Process for preparing 2-( tert-butoxy)-4-(3-methyl-3-(5-methylsulfonyl)isoindolin-2-YL)butyl)phenol

Abstract

The present invention provides processes for the preparation 2-(t-butoxy)-4-(3-methyl-3-(5-methylsulfonyl)isoindolin-2-yl)butyl)phenol The disclosed processes overcome drawbacks of prior art methods by providing safer, more efficient synthetic routes with improved yields and reduced impurity levels. A key improvement includes a novel photochemical bromination process using continuous flow technology. The invention also encompasses novel intermediates including compounds of Formula 12 and 13. The processes eliminate the use of hazardous reagents, reduce reaction times, and provide better control over product purity, making them suitable for large-scale pharmaceutical manufacturing.

Description

Attorney Docket No. 134851-002702PROCESS FOR PREPARING 2-(TEKT-BUTOXY)-4-(3-METHYL-3-(5- METHYLSULFONYL)ISOINDOLIN-2-YL)BUTYL)PHENOLGOVERNMENT INTEREST

[0001] This invention was made with government support under R01AG065248 awarded by the National Institute on Aging of the National Institute of Health. The government has certain rights in this invention.SUMMARY

[0002] In some aspects, the techniques described herein relate to a process for preparing a compound of Formula (I) or a salt thereofcomprising a) contacting a compound of Formula 4 with a compound of Formula 1 to form a compound ofFormula 12b) cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 13c) hydrogenating the compound of Formula 13 to form the compound of Formula (I) or a salt thereofAttorney Docket No. 134851-002702

[0003] In some aspects, the techniques described herein relate to a process for preparing a compound of Formula 4:comprising brominating a compound of Formula 5a to form the compound of Formula 4,wherein the brominating comprises a photochemical bromination.

[0004] In some aspects, the techniques described herein relate to a process for preparing a compound of Formula 5a> comprising coupling of a compound of Formula 5c with sodium methyl sulfinateto form the compound of Formula 5a.

[0005] In some aspects, the techniques described herein relate to a process for preparing a compound of Formula (I) or a salt thereofAttorney Docket No. 134851-002702 comprising a) heating a compound of Formula 4 with a compound of Formula 1 in the presence of aqueous potassium carbonate to form a compound of Formula 12b) combining a compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base to form the compound of Formula 13c) contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base to form the compound of Formula (I) or a salt thereof

[0006] In some aspects, the techniques described herein relate to a compound ofFormula 12:

[0007] In some aspects, the techniques described herein relate to a compound ofFormula 10’AcOH:Attorney Docket No. 134851-002702

[0008] In some aspects, the techniques described herein relate to a compound ofFormula 12:prepared by a process comprising contacting a compound of Formula 4 with a compound ofFormula 1 to form the compound of Formula 12

[0009] In some aspects, the techniques described herein relate to a process for preparing a compound of Formula 12:comprising contacting a compound of Formula 4 with a compound of Formula 1 to form the compound of Formula 12

[0010] In some aspects, the techniques described herein relate to a compound ofFormula 13:prepared by a process comprising cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 13Attorney Docket No. 134851-002702

[0011] In some aspects, the techniques described herein relate to a process for preparing a compound of Formula 13:comprising cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 13BRIEF DESCRIPTION OF DRAWINGS

[0012] FIG. 1 shows a process flow diagram of the flow photochemical bromination.

[0013] FIG. 2 shows the results of a solvent / base screen of the hydrogenation of alkyne 13 with 5% Pd / C (40 psi / 10 °C).

[0014] FIG. 3 shows the product distribution with 5 wt% catalyst in various solvent / base combinations for the hydrogenation of alkyne 13.

[0015] FIG 4. Shows a single-crystal X-ray Structure of CT1812 hemifumarate dihydrate crystal form E.DETAILED DESCRIPTION

[0016] CT1812 is a compound of Formula IAttorney Docket No. 134851-002702 also known as 2-(t-butoxy)-4-(3-methyl-3-(5-methylsulfonyl)isoindolin-2-yl)butyl)phenol, is a first-in-class, orally bioavailable investigational drug currently in Phase II clinical trials for Alzheimer’s Disease, Lewy body dementia and dry age-related macular degeneration (dry AMD).

[0017] CT1812 and its preparation are disclosed by this Applicant in InternationalPublication WO2015 / 116923, and by Rishton et. al. (ACS Med Chem Lett. 2021; 12(9): 1389— 1395). The process for preparing CT1812 is disclosed in these documents as described in Scheme 1.Scheme 1.Attorney Docket No. 134851-002702

[0018] The prior synthesis was driven by the commercially availability of 2- methylbut-3-yn-2-amine (1), which serves as a convenient linker between the right and left sides of the CT1812. Terminal alkyne arylation of 1 with catechol-derived 2-(f-butoxy)-4-iodophenyl acetate (2) followed by hydrogenation furnished alkylamine 3. The isoindoline formation arose from the double / V-alkylation of 3 with dibromo benzyl arene 4; the latter obtained from the corresponding o-xylene analog (5a) which was derived from o-xylene (5b).

[0019] The prior process suffers from several drawbacks, especially for large scale production as follows.

[0020] The route to intermediate 5a was found to be undesirable because 1) it utilized chloroform, a suspected carcinogen, chlorosulfonic acid, a known lachrymator, and toxic iodomethane; 2) the purity of intermediate 7 varied on multi-kg scale due to the relative instability of the product and 3) the overall yield from compound 5b to 5a was low.

[0021] The route to compound 4 also has several drawbacks. On a large scale, theAIBN-promoted thermal di-bromination of compound 5a with NBS lead to a complex mixture of monobrominated (4a), di-brominated (4), and tribrominated (4b) products (and the corresponding regioisomers)In addition, the reaction was initially run in DCE and required heating 5a, NBS and AIBN to initiate the free radical propagation. The exothermic nature of the reaction, combined with the modest boiling point of DCE (83.5 °C) presents an explosive risk without careful control of the internal reaction temperature. This made the route untenable from a safety perspective as timely moderation of the internal reaction temperature was near impossible on a larger scale. Nitrogen off-gassing from the AIBN decomposition further complicated the operational feasibility of this approach. Obtaining consistent yields and purities was challenging as a result of all of these factors. Recrystallization of compound 4 was needed to obtain adequate purity. Furthermore, the tribrominated compounds of Formula 4b result in downstream formation of isoindole 14 vide infra), which must be removed from the API.

[0022] The prior four-step route to intermediate 10 from catechol and final steps to form CT1812 also had some disadvantages. First, iodination of phenol 8 via addition of aq. sodium hydroxide and aq. NaOCl to a mixture of the catechol and potassium iodide lead to the formation of product (9) with purity ranges from 85-95 A% with the mass balance comprised ofAttorney Docket No. 134851-002702 starting material 8 (up to 7A%), di-iodo analog 9a (1-2 A%) and chlorinated analog 9b (up to 6 A%).Additionally, intermediate 9 required acetyl protection (to form compound 2) to avoid competing O-alkylation of the remaining -OH by the benzyl bromide intermediate 4, during the formation of isoindoline 11. Furthermore, the acetyl protecting group had to be removed to form CT1812. Thus, the protection / deprotection added two additional steps to the process. Applicant also discovered that that alkyne 10 (as the free base) is not stable in solution or the solid state. As a solid, its purity degraded from 99 A% to 91 A% after six months of storage at 25 °C.

[0023] The prior route required a total of eleven steps plus three additional non-bond forming unit operations (salt formation, free-basing of the salt and API recrystallization).

[0024] For the reasons noted above, there exists a need for an efficient and scalable route for the large-scale manufacturing of CT1812, in particular a high yielding synthesis with no potential toxicity, stability or safety concerns.

[0025] The present disclosure provides a number of processes which overcome these drawbacks. Generally, the process is summarized in Scheme 2 below:Attorney Docket No. 134851-002702Process for Preparing a Compound of Formula (I) or a Salt Thereof

[0026] In some aspects, the present disclosure describes a process for preparing a compound of Formula (I) or a salt thereofcomprising a) contacting a compound of Formula 4 with a compound of Formula 1 to form a compound of Formula 12b) cross coupling of the compound of Formula 12 with a compound of FormulaAttorney Docket No. 134851-00270212 9 13 5. c) hydrogenating the compound of Formula 13 to form the compound ofFormula (I) or a salt thereof13

[0027] In some aspects, the process further comprises d) converting the compound ofFormula (I) to a salt of the compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is the compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a salt of compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a fumarate salt of compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a fumarate salt as described in co-filed application U.S. Provisional Application Serial Number 63 / 696,061, entitled “Crystalline forms of 2-(terf-butoxy)-4-(3-methyl-3-(5- (methylsulfonyl)isoindolin-2-yl)butyl)phenol fumarate salt” filed concurrently herewith on September 18, 2024, the contents of which is incorporated herein by reference in its entirety. In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a hemi-fumarate dihydrate salt of compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a hemi-fumarate dihydrate salt crystal form E characterized by an X-ray powder diffraction pattern (XRPD) including characteristic 20 peaks at 9.69, 16.51, 17.23, 19.02, 25.10, and 26.49° (± 0.2°).

[0028] In some aspects, the contacting in step a) comprises treating the compound ofFormula 4 in a solvent with aqueous potassium carbonate. In some aspects, the solvent in step a) is THF or 2-methyl THF. In some aspects, the contacting in step a) further comprises heating. In some aspects, the compound of Formula 12 is isolated prior to step b). In some aspects, the compound of Formula 12 obtained by step a) comprises less than 4A% of a compound of Formula 12a impurityAttorney Docket No. 134851-002702In some aspects, the compound of Formula 12 obtained by step a) comprises less than 3A% of a compound of Formula 12a impurity. In some aspects, the compound of Formula 12 obtained by step a) comprises less than 2A% of a compound of Formula 12a impurity. In some aspects, the compound of Formula 12 obtained by step a) comprises less than 1 A% of a compound of Formula 12a impurity. In some aspects, the compound of Formula 4 in step a) comprises less than 12A% of monobrominated compounds of Formula 4a impurityIn some aspects, the compound of Formula 4 in step a) comprises less than 3A% of monobrominated compounds of Formula 4a impurity. In some aspects, the compound of Formula 4 in step a) comprises about 2.5A% of monobrominated compounds of Formula 4a impurity. In some aspects, the compound of Formula 4 in step a) comprises less than 9A% of tribrominated compounds of Formula 4b impurityIn some aspects, the compound of Formula 4 in step a) comprises less than 1A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 in step a) comprises about 0.3A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 in step a) comprises less than 12A% of monobrominated compounds of Formula 4a impurity and less than 9A% of tribrominated compounds of Formula 4b impurityAttorney Docket No. 134851-002702In some aspects, the compound of Formula 4 in step a) comprises less than 3A% of monobrominated compounds of Formula 4a impurity and less than 1A% of tribrominated compounds of Formula 4b impurity. In some aspects the compound of Formula 4 in step a) comprises about 2.5A% of monobrominated compounds of Formula 4a impurity and about 0.3A% of tribrominated compounds of Formula 4b impurity.

[0029] In some aspects, the cross coupling in step b) is a Sonogashira coupling. In some aspects, the cross coupling in step b) comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base. In some aspects, the palladium catalyst in step b) is Pd(DPEphos)C12. In some aspects, the copper cocatalyst in step b) is CuBr or Cui. In some aspects, the copper cocatalyst in step b) is Cui. In some aspects, the amine in step b) is triethylamine. In some aspects, the cross coupling in step b) comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of catalytic Pd(DPEphos)C12, catalytic Cui and triethylamine. In some aspects, the solvent in step b) is 2-methylTHF. In some aspects, the compound of Formula 13 is isolated prior to step c).

[0030] In some aspects, the hydrogenating in step c) comprises contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base. In some aspects, the palladium or platinum catalyst in step c) is selected from the group consisting of 5% Pd / C, 10% Pd / C, 20% Pd(OH)2 / C and PtCh. In some aspects, the palladium or platinum catalyst in step c) is 5% Pd / C. In some aspects, the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, DMAP, imidazole, tri-ra-butylamine, TMEDA, proton sponge, and potassium carbonate. In some aspects, the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, and potassium carbonate. In some aspects, the base in step c) is DBU. In some aspects, the solvent in step c) is selected from the group consisting of DMAc, DMF, methanol and NMP. In some aspects, the solvent in step c) is methanol. In some aspects, the palladium or platinum catalyst in step c) is 5% Pd / C, the base is DBU, and the solvent is methanol. In some aspects, the hydrogen in step c) is 290-300 psi. In some aspects, the hydrogenation in step c) is performed at about 5-10 °C.

[0031] In some aspects, the compound of Formula (I), or a salt thereof comprises less than about 5A% of the isoindole of Formula 14 impurityAttorney Docket No. 134851-002702

[0032] In some aspects,, the compound of Formula 4 in step a) is prepared by any method known in the art. In some aspects, the compound of Formula 4 in step a) is prepared as described in International Publication WO2015 / 116923, herein incorporated by reference in its entirety. In some aspects, the compound of Formula 4 is prepared according to any method described herein. In some aspects, the compound of Formula 4 is prepared by photochemical bromination of a compound of Formula 5aIn some aspects, the photochemical bromination comprises treating the compound of Formula 5a with light >400 nm in the presences of a brominating agent selected from NBS or dibromodimethylhydantoin in a solvent and optionally a Bronsted acid. In some aspects, the brominating agent is NBS. In some aspects, the Bronsted acid is present and is selected from the group consisting of HBr, AcOH, Citric acid, H2SO4 or a combination of HBr / AcOH. In some aspects, the Bronsted acid is H2SO4. In some aspects, the light is about 450 to about about 460 nm. In some aspects, the solvent is selected from the group consisting of DCE, EtOAc and MeCN. In some aspects, the solvent is MeCN. In some aspects, the photochemical bromination is continuous flow photochemical bromination.

[0033] In some aspects, the compound of Formula 4 in step a) is prepared by is prepared by continuous flow photochemical bromination of a compound of Formula 5acomprising: i) preparing a first solution of the Bronsted acid in the solvent and preparing a second solution of the compound of Formula 5a and the brominating agent in the solvent; ii) simultaneously transferring the first solution through a first tube and second solution through a second tube to a reactor coil, such that the first solution and second solution mix upon entry to the reactor coil and wherein the reactor coil has a LED panel operating at about 450 nm to about 460 nm located on at least one side of the reactor coil; iii) pumping the mix of step ii) through the reactor coil to form the compound of Formula 4; and collecting the compound of Formula 4. In some aspects, the brominating agent is NBS, the Bronsted acid is H2SO4, the solvent is MeCN and the light is about 450 to about 460 nm. In some aspects, the compound of Formula 4 obtainedAttorney Docket No. 134851-002702 by the continuous flow photochemical bromination process has a chemical purity of at least 90 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 91 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 92 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 93 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 94 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 95 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 96 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 97 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 98 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of at least 99 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 90 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 91 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 92 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 93 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 94 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 95 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 96 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 97 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 98 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of about 99 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 90 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical brominationAttorney Docket No. 134851-002702 process has a chemical purity of 91 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 92 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 93 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 94 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 95 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 96 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 97 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 98 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process has a chemical purity of 99 A%. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process comprises less than 12 A% of monobrominated compounds of Formula 4a impurityI^X^'SO2Me Br 4aIn some aspects, the compound of Formula 4 in step a) comprises less than 3 A% of monobrominated compounds of Formula 4a impurity. In some aspects, the compound of Formula 4 in step a) comprises about 2.5 A% of monobrominated compounds of Formula 4a impurity. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination comprises less than 9 A% of tribrominated compounds of Formula 4b impurityIn some aspects, the compound of Formula 4 in step a) comprises less than 1 A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 in step a) comprises about 0.3 A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemicalAttorney Docket No. 134851-002702 bromination comprises less than 12 A% of monobrominated compounds of Formula 4a impurity and less than 9 A% of tribrominated compounds of Formula 4b impurity

[0034] In some aspects, the compound of Formula 4 in step a) comprises less than 3A% of monobrominated compounds of Formula 4a impurity and less than 1 A% of tribrominated compounds of Formula 4b impurity. In some aspects the compound of Formula 4 in step a) comprises about 2.5 A% of monobrominated compounds of Formula 4a impurity and about 0.3 A% of tribrominated compounds of Formula 4b impurity.

[0035] In some aspects, the compound of Formula 5a is prepared by any method known in the art. In some aspects, the compound of Formula 5a is prepared as described in International Publication WO2015 / 116923. In some aspects, the compound of Formula 5a is prepared according to any method described herein. In some aspects, the compound of Formula 5a is prepared by coupling of a compound of Formula 5c with sodium methyl sulfinateIn some aspects, the coupling comprises treating the compound of compound of Formula 5c with the sodium methyl sulfinate in the presence of a base, a bidentate ligand, and catalytic CuX in a solvent; wherein X is bromide or iodide. In some aspects, the base is selected from the group consisting of NaOH, K3PO4, and K2CO3. In some aspects, the base is K2CO3. In some aspects, the base is K2CO3 of a mesh size selected from the group consisting of 30, 160 or 400 mesh. In some aspects, the base is K2CO3 of a mesh size of 160. In some aspects, the bidentate ligand is selected from the group consisting ofAttorney Docket No. 134851-002702In some aspects, the bidentate ligand is proline. In some aspects, the solvent is selected from the group consisting of CPME, THF, IPA and DMSO. In some aspects, the solvent is DMSO. In some aspects, X is bromide. In some aspects, the treating comprises heating to a temperature selected from the group consisting of about 85 °C, about 100 °C and about 115 °C. In some aspects, the treating comprises heating to a temperature of about 115 °C. In some aspects, the coupling comprises a) combining the compound of Formula 5c with DMSO and water (10:1 v / v) at 25 °C in a vessel; b) adding sodium methane sulfinate, CuBr, L-proline and 160 mesh K2CO3 to the vessel to form a mixture; and c) heating the mixture to form the compound of Formula 5a. In some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 5 A% of a compound of Formula 5d impurity5dIn some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 4 A% of a compound of Formula 5d impurity. In some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 3 A% of a compound of Formula 5d impurity. In some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 2.5 A% of a compound of Formula 5d impurity. In some aspects, the compound of Formula 5a has a chemical purity of at least 90 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 91 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 92 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 93A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 94 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 95 A%. In someAttorney Docket No. 134851-002702 aspects, the compound of Formula 5a has a chemical purity of at least 96 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 97 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 98 A%. In some aspects, the compound of Formula 5a has a chemical purity of at about 90 A %. In some aspects, the compound of Formula 5a has a chemical purity of at about 91 A %. In some aspects, the compound of Formula 5a has a chemical purity of at about 92 A %. In some aspects, the compound of Formula 5a has a chemical purity of at about 93 A %. In some aspects, the compound of Formula 5a has a chemical purity of at about 94 A %. In some aspects, the compound of Formula 5a has a chemical purity of at about 95 A %. In some aspects, the compound of Formula 5a has a chemical purity of at about 96 A%. In some aspects, the compound of Formula 5a has a chemical purity of at about 97 A%. In some aspects, the compound of Formula 5a has a chemical purity of at about 98 A%.

[0036] In some aspects,, the compound of Formula 9 is prepared by any method known in the art. In some aspects, the compound of Formula 9 is prepared as described in International Publication WO2015 / 116923. In some aspects, the compound of Formula 9 is prepared according to any method described herein.

[0037] In some aspects, the compound of Formula 8 is prepared by any method known in the art. In some aspects, the compound of Formula 8 is prepared as described in International Publication WO2015 / 116923. In some aspects, the compound of Formula 8 is prepared according to any method described herein.

[0038] In some aspects, the present disclosure describes a process for preparing a compound of Formula (I) or a salt thereofcomprising a) heating a compound of Formula 4 with a compound of Formula 1 in the presence of aqueous potassium carbonate to form a compound of Formula 12Attorney Docket No. 134851-002702 b) combining a compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base to form the compound of Formula 13c) contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base to form the compound of Formula (I) or a salt thereofIn some aspects, the process further comprises d) converting the compound of Formula (I) to a salt of the compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is the compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a salt of compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a fumarate salt of compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a fumarate salt as described in co-filed application U.S. Provisional Application Serial Number 63 / 696,061, entitled “Crystalline forms of 2-(terf-butoxy)-4-(3-methyl-3-(5- (methylsulfonyl)isoindolin-2-yl)butyl)phenol fumarate salt” filed concurrently herewith on September 18, 2024, the contents of which is incorporated herein by reference in its entirety. In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a hemi-fumarate dihydrate salt of compound of Formula (I). In some aspects, the compound of Formula (I) or a salt thereof prepared by a process according to any aspect described herein, is a hemi-fumarate dihydrate salt crystal form E characterized by an X-ray powder diffraction pattern (XRPD) including characteristic 20 peaks at from 9.69, 16.51, 17.23, 19.02, 25.10, and 26.49° (± 0.2°).

[0039] In some aspects, the solvent in step a) is THF or 2-methyl THF. In some aspects, the compound of Formula 12 is isolated prior to step b).Attorney Docket No. 134851-002702

[0040] In some aspects, the palladium catalyst in step b) is Pd(DPEphos)Ch. In some aspects, the copper cocatalyst in step b) is Cui. In some aspects, the amine in step b) is triethylamine. In some aspects, the palladium catalyst in step b) is Pd(DPEphos)Ch, the copper cocatalyst is Cui and the amine is triethylamine. In some aspects, the solvent in step b) is 2- methylTHF. In some aspects, the compound of Formula 13 is isolated prior to step c).

[0041] In some aspects, the palladium or platinum catalyst in step c) is selected from the group consisting of 5% Pd / C, 10% Pd / C, 20% Pd(OH)2 / C and PtCh. In some aspects, the palladium or platinum catalyst in step c) is 5% Pd / C. In some aspects, the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, DMAP, imidazole, tri-n-butylamine, TMEDA, proton sponge, and potassium carbonate. In some aspects, the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, and potassium carbonate. In some aspects, the base in step c) is DBU. In some aspects, the solvent in step c) is selected from the group consisting of DMAc, DMF, methanol and NMP. In some aspects, the solvent in step c) is methanol. In some aspects, the palladium or platinum catalyst in step c) is 5% Pd / C, the base is DBU, and the solvent is methanol. In some aspects, the hydrogen in step c) is 290-300 psi. In some aspects, the hydrogenation in step c) is performed at about 5-10 °C. In some aspects, in step c) the palladium or platinum catalyst is 5% Pd / C, the base is DBU, the solvent is methanol, the pressure of the hydrogen is 290-300 psi and the reaction is conducted at a temperature of 5-10 °C. In some aspects, the process further comprises isolating the compound of Formula (I) or a salt thereof.

[0042] In some aspects, the compound of Formula (I), or a salt thereof comprises less than about 5% of the isoindole of Formula 14 impurityProcess for Preparing a Compound of Formula 5a

[0043] In some aspects, the present disclosure describes a process for preparing a compound of Formula 5acomprising coupling of a compound of Formula 5c with sodium methyl sulfinateAttorney Docket No. 134851-002702to form the compound of Formula 5a. In some aspects, the coupling comprises treating the compound of compound of Formula 5c with the sodium methyl sulfinate in the presence of a base, a bidentate ligand, and catalytic CuX in a solvent; wherein X is bromide or iodide. In some aspects, the base is selected from the group consisting of NaOH, K3PO4, and K2CO3. In some aspects, the base is K2CO3. In some aspects, the base is K2CO3 of a mesh size selected from the group consisting of 30, 160 or 400 mesh. In some aspects, the base is K2CO3 of a mesh size of 160. In some aspects, the bidentate ligand is selected from the group consisting ofIn some aspects, the bidentate ligand is proline. In some aspects, the solvent is selected from the group consisting of CPME, THF, IPA and DMSO. In some aspects, the solvent is DMSO. In some aspects, X is bromide. In some aspects, the treating comprises heating to a temperature selected from the group consisting of about 85 °C, about 100 °C and about 115 °C. In some aspects, the treating comprises heating to a temperature of about 115 °C. In some aspects, the coupling comprises a) combining the compound of Formula 5c with DMSO and water (10:1 v / v) at 25 °C in a vessel; b) adding sodium methane sulfinate, CuBr, L-proline and 160 mesh K2CO3 to the vessel to form a mixture; and c) heating the mixture to form the compound of Formula 5a. In someAttorney Docket No. 134851-002702 aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 5 A% of a compound of Formula 5d impurityIn some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 4 A% of a compound of Formula 5d impurity. In some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 3 A% of a compound of Formula 5d impurity. In some aspects, the compound of Formula 5a prepared by the process coupling of a compound of Formula 5c with sodium methyl sulfinate comprises less than 2.5 A % of a compound of Formula 5d impurity. In some aspects, the compound of Formula 5a has a chemical purity of at least 90 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 91 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 92 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 93 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 94 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 95 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 96 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 97 A%. In some aspects, the compound of Formula 5a has a chemical purity of at least 98 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 90 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 91 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 92 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 93 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 94 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 95 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 96 A%. In some aspects, the compound of Formula 5a has a chemical purity of about 97A%. In some aspects, the compound of Formula 5a has a chemical purity of about 98 A%.Process for Preparing a Compound of Formula 4

[0044] In some aspects, the present disclosure describes a process for preparing a compound of Formula 4Attorney Docket No. 134851-002702comprising brominating a compound of Formula 5a to form the compound of Formula 4,wherein the brominating comprises a photochemical bromination. In some aspects, the photochemical bromination comprises treating the compound of Formula 5a with light >400 nm in the presences of a brominating agent selected from NBS or dibromodimethylhydantoin in a solvent and optionally a Bronsted acid. In some aspects, the brominating agent is NBS. In some aspects, the Bronsted acid is present and is selected from the group consisting of HBr, AcOH, citric acid, H2SO4 or a combination of HBr / AcOH. In some aspects, the Bronsted acid is H2SO4. In some aspects, the light is about 450-about 460 nm. In some aspects, the solvent is selected from the group consisting of DCE, EtOAc and MeCN. In some aspects, the solvent is MeCN. In some aspects, the photochemical bromination is continuous flow photochemical bromination.

[0045] In some aspects, the present disclosure describes a process for preparing a compound of Formula 4

[0046] is prepared by is prepared by continuous flow photochemical bromination of a compound of Formula 5acomprising: i) preparing a first solution of the Bronsted acid in the solvent and preparing a second solution of the compound of Formula 5a and the brominating agent in the solvent; ii) simultaneously transferring the first solution through a first tube and second solution through aAttorney Docket No. 134851-002702 second tube to a reactor coil, such that the first solution and second solution mix upon entry to the reactor coil and wherein the reactor coil has a LED panel operating at about 450 nm to about 460 nm located on at least one side of the reactor coil; iii) pumping the mix of step ii) through the reactor coil to form the compound of Formula 4; and collecting the compound of Formula 4. In some aspects, the brominating agent is NBS, the Bronsted acid is H2SO4, the solvent is MeCN and the light is about 450 to about 460 nm. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process is at least 95 A% chemically pure. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination process comprises less than 12 A% of monobrominated compounds of Formula 4a impurityIn some aspects, the compound of Formula 4 in step a) comprises less than 3 A% of monobrominated compounds of Formula 4a impurity. In some aspects, the compound of Formula 4 in step a) comprises about 2.5 A% of monobrominated compounds of Formula 4a impurity. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination comprises less than 9 A% of tribrominated compounds of Formula 4b impurityIn some aspects, the compound of Formula 4 in step a) comprises less than 1 A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 in step a) comprises about 0.3 A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 obtained by the continuous flow photochemical bromination comprises less than 12A% of monobrominated compounds of Formula 4a impurity and less than 9A % of tribrominated compounds of Formula 4b impurityAttorney Docket No. 134851-002702In some aspects, the compound of Formula 4 in step a) comprises less than 3A% of monobrominated compounds of Formula 4a impurity and less than 1 A% of tribrominated compounds of Formula 4b impurity. In some aspects, the compound of Formula 4 in step a) comprises about 2.5 A% of monobrominated compounds of Formula 4a impurity and about 0.3 A% of tribrominated compounds of Formula 4b impurity.Initial Improvements to Prior Synthesis

[0047] Initial Preparation of Compound 5a

[0048] The initial, three-step route to aryl sulfone 5a started with the sulfonylation of o-xylene (5b) with chlorosulfonic acid (2 equiv.) in chloroform at 25 °C followed by an aqueous workup to provide the corresponding aryl sulfonic acid 6 in 75% yield (96 A% purity). Reduction of 6 with sodium sulfite in aq. NaOH at 25 °C provided the corresponding aryl sulfinic acid 7 in 67% yield. The purity of this intermediate varied on multi-kg scale from 86-93 A% due to the relative instability of the product. A subsequent methylation with iodomethane (2 equiv.) and potassium carbonate in DMF at 45 °C gave the corresponding aryl methyl sulfoxide 5a in 60% yield (>99 A% purity) after purification with Darco G-60 in MTBE. The three-step route proceeded in 30% overall yield.Scheme 3. Synthesis of Intermediate 5a

[0049] Initial Studies to Improve the Preparation of Compound 5a

[0050] 4-Bromo-o-xylene (5c) was viewed as a viable starting material hoping to leverage a Cu-promoted coupling with sodium methyl sulfinate. Applying the literature procedure (Zhu, W.; Ma, D. Synthesis of Aryl Sulfones via L-Proline-Promoted Cui-Catalyzed Coupling Reaction of Aryl Halides with Sulfinic Acid Salts. J Org Chem 2005, 70, 2696-2700), the reaction proceeded with MeSChNa (1.3 equiv.), Cui (0.16 equiv.), L-proline (0.3 equiv.) and NaOH (0.3 equiv.) in DMSO at 110 °C. An isolation from 2V MTBE at 0 °C gave 5a in 66-70% isolated yield (adjusted for starting material purity) on 100 kg scale (>99 A% purity; regioisomer 5d <0.5 A%). Subsequently, the Cui was replaced by CuBr with no impact on yield or purity. The reaction with either copper promoter required prolonged reaction times (40 h) and multiple promoter kicker charges.

[0051] Due to the modest yield, prolonged reaction time, and cost of goods impact, a re-examination of both the discreet and continuous variables was undertaken. Using HighAttorney Docket No. 134851-002702Throughput Experimentation (HTE) platform, two bases (K3PO4, K2CO3; 1.0 equiv.), 22 bidentate ligands (Scheme 4) (0.3 equiv.) and five solvents (toluene, CPME, THF, IPA, DMSO; 3V) were screened at 115 °C for 16 h with 1.4 equiv. MeSO2Na and 0.15 equiv. CuBr. In all, 202 reactions were performed from which the original L-proline ligand, K2CO3, and DMSO emerged as the best combination based on yield and cost.Scheme 4: Structures of ligands screened in the synthesis of 5a

[0052] Next, optimization of the continuous variables was studied using Design ofExperiments (DoE); namely, equivalents of K2CO3 (0.5-1.5 equiv.), and MeSC Na (1.0-1.4 equiv.), and DMSO volume (3-7 V) at three temperatures (85 / 100 / 115 °C) for 16 h. The following factors were fixed: CuBr (0.10 equiv.) and L-proline (0.20 equiv.). Using a central composite design, a total of 60 reactions were performed on 50 mg scale. The highest yield of 5a was achieved with at least 1.0 equiv. K2CO3 at 115 °C while DMSO volume and MeSO2Na equiv. had no impact on the outcome.

[0053] Expectedly, the reaction rate was dependent on the particle size of the potassium carbonate (30-, 160- and 400-mesh. To mitigate the importance of mixing on scale up, water (0.3 V) was added to the reaction with 160-mesh carbonate. This served to markedly increase the reaction rate such that >99% conversion of the desired isomer was achieved in 3 h.Attorney Docket No. 134851-002702

[0054] A modified isolation from MTBE / heptane at 0-5 °C combined with the conditions informed by the DoE lead to an improved 85% assay yield of 5a (97.5 A%; 2.3 A% 5d) with a reduced reaction time and elimination of the kicker charges (Table 1).

[0055] Table 1: Optimized Synthesis of 5aX = I, Br*adjusted for purity of 5c (75A%)

[0056]

[0057] Initial Studies to Improve the Preparation of Compound 4

[0058] Due to the drawbacks of the prior art method for preparing compound 4, an initial measure was developed, in which a controlled addition of an NBS / AIBN solution to substrate 5a at 70-72 °C mitigated the exotherm (vida supra). The reaction was performed by first reacting 5a with 1 / 3 of the total NBS / AIBN needed (0.7 equiv., 0.02 equiv., respectively) in DCE at 72-75 °C for 2 h, followed by the addition of the remaining 2 / 3 of the reagents in MeCN over 2 h (due to lack of solubility, a complete replacement of DCE with MeCN was not possible.). The reaction was aged for an additional 8 h to achieve 99% consumption of starting material 5a. Eventual crystallization from ethanol, followed by ambient trituration with MTBE provided 4 in 35% overall yield (unadjusted; 92 A% purity). The MTBE trituration reduced the level of the isomeric tribrominated compounds (4b) from 13 A% to 6 A% (80% recovery). Minimizing this impurity was critical as it is transformed downstream into isoindole 14 vide infra) which must be removed in the final API crystallization. The isoindole is also a solid-state degradant of the drug product on storage, thus minimizing its level here was advantageous.

[0059] Extensive efforts to reduce the over-brominated species (4b) back to 4 with diethyl (and dimethyl) phosphite and DIPEA in various solvents offered little advantage, as overreduction to 4a was observed and reagent by-products complicated the isolation.Attorney Docket No. 134851-002702

[0060] Initial Preparation of Compound 10 from Catechol

[0061] The four-step route to intermediate 10 began with FhSCh-catalyzcd (0.1 equiv.) (9-t-butylation of catechol with isobutene (6.5 equiv.) in DCM at 35 °C / 24 h after which the reaction mixture was cooled to 0 °C and the acid neutralized with EtiN to minimize product decomposition. The modest level (11 A%) of the bis-O-alkylatcd species was easily removed by partitioning the post-reaction concentrate between hexanes (or / / -heptane) and aq. NaOH, leveraging the presence of a phenolic proton in 8. After neutralization with aq. HC1, the product was extracted into EtOAc, followed by evaporation to provide 8 as a liquid in 78% assay yield (>99 A% purity, Scheme 5).Scheme 5. Synthesis of Compound 8 from catechol isobutene (6.5 eq)

[0062] The original iodination of phenol 8 proceeded via the sequential addition of aq. sodium hydroxide (0.85 equiv.) and aq. NaOCI (0.95 equiv.) to a mixture of the substrate and potassium iodide (0.85 equiv.) in EtOH at 0-5 °C, followed by aging for 3 h at 5-10 °C (Scheme 6). The reaction was neutralized with aq. HC1 and extracted with DCM. The product (9) was obtained as a viscous oil after solvent evaporation in 89% mass yield (uncorrected). Typical product purity ranged from 85-95 A% with the mass balance comprised of starting 8 (up to 7A%), di-iodo analog 9a (1-2 A%) and chlorinated analog 9b (up to 6 A%).Scheme 6. Synthesis of Compound 9

[0063] The acetylation of iodo-phenol 9 was accomplished by reaction with acetyl chloride (1.1 equiv.) and EtiN (3.0 equiv.) in DCM at 0-25 °C to give 2 as a solid in 71-74% yield. The product was initially isolated from hexanes at -10 °C with 98.5 A% purity. Subsequent work showed that: (1) IpAc is a suitable replacement for DCM as the reaction solvent and (2) isolation from / / -heptane at -15 °C gave the product in 81% yield and 99.6 A% purity.Attorney Docket No. 134851-002702Scheme 7. Synthesis of Compound 10 from Compound 9

[0064] The initial multi-kg scale Sonogashira coupling of aryl iodide 2 with 1,1- dimethylpropargylamine (1) (2 equiv.) was performed with 3 mol% Pd(Ph3P)2C12 and 5 mol% Cui with EtsN (19 V) serving as base and solvent. The reaction proceeded at 25-30 °C / 17 h to provide 10 as a beige solid in 65% yield after chromatography (>98 A% purity; Pd: 1908 ppm). Subsequently, the catalyst charges were reduced to 0.3 mol% and 0.6 mol%, respectively, TEA was replaced with potassium carbonate (3.0 equiv.), and THF was employed as solvent (10 V). Under these modified conditions, the reaction proceeded to completion in 5 h at 45 °C. Alkyne 10 was crystallized from EtOAc / heptane in 79% yield (> 98 A% purity; Pd: 564 ppm, Scheme 7).

[0065] Initial Preparation of Compound CT1812 free base

[0066] The hydrogenation of 10 in THF with 5% Pd / C (20 wt% loading) at 45 psi / 15—20 °C for 3-6 h (>99 A% conversion) provided compound 3, which was processed directly without isolation into the following step after removal of the catalyst. Compound 4 was then combined with EtsN and the THF solution of 3 followed by heating to 40 °C for 18 h. After removal of the inorganics by filtration, the filtrate was concentrated, and the solvent switched to MTBE. Isoindoline (11) was isolated using / / -heptane as an anti-solvent in up to 56% yield (The low yield of 11 was attributed to the product co-precipitating with the inorganics.). The removal of the O- acetyl group was effected by reaction of 11 with catalytic sodium methoxide (0.13 equiv.) in methanol at 20 °C / 5 h. An equal volume of water was added to the reaction mixture followed by isolation of the solids to give CT1812 free base (95 A% purity). The stability of the free base prohibits drying beyond 30 °C, thus complete removal of the residual water was challenging. The water-wet material was converted into the mono fumarate salt by dissolution in THF at 45 °C followed by addition of fumaric acid (1.0 equiv.). A partial solvent switch to EtOAc crystallized the crude CT1812 fumarate 84% yield from 11. A recrystallization from EtOH provided CT1812 fumarate in 80% recovery (>99.5 A% purity, Scheme 8).Attorney Docket No. 134851-002702Scheme 8. Synthesis of CT1812 Fumarate from 10

[0067] Modified Preparation of Compound CT1812 free base

[0068] Subsequently, it was discovered that alkyne 10 (as the free base) is not stable in solution or the solid state. As a solid, its purity degraded from 99 A% to 91 A% after six months of storage at 25 °C. Accordingly, an acid screen identified AcOH as an acceptable salt-former as it displayed a better stability profile. The 10’ AcOH salt was formed by treating a DCM solution of 10 with AcOH (1.5 equiv.) at 15-25 °C. The addition of MTBE as anti-solvent and cooling to 15 °C provided the product in 86% yield (>99.5 A% purity). Incorporating 10’AcOH into the process was accomplished by neutralization with aq. potassium carbonate and extracting the free amine into 2-MeTHF which was directly treated with 5% Pd / C. The catalyst loading was reduced from 20 wt% to 5 wt% with no impact on reaction rate. The reaction proceeded at 45 psi at 25 °C for 6 h (>99 A% conversion). After removal of the catalyst, the filtrate containing 3 (100% yield assumed), was combined with dibromide 4 (0.80 equiv.) and TEA (3 equiv. vs. 4) and heated to 50 °C for 5 h to effect formation of 11. On cooling to RT, the reaction mixture was washed with water to dissolve the ammonium salts, the organic layer concentrated in vacuo by 50% and n- heptane added over 2 h at 40 °C. The resulting slurry was cooled to 10 °C and aged for 2 h to provide 11 in 76% yield over the two steps (97.5 A% purity). The de-acetylation, crude fumarate salt formation, and recrystallization were performed as before to provide CT 1812 fumarate in 64% overall yield from 11 (99.8 A% purity) as a colorless solid (Scheme 8).

[0069] This modified route to CT1812 fumarate was 11 steps overall with the longest linear sequence being nine steps. Thus, a more efficient approach was sought.New Route to CT1812Attorney Docket No. 134851-002702Scheme 9: New route to CT1812 via Alkyne 13CT1812

[0070] The new route to CT1812 relies on the formation of the isoindoline prior to cross-coupling with aryl iodide 9 and comprises three new reactions: !) formation of isoindoline 12 from dibenzyl bromide 4 and 2-methylbut-3-yn-2-amine (1); 2) Sonogashira coupling of aryl iodide 9 and alkyne 12; and 3) hydrogenation of alkyne 13 (Scheme 9).

[0071] Furthermore, a sustainable synthesis of compound 4 free from the prior art drawbacks was also developed.

[0072] Synthesis of dibenzyl bromide 4 via visible light-induced continuous benzylic bromination

[0073] A photochemical benzylic variation of the Wohl-Zeigler reaction was developed which eliminated the need for the azo radical initiator, and heating required in the prior method. This reaction was first conducted in batch before transitioning to flow. Initial reactions were run using 405 nm LEDs, as photochemical brominations proceed via homolysis of molecular bromine whose X max is 395 nm. A low steady-state concentration of Br2 arises from the reaction of HBr (or any Bronsted acid) with NBS via the established Goldfinger mechanism.

[0074] A scouting reaction with 2.1 equiv. NBS in MeCN (20 V) at 20 °C in jacked glass reactor with 50W 405 nm irradiation showed the reaction stalled after 140 min with complete consumption of the starting material 5a but only 36 A% of the desired dibromo species (4) and 64% of the under-reacted mono-bromo species (4a). The addition of various acids (Table 2) to the reaction improved the amount of desired compound 4, while decreasing compound 4a. The use of 10 mol% H2SO4 provided the best results showing complete conversion of the starting material and monobrominated species within 60 min.Attorney Docket No. 134851-002702

[0075] Table 2: Impact of various acids on selectivity and conversion with NBS(2.1 equiv.)**Reactions run in 20 vol MeCN at 20 °C

[0076] While reaction with the 10% H2SO4 did not produce monobrominated (4a) species, tribrominated species (4b) were produced. Maximizing formation of the tribrominated species was preferred over the under-reacted monobrominated species as the former had the potential to be reduced back to the desired di-bromo species 4. Again, efforts to remediate the over-brominated species back to 4 using diethyl phosphite and DIEA in MeCN were unproductive. In some cases, over-reaction of 4b to monobrominated species 4a was observed. Also, the byproducts of the reaction were difficult to remove from 4, resulting in complications with residual phosphorus interfering with the downstream Sonogashira reaction.

[0077] The use of DCE and EtOAc as reaction solvents offered no advantage overMeCN; while dibromodimethylhydantoin offered no advantage over NBS. Thus DCE, EtOAc or MeCN could be used in the reaction and NBS or dibromodimethylhydantoin could be used in the reaction.

[0078] In preparation for the transition to continuous processing (‘flow’), it was important to know the extent of reaction in the absence of light. A representative control reaction was stirred in the dark for 15 h at RT and showed no reaction. This allowed for the processing flexibility to turn the reaction on and off by merely controlling the irradiation.

[0079] In moving from batch to continuous reaction (flow) two separate MeCN streams, one with the 5c and NBS and the other containing the acid additive, were used to avoid material incompatibility with the 316 / 316L stainless steel fittings of the pump and reactor (FIG. 1).

[0080] A series of experiments aimed at optimizing the residence time to maximize throughput and product distribution was undertaken in a 100W IRIS Lab® photoreactor system with 1 / 8” PFA tubing (Table 3). The flow rates and concentrations were devised to ensure complete solubility of the solutes at 20 °C and stoichiometries of NBS (2.3 equiv.) and sulfuric acid (10 mol%). The residence time had a minimal effect on conversion and product distribution,Attorney Docket No. 134851-002702 indicating the reaction reaches full consumption of NBS at < 0.5 min. To maximize throughput, a residence time of 0.5 min was selected.

[0081] Table 3: Impact of Residence Time on Conversion and ProductDistributionThe following parameters were fixed:

[0082] To adjust for continuous photochemical bromination on a larger scale to 5 kWIRIS Max photoreactor system, irradiation with 460 nm LED was also studied (Table 4). Due to the lower UV absorption of Br2 at 460 nm, conversion to product 4 required 1 min residence time at higher power input to reach equivalent conversion, which resulted in lower substrate throughput. To compensate for lower UV absorption, larger tubing of 3.2 mm ID was used and which restored equivalent or better productivity with 81 A% 4 and 19 A% of the tribrominated species 4b.

[0083] Table 4. Impact of LED Wavelength, Reactor Pathlength on ProductDistribution and ProductivityAttorney Docket No. 134851-002702

[0084] A DoE study was conducted to optimize product 4 purity, yield, and throughput, as well as understand the design space of the process (PARs and NORs). A custom DoE design with three replicate center points resulted in 14 experiments (Table 5). The three center point runs (# 8, 10, 14), were included as a measure of the system reproducibility, showed consistent responses, indicating the data was robust and meaningful.

[0085] Table 5. DoE variables / ranges and responses for the synthesis of 4

[0086] The data analysis indicated that LED current, residence time and NBS equiv. were relevant factors while MeCN volume was not. Accordingly, the MeCN volume was set at 16 V. Two model verification runs were performed with residence times of 47 and 48.5 sec and showed good correlation with the prediction, although the model predicted higher levels of 4a (18 A%) than were actually observed (10-12 A%).Attorney Docket No. 134851-002702

[0087] Table 6. DoE prediction of optimal conditions vs Actual

[0088] The 4a:4b ratio could be tuned by adjusting the residence time to suit the ability of the isolation to reject these impurities. Since the tribrominated species 4b were more difficult to remove via crystallization and forms the isoindole impurity downstream, it was preferred to minimize its formation, by leveraging shorter residence times. A series of runs varying only the residence time showed that 40-60 sec was ideal (Table 7). A 500 g batch was performed with the optimized parameters of 2. 1 equiv NBS, 10 mol% H2SO4 using a 26 mL reactor volume with a 40s residence time and 80 W input power, resulting in a run time of 242 min. This was equivalent to about 120 g / h 5a (0.65 mol / h) throughput at an estimated 35 W radiant flux (-0.45 mol / h). This translates to about 250-300% quantum yield per bromination, consistent with radical chain reaction nature of the bromination chemistry.

[0089] Table 7. Impact of residence time on product distribution

[0090] The post-reaction solution was treated with aq. NazSCh to reduce any remaining active bromine and neutralize the sulfuric acid. The resulting inorganics were removed by filtration, and the filtrate concentrated and flushed with MeCN until the resulting water content was 270 ppm. The solution was again filtered, and the filtrate adjusted down to 3.2 V followed by the addition of water (0.68 V). The resulting solution was seeded at RT followed by the addition of aq. IPA (4.5 V). The resulting slurry was aged at 20 °C for 1 h before cooling to -10 °C and aging for 18 h. The product was isolated in 52% yield (uncorrected; 9% loss to MLs) with 90 A% purity.

[0091] For scale-up to 145 kg (5a input) adjustments to the initial conditions were necessary to accommodate the new mechanical / experimental setup. The photochemical bromination was run at 1.5 L reactor volume (ID: 8 mm, 30 m) operated at 450 nm (2.1 A LED current; 462 watts) with a 40 sec residence time at a throughput of 15.6 kg / h of 5a, while holding all other parameters consistent with the initial development. The post-reaction quench with aq.Attorney Docket No. 134851-002702 sodium sulfite was performed at 5 °C for stability reasons which rendered the initial orange solution colorless. The steady state specification for conversion was set as NMT 1.0% starting material and NMT 9.0 A% monobrominated species. Crystallization from water / MeCN / IPA as before provided 4 in 52% yield (assay adjusted) in 95.5 A% purity. The major impurity was the monobrominated species at 2.5 A%. The absence of the tribrominated impurity ensured that the corresponding isoindole impurity (12a) would not form in the downstream reaction (Scheme 10).Scheme 10: Synthesis of Indole 12a

[0092] Synthesis of Isoindoline 12 from Dibenzyl Bromide 4 and 2-Methylbut-3-yn-2-amine ( 1)Scheme 11: Synthesis of Isoindoline 12

[0093] The formation and isolation of isoindoline 12 was initially developed to accommodate up to 4 A% 4b impurities. The reaction of 1.2 equiv. alkyne 1 (The charge was adjusted based on the purity of the commercial material, 86% based on qNMR (KF: 12%); GC purity 97.4 A%) with 4 (containing 4 A% 4b) in 2-MeTHF (5 V) and aq. potassium carbonate (3 equiv.) at 55 °C showed 99% conversion after 10 h. Removal of the aqueous layer, followed by addition of heptane (4 V) at RT, crystallized 12 in 88% yield (7% loss to liquors) in 99 A% purity. This isolation rejected the majority of the 12a impurity as it was present at only 0.8 A% in the isolated product. Operationally though, 2-MeTHF presented a few challenges: (1) the crystallized product tended to adhere to the sides of the vessel, (2) the post-reaction layer separation required warming to 55 °C due to low product solubility, (3) the cost remains significantly higher than THF, and (4) lengthy reaction time. By comparison, the reaction in THF (3 V) with 2.5 equiv. aq. potassium carbonate was complete within 5 h (>99.5% conv.) at 55 °C and allowed the layer separation to be done at 30 °C. The addition of heptane (4 V) at 40 °C followed by product isolation at 0 °C gave a 90% corrected yield of 12 as a free-flowing solid in >99 A% purity (Scheme 11).Attorney Docket No. 134851-002702

[0094] Sonogashira Coupling of Compounds 9 and 12

[0095] Prior to the cross-coupling reaction of the compound of Formula 12 with the compound of Formula 9, a purer form of compound 9 was needed. Prior to Applicants invention, aryl iodide 9, had only been known to be a viscous oil of modest purity (90 A%; 84 wt%) (vide supra). Efforts to increase the purity by distillation or trituration with heptane proved unsuccessful. Purification by column chromatography eluting with DCM / heptane removed the colored impurities but with minimal increase in purity.

[0096] Initially, high purity 9 was accessed via an acetylation-deacetylation approach.The acetylation of 9 (90 A%) with Ac-Cl (1.1 equiv.) and TEA (1.5 equiv.) in DCM at 0 °C for 1 h gave a 73% yield of 2 (99 A%) after trituration of the crude product with hexanes. Base-induced deacetylation gave sufficiently pure 9, again as an oil (98 A%, 98.6 wt%) (Scheme 12).Scheme 12: Synthesis and Purification of 9 via 2

[0097] For the Sonogashira coupling a screen of seven common, pre-formed Pd catalysts (0.1 mol%) was performed with Cui (0.3 mol%), and EtiN (3.0 equiv.) in 2-MeTHF (10V) at 40 °C for 40 h (Table 8). Entry 1 (Pd(DPEphos)C12) performed the best, affording 70.5 A% of 13. Elevated reaction temperatures (60, 75 °C) offered no advantage while increasing the amount of the homo-coupled dimer (1.2, 2.4 A%, respectively). Ultimately, the reaction was run in 2-MeTHF (3 V ) with 0.2 mol% Pd(DPEphos)Ch and 0.6 mol% Cui at 40 °C for 19 h which gave 13 in 97.5 A%. An aq. workup with NH4CI (to sequester the copper) was used, followed by addition of heptane (1: 1.2 v / v) as an anti-solvent provided an 82% isolated yield of 13 with 98 A% purity. The residual Cu was 0. 1 ppm and Pd 230 ppm.Attorney Docket No. 134851-002702

[0098] Table 8. Pd Catalyst Screen for Sonogashira Coupling**screening conditions: 9 (1.0 equiv), 12 (1.1 equiv), TEA (3.0 equiv), Pd source (0.1 mol%), Cui (0.3 mole%), 2MeTHF (10 V), 40 °C / 40 h.

[0099] Characterization of 13 isolated from early crystallization efforts from 2-MeTHF / heptane revealed it exhibited four polymorphic forms with m.p. = 99, 103, 129, and 140 °C. Heating mixtures of the polymorphs to 130 °C followed by cooling was effective at converting all forms to the one melting at 140 °C. This technique was used to provide material as seed for subsequent crystallizations to insure polymorphic control. Form control is imperative for consistent rejection of impurities and metals for late-stage intermediates.

[0100] With reasonable Sonogashira conditions in hand, a telescoped process to include the deacetylation step was developed. Thus, combining 2 with MeOH (2.5 V) andNaOMe in MeOH (5.4 M; 0.13 equiv.) at RT for 5 h gave complete conversion to phenol 9. The reaction mixture was neutralized with IN aq. HC1 to pH 6-7, concentrated in vacuo at 25 °C and solvent swapped into 2-MeTHF (7.6 V) which was washed with water to remove the inorganics. The addition of more 2-MeTHF (6.6 V) followed by further concentration lowered the residual water level to 620 ppm. To this solution of 9 were added sequentially: alkyne 12 (1.0 equiv.), degassed TEA (3 equiv.), Cui (0.6 mol%) and Pd(DPEphos)Ch (0.2 mol%). The reaction proceeded to completion after 36 h at 50 °C in 95% assay yield. The workup and isolation with heptane gave 13 in 88% isolated yield (98 A%) as the desired polymorph (Pd: 270 ppm; Cu: 0.1 ppm; P: 290 PPm).Attorney Docket No. 134851-002702

[0101] During the downstream process development, it became evident that low levels of residual Pd and P were critical to the success of the hydrogenation of 13 (vide infra) to CT1812 free base. While the Cu levels were successfully controlled by aq. ammonium chloride washes to < 1 ppm, the other two elements needed consistent control to levels that were initially unclear. The Pd level was most easily reduced from an initial post-reaction level of 1190 ppm to ca. 20 ppm by filtration through celite, but this only had a minimal impact on the P level (lowered from 290 to 204 ppm). Ultimately, the post-celite filtrate was recycled through an activated carbon cartridge, followed by a solvent swap to IPA and crystallization using water as an anti-solvent. This work-up lowered the levels of Pd to 25 ppm and P to 5 ppm which ensured successful reproducible hydrogenations. Incorporating this new workup gave 13 in 77% assay yield (96.5 A% purity) on 115 kg scale.

[0102] Later, it was discovered that compound 9 exists as a low melting solid (m.p.:45.6 °C) after a sample partially crystallized on standing. This led to efforts to eliminate the acetylation / deacetylation steps and incorporate crystalline 9 directly in the synthesis.

[0103] The inconsistent yield and purity of the original iodination reaction (vide supra), led to a reinvestigation of the reaction solvent and reagent stoichiometries. A solvent screen (Table 9) revealed that ethanol remained the preferred choice.

[0104] Next, a DoE study was performed to improve the reaction robustness by understanding the impact of reagent stoichiometries (Table 10). A 23full factorial design with three center points replicates was performed (11 total reactions). A model was derived for each of the four responses and revealed that (1) a higher amount of NaOCl (1.05 eq) was the only factor relevant to both minimize the amount of starting material 8 and maximize desired product 9; (2) the amounts of NaOH and KI had no impact in the ranges studied; (3) minimizing formation of diiodo 9a was favored by a lower amount of NaOH at the higher level of NaOCl favored by 9 and 8a. Minimizing formation of 9b was best controlled by increasing the amount of KI under the higher levels of NaOCl favored by the other responses. Ultimately, the optimized conditions of KI (1.35 equiv), NaOCl (1.05 equiv) and NaOH (1.20 equiv) were chosen.Attorney Docket No. 134851-002702

[0105] Table 9: Solvent screen for the synthesis of 9aaFixed conditions: Solvent (11 vol), KI (1.2 eq), NaOH (1.1 eq) 13% NaOCl (0.92 eq); temp: 5 °C / 1 h

[0106] Table 10: DoE factor ranges and results for the synthesis of 9

[0107] A screening of alkane solvents identified / '.so-octane as a suitable choice to perform the post-iodination product extraction instead of DCM. Three extractions (3 V each), followed by concentration to 5 V and then cooling to -40 °C crystallized 9 in 74% yield (98.2 A%Attorney Docket No. 134851-002702 purity; 0.75 A% 9a) using the reaction conditions described above. This isolation rejects nearly 90% of the 9a formed.

[0108] The crystalline 9 was use-tested in the optimized Sonogashira reaction on 1 kg scale to give an 82% isolated yield of 13 (98.2 A% purity). Aside from the higher yield, the level of the isoindole impurity was markedly lower vs. the telescoped method (0.5 vs. 2.3 A%, respectively, Table 11).

[0109] Table 11. Comparison of Sonogashira Reactions with Compound 12

[0110] Hydrogenation of Alkyne 13 to CT1812

[0111] A high-throughput screening approach was undertaken to rapidly screen several of the discreet variables including catalyst, solvent, and additives (acid, base). In the first screen, 17 catalysts in six different representative solvents (MeOH, THF, CPME, z'PrOAc, CH3CN, toluene) were studied for the hydrogenation of 13 (Scheme 13) . The reactions were performed in 100 pl solvent at 25 °C / 100 psi H2 for 20 h with no additive. The data revealed that MeOH was the preferred solvent while four catalysts showed the best conversion: 5% Pd / C, 10% Pd / C, 20% Pd(OH)2 / C and PtO2, but ultimately, 5% Pd / C was chosen for further development.Scheme 13: Synthesis of CT1812 free base via hydrogenation of 13

[0112] During this initial screening, the two impurities,: isoindole (14) and isoindoline (15) ), and intermediate alkene 16 were identified by LC-MS and subsequently monitored (Scheme 15). (Scheme 14).Attorney Docket No. 134851-002702Scheme 14: Hydrogenation Intermediate and By-Products

[0113] Additional optimization revealed that acetic acid and formic acid hindered the reaction while triethylamine promoted it. Another solvent screen with 5% Pd / C (2.5 wt% dry basis) and 1 equiv. TEA at 40 psi / 10 °C / 18 h identified MeOH, THF and DMF as preferred solvents. IPA and toluene performed poorly due to low substrate solubility even at 10 V. The subambient reaction temperature was effective at minimizing formation of isoindole 14.

[0114] Next, a screen of eight solvents (25 V) and nine bases (1 equiv.) with 5% Pd / C(1.25 wt% dry basis) at 40 psi / 10 °C / 18 h reinforced that MeOH was still the preferred solvent. While DBU, DIPEA and potassium carbonate gave the best results (>80 A% CT1812) (FIG. 2), a review of the product distributions showed DBU generated fewer impurities than DIPEA or potassium carbonate.

[0115] Another solvent screen (MeOH, EtOH, DMAc, 2MeTHF, toluene) used a 5 wt% load of 5% Pd / C at 40 psi / 10 °C / 18 h to better understand the solvent effect on product distribution at near complete conversion with DBU and TEA (2 equiv.). DBU performed worse in the aprotic solvents, while EtiN in 2-MeTHF gave 89.9 A% CT 1812. However, the combination of EtOH and DBU resulted in 93.4 A% CT1812 with 4.9 A% isoindole 14 and no isoindoline impurity 15.

[0116] Accordingly, the next screen was performed at 120 psi with five bases (2 equiv.; DBU, DBN, DMAP, K2CO3, K3PO4) in MeOH and EtOH with 5% Pd / C for 18 h at 10 °C (FIG. 3). All five reactions in MeOH showed > 90 A% CT1812 with isoindole levels ranging from only 0.5-3.2 A% with low levels of the alkene (up to 5.8 A%). The reactions in EtOH were less effective, mostly due to higher levels of the alkene intermediate (up to 16 A%). All ten samples were reanalyzed after 24 h (unfiltered, under nitrogen) and revealed that significantly higher levels of isoindole 14 were present in all cases (7-19 A%). This confirmed that most of the isoindole formation occurs after the hydrogen is removed from the reaction. An appropriate catalyst quench, rapid filtration, and / or cold filtration (< 10 °C) were all investigated to minimize this post-reaction degradation.

[0117] Next, the stability of 13 was examined in the absence of hydrogen (under nitrogen) under standard reaction conditions (5 wt% 5% Pd / C; RT / 10 V MeOH / 2 equiv. DBU) to determine if any oxidation also occurs before the reaction solution is saturated with H2. Over the course of 7 h, no change in the starting material purity was observed, even after subsequentAttorney Docket No. 134851-002702 exposure to air for 23 h. The same experiment with CT 1812 showed no change after the 7 h under nitrogen but with a minor increase of isoindole over the 23 h after exposure to air (0.8 to 1.6 A%). But, as was learned in a subsequent stress reaction, a hydrogen atmosphere is needed to reduce the Pd catalyst to a more active form, which forms the isoindole at a faster rate. This was evident when CT 1812 was subj ected to the standard conditions for 18 h, and the isoindole level increased from 0.6 to 10.5 A%. This confirms that the product can undergo oxidation to form 14.

[0118] A study on the impact of temperature and hydrogen pressure with representative lots of alkyne 13 showed that isoindole levels increase with higher temperature and lower pressure. Ultimately, the combination of 10 °C and 300 psi was selected to assure high conversion while minimizing impurity formation.

[0119] The performance of several lots of alkyne 13 under the optimized hydrogenation conditions (Table 12) suggested that < 25 ppm was ideal for both Pd and P levels.

[0120] Table 12: Compound 13 Trace Metal Levels vs. HydrogenationPerformanceConditions: 2 equiv. DBU, 5 wt% of 5% Pd / C, 10 V MeOH, 300 psi Hj, 20 °C, 18 h *A% increase over starting material level

[0121] Next, the effect of pre- activating the catalyst with H2 before the substrate orDBU addition was examined. For these reactions, only the catalyst in MeOH was subjected to 300 psi H2 at 10 °C, then the substrate and DBU were added under nitrogen, and the reactions were either stirred at RT under nitrogen or repressurized to 300 psi H2 and maintained at 10 °C. Whether the catalyst was preactivated or not, there was no increase in formation of 14 when the reaction was run at 300 psi H2. However, when the reactions were stirred under a nitrogen atmosphere after the catalyst had been activated, there was a significant increase in isoindole: 10.8-11.3 A% after 2 h and 48.0-55.3 A% after 24 h. This confirms that exchanging the atmosphere and warming the reaction to RT after the reaction triggers rapid isoindole formation. Interestingly, this effect is diminished if the reactions are left under a nitrogen atmosphere at RT but not agitated (22.8 A% isoindole after 24 h), likely due to the reaction becoming diffusion limited.Attorney Docket No. 134851-002702

[0122] While cooling the post-reaction reaction mixture to 0 °C prior to nitrogen exchange was effective at minimizing formation of isoindole 14, implementing a post-reaction catalyst quench was seen as a more reliable means to accomplish this. Four common Pd catalyst poisons were added (1 equiv. relative to Pd) in MeOH to completed reactions after the gas exchange from hydrogen to nitrogen and monitored at RT for 2 and 24 h. The results show that PPhs, DPEPhos and thiophene were all effective while (methylthio)acetic acid was not (Table 12). Ultimately, thiophene was selected for its ease of removal based on its volatility.

[0123] Table 13: Effect of Catalyst Poisons on Isoindole (14) Formation

[0124] A 40 g run was performed to demonstrate the process (10 V MeOH / 2 equiv.DBU / 300 psi). After the reduction was complete (10 °C / 18 h), the reaction was depressurized to 1 atm H2 at 10 °C. Analysis showed CT1812 (92 A%) and isoindole 14 at 2.6 A%. Thiophene was added (10 mol% relative to Pd, in MeOH), and the reaction mixture filtered. The atmosphere was exchanged with nitrogen and the filtrate concentrated to 11 V and neutralized to pH 8 with aq. HC1. The addition of water crystallized the product in 83% yield (96.4 A%; 2.6 A% 14) free of any thiophene, as determined by NMR and LC. The results were fairly consistent at the 111 kg scale (Table 14).

[0125] Table 14: Impact of residual Pd and P in the hydrogenation of 13 at various scalesAttorney Docket No. 134851-002702

[0126] CT1812 API: Polymorph Selection and Isolation of Hemi-fumarateDihydrate salt.

[0127] The initially developed CT1812 polymorph, a mono fumarate anhydrate designated as Form A, was re-evaluated for its long-term suitability. This evaluation was based on a polymorph screen that identified three solvates (acetone, acetonitrile and methanol), two anhydrates of the mono fumarate (Forms A and D), one hemihydrate of a mono fumarate (Form F), and one hemifumarate dihydrate (Form E). See co-filed application U.S. Provisional Application Serial Number 63 / 696,061, entitled “Crystalline forms of 2-(tert-butoxy)-4-(3-methyl-3-(5- (methylsulfonyl)isoindolin-2-yl)butyl)phenol fumarate salt” filed concurrently herewith on September 18, 2024, the contents of which is incorporated herein by reference in its entirety

[0128] Several attributes are typically considered in selecting the ideal polymorph including intrinsic dissolution, solubility in biorelevant media, bioavailability, solid-state stability (physical and chemical), solution stability, hygroscopicity, downstream processibility (flowability, compressibility), morphology and synthetic accessibility. Among the Form A traits that triggered this re-evaluation were its: (1) sub-optimal flowability / processability, arising from its sticky needle-like (acicular) crystals, (2) propensity to undergo oxidative degradation in the oral solid dosage form, (3) reversable formation to its isostructural hemihydrate (Form F) upon exposure to RH > 40%, (4) disproportionation to Form E in water or solutions with a water activity (aw) > 0.4, and (5) only modest impurity rejection compared to Form E.

[0129] The equilibrium solubility profile of Form E in aq. EtOH mixtures with variable water content (5-20% vol%) at 20-50 °C, suggested this would be a suitable solvent system for a controlled crystallization. Additionally, the relative stability of Forms A, E, and F was assessed by a competitive slurry study that showed: (1) at aw> 0.4, only Form E, which presented a cubic morphology, was observed (by PLM, XPRD); (2) at aw< 0.3, only Form A was observed. This information coupled with data from a FBRM particle counts study to maximize impurity rejection while maximizing recovery, led to a crystallization of Form E from 90 / 10 v / v EtOH / water (8V; aw= 0.5) with seeding close to the solubility limit to discharge supersaturation along with a slow cooling profile from 50 to 20 °C. An in-situ Raman analysis of the slurry at 50Attorney Docket No. 134851-002702°C for 24 h confirmed that the crystal form was unaltered. This resulted in a process that can tolerate CT1812 fb with purity of 93 A% to be transformed into CT1812 hemifumarate dihydrate (Form E) with >99.5 A% purity in 88% assay yield on 94 kg scale.

[0130] A single crystal X-ray structure of Form E revealed a monoclinic unit cell that contains eight API molecules, four fumarate counterions, and 16 water molecules with an intricate hydrogen bonding network (see FIG 4.).

[0131] Additional Aspects

[0132] Aspect 1. A process for preparing a compound of Formula (I) or a salt thereofcomprising a) contacting a compound of Formula 4 with a compound of Formula 1 to form a compound ofFormula 12b) cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 13c) hydrogenating the compound of Formula 13 to form the compound of Formula (I) or a salt thereofAttorney Docket No. 134851-002702

[0133] Aspect 2. The process of Aspect 1, wherein the process further comprises d) converting the compound of Formula (I) to a salt of the compound of Formula (I).

[0134] Aspect 3. The process of Aspect 1, wherein the compound of Formula (I) or a salt thereof is the compound of Formula (I).

[0135] Aspect 4. The process of either of Aspects 1 or 3, wherein the compound ofFormula (I) or a salt thereof is a salt of compound of Formula (I).

[0136] Aspect 5. The process of any one of Aspects 1 or 3-4, wherein the compound of Formula (I) or a salt thereof is a fumarate salt of the compound of Formula (I).

[0137] Aspect 6. The process of any one of Aspects 1 or 3-5, wherein the compound of Formula (I) or a salt thereof is a hemifumarate dihydrate salt of compound of Formula (I).

[0138] Aspect 7. The process of any one of Aspects 1-5, wherein the contacting in step a) comprises treating the compound of Formula 4 in a solvent with aqueous potassium carbonate.

[0139] Aspect 8. The process of Aspect 7, wherein the solvent in step a) is THF or 2- methyl THF.

[0140] Aspect 9. The process of either of Aspects 7 or 8, wherein the contacting in step a) further comprises heating.

[0141] Aspect 10. The process of any one of Aspects 7-9, wherein the compound ofFormula 12 is isolated prior to step b).

[0142] Aspect 11. The process of any one of Aspects 7-10, wherein the compound ofFormula 12 obtained by step a) comprises less than 4 A% of a compound of Formula 12a impurity12a

[0143] Aspect 12. The process of any one of Aspects 7-10, wherein the compound ofFormula 12 obtained by step a) comprises less than 3 A% of a compound of Formula 12a impurity.

[0144] Aspect 13. The process of any one of Aspects 7-10, wherein the compound ofFormula 12 obtained by step a) comprises less than 2 A% of a compound of Formula 12a impurity.

[0145] Aspect 14. The process of any one of Aspects 7-10, wherein the compound ofFormula 12 obtained by step a) comprises less than 1 A% of a compound of Formula 12a impurity.

[0146] Aspect 15. The process of any one of Aspects 1-14, wherein the cross coupling in step b) is a Sonogashira coupling.Attorney Docket No. 134851-002702

[0147] Aspect 16. The process of any one of Aspects 1-15, wherein the cross coupling in step b) comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.

[0148] Aspect 17. The process of Aspect 16, wherein the palladium catalyst in step b) is Pd(DPEphos)Cl2.

[0149] Aspect 18. The process of either of Aspects 16 or 17, wherein the copper cocatalyst in step b) is Cui.

[0150] Aspect 19. The process of any one of Aspects 16-18, wherein the amine in step b) is triethylamine.

[0151] Aspect 20. The process of any one of Aspects 1-8, wherein the cross coupling in step b) comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of catalytic Pd(DPEphos)Ch, catalytic Cui and triethylamine.

[0152] Aspect 21. The process of Aspect 20, wherein the solvent in step b) is 2- methylTHF

[0153] Aspect 22. The process of any one of Aspects 1-21, wherein the compound ofFormula 13 is isolated prior to step c).

[0154] Aspect 23. The process of any one of Aspects 1-22, wherein the hydrogenating in step c) comprises contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base.

[0155] Aspect 24. The process of Aspect 23, wherein palladium or platinum catalyst in step c) is selected from the group consisting of 5% Pd / C, 10% Pd / C, 20% Pd(OH)2 / C and PtO2.

[0156] Aspect 25. The process of either of Aspects 23 or 24, wherein the palladium or platinum catalyst in step c) is 5% Pd / C.

[0157] Aspect 26. The process of any one of Aspects 23-25, wherein the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, DMAP, imidazole, tri-n- butylamine, TMEDA, proton sponge, and potassium carbonate.

[0158] Aspect 27. The process of any one of Aspects 23-25, wherein the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, and potassium carbonate.

[0159] Aspect 28. The process of any one of Aspects 23-26, wherein the base in step c) is DBU.

[0160] Aspect 29. The process of any one of Aspects 23-28, wherein the solvent in step c) is selected from the group consisting of DMAc, DMF, methanol and NMP.

[0161] Aspect 30. The process of any one of Aspects 23-29, wherein the solvent in step c) is methanol.Attorney Docket No. 134851-002702

[0162] Aspect 31. The process of Aspect 23, wherein the palladium or platinum catalyst in step c) is 5% Pd / C, the base is DBU, and the solvent is methanol.

[0163] Aspect 32. The process of Aspect 31, wherein the pressure of the hydrogen in step c) is 290-300 psi.

[0164] Aspect 33. The process of Aspect 32, wherein the hydrogenation in step c) is performed at about 5-10 °C.

[0165] Aspect 34. The process of any one of Aspects 1-33, further comprising isolating the compound of Formula (I) or a salt thereof.

[0166] Aspect 35. The process of any one of Aspects 1-34, wherein the compound ofFormula (I), or a salt thereof comprises less than about 5% of the isoindole of Formula 14 impurity

[0167] Aspect 36. The process of any one of Aspects 1-34, wherein the compound ofFormula 4 is prepared by photochemical bromination of a compound of Formula 5a

[0168] Aspect 37. The process of any one of Aspects 1-36, wherein the photochemical bromination comprises treating the compound of Formula 5a with light >400 nm in the presences of a brominating agent selected from NBS or dibromodimethylhydantoin in a solvent and optionally a Bronsted acid.

[0169] Aspect 38. The process of Aspect 37, wherein the brominating agent is NBS.

[0170] Aspect 39. The process of any one of Aspects 36-38, wherein the Bronsted acid is present and is selected from the group consisting of HBr, AcOH, citric acid, H2SO4 and a combination of HBr / AcOH.

[0171] Aspect 40. The process of Aspect 39, wherein the Bronsted acid is H2SO4.

[0172] Aspect 41. The process of any one of Aspects 36-40, wherein the light is about450-about 460 nm.

[0173] Aspect 42. The process of any one of Aspects 36-41, wherein the solvent is selected from the group consisting of DCE, EtOAc and MeCN.

[0174] Aspect 43. The process of Aspect 42, wherein the solvent is MeCN.Attorney Docket No. 134851-002702

[0175] Aspect 44. The process of any one of Aspects 36-43, wherein the photochemical bromination is continuous flow photochemical bromination.

[0176] Aspect 45. The process of Aspect 44, wherein the continuous flow photochemical bromination comprises: i) preparing a first solution of the Bronsted acid in the solvent and preparing a second solution of the compound of Formula 5a and the brominating agent in the solvent; ii) simultaneously transferring the first solution through a first tube and the second solution through a second tube to a reactor coil, such that the first solution and the second solution mix upon entry to the reactor coil and wherein the reactor coil has a LED panel operating at about 450 nm to about 460 nm located on at least one side of the reactor coil; and iii) pumping the mix of step ii) through the reactor coil to form the compound of Formula 4; and collecting the compound of Formula 4.

[0177] Aspect 46. The process of any one of Aspects 37-45, wherein the brominating agent is NBS, the Bronsted acid is H2SO4, the solvent is MeCN and the light is about 450 to about 460 nm.

[0178] Aspect 47. The process of any one of Aspects 36-46, wherein the compound of Formula 4 is at least 95 A% chemically pure.

[0179] Aspect 48. The process of any one of Aspects 36-46, wherein the compound of Formula 4 comprises less than 3 A% of monobrominated compounds of Formula 4a impurity ^X^'SO2Me Br 4a

[0180] Aspect 49. The process of any one of Aspects 36-46, wherein the compound of Formula 4 comprises less than 1A% of tribrominated compounds of Formula 4b impurity

[0181] Aspect 50. The process of any one of Aspects 36-46, wherein the compound of Formula 4 comprises less than 3A% of monobrominated compounds of Formula 4a impurity and less than 1A% of tribrominated compounds of Formula 4b impurityAttorney Docket No. 134851-002702

[0182] Aspect 51. The process of any one of Aspects 36-50, wherein the compound of Formula 5a is prepared by coupling of a compound of Formula 5c with sodium methyl sulfinate

[0183] Aspect 52. The process of Aspect 51 , wherein the coupling comprises treating the compound of Formula 5c with the sodium methyl sulfinate in the presence of a base, a bidentate ligand, and catalytic CuX in a solvent; wherein X is bromide or iodide.

[0184] Aspect 53. The process of Aspect 52, wherein the base is selected from the group consisting of NaOH, K3PO4, and K2CO3.

[0185] Aspect 54. The process of either of Aspects 52 or 53, wherein the base isK2CO3.

[0186] Aspect 55. The process of Aspect 54, wherein the base has amesh size selected from the group consisting of 30, 160 or 400 mesh.

[0187] Aspect 56. The process of Aspect 54, wherein the base has a mesh size of 160 mesh.

[0188] Aspect 57. The process of any one of Aspects 52-56, wherein the bidentate ligand is selected from the group consisting ofAttorney Docket No. 134851-002702

[0189] Aspect 58. The process of any one of Aspects 52-57, wherein the bidentate ligand is proline.

[0190] Aspect 59. The process of any one of Aspects 52-58, wherein the solvent is selected from the group consisting of CPME, THF, IPA and DMSO.

[0191] Aspect 60. The process of any one of Aspects 52-59, wherein the solvent isDMSO.

[0192] Aspect 61. The process of any one of Aspects 52-60, wherein X is bromide.

[0193] Aspect 62. The process of any one of Aspects 52-61, wherein the treating comprises heating to a temperature selected from the group consisting of about 85 °C, about 100 °C and about 115 °C.

[0194] Aspect 63. The process of any one of Aspects 52-61, wherein the treating comprises heating to a temperature of about 115 °C.

[0195] Aspect 64. The process of Aspect 52, comprising a) combining the compound of Formula 5c with DMSO and water (10: 1 v / v) at 25 °C in a vessel; b) adding sodium methane sulfinate, CuBr, L-proline and 160 mesh K2CO3 to the vessel to form a mixture; and c) heating the mixture to form the compound of Formula 5a.

[0196] Aspect 65. The process of any one of Aspects 52-64, wherein the compound of Formula 5a comprises less than 5A% of a compound of Formula 5d impurity5d

[0197] Aspect 66. The process of Aspect 65, wherein the compound of Formula 5a comprises less than 4A% of a compound of Formula 5d.

[0198] Aspect 67. The process of Aspect 65, wherein the compound of Formula 5a comprises about 3A% of a compound of Formula 5d.Attorney Docket No. 134851-002702

[0199] Aspect 68. The process of Aspect 65, wherein the compound of Formula 5a comprises about 2.5 A% of a compound of Formula 5d.

[0200] Aspect 69. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of at least 95%.

[0201] Aspect 70. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of at least 96%.

[0202] Aspect 71. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of at least 97%.

[0203] Aspect 72. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of at least 98%.

[0204] Aspect 73. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of about 95%.

[0205] Aspect 74. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of about 96%.

[0206] Aspect 75. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of about 97%.

[0207] Aspect 76. The process of any one of Aspects 52-64, wherein the compound of Formula 5a has a chemical purity of about 98%.

[0208] Aspect 77. A process for preparing a compound of Formula 4Br f^^SO2MeBr4comprising brominating a compound of Formula 5a to form the compound of Formula 4,wherein the brominating comprises a photochemical bromination.

[0209] Aspect 78. The process of Aspect 77, wherein the photochemical bromination comprises treating the compound of Formula 5a with light >400 nm in the presences of a brominating agent selected from NBS or dibromodimethylhydantoin in a solvent and optionally a Bronsted acid.

[0210] Aspect 79. The process of Aspect 78, wherein the brominating agent is NBS.Attorney Docket No. 134851-002702

[0211] Aspect 80. The process of Aspect 78-79, wherein the Bronsted acid is present and is selected from the group consisting of HBr, AcOH, Citric acid, H2SO4 and a combination of HBr / AcOH.

[0212] Aspect 81. The process of Aspect 80, wherein the Bronsted acid is H2SO4.

[0213] Aspect 82. The process of any one of Aspects 78-81, wherein the light is about450-about 460 nm.

[0214] Aspect 83. The process of any one of Aspects 78-82, wherein the solvent is selected from the group consisting of DCE, EtOAc and MeCN.

[0215] Aspect 84. The process of Aspect 83, wherein the solvent is MeCN.

[0216] Aspect 85. The process of any one of Aspects 77-84, wherein the photochemical bromination is continuous flow photochemical bromination.

[0217] Aspect 86. The process of Aspect 85 wherein the continuous flow photochemical bromination comprises: i) preparing a first solution of the Bronsted acid in the solvent and preparing a second solution of the compound of Formula 5a and the brominating agent in the solvent; ii) simultaneously transferring the first solution through a first tube and the second solution through a second tube to a reactor coil, such that the first solution and the second solution mix upon entry to the reactor coil and wherein the reactor coil has a LED panel operating at about 450 nm to about 460 nm located on at least one side of the reactor coil; iii) pumping the mix of step ii) through the reactor coil to form the compound of Formula 4; and collecting the compound of Formula 4.

[0218] Aspect 87. The process of any one of Aspects 78-86, wherein the brominating agent is NBS, the Bronsted acid is H2SO4, the solvent is MeCN and the light is about 450 to about 460 nm.

[0219] Aspect 88. The process of Aspect 77, wherein the compound of Formula 4 is95 A% chemically pure.

[0220] Aspect 89. The process of any one of Aspects 77-86, wherein the compound of Formula 4 comprises less than 3 A% of monobrominated compound of Formula 4a impurity^X^'SO2Me Br 4a

[0221] Aspect 90. The process of any one of Aspects 77-86, wherein the compound of Formula 4 comprises less than 1 A% of tribrominated compound of Formula 4b impurityAttorney Docket No. 134851-002702

[0222] Aspect 91. The process of any one of Aspects 77-86, wherein the compound of Formula 4 comprises less than 3 A of monobrominated compound of Formula 4a impurity and less than 1 A% of tribrominated compound of Formula 4b impurity

[0223] Aspect 92. A process for preparing a compound of Formula 5acomprising coupling of a compound of Formula 5c with sodium methyl sulfinateto form the compound of Formula 5a.

[0224] Aspect 93. The process of Aspect 92, wherein the coupling comprises treating the compound of Formula 5c with the sodium methyl sulfinate in the presence of a base, a bidentate ligand, and catalytic CuX in a solvent; wherein X is bromide or iodide.

[0225] Aspect 94. The process of Aspect 93, wherein the base is selected from the group consisting of NaOH, K3PO4, and K2CO3.

[0226] Aspect 95. The process of either of Aspects 93 or 94, wherein the base isK2CO3.

[0227] Aspect 96. The process of Aspect 95, wherein the base has a mesh size selected from the group consisting of 30, 160 or 400 mesh.

[0228] Aspect 97. The process of Aspect 95, wherein the base has a mesh size of 160 mesh.

[0229] Aspect 98. The process of any one of Aspects 93-97, wherein the bidentate ligand is selected from the group consisting ofAttorney Docket No. 134851-002702

[0230] Aspect 99. The process of any one of Aspects 93-98, wherein the bidentate ligand is L-proline.

[0231] Aspect 100. The process of any one of Aspects 93-99, wherein the solvent is selected from the group consisting of CPME, THF, IPA and DMSO.

[0232] Aspect 101. The process of any one of Aspects 93-100, wherein the solvent isDMSO.

[0233] Aspect 102. The process of any one of Aspects 93-101, wherein X is bromide.

[0234] Aspect 103. The process of any one of Aspects 93-102, wherein the treating comprises heating to a temperature selected from the group consisting of about 85 °C, about 100 °C and about 115 °C.

[0235] Aspect 104. The process of any one of Aspects 93-102, wherein the treating comprises heating to a temperature of about 115 °C.

[0236] Aspect 105. The process of Aspect 93, comprising a) combining the compound of Formula 5c with DMSO and water (10: 1 v / v) at 25 °C in a vessel; b) adding sodium methane sulfinate, CuBr, L-proline and 160 mesh K2CO3 to the vessel to form a mixture; and c) heating the mixture to form the compound of Formula 5a.

[0237] Aspect 106. The process of any one of Aspects 93-105, wherein the compound of Formula 5a contains less than 5 A% of a compound of Formula 5dAttorney Docket No. 134851-0027025d

[0238] Aspect 107. The process of Aspect 106, wherein the compound of Formula 5a contains less than 3 A% of a compound of Formula 5d.

[0239] Aspect 108. The process of Aspect 106, wherein the compound of Formula 5a contains about 3 A% of a compound of Formula 5d.

[0240] Aspect 109. The process of Aspect 106, wherein the compound of Formula 5a contains about 2.5 A% of a compound of Formula 5d.

[0241] Aspect 110. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of at least 95%.

[0242] Aspect 111. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of at least 96%.

[0243] Aspect 112. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of at least 97%.

[0244] Aspect 113. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of at least 98%.

[0245] Aspect 114. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of about 95%.

[0246] Aspect 115. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of about 96%.

[0247] Aspect 116. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of about 97%.

[0248] Aspect 117. The process of any one of Aspects 93-105, wherein the compound of Formula 5a has a chemical purity of about 98%.

[0249] Aspect 118. A process for preparing a compound of Formula (I) or a salt thereofcomprisingAttorney Docket No. 134851-002702 a) heating a compound of Formula 4 with a compound of Formula 1 in the presence of aqueous potassium carbonate to form a compound of Formula 12b) combining a compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base to form the compound of Formula 13c) contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base to form the compound of Formula (I) or a salt thereof13

[0250] Aspect 119. The process of Aspect 118, wherein the process further comprises d) converting the compound of Formula (I) to a salt of the compound of Formula (I).

[0251] Aspect 120. The process of Aspects 118, wherein the compound of Formula(I) or a salt thereof is the compound of Formula (I).

[0252] Aspect 121. The process of either of Aspects 118 or 120, wherein the compound of Formula (I) or a salt thereof is a salt of compound of Formula (I).

[0253] Aspect 122. The process of any one of Aspects 118 or 120-121, wherein the compound of Formula (I) or a salt thereof is a fumarate salt of compound of Formula (I).

[0254] Aspect 123. The process of any one of Aspect 118 or 120-122, wherein the compound of Formula (I) or a salt thereof is a hemifumarate dihydrate salt of compound of Formula (I).

[0255] Aspect 124. The process of Aspect 118, wherein the solvent in step a) is THF or 2-methyl THF.Attorney Docket No. 134851-002702

[0256] Aspect 125. The process of any one of Aspects 118-124, wherein the compound of Formula 12 in step a) is isolated prior to step b).

[0257] Aspect 126. The process of any one of Aspects 118-125, wherein the palladium catalyst in step b) is Pd(DPEphos)C12.

[0258] Aspect 127. The process of any one of Aspects 118-126, wherein the copper cocatalyst in step b) is Cui.

[0259] Aspect 128. The process of any one of Aspects 1 18-127, wherein the amine in step b) is triethylamine.

[0260] Aspect 129. The process of any one of Aspects 118-125, wherein in step b) the palladium catalyst is Pd(DPEphos)C12, the copper cocatalyst is Cui and the amine is triethylamine.

[0261] Aspect 130. The process of Aspect 129, wherein the solvent in step b) is 2- methyl THF.

[0262] Aspect 131. The process of any one of Aspects 118-130, wherein the compound of Formula 13 in step b) is isolated prior to step c).

[0263] Aspect 132. The process of any one of Aspects 1 18-131, wherein in step c) the palladium or platinum catalyst is selected from the group consisting of 5% Pd / C, 10% Pd / C, 20% Pd(OH)2 / C and PtO2.

[0264] Aspect 133. The process of Aspect 132, wherein the palladium or platinum catalyst is 5% Pd / C.

[0265] Aspect 134. The process of any one of Aspects 118 — 133, wherein the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, DMAP, imidazole, tri-ra-butylamine, TMEDA, proton sponge, and potassium carbonate.

[0266] Aspect 135. The process of Aspect 134, wherein the base in step c) is selected from the group consisting of triethylamine, DBU, DIPEA, and potassium carbonate.

[0267] Aspect 136. The process of Aspect 134, wherein the base in step c) is DBU.

[0268] Aspect 137. The process of any one of Aspects 118-136, wherein the solvent in step c) is selected from the group consisting of DMAc, DMF, methanol and NMP.

[0269] Aspect 138. The process of Aspect 137, wherein the solvent in step c) is methanol.

[0270] Aspect 139. The process of any one of Aspects 1 18-131, wherein in step c) the palladium or platinum catalyst is 5% Pd / C, the base is DBU, and the solvent is methanol.

[0271] Aspect 140. The process of any one of Aspects 118-132, wherein the pressure of the hydrogen is 290-300 psi.Attorney Docket No. 134851-002702

[0272] Aspect 141. The process of claim of any one of Aspects 118-140, wherein the reaction in step c) is performed at about 5-10 °C.

[0273] Aspect 142. The process of any one of Aspects 1 18-131, wherein in step c) the palladium or platinum catalyst is 5% Pd / C, the base is DBU, the solvent is methanol, the pressure of the hydrogen is 290-300 psi and the reaction is conducted at a temperature of 5-10

[0274] Aspect 143. The process of any one of Aspects 118-142, wherein the process further comprises isolating the compound of Formula (I) or a salt thereof.

[0275] Aspect 144. A compound of Formula 12:

[0276] Aspect 145. A compound of Formula 10’AcOH:

[0277] Aspect 146. A compound of Formula 12:prepared by a process comprising contacting a compound of Formula 4 with a compound ofFormula 1 to form the compound of Formula 12

[0278] Aspect 147. The compound of Aspect 146, wherein the contacting comprises treating the compound of Formula 4 in a solvent with aqueous potassium carbonate.

[0279] Aspect 148. The compound of Aspect 147, wherein the solvent is THF or 2- methyl THF.Attorney Docket No. 134851-002702

[0280] Aspect 149. The compound of either of Aspects 147 or 148, wherein the contacting in step a) further comprises heating.

[0281] Aspect 150. The process of any one of Aspects 147-149, wherein the compound of Formula 12 is isolated.

[0282] Aspect 151. The process of any one of Aspects 147-150, wherein the compound of Formula 12 comprises less than 4% of a compound of Formula 12a impurity12a

[0283] Aspect 152. The process of any one of Aspects 147-150, wherein the compound of Formula 12 comprises less than 3% of a compound of Formula 12a impurity.

[0284] Aspect 153. The process of any one of Aspects 147-150, wherein the compound of Formula 12 comprises less than 2% of a compound of Formula 12a impurity.

[0285] Aspect 154. The process of any one of Aspects 147-150, wherein the compound of Formula 12 comprises less than 1% of a compound of Formula 12a impurity.

[0286] Aspect 155. A process for preparing a compound of Formula 12comprising contacting a compound of Formula 4 with a compound of Formula 1 to form the compound of Formula 12

[0287] Aspect 156. The process of Aspect 155, wherein the contacting comprises treating the compound of Formula 4 in a solvent with aqueous potassium carbonate.

[0288] Aspect 157. The process of Aspect 156, wherein the solvent is THF or 2- methyl THF.

[0289] Aspect 158. The process of either of Aspects 156 or 157, wherein the contacting further comprises heating.

[0290] Aspect 159. The process of any one of Aspects 156-158, wherein the compound of Formula 12 is isolated prior to step b).Attorney Docket No. 134851-002702

[0291] Aspect 160. The process of any one of Aspects 156-159, wherein the compound of Formula 12 comprises less than 4 A% of a compound of Formula 12a impurity

[0292] Aspect 161. The process of any one of Aspects 156-159, wherein the compound of Formula 12 comprises less than 3 A% of a compound of Formula 12a impurity.

[0293] Aspect 162. The process of any one of Aspects 156-159, wherein the compound of Formula 12 comprises less than 2 A% of a compound of Formula 12a impurity.

[0294] Aspect 163. The process of any one of Aspects 156-159, wherein the compound of Formula 12 comprises less than 1 A% of a compound of Formula 12a impurity.

[0295] Aspect 164. A compound of Formula 13:13 prepared by a process comprising cross coupling of a compound of Formula 12 with a compound of Formula 9 to form the compound of Formula 13

[0296] Aspect 165. The compound of Aspect 164, wherein the cross coupling is aSonogashira coupling.

[0297] Aspect 166. The compound of either of Aspects 164 or 165, wherein the cross coupling comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.

[0298] Aspect 167. The compound of Aspect 166 wherein the palladium catalyst isPd(DPEphos)Ch.

[0299] Aspect 168. The compound of either of Aspects 166 or 167, wherein the copper cocatalyst is Cui.Attorney Docket No. 134851-002702

[0300] Aspect 169. The compound of any one of Aspects 166-168, wherein the amine is triethylamine.

[0301] Aspect 170. The compound of any one of Aspects 166-168, wherein the cross coupling comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of catalytic Pd(DPEphos)C12, catalytic Cui and triethylamine.

[0302] Aspect 171. The compound of Aspect 170, wherein the solvent is 2- methylTHF

[0303] Aspect 172. The compound of any one of Aspects 166-171, wherein the compound of Formula 13 is isolated.

[0304] Aspect 173. A process for preparing a compound of Formula 13:13 comprising cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 1312 9 13

[0305] Aspect 174. The process of Aspect 173, wherein the cross coupling is aSonogashira coupling.

[0306] Aspect 175. The process of either of Aspects 173 or 174, wherein the cross coupling comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.

[0307] Aspect 176. The process of Aspect 175 wherein the palladium catalyst isPd(DPEphos)Ch.

[0308] Aspect 177. The process of either of Aspects 175 or 176, wherein the copper cocatalyst is Cui.

[0309] Aspect 178. The process of any one of Aspects 175-177, wherein the amine is triethylamine.Attorney Docket No. 134851-002702

[0310] Aspect 179. The process of any one of Aspects 175-177, wherein the cross coupling comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of catalytic Pd(DPEphos)Ch, catalytic Cui and triethylamine.

[0311] Aspect 180. The process of Aspect 179, wherein the solvent is 2-methyl THF

[0312] Aspect 181. The process of any one of Aspects 175-180, wherein the compound of Formula 13 is isolated.Definitions

[0313] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, the preferred methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications that might be used in connection with the invention. Nothing herein is to be construed as an admission that the invention is not entitled to antedate such disclosure by virtue of prior invention.

[0314] The articles "a" and "an" as used herein mean "one or more" or "at least one," unless otherwise indicated. That is, reference to any element of the present disclosure by the indefinite article "a" or "an" does not exclude the possibility that more than one of the elements is present.

[0315] The term “about” when used before a numerical designation, e.g., temperature, time, amount, and concentration, including a range, indicates approximations which may vary by ±10%, ±5% or ±l%.

[0316] “Chemical purity” refers to the purity of a compound in relation to all other materials (impurities) detectable by chemical analysis. In some instances, the chemical purity is measured by HPLC. In some instances, the chemical purity is measured by GC. “Area percent chemical purity”, or “A%”, is the percent ratio of the peak area of the compound being measured, to the sum of all peak areas in a high-performance liquid chromatography (HPLC) or gas chromatography (GC) chromatogram.Peak AreaPurity (peak area%) =compoundX 100%Sum of all Peak AreasAttorney Docket No. 134851-002702The A% purity is determined by the amount of the compound compared to related substances that are detectable by the method and does not consider the amount of other impurities that are not detectable by the method.

[0317] Throughout the application, descriptions of various aspects use “comprising” language, however in some specific instances, an aspect can alternatively be described using the language “consisting essentially of’ or “consisting of’.

[0318] The term “hemi- fumarate” or “hemi- fumarate salt” is used to indicate that one half of an equivalent of fumaric acid is present for each CT1812 free base molecule. For CT 1812, the hemifumarate salt can be represented by the following chemical structure:

[0319] The term “mono-fumarate” or “mono-fumarate salt” is used to indicate that one fumaric acid equivalent is present for each CT1812 free base molecule. For CT1812, the fumarate salt can be represented by the following chemical structure:

[0320] Although the present invention has been described in considerable detail with reference to certain preferred embodiments thereof, other versions are possible. Therefore, the spirit and scope of the appended claims should not be limited to the description and the preferred versions contained within this specification. Various embodiments of the present invention will be illustrated with reference to the following non-limiting examples. The following examples are for illustrative purposes only and are not to be construed as limiting the invention in any manner.

[0321] As used herein the symbols and conventions used in these processes, schemes and examples are consistent with those used in the contemporary scientific literature, for example, the Journal of the American Chemical Society or the Journal of Biological Chemistry. UnlessAttorney Docket No. 134851-002702 otherwise noted, all starting materials were obtained from commercial suppliers and used without further purification. Specifically, the following abbreviations may be used in the examples and throughout the specification:

[0322] AbbreviationsAttorney Docket No. 134851-002702

[0323] Example 1: l,2,-dimethyl-4-(methylsulfonyl)benzene; Compound 5a

[0324] 4 -bromo- 1 ,2-dimethylbenzene (5c) (200 g, 1.08 moles, 1.0 equiv., 75 A% purity) was charged to a vessel containing DMSO (600 mL) and water (60 mL) at 25 °C, followed by sodium methane sulfinate (154.4 g; 1.51 moles, 1.4 equiv.), copper bromide (23.2 g; 0.16 moles, 0.15 equiv.), L-proline (37.3 g; 0.324 moles, 0.3 equiv.), and potassium carbonate (160 mesh; 149.4 g; 1.08 moles 1.0 equiv.). The contents were heated to 115 °C for 3 h (>99.0% conversion of desired isomer) followed by cooling to RT. The contents were treated with IN HC1 (1.2 L) and extracted with MTBE (1 x 1.0 L, then 2 x 600 mL). The combined organic layers were stirred with activated charcoal (10 g) at 25 °C for 30 min, then filtered, and rinsed with MTBE (400 mL). The filtrate was concentrated in vacuo to 400 mL, cooled to 0 °C followed by addition of / / -heptane (600 mL) over 1 h. The resulting slurry was aged for 2 h and filtered. The isolated product was washed with chilled / / -heptane (2 x 200 mL) to provide 124 g of compound 5a (83% yield; adjusted for purity of 5c; 97.4 A%; 2.5 A% regioisomer 5d) after drying in vacuo at 40 °C to constant weight, m.p.: 72 °C. NMR: consistent with literature values.

[0325] Example 2: l,2-Bis(bromomethyl)-4-(methylsulfonyl)benzene;Compound 4

[0326] The following two solutions were prepared: (A) sulfuric acid (7.8 kg; 79.5 moles, 0.1 equiv.) was dissolved in MeCN (238.2 kg) in a 1000L glass vessel at 25 °C then transferred to plastic drums; (B) compound 5a (147.8 kg, 802.2 moles, 1.0 equiv.) andNBS (300.0 kg, 1271.4 moles, 2.1 equiv.) were dissolved in MeCN (2094.4 kg) in a 3000L glass vessel at 25 °C in two portions, then transferred to plastic drums.

[0327] Elow reactor metrics: FEP (fluorinated ethylene propylene) coil ID: 8 mm / OD:10 mm; length: 30 m; internal volume 1.5 L. LED panels were located on either side of the coiled react operating at 450-460 nm (456-760 watts total). The discharge port of the coiled reactor was connected to a 5000 L glass-lined reactor.Attorney Docket No. 134851-002702

[0328] The pump transferring solution (A) operated at 17.2 kg / hr while that of solution (B) at 1.62 kg / hr. The coil reaction temperature was controlled at 20-30 °C over the course of the reaction via recirculating cooling water. After all the materials were transferred through the reactor, pump A was flushed with acetonitrile (15.7 kg) as was pump B (1.5 kg). The flushes were combined with the reactor output and cooled to 0-10 °C. The solution was treated with aq. sodium sulfite (18.8 wt%, 548 kg) for 30 min, leading to a colorless solution. The mixture was filtered, and the filter was rinsed with acetonitrile (116 kg). The combined streams were concentrated in vacuo at < 45 °C to ca 225 L and MTBE (1095 kg) was added (residual MeCN: 1%). The MTBE solution was washed with water (740 kg) at 25 °C. Activated carbon (14.8 kg) and silica gel (14.8 kg) were added to the resulting slurry stirred at RT for 1.5 h, followed by filtration and rising of the cake with MTBE (822 kg). The filtrate was concentrated in vacuo at below 45 °C and solvent switched into MeCN (residual MTBE <5%). The final volume was adjusted to ~222 L. Water (103 kg) was added at 20 °C, followed by seed (1.5 kg) and 3 / 1 w / w IPA-water (553 kg) over 4 h. The resulting slurry was stirred at 20 °C for 2 h followed by cooling to -7 °C and aging for 10 h. The slurry was filtered and the cake washed with 1 / 1 (wt) MeCN- water (414 kg), followed by drying in vacuo at 40 °C to constant weight. The product was isolated as a light brown solid (150.2 kg; 52% yield; 95.6 A%). m.p.: 97.2 °C.JH NMR (400 MHz, DMSO-de): 5 8.08 (d, J= 2.0 Hz, 1H), 7.91 (dd, , J= 2.0, 8.1 Hz, 1H), 7.77 (d, J= 8.1 Hz, 1H), 4.93 (s, 2H), 4.89 (s, 2H), 3.26 (s, 3H) ppm.13C NMR (75.476 MHz, DMSO-d6): 5 142.63, 141.64, 138.80, 129.82, 128.02, 43.79, 29.99, 29.67 ppm.

[0329] Example 3: 2-tert-butoxyphenol; Compound 8

[0330] Catechol (50 kg, 454 moles, 1.0 equiv.) was added to DCM (400 L) at RT, followed by cooling to -10 °C and the addition of cone, sulfuric acid (0.55 kg, 0. 012 eq). Isobutene (171 kg, 2942 moles, 6.5 equiv.) was condensed into the reactor followed by warming to 35 °C and aging for 24 h (> 95% conv.). The contents were cooled to 0 °C and TEA (1.1 kg) was added (note: exothermic) followed by warming to RT. The volatiles were removed in vacuo at < 45 °C. The concentrate was cooled to RT and then treated with aq. NaOH (7.4 wt%, 270 kg) and hexanes (100 L). The mixture was stirred at RT for 15 minutes. The layers were separated, and the aq. layer (containing the product) was washed with hexanes (100 L). The aq. layer was carefully neutralized to pH 7-8 with 2N aq HC1 at 5 °C, then was warmed to RT and extracted with EtOAc (2 x 150 L). The combined extracts were washed with 5% aq NaCl (1 x 250 L) and then concentrated in vacuo at < 45 °C. The resulting oil (54 kg; 72% yield; > 99 A%) was used directly in the next step.1H NMR was consistent with literature data. Note: / / -heptane can replace hexanes for the extraction step.Attorney Docket No. 134851-002702

[0331] Example 4: 4-iodo-2-tert-butoxyphenol; Compound 9

[0332] Compound 8 (50 assay g, 300.0 mmoles; 1.0 equiv.) and EtOH (550 mL) were combined at RT and treated with a solution of potassium iodide (67.4 g, 406.0 mmoles, 1.35 equiv.) in water (180.5 g) and then a solution of NaOH (14.4 g, 360.0 mmoles, 1.20 equiv.) in water (165.5 g). After cooling 5 °C, 7.9% aq. NaOCl (297.0 g, 315.2 mmoles, 1.05 equiv.) was added slowly to maintain the internal temp at 0-5 °C. The reaction was aged 1 h at 5 °C (> 97% conversion) and neutralized with 2 N HC1 at 0-5 °C to pH 7-8. The mixture was warmed to RT, and the product was extracted with Ao-octane (3 x 150 mL). The combined organic layers were washed with 10% aq. sodium thiosulfate (400 mL) and 10% aq. NaCl (400 mL). The organic layer was dried over sodium sulfate (50 g) and concentrated in vacuo at 30-40 °C to 250 mL, cooled to -10 °C, seeded (500 mg) and aged for 1 h. The slurry was further cooled to -40 °C, aged for 1.5 h and isolated by filtration. The product was washed with -40 °C iso-octane (50 mL) and dried in vacuo at 30 °C to constant weight to provide 9 as a beige solid (66.2 g; 74% yield; 98.2 A% purity). m.p - 45.6 °C.NMR (400 MHz, CDCh): 5 7.31 (d, J= 2.0 Hz 1H), 7.25 (dd, J= 2.0, 8.4 Hz, 1H), 6.71 (d, 8.4 Hz, 1H), 5.72 (s, 1H), 1.41 (s, 9H) ppm.13C NMR (100.62 MHz, CDCh): 5 149.86, 143.36, 132.94, 130.57, 116.86, 81.47, 80.27, 28.84 ppm.

[0333] Example 5: 4-[3-[l,3-Dihydro-5-(methylsulfonyl)-27 / -isoindol-2-yl]-3- methyl-l-butyne; Compound 12

[0334] Example 6: Compound 4 (133.8 assay kg, 391.2 moles, 1.0 equiv.) and 1,1- dimethylpropargylamine (1) (37.3 assay kg, 448.7 moles, 1.15 equiv.) were added to a vessel containing THE (358.4 kg), followed by the addition of a solution of potassium carbonate (135.2 kg, 978.3 moles, 2.5 equiv.) in water (402.0 kg). The contents were heated at 45-50 °C for 9 h (>99.5% conv), then cooled to 30 °C and the layers separated. The organic layer was diluted with THF (119 kg) then circulated through a CUNO carbon cartridge. The cartridge was rinsed with THF (120 kg), and the combined filtrate was concentrated in vacuo at < 40 °C until the volume was about 330 L. The concentrate temperature was adjusted to 35 °C, and / / -heptane (366.8 kg) was added over 5 h. The resulting slurry was cooled to 0 °C and aged for 3 h. The solids were filtered, and the cake was washed with chilled / / -heptane ( 184 kg). The product was dried in vacuo at 50 °C to constant weight to provide 98.0 kg of compound 12 (87% assay yield, 98.5 A%) as a faint yellow solid, m.p.: 211.3 °C.]H NMR (400 MHz, DMSO-d6): 5 7.81 (d, J= 1.8 Hz, 1H), 7.78 (dd, , J= 1.8, 7.9 Hz, 1H), 7.52 (d, J= 7.8 Hz, 1H), 4.08 (s, 4H), 3.32 (s, 1H), 3.19 (s, 3H), 1.40 (s, 6H) ppm.13C NMR: (101 MHz, DMSO-d6): 146.06, 141.35, 140.04, 126.39, 123.74, 121.63, 85.41, 76.65, 53.97, 53.90, 53.78, 44.25, 29.33 ppm.Attorney Docket No. 134851-002702

[0335] Example 7: 2-(tert-butoxy)phenyl)-4-(3-methyl-3-(5- methylsulfonyl)isoindolin-2-yl)but-l-yn-l-yl)phenol; Compound 13(a) Via coupling with compound 2

[0336] Methanol (225.6 kg) and compound 2 (113.3 assay kg, 339.1 moles, 1.0 equiv.) were combined at RT, followed by the addition of 30% sodium methoxide in MeOH (8.0 kg, 44.4 moles, 0.13 equiv.). The contents were stirred at 25 °C for 4 h (>99.5 % conv.). The temperature was adjusted to 20 °C, and the pH was adjusted to 6-7 with 1 N HC1. The volatiles were removed in vacuo at < 50 °C until 1-2 V remained. The residue was combined with 2- MeTHF (762.6 kg) at RT and washed with 15% aq. NaCl (2 x 385 kg). The organic layer was concentrated in vacuo at < 55 °C to the 2-3 V level, followed by the addition of alkyne 12 (89.2 assay kg, 338.7 moles, 1.0 equiv.). Nitrogen was sparged through the solution at 20 °C until the oxygen content was below < 100 ppm. To the reaction mixture was added: triethylamine (103.2 kg, 1019.9 moles, 3.0 equiv.), dichloro[bis(phenyl-phosphinophenyl)-ether Pd (II) (490 g, 0.684 moles, 0.002 equiv.), cuprous iodide (388 g, 2.04 moles, 0.006 equiv.). 2-MeTHF (5.8 kg) was used to rinse down the solids via the reactor charging port. The reactor headspace was evacuated and purged with nitrogen (3 x), and the contents were heated to 50-54 °C for 30 h (>99.0% conversion). An additional 2-MeTHF (386 kg) was added to the reactor, and the internal temp was adjusted to 50 °C followed by filtration through a bed of Celite (11.2 kg). The reactor and filter were rinsed with additional 2-MeTHF (298 kg) at 50 °C. The combined filtrates were washed with 50% aq. ammonium chloride (2 x 398 kg) and 5% aq. NaCl (1 x 398 kg) at 25 °C. The organic layer was circulated through a series of activated carbon cartridges until the residual P level was < 25 ppm. The carbon was rinsed with 2-MeTHF (193 kg) and combined with the primary filtrate, followed by concentration in vacuo at < 55 °C to about 280 L and solvent swapping into IPA until the residual 2-MeTHF level was < 10%. The solution volume was adjusted to about 735 L and heated to 80 °C to dissolve the solids. The solution was cooled to 58 °C, and water (566 kg) was added over 4 h at 50-60 °C, followed by aging for 1 h to crystallize the product. The slurry was cooled to 25 °C and aged for 3 h before isolating the product by filtration. The cake was washed with 44 wt% IPA in water (1 x 101 kg) and dried in vacuo at 55 °C to constant weight to afford 111.6 kg of compound 13 (77% assay yield, 96.5 A%). Residual P: 5 ppm, Pd: 25 ppm. m.p.: 125.8 °C.]H NMR (401 MHz, DMSO-de): 5 7.79 (dd, J= 1.9, 5.4 Hz 2H), 7.39 (d, 8.3 Hz, 1H), 7.08- 6.96 (m, 2H), 6.81 (d, 8.2 Hz, 1H), 5.92 (s, 1H), 4.23 (s, 4H), 3.02 (s, 3H), 1.57 (s, 6H), 1.39 (s, 9H) ppm.13C NMR (101 MHz, DMSO-d6): 5 152.78, 146.26, 142.74, 141.55, 139.99, 128.53, 128.43, 126.35, 123.73, 121.61, 117.13, 112.93, 88.79, 86.33, 80.08, 54.45, 54.03, 53.84, 44.25, 29.59, 28.70 ppm.Attorney Docket No. 134851-002702(b) Via coupling with compound 9

[0337] 2-MeTHF (2.50 L), compound 12 (0.902 kg, 3.42 moles, 1.0 equiv.), compound 9 (1.00 kg, 3.42 moles, 1.0 equiv.) and TEA (1.04 kg, 10.26 moles, 3.0 equiv.) were combined at RT. The vessel was evacuated and purged with nitrogen (3x), followed by the addition of dichloro[bis(phenylphosphinophenyl]ether Pd (II) (4.90 g, 6.84 mmoles, 0.002 equiv.), cuprous iodide (3.91 g, 20.5 mmoles, 0.006 equiv.). The vessel was evacuated, purged with nitrogen (3x), and heated to 50 °C. The reaction was complete after 50 h (compound 9 < 2.0 A%) and cooled to RT. The IPC assay showed: dimer (1.2 A%), isoindole (0.28 A%). 2-MeTHF (5.0 L) was added to the reaction mixture, and it was filtered through a celite pad (100 g). The cake was rinsed with 2-MeTHF (4.0 L). The combined filtrates were washed with 15% aq. ammonium chloride (3 x 3L) and 5% aq. NaCl (1 x 3 L). The organic layer was circulated through an activated carbon cartridge until the Pd level was < 25 ppm. The cartridge was rinsed with 2-MeTHF (1 x 2 L), and the combined filtrates were solvent swapped to IPA (6.5 vol) at NMT 55 °C. The resulting slurry was heated to 80 °C until dissolution of the solids then cooled to 55 °C. Water (5.0 L) was added to the IPA solution over 2 h at 50-60 °C, followed by aging for 1 h to crystallize the product. The slurry was cooled to 25 °C and aged for 3 h before isolating the product by filtration. The cake was washed with 44 wt% IPA in water (1 x 1.0 kg) and dried in vacuo at 55 °C to constant weight to afford 1.23 kg of compound 13 (82% assay yield, 98.3 A%). Residual P: 8 ppm, Pd: 21 ppm.1H NMR and13C NMR were consistent with published values.

[0338] Example 8: (2-(Z-butoxy)-4-(3-methyl-3-(5-methylsulfonyl)isoindolin-2- yl)butyl)phenol; CT1812 free base

[0339] Methanol (881 kg) was charged to a 3000 L autoclave with 13 (111.4 assay kg, 260.6 moles, 1.0 equiv.) and DBU (79.2 kg, 520.2 moles, 2.0 equiv.) at 5 °C. The mixture was purged with nitrogen subsurface then vented (3 x). The residual oxygen was < 0.1%. 5% Pd / C (5.5 kg dry basis) was added to the autoclave at 5 °C. The atmosphere exchanged with hydrogen and pressurized to 290-300 psi. The hydrogenation was continued until > 99% conversion was achieved (40 h). [defined as < 0.5 A% each of 13 and alkene 16]. The contents were cooled to -3 °C and purged with nitrogen until the hydrogen level was < 0.4%. The mixture was filtered, and the reactor was rinsed with MeOH (264 kg). The combined filtrates were concentrated in vacuo at < 30 °C to the 1350 L level, and the pH was adjusted to 7.5-8.0 with 2N HC1 at 20 °C. Then, water (362 kg) was added to the reaction mixture at 25 °C to induce crystallization followed by the remaining water (780 kg). The slurry was aged at 25 °C for 1 h before cooling to 3 °C and aging for 3 h (liquor losses were < 0.1 wt%). The product was isolated by filtration in two portions with each cake washed with chilled 10 wt% MeOH in water (1 x 332 kg). The product was driedAttorney Docket No. 134851-002702 in vacuo at 45 °C to constant weight to provide 86.5 assay kg of CT1812 free base in 77% assay yield. (93 A%, 4.9 A% isoindole 14). m.p.: 103.8 C. 'H NMR (400 MHz, DMSO-dd): 5 8.43 (s, 1H), 7.81 (s, 1H), 7.77 (d, J= 7.9 Hz), 7.51 (d, . / - 7.8 Hz, 1H), 6.84-6.70 (m, 3H ), 4.05 (s, 4H) , 3.18 (s, 3H), 1.77-1.60 (br m, 2H), 1.29 (s, 9H), 1.11 (s, 6H) ppm.nC NMR (101 MHz, DMSO- d6): 5 149.63, 146.59, 142.56, 141.85, 139.79, 133.61, 126.09, 125.45, 124.07, 123.70, 121.64, 116.61, 79.37, 54.82, 51.57, 44.30, 43.58, 29.45, 28.85, 22.82 ppm.

[0340] Example 9: (2-(Z-butoxy)-4-(3-methyl-3-(5-methylsulfonyl)isoindolin-2- yl)butyl)phenol; CT1812 hemifumarate dihydrate

[0341] Ethanol (429 kg), CT1812 free base (86.3 assay kg; 200.0 moles, 1.0 equiv.,93 A%) and fumaric acid (11.61 kg, 100.0 moles, 0.50 equiv.) were combined at RT. The mixture was warmed to 55 °C and aged for 30 min to dissolve the solids. The resulting solution was clarified through a 0.2 pm cartridge, and the vessel and filter were rinsed with warm EtOH (61.3 kg). The filtrate temperature was re-adjusted to 50 °C, and water (69.0 kg) was added over 1 h followed by seed crystals (0.86 kg). The resulting slurry was aged for 90 min at 50 °C followed by cooling to 20 °C over 11 h. The slurry was aged for 3 h, filtered, and the cake was washed with cold (5 °C) aq. EtOH (140 kg; 9: 1 wt / wt EtOH / water). The wet cake was dried in vacuo at 30 °C to constant weight to provide CT1812 hemifumarate dihydrate (94.1 kg) in 88% assay yield (99.7 A%). DSC: 115.7 °C (peak). 'H NMR (400 MHz, DMSO-d6): 5 7.81 (d, J= 1.65 Hz, 1H), 7.78 (dd, J= 1.65, 7.78 Hz, 1H), 7.51 (d, J= 7.78 Hz, 1H), 6.78-6.72 (m, 3 H), 6.62 (s, 1H), 4.09 (br s, 4H), 3.18 (s, 3H), 2.51 (m, 2H), 1.70-1.64 (br m, 2H), 1.29 (s, 9H), 1.12 (s, 6H) ppm.13C NMR (101 MHz, DMSO-de): 5 166.7, 149.6, 146.3, 142.6, 141.5, 139.9, 134.6, 133.5, 126.2, 125.5, 124.1, 123.8, 121.6, 116.6, 79.4, 55.4, 51.6, 51.4, 44.3, 43.3, 29.4, 28.9, 22.8 ppm. Elem. anal, for C26H39NO8S: calc.: H= 59.36, H= 7.42, N= 2.67, S= 6.10; found: H= 59.58, H= 7.59, N= 2.61, S= 6.21.

Claims

1. Attorney Docket No. 134851-002702CLAIMS1. A process for preparing a compound of Formula 4:comprising brominating a compound of Formula 5a to form the compound of Formula 4,wherein the brominating comprises a photochemical bromination.

2. The process of claim 1, wherein the photochemical bromination comprises treating the compound of Formula 5a with light >400 nm in the presences of a brominating agent selected from NBS or dibromodimethylhydantoin in a solvent and optionally a Bronsted acid.

3. The process of claim 2, wherein the brominating agent is NBS.

4. The process of either of claims 2 or 3, wherein the Bronsted acid is present and is selected from the group consisting of HBr, AcOH, Citric acid, H2SO4 and a combination of HBr / AcOH.

5. The process of claim 4, wherein the Bronsted acid is H2SO4.

6. The process of any one of claims 2-5, wherein the light is about 450-about 460 nm.

7. The process of any one of claims 2-6, wherein the solvent is selected from the group consisting of DCE, EtOAc and MeCN.

8. The process of claim 7, wherein the solvent is MeCN.

9. The process of any one of claims 1-8, wherein the photochemical bromination is continuous flow photochemical bromination.

10. The process of claim 9, wherein the continuous flow photochemical bromination comprises:Attorney Docket No. 134851-002702 i) preparing a first solution of the Bronsted acid in the solvent and preparing a second solution of the compound of Formula 5a and the brominating agent in the solvent; ii) simultaneously transferring the first solution through a first tube and the second solution through a second tube to a reactor coil, such that the first solution and the second solution mix upon entry to the reactor coil and wherein the reactor coil has a LED panel operating at about 450 nm to about 460 nm located on at least one side of the reactor coil; and iii) pumping the mix of step ii) through the reactor coil to form the compound of Formula 4; and collecting the compound of Formula 4.

11. The process of any one of claims 2-10, wherein the brominating agent is NBS, the Bronsted acid is H2SO4, the solvent is MeCN and the light is about 450 to about 460 nm.

12. The process of claim 1, wherein the compound of Formula 4 is 95 A% chemically pure.

13. The process of any one of claims 1-10, wherein the compound of Formula 4 comprises less than 3 A% of monobrominated compound of Formula 4a impurity14. The process of any one of claims 1-10, wherein the compound of Formula 4 comprises less than 1 A% of tribrominated compound of Formula 4b impurity15. A process for preparing a compound of Formula (I) or a salt thereofcomprisingAttorney Docket No. 134851-002702 a) contacting a compound of Formula 4 with a compound of Formula 1 to form a compound ofFormula 12b) cross coupling the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 13; and c) hydrogenating the compound of Formula 13 to form the compound of Formula (I) or a salt thereof1316. The process of claim 15, wherein the process further comprises d) converting the compound of Formula (I) to a salt of the compound of Formula (I).

17. The process of claims 15, wherein the compound of Formula (I) or a salt thereof is the compound of Formula (I).

18. The process of either of claims 15 or 16, wherein the compound of Formula (I) or a salt thereof is a hemifumarate dihydrate salt of the compound of Formula (I).

19. The process of any one of claims 15-17, wherein the contacting in step a) comprises treating the compound of Formula 4 in a solvent with aqueous potassium carbonate.

20. The process of claim 19, wherein the contacting in step a) further comprises heating.

21. The process of either of claims 19 or 20, wherein the compound of Formula 12 is isolated prior to step b).Attorney Docket No. 134851-00270222. The process of any one of claims 19-21, wherein the compound of Formula 12 obtained by step a) comprises less than 4 A% of a compound of Formula 12a impurity23. The process of any one of claims 15-22, wherein the cross coupling in step b) comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.

24. The process of any one of claims 15-23, wherein the compound of Formula 13 is isolated prior to step c).

25. The process of any one of claims 15-24, wherein the hydrogenating in step c) comprises contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base.

26. The process of any one of claims 15-25, further comprising isolating the compound of Formula (I) or a salt thereof.

27. The process of any one of claims 15-26, wherein the compound of Formula (I), or a salt thereof comprises less than about 5 A% of the isoindole of Formula 14 impurity28. The process of any one of claims 15-26, wherein the compound of Formula 4 is prepared by photochemical bromination of a compound of Formula 5a29. The process of any one of claims 15-28, wherein the photochemical bromination comprises treating the compound of Formula 5a with light >400 nm in the presences of a brominating agent selected from NBS or dibromodimethylhydantoin in a solvent and optionally a Bronsted acid.Attorney Docket No. 134851-00270230. The process of claim 28-29, wherein the Bronsted acid is present and is selected from the group consisting of HBr, AcOH, Citric acid, H2SO4 and a combination of HBr / AcOH.

31. The process of any one of claims 28-30, wherein the light is about 450-about 460 nm.

32. The process of any one of claims 28-31, wherein the solvent is selected from the group consisting of DCE, EtOAc and MeCN.

33. The process of any one of claims 28-32, wherein the photochemical bromination is continuous flow photochemical bromination.

34. The process of claim 33, wherein the continuous flow photochemical bromination comprises: i) preparing a first solution of the Bronsted acid in the solvent and preparing a second solution of the compound of Formula 5a and the brominating agent in the solvent; ii) simultaneously transferring the first solution through a first tube and the second solution through a second tube to a reactor coil, such that the first solution and the second solution mix upon entry to the reactor coil and wherein the reactor coil has a LED panel operating at about 450 nm to about 460 nm located on at least one side of the reactor coil; and iii) pumping the mix of step ii) through the reactor coil to form the compound of Formula 4; and collecting the compound of Formula 4.

35. The process of claim of any one of claims 28-34, wherein the compound of Formula 4 is 95 A% chemically pure.

36. The process of any one of claims 28-34, wherein the compound of Formula 4 comprises less than 3 A% of monobrominated compounds of Formula 4a impurity^X^^SO2MeBr 4a37. The process of any one of claims 28-34, wherein the compound of Formula 4 comprises less than 1 A% of tribrominated compounds of Formula 4b impurityAttorney Docket No. 134851-00270238. The process of any one of claims 28-37, wherein the compound of Formula 5a is prepared by coupling of a compound of Formula 5c with sodium methyl sulfinate39. The process of claim 38, wherein the coupling comprises treating the compound of Formula 5c with the sodium methyl sulfinate in the presence of a base, a bidentate ligand, and catalytic CuX in a solvent; wherein X is bromide or iodide.

40. The process of claim 39, wherein the compound of Formula 5a comprises less than 5 A% of a compound of Formula 5d impurity41. A process for preparing a compound of Formula 5acomprising coupling of a compound of Formula 5c with sodium methyl sulfinateto form the compound of Formula 5a.

42. The process of claim 41, wherein the coupling comprises treating the compound of Formula 5c with the sodium methyl sulfinate in the presence of a base, a bidentate ligand, and catalytic CuX in a solvent; wherein X is bromide or iodide.Attorney Docket No. 134851-00270243. The process of claim 42, wherein the compound of Formula 5a contains less than 5 A% of a compound of Formula 5d5d44. A process for preparing a compound of Formula (I) or a salt thereofcomprising a) heating a compound of Formula 4 with a compound of Formula 1 in the presence of aqueous potassium carbonate to form a compound of Formula 12b) combining a compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base to form the compound of Formula 13; and c) contacting the compound of Formula 13 in a solvent, with a palladium or platinum catalyst, hydrogen and a base to form the compound of Formula (I) or a salt thereofAttorney Docket No. 134851-00270245. The process of claim 44, wherein the process further comprises d) converting the compound of Formula (I) to a salt of the compound of Formula (I).

46. The process of claims 44, wherein the compound of Formula (I) or a salt thereof is the compound of Formula (I).

47. The process of either of claims 44 or 46, wherein the compound of Formula (I) or a salt thereof is a hemifumarate dihydrate salt of compound of Formula (I).

48. The process of any one of claims 44-47, wherein the compound of Formula 12 in step a) is isolated prior to step b).

49. The process of any one of claims 44-48, wherein the compound of Formula 13 in step b) is isolated prior to step c).

50. The process of any one of claims 44-49, wherein the process further comprises isolating the compound of Formula (I) or a salt thereof.

51. A compound of Formula 12:

52. A compound of Formula lO’AcOH:prepared by a process comprising contacting a compound of Formula 4 with a compound ofFormula 1 to form the compound of Formula 12Attorney Docket No. 134851-00270254. The compound of claim 53, wherein the contacting comprises treating the compound of Formula 4 in a solvent with aqueous potassium carbonate.

55. The compound of claim 54, wherein the solvent is THF or 2-methyl THF.

56. The compound of either of claims 54 or 55, wherein the contacting in step a) further comprises heating.

57. The process of any one of claims 54-56, wherein the compound of Formula 12 is isolated.

58. The process of any one of claims 54-57, wherein the compound of Formula 12 comprises less than 4 A% of a compound of Formula 12a impurity59. A process for preparing a compound of Formula 12:comprising contacting a compound of Formula 4 with a compound of Formula 1 to form the compound of Formula 1260. The process of claim 59, wherein the contacting comprises treating the compound of Formula 4 in a solvent with aqueous potassium carbonate.

61. The process of claim 60, wherein the compound of Formula 12 is isolated.Attorney Docket No. 134851-00270262. The process of any one of claims 60-61, wherein the compound of Formula 12 comprises less than 4 A% of a compound of Formula 12a impurity63. A compound of Formula 13:prepared by a process comprising cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 1364. The compound of claim 63, wherein the cross coupling comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.

65. The compound of claim 64, wherein the compound of Formula 13 is isolated.

66. A process for preparing a compound of Formula 13:comprising cross coupling of the compound of Formula 12 with a compound of Formula 9 to form a compound of Formula 13Attorney Docket No. 134851-00270267. The process of claim 66, wherein the cross coupling comprises combining the compound of Formula 9 and the compound of Formula 12 in a solvent in the presence of a palladium catalyst, a copper cocatalyst, and an amine base.

68. The process of claim 67, wherein the compound of Formula 13 is isolated.

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