Process for preparing 3-(4-(hexyloxy)-1,2,5-thiadiazol-3-YL)-1,2,5,6-tetrahydro-1-methylpyridine l-(+)-tartrate

Abstract

Disclosed is a process for preparing 3-(4-(Hexyloxy)-1,2,5-Thiadiazol-3-yl)-1,2,5,6-tetrahydro-1-1methylyypridine l (+)Tartrate of formula (I).

Description

[0001] PROCESS FOR PREPARING 3-(4-(HEXYLOXY)-l,2,5-THIADIAZOL-3-YL)-l,2,5,6- TETRAHYDRO- 1 -METHYLPYRIDINE L-(+)-T ARTRATE

[0002] CROSS REFERENCE TO RELATED APPLICATIONS

[0003] This application claims the benefit of U.S. Provisional Application Serial No.

[0004] 63 / 698,779 filed September 25, 2024 which is incorporated herein in its entirety.

[0005] FIELD OF THE INVENTION

[0006] T he present invention generally relates to a process for preparing 3-(4-(hexyloxy)~ l,2,5-thiadiazol-3-yl)-l,2,5,6-tetrahydro-l-methylpyridine l-(+)-tartrate.

[0007] BACKGROUND OF THE INVENTION

[0008] Xanomeline tartrate is a potent and selective M 1 / M4 muscarinic receptor agonist under evaluation as therapeutic agent for the treatment of bipolar, schizophrenia, cognitive impairment associated with schizophrenia, psychosis in Alzheimer disease, Alzheimer’s disease with agitation, and autism. Xanomeline tartrate has the following chemical structure of formula (1):

[0009] (D

[0010] U.S. Patent 5,043,345 discloses xanomeline and a preparation process from the precursor compound 3-(4-chloro-l,2,5-thiadiazol-3-yl)pyridine in Example 9.

[0011] The precursor compound, 3-(4-chloro- l ,2,5-thiadiazol-3-yl)pyridine, has the structure of Formula (IV):

[0012] Other chemical names for the compound of Formula (IV) include 3-(3-chloro-l ,2,5- thiadiazol-4-yl)pyridine and 3-chloro-4-(pyrid-3-yl)-l,2,5-thiadiazole.

[0013] In addition to the aforementioned process there remains a need for a process of preparing xanomeline tartrate with improved purity and yield. The present disclosure provides a process of preparing xanomeline tartrate that has a purity of greater that 99% and an overall yield greater than 30% (from a compound of Formula II described below).

[0014] SUMMARY OF THE INVENTION

[0015] The present disclosure provides a process of preparing substantially pure xanomeline tartrate that has a purity of greater that 99% and an overall yield greater than 30% (from compound of Formula II).

[0016] In one aspect, the present disclosure provides a process for preparing a substantially pure compound of Formula (1):

[0017] (i) (KTX-001) the process comprising the following steps:

[0018] (a) reacting a compound of Formula II to provide the compound of Formula

[0019] II (KTX-594) Ila III

[0020] (KTX-595) step (a) comprising:

[0021] (a-1) reacting a compound of Formula II with a reagent X in the presence of a solvent Y at a temperature ranging from about 0°C to about 35°C to provide the compound of Formula lia:

[0022] (a-2) reacting a compound of Formula lia with a reagent X1in the presence of a solvent Y at a temperature between about 0°C to about 35°C to provide the compound of Formula III;

[0023] (a-3) extracting the compound of Formula III at a temperature between about 20°C to about 35°C w'ith methylene chloride (CH2CI2) following saturation of the reaction m ixture with reagent X11; wherein

[0024] (i) said reagent X is selected from a group consisting of: ammonium chloride (NH4CI), or ammonium hydroxide (NH4OH), and mixtures thereof:

[0025] (ii) said reagent X!is sodium cyanide (NaCN);

[0026] (iii) said reagent X11is selected from sodium carbonate, sodium sulfate and mixtures thereof; and

[0027] (iv) said solvent Y is selected from the group consisting of: purified water, methylene chloride, or an ether-based solvent, and mixtures thereof;

[0028] (b) reacting the compound of Formula Ill w ith reagent Z in the presence of a solvent W at a temperature ranging from about 0°C to about 70°C to provide the compound of Formula (IV):

[0029] III (KTX 595) IV (KTX 478) step (b) comprising:

[0030] (b-1 ) reacting reagent Z at the temperature between about 0 °C to about 35°C with the compound of Formula III in the presence of N, N- dimethylformamide DMF; and

[0031] (b-2) extracting and isolating the compound of Formula IV at a temperature between about 25°C to about 30°C with solvent W: wherein:

[0032] (i) said reagent Z is selected from a group consisting of: sulfur monochloride (S2 CI2), N, N-dimethylformamide (DMF), or sodium hydroxide (NaOH), and mixtures thereof; and

[0033] (ii) said solvent W is selected from a group consisting of: toluene, n- heptane, 2-methyl tetrahydrofuran (2-MeTI IF), purified water, or N, N-dimethylformamide (DMF), and mixtures thereof;

[0034] (c) reacting the compound of Formula IV with a reagent XX at a temperature of 15°C to about 70°C in the presence of a solvent YY to provide the compound of Formula V : IV (KTX 478) V (KTX-480); wherein

[0035] (ii) said reagent XX is selected from a group consisting of: 1 -hexanol sodium, tert-pentoxide, or sodium chloride (NaCl), and mixtures thereof;

[0036] (iii) said solvent YY is selected from a group consisting of: purified water, toluene, acetone, and mixtures thereof; and

[0037] (d) reacting the compound of Formula V with a ZZ in the presence of a solvent WW at a temperature for reaction and isolation ranging from about 15°C to about 90°C to provide the compound of Formula VI:

[0038] V (KTX 480) VI (KTX481)

[0039] (i) said reagent ZZ is methyl iodide (CH3I); and

[0040] (iv) said solvent WW is selected from a group consisting of: toluene, or acetone, and mixtures thereof;

[0041] (e) reacting the compound of Formula VI with reagent X2followed by reagent X3in the presence of a solvent Y1at a temperature between about -32°C to about 70°C to provide the compound of Formula 1:

[0042] VI (KTX 481) I (KTX 001) wherein:

[0043] (i) said reagent X2is selected from a group consisting of: sodium borohydride ( NaBH-s), sodium hydroxide (NaOH), and methyl lert- buty! ether (MTBE), activated carbon, and mixtures thereof;

[0044] (ii) said reagent X3is selected from a group consisting of: sodium borohydride (NaBFh), hydrochloric acid (HCI), and sodium chloride (NaCl), and a mixture thereof;

[0045] (iii) said solvent Y1is selected from a group consisting of: purified water, methanol (MeOH), methyl tert-butyl ether (MTBE), or acetone and a mixture thereof;

[0046] (f) recrystallizing the compound of Formula 1 at a temperature between about 0°C to about 55°C with a solvent X42, wherein: said solvent X42is selected from a group consisting of: purified water or acetone, and a mixture thereof. BRIEF DESCRIPTION OF THE DRAWINGS

[0047] FIG. 1. shows a reaction schematic for the synthesis of 3-(4-(hexyloxy)-l,2,5- thiadiazol-3-yl)-l,2,5,6-tetrahydro-l-methylpyridine l-(+)-tartrate.

[0048] DETAILED DESCRIPTION

[0049] The following is a detailed process of preparing substantially pure xanomeline tartrate that has a purity of greater that 99% and a yield greater.

[0050] The first aspect, the present disclosure provides a process for preparing a substantially pure compound of Formula (I):

[0051] (1) (KTX-001) the process comprising the following steps:

[0052] (a) reacting a compound of Formula II to provide the compound of Formula

[0053] (KTX-595) step (a) comprising: (a- 1) reacting a compound of Formula II with a reagent X in the presence of a solvent Y at a temperature ranging from about 0°C to about 35°C to provide the compound of Formula Ila;

[0054] (a-2) reacting a compound of Formula Ila with a reagent X1in the presence of a solvent Y at a temperature between about 0°C to about 35°C to provide the compound of Formula III;

[0055] (a-3) extracting the compound of Formula III at a temperature between about 20°C to about 35°C with methylene chloride (CH2CI2) following saturation of the reaction mixture with reagent X11; wherein

[0056] (i) said reagent X is selected from a group consisting of: ammonium chloride (NH4CI), or ammonium hydroxide (NH4OH), and mixtures thereof;

[0057] (ii) said reagent X1is sodium cyanide (NaCN);

[0058] (iii) said reagent X11is selected from sodium carbonate, sodium sulfate and mixtures thereof; and

[0059] (iv) said solvent Y is selected from the group consisting of: purified water, methylene chloride, or an ether-based solvent, and mixtures thereof;

[0060] (b) reacting the compound of Formula III with reagent Z in the presence of a solvent W at a temperature ranging from about 0°C to about 70°C to provide the compound of Formula (IV):

[0061] III (KTX 595) IV (KTX 478) step (b) comprising: ((b-1) reacting reagent Z at the temperature between about 0 °C to about 35°C with the compound of Formula 111 in the presence of DMF; and (b-2) extracting and isolating the compound of Formula IV at a temperature between about 25°C to about 30°C with solvent W; wherein:

[0062] (i) said reagent Z is selected from a group consisting of: sulfur monochloride (S2CI2), N, A-dimethylformamide (DMF), or sodium hydroxide (NaOH), and mixtures thereof; and

[0063] (ii) said solvent W is selected from a group consisting of: toluene, n- heptane, 2-methyl tetrahydrofuran (2-MeTHF), purified water, or N, N-dimethylformamide (DMF), and mixtures thereof;

[0064] (c) reacting the compound of Formula IV with a reagent XX at a temperature of 1 5°C to about 70°C in the presence of a solvent YY to provide the compound of Formula V:

[0065] IV (KTX 478) V (KTX-480); wherein

[0066] (i) said reagent XX is selected from a group consisting of: 1 -hexanol sodium tert-pentoxide, or sodium chloride (NaCl), and mixtures thereof;

[0067] (ii) said solvent YY is selected from a group consisting of: purified water, toluene, acetone, and mixtures thereof; and (d) reacting the compound of Formula V with a ZZ in the presence of a solvent WW at a temperature for reaction and isolation ranging from about 15°C to about 90°C to provide the compound of Formula VI:

[0068] V (KTX 480 ) VI (KTX481)

[0069] (i) said reagent ZZ is methyl iodide (CHjl); and

[0070] (ii) said solvent WW is selected from a group consisting of: toluene, or acetone, and mixtures thereof;

[0071] (e) reacting the compound of Formula VI with reagent X2followed by reagent X3in the presence of a solvent Y1at a temperature between about -32CC to about 70°C to provide the compound of Formula I:

[0072] VI (KTX 481 ) I (KTX 001) wherein: (i) said reagent X2is selected from a group consisting of: sodium borohydride (NaBlh), sodium hydroxide (NaOM), and methyl ferr- butyl ether (MTBE), activated carbon, and mixtures thereof;

[0073] (ii) said reagent X3is selected from a group consisting of: sodium borohydride (NaBFh), hydrochloric acid (HC1), and sodium chloride (NaCl), and a mixture thereof;

[0074] (iii) said solvent Ysis selected from a group consisting of: purified water, methanol (MeOH), methyl / ert-butyl ether (MTBE), or acetone and a mixture thereof;

[0075] (f) recrystallizing the compound of Formula I at a temperature between about 0°C to about 55°C with a solvent X42, wherein: said solvent X42is selected from a group consisting of: purified water or acetone, and a mixture thereof.

[0076] In one embodiment, a process is provided according to the first aspect wherein: said reagent X is Sodium cyanide (NaCN); said reagent X1is a mixture of ammonium chloride (NH4CI) and ammonium hydroxide (NH4OH); said reagent X11is selected from sodium carbonate, sodium sulfate and mixtures thereof; and said solvent Y is purified water.

[0077] In one embodiment, a process is provided according to the first aspect wherein the compound of formula III is stable at a temperature between about 2°C to about 8°C.

[0078] In one embodiment, a process is provided according to the first aspect wherein the solvent W is present in the following amounts: toluene up to about 10.2 vol.; n-heptane in an amount of about 3.0 to about 15.9 vol.; purified water in an amount of about 10.2 vol. to up to about 21.0 vol: and A) A-dimethylformamide (DMF) in an amount of about 1.15 vol to up to about 4.6 vol. In one embodiment, a process is provided according to the first aspect wherein said reagent X ammonium chloride (NH4CI) is present in an amount of about 1 .0 to about 3.0 molar equivalents.

[0079] In one embodiment, a process is provided according to the first aspect wherein said reagent X1sodium cyanide (NaCN) is present in an amount of about 0.99 to about 1.19 molar equivalents.

[0080] In one embodiment, a process is provided according to the first aspect wherein said reagent X ammonium hydroxide (NH4OH) is present in an amount of about 0.53 to about 1 .0 molar equivalents.

[0081] In one embodiment, a process is provided according to the first aspect wherein said reagent Xnsodium carbonate (NasCCh) is present in an amount of about 0.9 to about 1.1 wt.

[0082] In one embodiment, a process is provided according to the first aspect wherein said reagent X11sodium sulfate (NasSCh) is present in an amount of about 0.5 to about 1 .5 wt.

[0083] In one embodiment, a process is provided according to the first aspect wherein said reagent Z sulfur monochloride is present in an amount of about 1 .63 to about 2.73 molar equivalents.

[0084] In one embodiment, a process is provided according to the first aspect wherein said reagent Z sodium hydroxide (NaOH) is present in an amount of about 0.75 molar equivalents to maintain a pH between 9 and 14.

[0085] In one embodiment, a process is provided according to the first aspect wherein the reagent XX sodium tert-pentoxide is present in an amount of about 1.40 to 1 .49 about molar equivalents. In one embodiment, a process is provided according to the first aspect wherein said reagent ZZ methyl iodide (CH3I) is present in an amount of about 1 . 10 to about 1 .50 molar equivalents.

[0086] In one embodiment, a process is provided according to the first aspect wherein said reagent XX 1 -hexanol is present in an amount of about 1.55 to about 1.80 molar equivalents.

[0087] In one embodiment, a process is provided according to the first aspect wherein said sol vent Y1methanol (MeOH) is present in an amount of about 4.0 to about 6.0 vol.

[0088] In one embodiment, a process is provided according to the first aspect wherein said solvent Y* purified water is present in an amount of about 13 vol.

[0089] In one embodiment, a process is provided according to the first aspect wherein said reagent X2sodium hydroxide (NaOH) is present in an amount from about 0. 10 to about 1 .04 molar equivalents).

[0090] In one embodiment, a process is provided according to the first aspect wherein said reagent X2sodium borohydride (NaBH4) is reacted with the compound of VI in as stepwise approach according to the following amounts (i) of about 0.88 to about 1.12 eq.; (ii) about 0.29 to about 0.41 eq.

[0091] In one embodiment, a process is provided according to the first aspect wherein said solvent Y1methyl te?7-butyl ether (MTBE) in an amount of about 7.0 to about 12 vol.

[0092] In one embodiment, a process is provided according to the first aspect wherein said reagent X3hydrochloric acid (HC1) is present in an amount enough to maintain a pH between 0.6 and 3. In one embodiment, a process is provided according to the first aspect wherein said reagent X3sodium chloride (NaCI) is present in an amount of about 0.03 to about 0.10 wt / wt. In one embodiment, a process is provided according to the first aspect wherein the yield of the compound of Formula VI from compound of Formula IV is at least 85%.

[0093] In one embodiment, a process is provided according to the first aspect wherein the compound of Formula I has a purity greater than about 99%.

[0094] In one embodiment, a process is provided according to the first aspect wherein the compound of Formula IV has a purity greater than about 99%; and yield of at least 60% from compound of Formula 11.

[0095] DEFINITIONS

[0096] The features and advantages of the invention may be more readily understood by those of ordinary skill in the art upon reading the following detailed description. It is to be appreciated that certain features of the invention that are, for clarity reasons, described above and below in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features of the invention that are, for brevity reasons, described in the context of a single embodiment, may also be combined so as to form sub-combinations thereof. Embodiments identified herein as exemplary or preferred are intended to be illustrative and not limiting.

[0097] Unless specifically stated otherwise herein, references made in the singular may be plural. For example, “a” and “an” may refer to either one, or one or more.

[0098] Unless otherwise indicated, any atom with unsatisfied valences is assumed to have hydrogen atoms sufficient to satisfy the valences.

[0099] The definitions set forth herein take precedence over definitions set forth in any patent, patent application, and / or patent application publication incorporated herein by reference.

[0100] Listed below are definitions of various terms used to describe the present invention. These definitions apply to the terms as they are used throughout the specification (unless they are otherwise limited in specific instances) either individually or as part of a larger group.

[0101] In addition, compounds of Formulas (I) and (IV) can be isolated and purified to obtain a composition containing an amount by weight equal to or greater than 99% of a compound of Formulas (I) and (IV). respectively.

[0102] “Stable compound” and “stable structure” are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture.

[0103] The compounds of the present invention are intended to include all isotopes of atoms occurring in the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include deuterium (D) and tritium (T). Isotopes of carbon include13C and!4C. Isotopically-labeled compounds of the invention can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described herein, using an appropriate isotopically-labeled reagent in place of the non-labeled reagent otherwise employed. For example, methyl (- Cfh) also includes deuterated methyl groups such as -CDs.

[0104] In addition the compounds described in this disclosure are represented by the following formulas with correspond to the identified KTX numbers as follows: KTX-001 is also represented by Formula I; KTX-594 is also represented by Formula II; KTX-595 is also represented by Formula HI; KTX 478 is also represented by Formula IV; KTX-480 is also represented by Formula V; and KTX481 is also represented by Formula VI

[0105] EXAMPLES

[0106] The invention is further defined in the Examples that follow which are provided as illustrations. From the above discussion and the Examples, one skilled in the art can practice the essential elements of the invention without departing from the spirit and scope thereof by making modifications of the aforementioned embodiments. The invention is therefore not limited by the illustrative examples set forth below.

[0107] ABBREVIATIONS aq. aqueous

[0108] MDC methylene chloride

[0109] DCM dichloromethane h, hr or hrs hour(s)

[0110] HPLC high performance liquid chromatography

[0111] LC liquid chromatography

[0112] LCMS liquid chromatography mass spectrometry¬

[0113] M molar mM millimolar

[0114] Me methyl

[0115] MHz megahertz min. minute(s) mins minute(s) MS mass spectrometry n.M nanomolar

[0116] Ret Time or Rt retention time sat. saturated

[0117] SFC supercritical fluid chromatography

[0118] THE tetrahydrofuran wt% weight % EXAMPLE 1

[0119] Stage 1 of KTX-001 synthesis

[0120] Process Description for KTX-478

[0121] KTX-594 to KTX-595: Charge water (A x 3.0 volumes), ammonium chloride (A x 0.75 w / w), and ammonium hydroxide (A x 1 .227 w / w) into a clean and dried RBF, then stir for Not Less than (NLT) 15 minutes. Adjust the batch temperature to 0 to 5°C, slowly add Nicotinaldehyde (A; 1 .0 ± 0.01 equiv,) at 0 to 5CC and stir the reaction for 90 min at 0 to 5°C. Add sodium cyanide solution (A x 0.50 w / w NaCN in A x 2.0 volumes water) to the reaction mass at 0 to 5°C and rinse the RBF rinsed with water A x 0.05. Warm the batch temperature to 26 to 30°C, at which the reaction was maintained for 60-120 min, and then pull the sample for TLC analysis (Compound 1 limit for information only). Without waiting for the result, charge sodium carbonate (A x 1.0 w / w) and sodium sulfate (A x 1.0 w / w) into a Round Bottom Flask (RBF) and stir it for 15 minutes. Extract the product mixture containing KTX-595 into MDC (A x [10 + 5 + 5] volumes), filter the combined organic layers through a hyflo bed, wash the filter bed with MDC (A x 2.0 volumes), and distill the MDC phases to dryness under vacuum below 35°C to obtain KTX-595.

[0122] KTX-595 to KTX-478: Charge N, N-dimethylformamide lot- 1 (A x 2.3 volumes) into a clean and dried RBF and cool to 0 to 10°C, followed by sulfur monochloride (A x 2.522 w / w; 1.91 -2.1 eq.) at 0 to 15°C. Prepare a solution of KTX-595 in N, N- dimethylformamide lot- 2 (A x 2.3 volumes) in a separate flask and add to the above reaction mixture containing sulfur monochloride in DMF at 0 to 20°C. Adjust the batch temperature to 25 to 35°C and maintain for 2.0 hours at the same temperature. Monitor the reaction progress by HPLC (Limit: KTX-595 NMT 2.0%). Cool the reaction mixture to 0 to 5°C and add water lot- 2 (A x 17.0 volumes) at below 15°C, stir the contents for 45 minutes at 0-5°C and filter the batch. Wash the filter cake with water lot- 3 (A x 2.3 volumes). Filter the combined filtrates through a hyflo and wash the hyflo bed with 1 vol of water. Adjust the reaction mass pH to NLT 10 using an aqueous NaOH solution at 15- 30°C and stir for 2 hr±10 min. Filter the precipitated crude KTX-478 and wash the solids with water (A x 2.3 volumes). Charge toluene (A x 5.7 volumes) to the aqueous filtrate, stir the contents for NLT 10 min, and allow' the mixture for NLT 30 min to settle the layers. Filter the contents through a hyflo bed and wash the hyflo bed with 1.1 vol of toluene. Stir the filtrates for NLT 10 min, and separate the phases. Charge extracted toluene layer and 3.4 volumes of fresh toluene to wet crude KTX-478, and then stir the mixture for NLT 30 min. Allow' the layers for NLT 30 min to settle, separate the aqueous layer, filter the organic phase through the celite bed and wash the filter bed with toluene (A x 1.1 volumes), and separate the aqueous layer from filtrates. Charge 1.1 volume of water to the toluene layer (organic phase), stir the contents for NLT 15 min, settle the layers, and separate the layers. Treat the organic layer (Toluene) w'ith activated charcoal (A x 0. 17 w / w), stir it for NLT 25 min, filter through a hyflo bed, wash the filter bed with 3.0 vol of toluene and distill the filtrates at NMT 60°C under vacuum to 1 .5 vol. Charge n-heptane (A x 2 x 3.4 volumes) to the resulting crude material and co-distill twice at below' 55°C to 1 .5 vol. Charge n-heptane (A x 8.0 volumes), warm the batch to 45-50°C and stir for 30 to 45 min. Cool the batch to 25-35°C and stir for 2 hours. Adjust the batch temperature to -5 to 0cC and stir for NLT 50 min. Filter the precipitated solid and wash the solids with pre-cooled (0 to 5°C) n-heptane (A x 1.1 volumes) and suck dry until no filtrate droplets were seen. Dry the product at 35-40°C under a vacuum while monitoring the water content (limit: NMT 0.2% w / w).

[0123] Yield: Approximately 60-70%; Purity’ >99.0%

[0124] Characterization of KTX-478:

[0125] ’H-NMR (300 MHz; MeOD) 5 7.62 (1 H, dd, J= 4.8 Hz and 7.7 Hz), 8.44 (1 H, d; J= 7.7 Hz), 8.70 (1H, d, .7= 4.8 Hz), 9.1 1 (1 H, s);, 3C-NMR (75 MHz; MeOD) 5 123.7, 127.5, 136.5, 143.3, 148.4, 150.0, 154.8. LCMS (ESI) found 197.99 (M+H) is consistent with the molecular ion form of KTX-478, [M+H] + = C7I I5CIN3SL

[0126] EXAMPLE 2

[0127] Stage 2 of KTX-001 synthesis

[0128] Process Description for the preparation of KTX -480 and KTX-481

[0129] General Procedure for Stage 2:

[0130] Charge distilled toluene (A x 7.0 volumes; 1PC for methanol in toluene NMT 100 ppm) and sodium tert-pentoxide (A x 0.802 w / w) into a reactor under a nitrogen atmosphere at 25-35°C, stir the contents for NLT 10 min. To the resulting reaction mass, add 1 -hexanol (A x 0.817 w / w) in NET 1.0 h time and stir for 90±I 0 min while maintaining the batch temperature 25-35°C. Charge KTX -478 (A x 1 .0 w / w) at 25-35°C, then raise the reaction temperature to 75 - 80°C and stir for 3-4 h while monitoring the reaction progress by HPLC. (Limit: Unreacted KTX-478 NMT 1 .0%). After the IPC complied, adjust the reaction temperature to 25-35°C, add water (A x 4.0 volumes), stir for NLT 10 mins, then separate the layers. Charge 4.0 vol of water followed by 0.05% w / w of sodium chloride to the separated organic layer and stir the mixture for NLT 15 min at 20-35°C, then separate the layers. Distill the organic layer containing KTX -480 at 50°C to 4.0 volumes of reaction mass remaining in the reactor. Adjust the reaction temperature to 20-30°C, sample for water content testing by KF (%w / v) in toluene solution containing KTX-480 (For Information Only), and charge acetone (A x 2.0 volumes) followed by the addition of methyl iodide (A x 0.876 w / w). Raise the reaction temperature gradually to 54-57°C and maintain the reaction for 14±1 h at the same temperature. Monitor the reaction progress by 1 IPLC (IPC Limit: Unreacted KTX-480 NMT 2.0%). Once the IPC complies, distill the solvent from the reaction mass at NMT 70°C atmospherically for NLT 2h (to remove unreacted Mel). Cool the resulting mass to NMT 50°C and distill the contents under vacuum to 3.0 volumes of solvent remains in the reactor. Charge 3.0 volumes of toluene and co-distill to -3.0 volumes of solvent remaining in the reactor, repeat this operation once again. Adjust the reaction temperature to 20-25°C, charge 4.5 volumes of toluene, and stir the contents for 50 min to 2 h at 20-25°C. Filter the precipitated product, wash the solids with toluene (A x 3.5), and suck dry until squeeze the mother liquor. Dry the wet Compound 5 (KTX-481) under vacuum at 45-50°C until LOD reaches NMT 1 .0%.

[0131] Yield: approximately 85-95%; Purity >98.0%

[0132] Characterization of KTX-480:

[0133] ’H-NMR (300 MHz; MeOD) 5 0.91 (3H, t, J = 6.9 Hz), 1.36- 1.41 (4H, m), 1.47-1.55 (2H, p, J= 7.0 Hz), 1.85-1.95 (2H, p, J = 6.7 Hz), 4.56 (2H, t, J = 6.5 Hz), 7.53-7.58 (1H, dd, .7= 4.9 Hz and 8.1 Hz), 8.53 (HI, dd, J= 1.9 Hz and 8.1 Hz), 8.60 (1H, dd, .7 = 1.5 Hz and 4.9 Hz), 9.29 (1 H, d, J= 2.0 Hz);,3C-NMR (75 MHz; MeOD) 8 12.9, 22.2, 25.4, 28.5, 31.2, 71.2, 123.8, 128.0, 135.2, 144.3, 147.3, 149.1, 162.7. LCMS (ESI) found 264. 12 (M+H) is consistent with the molecular ion form of KTX-480, [M+H] + = CBHJSNJOS’ .

[0134] Characterization of KTX-481:

[0135] ’H-NMR (300 MHz; MeOD) 8 0.9-0.95 (3H, t, <7 = 7.0 Hz), 1 .37-1.55 (6H, m), 1 .93-1 .98 (2H, q, J= 7.0 Hz), 4.52 (3H, s), 4.61-4.65 (2H, t, J = 6.7 Hz), 8.22 (1 H, dd, J= 6.4 Hz and 8.0 Hz), 8.97 (1H, d, .7= 6. 1 Hz), 9.24 (1 H, d, J = 8.3 Hz), 9.56 (1H, s);,3C-NMR (75 MHz; MeOD) 8 13.0, 22.2, 25.3, 28.4, 31.2, 48.4, 71.9, 127.9, 131.5, 140.4, 142.0, 143.9, 144.9, 163.1 . LCMS (ESI) found 278.13 (M-I) is consistent with the molecular ion form of KTX-481 , [M-I] = Cj4H2oN3OS!. EXAMPLE 3

[0136] Stage 3 of KTX-001 synthesis

[0137] Process Description for the preparation of Crude KTX-001 .

[0138] General Procedure for Stage 3 :

[0139] Charge methanol (A x4.6 volumes) and Compound 5 (KTX-481) (A) into a clean and dry RBF and stir the mixture for NLT 15 min for a clear solution at 25-35°C. Adjust the batch temperature to -30 to -25°C. Meanwhile, Prepare a solution of NaBFk (Lot-1 ; A x 0.1030 w / w) in aq. NaOH solution (A x 0.01 13 w / w ofNaOH in water A x 0.515 volumes) with a target pH of 8.0 to 9.0. Slowly add NaBH4 solution to the reaction mixture -31 to -24°C in NLT 1 h. Adjust the batch temperature to -6 to - I °C and stir the batch for 3-4 h while monitoring the reaction by HPLC (Report result). Adjust the batch temperature to -30 to -20°C. Meanwhile, prepare a solution of NaBIh (Lot-2; A x 0.0375 w / w) in aq. NaOH solution (A x 0.003 w / w NaOH in A x 0.155 volumes of water).

[0140] Slowly add NaBH4 lot-2 to the reaction mixture. Adjust the temperature to -5 to 0°C and stir for 1 -2 h. Monitor the reaction by HPLC (IPC limit KTX-481 : NMT 5.0%). Adjust the reaction mass pH to below 3 with HC1. Charge water (A x 7.0 volumes) at 20-35 °C and stir the contents for NLT 15 min, then charge MTBE (A x 8.0 volumes) and stir for NLT 15 min. Charge aqueous NaOH solution to adjust the pH to 8-9, stir the contents for NLT 15 min, and separate the layers. Charge 5 vol of water to the organic layer followed by sodium chloride (A x 0.05 w / w), and stir the contents for NLT 15 min. Separate the layers, charge sodium sulfate (A x 0.25 w / w) to the organic layer and filter the batch to remove sodium sulfate, wash the filter bed with 0.5 vol of MTBE. Add activated carbon (A x 0.06 w / w) to the filtrates and stir for 60-90 min. Filter through the hyflo bed and wash the filter with 1 vol of'MTBE. Distill the contents under a vacuum below 45°C up to ~1 .0 volume, charge acetone (A x 3.0 volumes), and co-distill under vacuum to 2.0 volumes. Charge acetone (A x 2.0 volumes) and co-distill under vacuum to 2.0 volumes. Cool the batch to NMT 35°C. Charge acetone (A x 2.0 volumes) followed by !_-(+)- tartaric acid (A x 0.4073 w / w; 1.1 eq.) and stir the batch at 48-52°C for 25-60 minutes under a nitrogen atmosphere. Cool the batch to 20-25°C and stir for NLT 3 h. at 20-25°C. Cool the batch to 0-5°C and stir the batch for NLT 50 min. Filter the solids and wash the cake with 1 vol of acetone. Dry the wet compound under a vacuum at NMT 60°C. Drying 1PC: Water content NMT 2.0%w / w.

[0141] Yield: approximately 65-75%; Purity >99.0%

[0142] EXAMPLE 4

[0143] Stage 4 ofKTX-001 preparation

[0144] Process Description for Stage 4, a recrystallization of crude KTX-001

[0145] General Procedure for Stage 4

[0146] Charge acetone (A x 9.0 volumes) and crude Xanomeline Tartrate into a cylindrical reactor. Adjust the batch temperature to 25-30°C and stir the batch for NLT 15 min. Warm the batch to 50±2°C, and slowly add water (~ 0.20 - 0.30 volumes) to the reaction mixture to get a clear solution. Stir the batch at 50±2°C for 25-45 min. Filter the contents of the batch through a pressure filter followed by a micron filter and collect the filtrate into a clean reactor, wash the filter with acetone (0.4 to 1 .0 volume). Warm the batch to 45-50°C and stir the batch for 30 minutes. Cool the batch gradually to 20-25°C, over 6.5 - 8.5 hours, and stir the batch for 60-90 min at 20-25°C. Filter the batch, wash with acetone (2.0 volumes), and suck-dry for 30 minutes. Unloaded the wet compound and diy it under a vacuum at NMT 60 °C. Drying IPC: water content NMT 0.5%w / w

[0147] Yield approximately 80-90%; Purity >99.0%

[0148] Characterization of KTX-001: ‘H-NMR (300 MHz; DMSO-d6) 6 0.85-0.90 (3H, t, J = 6.0 Hz), 1.29- 1.34 (4H, m), 1.39- 1 .44 (2H, m), 1.77-1.82 (2H, m), 2.47-2.49 (2H, m), 2.61 (3H, s), 2.66-2.71 (2H, t, 6.0 Hz), 3.52 (2H, s), 4.17 (2H, s), 4.42-4.46 (2H, t, .7= 6.0 Hz), 7.06 (1H, t, .7 = 3.0 Hz);13C- NMR (75 MHz; DMSO-d6) 6 13.7, 21.9, 24.1, 25.0, 28.1, 30.8, 43.6, 49.4, 52.6, 70.9, 72.0, 126.5, 128.1 , 145.5, 162.1 , 173.9. LCMS (ESI) found 282.34 (M+H) is consistent with the molecular ion form of KTX-001 , [M+H] = C14H24N3OSb.

Claims

What is claimed is:1 . A process for preparing a substantially pure compound of Formula (I):(I) (KTX-001) said process comprising the following steps:(a) reacting a compound of Formula II to provide the compound of FormulaIII:step (a) comprising:(a-1) reacting a compound of Formula II with a reagent X in the presence of a solvent Y at a temperature ranging from about 0°C to about 35°C to provide the compound of Formula Ila:(a-2) reacting a compound of Formula Ila with a reagent X!in the presence of a solvent Y at a temperature between about 0°C to about 35°C to provide the compound of Formula III;(a-3) extracting the compound of Formula III at a temperature between about 20°C to about 35°C with Methylene chloride (CH2CI2) following saturation of the reaction mixture with reagent Xl); wherein(i) said reagent X is selected from a group consisting of: ammonium chloride (NI UCl), or ammonium hydroxide (NH4OH), and mixtures thereof;(ii) said reagent X1is sodium cyanide (NaCN);(iii) said reagent X11is selected from sodium carbonate, sodium sulfate and mixtures thereof; and(i v) said solvent Y is selected from the group consisting of: purified water, methylene chloride, or an ether-based solvent, and mixtures thereof;(b) reacting the compound of Formula Ill with reagent Z in the presence of a solvent W at a temperature ranging from about 0°C to about 70°C to provide the compound of Formula (IV):III (KTX 595) I V (KTX 478) step (b) comprising:(b- 1 ) reacting reagent Z at the temperahire between about 0 °C to about 35°C with the compound of Formula Ill in the presence of DMF; and (b-2) extracting and isolating the compound of Formula IV at a temperature between about 25°C to about 30°C with solvent W: wherein:(i) said reagent Z is selected from a group consisting of: sulfur monochloride (S2 CI2), N, AMimethylformamide (DMF), or sodium hydroxide (NaOH), and mixtures thereof; and(ii) said solvent W is selected from a group consisting of: toluene, n- heptane, 2-methyl tetrahydrofuran (2-MeTl IF), purified water, or N, N -dimethylformamide (DMF), and mixtures thereof;(c) reacting the compound of Formula IV with a reagent XX at a temperature of 15°C to about 70°C in the presence of a solvent YY to provide the compound of Formula V:IV (KTX 478) V (KTX-480); wherein(i) said reagent XX is selected from a group consisting of: 1 -hexanol, Sodium / ert-pentoxide, or sodium chloride (NaCl), and mixtures thereof;(ii) said solvent YY is selected from a group consisting of: purified water, toluene, acetone, and mixtures thereof, and(d) reacting the compound of Formula V with a ZZ in the presence of a solvent WW at a temperature for reaction and isolation ranging from about 15°C to about 90°C to provide the compound of Formula VI:(i) said reagent ZZ is Methyl iodide (CHsl); and(ii) said solvent WW is selected from a group consisting of: toluene, or acetone, and mixtures thereof;(e) reacting the compound of Formula VI with reagent X2followed by reagent X3in the presence of a solvent Y’ at a temperature between about -32°C to about 70°C to provide the compound of Formula 1:VI (KTX 481 ) I (KTX 001) wherein:(i) said reagent X2is selected from a group consisting of: sodium borohydride (NaBEk), sodium hydroxide (NaOH), and methyl tertbutyl ether (MTBE), activated carbon, and mixtures thereof;(ii) said reagent X3is selected from a group consisting of: sodium borohydride (NaBEk), hydrochloric acid (HC1), and sodium chloride (NaCl), and a mixture thereof;(iii) said solvent Y’ is selected from a group consisting of: purified water, methanol (MeOH), methyl tert-butyl ether (MTBE), or acetone and a mixture thereof;(f) recrystallizing the compound of Formula 1 at a temperature between about 45°C to about 55°C with a solvent X42, wherein: said solvent X42is selected from a group consisting of: purified water or acetone, and a mixture thereof.

2. The process according to claim 1 , wherein: said reagent X is a mixture of ammonium chloride (NFhCl) and ammonium hydroxide (NlhOII), said reagent XJis sodium cyanide (NaCN), said reagent XlJis selected from sodium carbonate, sodium sulfate and mixtures thereof; and said solvent Y is purified water.

3. The process according to claim 1 , wherein the compound of formula III is stable at a temperature between about 2°C to about 8°C.

4. The process according to claim 1 , wherein the solvent W is present in the following amounts: toluene up to about 10.2 vol.; n-heptane in an amount of about 3.0 to about 15.9 vol.; purified water in an amount of about 10.2 vol. to up to about 21 .0 vol; and N, N-dimethylformamide (DMF) in an amount of about 1.15 vol to up to about 4.6 vol.

5. The process according to claim 1 wherein said reagent X ammonium chloride (NFUCl) is present in an amount of about 1.0 to about 3.0 molar equivalents.

6. The process according to claim 1 wherein said reagent XJsodium cyanide (NaCN) is present in an amount of about 0.99 to about 1.19 molar equivalents.

7. The process according to claim 1 wherein said reagent X ammonium hydroxide (NH4OH) is present in an amount of about 0.53 to about 1 .0 molar equivalents.

8. The process according to claim 1 wherein said reagent XJ !sodium carbonate (NazCOs) is present in an amount of about 0.9 to about 1.1 wt.

9. The process according to claim 1 wherein said reagent XHsodium sulfate (Na2SO4) is present in an amount of about 0.5 to about 1.5 wt.

10. The process according to claim 1 wherein said reagent Z sulfur monochloride is present in an amount of about 1 .63 to about 2.73 molar equivalents.1 1. The process according to claim 1, wherein said reagent Z sodium hydroxide (NaOl l) is present in an amount of about 0.75 molar equivalents to maintain a pH between 9 and 14.

12. The process according to claim 1 , wherein the reagent XX sodium ZerZ-pentoxide is present in an amount of about 1 .40 to 1.49 about molar equivalents.

13. The process according to claim 1 wherein said reagent ZZ methyl iodide (CH3I) is present in an amount of about 1.10 to about 1 .50 molar equivalents.

14. The process according to claim 1 wherein said reagent XX 1 -hexanol is present in an amount of about 1.55 to about 1 .80 molar equivalents.

15. The process according to claim 1 wherein said solvent Ylmethanol (MeOH) is present in an amount of about 4.0 to about 6.0 vol.

16. The process according to claim 1 wherein said solvent Y1purified water is present in an amount of about 13 vol.

17. The process according to claim I wherein said reagent X2sodium hydroxide (NaOH) is present in an amount from about 0.10 to about 1.04 molar equivalents).

18. The process according to claim 1 wherein said reagent X2is reacted with the compound of VI in as stepwise approach according to the following amounts (i) of about 0.88 to about 1 .12 eq.; (ii) about 0.29 to about 0.41 eq.

19. The process according to claim 1 wherein said solvent Y1methyl Zert-butyl ether (MTBE) in an amount of about 7.0 to about 12 vol.

20. The process according to claim 1 wherein said reagent X3hydrochloric acid (HC1) is present in an amount enough to maintain a pH between 0.6 and 3.21 . The process according to claim 1 wherein said reagent X3sodium chloride (NaCl) is present in an amount of about 0.03 to about 0.10 wt / wt.

22. The process according to claim 1 wherein the yield of the compound of formula VI is at least 85% of compound of Formula IV.

23. The process according to claim 1 , wherein the compound of Formula 1 has a purity greater than about 99%.

24. The process according to claim 1 , wherein the compound of Formula TV has a purity greater than about 99%; and yield of at least 60% from compound of Formula II.

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