A novel synthesis of ethyl 3-amino-1((3r,4s)-4-cyanotetrahydro-2h-pyran-3-YL)-1h-pyrazole-4-carboxylate

Abstract

A novel synthesis of ethyl 3-amino-l-((3R,4S)-4-cyanotetrahydro-2H- pyran-3-yl)-lH-pyrazole-4-carboxylate, an intermediate used in the manufacturing of atinvicitinib, without the use of chiral chromatographic separation.

Description

A NOVEL SYNTHESIS OF ETHYL 3-AMINO-1((3R,4S)-4-CYANOTETRAHYDRO-2H-PYRAN-3-YL)-1H-PYRAZOLE-4-CARBOXYLATEFIELD

[0001] The synthesis of organic compounds useful in the preparation of pharmaceutical compositions.BACKGROUND

[0002] WO 2013 / 041042 discloses pyrazole carboxamides as Janus kinase inhibitors that are useful for the treatment of rheumatoid arthritis, asthma, chronic obstructive pulmonary disease (COPD) and cancer. The compounds of this disclosure are of the following formula.

[0003] WO 2018 / 108969 discloses compounds of formula I which are selective Janus kinase (JAK) inhibitors, and as such are useful for the treatment of JAK-mediated diseases such as atopic dermatitis, arthritis, and cancer. Specifically, 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3- [(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) is disclosed.Formula (I)

[0004] The common name for the compound of Formula (I) is atinvicitinib and the CAS # is 2169273-59-8.

[0005] A synthesis of 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) was articulated around the key intermediate 3-amino- 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxamide((See Compound (6) of theScheme 1 below). Due to the poor solubility of this intermediate in organic solvents, the chiral separation of the parent racemate (5) had to be performed by chiral supercritical fluid chromatography (SFC).Scheme 1(trans, racemic)N2H4

[0006] WO 2020 / 120673 discloses alternative method of preparing 1-[(3R,4S)-4-cyanotetrahydropyran-3-yl]-3-[(2-fluoro-6-methoxy-4-pyridyl)amino]pyrazole-4-carboxamide (I) utilizing ethyl 3-amino-l-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-lH-pyrazole-4-carboxylate (ECPC). See Scheme 2, compound (VI). However, this process requires separation of chiral intermediates via simulated moving bed (SMB) chromatography to achieve compound (VI). Scheme 2

[0007] WO2020221914 discloses a process for the production of ethyl 3-amino-l-[(3R,4S)-4-cyanotetrahydropyran-3-yl]pyrazole-4-carboxylate through chiral separation of a racemic mixture.There is a need for improved methods of synthesis and resolution of chiral ECPC (Compound VI of Scheme 2) without the need for chromatography.SUMMARY OF INVENTION

[0008] An embodiment of the invention is a process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3),0wherein the catalyst isowherein R is TMS, TES, TBDMS, MDPS, or TPS, R1is C1-C4 alkyl and R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehye or p-nitrobenzaldehyde;b) reacting the compound of Formula (3-3) with ammonium hydroxide to yield a compound of Formula (3-2)Oc) reacting the compound of Formula (3-2) with trifluoroacetic acid to yield the compound of Formula (3-1).DESCRIPTION OF EMBODIMENTS

[0009] A novel synthesis of ethyl 3-amino-l-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-lH-pyrazole-4-carboxylate (compound (3-1) in Scheme 3, compound (VI) from Scheme 2 when R1is ethyl), also identified as (+) ECPC, an intermediate used in the manufacturing of atinvicitinib active substance has been developed. See Scheme 3 below.Scheme 3Stage-3 (3-2)Stage-4 0 R-Catalyst is C _calkyl3 8 R = TMSn1 43-9; R = TES R2 is p-methoxybenzaldehyde, 3-10; R = TBDMS dimethoxybenzaldehyde or p-nitrobenzaldehyde 3-11; R = MDPS (3-1),3-12; R = TPS (+J-ECPC Ester.+..is ethylCompound (VI) when R1

[0010] Previous attempts at asymmetric chiral synthesis of ethyl 3-amino-l-((3R,4S)-4-cyanotetrahydro-2H-pyran-3-yl)-lH-pyrazole-4-carboxylate (Compound VI) have been unsuccessful. Current processes rely on the separation of compound (3-1) from its racemate by chromatography (e.g., chiral chromatographic separation or simulated moving bed chromatography). In the inventive process, the protected ethyl 3-amino-lH-pyrazole-4-carboxylate Compound (3-6) undergoes a stereoselective conjugate addition to compound (3-4) in presence of the R-catalyst preferentially producing the 3R, 4S anti enantiomer compound with 15% of the syn diastereomer (3S, 4S or 3R, 4R), which can be easily removed. In typical reaction without the R-catalyst, a racemic mixture of compound (3-3) is formed. The R- catalyst used in this synthesis brings the required enantioselectivity by allowing the addition to happened from one plane of compound (3-4) leading to the trans compound (3-3) during the stage 2 of Scheme 3. In the additional steps of stage 3 and stage 4 of Scheme 3, the configuration of the 3R and 4S is retained in the molecule from Compound (3-2) to Compound (3-1). Chiral analytical HPLC was deployed to compare the Rt of compound (3-1) with standard prepared from the racemic mixture and structure of compound (3-1) was further supported by mass spectrometry, ’H NMR and13C NMR.

[0011] As noted above in Scheme 3, when compound (3-7) is protected, the reaction leads to the enantiomer compound (3-1). When compound (3-7) is unprotected, the reaction leads to the racemate of compound (3-1). Compound (3-4), which is formed from compound (3-5) is a unique cyclic conjugated aldehyde. Indeed, the conjugate addition reaction (stage 2 of Scheme 3) does not proceed if compound (3-5) is reacted with compound (3-6) without conversion to (3-4) first.

[0012] Reaction Scheme 3 offers the advantage of a direct asymmetric synthesis of compound (3-1), as compared to prior art that produces racemic mixtures of compound (3-1) and then separates the desired enantiomer. By establishing the desired chirality early in the process, theinventive process eliminates the need to carry forward the undesired enantiomer. This reduces the requirements for additional reagents and decreases the amount of waste produced. These in turn lowers the cost of production.

[0013] A further advantage of the process of Scheme 3 is that the crude product of Stage 2 can be carried forward to the reaction of Stage 3 without further purification.

[0014] In scheme 3, compound (3-7) is protected by protecting group and is transformed into compound (3-6). This protecting group can be para-methoxy benzaldehyde (PMB). Compound (3-7) can also be protected with dimethoxybenzaldehye or p-nitorbenzadehyde.

[0015] R-catalysts or chiral catalysts of the following structure were evaluated in the reaction to prepare compound (3-3) shown above.R-Catalyst(3-8); R = TMS(3-9); R = TES(3-10); R = TBDMS(3-11); R = MDPS(3-12); R = TPS

[0016] All of the catalysts were successful in the stage 2 reaction; however, (3-10) and (3-11) gave better yields.

[0017] The stage 2 reaction was successfully conducted with 2-nitro benzoic acid. The stage 2 reaction was also successfully conducted with 4 -nitro benzoic acid.

[0018] The stage 2 reaction was conducted in methyl tertiary butyl ether (MTBE) as a solvent. The stage 2 reaction was also conducted using toluene as a solvent.

[0019] The compound of formula (VI) can then be converted to atinvicitinib by methods known in the art. For example, the processes of Scheme 1 (WO 2018 / 108969) or Scheme 2 (WO 2020 / 120673) above can be used to convert the compound of formula (VI) to atinvicitinib (Compound 1).DefinitionsPMB - para-methoxy benzaldehyde.TMS - trimethyl silylTES - triethylsilylTBDMS - tertbutyldimethylsilylMDPS - methyldiphenylsilylTPS - triphenysilylDIBAL-H - Diisobutylaluminium hydrideREDAL-H - sodium bis(2-methoxyethoxy)aluminum hydrideMTBE - methyl tertiary butyl etherDCM - Dichloromethane

[0020] An embodiment of the invention is a process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3),Owherein the catalyst iswherein R is TMS, TES, TBDMS, MDPS, or TPS;b) reacting the compound of Formula (3-3) with ammonium hydroxide to yield a compound of Formula (3-2)NR2HN / / CNc) reacting the compound of Formula (3-2) with trifluoroacetic acid to yield the compound of Formula (3-1), wherein greater than 80%, preferably greater than 85%, of the desired 3R,4S enantiomer is produced.

[0021] In another embodiment, the reaction of step a) further comprises 2-nitro benzoic acid or 4 -nitro benzoic acid.

[0022] In another embodiment, the reaction of step a) further comprises methyl tertiary butyl ether (MTBE) or toluene.

[0023] In another embodiment, the compound of Formula (3-3) is carried forward to the reaction to product the compound of Formula (3-2) without purification.

[0024] Another embodiment is a process for making a compound of Formula (3-6)R2HN(3-6)comprising reacting a compound of Formula (3-7),RXO2C(3-7)wherein R1is C1-C4 alkylwith a protecting group R2to yield the compound of Formula (3-6), wherein R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehyde or p-nitrobenzaldehyde.

[0025] In another embodiment, R2is is para-methoxy benzaldehyde (PMB).

[0026] Another embodiment is a process for making a compound of Formula (3-3)comprising reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3), wherein the catalyst isowherein R is TMS, TES, TBDMS, MDPS, or TPS.

[0027] Another embodiment is a process for making a compound of Formula (3-4) O(3-4)comprising reacting a compound of Formula (3-5)O(3-5)with a reducing agent to yield the compound of Formula (3-4).

[0028] In another embodiment, the reducing agent is DIBAL-H or REDAL-H.

[0029] Another embodiment is a process for making a compound of Formula (3-1)comprisinga) reacting the compound of Formula (3-3)with ammonium hydroxide to yield a compound of Formula (3-2)b) reacting the compound of Formula (3-2) with trifluoroacetic acid to yield the compound of Formula (3-1).

[0030] Another embodiment is a process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3),0wherein the catalyst iswherein R is TMS, TES, TBDMS, MDPS, or TPS; andb) further reacting the compound of Formula (3-3) to yield the compound of Formula (3-1).

[0031] Another embodiment is a process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-5)O(3-5)with a reducing agent to yield a compound of Formula (3-4)O(3-4)wherein the reducing agent is DIB AL-H or REDAL-H,b) reacting the compound of Formula (3-4) with a compound of Formula (3-6) RXO2C(3-6)in the presence of a catalyst to yield a compound of Formula (3-3),Owherein the catalyst iswherein R is TMS, TES, TBDMS, MDPS, or TPS; andc) further reacting the compound of Formula (3-3) to yield the compound of Formula (3-1).

[0032] In another embodiment, greater than 80%, preferably greater than 85%, of the desired 3R,4S enantiomer (the compound of Formula (3-1) is produced.

[0033] In another embodiment, the compound of Formula (3-3) is carried forward to the reaction to product the compound of Formula (3-2) without purification.In another embodiment, R is TBDMS.

[0034] Another embodiment is a process for making atinvicitinibcomprisinga) making a compound of Formula (3-1)wherein R1is ethylby any of the above processes, andb) further reacting the compound of Formula (3-1) to yield atinvicitinib.

[0035] An embodiment of the invention is a process for making a compound of Formula (3-1)wherein R1is C1-C4 alkyl, preferably C1-C2 alkyl, most preferably ethyl, comprisinga) reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)R¹O₂C(3-6)wherein R2is a protecting group selected from para-methoxy benzaldehyde (PMB), dimethoxybenzaldehyde and p-nitrobenzaldehyde, in the presence of a catalyst to yield the compound of Formula (3-3),b) reacting the compound of Formula (3-3) with a base to yield a compound of Formula (3-2)Oc) reacting the compound of Formula (3-2) with an acid to yield the compound of Formula (3-1).

[0036] In another embodiment, the catalyst is a chiral catalyst, preferably of the following formulawherein R is TMS, TES, TBDMS, MDPS, or TPS.

[0037] In another embodiment, R is TBDMS.

[0038] In another embodiment, greater than 80%, preferably greater than 85%, of the desired 3R,4S enantiomer the compound of Formula (3-1) is produced.

[0039] In another embodiment, the base is ammonium hydroxide.

[0040] In another embodiment, the acid is trifluoroacetic acid.

[0041] An embodiment of the invention is a process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3),wherein the catalyst iswherein R is TBDMS, R1is ethyl and R2is para-methoxy benzaldehyde (PMB);b) reacting the compound of Formula (3-3) with ammonium hydroxide to yield a compound of Formula (3-2)Oc) reacting the compound of Formula (3-2) with trifluoroacetic acid to yield the compound of Formula (3-1).

[0042] In another embodiment, the reaction of step a) further comprises 2-nitro benzoic acid or 4 -nitro benzoic acid.

[0043] In another embodiment, the reaction of step a) further comprises methyl tertiary butyl ether (MTBE) or toluene.

[0044] Another embodiment is a process for making atinvicitinibcomprisinga) making a compound of Formula (3-1)wherein R1is ethyl by any of the above processes, andb) further reacting the compound of Formula (3-1) to yield atinvicitinib.

[0045] Another embodiment is a compound of Formula (3-4)0(3-4)EXAMPLESScheme 3ADIBAL-H or REDAL - H Toluene Stage-laEtO2C 4-Methoxy Benzaldehyde TFA, Et3SiH, (7) DCM Stage-1R-Catalyst (+)-ECPC Ester (R)-8; R = TMS (R)-9; R = TES (R)-10; R = TBDMS (R)-ll; R = MDPS(R)-12; R = TPS

[0046] 1H NMR spectra were acquired at 400 MHz and chemical shifts were recorded relative to SiMe4 (δ 0.00) or residual protonated solvents (CDCl3: δ 7.26) or ((CD₃)₂SO: δ 2.5).Multiplicities were given as: s(singlet), d (doublet), t (triplet), q (quartet) and m (multiplet). The number of protons (n) for a given resonance was indicated by nH. Coupling constants were reported as a J value in Hz.13C NMR spectra were obtained at 100 MHz on 400 MHz instruments and chemical shifts were recorded relative to solvent resonance (CDCl3: δ 77.16) or (CD3)2SO: δ 39.52).

[0047] Chiral HPLC analysis was performed on a Shimadzu LC-2050 instrument using CHIRALPAK IG columns.

[0048] LCMS was performed on Agilent triple quad.Stage- la: Preparation of Compound 4DIBAL-HorStage-la(S) (4)

[0049] A solution of 3,6-dihydro-2H-pyran-4-carbonitrile (5) (200.0 g, 1.83 mol) in toluene (2400 mL) was cooled to -10 to -5 °C. Then DIBAL-H (25% in toluene, 1356 mL, 2.38 mol) was added for 60 min and stirring was continued for 60 min at -10 to -5 °C. Then the reaction mixture was added to 4M Aq. HC1 solution (2400 mL) over 30 min at 25-30 °C. Then saturated aqueous NaCl solution (500 mL) was added and stirred for 20 min at 25-30 °C. The organic layer was separated, and the aqueous layer was extracted twice with toluene (2x500 mL). The combined organic layers were concentrated under reduced pressure to obtain compound 4 as viscous oil (125.0 g, molar yield = 60%, w / w yield: 62.5%).

[0050] 1HNMR (400 MHz, CDC13): δ 9.48 (s, 1H), 6.81-6.83 (m, 1H), 4.39-4.42 (m, 2H), 3.79-3.83 (dd, 2H), 2.32-2.36 (m, 2H).

[0051] 13C NMR: (100 MHz, CDC13): 5 192.2, 147.4, 138.3, 65.2, 63.5, 21.8.

[0052] HPLC purity: 98.51 %

[0053] No ionization found in LCMSStage 1: Preparation of Compound 64-Methoxy EtO2CBenzaldehyde_ PMBHNTFA, Et3SiH,DCM (6)

[0054] To a solution of ethyl-4-amino-1H-pyrazole-4-carboxylate (7) (200g,1.289mol) in toluene (1200mL), was added 4-methoxybenzaldehyde (210.6g,1.547mol) atRT. The reaction mixture was cooled to 05°C and trifluoroacetic acid (440.9g,3.867mol) and triethyl silane (389.6g,3.351mol) were added to reaction mixture. The reaction mixture was warmed to room temperature (RT) and stirred for 12-16h. After completion of reaction, the reaction mixture was quenched with water. The precipitated solid was filtered. The solid was washed with water (400mL) followed by n-heptane (400mL) and dried under vacuum to obtain compound 6 as off-white solid (320.0g, molar yield~90%, w / w yield=160%).

[0055] 1HNMR (400MHz, (CD3)2SO):δ 7.75(s, 1H), 7.26-7.28(d,2H), 6.87-6.89(d,2H), 4.33(s,2H), 4.14-4.19(dd,2H), 3.72(s,3H), 1.21-1.25 (t,3H)

[0056] 13CNMR (100MHz,(CD3)2SO): 164.4,158.8, 154.6,136.3, 132.2,129.0, 114.1, 95.4, 59.2, 55.4, 46.3, 14.8.LCMS(ESI): Calculated for C14H18N3O3+[M+H]+: 276, Found:276

[0057] HPLC purity: 99.51%

[0058] Preparation of Compound (3-6) wherein R1is ethyl and R2is dimethoxybenzaldehyde. R1O2C Dimethoxy RXO2CBenzaldehydeR2H3HTFA, Et3SiH,(3-7) DCM (3-6)

[0059] To a solution of ethyl-4-amino-1H-pyrazole-4-carboxylate (7) (1.3 mol) in toluene (1200mL), is added dimethoxybenzaldehyde (1.5 mol) at RT. The reaction mixture is cooled to 05°C and trifluoroacetic acid (3.9 mol) and triethyl silane (3.4 mol) is added to the reaction mixture. The reaction mixture is warmed to room temperature (RT) and stirred for 12-16h. After completion of reaction, the reaction mixture is quenched with water. The precipitated solid is filtered. The solid is washed with water (400mL) followed by n-heptane (400mL) and dried under vacuum to obtain compound (3-6) wherein R1is ethyl and R2is dimethoxybenzaldehyde.

[0060] Preparation of Compound (3-6) wherein R1is ethyl and R2is p-nitrobenzaldehyde.p-nitro Rhbenzaldehyde_ R2HNTFA, Et3SiH,(3-7) DCM (3-6)

[0061] To a solution of ethyl-4-amino-1H-pyrazole-4-carboxylate (7) (1.3 mol) in toluene (1200mL), is added p-nitrobenzaldehyde (1.5 mol) at RT. The reaction mixture is cooled to 05°C and trifluoroacetic acid (3.9 mol) and tri ethyl silane (3.4 mol) is added to reaction mixture. The reaction mixture is warmed to room temperature (RT) and stirred for 12-16h. After completion of reaction, the reaction mixture is quenched with water. The precipitated solid is filtered. The solid is washed with water (400mL) followed by n-heptane (400mL) and dried under vacuum to obtain compound (3-6) wherein R1is ethyl and R2is p-nitrobenzaldehyde.Stage-2: Preparation of Compound 3

[0062] To a solution of 3,6-dihydro -2H-pyran-4-carbaldehyde (4) (50.0 g, 445.9 mmol) in MTBE (1000 mL) was added (R)-2-(((tertbutyldimethylsilyl)oxy)diphenylmethyl)pyrrolidine (3-10) (12.28 g, 33.4 mmol) at RT. Then 2-nitro-benzoic acid (7.45 g, 44.6 mmol) and compound 3 (245 g, 891.8 mmol) were added to reaction mixture at RT. The resulting reaction mixture was stirred for 20 h at RT. The reaction mixture was concentrated under reduced pressure to obtained crude compound 3.Stage-3: Preparation of Compound 2

[0063] To the crude compound 3, hydroxylamine hydrochloride (61.97 g, 891.8mmol), pyridine (1000 mL), and TiC14 (211.5 g, 1.115 mol) was added and heated to 45°C. The reaction mixture was stirred for 10-15 h at 40-50 °C. After completion of reaction, ethyl acetate (250 mL) was added to reaction mass. Then resulting precipitate was filtered and washed with ethyl acetate (50 mL). The filtrate was acidified with 4M Aq HC1 (-500 mL) to pH 3-4. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was concentrated, and the obtained crude material was recrystallized with MeOH to obtain compound 2 as white solid (75.0 g, molar yield=43.5%, w / w yield= 150%). The syn isomer of compound 2 remained in the mother liquor.

[0064] 1HNMR (400 MHz, (CD3)2SO): δ 8.18 (s, 1H), 7.30-7.32 (d, 2H), 6.86-6.88 (d, 2H), 5.85-5.88 (t, 1H), 4.43-4.48 (dt, 1H), 4.29-4.31 (d, 2H), 4.15-4.20 (dd, 2H), 3.86-3.94 (m, 2H),3.72 (s, 3H), 3.41-3.66 (m, 2H), 3.32-3.38 (t, 1H), 2.12-2.16 (dd, 1H) 1.88-1.92 (ddd, 1H) 1.22- 1.26 (t, 3H)

[0065] 13C NMR (100 MHZ, (CD3)2SO): 5 163.5, 158.2, 156.8, 133.9, 132.1, 129.0, 119.6, 113.6, 97.3, 68.9, 65.2, 59.2, 57.5, 55.0, 45.7, 31.0, 28.2, 14.4.

[0066] LCMS (ESI): Calculated for C20H25N4O4+[M+H]+:385, Found:385

[0067] Chiral purity: 99.85%

[0068] HPLC purity: 97.36%Stage-4: preparation of (+)-ECPC ester compounded)TFA Stage-4(+)-ECPC

[0069] Trifluoroacetic acid (30 mL) was added to compound 6 (10 g, 26.01 mmol) in a round bottom flask at 20-25°C. The reaction mixture was stirred for 30-60 min at 20-25 °C. Water (100 mL) was added to reaction mixture and stirred for 30 min. The precipitated solid was filtered. The pH of the filtrate (aqueous layer) was adjusted ~7 to 8 by adding 10% aqueous NaHCCh solution. The reaction mass was extracted with DCM (100 mL). Then the organic layer was washed water (50 mL). The organic layer was concentrated under reduced pressure. The obtained crude material was triturated with MTBE (20 mL). The solid was filtered and dried to obtain (+)-ECPC ester 1 as white solid (5.8 g, molar yield~85%, w / w yield = 58%).

[0070] 1HNMR (400 MHz, (CD3)2SO): 58.14 (s, 1H), 5.48 (s, 2H), 4.41-4.44 (dt, 1H), 4.16-4.21 (dd, 2H), 3.87-3.94 (m, 2H), 3.49-3.58 (m, 2H), 3.37-3.40 (d, 1H), 2,12-2.16 (dd, 1H), 1.87-1.91 (ddd, 1H), 1.24-1.27 (t, 3H)

[0071] 13C NMR (100 MHz, (CD3)2SO): 5 163.5, 156.6, 133.7, 119.6, 97.9, 69.0, 65.4, 59.2, 57.4, 31.2, 28.2, 14.4.

[0072] LCMS (ESI): Calculated for C12H17N4O3+[M+H]+:265, Found:265

[0073] Chiral purity: 99.80%

[0074] HPLC purity: 97.30%

Claims

CLAIMS1. A process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-4)O(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3),0wherein the catalyst isowherein R is TMS, TES, TBDMS, MDPS, or TPS, R1is C1-C4 alkyl and R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehye or p-nitrobenzaldehyde;b) reacting the compound of Formula (3-3) with ammonium hydroxide to yield a compound of Formula (3-2)Oc) reacting the compound of Formula (3-2) with trifluoroacetic acid to yield the compound of Formula (3-1).

2. A process for making a compound of Formula (3-6)RXO2C(3-6)comprising reacting a compound of Formula (3-7),(3-7)R1is Ci-C4alkylwith a protecting group R2to yield the compound of Formula (3-6), wherein R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehyde or p-nitrobenzaldehyde.

3. A process for making a compound of Formula (3-3)comprising reacting a compound of Formula (3-4)0(3-4)with a compound of Formula (3-6)(3-6)in the presence of a catalyst to yield the compound of Formula (3-3), wherein the catalyst iswherein R is TMS, TES, TBDMS, MDPS, or TPS, R1is C1-C4 alkyl and R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehye or p-nitrobenzaldehyde.

4. A process of for making a compound of Formula (3-4)O(3-4)comprising reacting a compound of Formula (3-5)OI’-5’with a reducing agent to yield the compound of Formula (3-4), wherein the reducing agent is DIBAL-H or RED AL-H.

5. A process for making a compound of Formula (3-1)comprisingreacting the compound of Formula (3-3)wherein, R1is C1-C4 alkyl and R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehyde or p-nitrobenzaldehydewith ammonium hydroxide to yield a compound of Formula (3-2)Oreacting the compound of Formula (3-2) with trifluoroacetic acid to yield the compound of Formula (3-1).

6. A process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-4)0(3-4)with a compound of Formula (3-6)RXO2C(3-6)in the presence of a catalyst to yield the compound of Formula (3-3),0wherein the catalyst iswherein R is TMS, TES, TBDMS, MDPS, or TPS, R1is C1-C4 alkyl and R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehye or p-nitrobenzaldehyde; andb) further reacting the compound of Formula (3-3) to yield the compound of Formula (3-1).

7. A process for making a compound of Formula (3-1)comprisinga) reacting a compound of Formula (3-5)O(3-5)with a reducing agent to yield a compound of Formula (3-4)O(3-4)wherein the reducing agent is DIB AL-H or REDAL-H,b) reacting the compound of Formula (3-4) with a compound of Formula (3-6)R2HN-in the presence of a catalyst to yield a compound of Formula (3-3),0NR2HN^CHOwherein the catalyst isQ-wherein R is TMS, TES, TBDMS, MDPS, or TPS, R1is C1-C4 alkyl and R2is para-methoxy benzaldehyde (PMB), dimethoxybenzaldehye or p-nitrobenzaldehyde; andc) further reacting the compound of Formula (3-3) to yield the compound of Formula (3-1).

8. The process of any one of claims 1-7, wherein R1is ethyl and R2is PMB.

9. The process of any one of claims 1, 5, 6 or 7, wherein greater than 80%, preferably greater than 85%, of the desired 3R,4S enantiomer (the compound of Formula (3-1) is produced.

10. The process of any one of claims 1,3 and 6-9, wherein R is TBDMS.

11. A process for making atinvicitinibl2N'Nicomprisinga) making a compound of Formula (3-1)(3-1)wherein R1is ethylby any of the processes of anyone of claims 1 and 5-10,b) further reacting the compound of Formula (3-1) to yield atinvicitinib.

12. A compound of Formula (3-4)0Interne' -1— —Kl~ WO 2026 / 132007 PCT / EP2025 / 087661 INTERNATIONAL SEARCH REPORTBox No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons:

1. Claims Nos.:because they relate to subject matter not required to be searched by this Authority, namely:Claims Nos.:because they relate to parts of the international application that do not comply with the prescribed requirements to such an extent that no meaningful international search can be carried out, specifically:3 Claims Nos.:because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).Box No. Ill Observations where unity of invention is lacking (Continuation of item 3 of first sheet)This International Searching Authority found multiple inventions in this international application, as follows:see additional sheetAs all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims.2 As all searchable claims could be searched without effort justifying an additional fees, this Authority did not invite payment of additional fees.As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:4 x| No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims;; it is covered by claims Nos.:1, 3, 6 - 12Remark on Protest The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee.The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation.No protest accompanied the payment of additional search fees.Form PCT / ISA / 210 (continuation of first sheet (2)) (April 2005)INTERNATIONAL SEARCH REPORTInternational application NoWO 2026 / 132007 PCT / EP2025 / 087661 A. CLASSIFICATION OF SUBJECT MATTERINV. C07D309 / 26 C07D405 / 04ADD.According to International Patent Classification (IPC) or to both national classification and IPCB. FIELDS SEARCHEDMinimum documentation searched (classification system followed by classification symbols)C07DDocumentation searched other than minimum documentation to the extent that such documents are included in the fields searchedEPO InternalRelevant to claim No.X GNAIM SAMER ET AL: " Electrochemically 12driven desaturation of carbonylcompounds "NATURE CHEMISTRY NATURE PUBLISHING GROUP UK LONDONvol 13 no 4 23 March 2021 (2021 03 23pages 367 372 XP037424383ISSN: 1755 4330 DOI:10 1038 / S41557 021 00640 2[retrieved on 2021 03 23]compound 33A WO 2020 / 120673 Al (INTERVET INT BV [NL] 1, 3, 6 - 11 INTERVET INC [US]18 June 2020 (2020 06 18cited in the applicationclaim 1020 March 2026 29 / 05 / 2026Bakboord JoanINTERNATIONAL SEARCH REPORTInternational application No WO 2026 / 132007 Information on patent family membersPCT / EP2025 / 087661 Patent document Publication Patent family Publication cited in search report date member(s) date WO 2020120673 Al 18 - 06 - 2020 BR 112021011084 A2 31 - 08 - 2021CA 3122183 Al 18 - 06 - 2020 CN 113227077 A 06 - 08 - 2021 CN 119350306 A 24 - 01 - 2025 EP 3894403 Al 20 - 10 - 2021 JP 7497357 B2 10 - 06 - 2024 JP 7759167 B2 23 - 10 - 2025 JP 2022511948 A 01 - 02 - 2022 JP 2024054201 A 16 - 04 - 2024 JP 2025138768 A 25 - 09 - 2025 US 2022017499 Al 20 - 01 - 2022 WO 2020120673 Al 18 - 06 - 2020International Application No. PCT / EP2025 / 087661 FURTHER INFORMATION CONTINUED FROM PCT / ISA / 210This International Searching Authority found multiple (groups of ) inventions in this international application, as follows:

1. claims: 1, 3, 6 - 12A process for making a compound of formula 3 - 1 using acompound of formula 3 - 4 as intermediate2. claim: 2A process for making a compound of formula 3 - 63. claim: 4A process for making a compound of formula 3 - 44. claim: 5A process for making a compound of formula 3 - 1

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