH ₃ ), 13.9 (CH ₃ ), 13.9 ( CH ₃ ).

[0171] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₂₂ H ₃₁ O ₅ , 375.2166; found 375,2158.

Example 4

Synthesis of (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula (VI))

Method A

[0172] 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 , diluted with acetic acid (50 ml) and at 60°C was added dropwise over 1 hour to a stirred solution consisting of acetic acid (100 ml) and concentrated aqueous hydrochloric acid (75 ml). Upon completion of the addition, the resulting solution was stirred for 4 hours at 60°C. The product mixture was allowed to cool over 30 minutes to 20° C. and water (200 ml) was added. The two layers were vigorously stirred at 20° C. and then allowed to stand. The aqueous layer was then removed 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 allowed to cool slowly to 20°C over 1 hour, after which (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid was precipitated from the solution (compound of formula (VI)). The solid was then filtered off and the wet cake was washed with toluene (100 ml). The wet cake was then dried in vacuo at 30°C for 12 hours to obtain (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% based on cinnamaldehyde (compound of formula (IX)).

Method B

[0173] To a toluene solution of (E)-diethyl-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonate of Example 3 (about 7.6 mol, compound of formula (VIIa) ) at 20-30°C, 6 M aqueous sodium hydroxide solution (5.05 L, 4 eq.), toluene (0.5 L or 0.5 vol.) and ethanol 200 g (2 vol.) were loaded and the contents were stirred for at least 4 h at T _J =20°C. Upon completion, the temperature was brought to 35-50° C. and after stirring for at least 30 minutes, stirring was stopped and the layers were separated. The aqueous layer was cooled to 0-5°C and the pH was adjusted to pH 0-1 with concentrated HCl (required 2.9 L or 4.7 eq.), maintaining the temperature at or below 10°C during the addition. Once the desired pH was reached, TBME (3 L, 3 vol) was loaded into the vessel and the biphasic mixture was heated to 20-25°C. The mixture was stirred for 15-30 minutes and the layers were 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 until they reached a filling of 16-18 vol. (3 l, 3 vol.). The mixture was distilled to about 9-9.5 vol. using vacuum distillation, the temperature was brought to 40-45° C. and the mixture was seeded with 5 g of compound VI (0.2% w/w of theoretical yield). The mixture was stirred at 40-45°C for 30-60 minutes. After visually determining the nucleation of crystals, the mixture was diluted with toluene to 12 volumes and kept at 40-45°C for at least 1 hour. The suspension was cooled to 10-20°C at a rate of 0.5°C/min and kept at 10-20°C for at least 1 hour. The solid was isolated by filtration and the filter cake was washed with toluene (2 x 7 vol). The solid was dried at 25-35°C overnight in a vacuum oven to give (E)-2-(7-methyl-5-oxo-1-phenyloct-1-en-3-yl)malonic acid (compound of formula ( VI))

[0174] ¹ H NMR (400 MHz, DMSO) δ 12.78 (br s, 2H), 7.32-7.27 (m, 4H), 7.23-7.19 (m, 1H), 6.39 (d, 1H, J=16 Hz), 6.17 (dd, 1H, J=16, 8.4 Hz), 3.43 (d, 1H, J=8.4 Hz), 3, 31-3.24 (m, 1H), 2.72 (dd, 1H, J=16.8, 8.8 Hz), 2.63 (dd, 1H, J=16.4, 4 Hz), 2 .28 (d, 2H, J=7.2 Hz), 1.98 (sept, 1H, J=6.8 Hz), 0.81 (d, 3H, J=6.4 Hz), 0.80 (d, 3H, J=6.4 Hz).

[0175] ¹³ C NMR (100 MHz, DMSO) δ 208.4 (C), 169.6 (C), 169.5 (C), 136.8 (C), 130.9 (CH), 129, 6 (CH), 128.5 (CH), 127.3 (CH), 126.0 (CH), 55.7 (CH), 51.4 (CH ₂ ), 45.1 (CH ₂ ), 37 .6 (CH), 23.9 (CH), 22.3 (CH ₃ ), 22.2 (CH ₃ ).

[0176] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₁₈ H ₂₃ O ₅ , 319.1540; found 319,1528.

Example 5

Synthesis of (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III))

[0177] Triethylamine (4.4 ml, 31.4 mmol, 0.25 eq.) was loaded into a stirred suspension 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 eq.) in toluene (210 ml). The resulting mixture was heated to 110°C and left to stir for 2 hours. Then the reaction mixture containing intermediate (E)-7-methyl-5-oxo-3-styryloctanoic acid (compound of formula V) not isolated in pure form was left to cool to 20° C., methanol (120 ml) and concentrated aqueous hydrochloric acid were charged. acid (10.5 ml). The resulting solution was stirred for 4 hours at 60°C. The resulting mixture, containing the intermediate (E)-methyl-7-methyl-5-oxo-3-styryloctanoate (compound of formula (IVa)) not isolated in pure form, was left to cool 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. A solution of (E)-methyl-7-methyl-5-oxo-3-styryloctanoate methyl ester (compound of formula IVa) was then cooled to 0°C. Then a solution of potassium tert-butoxide (19.7 g, 176 mmol, 1.4 eq.) in 2-methyltetrahydrofuran (80 ml) was added dropwise over 1 hour to a cooled solution of (E)-methyl 7-methyl-5- oxo-3-styryloctanoate (compound of formula (IVa)). After completion of the addition, the reaction mixture was heated for 30 minutes to 20°C. The heated solution was stirred for 1 hour at 20°C. 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 removed and the organic layer was washed with 10% aqueous sodium chloride solution (2×160 ml). To a solution of (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III)) was then added methylcyclohexane (400 ml) dropwise over 1 hour, after which the product began to precipitate. The suspension was then filtered and the wet cake was washed with methylcyclohexane (120 ml). The wet cake was then dried in vacuo 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 (compounds of formula (VI)).

[0178] ¹ H NMR (400 MHz, DMSO) δ 10.33 (broad 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=16 Hz), 6.27 (dd, 1H, J=16, 7.2 Hz), 3.08 (sept, 1H, J=7.2 Hz), 2.87-2.78 (m, 1H), 2.40 (broad, 4H), 1.08 (d, 6H, J=7.2 Hz ).

[0179] 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 ₃ ), other carbon atoms undergo tautomerization with enol.

[0180] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₁₇ H ₂₁ O ₂ , 257.1536; found 257,1519.

Example 6

Synthesis of (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa))

[0181] A 1 liter laboratory jacketed reactor was charged with (E)-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (III)) (55 g, 215 mmol, 1 eq.) and methanol ( 495 ml), resulting in a heterogeneous suspension. The mixture was heated to an internal temperature of ~45-50° C., at which point a homogeneous solution was obtained. Solid 1,3-dichloro-5,5-dimethylhydantoin (23.3 g, 118 mmol, 0.55 eq.) was charged sequentially to this solution in five equal portions. The product solution was then cooled to 40° C. over 10 minutes and seeded with 146 mg of (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)). The mixture was held for 30 minutes, then cooled to 23°C over 60 minutes. Water (330 ml) was then added dropwise to the suspension over 1 hour, and the mixture was stirred for 30 minutes at 20°C. The suspension was then filtered and the wet cake was washed with a 1:1 mixture of methanol and water (2×110 ml). The wet cake was then dried in vacuo at 45°C for 12 hours to give (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)) as a white crystalline solid , existing as a ~2:1 mixture of diastereomers (60.0 g, 96%).

Isomer 1:

[0182] ¹ H NMR (400 MHz, DMSO) δ 7.41-7.39 (m, 2H), 7.36-7.32 (m, 2H), 7.23-7.22 (m, 1H ), 6.54 (d, 1H, J=16 Hz), 6.32 (dd, 1H, J=16, 7.2 Hz), 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) ).

[0183] ¹³ C NMR (100 MHz, DMSO) δ 198.5 (C), 136.5 (C), 130.4 (CH), 129.9 (CH), 128.6 (CH), 127, 5 (CH), 126.1 (CH), 94.6 (C), 43.4 (CH ₂ ), 35.0 (CH), 32.8 (CH), 16.7 (CH ₃ ).

Isomer 2:

[0184] ¹ H NMR (400 MHz, DMSO) δ 7.33-7.28 (m, 4H), 7.25-7.21 (m, 2H), 6.35 (dd, 1H, J=16 , 2 Hz), 6.03 (dd, 1H, J=16, 5.6 Hz), 3.48 (dd, 1H, J=14.8, 6 Hz), 3.24-3.18 (m , 1H), 3.10 (sept, 1H, J=6.4 Hz), 2.86 (dd, 1H, J=14.8, 3.6 Hz), 0.83 (d, 6H, J= 6.4 Hz).

[0185] ¹³ C NMR (100 MHz, DMSO) δ 199.6 (C), 136.1 (C), 130.3 (CH), 130.1 (CH), 128.6 (CH), 127, 7 (CH), 126.1 (CH), 94.5 (C), 42.2 (CH ₂ ), 34.7 (CH), 30.9 (CH), 16.9 (CH ₃ ).

[0186] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₁₇ H ₂₀ ClO ₂ , 291.1146; found 291.1132.

Example 7

Synthesis of (E)-2-isopropyl-5-styrylbenzene-1,3-diol (compound of formula (I))

[0187] A laboratory jacketed reactor was charged with (E)-2-chloro-2-isopropyl-5-styrylcyclohexane-1,3-dione (compound of formula (IIa)) (407 g, 1.4 mol, 1 eq.) , tetraethylammonium chloride (464 g, 2.8 mol, 2 eq.) and acetonitrile (1.2 L). The mixture was heated to 75-80°C for 6 hours. The product mixture was then cooled over 30 minutes to 20° C. and diluted with tert-butyl methyl ether (3.26 L). The resulting solution was washed four times with water (2 L each time). The resulting solution was concentrated to a volume of ~610 ml. Acetic acid (815 ml) was charged and the solution was concentrated under reduced pressure to a volume of ~1.3 L. The resulting suspension was heated to 55°C until it reached a homogeneous state, then slowly cooled to 35°C over 1 hour, during which the precipitation of the product began. Methylcyclohexane (6.5 L) was added to the suspension over 2 hours. After completion of the addition, the mixture was further cooled to ~23°C for one hour. The solids were filtered off and washed twice with a 6:1 mixture of methylcyclohexane and AcOH. The isolated solid was then dried in vacuo 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%).

[0188] ¹ H NMR (400 MHz, DMSO) δ 9.05 (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=16.4 Hz), 6.87 (d, 1H, J=16.4 Hz), 6.47 (s , 2H), 3.43 (sept, 1H, J=7.2 Hz), 1.24 (d, 6H, J=7.2 Hz).

[0189] ¹³ C NMR (100 MHz, DMSO) δ 156.4 (C), 137.0 (C), 134.7 (C), 128.9 (CH), 128.7 (CH), 127, 4 (CH), 126.7 (CH), 126.3 (CH), 120.1 (C), 105.1 (CH), 23.7 (CH), 20.6 (CH ₃ ).

[0190] MCBP-APCI (m/z) [M+H] ⁺ calculated for C ₁₇ H ₁₉ O ₂ , 255.1380; found 255,1376.

Claims (144)

1. Process for the preparation of a compound of formula (I) or a salt or solvate thereof

comprising aromatization of a compound of formula (II)

where X is Cl, Br or I to give a compound of formula (I). 2. The method according to p. 1, further comprising halogenation of the compounds of formula (III)

with a halogenating reagent to give a compound of formula (II). 3. The method according to p. 2, further comprising cyclization of the compounds of formula (IV)

where R is C _1-4 alkyl to give a compound of formula (III). 4. The method according to p. 3, further comprising the esterification of the compounds of formula (V) or its salts

to obtain a compound of formula (IV). 5. The method of claim 4 further comprising decarboxylation of a compound of formula (VI)

in the presence of a base to give a compound of formula (V) or a salt thereof. 6. The method according to p. 5, further comprising hydrolysis of the compounds of formula (VII)

where each of R ₁ and R ₂ independently represents C _1-4 alkyl; to obtain a compound of formula (VI). 7. The method of claim 6, further comprising adding a dialkylmalonic ether to a compound of formula (VIII)

to obtain a compound of formula (VII). 8. The method according to p. 7, further comprising the condensation of trans-cinnamic aldehyde (IX)

with methyl isobutyl ketone to form a compound of formula (VIII). 9. Process for the preparation of a compound of formula (I) or a salt or solvate thereof

including: a) decarboxylation of a compound of formula (VI)

to form a compound of formula (V) or a salt thereof

b) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IV)

where R represents C _1-4 alkyl; c) cyclization of a compound of formula (IV) to form a compound of formula (III)

d) halogenation of a compound of formula (III) to form a compound of formula (II)

where X is selected from Br, Cl and I; And e) aromatizing a compound of formula (II) to form a compound of formula (I) or a salt or solvate thereof. 10. The method of claim 9 further comprising one or more of the following steps: aa) obtaining a compound of formula (VI) by a method comprising: i. condensation of trans-cinnamic aldehyde with methyl isobutyl ketone to form a compound of formula (VIII)

ii. adding a dialkylmalonic ester of formula R ₁ O(O)C-CH ₂ -C(O)OR ₂ , where R ₁ and R ₂ are each independently C _1-4 alkyl, to a compound of formula (VIII) to form a compound of formula ( VII)

where each of R ₁ and R ₂ is as defined for dialkylmalonic ether; iii. hydrolysis of a compound of formula (VII) to form a compound of formula (VI); or f) purification of the compound of formula (I) obtained in step (e) by crystallization. 11. The method according to claim 9, wherein R in step (b) is methyl and X in step (d) is chlorine. 12. The method according to p. 10, characterized in that each of R ₁ and R ₂ independently represents ethyl. 13. Process for the preparation of a compound of formula (I) or a salt or solvate thereof

including: a) heating the compound of formula (VI)

with catalytic triethylamine to form a compound of formula (V)

b) heating a compound of formula (V) with methanol and aqueous hydrochloric acid to form a compound of formula (IVa)

c) treating the cooled solution of a compound of formula (IVa) with potassium tert-butoxide to form a compound of formula (III)

d) heating a compound of formula (III) with 1,3-dichloro-5,5-dimethylhydantoin to form a compound of formula (IIa)

e) heating a compound of formula (IIa) with tetraethylammonium chloride to form a compound of formula (I). 14. The method of claim 13, further comprising one or more of the following steps: i. treatment of methyl isobutyl ketone with trans-cinnamic aldehyde in the presence of methanolic sodium hydroxide to form a compound of formula (VIII)

ii. treating a compound of formula (VIII) with diethyl malonate in the presence of lithium bromide and triethylamine to form a compound of formula (VIIa)

iii. hydrolysis of a compound of formula (VIIa) with sodium hydroxide and ethanol to obtain a compound of formula (VI), f) purification of the compound of formula (I) obtained in step (e) by crystallization. 15. Process for the preparation of a compound of formula (V) or a salt thereof

comprising decarboxylation of a compound of formula (VI)

in the presence of a base to form a compound of formula (V) or a salt thereof. 16. Process for the preparation of a compound of formula (IVa)

comprising the esterification of a compound of formula (V) or a salt thereof,

to form a compound of formula (IVa). 17. The method according to p. 16, characterized in that the compound of formula (V) or its salt is obtained by a method including decarboxylation of the compound of formula (VI)

in the presence of a base to form a compound of formula (V) or a salt thereof. 18. Process for the preparation of a compound of formula (IIa)

comprising halogenation of a compound of formula (III)

to form a compound of formula (IIa). 19. The method according to p. 18, characterized in that the compound of formula (III) is obtained by a method including cyclization of the compound of formula (IVa)

to form a compound of formula (III). 20. The method according to p. 19, characterized in that the compound of formula (IVa) is obtained by a method including the esterification of the compound of formula (V) or its salt

to form a compound of formula (IVa). 21. The method according to p. 20, characterized in that the compound of formula (V) or its salt is obtained by a method including decarboxylation of the compound of formula (VI)

in the presence of a base to form a compound of formula (V) or a salt thereof. 22. The method according to any one of paragraphs. 15, 17 or 21, characterized in that the compound of formula (VI) is obtained by a method including: i. condensation of trans-cinnamic aldehyde with methyl isobutyl ketone to form a compound of formula (VIII)

ii. adding diethylmalonate to a compound of formula (VIII) to form a compound of formula (VIIa)

iii. hydrolysis of a compound of formula (VIIa) to form a compound of formula (VI). 23. A compound of formula (V) or a salt thereof

obtained by a method including: a) condensation of trans-cinnamic aldehyde with methyl isobutyl ketone to form a compound of formula (VIII)

b) adding diethyl malonate to a compound of formula (VIII) to form a compound of formula (VIIa)

c) hydrolysis of a compound of formula (VIIa) to form a compound of formula (VI)

d) decarboxylation of a compound of formula (VI) in the presence of a base to form a compound of formula (V). 24. Compound of formula (IVa)

obtained by a method including: a) condensation of trans-cinnamic aldehyde with methyl isobutyl ketone to form a compound of formula (VIII)

b) adding diethyl malonate to a compound of formula (VIII) to form a compound of formula (VIIa)

c) hydrolysis of a compound of formula (VIIa) to form a compound of formula (VI)

d) decarboxylation of a compound of formula (VI) in the presence of a base to form a compound of formula (V) or a salt thereof

e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa). 25. Compound of formula (IIa)

obtained by a method including: a) condensation of trans-cinnamic aldehyde with methyl isobutyl ketone to form a compound of formula (VIII)

b) adding diethyl malonate to a compound of formula (VIII) to form a compound of formula (VIIa)

c) hydrolysis of a compound of formula (VIIa) to form a compound of formula (VI)

d) decarboxylation of a compound of formula (VI) in the presence of a base to form a compound of formula (V) or a salt thereof

e) esterifying a compound of formula (V) or a salt thereof to form a compound of formula (IVa)

f) cyclization of a compound of formula (IVa) to form a compound of formula (III)

g) halogenating a compound of formula (III) to form a compound of formula (IIa). 26. Compound of formula (IIa)

27. Compound of formula (IVa)

28. Compound of formula (V) or salt thereof

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