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US20220177482A1 - Process for the preparation of n-((1r,2s,5r)-5-(tert-butylamino)-2-((s)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide - Google Patents

Process for the preparation of n-((1r,2s,5r)-5-(tert-butylamino)-2-((s)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide Download PDF

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US20220177482A1
US20220177482A1 US17/677,312 US202217677312A US2022177482A1 US 20220177482 A1 US20220177482 A1 US 20220177482A1 US 202217677312 A US202217677312 A US 202217677312A US 2022177482 A1 US2022177482 A1 US 2022177482A1
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compound
reactor
tert
mixture
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US17/677,312
Inventor
Burcu Selin Aytar
Alina Borovika
Collin Chan
Joerg Deerberg
Nathan R. DOMAGALSKI
Martin D. Eastgate
Yu Fan
Michael David Bengt Fenster
Robert V. Forest
Francisco Gonzalez-Bobes
Rebecca A. Green
Matthew R. Hickey
Nathaniel David Kopp
Thomas E. La Cruz
Kathleen Lauser
Hong Geun LEE
David K. Leahy
Helen Y. Luo
Thomas M. Razler
Scott A. Savage
Chris Sfouggatakis
Maxime C.D. Soumeillant
Serge Zaretsky
Bin Zheng
Ye Zhu
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to US17/677,312 priority Critical patent/US20220177482A1/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/22—Esters of monothiocarboxylic acids having carbon atoms of esterified thiocarboxyl groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/18—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member
    • C07D207/22—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/24—Oxygen or sulfur atoms
    • C07D207/26—2-Pyrrolidones
    • C07D207/273—2-Pyrrolidones with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D235/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings
    • C07D235/02—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, condensed with other rings condensed with carbocyclic rings or ring systems
    • C07D235/04—Benzimidazoles; Hydrogenated benzimidazoles
    • C07D235/06—Benzimidazoles; Hydrogenated benzimidazoles with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 2
    • 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
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the invention generally relates to an improved processes for the preparation of N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, a dual modulator of chemokine receptor activity.
  • Compound I crystalline forms of Compound I, compositions comprising Compound I, and an alternate process of preparing Compound I are disclosed in U.S. Pat. No. 8,383,812, which is assigned to the present assignee and is incorporated herein by reference in its entirety.
  • Compound I may be useful in combination with certain anticancer agents for the treatment of various types of cancer.
  • the invention provides a process for preparing Compound I of the formula:
  • R 1 is a leaving group such as halogen, OAc, etc. and an acid, such as a mineral or organic acid such as MSA, CSA, ESA, or a Lewis acid, such as, LiX, BF 3 -etherate, in a suitable solvent such as DCM, DCE, CHCl 3 , CCl 4 , diethyl ether, THF, methyl t-butyl ether or other ethereal solvents, to afford Compound 3 of the formula
  • R 2 and R 3 are hydrogen or C 1 -C 6 alkyl
  • Compound 4 can exist as the free base or the ammonium salt, wherein X is an inorganic counter ion such as a halogen, sulfate, or an organic counter ion such as a tartrate, or citrate; c) subsequently reacting the salt of Compound 4 with i-PrOH/H 2 SO 4 or free basing first with NaOH and then with an appropriate acid/solvent mixture such as MSA/DCM in a ratio of 1:21.4 or H 2 SO 4 /IPA in a ratio of 1:588, to afford Compound 5 of the formula
  • Compound 5 can exist as the free base or the ammonium salt, wherein X is an inorganic counter ion such as a halogen, sulfate or an organic counter ion such as a tartrate, or citrate; d) reacting Compound 5, or a salt thereof, in a reductive amination, in an appropriate solvent and using a hydride source such as triacetoxyborohydride, with Compound 6 of the formula
  • X is a leaving group such as halogen, nitrogen or OR, where R is alkyl, aryl, a suitable phospho or sulfate ester, to afford Compound I, which is crystallized from a suitable solvent mixture such as 2-MeTHF/n-Heptane, or other ethereal/hydrocarbons.
  • the leaving group in step a) of the first aspect is a halogen or OAc leaving group.
  • step a) of the first aspect is a mineral or organic acid.
  • step a) of the first aspect is MSA, CSA or ESA.
  • step a) of the first aspect is a Lewis acid.
  • the Lewis acid is LiX, where X is halogen, or BF 3 -etherate.
  • step a) of the first aspect is DCM, DCE, CHCl 3 or CCl 4 or a mixture thereof.
  • step c) of the first aspect is MSA/DCM in a ratio of 1:21.4.
  • step e) of the first aspect is TFA and the solvent is toluene.
  • step b) of the first aspect uses Pd/C and MeOH and the reductive amination in step d) uses sodium triacetoxyborohydride.
  • step h) of the first aspect Compound 11 is activated with 1-methylimidazole and diphenyl phosphoryl chloride to afford Compound 11a.
  • R 1 is C 1 -C 6 alkyl or benzyl
  • R 2 is C 1 -C 6 alkyl, —C(O)O C 1 -C 6 alkyl, —C(O)O benzyl, —SO 2 NH C 1 -C 6 alkyl, —SO 2 NH benzyl, —P(O)—N C 1 -C 6 alkyl, —P(O)—N benzyl, —N— C 1 -C 6 alkyl or N-benzyl.
  • R 3 is hydrogen, C 1 -C 12 alkyl or benzyl.
  • step b) of the second aspect is DCC, Piv 2 O, PivCl, or (COCl) 2
  • step b) of the second aspect is dodecanethiol or other thiols (R 3 )
  • step c) of the second aspect is Pd/C and the reducing agent is Et 3 SiH.
  • Another aspect of the invention provides Compound I prepared by the processes described herein.
  • a final aspect of the invention provides a method for treating cancer, comprising administering to a mammalian species, preferably a human, in need thereof, a therapeutically effective amount of Compound I in combination with another anti-cancer agent, preferably nivolumab, wherein Compound I is prepared utilizing the novel process steps of the invention.
  • the processes of the invention have several important advantages over prior syntheses of Compound I.
  • the throughput, cycle-time and overall yield have been dramatically improved.
  • the process consistently provides Compound I in high quality for use as a pharmaceutical API.
  • the reaction was quenched with the addition of aq. NaOAc (0.5 M, 125 ml) and followed by an additional charge of DCM (175 mL).
  • the biphasic mixture was mixed and the phases were split.
  • the product rich organic phase was washed with water (150 mL) and then with 10% (w/w) Na 2 HPO 4(aq) ( ⁇ 150 mL, until the pH of the aqueous layer >7). The layers were allowed to settle and then separated.
  • the product rich organic stream was distilled to a minimum volume and then followed by constant volume distillation by the portion wise addition of MTBE ( ⁇ 100 mL portions 80° C. jacket temperature) until the molar ratio contents of distillate were ⁇ 200:1 MTBE/DCM and residual water was measured ⁇ 0.1 wt %.
  • the product stream was then concentrated to a final volume of ⁇ 130 mL ( ⁇ 31 wt % Compound 3 in MTBE).
  • the product rich stream was cooled to 50° C. and n-Heptane (50.5 mL) was slowly added over a 10 min period ( ⁇ 25 wt % solution of Compound 3 in ⁇ 35% n-Heptane/MTBE (vol/vol)).
  • Solid Compound 3 (0.63 g, equivalent to ⁇ 2 wt % of Compound 3 present in the process stream) was then added and the mixture was aged at ⁇ 50° C. for ⁇ 30 min.
  • the subsequent slurry was cooled to ⁇ 22° C. over a 3 h period, aged at 22° C. for 3 h, further cooled to ⁇ 0° C. over a 3 h period and aged at this temperature until ⁇ 6 wt % of the Compound 3 mass initially present remained in the supernatant.
  • the slurry was filter slurry at 0° C. and washed twice with 50:50 n-Heptane/MTBE (vol/vol) ( ⁇ 75-100 mL).
  • Reactor B Into a 5 L Buchi reactor (Reactor B) was added Pd/C (54% wet; 5 wt %, 13.5 mmol) and MeOH (0.67 L/kg). The mixture was filtered and rinsed with THE (0.5 L/kg ⁇ 3) then transferred back to Reactor B. The imine mixture from Reactor A was then added to Reactor B. Reactor A was rinsed with THE (0.67 L/kg) and the rinse was added to Reactor B. Reactor B was flushed with nitrogen three times, followed by hydrogen two times. Reactor B was then pressurized with hydrogen to 30 psi and stirred at 600 rpm for 2 h.
  • reaction mixture was filtered through a 0.5 micron Cuno filter.
  • Reactor B was then rinsed with THF (0.83 L/kg ⁇ 2).
  • the combined filtrate and rinse was added to a 10 L Chemglass reactor (Reactor C) followed by 2-propaneamine (2.0 equiv, 2.12 mol), and 5 N NaOH (0.37 equiv, 375 mmol).
  • the mixture was stirred for 16 h at room temperature, and then filtered.
  • the reactor and cake were washed with THF (4 L/kg ⁇ 2), then the cake was washed with additional THE (3.3 L/kg).
  • the cloudy filtrate was filtered again, then added to a 10 L Chemglass reactor (Reactor D) followed by the rinses.
  • the mixture in Reactor D was concentrated under reduced pressure to 2.7 L/kg, then the solvent was swapped to acetone through a put and take distillation. During this operation, acetone (5.4 L/kg) was used and 5.4 L/kg solvent was removed from Reactor D. To the mixture was added acetone (10.6 L/kg), then a solution of L-tartaric acid (0.93 equiv, 988 mmol) in MeOH (1 L/kg), and then additional acetone (5.7 L/kg) at 45° C. The resulting mixture was cooled to 25° C. over 2 h and aged for 16 h.
  • Reactor B was evacuated with nitrogen. The reaction solution from Reactor A was transferred to Reactor B. 5% Platinum on Alumina (Pt/Al, 0.10 kg, 0.10 kg/kg) was charged into Reactor B, followed by a rinse with tetrahydrofuran from Reactor A to Reactor B (1.0 L, 0.89 kg, 1.0 L/kg). Reactor B was purged twice with nitrogen at 20-30° C. The mixture was stirred at 25° C., 0.45-0.55 MPa for 16 h. Reactor B and then vented and purged with nitrogen. The mixture was filtered into Reactor A and tetrahydrofuran (1.0 L, 0.89 kg, 1.0 L/kg) was used as a rinse.
  • Pt/Al Platinum on Alumina
  • Reactor C Water (7.5 L, 7.5 kg, 7.5 L/kg) and ammonium citrate tribasic (4.39 kg, 5.1 equiv) were charged to Reactor C.
  • Reaction stream from Reactor A was transferred to Reactor C at a rate such that the temperature did not exceed 30° C.
  • the mixture in Reactor C was heated to 40-50° C. and aged for 1 h.
  • the mixture in Reactor C was cooled to 15-25° C. and stirred for 0.5 h. Agitation was stopped and phases were allowed to settle for 1 h at 15-25° C. (target 20° C.). The phases were separated and the lower aqueous layer from Reactor C was sent to waste.
  • Reactor A (prerinsed) was charged with water (0.94 L, 0.94 kg, 0.94 L/kg) and sodium chloride (0.10 kg, 0.10 kg/kg). Temperature of the mass in Reactor C was adjusted to 15-25° C. The sodium chloride solution from Reactor A was added to the mass in Reactor C and agitated for 0.5 h. Agitation was stopped and phases allowed to settle for 1 h at 15-25° C. target 20° C. Phases were then separated and the lower aqueous layer from Reactor C was sent to waste.
  • reaction stream from Reactor C was filtered into a clean and nitrogen-filled Reactor D.
  • Methanol 5.0 L, 3.96 kg, 5.0 L/kg
  • the batch in reactor D was concentrated until 2-3 L/kg remained with respect to Compound 3.
  • Methanol to Reactor D (4.0 L, 3.16 kg, 4.0 L/kg) through an in-line filter at NMT 50° C.
  • the amount of Compound 4 in solution was quantified.
  • the solution of L-(+)-Tartaric Acid was then transferred to Reactor D through an in-line filter at 20-30° C. and the solution in Reactor D was heated to 48-53° C.
  • MTBE (18.0 L, 13.3 kg, 18.0 L/kg) was then charged to Reactor D at 48-53° C. at a rate such that the temperature stays above 48° C.
  • the reaction mixture was aged at 48-53° C. until solid precipitation is observed, then cooled to 20-25° C. at a rate of 5-10° C./h, and aged for 4 h.
  • Methyl tert-Butyl Ether (2.0 L, 1.48 kg, 2.0 L/kg) was charged to Reactor D through an in-line filter and used to rinse the product cake.
  • the cake was dried at a jacket set point of 45-50° C., under reduced pressure with a nitrogen sweep for NLT 10 h.
  • Steps 2 through 5 All the equivalencies were calculated based on Compound 5a.
  • the upper organic layer was treated with 220 mL of 17 wt % aqueous K 3 PO 4 at 5° C. for 1 hour with agitation and for 30 minutes without agitation to allow the phases to split.
  • the upper organic layer was washed at 10° C. with 232 mL of 14 wt % aqueous NaCl (4 L/kg) for 30 min with agitation and 30 minutes without agitation to allow the phase separation.
  • the upper organic layer was concentrated to a residual volume of 290 mL (5 L/kg) under a reduced pressure of 100 mbar whereupon toluene (464 mL, 8 L/kg) was added and the resulting mixture was concentrated a second time down to 290 mL at 100 mbar and a jacket temperature ⁇ 70° C.
  • a second toluene addition (464 mL, 8 L/kg) followed by a third concentration to 5 L/kg residual was performed under the same temperature and pressure conditions whereupon the distillation residue was diluted with more toluene (232 mL, 4 L/kg) to give a dry toluene solution of Compound 8 ready for processing in the next step.
  • the Compound 8 rich toluene solution was treated with acetic acid (14.15 g, 1.75 equiv. 235.6 mmol) and the resulting mixture was heated under agitation at 57° C. for 5 hours at which point the reaction was complete as indicated by HPLC analysis.
  • the reaction mixture was cooled to 25° C. whereupon water (523 mL, 9 L/kg) was added and the biphasic mixture was kept for 1 hour with agitation and 1 hour without agitation before transferring the Compound 9 rich aqueous layer into a new reactor.
  • the aqueous layer was mixed with IPAc (1.16 L, 20 L/kg) at 25-30° C.
  • the distillation residue was diluted with IPAc (60 mL, 1 L/kg) and the temperature was adjusted to 60° C. and 1 wt % of Compound 9 seeds (580 mg) were added to promote crystallization.
  • the resulting slurry was aged for 2 hours at 55-60° C. whereupon further crystallization was promoted by the slow addition of n-Heptane (270 mL, 4.65 L/kg).
  • the slurry was cooled to 20° C. in at least 2 hours, agitated for several hours before the solids were collected by filtration, washed once with IPAc/n-heptane 35/65 v/v (4.5 L/kg) and once with n-heptane (7.5 L/kg).
  • the filter cake was dried under vacuum at 60° C. to provide Compound 9 as a white solid (45.87 g, 76.2 yield).
  • the atmosphere was changed to hydrogen by performing the sequence of pressurizing to 30 psig with H 2 , then venting down to 8 psig three times.
  • the pressure was set to 30 psig, and set to keep at constant pressure throughout the course of the reaction.
  • the jacket was set to heat the reaction mixture to 35° C.
  • the agitation was set such that the kLa >0.02 s ⁇ 1 .
  • the mixture was stirred at 35° C. and 30 psig for 3-5 hours.
  • the vessel was vented, then flushed with N 2 by pressurizing to 30 psig and venting the vessel down to 8 psig three times.
  • HPLC analysis showed ⁇ 0.30 RAP starting material.
  • reaction mixture was filtered through a 0.5 ⁇ m filter, then a 0.2 ⁇ m Cuno cartridge filter and rinsed with 2-propanol (2 L/kg) into a clean reactor.
  • a vessel was charged with 7.9 kg/kg (10 L/kg) of i-PrOH, heated to 50° C. under an inert atmosphere followed by HBr 0.95 kg/kg (2.5 mol/mol; 48 wt %, aqueous). 1.88 kg/kg (18 wt % of total process stream) containing free base compound 10 was added to the HBr solution and aged for 1-3 h at 45-50° C. 8.54 kg/kg (82 wt % of total process stream) of free base process stream was charged over a 1 h period, the solution was aged at 50° C. for 1 h and then cooled to 20° C. over the course of 1 h.
  • Solvent A Water: MeCN:MeOH (90:8:2+0.05% NH 4 OH)
  • step 1 The process stream in step 1 was diluted with DCM (25 ml), Compound 10a (1.0 equiv, 10.0 g) was added to the reaction mixture at 0° C., followed by a second DCM charge (25 ml) and the process stream aged for 5-20 h.
  • the reaction mixture was diluted with DCM (60 mL) and then quenched by the slow addition of a solution of citric acid monohydrate (57.4 g) in water (77.6 ml) to the process stream, followed by the addition of saturated NaCl(aq) solution (26 wt % in water, 82.5 ml).
  • the phases were separated, the product rich DCM layer was washed with a solution of NaOH (10 equiv) dissolved in water (150 ml); the phases were mixed, split, and the product rich DCM layer was extracted with water HCl (5 equiv in 150 ml water).
  • the phases were separated; the organic layer discarded, and the product rich aqueous phase was treated with DCM (150 ml) and NaOH (6 equiv), the layers mixed and then separated.
  • the product rich DCM layer was washed with water (50 ml).
  • the wet product rich DCM process stream was polish filtered into a reactor, concentrated by vacuum distillation (300 mbar, jacket 30° C.) to 5 L/kg, then constant volume solvent swap to 2-methyl THE (9 L/kg), maintaining volume at 5 L/kg. When distillation was complete, 7 L/kg 2-methyl THE was added. Distillation and solvent swap were complete when KF ( ⁇ 0.1 wt %) and residual DCM level ( ⁇ 3 wt % DCM) met specifications.
  • the batch was heated to 60° C. until the solids dissolved, and the reaction was cooled to 40° C.
  • the reaction was charged with 1 wt % compound I and aged for 2 h.
  • the batch was cooled to 20° C. over a 2 h period, and n-heptane (23 L/kg) was charged over a 2 h period.
  • the slurry was aged overnight, filtered, and the reactor and cake were washed with 5 L/kg of 40:60 (wt/wt) 2-methyl THE to n-heptane.
  • the cake was washed twice with 5 L/kg n-heptane and then dried under vacuum at 60° C.
  • the final product, Compound I was isolated as a white solid (80% yield)
  • Neat 1-Methylimidazole (3.0 equiv.) was added to an ice-cooled clear colorless solution of TCFH (1.25 equiv.) in acetonitrile (10 mL/g Z-ASP-OBL). Cooling was discontinued and the resulting clear solution was allowed to warm to 20° C. Solid Z-ASP-OBL (1.0 equiv.) was added to the stirred solution in a single portion, and the resulting clear colorless to faint yellow solution was stirred at 20° C. for 1 h. Neat 1-dodecanethiol (1.05 equiv.) was added in a single portion and the reaction mixture was stirred until complete as judged by HPLC.
  • the reaction mixture was cooled to an internal temperature of 12° C. and water (0.02 mL/g Z-ASP-OBL) was added.
  • the thin suspension was stirred for 1-2 h, then a solution of 50/50 acetonitrile-water (10 mL/g Z-ASP-OBL) was added to the reaction mixture resulting in a thick suspension of white solid.
  • the suspension was stirred at 12° C. for 2 h, then the solid product was collected by filtration, washed with 50/50 acetonitrile-water and dried in a drying oven to give compound 14a as a white solid in 85% yield.
  • Solid 5% Pd/Al 2 O 3 (4 wt % relative to compound 14a) was charged to a reaction flask under nitrogen.
  • compound 14a limiting reagent, 1.0 Equiv.
  • acetonitrile 3.0 mL/g relative to compound 14a
  • the solution was sparged by bubbling N2 through the solution for 15 minutes at room temperature.
  • the solution was added to the catalyst in the flask and the mixture was stirred at room temperature (22-23° C.).
  • the catalyst was then removed by filtration and the catalyst bed was washed with 1 mL/g acetonitrile. The filtrate was then extracted with twice with n-heptane (4 mL/g).
  • sodium bisulfite (0.48 g/g compound 14a) was combined with water (6.0 mL/g compound 14a) and the mixture stirred until a homogenous solution resulted.
  • the product stream was diluted with methyl tert-butyl ether (4.0 mL/g) and the sodium bisulfite solution was added to the product solution and the biphasic mixture stirred vigorously until compound 6 was not detected in the organic phase.
  • the phases were separated and the aqueous product stream extracted twice more with methyl tert-butyl ether (4.0 mL/g compound 14a). The aqueous product solution was cooled to 5° C.
  • disodium hydrogenphosphate 0.2 g/g compound 14a
  • monosodium phosphate 0.16 g/g compound 14a
  • water 1.0 mL/g/compound 14a
  • Methyl tert-butyl ether 10 mL/g compound 14a
  • a commercial 37 wt % solution of formaldeyde 0.6 g/g compound 14a was then added to the biphasic mixture at 5° C. The reaction mixture as stirred at 5° C.
  • Solid 5% Pd/C (651 mg, 0.30586 mmol, 5 mass %) was charged to a 100 mL stainless steel hydrogenation vessel and the vessel sealed up.
  • the prepared compound 14a solution was charged to the vessel under nitrogen.
  • Neat triethylsilane (8.2 mL, 50 mmol, 99 mass %) was added over 1 min under nitrogen, then the vessel was sealed. The reaction was allowed to stir for 4 h.
  • the reaction mixture was removed from the reactor and filtered through a 0.45 um PTFE filter.
  • the solid in the filter was rinsed with acetonitrile (25 mL, 126 mmol, 99.9 mass %).
  • the combined filtrate was biphasic having a dark colored phase that settled to the bottom of the flask.
  • the biphasic product stream was well mixed and 55 mL heptane were added.
  • the jacket was set at 20° C. and the biphasic mixture agitated for 15 minutes.
  • the phases were allowed to separate and the bottom acetonitrile phase was clear and colorless.
  • the top phase was dark burnt orange color.
  • the mixture was a suspension of white solid.
  • Neat cyclohexane (21 mL, 194 mmol, 99.9 mass %) was added to the suspension via syringe pump over 2 h and the suspension stirred for 5 h at 20° C.
  • the solid product was collected on a 55 mm Whatman #1 filter paper.
  • the mother liquor was recycled to the rinse out the reactor, then the cake was washed with 20 mL cyclohexane.
  • the cake was air dried for 15 minutes, before transfer to a 20° C. drying oven to dry over the weekend to give 5.6 g, 62.7% yield of compound 6.

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Abstract

The invention generally relates to an improved process for the preparation of N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide,as well as novel intermediates employed in the process, which may be useful for the treatment of cancer.

Description

    CROSS-REFERENCE TO RELATED APPLICATIONS
  • This application is a divisional of U.S. Ser. No. 16/631,915, filed Jan. 17, 2020, now allowed, which is a national phase application under 35 U.S.C. § 371 of International Patent Application No. PCT/US2018/042797, filed Jul. 19, 2018, which claims the benefit of U.S. Provisional Application No. 62/534,908, filed Jul. 20, 2017, the disclosure of which is incorporated herein by reference in its entirety.
    • FIELD OF THE INVENTION
  • The invention generally relates to an improved processes for the preparation of N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, a dual modulator of chemokine receptor activity.
    • BACKGROUND OF THE INVENTION
  • There is disclosed an improved processes for the preparation of N-((1R,2S,5R)-5-(tert-butylamino)-2-((S)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide, of formula I:
  • Figure US20220177482A1-20220609-C00002
  • Compound I, crystalline forms of Compound I, compositions comprising Compound I, and an alternate process of preparing Compound I are disclosed in U.S. Pat. No. 8,383,812, which is assigned to the present assignee and is incorporated herein by reference in its entirety. Compound I may be useful in combination with certain anticancer agents for the treatment of various types of cancer.
    • SUMMARY OF THE INVENTION
  • In a first aspect, the invention provides a process for preparing Compound I of the formula:
  • Figure US20220177482A1-20220609-C00003
  • comprising the steps of
    a) reacting Compound 1 of the formula
  • Figure US20220177482A1-20220609-C00004
  • with Compound 2 of the general formula
  • Figure US20220177482A1-20220609-C00005
  • where R1 is a leaving group such as halogen, OAc, etc. and an acid, such as a mineral or organic acid such as MSA, CSA, ESA, or a Lewis acid, such as, LiX, BF3-etherate, in a suitable solvent such as DCM, DCE, CHCl3, CCl4, diethyl ether, THF, methyl t-butyl ether or other ethereal solvents, to afford Compound 3 of the formula
  • Figure US20220177482A1-20220609-C00006
  • b) reacting Compound 3 in a reductive amination reaction with a primary or secondary amine (HNR2R3) wherein
  • R2 and R3 are hydrogen or C1-C6 alkyl;
  • mediated by a Lewis acid such as Ti(Oi-Pr)4, followed by reaction with a suitable hydride donor, such as NaBH4, or a combination of a catalyst such as Pt/Al or Pd/C and hydrogen gas, to afford Compound 4 of the formula
  • Figure US20220177482A1-20220609-C00007
  • wherein Compound 4 can exist as the free base or the ammonium salt,
    wherein X is an inorganic counter ion such as a halogen, sulfate, or an organic counter ion such as a tartrate, or citrate;
    c) subsequently reacting the salt of Compound 4 with i-PrOH/H2SO4 or free basing first with NaOH and then with an appropriate acid/solvent mixture such as MSA/DCM in a ratio of 1:21.4 or H2SO4/IPA in a ratio of 1:588, to afford Compound 5 of the formula
  • Figure US20220177482A1-20220609-C00008
  • wherein Compound 5 can exist as the free base or the ammonium salt, wherein X is an inorganic counter ion such as a halogen, sulfate or an organic counter ion such as a tartrate, or citrate;
    d) reacting Compound 5, or a salt thereof, in a reductive amination, in an appropriate solvent and using a hydride source such as triacetoxyborohydride, with Compound 6 of the formula
  • Figure US20220177482A1-20220609-C00009
  • to afford Compound 7 of the formula,
  • Figure US20220177482A1-20220609-C00010
  • e) which is then reacted with an acid such as TFA, in the presence of NH2OH, or its salt, and a suitable solvent to afford Compound 8 of the formula
  • Figure US20220177482A1-20220609-C00011
  • f) which is further reacted with an acid such as TFA, a base, and heated to 45-70° C. in an appropriate solvent, such as toluene, iso-propyl acetate, n-heptane, NMP, DMF, diethyl ether, THF, methyl t-butyl ether or other ethereal solvents or solvent mixtures to afford Compound 9 of the formula
  • Figure US20220177482A1-20220609-C00012
  • g) subsequently removing the protecting group by a suitable method, such as hydrogenation with Pd/C which can be isolated as the free base or a mono or bis salt formed by reacting with an acid such as HCl or HBr, where X is a halogen, to afford Compound 10 of the formula
  • Figure US20220177482A1-20220609-C00013
  • h) which is then reacted with Compound 11a of the formula
  • Figure US20220177482A1-20220609-C00014
  • where X is a leaving group such as halogen, nitrogen or OR, where R is alkyl, aryl, a suitable phospho or sulfate ester, to afford Compound I, which is crystallized from a suitable solvent mixture such as 2-MeTHF/n-Heptane, or other ethereal/hydrocarbons.
  • In a second aspect, there is provided a process for the preparation of Compound 6 of the formula:
  • Figure US20220177482A1-20220609-C00015
  • which comprises
  • a) reacting aspartic acid of the formula
  • Figure US20220177482A1-20220609-C00016
  • with a suitable reagent to protect the carboxylic acid group as an ester (R1) and the amine group as an amide (R2) such as a carbamate, sulfamide, phosphoramide, etc., to afford Compound 13 of the formula
  • Figure US20220177482A1-20220609-C00017
  • b) which is activated with a suitable reagent, such as DCC, Piv2O, PiVCl, TCFH, or (COCl)2 and then with a thiolating reagent such as dodecanethiol or other thiols (R3) to afford Compound 14 of the formula
  • Figure US20220177482A1-20220609-C00018
  • c) and, subsequently reacting Compound 14 with a suitable reducing agent such Et3SiH in the presence of a catalyst such as Pd/C or Pd/Al to afford Compound 6.
  • In a third aspect of the invention, there are provided novel intermediate compounds as shown in the table below;
  • Compound No. Structure
    3
    Figure US20220177482A1-20220609-C00019
    4
    Figure US20220177482A1-20220609-C00020
    4a
    Figure US20220177482A1-20220609-C00021
    5
    Figure US20220177482A1-20220609-C00022
    5a
    Figure US20220177482A1-20220609-C00023
    7
    Figure US20220177482A1-20220609-C00024
    8
    Figure US20220177482A1-20220609-C00025
    9
    Figure US20220177482A1-20220609-C00026
    10
    Figure US20220177482A1-20220609-C00027
    10a
    Figure US20220177482A1-20220609-C00028
    14
    Figure US20220177482A1-20220609-C00029
    14a
    Figure US20220177482A1-20220609-C00030
  • which are used in the process of the invention.
  • In one embodiment of the invention, there is disclosed the process wherein the leaving group in step a) of the first aspect is a halogen or OAc leaving group.
  • In one embodiment of the invention, there is disclosed the process wherein the acid in step a) of the first aspect is a mineral or organic acid.
  • In another embodiment of the invention, there is disclosed the process wherein the acid in step a) of the first aspect is MSA, CSA or ESA.
  • In another embodiment of the invention, there is disclosed the process wherein the acid in step a) of the first aspect is a Lewis acid.
  • In another embodiment of the invention, there is disclosed the process wherein the Lewis acid is LiX, where X is halogen, or BF3-etherate.
  • In another embodiment of the invention, there is disclosed the process wherein the solvent in step a) of the first aspect is DCM, DCE, CHCl3 or CCl4 or a mixture thereof.
  • In another embodiment of the invention, there is disclosed the process wherein Compound 4 of the first aspect is the free base.
  • In another embodiment of the invention, there is disclosed the process wherein Compound 4 of the first aspect is the ammonium salt.
  • In another embodiment of the invention, there is disclosed the process wherein the acid/solvent mixture in step c) of the first aspect is MSA/DCM in a ratio of 1:21.4.
  • In another embodiment of the invention, there is disclosed the process wherein the acid in step e) of the first aspect is TFA and the solvent is toluene.
  • In another embodiment of the invention, there is disclosed the process wherein Compound 8 of the first aspect is reacted with an acid or a base.
  • In another embodiment of the invention, there is disclosed the process wherein Compound 8 is heated in a solvent/solvent mixture where the solvents are toluene, iso-propyl acetate, n-heptane, NMP, DMF, diethyl ether, THF, methyl t-butyl ether or other ethereal solvents.
  • In another embodiment of the invention, there is disclosed the process wherein the reductive amination in step b) of the first aspect uses Pd/C and MeOH and the reductive amination in step d) uses sodium triacetoxyborohydride.
  • In another embodiment of the invention, there is disclosed the process wherein the HBr salt of Compound 10 is formed in step g).
  • In another embodiment of the invention, there is disclosed the process wherein in step h) of the first aspect Compound 11 is activated with 1-methylimidazole and diphenyl phosphoryl chloride to afford Compound 11a.
  • In one embodiment of the invention, in step a) of the second aspect, R1 is C1-C6 alkyl or benzyl; and R2 is C1-C6 alkyl, —C(O)O C1-C6 alkyl, —C(O)O benzyl, —SO2NH C1-C6 alkyl, —SO2NH benzyl, —P(O)—N C1-C6 alkyl, —P(O)—N benzyl, —N— C1-C6 alkyl or N-benzyl.
  • In one embodiment of the invention, in step b) of the second aspect, R3 is hydrogen, C1-C12 alkyl or benzyl.
  • In another embodiment of the invention, there is disclosed the process wherein the activating reagent in step b) of the second aspect is DCC, Piv2O, PivCl, or (COCl)2
  • In another embodiment of the invention, there is disclosed the process wherein the activating reagent in step b) of the second aspect is dodecanethiol or other thiols (R3)
  • In another embodiment of the invention, there is disclosed the process wherein the reducing agent in step c) of the second aspect is Pd/C and the reducing agent is Et3SiH.
  • Another aspect of the invention provides Compound I prepared by the processes described herein.
  • A final aspect of the invention provides a method for treating cancer, comprising administering to a mammalian species, preferably a human, in need thereof, a therapeutically effective amount of Compound I in combination with another anti-cancer agent, preferably nivolumab, wherein Compound I is prepared utilizing the novel process steps of the invention.
  • The processes of the invention have several important advantages over prior syntheses of Compound I. In particular, due to the short sequence of chemical steps, high yields and process improvement, the throughput, cycle-time and overall yield have been dramatically improved. Additionally, the process consistently provides Compound I in high quality for use as a pharmaceutical API.
    • DETAILED DESCRIPTION OF THE INVENTION Examples
  • The invention will now be further described by the following working example(s), which are preferred embodiments of the invention. All temperatures are in degrees Celsius (° C.) unless otherwise indicated. These examples are illustrative rather than limiting and it is to be understood that there may be other embodiments that fall within the spirit and scope of the invention as defined by the claims appended hereto.
  • For ease of reference, the following abbreviations may be used herein.
  • Abbreviations Name
    CH3CN, acetonitrile
    MeCN
    aq. aqueous
    Bn benzyl
    Boc t-butyl carbamate
    Boc2O di-t-butyl dicarbonate
    Bu butyl
    Cbz benzyl carbamate
    conc. concentrated
    DCC dicyclohexylcarbodiimide
    DCE dichloroethane
    DCM dichloromethane
    DEA diethanolamine
    DMAP 4-N,N-dimethylaminopyridine
    DMF dimethyl formamide
    DMSO dimethyl sulfoxide
    eq. equivalents
    Et ethyl
    EtOAc ethyl acetate
    EtOH ethanol
    Et2O diethyl ether
    Et3N triethylamine
    Et3SiH triethylsilane
    h hour(s)
    HPLC high pressure liquid chromatography
    H2SO4 sulfuric acid
    IPAc isopropyl acetate
    i-PrOH isopropanol
    Kf, kf Karl Fischer
    kLa mass-transfer coefficient
    LAH lithium aluminum hydride
    Me methyl
    MeOH methanol
    MSA methanesulfonic acid
    MTBE methyl t-butyl ether
    NH2OH hydroxylamine
    NMI 1-Methylimidazole
    NMR nuclear magnetic resonance
    Pt/Al platinum on alumina
    Pd/Al2O3 palladium on alumina
    Pd/C palladium on carbon
    Ph phenyl
    RAP Relative area percent
    rt/RT room temperature
    sat. saturated
    STAB sodium triacetoxyborohydride
    t-Bu tertiary butyl
    t-BuOH tertiary butanol
    TCFH tetramethylchloroformamidinium
    hexafluorophosphate
    TFA trifluoroacetic acid
    THF tetrahydrofuran
    Ti(OPr)4 titanium(IV) isopropoxide
    Z-ASP-OBZL N-Cbz-L-aspartic acid β-benzyl ester
    • Example 1 Preparation of Compound 3
  • Figure US20220177482A1-20220609-C00031
  • 25 g Compound 1 scale, equivalencies calculated based on Compound 1
    • Step 1: Reaction
  • A 250 ml Chemglass reactor was charged with Compound 1 (25.0 g), Compound 2 (24.8 g, 1.6 equiv.) and DCM (47.4 mL). The reaction mixture was stirred until all solids dissolved and then cooled to 0° C. To the reaction mixture was added a solution of MSA, (3.07 ml, 0.40 equiv.) in DCM (11.8 mL) dropwise at a rate such that the internal temperature of the reaction mixture did not increase above 2° C. (˜30 min). The reaction stream was then aged at ˜0° C. for 21-24 h.
    • Step 2: Work-Up
  • The reaction was quenched with the addition of aq. NaOAc (0.5 M, 125 ml) and followed by an additional charge of DCM (175 mL). The biphasic mixture was mixed and the phases were split. The product rich organic phase was washed with water (150 mL) and then with 10% (w/w) Na2HPO4(aq) (˜150 mL, until the pH of the aqueous layer >7). The layers were allowed to settle and then separated.
    • Step 3: Drying
  • The product rich organic stream was distilled to a minimum volume and then followed by constant volume distillation by the portion wise addition of MTBE (˜100 mL portions 80° C. jacket temperature) until the molar ratio contents of distillate were ˜200:1 MTBE/DCM and residual water was measured <0.1 wt %. The product stream was then concentrated to a final volume of ˜130 mL (˜31 wt % Compound 3 in MTBE).
    • Step 4: Crystallization
  • The product rich stream was cooled to 50° C. and n-Heptane (50.5 mL) was slowly added over a 10 min period (˜25 wt % solution of Compound 3 in ˜35% n-Heptane/MTBE (vol/vol)). Solid Compound 3 (0.63 g, equivalent to ˜2 wt % of Compound 3 present in the process stream) was then added and the mixture was aged at ˜50° C. for ˜30 min. The subsequent slurry was cooled to ˜22° C. over a 3 h period, aged at 22° C. for 3 h, further cooled to ˜ 0° C. over a 3 h period and aged at this temperature until <6 wt % of the Compound 3 mass initially present remained in the supernatant.
    • Step 5: Isolation
  • The slurry was filter slurry at 0° C. and washed twice with 50:50 n-Heptane/MTBE (vol/vol) (˜75-100 mL).
    • Step 6: Drying
  • Isolated Compound 3 was dried at room temperature under full vacuum. 27.70 g of Compound 3 was isolated (82.9% yield, >99% LCAP at λ205 nm, 100% potency) of as a white solid.
  • HPLC analysis:
    Compound 3: 98.9 AP (8.46 min);
    • Gradient=Start % B=0
      • Final % B=100
    Gradient Time=10 min
  • Flow Rate=1 ml/min
    • Wavelength1=205 Wavelength2=220 Solvent A=0.05% TFA in MeOH:Water (20:80) Solvent B=0.05% TFA in MeOH:CH3CN (20:80) Column: Phenomenex Luna C18(2) 3 um 4.6×150 mm
  • NMR data is presented as a mixture of rotamers:
  • 1H NMR (400 MHz, CHLOROFORM-d) δ 1.45 (s, 38H), 1.94-2.08 (m, 13H), 2.08-2.47 (m, 17H), 2.48-2.61 (m, 1H), 2.62-2.83 (m, 8H), 4.25-4.34 (m, 3H), 4.36 (br. s., 1H), 4.42-4.56 (m, 2H), 4.64 (d, J=6.82 Hz, 3H), 4.70-4.81 (m, 3H), 4.93 (br. s., 3H), 5.19 (br. s., 1H) ppm.
  • 13C NMR (101 MHz, CHLOROFORM-d) δ 21.30 (s, 1 C), 22.57 (s, 1 C), 28.21 (s, 1 C), 34.76 (s, 1 C), 40.86 (s, 1 C), 42.88 (s, 1 C), 53.45 (s, 1 C), 54.11 (s, 1 C), 54.81 (s, 1 C), 55.40 (s, 1 C), 60.27 (s, 1 C), 61.48 (s, 1 C), 81.10 (s, 1 C), 152.65 (s, 1 C), 153.02 (s, 1 C), 167.54 (s, 1 C), 208.30 (s, 1 C), 209.51 (s, 1 C) ppm.
    • Example 2 Preparation of Compound 4a
  • Figure US20220177482A1-20220609-C00032
  • All the equivalencies were calculated based on Compound 3 (300.0 g).
    • Step 1: Imine Formation
  • Into a 4 liter bottle (Reactor A) was added (3aR,7aS)-tert-butyl 3-acetyl-5-oxooctahydro-1H-benzo[d]imidazole-1-carboxylate (Compound 3, 1.0 equiv, 1.06 mol), THE (5 L/kg), titanium tetra(isopropoxide) (1.7 equiv, 1.81 mol) and 2-methyl-2-propanamine, (1.5 equiv, 1.59 mol). The resulting mixture was aged for 4-16 h at 25° C.
    • Step 2: Reductive Amination
  • Into a 5 L Buchi reactor (Reactor B) was added Pd/C (54% wet; 5 wt %, 13.5 mmol) and MeOH (0.67 L/kg). The mixture was filtered and rinsed with THE (0.5 L/kg×3) then transferred back to Reactor B. The imine mixture from Reactor A was then added to Reactor B. Reactor A was rinsed with THE (0.67 L/kg) and the rinse was added to Reactor B. Reactor B was flushed with nitrogen three times, followed by hydrogen two times. Reactor B was then pressurized with hydrogen to 30 psi and stirred at 600 rpm for 2 h.
    • Step 3: Reaction Workup
  • The reaction mixture was filtered through a 0.5 micron Cuno filter. Reactor B was then rinsed with THF (0.83 L/kg×2). The combined filtrate and rinse was added to a 10 L Chemglass reactor (Reactor C) followed by 2-propaneamine (2.0 equiv, 2.12 mol), and 5 N NaOH (0.37 equiv, 375 mmol). The mixture was stirred for 16 h at room temperature, and then filtered. The reactor and cake were washed with THF (4 L/kg×2), then the cake was washed with additional THE (3.3 L/kg). The cloudy filtrate was filtered again, then added to a 10 L Chemglass reactor (Reactor D) followed by the rinses.
    • Step 4: Crystallization
  • The mixture in Reactor D was concentrated under reduced pressure to 2.7 L/kg, then the solvent was swapped to acetone through a put and take distillation. During this operation, acetone (5.4 L/kg) was used and 5.4 L/kg solvent was removed from Reactor D. To the mixture was added acetone (10.6 L/kg), then a solution of L-tartaric acid (0.93 equiv, 988 mmol) in MeOH (1 L/kg), and then additional acetone (5.7 L/kg) at 45° C. The resulting mixture was cooled to 25° C. over 2 h and aged for 16 h.
    • Step 5: Isolation:
  • The slurry in Reactor D was filtered. The reactor was rinsed with acetone (2.7 L/kg). The cake was then washed with this reactor rinse, followed by acetone (2.3 L/kg). The product was dried under vacuum at 35° C. for 5 h. The product, Compound 4a, (3aR,5R,7aS)-tert-butyl 3-acetyl-5-(tert-butylamino)octahydro-1H-benzo[d]imidazole-1-carboxylate 2,3-dihydroxysuccinate was isolated as a white solid powder. 462 g, 89% yield.
    • Alternative Procedures Step 2: Alternative Reductive Amination
  • Reactor B was evacuated with nitrogen. The reaction solution from Reactor A was transferred to Reactor B. 5% Platinum on Alumina (Pt/Al, 0.10 kg, 0.10 kg/kg) was charged into Reactor B, followed by a rinse with tetrahydrofuran from Reactor A to Reactor B (1.0 L, 0.89 kg, 1.0 L/kg). Reactor B was purged twice with nitrogen at 20-30° C. The mixture was stirred at 25° C., 0.45-0.55 MPa for 16 h. Reactor B and then vented and purged with nitrogen. The mixture was filtered into Reactor A and tetrahydrofuran (1.0 L, 0.89 kg, 1.0 L/kg) was used as a rinse.
    • Step 3: Alternative Reaction Work-Up
  • Water (7.5 L, 7.5 kg, 7.5 L/kg) and ammonium citrate tribasic (4.39 kg, 5.1 equiv) were charged to Reactor C. Reaction stream from Reactor A was transferred to Reactor C at a rate such that the temperature did not exceed 30° C. The mixture in Reactor C was heated to 40-50° C. and aged for 1 h. The mixture in Reactor C was cooled to 15-25° C. and stirred for 0.5 h. Agitation was stopped and phases were allowed to settle for 1 h at 15-25° C. (target 20° C.). The phases were separated and the lower aqueous layer from Reactor C was sent to waste.
  • The batch was concentrated until 2-3 L/kg remained with respect to (3aR,7aS)-tert-butyl 3-acetyl-5-oxooctahydro-1H-benzo[d]imidazole-1-carboxylate (Compound 3). Methyl tert-butyl ether was charged (5.0 L, 3.7 kg, 5.0 L/kg) at NMT 50° C. into Reactor C. The batch was again concentrated until 2-3 L/kg remaining with respect to Compound 3. Methyl-tert-butyl ether (10.0 L, 7.4 kg, 10.0 L/kg) was then charged into Reactor C.
  • Reactor A (prerinsed) was charged with water (0.94 L, 0.94 kg, 0.94 L/kg) and sodium chloride (0.10 kg, 0.10 kg/kg). Temperature of the mass in Reactor C was adjusted to 15-25° C. The sodium chloride solution from Reactor A was added to the mass in Reactor C and agitated for 0.5 h. Agitation was stopped and phases allowed to settle for 1 h at 15-25° C. target 20° C. Phases were then separated and the lower aqueous layer from Reactor C was sent to waste.
  • The reaction stream from Reactor C was filtered into a clean and nitrogen-filled Reactor D. Added Methanol (5.0 L, 3.96 kg, 5.0 L/kg) into Reactor C, then transferred to Reactor D. The batch in reactor D was concentrated until 2-3 L/kg remained with respect to Compound 3.
    • Step 4: Alternative Crystallization
  • Charged Methanol to Reactor D (4.0 L, 3.16 kg, 4.0 L/kg) through an in-line filter at NMT 50° C. The amount of Compound 4 in solution was quantified. Added Methanol (2.0 L, 1.58 kg, 2.0 L/kg) and L-(+)-Tartaric Acid (1.15 equiv relative to compound 4 in solution) into Reactor C at 10-30° C. The solution of L-(+)-Tartaric Acid was then transferred to Reactor D through an in-line filter at 20-30° C. and the solution in Reactor D was heated to 48-53° C. MTBE (18.0 L, 13.3 kg, 18.0 L/kg) was then charged to Reactor D at 48-53° C. at a rate such that the temperature stays above 48° C. The reaction mixture was aged at 48-53° C. until solid precipitation is observed, then cooled to 20-25° C. at a rate of 5-10° C./h, and aged for 4 h.
    • Step 5: Alternative Isolation
  • The solids were then filtered. Methyl tert-Butyl Ether (2.0 L, 1.48 kg, 2.0 L/kg) was charged to Reactor D through an in-line filter and used to rinse the product cake. The cake was dried at a jacket set point of 45-50° C., under reduced pressure with a nitrogen sweep for NLT 10 h.
  • HPLC analysis:
    Compound 4a: 99.6 AP (6.8 min)
    • Column: YMC ProC18 Sum 50×4.6 mm Solvent A: 0.05% TFA in CH3CN:Water (5:95) Solvent B: 0.05% TFA in CH3CN Gradient: % B: 0 Min. 0%; 8 Min. 25%; 0 Min. 100%; Stop Time: 12 min
  • Flow Rate: 1.0 ml/min
    • Wavelength: 205 nm
  • 1H NMR (400 MHz, Methanol-d4) δ 4.98 (d, J=8.6 Hz, 1H), 4.92 (d, J=7.1 Hz, 1H), 4.58 (d, J=8.8 Hz, 1H), 4.45 (dt, J=10.9, 5.8 Hz, 1H), 4.36-4.30 (m, 4.4H), 3.85-3.82 (m, 1H), 3.76-3.73 (m, 1H), 3.42-3.35 (m, 2H), 3.27 (ddd, J=4.8, 3.3, 1.5 Hz, 4.4H), 2.93 (d, J=14.4 Hz, 1H), 2.81 (d, J=15.9 Hz, 1H), 2.39-2.33 (m, 1H), 2.27-2.21 (m, 1H), 2.09 (s, 3H), 2.02 (s, 3H), 1.90-1.83 (m, 2H), 1.82-1.71 (m, 2H), 1.65-1.51 (m, 3H), 1.46 (s, 9H), 1.45 (s, 9H), 1.39 (s, 9H), 1.38 (s, 9H), 1.32-1.21 (m, 1H).
  • 13C NMR (100 MHz, Methanol-d4) δ 177.3, 170.2, 170.1, 156.2, 155.9, 82.6, 82.4, 74.4, 62.3, 61.4, 59.5, 59.4, 57.9, 56.5, 55.6, 55.4, 51.6, 51.3, 50.0, 33.4, 31.8, 30.9, 28.8, 26.7, 26.7, 26.6, 26.5, 24.9, 22.1, 21.2.
    • Example 3 Preparation of Compound 9
  • Figure US20220177482A1-20220609-C00033
    • Step 1: Boc-Deprotection
  • Compound 4a 50 g, (102.13 mmol) and 2-propanol (4 mL/gram limiting reagent) are mixed, and heated to 58° C. Concentrated sulfuric acid (0.63 g/gram of limiting reagent or 3 equiv) was charged to the reaction mixture over ˜1 h and aged at 58° C. for 4 h total. The batch was cooled to 40° C., and the solids were then filtered. The cake was washed with 2-propanol (2 ml/gram limiting reagent), and dried at 60° C. for 12 h to give compound 5a.
  • 1H NMR (500 MHz, DMSO-d6) δ 10.53-8.96 (m, 9H), 8.38-8.03 (m, 5H), 7.98 (br d, J=7.0 Hz, 1H), 7.86 (br d, J=2.7 Hz, 1H), 4.86 (d, J=7.9 Hz, 1H), 4.74 (d, J=7.9 Hz, 1H), 4.68-4.52 (m, 4H), 4.46 (dt, J=11.3, 6.0 Hz, 1H), 3.90 (br s, 2H), 3.78 (br d, J=4.6 Hz, 1H), 3.40 (br s, 3H), 2.41-2.21 (m, 3H), 2.21-1.95 (m, 13H), 1.93-1.77 (m, 5H), 1.61 (q, J=12.2 Hz, 2H), 1.52-1.40 (m, 1H), 1.33 (br d, J=12.2 Hz, 24H), 1.04 (d, J=6.1 Hz, 1H).
  • Steps 2 through 5: All the equivalencies were calculated based on Compound 5a.
    • Step 2: Reductive Amination
  • In a 2 L reactor containing a mixture of Compound 5a (58.01 g, 1.0 equiv., 133.8 mmol), Compound 6 (47.95 g, 1.05 equiv., 140.5 mmol) and DIPEA (69.02 g, 4.0 equiv., 535.2 mmol) in methylene chloride (DCM, 870 mL, 15 L/kg) was added sodium triacetoxyborohydride (32.16 g, 1.13 equiv., 151.7 mmol) and the resulting reaction mass was stirred at room temperature. Upon reaction completion as per HPLC analysis, water (580 mL, 10 L/kg) was added slowly and the resulting biphasic liquid mixture was stirred for 12 hours whereupon the agitation was stopped to allow the phase separation. The lower organic layer was concentrated down to 290 mL residual volume under reduced pressure and isopropyl acetate (IPAc, 580 mL, 10 L/kg) was charged in the reactor. The resulting homogeneous mixture was concentrated again to a residual volume of 290 mL under a reduced pressure of 200 mbar. Upon a second addition of IPAc (290 mL, 5 L/kg) the mixture was concentrated a third time to a residual volume of 290 mL and a third IPAc charge (232 mL, 4 L/kg) was performed providing a rich solution of Compound 7 in IPAc (9 L/kg) ready for processing in the next step.
    • Step 3: Cleavage of the Methylene Tether
  • To the aforementioned solution of Compound 7 cooled to 10° C., was added a solution of 50 wt % aqueous hydroxylamine (11.36 g, 1.30 equiv., 172.0 mmol) followed by TFA (51.84 g, 3.4 equiv., 454.6 mmol). The resulting mixture was heated at 56-57° C. for 4.5 hours. Upon completion of the reaction as per HPLC analysis, the heterogeneous mixture was cooled to 0° C. and 290 mL of 2 N aqueous NaOH (580 mmol, 4.35 eq) was slowly added between 5 and 10° C. The biphasic mixture was stirred for 1 hour at 5-10° C. before stopping agitation to allow the phase split. The upper organic layer was treated with 220 mL of 17 wt % aqueous K3PO4 at 5° C. for 1 hour with agitation and for 30 minutes without agitation to allow the phases to split. The upper organic layer was washed at 10° C. with 232 mL of 14 wt % aqueous NaCl (4 L/kg) for 30 min with agitation and 30 minutes without agitation to allow the phase separation. The upper organic layer was concentrated to a residual volume of 290 mL (5 L/kg) under a reduced pressure of 100 mbar whereupon toluene (464 mL, 8 L/kg) was added and the resulting mixture was concentrated a second time down to 290 mL at 100 mbar and a jacket temperature <70° C. A second toluene addition (464 mL, 8 L/kg) followed by a third concentration to 5 L/kg residual was performed under the same temperature and pressure conditions whereupon the distillation residue was diluted with more toluene (232 mL, 4 L/kg) to give a dry toluene solution of Compound 8 ready for processing in the next step.
    • Step 4: Annulation to Form Compound 9
  • The Compound 8 rich toluene solution was treated with acetic acid (14.15 g, 1.75 equiv. 235.6 mmol) and the resulting mixture was heated under agitation at 57° C. for 5 hours at which point the reaction was complete as indicated by HPLC analysis. The reaction mixture was cooled to 25° C. whereupon water (523 mL, 9 L/kg) was added and the biphasic mixture was kept for 1 hour with agitation and 1 hour without agitation before transferring the Compound 9 rich aqueous layer into a new reactor. The aqueous layer was mixed with IPAc (1.16 L, 20 L/kg) at 25-30° C. and 40 wt % aqueous K3PO4 (149 mL, 3 equiv.) was added and the biphasic mixture was stirred for 45 min before allowing the phase split and transfer of Compound 9 from the aqueous layer to the organic layer. The organic layer was washed with water (175 mL, 3 L/kg) at 25-30° C. with agitation before discarding the aqueous wash upon phase split. The organic layer was concentrated down to 525 mL (9 L/kg) residual under a pressure of 300 mbar with the jacket temperature <75° C. whereupon IPAc (290 mL) was charged and distilled to 525 mL performed again to dry the mixture to no more than 500 ppm of residual water.
    • Step 5: Crystallization and Isolation
  • The distillation residue was diluted with IPAc (60 mL, 1 L/kg) and the temperature was adjusted to 60° C. and 1 wt % of Compound 9 seeds (580 mg) were added to promote crystallization. The resulting slurry was aged for 2 hours at 55-60° C. whereupon further crystallization was promoted by the slow addition of n-Heptane (270 mL, 4.65 L/kg). The slurry was cooled to 20° C. in at least 2 hours, agitated for several hours before the solids were collected by filtration, washed once with IPAc/n-heptane 35/65 v/v (4.5 L/kg) and once with n-heptane (7.5 L/kg). The filter cake was dried under vacuum at 60° C. to provide Compound 9 as a white solid (45.87 g, 76.2 yield).
  • HPLC analysis:
    BnOH: 0.1 AP (5.33 min); Compound 9, benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate: 99.5 AP (6.91 min); unidentified impurity I: 0.3 AP (7.63 min); unidentified impurity II; 0.2 AP (9.86 min).
    • Column: YMC ProC18 Sum 4.6×50 mm Solvent A: 0.05% TFA in CH3CN:Water (5:95) Solvent B: 0.05% TFA in CH3CN Gradient: % B: 0 Min. 0%; 8 Min. 25%; 15 Min. 100%
  • Flow Rate: 1.0 mL/min
    • Wavelength: 205 nm
  • 1H NMR (400 MHz, CDCl3) δ 9.35 (br s, 1H), 7.37-7.26 (m, 5H), 6.00 (br d, J=7.1 Hz, 1H), 5.10 (s, 2H), 4.56 (br s, 1H), 4.31 (q, J=7.4 Hz, 1H), 3.93 (br d, J=11.6 Hz, 1H), 3.36 (br t, J=6.6 Hz, 2H), 3.15 (br t, J=3.0 Hz, 1H), 2.47-2.31 (m, 1H), 2.12-1.99 (m, 1H), 1.91 (s, 3H), 1.87-1.57 (m, 6H), 1.12 (s, 9H) ppm.
  • 13C NMR (101 MHz, CDCl3) δ 172.22, 169.57, 156.60, 136.65, 128.36, 127.94, 127.83, 83.64, 66.60, 53.66, 52.99, 51.61, 47.81, 45.89, 42.91, 34.32, 33.59, 29.66, 28.32, 23.81, 19.86 ppm.
    • Example 4 Preparation of Compound 10a
  • Figure US20220177482A1-20220609-C00034
  • All the equivalencies were calculated based on benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate (Compound 9; 10.0 g).
    • Step 1: Hydrogenation Reaction
  • A 300 mL Parr bomb reactor was charged with 7.1 kg/kg (9 L/kg) i-PrOH, benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate (Compound 9; 10.0 g), and 0.05 kg/kg (5 wt %) of 5% Pd/C 50% water catalyst. The vessel was then sealed and made inert. The sequence of pressurizing to 30 psig with N2, then venting down to 8 psig was repeated three times. The atmosphere was changed to hydrogen by performing the sequence of pressurizing to 30 psig with H2, then venting down to 8 psig three times. The pressure was set to 30 psig, and set to keep at constant pressure throughout the course of the reaction. The jacket was set to heat the reaction mixture to 35° C. The agitation was set such that the kLa >0.02 s−1. The mixture was stirred at 35° C. and 30 psig for 3-5 hours. The vessel was vented, then flushed with N2 by pressurizing to 30 psig and venting the vessel down to 8 psig three times. HPLC analysis showed <0.30 RAP starting material.
    • Step 2: Reaction Workup
  • The reaction mixture was filtered through a 0.5 μm filter, then a 0.2 μm Cuno cartridge filter and rinsed with 2-propanol (2 L/kg) into a clean reactor.
    • Step 3: Crystallization
  • A vessel was charged with 7.9 kg/kg (10 L/kg) of i-PrOH, heated to 50° C. under an inert atmosphere followed by HBr 0.95 kg/kg (2.5 mol/mol; 48 wt %, aqueous). 1.88 kg/kg (18 wt % of total process stream) containing free base compound 10 was added to the HBr solution and aged for 1-3 h at 45-50° C. 8.54 kg/kg (82 wt % of total process stream) of free base process stream was charged over a 1 h period, the solution was aged at 50° C. for 1 h and then cooled to 20° C. over the course of 1 h. The slurry was filtered and the reactor was rinsed with 3 L/kg of i-PrOH. The cake was then washed with the reactor rinse. The cake was washed twice with 2-propanol (3 L/kg). The wet cake was dried in a vacuum oven at 70° C. under vacuum for 24 h. The product (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylammonio)cyclohexyl)-2-oxopyrrolidin-3-aminium bromide (Compound 10a) was isolated as a white solid powder (86% yield).
    • HPLC Analysis:
  • Benzyl alcohol: <0.20 AP (3.7 min); N-((1R,2S,5R)-2-((S)-3-amino-2-oxopyrrolidin-1-yl)-5-(tert-butylamino)cyclohexyl)acetamide (Compound 9): >99.60 AP (4.7 min); benzyl ((S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-yl)carbamate (Compound 8): <0.20 AP (13.3 min).
    • Column: Waters XBridge Phenyl, 3.5 μm, 4.6×150 mm Solvent A: Water: MeCN:MeOH (90:8:2+0.05% NH4OH) Solvent B: MeCN:MeOH (80:20+0.05% NH4OH)
  • Gradient: % B: 0 min 22%; 20 min 55%; 25 min 90%; 30 min 22%; 35 min 22%; Stop time=35 min
    Flow rate: 1 mL/min
    • Wavelength: 220 and 205 nm
  • Injection volume: 10 μL
    Column temperature: ambient
  • 1H NMR (400 MHz, DMSO-d6) δ 8.39 (br s, 5H), 7.80 (d, J=8.6 Hz, 1H), 4.23-4.06 (m, 2H), 3.95 (t, J=9.2 Hz, 1H), 3.87 (br t, J=8.6 Hz, 1H), 3.67-3.51 (m, 2H), 2.45-2.32 (m, 1H), 2.15 (dq, J=12.4, 9.0 Hz, 1H), 2.02-1.67 (m, 9H), 1.45-1.28 (m, 9H); 13C NMR (101 MHz, DMSO-d6) δ 170.5, 168.9, 57.8, 51.0, 49.8, 47.5, 47.2, 45.2, 32.7, 26.5, 26.0, 24.8, 23.6, 22.7
    • Example 5
  • Figure US20220177482A1-20220609-C00035
    • Example 5 Preparation of Compound I Step 1: Activation of Compound 11
  • Compound 11 (7.16 g, 1.76 equiv), 1-methylimidazole (66 ml) and dichloromethane (DCM, 44 ml) were charged into a jacketed-reactor equipped with overhead stirring. The jacket temperature was set to 0° C. Diphenyl phosphoryl chloride (1.76 equiv., 7.75 mL) was added dropwise at a rate such that the batch temperature was maintained <5° C. The reaction mixture was aged for ˜ 20 h at 0° C. and sampled (25 uL in 10 ml anhydrous MeOH) for reaction completion.
    • Step 2: Coupling Reaction
  • The process stream in step 1 was diluted with DCM (25 ml), Compound 10a (1.0 equiv, 10.0 g) was added to the reaction mixture at 0° C., followed by a second DCM charge (25 ml) and the process stream aged for 5-20 h.
    • Step 3: Work-Up
  • The reaction mixture was diluted with DCM (60 mL) and then quenched by the slow addition of a solution of citric acid monohydrate (57.4 g) in water (77.6 ml) to the process stream, followed by the addition of saturated NaCl(aq) solution (26 wt % in water, 82.5 ml). After mixing, the phases were separated, the product rich DCM layer was washed with a solution of NaOH (10 equiv) dissolved in water (150 ml); the phases were mixed, split, and the product rich DCM layer was extracted with water HCl (5 equiv in 150 ml water). The phases were separated; the organic layer discarded, and the product rich aqueous phase was treated with DCM (150 ml) and NaOH (6 equiv), the layers mixed and then separated. The product rich DCM layer was washed with water (50 ml).
    • Step 4: Distillation-Polish Filtration
  • The wet product rich DCM process stream was polish filtered into a reactor, concentrated by vacuum distillation (300 mbar, jacket 30° C.) to 5 L/kg, then constant volume solvent swap to 2-methyl THE (9 L/kg), maintaining volume at 5 L/kg. When distillation was complete, 7 L/kg 2-methyl THE was added. Distillation and solvent swap were complete when KF (<0.1 wt %) and residual DCM level (<3 wt % DCM) met specifications.
    • Step 5: Crystallization-Isolation
  • The batch was heated to 60° C. until the solids dissolved, and the reaction was cooled to 40° C. The reaction was charged with 1 wt % compound I and aged for 2 h. The batch was cooled to 20° C. over a 2 h period, and n-heptane (23 L/kg) was charged over a 2 h period. The slurry was aged overnight, filtered, and the reactor and cake were washed with 5 L/kg of 40:60 (wt/wt) 2-methyl THE to n-heptane. The cake was washed twice with 5 L/kg n-heptane and then dried under vacuum at 60° C. The final product, Compound I, was isolated as a white solid (80% yield)
  • Figure US20220177482A1-20220609-C00036
  • The numbering system shown above is for convenience only and may not be consistent with IUPAC nomenclature.
    • 1H NMR Assignments of Compound I
  • Assignment Chemical Shifta, b Multiplicityc, J Hz Number of Protons
    2 4.86 t, 8.9 1
    3 2.36 m 1
    2.05 m 1
    4 3.48 m 2
    5 3.84 m 1
    6 2.12 m 1
    1.58 m 1
    7 1.64 m 2
    8 2.93 br s 1
    9 1.58 m 2
    10 4.26 br s 1
    12 1.81 s 3
    14, 15, 16 1.04 s 9
    18 8.07 s 1
    20 6.39 s 1
    24, 25, 26 1.34 s 9
    10′ 8.94 br s 1
    (a) δ ppm, relative to the residual proton in solvent DMSO-d6 at 2.49 ppm
    (b) The very broad singlet at δ8.35 is from either H-2′ or H-8′. One of these protons was not observed.
    (c) s = singlet, d = doublet, m = multiplet, br = broad
    • 13C NMR Assignments of Compound I
  • Assignment Chemical Shifts Multiplicityb
    1 171.2 C
    2 51.7 CH
    3 25.9 CH2
    4 43.1 CH2
    5 52.5 CH
    6 21.3 CH2
    7 32.2 CH2
    8 46.5 CH
    9 35.5 CH2
    10 47.7 CH
    11 168.5 C
    12 23.3 CH3
    13 50.7 C
    14, 15, 16 29.3 CH3
    17 148.8c C
    18 152.9 CH
    19 148.7c C
    20 92.3 CH
    21 167.3 C
    22 32.6 C
    23, 24, 25 30.0 CH3
    (a) δ ppm, relative to DMSO-d6 at 39.5 ppm
    (b) Multiplicity was obtained from DEPT-135 spectrum
    (c) Assignments may be reversed
    • Example 6 Preparation of Compound 6
  • Figure US20220177482A1-20220609-C00037
    • Step 1 Preparation of Compound 14a
  • Neat 1-Methylimidazole (3.0 equiv.) was added to an ice-cooled clear colorless solution of TCFH (1.25 equiv.) in acetonitrile (10 mL/g Z-ASP-OBL). Cooling was discontinued and the resulting clear solution was allowed to warm to 20° C. Solid Z-ASP-OBL (1.0 equiv.) was added to the stirred solution in a single portion, and the resulting clear colorless to faint yellow solution was stirred at 20° C. for 1 h. Neat 1-dodecanethiol (1.05 equiv.) was added in a single portion and the reaction mixture was stirred until complete as judged by HPLC. The reaction mixture was cooled to an internal temperature of 12° C. and water (0.02 mL/g Z-ASP-OBL) was added. The thin suspension was stirred for 1-2 h, then a solution of 50/50 acetonitrile-water (10 mL/g Z-ASP-OBL) was added to the reaction mixture resulting in a thick suspension of white solid. The suspension was stirred at 12° C. for 2 h, then the solid product was collected by filtration, washed with 50/50 acetonitrile-water and dried in a drying oven to give compound 14a as a white solid in 85% yield.
  • 1H NMR (500 MHz, CHLOROFORM-d) δ 7.39-7.26 (m, 10H), 5.72 (br d, J=8.2 Hz, 1H), 5.21-5.07 (m, 4H), 4.65 (dt, J=8.2, 4.4 Hz, 1H), 3.30-3.06 (m, 2H), 2.83 (t, J=7.5 Hz, 2H), 1.63 (br s, 1H), 1.51 (quin, J=7.3 Hz, 2H), 1.37-1.20 (m, 19H), 0.88 (t, J=6.9 Hz, 3H)
  • 13C NMR (126 MHz, CHLOROFORM-d) δ 196.9, 170.4, 155.9, 136.2, 135.2, 128.6, 128.5, 128.4, 128.3, 128.2, 128.1, 67.6, 67.1, 50.9, 45.2, 31.9, 29.6, 29.5, 29.2, 29.2, 22.7, 14.1
    • Step 2 Preparation of Compound 6
  • Solid 5% Pd/Al2O3 (4 wt % relative to compound 14a) was charged to a reaction flask under nitrogen. In a separate flask, compound 14a (limiting reagent, 1.0 Equiv.) was combined with acetonitrile (3.7 mL/g relative to compound 14a) and the mixture stirred under a homogenous solution resulted. The solution was sparged by bubbling N2 through the solution for 15 minutes at room temperature. The solution was added to the catalyst in the flask and the mixture was stirred at room temperature (22-23° C.). Neat triethylsilane (1.15 equiv.) was added dropwise to the mixture over 5 minutes and the reaction mixture stirred until compound 14a was consumed as judged by HPLC analysis. The catalyst was then removed by filtration and the catalyst bed was washed with 1 mL/g acetonitrile. The filtrate was then extracted with twice with n-heptane (4 mL/g).
  • In a separate flask, sodium bisulfite (0.48 g/g compound 14a) was combined with water (6.0 mL/g compound 14a) and the mixture stirred until a homogenous solution resulted. The product stream was diluted with methyl tert-butyl ether (4.0 mL/g) and the sodium bisulfite solution was added to the product solution and the biphasic mixture stirred vigorously until compound 6 was not detected in the organic phase. The phases were separated and the aqueous product stream extracted twice more with methyl tert-butyl ether (4.0 mL/g compound 14a). The aqueous product solution was cooled to 5° C.
  • In a separate flask, disodium hydrogenphosphate (0.2 g/g compound 14a) and monosodium phosphate (0.16 g/g compound 14a) were dissolved in water (1.0 mL/g/compound 14a). This solution was added to the 5° C. aqueous product solution such that the internal temperature remained below 10° C. Methyl tert-butyl ether (10 mL/g compound 14a) was added and the biphasic mixture stirred vigorously. A commercial 37 wt % solution of formaldeyde (0.6 g/g compound 14a) was then added to the biphasic mixture at 5° C. The reaction mixture as stirred at 5° C. until the bisulfite adduct of compound 6 was not detected in the aqueous phase by HPLC. The phases were separated and the organic product stream was washed with 5% aqueous sodium chloride (3.0 mL/g compound 14a) solution twice. The organic product phase was concentrated to a final volume of 2.0 mL/g compound 14a. n-Heptane (8.0 mL/g compound 14a) was added to the 20° C. product solution in MTBE to crystallize the product. The solid compound 6 was collected by filtration and washed with n-heptane (2.0 mL/g). The solid was dried at 40° C. The isolated yield was 65%.
  • 1H NMR (500 MHz, CHLOROFORM-d) δ 9.68 (s, 1H), 7.43-7.24 (m, 11H), 5.71 (br d, J=7.9 Hz, 1H), 5.27-5.01 (m, 4H), 4.68 (dt, J=8.2, 4.4 Hz, 1H), 3.17-3.08 (m, 1H), 3.07-2.98 (m, 1H).
  • 13C NMR (126 MHz, CHLOROFORM-d) δ 199.1, 170.5, 155.9, 136.1, 135.0, 128.6, 128.6, 128.3, 128.2, 128.1, 67.7, 67.2, 49.2, 45.8.
    • Preparation of Compound 6—Alternate Procedure
  • Compound 14a (13.48 g, 24.88 mmol, 100.0 mass %) dissolved in acetonitrile (50 mL, 252 mmol, 99.9 mass %) in a 250 mL single necked round bottomed flask.
  • Solid 5% Pd/C (651 mg, 0.30586 mmol, 5 mass %) was charged to a 100 mL stainless steel hydrogenation vessel and the vessel sealed up. The prepared compound 14a solution was charged to the vessel under nitrogen. Neat triethylsilane (8.2 mL, 50 mmol, 99 mass %) was added over 1 min under nitrogen, then the vessel was sealed. The reaction was allowed to stir for 4 h.
  • The reaction mixture was removed from the reactor and filtered through a 0.45 um PTFE filter. The solid in the filter was rinsed with acetonitrile (25 mL, 126 mmol, 99.9 mass %). The combined filtrate was biphasic having a dark colored phase that settled to the bottom of the flask.
  • The biphasic product stream was well mixed and 55 mL heptane were added. The jacket was set at 20° C. and the biphasic mixture agitated for 15 minutes. The phases were allowed to separate and the bottom acetonitrile phase was clear and colorless. The top phase was dark burnt orange color.
  • Pressure was reduced to 60 torr and distillation began immediately. The internal temperature dropped to 13-14° C., so the jacket temperature was increased to 25° C. Once the landmark of 21 mL was reached, 50 mL toluene were added by vacuum transfer. The pressure was reduced to 25 torr; jacket temperature was adjusted to 35° C. and the internal temperature started at 11-12° C. The internal temperature increased to 29.5° C. Once the distillation was complete, the jacket was set at 40° C. and cyclohexane (21 mL, 194 mmol, 99.9 mass %) was added. Solid compound 6 (100 mg, 0.2783 mmol, 95.00 mass %) was added in a single portion. The batch was held at 40° C. jacket temperature for 1 h, then cooled to 20° C. over 2 h and held at 20° C. overnight.
  • The mixture was a suspension of white solid. Neat cyclohexane (21 mL, 194 mmol, 99.9 mass %) was added to the suspension via syringe pump over 2 h and the suspension stirred for 5 h at 20° C. The solid product was collected on a 55 mm Whatman #1 filter paper. The mother liquor was recycled to the rinse out the reactor, then the cake was washed with 20 mL cyclohexane. The cake was air dried for 15 minutes, before transfer to a 20° C. drying oven to dry over the weekend to give 5.6 g, 62.7% yield of compound 6.

Claims (1)

We claim:
1. A compound as shown in the table below;
Compound No. Structure 3
Figure US20220177482A1-20220609-C00038
 4
Figure US20220177482A1-20220609-C00039
 4a
Figure US20220177482A1-20220609-C00040
 5
Figure US20220177482A1-20220609-C00041
 5a
Figure US20220177482A1-20220609-C00042
 7
Figure US20220177482A1-20220609-C00043
 8
Figure US20220177482A1-20220609-C00044
 9
Figure US20220177482A1-20220609-C00045
 10
Figure US20220177482A1-20220609-C00046
 10a
Figure US20220177482A1-20220609-C00047
 14
Figure US20220177482A1-20220609-C00048
 14a
Figure US20220177482A1-20220609-C00049
US17/677,312 2017-07-20 2022-02-22 Process for the preparation of n-((1r,2s,5r)-5-(tert-butylamino)-2-((s)-3-(7-tert-butylpyrazolo[1,5-a][1,3,5]triazin-4-ylamino)-2-oxopyrrolidin-1-yl)cyclohexyl)acetamide Abandoned US20220177482A1 (en)

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