Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
  • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
  • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C313/00—Sulfinic acids; Sulfenic acids; Halides, esters or anhydrides thereof; Amides of sulfinic or sulfenic acids, i.e. compounds having singly-bound oxygen atoms of sulfinic or sulfenic groups replaced by nitrogen atoms, not being part of nitro or nitroso groups
  • C07C313/02—Sulfinic acids; Derivatives thereof
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
  • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
  • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
  • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
  • C07D211/10—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms
  • C07D211/14—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with radicals containing only carbon and hydrogen atoms attached to ring carbon atoms with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
  • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
  • C07D221/20—Spiro-condensed ring systems
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
  • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
  • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
  • C07F3/00—Compounds containing elements of Groups 2 or 12 of the Periodic Table
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
  • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
  • C07B2200/13—Crystalline forms, e.g. polymorphs
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
  • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
  • Y02P20/00—Technologies relating to chemical industry
  • Y02P20/50—Improvements relating to the production of bulk chemicals
  • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

• the present invention relates to an improved, efficient, scalable process to prepare a KIF18A inhibitor compound, namely N-(2-(4,4-difluoropiperidin-l-yl)-6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 1), or a pharmaceutically acceptable salt thereof, which is performed in batch process, continuous process, or mixture thereof.
• the present invention also relates to preparation of key intermediate compounds useful for preparing the Compound 1 or a pharmaceutically acceptable salt thereof.
• the present invention further relates to solid form of Compound 6a, preferably the crystalline hydrate form of Compound 6a (Compound 6a-I).
• Kinesins are molecular motors that play important roles in cell division and intracellular vesicles and organelle transport. Mitotic kinesin plays roles in several aspects of spindle assembly, chromosome segregation, centrosome separation, and dynamics. Human kinesins are categorized into 14 subfamilies based on sequence homology within the so-called “motor domain”; this domain’s ATPase activity drives unidirectional movement along microtubules (MT). The nonmotor domain of these proteins is responsible for cargo attachment; a “cargo” can include any one of a variety of different membranous organelles, signal transduction scaffolding systems, and chromosomes. Kinesins use the energy of ATP hydrolysis to move cargo along polarized microtubules. Thus, kinesins are often called “plus-end” or “minus-end” directed motors.
• KIF18A gene belongs to the Kinesin-8 subfamily and is a plus-end-directed motor. KIF18A is believed to influence dynamics at the plus end of kinetochore microtubules to control correct chromosome positioning and spindle tension. Depletion of human KIF18A leads to longer spindles, increased chromosome oscillation at metaphase, and activation of the mitotic spindle assembly checkpoint in HeLa cervical cancer cells. KIF18A appears to be a viable target for the treatment of cancer. KIF18A is overexpressed in various types of cancers, including but not limited to colon, breast, lung, pancreas, prostate, bladder, head, neck, cervix, and ovarian cancers.
• KIF18A affects mitotic spindle apparatus in cancer cell lines. Particularly, inhibition of KIF18A has been found to induce mitotic cell arrest, a known vulnerability that can promote cell death in mitosis via apoptosis, mitotic catastrophe, or multipolarity driven lethality or death after mitotic slippage in interphase.
• U.S. Patent No. 11/236,069 disclosed a method of preparing Compound 1, which relied on the introduction of key intermediate compounds in the penultimate step. It was found that the disclosed process involved a key intermediate compound that had undesirable physical properties (hygroscopicity), and had an unpredictive impurity control strategy requiring multiple recrystallizations of the key intermediate compounds. To overcome the commercial risks identified with the disclosed method, the present inventors developed the present novel improved method to prepare Compound 1, or a pharmaceutically acceptable salt thereof, preferably HC1 salt thereof, that would improve the impurity control strategy, improve convergency, scalability, and leverage key intermediate compounds with improved stability.
• Key intermediate compounds of the present invention that may be used in the synthesis of Compound 1 or a pharmaceutically acceptable salt thereof are Compound 2a, Compound 3a, Compound 5 or a salt thereof, and Compound 6a, of the formulae: preferably the hydrate of Compound 6a: (Compound 6a-I).
• the novel key intermediate compounds are named: [0008] (1) 4-((2-(benzyloxy)ethyl)sulfonamido)-N-(2-(4,4-difluoropiperidin-l-yl)-6- methylpyrimidin-4-yl)-2-(6-azaspiro[2.5]octan-6-yl)benzamide (Compound 2a);
• the present invention further relates to solid form of Compound 6a, preferably the crystalline hydrate form of Compound 6a (Compound 6a-I).
• the invention provides a new method for preparing a KIF18A inhibitor having the following chemical structure: p ; y y p g group selected from Chalky I. Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; with a suitable deprotection agent in a suitable solvent to form said Compound 1.
• the invention provides the method of aspect 1 further comprising preparing said Compound 2, comprising: reacting a Compound 3, having the formula: (Compound 3), or a salt thereof; wherein PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; with a Compound 4, having the formula (Compound 4), or a salt thereof; in the presence of an amide coupling reagent and a base in an organic solvent, to form said Compound 2.
• PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyr
• the invention provides the method of aspect 2, further comprising preparing said Compound 3, or a salt thereof, comprising: reacting a Compound 5, having the formula: (Compound 5), or a salt thereof; with a Compound 6, having the formula (Compound 6); wherein PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; M is metal, including an alkali, alkaline earth metal, or transition metal, preferably sodium, calcium, or zinc metal, more preferably calcium; and n is an integer selected from 1 or 2, preferably 2; or a hydrate thereof; and a base optionally in the presence of a catalyst in an organic solvent at elevated temperature to form said Compound 3, or a salt thereof.
• PG is a hydroxyl protecting group
• the invention provides the method of aspect 2, further comprising preparing said Compound 4, comprising: reacting a Compound 9, having the formula:
• the invention provides a compound, which is Compound 2; wherein
• PG is benzyl having the structure (Compound 2a).
• the invention provides a compound, which is Compound 3; wherein
• PG is benzyl, having the structure: (Compound 3a).
• the invention provides a compound, which
• the invention provides the method of aspect 3, further comprising preparing said Compound 6 having the following chemical structure: ; wherein PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; M is metal, including an alkali, alkaline earth metal, or transition metal, preferably sodium, calcium, or zinc metal, more preferably calcium; and n is an integer selected from 1 or 2, preferably 2; or a hydrate thereof; comprising reacting a Compound 11 having the structure
• Compound 11 wherein PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O- Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; with a base in a polar solvent at a moderately elevated temperature to form said Compound 6; or preferably a hydrate thereof, most preferably (Compound 6a-I).
• PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O- Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; with a base in a polar solvent at a moderately elevated temperature to form said Compound 6; or preferably
• the invention provides the method of aspect 9, further comprising preparing said Compound 11 by reacting a Compound 12 having the following chemical structure:
• OPG (Compound 12); wherein PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-ealkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; with an oxidizing agent; in the presence of a catalyst, in a solvent and a slightly elevated temperature to form said Compound 11.
• PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-ealkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; with an oxidizing agent; in the presence of a catalyst, in a solvent and a slightly elevated temperature to form said Compound 11.
• the invention provides the method of aspect 10, further comprising preparing said Compound 12 by reacting a Compound 13 having the following chemical structure: a s
• the invention provides the method of aspect 1, wherein PG is a benzyl and said suitable deprotection agent is palladium on carbon catalyst.
• the invention provides the method of aspect 1, wherein said solvent is a polar solvent.
• the invention provides the method of aspect 13, wherein said solvent is acetone and water mixture.
• the invention provides the method of aspect 2, wherein said amide coupling reagent is selected from a chloroformamidinium salt, 2-chloro-l,3-dimethylimidazolinium chloride (DMC), l-(chloro-l- pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyCIU), 2- chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), or N-Ethoxycarbonyl-2-ethoxy-l,2-dihydroquinoline (EEDQ).
• a chloroformamidinium salt 2-chloro-l,3-dimethylimidazolinium chloride (DMC), l-(chloro-l- pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate (PyCIU), 2- chloro-4,6-dimethoxy-l,3,5-triazine (CDMT), or N-Ethoxycarbon
• the invention provides the method of aspect 2, wherein said base is selected from N-methylmorpholine (NMM), N,N-Diisopropylethylamine (DIPEA), triethylamine (TEA), 2,4,6-trimethylpyridine (collidine), or 2,6-lutidine.
• NMM N-methylmorpholine
• DIPEA N,N-Diisopropylethylamine
• TAA triethylamine
• 2,4,6-trimethylpyridine collidine
• 2,6-lutidine 2,6-lutidine.
• the invention provides the method of aspect 2, wherein said chloroformamidinium salt is chloro-N.N.N'.N'-tctramcthylformamidinium hexafluorophosphate (TCFH) and said base is 2,4,6-trimethylpyridine (collidine).
• said chloroformamidinium salt is chloro-N.N.N'.N'-tctramcthylformamidinium hexafluorophosphate (TCFH) and said base is 2,4,6-trimethylpyridine (collidine).
• the invention provides the method of aspect 2, wherein said method is conducted at a temperature from 25°C to 50°C, preferably 40°C to 50°C, more preferably 50°C.
• the invention provides the method of aspect 2, wherein said solvent is organic solvent selected from 2-methyl THF, acetonitrile, isopropyl acetate, dichloromethane, THF, DMF, NMP, methylene chloride, or mixture thereof; preferably 2-methyl THF and acetonitrile.
• organic solvent selected from 2-methyl THF, acetonitrile, isopropyl acetate, dichloromethane, THF, DMF, NMP, methylene chloride, or mixture thereof; preferably 2-methyl THF and acetonitrile.
• the invention provides the method of aspect 3, wherein said method is performed catalyst free or in the presence of a metal catalyst selected from iron, gold, or palladium catalyst.
• the invention provides the method of aspect 20, wherein said method is performed in the presence of a metal catalyst, wherein said catalyst is iron(III) chloride hexahydrate.
• the invention provides the method of aspect 3, wherein said base is sodium bisulfite.
• the invention provides the method of aspect 3, wherein said elevated temperature is at solvent reflux temperature or from 60°C to 100°C; preferably 70°C to 90°C; more preferably 70°C.
• the invention provides the method of aspect 3, wherein said solvent is NMP.
• the invention provides the method of aspect 4, wherein said base is hydroxide or amine, preferably hydroxide.
• the invention provides the method of aspect 25, wherein said base is potassium hydroxide or diisopropyl ethyl amine; preferably potassium hydroxide.
• the invention provides the method of aspect 4, wherein said solvent is polar aprotic solvent selected from NMP, DMAC, DMF, or DMSO; preferably NMP.
• the invention provides the method of aspect 4, wherein said elevated temperature is at solvent reflux temperature or from 80°C to 140°C; preferably 100°C to 140°C C; more preferably 120°C.
• the invention provides the method of aspect 4, wherein said compound 5 is crystallized by addition of an acid.
• the invention provides the method of aspect 29, wherein said acid is phosphoric acid.
• the invention provides the method of aspect 5, wherein said base is amine or hydroxide, preferably amine.
• the invention provides the method of aspect 31, wherein said base is triethyl amine.
• the invention provides the method of aspect 5, wherein said elevated temperature is at solvent reflux temperature or from 60°C to 100°C; preferably 60°C to 85°C C; more preferably 80°C.
• the invention provides the method of aspect 5, wherein said solvent is acetonitrile and water mixture.
• the invention provides the method of aspect 9, wherein said base is hydroxide, preferably calcium hydroxide, sodium hydroxide; more preferably calcium hydroxide.
• the invention provides the method of aspect 9, wherein said solvent is a mixture of C i-ealkyl alcohol and water, preferably methanol and water.
• the invention provides the method of aspect 9, wherein said Compound 6 is crystallized in mixture of methanol/ethanol/water to form a hydrate Compound 6a-I o ii o ii
• the invention provides the method of aspect 9, wherein said temperature is from 25°C to 50°C; from 40°C to 50°C; preferably 50°C.
• the invention provides the method of aspect 10, wherein said oxidizing agent is peroxide or peroxycarboxylic acid; preferably hydrogen peroxide or meta peroxycarboxylic acid (mCPBA); more preferably hydrogen peroxide.
• said oxidizing agent is peroxide or peroxycarboxylic acid; preferably hydrogen peroxide or meta peroxycarboxylic acid (mCPBA); more preferably hydrogen peroxide.
• the invention provides the method of aspect 10, wherein said catalyst is sodium tungstate.
• the invention provides the method of aspect 10, wherein said temperature is from 25°C to 40°C; preferably 30°C to 35°C C; more preferably 30°C.
• the invention provides the method of aspect 10, wherein said solvent is acetonitrile and water mixture.
• the invention provides the method of aspect 10, wherein said Compound 12 is crystallized in acetone or mixture of acetone and water.
• the invention provides the method of aspect 10, wherein said Compound 12 is not isolated and said solvent is acetonitrile.
• the invention provides the method of aspect 11, wherein said [0059] base is bicarbonate, carbonate, hydroxide, or phosphate; preferably potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide; more preferably potassium carbonate.
• the invention provides the method of aspect 11, wherein said base is calcium carbonate.
• the invention provides the method of aspect 11, wherein said solvent is alcohol, preferably methanol.
• the invention provides the method of aspect 11, wherein said temperature is at solvent reflux temperature or from 70°C to 100°C; preferably 75°C to 90°C C; more preferably 82°C.
• the invention provides the method of any one of aspects 1-5 or 9- 48, further comprising reacting said Compound 1 with an acid HA in a solvent to form a pharmaceutically acceptable salt of Compound 1 having a formula (Compound la).
• the invention provides the method of aspect 49, wherein said acid HX is HC1, methanesulfonic acid, or para toluenesulfonic acid.
• the invention provides the method of aspect 49, wherein said acid HX is HC1 in DMSO.
• the invention provides the method of aspect 49, wherein said solvent is water.
• the invention provides the method of any one of aspects 1-5 or 9- 52, wherein said PG is benzyl.
• the invention provides a compound 6 having a chemical structure:
• PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl; M is a metal, including monovalent metal, divalent metal, or trivalent metal; preferably M is monovalent metal or divalent metal; more preferably M is Na, Ca, or Zn; most preferably M is Ca; and n is an integer selected from 1, 2, or 3; preferably n is 1 or 2; more preferably n is 2; or a solid form thereof.
• the invention provides the compound of aspect 54, wherein PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-
• the invention provides the solid form of said Compound 6a according to aspect 55, which is crystalline or amorphous.
• the invention provides the solid form of said Compound 6a according to aspect 55, which is a Compound 6a hydrate having the formula (Compound 6a-I); wherein said compound contains 4/3 water molecules, which is crystalline.
• the invention provides the solid form of said Compound 6a according to aspect 55, which is the crystalline Form 1 of said Compound 6a hydrate (Compound 6a- I), further characterized by XRPD pattern peaks at 4.2, 8.2, and 12.2 ⁇ 0.2° 20 using Cu Ka radiation.
• the invention provides the solid form of said Compound 6a according to aspect 58, which is the crystalline Form 1 of said Compound 6a-I of aspect 58, further characterized by XRPD pattern peaks at 13.6, 14.2, 18.3, 19.5, 20.6, 20.9, and 22.9 ⁇ 0.2° 20 using Cu Ka radiation.
• the invention provides the solid form of said Compound 6a according to aspect 59, which is the crystalline Compound 6a-I of aspect 59, further characterized by XRPD pattern peaks at 16.2, 16.7,19.2, 21.4, 23.9, 24.4, 24.7, 25.5, 27.6, 28.1, 30.3, 33.3, and 36.6 ⁇ 0.2° 20 using Cu Ka radiation.
• the invention provides the solid form of said Compound 6a according to aspect 60, which is the crystalline Compound 6a-I having an XRPD pattern substantially as shown in Figure 1.
• the invention provides the solid form of said Compound 6a according to aspect 58, which is the crystalline Compound 6a-I having a first endothermic transition at 124.96°C to 130.96°C; and a second endothermic transition at 256.11°C to 262.11°C; as measured by Differential Scanning Calorimetry substantially as shown in Figure 2.
• the invention provides the solid form of said Compound 6a according to aspect 58, which is the crystalline Compound 6a-I wherein the first endothermic transition is at 127.96 °C ⁇ 3°C; and the second endothermic transition is at 259.11 °C ⁇ 3°C.
• the invention provides the solid form of said Compound 6a according to aspect 58, which is the crystalline Compound 6a-I having a Thermogravimetric Analysis (TGA) substantially as shown in Figure 3.
• TGA Thermogravimetric Analysis
• the invention provides the solid form of said Compound 6a according to aspect 58, which crystalline form is stable and low in hygroscopicity.
• the solid form stability can be identified by no change in crystalline forms and substantially identical XRPD peaks shown in the XRPD peaks of the crystalline sample pre DVS and post DVS.
• the low in hygroscopicity feature of the crystalline sample can be shown by measuring the mass of the sample at the beginning and at the end of the DVS experiment, wherein the mass change is calculated to be between 0.10% to 0.20%; preferably 0.15%.
• the invention provides the solid form of said Compound 6a according to aspect 58, which is the crystalline Compound 6a-I having a single crystal structure substantially as shown in Figure 4.
• FIG. 1 depicts an X-ray powder diffraction (“XRPD”) pattern of (1) the crystalline Compound 6a-I pre and post humidity stress measured on Dynamic Vapor Sorption (DVS); and (2) simulated XRPD pattern from Compound 6a-I single crystal structure.
• XRPD X-ray powder diffraction
• FIG. 2 depicts a Differential Scanning Calorimetry (DSC) thermograph of the crystalline Compound 6a-I.
• FIG. 3 depicts a Thermogravimetric analysis (TGA) of the crystalline Compound 6a-I.
• FIG. 4 depicts a single crystal structure of the crystalline Compound 6a-I.
• C x-y alkyl refers to substituted or unsubstituted saturated hydrocarbon groups, including straight-chain alkyl and branched-chain alkyl groups that contain from x to y carbons in the chain.
• haloalkyl refers to alkyl groups in which at least one hydrogen atom is replace by a halo (e.g., fluoro, chloro, bromo, iodo), e.g., CH 2 F, CHF 2 , trifluoromethyl and 2,2,2-trifluoroethyl.
• a halo e.g., fluoro, chloro, bromo, iodo
• pharmaceutically acceptable salt refers to the relatively non-toxic, inorganic and organic acid addition salts of the compound 5 of the invention.
• the nature of the salt is not critical, provided that it is pharmaceutically -acceptable.
• These salts can be prepared in situ during the final isolation and purification of the compound(s), or by separately reacting a purified compound in its free base form with a suitable organic or inorganic acid, and isolating the salt thus formed.
• Suitable pharmaceutically-acceptable acid addition salts of the compound may be prepared from an inorganic acid or from an organic acid. Examples of such inorganic acids include, without limitation, hydrochloric, hydrobromic, hydroiodic, nitric, carbonic, sulfuric and phosphoric acid.
• organic acids include, without limitation, aliphatic, cycloaliphatic, aromatic, arylaliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are formic, acetic, adipic, butyric, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic, fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic, 4-hydroxybenzoic, phenylacetic, mandelic, embonic (pamoic), methanesulfonic, ethane sulfonic, ethanedisulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluene sulfonic, sulfanilic, cyclohexylaminosulfonic, camphoric, camphors,
• hydroxyl protecting group means a protecting group suitable for preventing undesirable reactions at a hydroxyl group.
• Representative hydroxyl protecting groups include, but are not limited to, silyl groups including tri(Ci-salkyl)silyl groups, such as trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl (TBS) and the like; esters (acyl groups) including Ci-salkanoyl groups, such as formyl, acetyl and the like; arylmethyl groups, such as benzyl (Bn), p- methoxybenzyl (PMB), 9-fluorenylmethyl (Fm), diphenylmethyl (benzhydryl, DPM) and the like. Numerous protecting groups, and their introduction and removal, are described in T. W. Greene and P. G. M. Wuts, Protecting Groups in Organic Synthesis, Third Edition, Wiley, New York.
• metal refers to “monovalent metal”, “divalent metal”, or “ trivalent metal”.
• the term “monovalent metal” refers to a metal which is part of an ionic bond wherein said metal forms an ion having a charge of +1 .
• monovalent metals are the metals ( thus not including hydrogen ) of Group 1 of the IUPAC periodic table.
• Preferred monovalent metals are Na, K, and Li.
• divalent metal refers to a metal which is part of an ionic bond wherein said metal forms an ion having a charge of +2 .
• divalent metals are the metals of Group 2 of the IUPAC periodic table.
• Preferred divalent metals are Mg, Zn, or Ca.
• trivalent metal refers to a metal which is part of an ionic bond wherein said metal forms an ion having a charge of +3 .
• examples of trivalent metals are Al and Fe.
• solvent includes “aqueous solvent” or “organic solvent”.
• aqueous solvent means solvent containing water.
• organic solvent refers to an organic molecule capable of dissolving another substance (i.e., the solute).
• Organic solvents may be liquids at room temperature.
• examples of organic solvents that may be used for the present invention include, but are not limited to: hydrocarbon solvents (e.g., n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane, decahydronaphthalene, etc.) which also includes aromatic hydrocarbon solvents (e.g., benzene, toluene, o-xylene, m-xylene, and p-xylene), halogenated hydrocarbon solvents (e.g., carbon tetrachloride, 1,2- dichloroethane, dichloromethane, chloroform, etc.), ester solvents (e.g., ethyl formate,
• polar solvent means a solvent having a dielectric constant of at least 3, said dielectric constant being the ratio of the electrical capacity of a capacitor fdled with the solvent to the electrical capacity of the evacuated capacitor at 20°C to 25°C.
• dielectric constant of solvents are disclosed in Vogel's Textbook of Practical Organic Chemistry 5th Edition, Appendix 5.
• polar solvents examples include dichloromethane, tetrahydrofuran, ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2-butanone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), amine solvents (e.g., propyl amine, diethylamine, triethylamine, aniline, pyridine), alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 1 -butanol, 1 -octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acid solvents (e.g.,
• alcohol refers to a hydrocarbon derivative in which one or more hydrogen atoms have been replaced by an -OH group, known as hydroxyl group.
• Suitable alcohols for the present invention include linear, cyclic or branched Ci-salkyl alcohols and any mixtures thereof. It also includes commercially available alcohols. Examples of alcohols are methanol, ethanol, isopropanol, 1-propanol, 1-butanol, 1-pentanol, 3-methyl-l-butanol, tert-butanol, 1-octanol, benzyl alcohol and phenol.
• benzyl refers to a substituent group having the structure CsH 5 CH2-.
• the term “reflux” refers to the temperature at which the reaction mixture boils, depending on the solvent being used in the reaction. For example, when water is used as a solvent, the reflux temperature is up to 100° C.
• oxidizing agent refers to a substance that can oxidize other substances, as electrons acceptor.
• Common oxidizing agents include oxygen (O 2 ); ozone (O3); Hydrogen peroxide (H2O2), including other inorganic peroxides or Fenton's reagent; Organic peroxides, such as peroxycarboxylic acid having the formula RCO3H, wherein R is an alkyl or aryl group, including peracetic acid or meta-Chloroperoxybenzoic acid (mCPBA); Fluorine (F 2 ), chlorine (Cl 2 ), or other halogens; Nitric acid (HNO3) or nitrate compounds; Sulfuric acid (H2SO4); Peroxydisulfuric acid (H2S2O8); Peroxymonosulfuric acid (H2SO5); Hypochlorite, Chlorite, chlorate, perchlorate, or other analogous halogen compounds, including household bleach (na
• substituted refers to moieties having substituents replacing a hydrogen on one or more non-hydrogen atoms of the molecule.
• substitution or “substituted with” includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc.
• substituted is contemplated to include all permissible substituents of organic compounds.
• the permissible substituents include acyclic and cyclic, branched and unbranched, carbocyclic and heterocyclic, aromatic and non-aromatic substituents of organic compounds.
• the permissible substituents can be one or more and the same or different for appropriate organic compounds.
• the heteroatoms such as nitrogen may have hydrogen substituents and/or any permissible substituents of organic compounds described herein which satisfy the valences of the heteroatoms.
• Substituents can include, for example, a halogen, a hydroxyl, a carbonyl (such as a carboxyl, an alkoxycarbonyl, a formyl, or an acyl), a thiocarbonyl (such as a thioester, a thioacetate, or a thioformate), an alkoxyl, a phosphoryl, a phosphate, a phosphonate, a phosphinate, an amino, an amido, an amidine, an imine, a cyano, a nitro, an azido, a sulfhydryl, an alkylthio, a sulfate, a sulfonate, a sulfamoyl, a sulfonamido, a sulfonyl, a heterocyclyl, an aralkyl, or an aromatic or heteroaromatic moiety. It will be understood by
• continuous process refers to a manufacturing process which uses one or more reagent or product stream(s) that flow continuously from one unit operation to the next, with all operations occurring simultaneously while the system is at steady state.
• batch process or “batch” refers to a manufacturing process in which a given unit operation must be run to completion prior to the start of the next unit operation. Usually, the product of the prior unit operation is isolated or purified before it is used as a starting material in the next unit operation.
• DSC Differential scanning calorimetry
• a tau lag adjustment is performed with indium, tin, and zinc.
• the temperature and enthalpy are adjusted with octane, phenyl salicylate, indium, tin and zinc.
• the adjustment is then verified with octane, phenyl salicylate, indium, tin, and zinc.
• the sample was placed into a hermetically sealed aluminum DSC pan, and the weight was accurately recorded.
• the pan lid was pierced by the instrument and then inserted into the DSC cell for analysis.
• a weighed aluminum pan configured as the sample pan was placed on the reference side of the cell.
• DSC Differential scanning calorimetry
• TGA Thermal gravimetric analysis
• Solution proton NMR spectra were acquired by Spectral Data Services of Champaign (SSCI), IL at 25 °C with a Varian UNITY/A01M-400 spectrometer. Unless specified otherwise, samples were dissolved in DMSO-c/6. In some cases, the solution NMR spectra were also acquired at SSCI with an Agilent DD2-400 spectrometer using deuterated DMSO or methanol.
• the present inventors have developed the present novel improved method of preparation of Compound 1 and a pharmaceutically acceptable salt thereof, preferably the HC1 salt thereof (Compound la), from five key starting material/intermediate compounds: Compound 6, Compound 7, Compound 8, Compound 9, and Compound 10.
• the present novel route of synthesis for Compound 1 and a pharmaceutically acceptable salt of Compound 1 employs a late stage amide coupling strategy.
• the present method leverages the innate reactivity of 2-fluoro-4-nitrobenzoic acid (Compound 8, or a salt thereof) through sequential C-N and S-N bond formations to provide the hydroxy protected, preferably benzyl ether protected, Compound 2, which undergoes deprotection to form the free base Compound 1.
• Subsequent reaction of Compound 1 with acid HA in a salt formation affords a pharmaceutically acceptable salt of Compound 1.
• LG 4 -SH Compound 14 LG 4 -S-CH 2 CH 2 -OPG catalyst
• Scheme A depicts Steps 1-3 to prepare Compound 6 of the present invention.
• Compound 6 is a novel calcium sulfinate (sulfinic acid) salt compound and Scheme A describes a new, robust route to prepare calcium sulfinate salts.
• Literature routes to prepare sulfinate salts for example: (a) Liang et. al., “Recent Advances in the Synthesis and Direct Application of Sulfinate Salts”, Em. J. Org. Chem. 2020, 4664 -4676; (b) Gianatassio et. al., “Simple Sulfinate Synthesis Enables C-H Trifluoromethyl- cyclopropanation”, Angew. Chem. Int. Ed.
• Scheme B Current literature methods to prepare sulfinate salts RSO2M; wherein R is an organic functional group; Each Het and Ar is as defined above; and M is metal.
• R is an organic functional group
• M is metal.
• the sodium sulfinate product can be highly hygroscopic or can be found to have non-ideal physical properties.
• the present methods presented herein produce metal sulfinate salts, such as zinc, sodium, and calcium sulfinate salts, having improved physical properties and stability.
• Step 1 Compound 13, having the formula LG4-SH, wherein LG4 is an organic leaving group, preferably unsubstituted benzothiazolyl, is reacted with Compound 14, having the formula PG-O-CH2CH2-LG3, in the presence of a base in a solvent, to form a Compound 12, having the a s
• said Compound 14 has the formula u ; wherein PG is a hydroxyl protecting group selected from Chalky I. Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl.
• LG3 is a leaving group; preferably LG3 is a halo, more preferably fluoro, chloro, or bromo, more preferably bromo.
• said Compound 12 has the formula ; wherein PG is a hydroxyl protecting group selected from Ci-ealkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl.
• said base is bicarbonate, carbonate, hydroxide, or phosphate; preferably potassium carbonate, sodium carbonate, sodium hydroxide, or potassium hydroxide; more preferably potassium carbonate or calcium carbonate; more preferably potassium carbonate.
• said solvent is alcohol, more preferably methanol.
• said reaction is conducted at temperature at solvent reflux temperature or from 70°C to 100°C; preferably 75°C to 90°C C; more preferably 82°C.
• Step 1 is performed in the presence of potassium carbonate base to generate a stable stream of said Compound 12 in acetonitrile.
• Step 2 Compound 12, as defined above, is reacted with an oxidizing agent; in the presence of a catalyst, in a solvent and a slightly elevated temperature to form a Compound 11.
• PG is a hydroxyl protecting group selected from Ci-salkyl, Ci-salkyl-O-Ci-salkyl, tetrahydropyranyl, allyl, or benzyl; preferably methyl-O-methyl, tetrahydropyranyl, or benzyl; more preferably benzyl.
• said oxidizing agent is peroxide or peroxycarboxylic acid; preferably hydrogen peroxide or meta peroxy carboxy lie acid; more preferably hydrogen peroxide.
• Example of said catalyst is sodium tungstate.
• said reaction is conducted at temperature from 25°C to 40°C; preferably 30°C to 35°C C; more preferably 30°C.
• said solvent is acetonitrile and water mixture.
• said Compound 12 is crystallized as crystalline solid in acetone or mixture of acetone and water.
• Step 2 said Compound 12 was not isolated from Step 1 and said solvent is acetonitrile. Subsequent oxidation of said Compound 12 was performed with sodium tungstate as a catalyst and hydrogen peroxide as the stoichiometric oxidant.
• Step 2 was a batch reaction process and faced a safety issue in using H2O2, which required proper safety control.
• the present inventors developed a continuous process during scale up. There were two major challenges during the initial continuous process development, one was the poor solubility of Compound 12, and the other was the slow conversion rate of the oxidation reaction of Compound 12.
• the present inventors further screened the combined solvents volume in the continuous process and successfully used the continuous process for scale up production which improved the efficiency and safety of Step 2 production.
• H2O2 was adjusted to 30% w/w, 3.0eq, pH range was maintained at 3-4, H2O2 addition was optimized to 3-4 parts, 33% NaHSCh solution was taken as quenching solvent.
• Step 3 Compound 11, as defined above, is reacted with a base in a polar solvent at a moderately elevated temperature to form said (Compound 6); wherein PG is benzyl, M is calcium, and n is 2.
• Compound 6 has the structure (Compound 6a-I).
• said base is hydroxide, preferably calcium hydroxide, sodium hydroxide; more preferably calcium hydroxide.
• said solvent is a mixture of Ci-salkyl alcohol and water, preferably methanol and water; or methanol.
• Compound 6 product is crystallized, preferably Compound 6 is crystallized in mixture of methanol/ethanol/water to form Compound 6a-I.
• said reaction is conducted at temperature from 25°C to 50°C; from 40°C to 50°C; preferably 50°C.
• cleavage of the benzothiazole leaving group was accomplished employing calcium hydroxide in aqueous methanol generating the calcium sulfinate Compound 6, which was isolated via crystallization with acetone as a crystalline hydrate form. Water was found to be critical due to its ability to accelerate mass transfer of calcium hydroxide and presence in the lattice of the crystal structure of said Compound 6a.
• the crystallized product of Compound 6a is a crystalline hydrate compound that contains about 1 water molecule, more specifically and preferably 4/3 water molecules or about 1.33 water molecules (Compound 6a-I).
• Scheme B depicts Step 4 to Step 5 of the present invention.
• the present method leverages a base-mediated aromatic substitution reaction of Compound 7 and Compound 8 to generate a key intermediate Compound 5.
• the synthesis of Compound 5 is an aromatic substitution (SNAr) reaction, which is preferably performed by treatment of Compound 8; wherein LGi is a leaving group, preferably halo, more preferably chloro or fluoro, most preferably fluoro; and Compound 7, wherein Xi is a halide, preferably chloride or bromide, more preferably chloride, in NMP with KOH at elevated reaction conditions.
• SNAr reaction proceeds with high conversion with the desired product is directly isolated following pH adjustment with aqueous phosphoric acid and precipitation with water to afford the Compound 5 product as a crystalline solid.
• Step 5 subsequent nitroarene/sulfinate coupling of Compound 5 and Compound 6; or hydrate thereof (Compound 6a-I); leads to the formation of Compound 3 as a key intermediate compound.
• the synthesis of Compound 3 is preferably performed by an iron-catalyzed coupling of Compound 5 and Compound 6 or hydrate thereof (Compound 6a-I) in NMP with sodium bisulfite as the stoichiometric reductant.
• the nitroarene/sulfinate coupling reaction proceeds with high conversion and good chemo-selectivity for the desired sulfonamide product.
• the product is preferably isolated following aqueous work-up to purge inorganic impurities.
• the product is preferably solvent swapped into THF and crystallized from an MTBE anti-solvent crystallization affording Compound 3 product as a crystalline solid.
• Scheme C depicts Step 6 of the present invention.
• Compound 4 is synthesized through an acid-mediated aromatic substitution reaction of Compound 9 and Compound 10.
• the synthesis of Compound 4 has been improved from the previously disclosed synthesis of Compound 4 in the U.S. Patent No. 11/236,069.
• the Compound 4 product is generated under an acid-catalyzed SNAr reaction of Compound 9 and Compound 10, wherein X 2 is chloride, in a tert butyl alcohoktoluene solvent mixture at elevated reaction conditions.
• the SNAr reaction proceeds with high conversion and the desired product is isolated following salt break with aqueous NaOH and crystallization from a toluene/n-heptane solvent system to afford the product as a crystalline solid.
• Scheme D depicts Steps 7-8 of the present invention to prepare Compound 1 in free base form.
• Step 7 the late stage fragment coupling of Compound 3 and Compound 4 under amide-coupling conditions generates the penultimate intermediate Compound 2 as a crystalline intermediate.
• the synthesis of Compound 2 is preferably performed by the chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate (TCFH) mediated amide-coupling of Compound 3 and Compound 4 in 2-methyl THF, acetonitrile, isopropyl acetate, dichloromethane, THF, NMP, or mixture thereof; preferably 2- methyl THF and acetonitrile, in the presence of a base, preferably 2,4,6-trimethylpyridine (collidine), at elevated reaction conditions.
• THFH chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate
• Step 8 Pd-catalyzed hydrogenation of Compound 2 to remove the benzyl ether protecting group leads to the generation of Compound 1 as a crystalline free base compound.
• the synthesis of Compound is performed by hydrogenation of Compound 2 in the presence of Pd/C as a heterogenous catalyst in acetic acid/water mixture . The hydrogenation proceeded with high conversion and product isolation was accomplished following filtration of the catalyst and anti-solvent addition of 1 -propanol to afford the Compound 1 product as a crystalline solid.
• Scheme E depicts Step 9 of the present invention.
• salt formation is performed through treatment of the crystalline free base Compound 1 with HC1 to generate the HC1 salt of Compound 1 (Compound la) with optional milling which could be performed to reduce the particle size distribution (PSD).
• the synthesis of Compound la is performed by treatment of a solution of Compound 1 in DMSO with aqueous HC1. The product was precipitated via water anti-solvent addition to provide the product as a crystalline solid. Milling can be performed to reduce the particle size.
• Other preferred salts of Compound 1 include mesylate salt or tosylate salt.
• the solution was passed through a continuously stirred-tank reactor for 10 min at 60 °C followed by another plug flow reactor for 15 min at 65 °C.
• the mixture was cooled to 20°C and 55 L of water were added.
• Aqueous NaHSO 3 (10 L of 33% w/w solution, 1.9 equiv.) was added while maintaining the temperature at 20°C.
• the mixture was fdtered, and the cake washed twice with 15 L of water.
• the cake was washed with 15 L of heptane and dried at 40 °C under vacuum to yield the product 2-((2-(benzyloxy)ethyl)sulfonyl)benzo[d]thiazole.
• Example 3 Preparation of calcium 2-(benzyloxy)ethane-l-sulfinate and the crystalline hydrate salt thereof
• the mixture was cooled to 5 °C over 4 hours and agitated at that temperature for 10 hours.
• the slurry was fdtered and the cake washed with 22 L of ethanol.
• To the cake was added 4.4 L of methanol and the mixture was warmed to 55 °C. Water (1.1 L) and then ethanol (16.5 L) were added at 55 °C.
• the mixture was cooled to 5 °C over 4 hours and agitated at that temperature for 10 hours.
• the slurry was fdtered and the cake washed with 44 L of ethanol.
• X-Rav Powder Diffraction The XRPD pattern of the Crystalline Compound 6a-I is shown in FIG. 1. Samples were scanned at ambient temperature in continuous mode from 5-45 degrees or 2-45 degrees (20) with step size of 0.0334 degrees at 45 kV and 40 mA with CuKa radiation (1.54 A). The incident beam path was equipped with a 0.02 radian soller slit, 15 mm mask, 4 degrees fixed anti-scatter slit, and a programmable divergence slit. The diffracted beam was equipped with a 0.02 rad soller slit, programmable anti-scatter slit and a 0.02 mm nickel filter. Samples were prepared on a low background sample holder and placed on a spinning stage with a rotation time of 2 seconds.
• Table 1 XRPD pattern of the Crystalline Compound 6a-I taken pre-DVS experiment.
• Table 2 XRPD patern of the Crystalline Compound 6a-I taken post-DVS experiment.
• the crystalline Compound 6a-I was further characterized by an X-ray powder diffraction pattern (XPRD) and was found to be a stable polymorph form, having peaks at 4.2, 8.2, and 12.2 ⁇ 0.2° 20 using Cu Ka radiation.
• the crystalline Compound 6a-I optionally can be further characterized by an X-ray powder diffraction pattern having additional peaks at 13.6, 14.2, 18.3, 19.5, 20.6, 20.9, and 22.9 ⁇ 0.2° 20 using Cu Ka radiation.
• the crystalline Compound 6a-I optionally can be further characterized by an X-ray powder diffraction pattern having additional peaks at 16.2, 16.7,19.2, 21.4, 23.9, 24.4, 24.7, 25.5, 27.6, 28.1, 30.3, 33.3, and 36.6 ⁇ 0.2° 20 using Cu Ka radiation.
• crystalline Compound 6a-I has an X-ray powder diffraction pattern substantially as shown in Figure 1, wherein by “substantially” is meant that the reported peaks can vary by ⁇ 0.2°.
• DSC Differential scanning calorimetry
• the crystalline Compound 6a-I can be characterized by a weight loss in a range of about 4.5% to about 4.7% with an onset temperature of 124.96°C to 130.96°C.
• the crystalline Compound 6a-I can be characterized by a weight loss of about 4.62%, up to about 127.96°C.
• the crystalline Compound 6a-I has a thermogravimetric analysis substantially as depicted in Figure 3, wherein by “substantially” is meant that the reported TGA features can vary by ⁇ 3°C.
• Dynamic Vapor Sorption The crystalline Compound 6a-I can be characterized by a DVS moisture sorption profde. XPRD peaks characterization pre and post DVS showed that the crystalline Compound 6a-I has a stable crystalline polymorph form and is low in hygroscopicity, in that the weight loss, which corresponded to water loss, was only 0.15%.
• Example 5 Preparation of 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6- vDbenzoic acid
• 20% w/w Aqueous sodium chloride (1.5 L) was added and the contents were warmed to 50 °C.
• the mixture was agitated for 20 minutes, the layers allowed to separate, and the lower aqueous layer drained.
• 20% w/w Aqueous sodium chloride (1.5 L) was added and the contents were warmed to 50 °C.
• the mixture was agitated for 20 minutes, the layers allowed to separate, and the lower aqueous layer drained.
• the organic layer was distilled under vacuum from 3 L to 750 mL twice while adding fresh THF.
• the organic layer was diluted to 3 L with THF and polish fdtered.
• the organic layer was concentrated to 750 mL.
• the mixture was heated to 50 °C, ensuring full dissolution.
• the cake was washed with premixed 1:2 THF/toluene (900 mL) and then with toluene (900 mL).
• the cake was vacuum dried under a stream of nitrogen at 40 °C and the product 4-((2-(benzyloxy)ethyl)sulfonamido)-2-(6- azaspiro[2.5]octan-6-yl)benzoic acid was isolated as a crystalline solid in 79% yield. Without the crystal seed, the yield was about 1% less.
• the mixture was cooled to 5 °C and 2- (4,4-difluoropiperidin-l-yl)-6-methylpyrimidin-4-amine seed, which was obtained from previous batch, (24 gl) was added.
• the mixture was agitated for 15 minutes and aqueous KOH (1.1 M, 150 mL) was added.
• the mixture was agitated for 1 hour and aqueous KOH (1.1 M, 1.62 L) was added over 10 hours.
• the mixture was agitated for 1 hour and fdtered.
• the cake was washed with a pre-agitated mixture of acetonitrile (60 mL) and water (540 mL).
• 2,4,6-trimethylpyridine (collidine) (109 mL, 2.5 equiv) was added and the reaction mixture was agitated at 25 °C for 90 min. The reaction mixture was warmed to 50 °C and agitated for an additional 4 hours. Upon reaction completion, a 2 M NaOH solution (600 mL) was added followed by aqueous sodium chloride (600 mL, 15 wt%). The resultant mixture was agitated for 10 min at 50 °C. The phases were separated, and the organic layer was further washed with an aqueous NaFEPCL (1200 mL, 25 wt %). The resultant mixture was agitated for 10 min at 50 °C.
• the phases were separated and to the organic layer was added 1200 mL of water.
• the resultant mixture was agitated for 10 minutes at 50 °C and the layers were separated.
• the organic layer was concentrated to a volume of approximately 525 mL.
• 2-MeTHF was added (975 mL), and the organic layer was concentrated to a volume of approximately 525 mL.
• 2- MeTHF was added (975 mL), and the organic layer was concentrated to a volume of approximately 525 mL.
• 2-MeTHF was added (975 mL) and charcoal was added (3 g, 2 wt %).
• the resultant suspension was agitated for 12 hours at 20 °C.
• the suspension was filtered over CELITE® and washed with 150 mL MeTHF.
• the filtered solution was warmed to 50 °C.
• the mixture was seeded with 2- (4,4-difluoropiperidin-l-yl)-6-methylpyrimidin-4-amine (1.5g, l wt %), which was obtained from previous batch, and agitated for 1 h.
• the mixture was cooled to 35 °C and IP A (788 mL) was added over 3 hours.
• the mixture was agitated for an additional 1 hour and IPA (788 mL) was added over 1 h.
• the mixture was agitated for an additional 1 h, and cooled to 20 °C.
• the mixture was agitated for 12 hours and filtered.
• Example 8 Preparation of r -(2-(4.4-difluoropiperidin-l-yl)-6-methylpyrimidin-4-yl)-4-((2- hvdroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide
• the filtrate was washed with water (7 L) and the aqueous layer extracted twice with MIBK (2x 3.5 L). The combined MIBK extracts were washed twice with aqueous NaOH (7 L, 3 wt%).
• the solution was concentrated to a total of 7 L and polish fdtered.
• the polish filtration was chased with a 2 L MIBK rinse.
• the solution was concentrated under reduced pressure to a total of 1.5 volume, heated to 100 °C, and toluene (7 L) was added.
• the solution was cooled to 85 °C and seeded with A-(2-(4,4-difluoropiperidin-l-yl)-6-methylpyrimidin-4-yl)-4-((2- hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide, which was obtained from previous batch, (11 g).
• the mixture was agitated at 85 °C for 1 hour, cooled to 50 °C over 3 hours, and heated to 70 °C in hour.
• the suspension was agitated at 70 °C for 1 hour and cooled to 15 °C over 6 hours.
• the suspension was agitated at 15 °C for 2 hours and filtered.
• A-(2-(4,4-difluoropiperidin-l-yl)-6- methylpyrimidin-4-yl)-4-((2-hydroxyethyl)sulfonamido)-2-(6-azaspiro[2.5]octan-6-yl)benzamide was isolated as a crystalline product in 85% yield. Without the crystal seed, the yield was about 1% less.

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