WO2018183649A1 - Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide - Google Patents

Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide Download PDF

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WO2018183649A1
WO2018183649A1 PCT/US2018/025100 US2018025100W WO2018183649A1 WO 2018183649 A1 WO2018183649 A1 WO 2018183649A1 US 2018025100 W US2018025100 W US 2018025100W WO 2018183649 A1 WO2018183649 A1 WO 2018183649A1
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compound
formula
afford
reacting
base
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PCT/US2018/025100
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French (fr)
Inventor
Ke Chen
Joerg Deerberg
Dong Lin
Michael DUMMELDINGER
Bahar INANKUR
Sergei V. Kolotuchin
Jun Li
Amanda J. ROGERS
Victor W. Rosso
Eric M. SIMMONS
Maxime C. D. SOUMEILLANT
Daniel S. Treitler
Jianji Wang
Bin Zheng
Michael J. Smith
Neil A. Strotman
Steven Tymonko
Tamas BENKOVICS
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Bristol Myers Squibb Co
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Bristol Myers Squibb Co
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Priority to CA3058177A priority patent/CA3058177A1/en
Priority to PL18718340T priority patent/PL3601268T3/en
Priority to EP23209227.0A priority patent/EP4296258A3/en
Priority to RS20210559A priority patent/RS61816B1/en
Priority to EA201992308A priority patent/EA201992308A1/en
Priority to US16/498,442 priority patent/US10899745B2/en
Priority to KR1020247034512A priority patent/KR102857398B1/en
Priority to SG11201908947Q priority patent/SG11201908947QA/en
Priority to EP18718340.5A priority patent/EP3601268B1/en
Priority to SI201830252T priority patent/SI3601268T1/en
Priority to CN201880021649.8A priority patent/CN110475774B/en
Priority to EP21155321.9A priority patent/EP3882237B1/en
Priority to IL269586A priority patent/IL269586B/en
Priority to CN202310552731.6A priority patent/CN116813561B/en
Priority to HRP20210764TT priority patent/HRP20210764T1/en
Application filed by Bristol Myers Squibb Co filed Critical Bristol Myers Squibb Co
Priority to KR1020197031634A priority patent/KR102720054B1/en
Priority to SM20210239T priority patent/SMT202100239T1/en
Priority to KR1020257017189A priority patent/KR20250080914A/en
Priority to ES18718340T priority patent/ES2864450T3/en
Priority to MX2019011092A priority patent/MX392693B/en
Priority to JP2019553452A priority patent/JP7113023B2/en
Priority to AU2018244916A priority patent/AU2018244916B2/en
Publication of WO2018183649A1 publication Critical patent/WO2018183649A1/en
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Priority to US17/131,718 priority patent/US11649226B2/en
Priority to CY20211100374T priority patent/CY1124194T1/en
Priority to AU2021261839A priority patent/AU2021261839B2/en
Priority to JP2022117894A priority patent/JP7457758B2/en
Priority to US18/134,564 priority patent/US12565487B2/en
Priority to JP2023208420A priority patent/JP7837938B2/en
Priority to JP2025284416A priority patent/JP2026067880A/en
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    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/501—Pyridazines; Hydrogenated pyridazines not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
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Definitions

  • the invention generally relates to a process for the preparation of 6- (cyclopropaneamido)-4-((2-methoxy-3-(l-methyl-lH-l,2,4 riazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide, a Tyk2 inhibitor currently in clinical trials for the treatment of auto-immune and auto-inflammatory diseases such as psoriasis, as well as novel intermediates used in the process.
  • the invention provides a process for preparing Compound I of the formula:
  • R is C1-C6 alkyl or an ;
  • the invention provides a process for preparing Compound I of the formula:
  • Compound 13 can be isolated as the free base, or as an HCl or HBr salt.
  • Compound 9b Another aspect of the invention provides Compound I prepared by the process of
  • a final aspect of the invention provides a method for treating auto-immune and auto-inflammatory diseases such as psoriasis comprising administering to a mammalian species, preferably a human, in need thereof, a therapeutically effective amount of Compound I, 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.
  • Preferred palladium catalysts include, but are not limited to Pd(OAc)2, PdCh(MeCN)2, Pd2(dba)3, Pd(dba) 2 , [(Allyl)PdCl] 2 , [(Crotyl)PdCl] 2 .
  • ligands include, but are not limited to phosphine ligands such as SL- J009-1, SL-J009-2, SL-J002-1, SL-J002-2, DPEphos, Xantphos, DPPF, DCyPF, BINAP, or derivatives thereof.
  • the processes of the first and second aspects are also conducted in the presence of a base.
  • Preferred bases include, but are not limited to, K2CO3, K3PO4, CS2CO3, DBU, DBN, TMG, or combinations thereof, particularly DBU/K2CO3.
  • Compound la is reacted with an activating reagent to give 4,6-diactivatedpyridazine Compound 2a.
  • Ester hydrolysis occurs in the presence of a base to generate compound 3a as carboxylic acid or its salt form.
  • Compound 3a can be selectively substituted at C4 position with compound 7 through contact with an appropriate acid, base or metal salt, or under neutral conditions in the absence of any additives, yielding Compound 8a.
  • Compound 8a can be isolated as its free form, or optionally as a salt with an appropriate base.
  • Compound 8a in the presence of a metal, an appropriate ligand, and a base, will undergo a coupling process with compound 10 to form Compound 9a.
  • the coupling of compound 9a with compound 13 occurs in the presence of an activating reagent and an optional base generates compound I.
  • Diethyl 1,3-acetonedicarboxylate is sequentially treated with 4-acetamidobenzenesulfonyl azide and Hunig's base, tributylphosphine and water, and acetic acid, to generate Ethyl 4,6-dihydroxypyridazine-3-carboxylate (Compound 1).
  • Chlorodehydration with phosphorus oxy chloride affords the corresponding dichloride (Compound 2), which undergoes hydrolysis in the presence of lithium bromide and Hunig's base in aqueous acetonitrile to yield the lithium carboxylate (Compound 3).
  • Compound 4 reacts with N-methyl-N-formylhydrazine in the presence of potassium tert- butoxide to give compound 5.
  • Treatment of compound 5 with nitric acid and concentrated sulfuric acid delivers compound 6, which reacts with hydrogen gas in the presence of Pd/C and sodium carbonate or sodium bicarbonate to give compound 7.
  • toluene (3.46 Kg, 4.0 L/Kg) and ACN (1.57 Kg, 2.0 L/Kg) were charged to a glass-lined reactor flushed with nitrogen.
  • Compound 8 (1.00 Kg) was added, followed by DBU (0.39 kg, 1.00 equiv).
  • the reactor line was rinsed with toluene (0.43 Kg, 0.5 L/Kg).
  • Compound 10 (0.54 Kg, 2.5 equiv) and K2CO3 (325 mesh grade, 0.70 Kg, 2.0 equiv) were added to the reaction mixture, followed by toluene (1.30 Kg, 1.5 L/Kg) and ACN (0.79 Kg, 1.0 L/Kg).
  • the pre-formed catalyst solution was transferred into the reaction mixture, which was then heated to 75 °C and agitated until the reaction reached completion.
  • the reaction crude was cooled to 20 °C.
  • Aq. acetic acid (50 Volume %, 4.0 Kg, 4.0 L/Kg) was charged slowly over the course of 1 h. Glacial acetic acid (10.5 Kg, 10.0 L/Kg) was then added. The resulting homogeneous solution was washed twice with heptane (2 ⁇ 3.42 kg, 2 ⁇ 5.0 L/Kg). The bottom aq. layer was collected and transferred to a clean reactor. Water (5.0 Kg, 5.0 L/Kg) was added, followed by compound 9 seeds (0.01 Kg, 1.0 wt%). The slurry was aged for 2 h at 20 °C.
  • NMP (2.06 Kg, 2.0 L/Kg) and ACN (0.78 Kg, 1.0 L/Kg) were charged to a glass- lined reactor and agitated at 20 °C.
  • Compound 13 (0.17 Kg, 1.2 eq)
  • Compound 9 (1.00 Kg) were charged to the reaction mixture.
  • the mixture was heated to 65 °C and aged until homogeneous.
  • EDC HC1 (0.54 Kg, 1.4 eq
  • the reactor was rinsed with ACN (0.78 Kg, 1.0 L/Kg), then the resulting mixture was aged at 65 °C until reaction reaches completion.
  • the reaction was quenched by charging water (1.0 Kg, 1 L/Kg), then diluted with ACN (3.0 Kg, 3 L/Kg).
  • the reaction mixture was aged at 65 °C for 1 h, before cooling to 0 °C, and aged for an additional 12 h at 0 °C.
  • the product was isolated by filtration.
  • the wet cake was washed with 2: 1 Water: ACN (2.8 Kg, 3 L/Kg) then ACN (2.4 Kg, 3 L/Kg), before drying under full vacuum at 65 °C.
  • Compound I was isolated in >99.5% purity and 91% yield
  • the product can be subjected to optional recrystallization as follows.
  • NMP 6.2 kg, 6.0 L/Kg
  • Compound I 1.0 Kg
  • the batch was heated to 70°C to form a pale yellow solution, which was then transferred through a polish filter to a clean vessel at 70 °C.
  • 2-Propanol 2.4 kg, 3 L/Kg
  • Compound I seeds 0.005 Kg, 0.005 Kg/Kg.
  • additional 2-propanol 4.8 kg, 6 L/Kg was charged over the course of 2 h (3 L/Kg/hr).
  • the crude was warmed up to 20 °C and aged for additional 6 h.
  • the crude was distilled under vacuum until total volume became approximately 0.5 L/Kg.
  • Five put/take distillations with 2-MeTHF (5 x 3.6 Kg/Kg) were undertaken for the purpose of azeotropic drying.
  • the crude was cooled to 20 °C.
  • N-Methyl-N-formylhydrazine was isolated as 89-90 wt% solution in 89-91% yield.
  • the collected organic layer was diluted with MTBE (4.0 Kg, 5.4 L/Kg), washed with brine twice (25 wt%, 4.0 Kg followed by 12 Kg).
  • the organic layer was distilled under vacuum until total volume became approximately 10 L/Kg.
  • Two put/take distillations with ACN (2 x 10 L/Kg) were undertaken for the purpose of azeotropic drying.
  • the crude was cooled to 20 °C.
  • ACN (10.0 Kg, 12.8 L/Kg) and NaN(CHO) 2 (3.3 Kg, 1.2 equiv) were added.
  • the crude was heated to 65 °C and agitated until reaction reached completion.
  • the product can be subjected to optional recrystallization as follows.
  • Methanol (5.6 Kg, 8.3 L/Kg) and Compound 13 (1.0 Kg) were charged to a glass-lined reactor.
  • DBU (0.1 Kg) was added slowly.
  • the crude was agitated for 1 h.
  • THF (12.4 Kg, 13.9 L/Kg) was added slowly, and the resulting slurry was aged for 2 h.
  • the product was isolated by filtration.
  • the cake was washed with THF (2.6 Kg, 2.9 L/Kg), and dried under vacuum at 45 °C.
  • Compound 13 was isolated in 60% yield (1 st crop).
  • the mother liquor was distilled under vacuum until total volume became approximately 1 L/Kg.

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Abstract

The invention relates to an improved process for synthesizing 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide of the formula: [INSERT CHEMICAL STRUCTURE HERE] Compound I is currently in clinical trials for the treatment of auto-immune and auto-inflammatory diseases such as psoriasis.

Description

PROCESS FOR THE PREPARATION OF 6-(CYCLOPROPANEAMIDO)-4-((2- METHOXY-3-(l-METHYL-lH-l,2,4-TRIAZOL-3-YL)PHENYL)AMINO)-N- (METHYL-D3)PYRIDAZINE-3-CARBOXAMIDE CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of U.S. Provisional Application No.
62/478,789, filed March 30, 2017, the disclosure of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The invention generally relates to a process for the preparation of 6- (cyclopropaneamido)-4-((2-methoxy-3-(l-methyl-lH-l,2,4 riazol-3-yl)phenyl)amino)- N-(methyl-d3)pyridazine-3-carboxamide, a Tyk2 inhibitor currently in clinical trials for the treatment of auto-immune and auto-inflammatory diseases such as psoriasis, as well as novel intermediates used in the process.
BACKGROUND OF THE INVENTION
There is disclosed a process for the preparation of 6-(cyclopropaneamido)-4-((2 methoxy-3-(l-methyl-lH-l,2,4 riazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3- carboxamide, of formula I:
Figure imgf000003_0001
(I)
Compound I, compositions comprising Compound I, and methods of using Compound I are disclosed in U.S Patent No. 9,505,748 B2, which is assigned to the present assignee and is incorporated herein by reference in its entirety.
SUMMARY OF THE INVENTION In a first aspect, the invention provides a process for preparing Compound I of the formula:
Figure imgf000004_0001
comprising the steps of
a) reacting compound la of the formula,
Figure imgf000004_0002
Compound la
where R is C1-C6 alkyl or an ;
with activating reagents to afford Compound 2a of the formula,
Figure imgf000004_0003
Compound 2a where Xi and X2 are independently halide or sulfonate; and R is defined as above, b) subsequently reacting Compound 2a with an aqueous base to afford Compound 3a of the formula,
Figure imgf000005_0001
Compound 3 a where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and Xi and X2 are as defined above, c) reacting Compound 3a, with Compound 7 of the formula
Figure imgf000005_0002
Compound 7 in a suitable solvent, and optionally in the presence of an acid, a base, or metal salts to afford Compound 8a of the formula,
Figure imgf000005_0003
Compound 8a where M and X2 are defined as above, d) reacting Compound 8a with Compound 10 of the formula NH2
Compound 10 in the presence of a suitable transition metal catalyst, a ligand, one or more bases, and one or more suitable solvents to afford Compound 9a of the formula,
Figure imgf000006_0001
Compound 9a where M is defined as above,
e) reacting Compound 9a with Compound 13 (free base or salts thereof) of the formula
D3C-NH2
Compound 13 in the presence of one or more suitable activators, one or more suitable solvents, and optionally a base, to afford final product Compound I. In a second aspect, the invention provides a process for preparing Compound I of the formula:
Figure imgf000007_0001
(I)
comprising the steps of
a) reacting a compound 1 of the formula
Figure imgf000007_0002
with POCh and optionally an amine base, followed optionally by a buffered aqueous workup to afford Compound 2 of the formula
Figure imgf000007_0003
Compound 2 b) subsequently reacting Compound 2 with LiBr and DiPEA in water and acetonitrile to afford Compound 3 of the formula
Figure imgf000007_0004
Compound 3 c) reacting Compound 3, with Compound 7 of the formula
Figure imgf000008_0001
Compound 7 in the presence of zinc acetate in water and 2-propanol, to afford Compound 8 of the formula,
Figure imgf000008_0002
Compound 8
a hydrate or solvate thereof;
reacting Compound 8 with Compound 10 of the formula
Figure imgf000008_0003
Compound 10 in a palladium catalyzed C-N coupling reaction in the presence of a phosphine ligand, and base, using a dual-base system comprised of potassium carbonate and DBU, followed optionally by isolation from aqueous acetic acid, to afford Compound 9 of the formula
Figure imgf000009_0001
Compound 9
or a hydrate or solvate thereof;
e) reacting Compound 9 with EDC or other coupling agents and Compound 13 of the formula
CD3NH2 HCI
Compound 13 to afford final product Compound I, which may be further purified by crystallization from NMP/IPA.
In a third aspect of the invention, there is provided a process of preparing
Compound 7 of the formula
Figure imgf000009_0002
Compound 7
comprising
a) reacting compound 4a of the formula
Figure imgf000009_0003
Compound 4a where X3 is CI, Br, I or F;
with N-methyl-N-formylhydrazine and a suitable base to afford Compound 5a of the formula
Figure imgf000010_0001
Compound 5 a where X3 is defined as above
b) which is then nitrated to afford Compound 6a of the formula
Figure imgf000010_0002
Compound 6a
where X3 is defined as above
c) which is subsequently reduced to afford Compound 7.
In a fourth aspect of the invention, there is provided a process of preparing Compound 7 of the formula
Figure imgf000010_0003
Compound 7
comprising
a) reacting compound 4 of the formula
Figure imgf000011_0001
Compound 4 with N-methyl-N-formylhydrazine in the presence of potassium tert-butoxide to afford Compound 5 of the formula
Figure imgf000011_0002
Compound 5
b) which is then reacted with nitric acid in the presence of concentrated sulfuric acid to afford Compound 6 of the formula
Figure imgf000011_0003
Compound 6 c) which is subsequently reacted with hydrogen gas in the presence of Pd/C, bicarbonate or sodium carbonate and methanol to afford Compound 7.
In a 5th aspect of the invention, there is provided a general process of preparing Compound 13 of the formula
CD3NH2
Compound 13 comprising
a) reacting d4-methanol of the formula
CD3OD with activating reagents to afford compound 1 la of the formula:
CD3X4
Compound 11a
where X4 is independently halide or sulfonate, b) which is then reacted with sodium diformylamide to afford Compound 12 of the formula
CHO
D3C-N
CHO
Compound 12 c) which is then hydrolyzed to afford Compound 13 of the formula
CD3NH2
Compound 13
Compound 13 can be isolated as the free base, or as an HCl or HBr salt.
In a 6th aspect of the invention, there is provided a process of preparing Compound 13 of the formula
CD3NH2
Compound 13 comprising
a) reacting d4-methanol of the formula CD3OD with tosyl chloride in the presence of aqueous sodium hydroxide to afford compound 11 of the formula:
CD3OTS
Compound 11 b) which is then reacted with sodium diformylamide to afford Compound 12 of the formula
CHO
D3C-N
CHO
Compound 12 c) which is then hydrolyzed in the presence of hydrochloride in methanol to afford Compound 13 (as hydrochloride salt) of the formula
CD3NH2 HCI
Compound 13. In a 7th aspect of the invention, there are provided novel intermediates identified above as Compounds 5, 6, 8, 9 and 12.
In an 8th aspect of the invention, there are provided compound 3, 5, 8 and 9 of the formula as its salt or hydrate form. In particular,
Figure imgf000013_0001
• x H20
Compound 3b
Figure imgf000014_0001
Compound 5b or 5 c
Figure imgf000014_0002
Compound 8b
Figure imgf000014_0003
Compound 9b Another aspect of the invention provides Compound I prepared by the process of
Claim 1.
A final aspect of the invention provides a method for treating auto-immune and auto-inflammatory diseases such as psoriasis comprising administering to a mammalian species, preferably a human, in need thereof, a therapeutically effective amount of Compound I, 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.
For the conversion of Compound 8(a) to Compound 9(a), the processes of the first and second aspects are conducted in the presence of a palladium catalyst. Preferred palladium catalysts include, but are not limited to Pd(OAc)2, PdCh(MeCN)2, Pd2(dba)3, Pd(dba)2, [(Allyl)PdCl]2, [(Crotyl)PdCl]2.
The processes of the first and second aspects are also conducted in the presence of a ligand. Preferred ligands include, but are not limited to phosphine ligands such as SL- J009-1, SL-J009-2, SL-J002-1, SL-J002-2, DPEphos, Xantphos, DPPF, DCyPF, BINAP, or derivatives thereof.
The processes of the first and second aspects are also conducted in the presence of a base. Preferred bases include, but are not limited to, K2CO3, K3PO4, CS2CO3, DBU, DBN, TMG, or combinations thereof, particularly DBU/K2CO3.
DETAILED DESCRIPTION OF THE INVENTION
The following schemes illustrate the improved synthetic steps of the invention. These Schemes are illustrative and are not meant to limit the possible techniques one skilled in the art may use to manufacture compounds disclosed herein.
As shown below in Scheme 1, the general preparation of compound I is described.
Compound la is reacted with an activating reagent to give 4,6-diactivatedpyridazine Compound 2a. Ester hydrolysis occurs in the presence of a base to generate compound 3a as carboxylic acid or its salt form. Compound 3a can be selectively substituted at C4 position with compound 7 through contact with an appropriate acid, base or metal salt, or under neutral conditions in the absence of any additives, yielding Compound 8a.
Compound 8a can be isolated as its free form, or optionally as a salt with an appropriate base. Compound 8a, in the presence of a metal, an appropriate ligand, and a base, will undergo a coupling process with compound 10 to form Compound 9a. Lastly, the coupling of compound 9a with compound 13 occurs in the presence of an activating reagent and an optional base generates compound I.
Scheme 1
Figure imgf000016_0001
Figure imgf000016_0002
As shown below in Scheme 2, the preparation of Compound I is described.
Diethyl 1,3-acetonedicarboxylate is sequentially treated with 4-acetamidobenzenesulfonyl azide and Hunig's base, tributylphosphine and water, and acetic acid, to generate Ethyl 4,6-dihydroxypyridazine-3-carboxylate (Compound 1). Chlorodehydration with phosphorus oxy chloride affords the corresponding dichloride (Compound 2), which undergoes hydrolysis in the presence of lithium bromide and Hunig's base in aqueous acetonitrile to yield the lithium carboxylate (Compound 3). Nucleophilic aromatic substitution with compound 7 takes place at C4 position of compound 3, in the presence of zinc acetate, leading to the formation of compound 8 as a zinc salt. Subsequent coupling with compound 10 is catalyzed by palladium acetate and a Josiphos ligand to generate compound 9. Finally, compound 9 undergoes an amidation with compound 13 in the presence of EDC, HOBt and NMI, affording compound I.
Scheme 2
Figure imgf000017_0001
Toluene
Step 1 Step 2
Zn(OAc)2 water 2-propanol
65 °C Step 3
Figure imgf000017_0002
DBU, K2C03, 75 °C
Step 5 Step 4
Scheme 3
Another process of the invention is disclosed in Scheme 3 shown below. The general preparation of compound 7 is described. A cyclocondensation of compound 4a with N-methyl-N-formylhydrazine affords compound 5a, which undergoes nitration to give compound 6a. Reduction then delivers the corresponding compound 7.
Figure imgf000017_0003
As shown below in Scheme 4, the preparation of Compound 7 is described.
Compound 4 reacts with N-methyl-N-formylhydrazine in the presence of potassium tert- butoxide to give compound 5. Treatment of compound 5 with nitric acid and concentrated sulfuric acid delivers compound 6, which reacts with hydrogen gas in the presence of Pd/C and sodium carbonate or sodium bicarbonate to give compound 7.
Scheme 4
Figure imgf000018_0001
Another process of the invention is disclosed in Scheme 5 shown below. The general preparation of compound 13 is described. D4-methanol reacts with a suitable activating reagent to generate compound 11a, which undergoes displacement upon treatment of sodium diformylamide to form compound 12. The subsequent hydrolysis generates compound 13.
Scheme 5
Activation NaN(CHO)2 CHO hydrolysis
CD3OD CD3X D3C-N CD3NH2
CHO
11a 12 13
As shown below in Scheme 6, the preparation of Compound 13 is described. D4-methanol reacts with tosyl chloride in the presence of aq sodium hydroxide to give compound 11. Reaction of this compound with sodium diformylamide affords compound 12, which hydrolyzes in the presence of acidic methanol to give compound 13 as it hydrochloride salt.
Scheme 6
TsCI NaN(CHO)2 CHO HCI, eOH
CD3OD CD3OTS D3C-N - CD3NH2' HCI aq NaOH CHO
11 12 13
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
Figure imgf000019_0001
Example 1
Figure imgf000020_0001
To a glass lined reactor were charged toluene (0.26 Kg), sulfolane (3.4 Kg), compound 1 (1.0 Kg) and POCh (2.7 Kg). The crude was cooled to 0 °C. Triethylamine (0.89 Kg) was charged, and the resulting crude mixture was heated to 65 °C and aged till reaction reached completion. The reaction mass was cooled to 5 °C.
In a separate reactor, water (7.5 Kg) was charged and cooled to 5 °C. The reaction mass was added slowly to the water solution, maintaining the internal temperature below 5 °C. Additional water (0.5 Kg) was used to rinse the reactor and aid the transfer. The resulting mixture was agitated at 5 °C for 3 hours, then extracted with MTBE three times (3 x 4.5 Kg). The combined organic layers were washed sequentially with aq pH 7 buffer solution (5.0 L/Kg, 15 wt% KH2PO4/K2HPO4) and water (2.5 Kg). The crude was distilled under vacuum until total volume became approximately 3 L/Kg. ACN (2 x 6.3 Kg) was added followed by additional distillations back to ~3 L/Kg. The crude was cooled to 20 °C to afford Compound 2 as a 30-36 wt% solution in 90-95% yield.
Example 2
Figure imgf000020_0002
2 3
ACN (2.7 Kg), lithium bromide (1.18 Kg) and water (0.65 Kg) were charged to a glass-lined reactor at 25 °C. Compound 2 crude solution prepared above (limiting reagent) was added, followed by DIPEA (1.82 Kg). The resulting slurry was agitated at 25 °C until reaction reached completion. The product was isolated by filtration. The crude solid was washed with ACN (1.6 Kg). The cake was dried under vacuum at 45 °C. Compound 3 was isolated in 98 AP and 83% yield.
Example 3
Figure imgf000021_0001
Water (6.0 Kg, 6.0 L/Kg) and compound 7 (1.0 Kg) were charged to a glass-lined reactor at 25 °C. Zinc acetate dehydrate (1.08 Kg, 1.0 equiv) was added, followed by compound 3 (1.28 Kg, 1.20 equiv). The reactor line was rinsed with 2-propanol (0.79 Kg, 1.0 L/Kg) and water (1.50 Kg, 1.50 L/Kg). The resulting homogeneous solution was heated to 65 °C and aged until reaction reached completion. Water (7.0 Kg, 7.0 L/Kg) was added, and the crude mixture was cooled to 20 °C and aged for 30 min. The product was isolated by filtration. The crude solid was washed sequentially with water (6.0 Kg, 6.0 L/Kg), water (6.0 Kg, 6.0 L/Kg), THF (5.3 Kg, 6.0 L/Kg) and THF (5.3 Kg, 6.0 L/Kg). The cake was dried under vacuum at 70 °C. Compound 8 was isolated in 98 AP and 94% yield.
Example 4
Figure imgf000021_0002
A separate glass-lined reactor was flushed with nitrogen. Toluene (0.87 Kg, 1.0 L/Kg) and MeCN (0.79 Kg, 1.0 L/Kg) were charged, followed by (2R)-1-[(1R)-1- [bis(l,l-dimethylethyl) phosphino] ethyl] -2-(dicyclohenxyphosphino)ferrocene (Josiphos SL-009-01) (14.1 g, 1.0 mol%) and palladium acetate (2.9 g, 0.5 mol%). The reactor line was rinsed with toluene (0.43 Kg, 0.5 L/Kg). The resulting pre-formed catalyst solution was kept under nitrogen until further usage.
At 20 °C, toluene (3.46 Kg, 4.0 L/Kg) and ACN (1.57 Kg, 2.0 L/Kg) were charged to a glass-lined reactor flushed with nitrogen. Compound 8 (1.00 Kg) was added, followed by DBU (0.39 kg, 1.00 equiv). The reactor line was rinsed with toluene (0.43 Kg, 0.5 L/Kg). Compound 10 (0.54 Kg, 2.5 equiv) and K2CO3 (325 mesh grade, 0.70 Kg, 2.0 equiv) were added to the reaction mixture, followed by toluene (1.30 Kg, 1.5 L/Kg) and ACN (0.79 Kg, 1.0 L/Kg). The pre-formed catalyst solution was transferred into the reaction mixture, which was then heated to 75 °C and agitated until the reaction reached completion.
The reaction crude was cooled to 20 °C. Aq. acetic acid (50 Volume %, 4.0 Kg, 4.0 L/Kg) was charged slowly over the course of 1 h. Glacial acetic acid (10.5 Kg, 10.0 L/Kg) was then added. The resulting homogeneous solution was washed twice with heptane (2 χ 3.42 kg, 2 χ 5.0 L/Kg). The bottom aq. layer was collected and transferred to a clean reactor. Water (5.0 Kg, 5.0 L/Kg) was added, followed by compound 9 seeds (0.01 Kg, 1.0 wt%). The slurry was aged for 2 h at 20 °C. Additional water (2.0 Kg, 2.0 L/Kg) was added, and the slurry was further aged for 6 h. The product was isolated by filtration. The crude cake was washed with aq. ACN (50 Volume %,4.5 Kg, 5.0 L/Kg) followed by ACN (3.9 Kg, 5.0 L/Kg). The cake was dried under vacuum at 65 °C.
Compound 9 was isolated in 98.5AP and 84% yield.
Example 5
Figure imgf000023_0001
9 13 I
NMP (2.06 Kg, 2.0 L/Kg) and ACN (0.78 Kg, 1.0 L/Kg) were charged to a glass- lined reactor and agitated at 20 °C. N-Methylimidazole (0.13 Kg, 0.7 eq), Compound 13 (0.17 Kg, 1.2 eq) and Compound 9 (1.00 Kg) were charged to the reaction mixture. The mixture was heated to 65 °C and aged until homogeneous. HOBt 20% wet (0.17 Kg, 0.5 eq), followed by EDC HC1 (0.54 Kg, 1.4 eq) were then charged to the reaction mixture. The reactor was rinsed with ACN (0.78 Kg, 1.0 L/Kg), then the resulting mixture was aged at 65 °C until reaction reaches completion. The reaction was quenched by charging water (1.0 Kg, 1 L/Kg), then diluted with ACN (3.0 Kg, 3 L/Kg). The reaction mixture was aged at 65 °C for 1 h, before cooling to 0 °C, and aged for an additional 12 h at 0 °C. The product was isolated by filtration. The wet cake was washed with 2: 1 Water: ACN (2.8 Kg, 3 L/Kg) then ACN (2.4 Kg, 3 L/Kg), before drying under full vacuum at 65 °C. Compound I was isolated in >99.5% purity and 91% yield
If needed, the product can be subjected to optional recrystallization as follows. NMP (6.2 kg, 6.0 L/Kg) and Compound I (1.0 Kg) were charged to a glass-lined reactor. The batch was heated to 70°C to form a pale yellow solution, which was then transferred through a polish filter to a clean vessel at 70 °C. 2-Propanol (2.4 kg, 3 L/Kg) was added, followed by Compound I seeds (0.005 Kg, 0.005 Kg/Kg). After aging for 1 h, additional 2-propanol (4.8 kg, 6 L/Kg) was charged over the course of 2 h (3 L/Kg/hr). The slurry was aged for 1 h at 70 °C, cooled slowly to 0 °C and aged for additional 12 h at 0 °C. Product was isolated by filtration. The wet cake was washed with 2-propanol (2 x 3.1 kg, 2 x 4 L/Kg) before drying under full vacuum at 65 °C. Compound I was isolated in >99.9% purity and 83% yield.
Example 6 + ME0H
Figure imgf000024_0001
To a glass lined reactor were charged methanol (1.6 Kg/Kg, 2.0 L/Kg) and methyl hydrazine (1 Kg) at 0 °C. Methyl formate (0.57 Kg/Kg, l . lequiv) was added drop-wise.
The crude was warmed up to 20 °C and aged for additional 6 h. The crude was distilled under vacuum until total volume became approximately 0.5 L/Kg. Five put/take distillations with 2-MeTHF (5 x 3.6 Kg/Kg) were undertaken for the purpose of azeotropic drying. The crude was cooled to 20 °C. N-Methyl-N-formylhydrazine was isolated as 89-90 wt% solution in 89-91% yield.
Figure imgf000024_0002
To a glass lined reactor were charged potassium tert-butoxide (1.5 Kg/Kg, 2.4 equiv) and THF (12.2 Kg/Kg) at 0 °C. A mixture of compound 4 (1.0 Kg), N-Methyl-N- formylhydrazine (1.0 Kg/Kg, 2.30 equiv) and THF (5.3 Kg/Kg, 6.0 L/Kg) was added slowly. The reactor line was rinsed with THF (0.5 Kg/Kg). The reaction crude was aged at 0 °C until reaction reached completion. Water (5.0 Kg/Kg) was added, and the resulting mixture was aged at 0 °C for 30 min, heated to 40 °C and aged for additional 30 min. The layers were separated and the aq layer discarded. The organic layer was washed with brine (15 wt%, 5.7 Kg/Kg) before distilling under vacuum until total volume became approximately 5 L/Kg. Four put/take distillations with ethyl acetate (4 x 10 L/Kg) were undertaken for the purpose of azeotropic drying. The crude was cooled to 20 °C. Sulfuric acid (0.66 Kg/Kg, 1.10 equiv) was added, and the slurry was agitated for 2-3 h. Product was isolated by filtration. The cake was consecutively washed with ethyl acetate (2 χ 6.5 L/Kg) and heptane (8 L/Kg), and dried under vacuum at 45 °C. Compound 5 was isolated in 99 AP and 83% yield. Example 8
Figure imgf000025_0001
5 6
To a glass lined reactor were charged concentrated sulfuric acid (4.5 Kg/Kg) and compound 5 (1.0 Kg) at 0-5 °C. Nitric acid (68 wt%, 0.35 Kg/Kg, 1.2 equiv) was added drop-wise. The mixture was agitated at 0-5 °C until reaction reached completion.
In a separate reactor, water (12 Kg/Kg) and methanol (6.5 Kg/Kg, 8.3 L/Kg) were mixed well at 20 °C. The nitration crude was transferred slowly into the methanol water mixture. The reactor line was rinsed with methanol (0.5 Kg/Kg). The crude was heated to 40-45 °C. Aq. ammonium hydroxide (25 wt%, 7.4 Kg/Kg) was added slowly. The resulting slurry was cooled to 20 °C and agitated for 3 h. Product was isolated by filtration. The cake was washed with water (2 x 6 L/Kg), and dried under vacuum at 45 °C. Compound 6 was isolated in 99 AP and 95% yield.
Example 9
Figure imgf000025_0002
6 7
To a high pressure reactor flushed with nitrogen were charged methanol (8.0 Kg/Kg) and compound 6 (1.0 Kg). With careful exclusion of oxygen, sodium bicarbonate (0.6 Kg/Kg, 2.0 equiv) and Pd/C (10% loading, 50 % wet, 0.02 Kg/Kg) were added. The reactor was pressurized with hydrogen (41-46 psi), and the reaction mixture was aged at 20 °C for 6 h then heated to 45 °C and aged till reaction reached completion. The reactor was flushed with nitrogen, and the reaction crude was filtered to remove Pd/C. Methanol (5 Kg/Kg) was used to aid the transfer. The combined filtrates were distilled under vacuum until total volume became approximately 2.5 L/Kg. Water (10 Kg/Kg) was added, and the crude was distilled under vacuum until total volume became approximately 2.5 L/Kg. The crude was heated to 70 °C. Brine (25 wt%, 9.0 Kg/Kg) was added, and the resulting crude was agitated for 6 h at 70 °C. After cooling down to 0 °C, the crude was further aged for 6 h. Product was isolated by filtration. The cake was washed with brine (pre-cooled to 0 °C, 25 wt%, 2.0 Kg/Kg), and dried under vacuum at 45 °C. Compound 7 was isolated in 99 AP and 88% yield.
Example 10
Figure imgf000026_0001
1 1 12 To a glass lined reactor flushed with nitrogen were charged water (16.3 L/Kg) and sodium hydroxide (3.3 Kg, 3.0 equiv). The mixture was aged till sodium hydroxide reached full dissolution. The crude was cooled to 0 °C. D4-Methanol (1.0 Kg) and THF (, 4.5 L/Kg) were charged. A solution of TsCI (6.3 Kg, 1.2 equiv) in THF (6.3 Kg, 7.1 L/Kg) was added over the course of 2 h. The crude was agitated at 0 °C until reaction reached completion. The batch was warmed to 20 °C. The layers were separated. The collected organic layer was diluted with MTBE (4.0 Kg, 5.4 L/Kg), washed with brine twice (25 wt%, 4.0 Kg followed by 12 Kg). The organic layer was distilled under vacuum until total volume became approximately 10 L/Kg. Two put/take distillations with ACN (2 x 10 L/Kg) were undertaken for the purpose of azeotropic drying. The crude was cooled to 20 °C. ACN (10.0 Kg, 12.8 L/Kg) and NaN(CHO)2 (3.3 Kg, 1.2 equiv) were added. The crude was heated to 65 °C and agitated until reaction reached completion. After cooling down to 5 °C, the mixture was filtered, and the crude cake was washed with ACN twice (2 χ 2.5 Kg, 2 x 3.2 L/Kg). The combined filtrates were distilled under vacuum until total volume became approximately 3 L/Kg. The crude was cooled to 20 °C Compound 12 was isolated as an oil with 80-85 wt% in 60-70% yield. Example 11
CHO HCI
:-N CD3NH2 « HCI
CHO
12 13 To a glass lined reactor were charged compound 12 (1.0 Kg) and methanol (3.9
Kg, 5.0 L/Kg) at 20 °C. A solution of HCI in IPA (5-6 N, 4.5 Kg, 1.5 equiv) was added. The resulting mixture was heated to 50 °C and agitated until reaction reached completion. THF (10 Kg, 1 1.2 L/Kg) was added slowly andthe crude was cooled to 0 °C over 2 h to afford a slurry. The product was isolated by filtration. The cake was washed with THF (3.7 Kg, 4.1 L/Kg), and dried under vacuum at 45 °C. Compound 13 was isolated in 80% yield.
If needed, the product can be subjected to optional recrystallization as follows. Methanol (5.6 Kg, 8.3 L/Kg) and Compound 13 (1.0 Kg) were charged to a glass-lined reactor. DBU (0.1 Kg) was added slowly. The crude was agitated for 1 h. THF (12.4 Kg, 13.9 L/Kg) was added slowly, and the resulting slurry was aged for 2 h. The product was isolated by filtration. The cake was washed with THF (2.6 Kg, 2.9 L/Kg), and dried under vacuum at 45 °C. Compound 13 was isolated in 60% yield (1 st crop). The mother liquor was distilled under vacuum until total volume became approximately 1 L/Kg. Two put/take distillations with methanol (2 χ 2.8 Kg, 2 χ 3.6 L/Kg) were performed and the solution was concentrated back to ~ 1 L/Kg. The crude was cooled to 20 °C. THF (4.8 Kg, 5.4 L/Kg) was added, and the resulting slurry was aged for 2 h. The product was isolated by filtration. The cake was washed with THF (1.0 Kg), and dried under vacuum at 45 °C. Compound 13 was isolated in 25% yield (2nd crop).

Claims

We Claim:
1. A process for the preparation of Compound I of the formula
Figure imgf000028_0001
(I)
comprising the steps of
a) reacting compound l a of the formula,
Figure imgf000028_0002
Compound l a
where R is Ci-C6 alkyl or aryl;
with activating reagents to afford Compound 2a of the formula,
Figure imgf000028_0003
Compound 2a where Xi and X2 are independently halide or sulfonate; and R is defined as above, b) subsequently reacting Compound 2a with an aqueous base to afford Compound 3a of the formula,
Figure imgf000029_0001
Compound 3 a where M is H, Li, Na, K, Cs, Ca, Mg, or Zn, and Xi and X2 are as defined above, c) reacting Compound 3a, with Compound 7 of the formula
Figure imgf000029_0002
Compound 7 in a suitable solvent, and optionally in the presence of an acid, a base, or metal salts to afford Compound 8a of the formula,
Figure imgf000029_0003
Compound 8a where M and X2 are defined as above, d) reacting Compound 8a with Compound 10 of the formula NH2
Compound 10 in the presence of a suitable transition metal catalyst, a ligand, one or more bases, and one or more suitable solvents to afford Compound 9a of the formula,
Figure imgf000030_0001
Compound 9a where M is defined as above,
e) reacting Compound 9a with Compound 13, or a free base or salt thereof, of the formula
D3C-NH2
Compound 13 in the presence of one or more suitable activators, one or more suitable solvents, and optionally a base, to afford Compound I.
2. A process for the preparation of Compound I of the formula
Figure imgf000031_0001
(I)
comprising the steps of
a) reacting compound 1 of the formula
Figure imgf000031_0002
with POCh and optionally an amine base, followed optionally by a buffered aqueous workup to afford Compound 2 of the formula
Figure imgf000031_0003
Compound 2 b) subsequently reacting Compound 2 with LiBr and DiPEA in water and acetonitrile to afford Compound 3 of the formula
Figure imgf000031_0004
Compound 3 c) reacting Compound 3, with Compound 7 of the formula
Figure imgf000032_0001
Compound 7 in the presence of zinc acetate in water and 2-propanol, to afford Compound 8 of the formula,
Figure imgf000032_0002
Compound 8
a hydrate or solvate thereof;
reacting Compound 8 with Compound 10 of the formula
Figure imgf000032_0003
Compound 10 in a palladium catalyzed C-N coupling reaction in the presence of a phosphine ligand, and base, using a dual-base system comprised of potassium carbonate and DBU, followed optionally by isolation from aqueous acetic acid, to afford Compound 9 of the formula
Figure imgf000033_0001
Compound 9
or a hydrate or solvate thereof;
e) reacting Compound 9 with EDC or other coupling agents and Compound 13 of the formula
CD3NH2 HCI
Compound 13 to afford Compound I, which may be further purified by crystallization from NMP/IPA.
A process for preparing Compound 7 of the formula
Figure imgf000033_0002
Compound 7
comprising
b) reacting compound 4a of the formula
Figure imgf000033_0003
where X3 is CI, Br, I or F;
with N-methyl-N-formylhydrazine and a suitable base to afford Compound 5a formula
Figure imgf000034_0001
Compound 5 a which is then nitrated to afford Compound 6a of the formula
Figure imgf000034_0002
Compound 6a
c) which is subsequently reduced to afford Compound 7. 4. A process for preparing Compound 7 of the formula
Figure imgf000034_0003
Compound 7
comprising
a) reacting compound 4 of the formula
Figure imgf000035_0001
Compound 4 with N-methyl-N-formylhydrazine in the presence of potassium tert-butoxide to afford Compound 5 of the formula
Figure imgf000035_0002
Compound 5
b) which is then reacted with nitric acid in the presence of concentrated sulfuric acid to afford Compound 6 of the formula
Figure imgf000035_0003
Compound 6 c) which is subsequently reacted with hydrogen gas in the presence of Pd/C, sodium bicarbonate or sodium carbonate and methanol to afford Compound 7.
5. A process for preparing Compound 13 of the formula
CD3NH2
a salt thereof, comprising
reacting d4-methanol of the formula
CD3OD with activating reagents to afford compound 11a of the formula:
CD3X4
Compound 11a
where X4 is independently halide or sulfonate, b) which is then reacted with sodium diformylamide to afford Compound 12 of the formula
CHO
D3C-N
CHO
Compound 12 c) which is then hydrolyzed to afford Compound 13. 6. A process for preparing Compound 13 of the formula
CD3NH2
Compound 13 comprising
a) reacting d4-methanol of the formula
CD3OD with tosyl chloride in the presence of aqueous sodium hydroxide to afford compound 11 of the formula:
CD3OTS
Compound 11 b) which is then reacted with sodium diformylamide to afford Compound 12 of the formula CHO
D3C-N
CHO
Compound 12 c) which is then hydrolyzed in the presence of hydrochloride in methanol to afford Compound 13 as its hydrochloride salt of the formula
CD3NH2 HCI
Compound 13. 7. A compound selected from the following
Figure imgf000037_0001
or a salt or hydrate thereof
8. A compound according to Claim 7 which is
Figure imgf000038_0001
a hydrate thereof.
A compound according to Claim 7 which i
Figure imgf000038_0002
or a hydrate thereof.
10. A compound according to Claim 7 which is
Figure imgf000038_0003
11. A compound of the formula
Figure imgf000039_0001
• x H20
Compound I of the formula
Figure imgf000039_0002
prepared by the process of Claim 1.
PCT/US2018/025100 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide Ceased WO2018183649A1 (en)

Priority Applications (32)

Application Number Priority Date Filing Date Title
BR112019020169-6A BR112019020169B1 (en) 2017-03-30 2018-03-29 PROCESS FOR THE PREPARATION OF 6-(CYCLOPROPANOAMIDO)-4-((2-METHOXY-3-(1-METHYL-1H-1,2,4-TRIAZOL-3-YL)PHENYL)AMINO)-N-(METHYL-D3)PYRIDAZINE-3-CARBOXAMIDE, INTERMEDIATES, THEIR USES AND PHARMACEUTICAL COMPOSITION
DK18718340.5T DK3601268T3 (en) 2017-03-30 2018-03-29 PROCEDURE FOR PREPARING 6- (CYCLOPROPANAMIDO) -4 - ((2-METHOXY-3- (1-METHYL-1H-1,2,4-TRIAZOL-3-YL) PHENYL) AMINO) -N- (METHYL-D3 ) PYRIDAZINE-3- CARBOXAMIDE
CA3058177A CA3058177A1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
PL18718340T PL3601268T3 (en) 2017-03-30 2018-03-29 PREPARATION PROCESS 6- (CYCLOPROPANAMIDO) -4 - ((2-METHOXY-3- (1-METHYL-1H-1,2,4-TRIAZOL-3-YLO) PHENYL) AMINO) -N- (METHYL-D3) PYRIDINE -3-CARBOXYAMIDE
EP23209227.0A EP4296258A3 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
RS20210559A RS61816B1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
EA201992308A EA201992308A1 (en) 2017-03-30 2018-03-29 METHOD FOR PRODUCING 6- (CYCLOPROPANAMIDO) -4 - ((2-METHOXY-3- (1-METHYL-1H-1,2,4-TRIAZOL-3-IL) Phenyl) AMINO) -3- (METHYL-d3) PYRIDAZINE -3-CARBOXAMIDE
US16/498,442 US10899745B2 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
KR1020247034512A KR102857398B1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
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EP18718340.5A EP3601268B1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
SI201830252T SI3601268T1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
CN201880021649.8A CN110475774B (en) 2017-03-30 2018-03-29 Methods for preparing Tyk2 inhibitors
EP21155321.9A EP3882237B1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
IL269586A IL269586B (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
HRP20210764TT HRP20210764T1 (en) 2017-03-30 2018-03-29 PROCEDURE FOR PREPARATION 6- (CYCLOPROPANAMIDO) -4 - ((2-METHOXY-3- (1-METHYL-1H-1,2,4-TRIAZOL-3-YL) PHENYL) AMINO) -N- (METHYL-D3) PYRIDAZINE-3-CARBOXAMIDE
CN202310552731.6A CN116813561B (en) 2017-03-30 2018-03-29 Methods for preparing Tyk2 inhibitors
LTEP18718340.5T LT3601268T (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
KR1020197031634A KR102720054B1 (en) 2017-03-30 2018-03-29 Method for preparing 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide
SM20210239T SMT202100239T1 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
KR1020257017189A KR20250080914A (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
ES18718340T ES2864450T3 (en) 2017-03-30 2018-03-29 Process for the preparation of 6- (cyclopropanamido) -4 - ((2-methoxy-3- (1-methyl-1h-1,2,4-triazol-3-yl) phenyl) amino) -N- (methyl- d3) pyridazine-3-carboxamide
MX2019011092A MX392693B (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
JP2019553452A JP7113023B2 (en) 2017-03-30 2018-03-29 6-(Cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine -Method for producing 3-carboxamide
AU2018244916A AU2018244916B2 (en) 2017-03-30 2018-03-29 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
US17/131,718 US11649226B2 (en) 2017-03-30 2020-12-22 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl- D3)pyridazine-3-carboxamide
CY20211100374T CY1124194T1 (en) 2017-03-30 2021-04-29 PROCESS FOR THE PREPARATION OF 6-(CYCLOPROPANAMIDE)-4-((2-METHOXY-3-(1-METHYL-1,2,4-TRIAZOL-3-YL)PHENYL)AMINO-N-(METHYL-D3)-PYRIDAZINE -3-CARBOXAMIDE
AU2021261839A AU2021261839B2 (en) 2017-03-30 2021-11-01 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
JP2022117894A JP7457758B2 (en) 2017-03-30 2022-07-25 Method for preparing 6-(cyclopropanamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide
US18/134,564 US12565487B2 (en) 2017-03-30 2023-04-13 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-d3)pyridazine-3-carboxamide
JP2023208420A JP7837938B2 (en) 2017-03-30 2023-12-11 Method for producing 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide
JP2025284416A JP2026067880A (en) 2017-03-30 2025-12-26 Method for producing 6-(cyclopropanamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide

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US17/131,718 Division US11649226B2 (en) 2017-03-30 2020-12-22 Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl- D3)pyridazine-3-carboxamide

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Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP3495358A1 (en) * 2012-11-08 2019-06-12 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
CN111484480A (en) * 2019-01-29 2020-08-04 上海翰森生物医药科技有限公司 A kind of polycyclic derivative inhibitor, its preparation method and application
WO2020251911A1 (en) * 2019-06-12 2020-12-17 Bristol-Myers Squibb Company Crystalline salt forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3) pyridazine-3-carboxamide
WO2021055652A1 (en) 2019-09-18 2021-03-25 Bristol-Myers Squibb Company Dosage forms for tyk2 inhibitors
WO2021170046A1 (en) * 2020-02-26 2021-09-02 Beigene, Ltd. Tyk-2 inhibitor
WO2021259208A1 (en) 2020-06-22 2021-12-30 Beigene, Ltd. Tyk-2 inhibitor
WO2022061149A1 (en) 2020-09-18 2022-03-24 Bristol-Myers Squibb Company Dosage forms for tyk2 inhibitors comprising swellable cores
WO2023049241A1 (en) * 2021-09-23 2023-03-30 Bristol-Myers Squibb Company Methods of treating hair-loss disorders with tyk2 inhibitors
WO2023102085A1 (en) 2021-12-01 2023-06-08 Teva Czech Industries S.R.O. Solid state forms of deucravacitinib, deucravacitinib hcl and process for preparation of deucravacitinib and intermediates
WO2024236491A1 (en) * 2023-05-15 2024-11-21 Glenmark Life Sciences Limited Process for the preparation of deucravacitinib, and crystalline forms thereof
EP4538259A1 (en) 2023-10-09 2025-04-16 Farmhispania Group, S.L. Processes for the preparation of deucravacitinib
WO2025186427A1 (en) 2024-03-08 2025-09-12 Curia Spain, S.A.U. Process for the preparation of deucravacitinib and intermediates thereof and method for purifying deucravacitinib
ES3059443A1 (en) * 2024-09-17 2026-03-20 Moehs Iberica Sl SOLID FORM OF 6-(CYCLOPROPANOCARBOXAMIDO)-4-((2-METHOXY-3-(1-METHYL-1H-1,2,4-TRIAZOL-3-YL)PHENYL)AMINO)PYRIDAZINE-3-CARBOXYLATE OR A SALT THEREOF, PROCESS FOR ITS PREPARATION AND ITS USE IN THE SYNTHESIS OF DEUCRAVACITINIB

Families Citing this family (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LT3601268T (en) * 2017-03-30 2021-05-25 Bristol-Myers Squibb Company Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
CN118994118A (en) * 2018-05-31 2024-11-22 百时美施贵宝公司 Crystalline forms of a compound
KR102943760B1 (en) * 2019-01-28 2026-03-26 장쑤 한서 파마슈티칼 그룹 캄파니 리미티드 Pyridazine derivative inhibitor, and its manufacturing method and use
CN114787152A (en) * 2019-12-27 2022-07-22 苏州科睿思制药有限公司 BMS-986165 crystal form, and preparation method and application thereof
WO2021143430A1 (en) * 2020-01-19 2021-07-22 苏州科睿思制药有限公司 Bms-986165 hydrochloride crystal form, preparation method therefor and use thereof
CN114787154A (en) * 2020-01-19 2022-07-22 苏州科睿思制药有限公司 Crystal form of Deucravicitinib, preparation method and application thereof
CN113735836B (en) * 2020-05-28 2023-05-30 江苏先声药业有限公司 Pyridazine compound and application thereof
CN113773262B (en) * 2020-06-09 2024-08-09 江苏先声药业有限公司 Pyridazines compounds
CN115667246B (en) * 2020-07-24 2024-08-23 上海翰森生物医药科技有限公司 A crystalline form of a free base of a pyridazine derivative, and its preparation method and application
WO2022021684A1 (en) * 2020-07-31 2022-02-03 苏州科睿思制药有限公司 Crystalline form csv of bms-986165 hydrochloride, preparation method therefor, and uses thereof
CN116615200B (en) * 2020-10-20 2025-04-29 杭州领业医药科技有限公司 Crystalline forms of pyridazine derivatives
AU2022214313A1 (en) 2021-01-29 2023-08-17 Bristol-Myers Squibb Company Crystal form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
CN117377667A (en) * 2021-03-29 2024-01-09 百时美施贵宝公司 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -Crystalline form of (methyl-d3)pyridazine-3-carboxamide
PE20250262A1 (en) 2021-05-14 2025-01-29 Bristol Myers Squibb Co SUBSTITUTED HETEROCYCLIC COMPOUNDS
JP2024529763A (en) * 2021-08-20 2024-08-08 ブリストル－マイヤーズ スクイブ カンパニー Crystalline form of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide
JP2024539703A (en) 2021-10-28 2024-10-29 ブリストル－マイヤーズ スクイブ カンパニー Topical formulation of deuclavacitinib
US12222104B2 (en) * 2022-03-21 2025-02-11 General Electric Company Turbine engine combustor and combustor liner
WO2023181075A1 (en) * 2022-03-24 2023-09-28 Dr. Reddy's Laboratories Limited Amorphous solid dispersions of deucravacitinib and processes for the preparation thereof
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CN120187715A (en) * 2022-10-28 2025-06-20 浙江华海药业股份有限公司 A pyridazinamide compound, a pharmaceutical composition thereof and use thereof as a TYK2 inhibitor
WO2025131031A1 (en) 2023-12-22 2025-06-26 上海奥博生物医药股份有限公司 Tyk2 inhibitor and preparation method for intermediates thereof
WO2025173029A1 (en) * 2024-02-14 2025-08-21 Natco Pharma Limited An improved process for the preparation of deucravacitinib
WO2025259267A1 (en) 2024-06-11 2025-12-18 Vector Vitale Ip Llc Pharmaceutical compositions for modulating inflammation and oxidative stress comprising chemically enriched elements

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9505748B2 (en) 2012-11-08 2016-11-29 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses

Family Cites Families (23)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6023649B2 (en) 1976-09-08 1985-06-08 東ソー株式会社 Method for producing methyl bromide using hydrobromic acid
JPS5455501A (en) 1977-10-05 1979-05-02 Toyo Soda Mfg Co Ltd Continuous preparation of methyl bromide
US4254061A (en) * 1979-09-11 1981-03-03 E. I. Du Pont De Nemours And Company Preparation of monomethylamine
EP1184376B1 (en) 1999-06-09 2005-02-02 Yamanouchi Pharmaceutical Co. Ltd. Novel heterocyclic carboxamide derivatives
CN100579579C (en) 2002-10-01 2010-01-13 诺华疫苗和诊断公司 Anti-cancer and anti-infectious disease compositions and methods of use thereof
US7507832B2 (en) 2003-12-22 2009-03-24 Eli Lilly And Company Triazole PPAR modulators
ES2394522T3 (en) * 2005-09-29 2013-02-01 Basf Se Molded body containing an aluminum silicate and an aluminum oxide and process for the continuous production of methylamines
ES2547303T3 (en) 2007-01-19 2015-10-05 Ardea Biosciences, Inc. MEK inhibitors
CN102573478B (en) * 2009-10-12 2015-12-16 拜尔农作物科学股份公司 1-(Pyridin-3-yl)-pyrazoles and 1-(pyrimidin-5-yl)-pyrazoles as insecticides
WO2011109799A1 (en) * 2010-03-05 2011-09-09 Karyopharm Therapeutics, Inc. Nuclear transport modulatiors and uses thereof
CN102190616B (en) * 2010-03-18 2015-07-29 苏州泽璟生物制药有限公司 A kind of deuterated synthesis of ω-diphenyl urea and the Method and process of production
US8748666B2 (en) * 2010-03-18 2014-06-10 Suzhou Zelgen Biopharmaceutical Co., Ltd. Preparation methods of methyl-D3-amine and salts thereof
WO2013047813A1 (en) 2011-09-30 2013-04-04 大鵬薬品工業株式会社 1,2,4-triazine-6-carboxamide derivative
CN104125947A (en) 2011-12-21 2014-10-29 生物区欧洲有限公司 Heterocyclic urea compounds
KR20140108594A (en) * 2012-01-10 2014-09-11 에프. 호프만-라 로슈 아게 Pyridazine amide compounds and their use as syk inhibitors
WO2013171643A1 (en) 2012-05-14 2013-11-21 Piramal Enterprises Limited An improved process for preparation of irbesartan
EP2922841B8 (en) * 2012-11-08 2017-08-02 Bristol-Myers Squibb Company Alkyl-amide-substituted pyridyl compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
AR094537A1 (en) 2013-11-07 2015-08-12 Bristol Myers Squibb Co PIRIDIL COMPOUNDS REPLACED WITH USEFUL ALQUILAMIDE AS MODULATORS OF THE ANSWERS OF IL-12, IL-23 AND / OR IFNa
LT3601268T (en) * 2017-03-30 2021-05-25 Bristol-Myers Squibb Company Process for the preparation of 6-(cyclopropaneamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
CN118994118A (en) * 2018-05-31 2024-11-22 百时美施贵宝公司 Crystalline forms of a compound
RS66346B1 (en) * 2018-10-22 2025-01-31 Alumis Inc Tyk2 inhibitors and uses thereof
AU2022214313A1 (en) * 2021-01-29 2023-08-17 Bristol-Myers Squibb Company Crystal form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3)pyridazine-3-carboxamide
CN117377667A (en) * 2021-03-29 2024-01-09 百时美施贵宝公司 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N -Crystalline form of (methyl-d3)pyridazine-3-carboxamide

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9505748B2 (en) 2012-11-08 2016-11-29 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
USRE47929E1 (en) 2012-11-08 2020-04-07 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFNα responses
US11021475B2 (en) 2012-11-08 2021-06-01 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of IL-12, IL-23 and/or IFN alpha responses
EP3495358A1 (en) * 2012-11-08 2019-06-12 Bristol-Myers Squibb Company Amide-substituted heterocyclic compounds useful as modulators of il-12, il-23 and/or ifn alpha responses
CN111484480A (en) * 2019-01-29 2020-08-04 上海翰森生物医药科技有限公司 A kind of polycyclic derivative inhibitor, its preparation method and application
CN111484480B (en) * 2019-01-29 2023-08-11 上海翰森生物医药科技有限公司 Polycyclic derivative inhibitor, preparation method and application thereof
JP2022536489A (en) * 2019-06-12 2022-08-17 ブリストル－マイヤーズ スクイブ カンパニー 6-(Cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine -Crystalline salt form of 3-carboxamide
WO2020251911A1 (en) * 2019-06-12 2020-12-17 Bristol-Myers Squibb Company Crystalline salt forms of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyl-d3) pyridazine-3-carboxamide
JP2025138809A (en) * 2019-06-12 2025-09-25 ブリストル－マイヤーズ スクイブ カンパニー Crystalline salt form of 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide
US12570637B2 (en) 2019-06-12 2026-03-10 Bristol-Myers Squibb Company Crystalline salt forms 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazol-3-yl)phenyl)amino)-n-(methyld3) pyridazine-3-carboxamide
JP7881805B2 (en) 2019-06-12 2026-06-29 ブリストル－マイヤーズ スクイブ カンパニー Crystalline salt form of 6-(cyclopropanecarboxamide)-4-((2-methoxy-3-(1-methyl-1H-1,2,4-triazole-3-yl)phenyl)amino)-N-(methyl-D3)pyridazine-3-carboxamide
WO2021055652A1 (en) 2019-09-18 2021-03-25 Bristol-Myers Squibb Company Dosage forms for tyk2 inhibitors
EP4706778A2 (en) 2019-09-18 2026-03-11 Bristol-Myers Squibb Company Dosage forms for tyk2 inhibitors
WO2021055651A1 (en) 2019-09-18 2021-03-25 Bristol-Myers Squibb Company Extended release dosage forms for tyk2 inhibitors
CN115003667A (en) * 2020-02-26 2022-09-02 百济神州有限公司 TYK-2 inhibitors
WO2021170046A1 (en) * 2020-02-26 2021-09-02 Beigene, Ltd. Tyk-2 inhibitor
US12606556B2 (en) 2020-02-26 2026-04-21 Beone Medicines I Gmbh TYK-2 inhibitor
WO2021259208A1 (en) 2020-06-22 2021-12-30 Beigene, Ltd. Tyk-2 inhibitor
WO2022061149A1 (en) 2020-09-18 2022-03-24 Bristol-Myers Squibb Company Dosage forms for tyk2 inhibitors comprising swellable cores
WO2023049241A1 (en) * 2021-09-23 2023-03-30 Bristol-Myers Squibb Company Methods of treating hair-loss disorders with tyk2 inhibitors
WO2023102085A1 (en) 2021-12-01 2023-06-08 Teva Czech Industries S.R.O. Solid state forms of deucravacitinib, deucravacitinib hcl and process for preparation of deucravacitinib and intermediates
WO2024236491A1 (en) * 2023-05-15 2024-11-21 Glenmark Life Sciences Limited Process for the preparation of deucravacitinib, and crystalline forms thereof
WO2025078335A1 (en) 2023-10-09 2025-04-17 Farmhispania Group, S.L. Processes for the preparation of deucravacitinib
EP4538259A1 (en) 2023-10-09 2025-04-16 Farmhispania Group, S.L. Processes for the preparation of deucravacitinib
WO2025186427A1 (en) 2024-03-08 2025-09-12 Curia Spain, S.A.U. Process for the preparation of deucravacitinib and intermediates thereof and method for purifying deucravacitinib
ES3059443A1 (en) * 2024-09-17 2026-03-20 Moehs Iberica Sl SOLID FORM OF 6-(CYCLOPROPANOCARBOXAMIDO)-4-((2-METHOXY-3-(1-METHYL-1H-1,2,4-TRIAZOL-3-YL)PHENYL)AMINO)PYRIDAZINE-3-CARBOXYLATE OR A SALT THEREOF, PROCESS FOR ITS PREPARATION AND ITS USE IN THE SYNTHESIS OF DEUCRAVACITINIB
WO2026061642A1 (en) 2024-09-17 2026-03-26 Moehs Iberica, S.L. Solid form of methyl 6-(cyclopropanecarboxamido)-4-((2-methoxy-3-(1-methyl-1h-1,2,4-triazol-3-yl)phenyl)amino)pyridazine-3-carboxylate or a salt thereof, method for the preparation thereof, and use thereof in the synthesis of deucravacitinib

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