The present invention provides processes of synthesis and purification of a bromodomain inhibitor, Compound 1, which compound includes crystalline forms, amorphous forms, solvates, and hydrates thereof. Embodiments of the disclosure relate to chemical synthesis routes of Compound 1 that provide a scalable method that results in highly pure final product. A further embodiment relates to methods to isolate the most stable polymorph of Compound 1 by crystallization from formic acid and water.

CROSS-REFERENCE TO RELATED APPLICATION

(1) This application is the U.S. National Stage of International Patent Application No. PCT/US2019/042914, filed Jul. 23, 2019, which claims priority to U.S. Provisional Patent Application No. 62/702,085, filed Jul. 23, 2018, the entire contents of these applications is incorporated herein by reference in their entirety.

TECHNICAL FIELD

(1) The present invention relates to methods for preparing pharmaceutical compositions and in particular to processes of synthesis and purification of a bromodomain inhibitor useful for the treatment of cancer.

BACKGROUND

(2) The bromodomain (BRD) proteins are an important class of histone reader proteins that recognize acetylated lysine residues (KAc) on histone tails and direct transcription complexes to turn on genes. Among the eight BRD families, the BRD and BET (bromodomain and extra-terminal) proteins have been found to be tractable for drug discovery. Chemical inhibition of BET proteins exerts a broad spectrum of desirable biological effects such as anticancer, anti-inflammatory, and male contraceptive properties.

(3) U.S. Pat. No. 9,034,900 discloses a series of bromodomain inhibitors with nanomolar affinity for BET proteins. The discovery of these potent, selective, and permeable inhibitors for BET bromodomain proteins has stimulated research activity in diverse therapeutic areas, particularly in oncology. Several cancer clinical trials for small molecule inhibitors of BET bromodomain proteins have been initiated. In particular, the bromodomain inhibitor 4-[2 (cyclopropylmethoxy)-S-methylsulfonylphenyl]-2-methylisoquinolin-1-one disclosed in U.S. Pat. No. 9,034,900 is in a clinical trial for the treatment of advanced solid tumors and relapsed/refractory Non-Hodgkin's lymphomas (NCT03220347).

(4) 4-[2-(cyclopropylmethoxy)-S-methylsulfonylphenyl]-2-methylisoquinolin-1-one, referred to herein as Compound 1, has the following structure:

(5) ##STR00001##

(6) The synthesis route and purification process of bromodomain inhibitors disclosed in U.S. Pat. No. 9,034,900 require multiple silica gel column chromatography or preparative HPLC purifications of intermediates and final compound, and thus have overall modest yield and impure final product. To realize the medical benefits of the bromodomain inhibitor for cancer treatment, the industry needs a scalable and robust purification process for the preparation of bromodomain inhibitors. This disclosures satisfies this need.

SUMMARY

(7) Described herein is an improved process for the industrial scale production of bromodomain inhibitors. Another object of the invention is to provide a suitable purification method for preparation of the final product.

(8) The present embodiments provide processes of synthesis and purification of a bromodomain inhibitor, the compound 4-[2 (cyclopropylmethoxy)-S-methylsulfonylphenyl]-2-methylisoquinolin-1-one (“Compound 1”), which compound includes crystalline forms, amorphous forms, solvates, and hydrates thereof; as well as pharmaceutical compositions that include this compound.

(9) Certain embodiments of the disclosure relate to chemical synthesis routes of Compound 1 that do not require column chromatography and are amenable to large scale synthesis. The overall synthetic sequence and intermediates are not changed as disclosed in U.S. Pat. No. 9,034,900 but many reagents, procedures and isolation techniques are modified and improved for the good manufacturing practices (GMP) manufacture of kilograms of Compound 1.

(10) In one embodiment, provided is a process for the preparation of a compound of formula I, a hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof:

(11) ##STR00002##

wherein the process comprises coupling a compound of formula II with a compound of formula III, to provide the compound of formula I;

(12) ##STR00003##

wherein:

(13) X is Cl, Br, or I; and

(14) R.sup.1 and R.sup.2 are each independently selected from H, OH, optionally substituted C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.1-C.sub.8 alkoxy, optionally substituted C.sub.1-C.sub.5 alkenyl, optionally substituted C.sub.1-C.sub.5 alkynyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 5-10 membered heteroaryl, optionally substituted 6-10 membered aryl, or an optionally substituted 4-7 membered cycloalkyl; or R.sup.1, R.sup.2 and the boron to which they are attached together form an optionally substituted 5-10 membered ring comprising carbon and from 0 to 5 heteroatoms.

(15) In other aspects of this method, (i) X is Br; and/or (ii) R.sup.1, R.sup.2 and the boron to which they are attached together form an optionally substituted 5-10 membered ring comprising carbon and from 0 to 5 heteroatoms selected from O and N. Further, in yet another aspect of the methods of the disclosure, R.sup.1, R.sup.2 and the boron to which they are attached together form an optionally substituted 5-10 membered ring wherein the two atoms of the ring directly attached to boron are oxygens. In another aspect of the methods, the optionally substituted 5-10 membered ring comprising boron comprises from 1 to 3 nitrogen atoms. Further, the optionally substituted ring comprising boron can be an 8 membered ring.

(16) In another embodiment of the disclosure, the compound of formula II has the formula II-a:

(17) ##STR00004##

wherein:

(18) each Q is independently selected from —O—, —NH—, —N(R.sup.5)—, or optionally substituted methylene;

(19) W is —O—, —NH— or —N(R.sup.5)—;

(20) each R.sup.4 is independently selected from H, OH, CN, optionally substituted amino, —C(O)R.sup.5, —COOR.sup.5, —C(O)N(R.sup.5).sub.2, —SO2R.sup.5, an optionally substituted C.sub.1-C.sub.5 alkyl, an optionally substituted C.sub.1-C.sub.5 alkenyl, an optionally substituted C.sub.1-C.sub.5 alkynyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 6-10 membered aryl, or an optionally substituted 4-7 membered cycloalkyl;

(21) each R.sup.5 is independently selected from H, an optionally substituted C.sub.1-C.sub.5 alkyl, an optionally substituted C.sub.1-C.sub.5 alkenyl, an optionally substituted C.sub.1-C.sub.5 alkynyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 6-10 membered aryl, or an optionally substituted 4-7 membered cycloalkyl; and

(22) p is 0 to 4.

(23) Alternatively, the compound of formula II has the following formula II-b:

(24) ##STR00005##

wherein:

(25) each R.sup.4 is independently selected from H, OH, CN, optionally substituted amino, —C(O)R.sup.5, —COOR.sup.5, —C(O)N(R.sup.5).sub.2, —SO.sub.2R.sup.5, an optionally substituted C.sub.1-C.sub.5 alkyl, an optionally substituted C.sub.1-C.sub.5 alkenyl, an optionally substituted C.sub.1-C.sub.5 alkynyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 6-10 membered aryl, or an optionally substituted 4-7 membered cycloalkyl;

(26) each R.sup.5 is independently selected from H, an optionally substituted C.sub.1-C.sub.5 alkyl, an optionally substituted C.sub.1-C.sub.5 alkenyl, an optionally substituted C.sub.1-C.sub.5 alkynyl, an optionally substituted 4-10 membered heterocyclyl, an optionally substituted 5-10 membered heteroaryl, an optionally substituted 6-10 membered aryl, or an optionally substituted 4-7 membered cycloalkyl; and

(27) p is 0 to 4.

(28) In one embodiment of the disclosure, the compound of formula II is:

(29) ##STR00006##

(30) The compound of formula II can be formed by contacting a compound of formula IV with bis(pinacolato)diboron (B.sub.2pin.sub.2), a palladium catalyst, and diethanolamine (DEA) (DEA is added after the first reaction is complete), wherein the compound of formula IV has the following structure:

(31) ##STR00007##

(32) wherein X′ is Cl, Br, or I.

(33) Further, the compound of formula IV can be produced by monobromination of a compound of formula V:

(34) ##STR00008##

to produce a compound of formula VI:

(35) ##STR00009##

and O-alkylating the compound of formula VI to produce the compound of formula IV, wherein X′ is Br. The monobromination can proceed over dibromination of the compound of formula V at a ratio of about 95:5 or greater. In another aspect, monobromination can proceed over dibromination of the compound of formula V at a ratio of about 99:1 or greater.

(36) In another aspect of the disclosure, the methods described herein further comprise crystallizing the compound of formula I from a mixture of formic acid and water. The crystallized compound of formula I can comprise the X-ray powder diffraction (XRPD) pattern having the following specifications:

(37) TABLE-US-00001 TABLE 1 Pos. d-spacing Rel. Int. No. [°2θ] [Å] [%] 1 7.807098 11.32447 13.16 2 8.691139 10.17446 15.67 3 8.944468 9.88685 40.82 4 11.47771 7.70979 20.22 5 13.75333 6.43883 19.45 6 15.27651 5.80009 8.04 7 15.69109 5.64776 64.51 8 15.99297 5.54183 66.46 9 16.27756 5.44557 7.77 10 16.89633 5.24752 43.12 11 17.50072 5.06763 36.25 12 17.96524 4.93763 88.03 13 19.20236 4.62223 11.22 14 19.70334 4.50582 15.85 15 20.50266 4.33193 20.82 16 21.13626 4.20348 38.66 17 21.89583 4.05935 81.05 18 22.10196 4.02195 61.36 19 22.57031 3.93954 13.52 20 22.97552 3.87097 16.48 21 23.32722 3.8134 25.65 22 23.5865 3.77206 13.16 23 24.44054 3.64216 100 24 25.17524 3.53751 6.64 25 25.60385 3.47925 14.72 26 26.41086 3.37474 9.88 27 27.71849 3.21844 12.35 28 28.72787 3.10761 4.64 29 29.60304 3.0177 3.73 30 31.95225 2.801 2.61 31 32.84832 2.72661 5.47 32 33.83981 2.64895 2.15 33 34.39729 2.60729 2.3 34 35.02682 2.56186 3.75 35 35.70021 2.51506 2.55 36 37.16499 2.41923 2.11 37 38.06795 2.3639 8.22 38 38.94192 2.31284 1.09.

(38) In one embodiment, the methods or processes described herein result in a compound of formula I having a purity of at least about 90%, about 95%, or about 99%.

(39) Described in the disclosure are compounds of formula I, a hydrate, solvate, prodrug, or pharmaceutically acceptable salt thereof, produced by any of the processes described herein.

(40) In one aspect of the disclosure, described is a process of monobrominating a compound of formula VII, the process comprising monobrominating the compound of formula VII to produce a compound of formula VIII.

(41) Two processes are described herein to make a compound of formula VIII. Process 1 (methylene chloride process) relies on the differentially in solubilities of this particular compound. Process 2 (TFA process) relies on the solution chemistry; the latter process may provide better control over a wider range of substrates, although both processes provide suitable compounds.

(42) Thus, the methylene chloride procedure may not work for any meta-directing group besides SO.sub.2Me (halogens are electron withdrawing groups (EWGs), as this process relies on specific physical attributes for bromination control (the mono-bromide is crystallized). However, the MeCN/TFA procedure should be more general to any meta directing EWG

(43) The compounds of formula VII and formula VIII have the following structures:

(44) ##STR00010##

wherein:

(45) R.sup.3 is selected from the group consisting of SO.sub.2R.sup.4, NO.sub.2, CN, SO.sub.3H, CHO, C(O)R.sup.4, COOR.sup.4, CO.sub.2H, C(O)N(R.sup.4).sub.2, and C(O)NH.sub.2;

(46) R.sup.4 is H optionally substituted C.sub.1-C.sub.8 alkyl, optionally substituted C.sub.1-C.sub.8 cycloalkyl, optionally substituted 4-10 membered heterocyclyl, optionally substituted 6-10 membered aryl, and optionally substituted 5-10 membered heteroaryl; and

(47) wherein the compound of formula VIII has a purity of greater than about 99% by weight.

(48) In one aspect of this method or process, the compound of formula VIII is washed with water at a temperature between about 18° C. and 23° C. In another aspect, the method or process further comprises subjecting the washed compound of formula VIII to drying at a temperature from about 23° C. to about 85° C. In addition, the compound of formula VIII can be washed with acetonitrile (MeCN) prior to washing with water.

(49) Both the foregoing summary and the following brief description of the drawings and detailed description are exemplary and explanatory. They are intended to provide further details, but are not to be construed as limiting. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description.