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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK LIFE SCIENCES LTD, Research Centre as Principal Scientist, Process Research (bulk actives) at Mahape, Navi Mumbai, India. Total Industry exp 30 plus yrs, Prior to joining Glenmark, he has worked with major multinationals like Hoechst Marion Roussel, now Sanofi, Searle India Ltd, now RPG lifesciences, etc. He has worked with notable scientists like Dr K Nagarajan, Dr Ralph Stapel, Prof S Seshadri, Dr T.V. Radhakrishnan and Dr B. K. Kulkarni, etc, He did custom synthesis for major multinationals in his career like BASF, Novartis, Sanofi, etc., He has worked in Discovery, Natural products, Bulk drugs, Generics, Intermediates, Fine chemicals, Neutraceuticals, GMP, Scaleups, etc, he is now helping millions, has 9 million plus hits on Google on all Organic chemistry websites. His friends call him Open superstar worlddrugtracker. His New Drug Approvals, Green Chemistry International, All about drugs, Eurekamoments, Organic spectroscopy international, etc in organic chemistry are some most read blogs He has hands on experience in initiation and developing novel routes for drug molecules and implementation them on commercial scale over a 30 PLUS year tenure till date June 2021, Around 35 plus products in his career. He has good knowledge of IPM, GMP, Regulatory aspects, he has several International patents published worldwide . He has good proficiency in Technology transfer, Spectroscopy, Stereochemistry, Synthesis, Polymorphism etc., He suffered a paralytic stroke/ Acute Transverse mylitis in Dec 2007 and is 90 %Paralysed, He is bound to a wheelchair, this seems to have injected feul in him to help chemists all around the world, he is more active than before and is pushing boundaries, He has 9 million plus hits on Google, 2.5 lakh plus connections on all networking sites, 90 Lakh plus views on dozen plus blogs, 233 countries, 7 continents, He makes himself available to all, contact him on +91 9323115463, email amcrasto@gmail.com, Twitter, @amcrasto , He lives and will die for his family, 90% paralysis cannot kill his soul., Notably he has 33 lakh plus views on New Drug Approvals Blog in 233 countries......https://newdrugapprovals.wordpress.com/ , He appreciates the help he gets from one and all, Friends, Family, Glenmark, Readers, Wellwishers, Doctors, Drug authorities, His Contacts, Physiotherapist, etc

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Pemigatinib


Pemigatinib.svg
img

Pemigatinib

INCB054828

FormulaC24H27F2N5O4
CAS1513857-77-62379919-96-5  HCL
Mol weight487.4991

2020/4/17FDA APPROVED, PEMAZYRE

佩米替尼 [Chinese] [INN]

3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholinomethyl)-1,3,4,6-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

2H-Pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one, 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-8-(4-morpholinylmethyl)-

3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one 

  • Originator Incyte Corporation
  • Developer Incyte Corporation; Innovent Biologics
  • ClassAntineoplastics; Ethers; Fluorobenzenes; Morpholines; Pyridines; Pyrimidinones; Pyrroles; Small molecules
  • Mechanism of Action Type 1 fibroblast growth factor receptor antagonists; Type 3 fibroblast growth factor receptor antagonists; Type 4 fibroblast growth factor receptor antagonists; Type-2 fibroblast growth factor receptor antagonists
  • Orphan Drug Status Yes – Myeloproliferative disorders; Lymphoma; Cholangiocarcinoma
  • MarketedCholangiocarcinoma
  • Phase IIBladder cancer; Lymphoma; Myeloproliferative disorders; Solid tumours; Urogenital cancer
  • Phase I/IICancer
  • 05 Nov 2020Preregistration for Cholangiocarcinoma (Late-stage disease, Metastatic disease, First line therapy, Inoperable/Unresectable) in Japan (PO) in November 2020
  • 05 Nov 2020Incyte Corporation stops enrolment in the FIGHT-205 trial for Bladder cancer due to regulatory feedback
  • 26 Oct 2020Preregistration for Cholangiocarcinoma (Second-line therapy or greater, Inoperable/Unresectable, Late-stage disease, Metastatic disease) in Canada (PO)

Pemigatinib, also known as INCB054828, is an orally bioavailable inhibitor of the fibroblast growth factor receptor (FGFR) types 1, 2, and 3 (FGFR1/2/3), with potential antineoplastic activity. FGFR inhibitor INCB054828 binds to and inhibits FGFR1/2/3, which may result in the inhibition of FGFR1/2/3-related signal transduction pathways. This inhibits proliferation in FGFR1/2/3-overexpressing tumor cells.

Pemigatinib (INN),[2] sold under the brand name Pemazyre, is a medication for the treatment of adults with previously treated, unresectable locally advanced or metastatic bile duct cancer (cholangiocarcinoma) with a fibroblast growth factor receptor 2 (FGFR2) fusion or other rearrangement as detected by an FDA-approved test.[3][4] Pemigatinib works by blocking FGFR2 in tumor cells to prevent them from growing and spreading.[3]

Pemigatinib belongs to a group of medicines called protein kinase inhibitors.[5] It works by blocking enzymes known as protein kinases, particularly those that are part of receptors (targets) called fibroblast growth factor receptors (FGFRs).[5] FGFRs are found on the surface of cancer cells and are involved in the growth and spread of the cancer cells.[5] By blocking the tyrosine kinases in FGFRs, pemigatinib is expected to reduce the growth and spread of the cancer.[5]

PEMAZYRE®: Prescription Medicine that is Used to Treat Adults with Bile Duct Cancer| Pemazyre.com

The most common adverse reactions are hyperphosphatemia and hypophosphatemia (electrolyte disorders), alopecia (spot baldness), diarrhea, nail toxicity, fatigue, dysgeusia (taste distortion), nausea, constipation, stomatitis (sore or inflammation inside the mouth), dry eye, dry mouth, decreased appetite, vomiting, joint pain, abdominal pain, back pain and dry skin.[3][4] Ocular (eye) toxicity is also a risk of pemigatinib.[3][4]

Medical uses

Cholangiocarcinoma is a rare form of cancer that forms in bile ducts, which are slender tubes that carry the digestive fluid bile from the liver to gallbladder and small intestine.[3] Pemigatinib is indicated for the treatment of adults with bile duct cancer (cholangiocarcinoma) that is locally advanced (when cancer has grown outside the organ it started in, but has not yet spread to distant parts of the body) or metastatic (when cancer cells spread to other parts of the body) and who have tumors that have a fusion or other rearrangement of a gene called fibroblast growth factor receptor 2 (FGFR2).[3] It should be used in patients who have been previously treated with chemotherapy and whose cancer has a certain type of abnormality in the FGFR2 gene.[6]

History

Pemigatinib was approved for use in the United States in April 2020 along with the FoundationOne CDX (Foundation Medicine, Inc.) as a companion diagnostic for patient selection.[3][4][7]

The approval of pemigatinib in the United States was based on the results the FIGHT-202 (NCT02924376) multicenter open-label single-arm trial that enrolled 107 participants with locally advanced or metastatic cholangiocarcinoma with an FGFR2 fusion or rearrangement who had received prior treatment.[3][4][6] The trial was conducted at 67 sites in the United States, Europe, and Asia.[6] During the clinical trial, participants received pemigatinib once a day for 14 consecutive days, followed by 7 days off, in 21-day cycles until the disease progressed or the patient experienced an unreasonable level of side effects.[3][4][6] To assess how well pemigatinib was working during the trial, participants were scanned every eight weeks.[3] The trial used established criteria to measure how many participants experienced a complete or partial shrinkage of their tumors during treatment (overall response rate).[3] The overall response rate was 36% (95% CI: 27%, 45%), with 2.8% of participants having a complete response and 33% having a partial response.[3] Among the 38 participants who had a response, 24 participants (63%) had a response lasting six months or longer and seven participants (18%) had a response lasting 12 months or longer.[3][4]

The U.S. Food and Drug Administration (FDA) granted the application for pemigatinib priority reviewbreakthrough therapy and orphan drug designations.[3][4][8][9] The FDA granted approval of Pemazyre to Incyte Corporation.[3]

On 24 August 2018, orphan designation (EU/3/18/2066) was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of biliary tract cancer.[5] On 17 October 2019, orphan designation EU/3/19/2216 was granted by the European Commission to Incyte Biosciences Distribution B.V., the Netherlands, for pemigatinib for the treatment of myeloid/lymphoid neoplasms with eosinophilia and rearrangement of PDGFRA, PDGFRB, or FGFR1, or with PCM1-JAK2.[10]

PATENT

US 20200281907

The present disclosure is directed to, inter alia, methods of treating cancer in a patient in need thereof, comprising administering pemigatinib, which is 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one, having the structure shown below:

 Pemigatinib is described in U.S. Pat. No. 9,611,267, the entirety of which is incorporated herein by reference. Pemigatinib is further described in US Publication Nos.: 2019/0337948 and 2020/0002338, the entireties of which are incorporated herein by reference.

      Provided herein is a method of treating cancer comprising administering a therapy to a patient in need thereof, wherein the therapy comprises administering a therapeutically effective amount of pemigatinib to the patient while avoiding the concomitant administration of a CYP3A4 perpetrator.

Example 1. Synthesis of Pemigatinib

Step 1: 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde


 
      A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (CAS #958230-19-8, Lakestar Tech, Lot: 124-132-29: 3.0 g, 17 mmol) and ethylamine (10M in water, 8.3 mL, 83 mmol) in 2-methoxyethanol (20 mL, 200 mmol) was heated to 130° C. and stirred overnight. The mixture was cooled to room temperature then concentrated under reduced pressure. The residue was treated with 1N HCl (30 mL) and stirred at room temperature for 1 h then neutralized with saturated NaHCO aqueous solution. The precipitate was collected via filtration then washed with water and dried to provide the desired product (2.9 g, 92%). LC-MS calculated for C 10123O [M+H] + m/z: 190.1; found: 190.1.

Step 2: 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine


 
      A mixture of 4-(ethylamino)-1H-pyrrolo[2,3-b]pyridine-5-carbaldehyde (7.0 g, 37 mmol), 2,6-difluoro-3,5-dimethoxyaniline (9.1 g, 48 mmol) and [(1S)-7,7-dimethyl-2-oxobicyclo[2.2.1]hept-1-yl]methanesulfonic acid (Aldrich, cat #21360: 2 g, 7 mmol) in xylenes (250 mL) was heated to reflux with azeotropic removal of water using Dean-Stark for 2 days at which time LC-MS showed the reaction was complete. The mixture was cooled to room temperature and the solvent was removed under reduced pressure. The residue was dissolved in tetrahydrofuran (500 mL) and then 2.0 M lithium tetrahydroaluminate in THF (37 mL, 74 mmol) was added slowly and the resulting mixture was stirred at 50° C. for 3 h then cooled to room temperature. The reaction was quenched by addition of water, 15% aqueous NaOH and water. The mixture was filtered and washed with THF. The filtrate was concentrated and the residue was washed with CH 2Cl and then filtered to get the pure product (11 g, 82%). LC-MS calculated for C 1821242[M+H] + m/z: 363.2; found: 363.1.

Step 3: 3-(2,6-Difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one


 
      A solution of triphosgene (5.5 g, 18 mmol) in tetrahydrofuran (30 mL) was added slowly to a mixture of 5-{[(2,6-difluoro-3,5-dimethoxyphenyl)amino]methyl}-N-ethyl-1H-pyrrolo[2,3-b]pyridin-4-amine (5.6 g, 15 mmol) in tetrahydrofuran (100 mL) at 0° C. and then the mixture was stirred at room temperature for 6 h. The mixture was cooled to 0° C. and then 1.0 M sodium hydroxide in water (100 mL, 100 mmol) was added slowly. The reaction mixture was stirred at room temperature overnight and the formed precipitate was collected via filtration, washed with water, and then dried to provide the first batch of the purified desired product. The organic layer in the filtrate was separated and the aqueous layer was extracted with methylene chloride. The combined organic layer was concentrated and the residue was triturated with methylene chloride then filtered and dried to provide another batch of the product (total 5.5 g, 92%). LC-MS calculated for C 1919243[M+H] + m/z: 389.1; found: 389.1.

Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one


 
      To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH 4Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C 2523245S [M+H] + m/z: 529.1; found: 529.1.

Step 5: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde


 
      To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO and concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C 2623246S (M+H) + m/z: 557.1; found: 556.9.

Step 6: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one


 
      To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCO then extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO and concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C 3032256S (M+H) + m/z: 628.2; found: 628.0.

Step 7: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (pemigatinib)

      To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′: 5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na 2SO and concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H 2O). LC-MS calculated for C 242825(M+H) + m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).

PATENT

WO 2019213506

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2019213506

PATENT

WO 2019213544

The present disclosure is directed to, inter alia, solid forms, including crystalline forms and amorphous forms, of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)- 1 ,3,4,7 -tetrahydro-2H-pyrrolo [3 ‘,2’ : 5 ,6]pyrido [4,3 -d]pyrimidin-2-one

(Compound 1), and processes and intermediates for preparing the compound. The structure of Compound 1 is shown below.

Compound 1

Compound 1 is described in US Patent No. 9,611,267, the entirety of which is incorporated herein by reference.

Example 1

Synthesis of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l^, 4,7-tetrahydro-2H-pyrrolo[3f,2f:5,6]pyrido[4r3-d]pyrimidin-2-one (Compound 1) Scheme 1.

Step 1: Synthesis of 4-((4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b ] pyridin-2-yl) methyl) morpholine

To a l-L flask was added 4-chloro-5-(l,3-dioxolan-2-yl)-l-(phenylsulfonyl)-lH-pyrrolo [2,3-b] pyridine (50.0 g, 137 mmol) (see, e.g., Example 2) and tetrahydrofuran (THF, 266 g, 300 mL) under N2. To this mixture at -70 °C was added 2.0 M lithium

diisopropylamide in THF/heptane/ethyl benzene (77.4 g, 95 mL, 190 mmol, 1.4 eq.). The mixture was stirred at -70 °C for 1 h. To the mixture was added /V- formyl morpholine (29.7 g, 258 mmol, 1.9 eq.) in THF (22. 2 g, 25 mL) dropwise. The reaction was done in 30 min after addition. LC/MS showed that the desired product, 4-chloro-5-(l, 3-dioxolan-2-yl)-l-(phenylsulfonyl)- 1 //-pyrrolo [2, 3-61 pyridine-2-carbaldehyde, was formed cleanly. The reaction was quenched with acetic acid (16.4 g, 15.6 mL, 274 mmol, 2.0 eq.) and the dry ice cooling was removed. To the mixture was added morpholine (33.7 g, 33.5 mL, 387 mmol, 2.83 eq.) followed by acetic acid (74.0 g, 70 mL, 1231 mmol, and 9.0 eq.) at 0 °C (internal temperature rose from 0 °C to 18 °C) and stirred overnight. Sodium triacetoxyborohydride (52.50 g, 247.7 mmol, 1.8 eq.) was added and the reaction mixture temperature rose from 20 °C to 32 °C. The mixture was stirred at room temperature for 30 min. HPLC & LC/MS indicated the reaction was complete. Water (100 g, 100 mL) was added followed by 2.0 M sodium carbonate (Na2C03) in water (236 g, 200 mL, 400 mmol, 2.9 eq.) slowly (off gas!). The mixture was stirred for about 30 min. The organic layer was separated and water (250 g, 250 mL) and heptane (308 g, 450 mL) were added. The resulting slurry was stirred for 1 h and the solid was collected by filtration. The wet cake was washed with heptane twice (75.00 mL x 2, 51.3 g x 2) before being dried in oven at 50 °C overnight to give the desired product, 4-((4-chloro-5-( 1 3-dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-2-yl)methyl)morpholine as a light brown solid (52.00 g, 81.8 % yield): LCMS calculated for C21H23CIN2O5S [M+H]+: 464.00; Found: 464.0; ftf NMR ^OO MHz, DMSO-de) d 8.48 (s, 1 H), 8.38 (m, 2H), 7.72 (m, 1H), 7.64 (m, 2H), 6.83 (s, 1H), 6.13 (s, 1H), 4.12 (m, 2H), 4.00 (m, 2H), 3.92 (s, 2H), 3.55 (m, 4H), 2.47 (m, 4H).

Step 2: Synthesis of 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo[2, 3-b] pyridine-5 -carbaldehyde

To a 2 L reactor with a thermocouple, an addition funnel, and a mechanical stirrer was charged 4-((4-chloro-5 -(1 ,3 -dioxolan-2-yl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo [2,3 -6]pyridin-2-yl)methyl)morpholine (20.00 g, 43.1 mmol) and dichloromethane (265 g, 200 mL) at room temperature. The resulting mixture was stirred at room temperature (internal temperature

was 19.5 °C) to achieve a solution. To the resulting solution was added an aqueous hydrochloric acid solution (0.5 M, 240 g, 200.0 ml, 100 mmol, 2.32 eq.) at room temperature in 7 min. After over 23 h agitations at room temperature, the bilayer reaction mixture turned into a thick colorless suspension. When HPLC showed the reaction was complete, the slurry was cooled to 0-5 °C and aqueous sodium hydroxide solution (1 N, 104 g, 100 mL, 100 mmol, and 2.32 eq.) was added in about 10 min to adjust the pH of the reaction mixture to 10-11. «-Heptane (164 g, 240 mL) was added and the reaction mixture and the mixture were stirred at room temperature for 1 h. The solid was collected by filtration and the wet cake was washed with water (2 x 40 mL), heptane (2 x 40 ml) before being dried in oven at 50 °C under vacuum to afford the desired product, 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-/i |pyridine-5-carbaldehyde as a light brown solid (16.9 g, 93% yield): LCMS calculated for C19H19CIN3O4S [M+H]+: 420.00; Found: 420.0; ¾ NMR (400 MHz, DMSO-de) d 10.33 (s, 1H), 8.76 (s, 1 H), 8.42 (m, 2H), 7.74 (m, 1H), 7.65 (m, 2H), 6.98 (s, 1H), 3.96 (m, 2H), 3.564 (m, 4H), 2.51 (m, 4H).

Step 3: Synthesis ofN-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-h] pyridin-5-yl) methyl) -2, 6-difluoro-3,5-dimethoxyaniline

To a 2-L reactor equipped with a thermocouple, a nitrogen inlet and mechanical stirrer were charged AOV-dimethyl formamide (450 mL, 425 g), 4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridine-5-carbaldehyde (30.0 g, 71.45 mmol) and 2,6-difluoro-3,5-dimethoxyanihne (14.2 g, 75.0 mmol). To this suspension (internal temperature 20 °C) was added chlorotrimethylsilane (19.4 g, 22. 7 mL, 179 mmol) dropwise in 10 min at room temperature (internal temperature 20-23 °C). The suspension changed into a solution in 5 min after the chlorotrimethylsilane addition. The solution was stirred at room temperature for 1.5 h before cooled to 0-5 °C with ice-bath. Borane-THF complex in THF (1.0 M, 71.4 mL, 71.4 mmol, 64.2 g, 1.0 eq.) was added dropwise via additional funnel over 30 min while maintaining temperature at 0-5 °C. After addition, the mixture was stirred for 4 h. Water (150 g, 150 mL) was added under ice-bath cooling in 20 min, followed by slow addition of ammonium hydroxide solution (28% N¾, 15.3 g, 17 ml, 252 mmol, 3.53 eq.) to pH 9-10 while maintaining the temperature below 10 °C. More water (250 mL, 250 g) was added through the additional funnel. The slurry was stirred for 30 min and the solids were collected by filtration. The wet cake was washed with water (90 g x 2, 90 ml x 2) and heptane (61.6 g x2, 90 ml x 2). The product w as suction dried overnight to give the desired product LG-((4-chloro-2-(morphohnomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-Z>]pyridin-5-yl)methyl)-2,6- difluoro-3,5-dimethoxyaniline (41.6 g, 96% yield): LCMS calculated for C27H28ClF2N405S[M+H]+: 593.10; Found: 593.1 ; ¾ NMR (400 MHz, DMSO-d6) 5 8.36 (m, 2H), 8.28 (s, 1H), 7.72 (m, 1H), 7.63 (m, 2H), 6.78 (s, 1H), 6.29 (m, 1H), 5.82 (m, 1H), 4.58 (m, 2H), 3.91 (s, 2H), 3.76 (s, 6H), 3.56 (m, 4H), 2.47 (m, 4H).

Step 4: Synthesis of l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-lH-pyrrolo [2, 3-b ] pyridin-5-yl) methyl)-! -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea

To a 2-L, 3-neck round bottom flask fitted with a thermocouple, a nitrogen bubbler inlet, and a magnetic stir were charged /V-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-li/-pyrrolo[2,3-b]pyridin-5-yl)methyl)-2,6-difluoro-3,5-dimethoxyaniline (67.0 g, 113 mmol) and acetonitrile (670 ml, 527 g). The suspension was cooled to 0-5 °C.

To the mixture was charged ethyl isocyanate (17.7 mL, 15.9 g, 224 mmol, 1.98 eq.) over 30 sec. The temperature stayed unchanged at 0.7 °C after the charge. Methanesulfonic acid (16.1 mL, 23.9 g, 248 mmol, 2.2 eq.) was charged dropwise over 35 min while maintaining the temperature below 2 °C. The mixture was warmed to room temperature and stirred overnight. At 24 h after addition showed that the product was 93.7%, unreacted SM was 0.73% and the major impurity (bis-isocyanate adduct) was 1.3%. The mixture was cooled with an ice-bath and quenched with sodium hydroxide (NaOH) solution (1.0M, 235 mL, 244 g, 235 mmol, 2.08 eq.) over 20 min and then saturated aqueous sodium bicarbonate

(NaHCCh) solution (1.07 M, 85 mL, 91 g, 0.091 mol, 0.80 eq.) over 10 min. Water (550 mL, 550 g) was added and the liquid became one phase. The mixture was stirred for 2 h and the solids were collected by filtration, washed with water (165 mL, 165 g) to give l-((4-chloro-2-(morpholinomethyl)- 1 -(phenylsulfonyl)- 1 //-pyrrolo| 2.3-6 |p\ ri din-5 -y l (methy l )- 1 -(2,6-difluoro-3,5-dimethoxyphenyl)-3-ethylurea ( 70.3 g, 93.7% yield).

The crude l-((4-chloro-2-(morpholinomethyl)-l -(phenylsulfonyl)- li/-pyrrolo [2, 3-61 pyridin-5-yl) methyl)- 1 -(2, 6-difluoro-3, 5-dimethoxyphenyl)-3-ethylurea (68.5 g, 103 mmol) was added in to acetonitrile (616 mL, 485 g). The mixture was heated 60-65 °C and an amber colored thin suspension was obtained. The solid was filtered off with celite and the celite was washed with acetonitrile (68.5 mL, 53.8 g). To the pale yellow filtrate was added water (685 g, 685 ml) to form a slurry. The slurry was stirred overnight at room temperature and filtered. The solid was added to water (685 mL, 685 g) and stirred at 60 °C for 2 h. The solid was filtered and re-slurred in heptane (685 mL, 469 g) overnight. The product was dried in an oven at 50 °C under vacuum for 48 h to afford l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)- 1 //-pyrrolo|2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-difluoro-3.5-

dimethoxyphenyl)-3-ethylurea as a colorless solid (62.2 g, 90.8% yield, 99.9% purity by HPLC area%). KF was 0.028%. Acetonitrile (by ‘H NMR) was about 1.56%, DCM (by ‘H NMR) 2.0%: LCMS calculated for C30H33CIF2N5O6S [M+H]+: EM: 664.17; Found: 664.2; ¾ NMR (400 MHz, DMSO-de) d 8.33 (m, 2H), 8.31 (s, 1H), 7.72 (m, 1H), 7.64 (m, 1H), 6.96 (m, 2H), 6.73 (s, 1H), 6.43 (m, 1H), 4.87 (s, 2H), 3.90 (s, 2H), 3.77 (s, 6H), 3.54 (m, 4H),

3.03 (m, 2H), 2.46 (m, 4H), 0.95 (m, 3H).

Step 5: Synthesis of 3-(2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l, 3, 4, 7-tetrahydro-2H-pyrrolo[ 3 2’:5, 6 ]pyrido[ 4, 3-d]pyrimidin-2-one

To a 2000 mL flask equipped with a thermal couple, a nitrogen inlet, and a mechanical stirrer were charged dry l-((4-chloro-2-(morpholinomethyl)-l-(phenylsulfonyl)-1 //-pyrrolo| 2.3-6 |pyridin-5-yl)methyl)- 1 -(2.6-dinuoro-3.5-dimetho\yphenyl)-3-ethylurea (30.0 g, 45.2 mmol, KF=0. l l%) and tetrahydrofuran (1200 mL, 1063 g). To this suspension at room temperature was charged 1.0 M lithium hexamethyldisilazide in THF (62.3 mL, 55.5 g, 62.3 mmol, 1.38 eq). The mixture turned into a solution after the base addition. The reaction mixture was stirred for 2 h and HPLC shows the starting material was not detectable. To this mixture was added 1.0 M hydrochloric acid (18.1 mL, -18.1 g. 18.1 mmol, 0.4 eq.). The solution was concentrated to 600 mL and water (1200 mL, 1200 g) was added. Slurry was formed after water addition. The slurry was stirred for 30 min at room temperature and the solid was collected by filtration. The wet cake was washed with water twice (60 mLx2,

60 gx2) and dried at 50 °C overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4, 3-d]pyrimidin-2-one as a light brown solid (26.58 g, as-is yield 93.7%): THF by ‘H NMR 0.32%, KF 5.26%, adjusted yield was 88.5%: LCMS calculated for C30H32F2N5O6S [M+H]+: EM: 628.20; Found: 628.2; ¾ NMR (400 MHz, DMSO-de) d 8.41 (m, 2H), 8.07 (s, 1H), 7.70 (m, 1H), 7.63 (m, 2H), 7.05 (m, 1H), 6.89 (s, 1H), 4.76 (s, 2H), 4.09 (m, 2H), 3.93 (s, 2H), 3.89 (s, 6H), 3.60 (m, 4H), 2.50 (m, 4H), 1.28 (m, 3H).

Step 6: Synthesis of 3-( 2, 6-difluoro-3, 5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-1,3, 4, 7 -tetrahydro-2H-pyrrolo [ 3 ‘, 2 5, 6 ]pyrido[ 4, 3-dJpyrimidin-2-one

To a stirring suspension of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholinomethyl)-7-(phenylsulfonyl)-l,3,4,7-tetrahydro-2i/-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (10.0 g, 15.93 mmol) in l,4-dioxane (100 ml, 103 g) in a 500 mL flask equipped with a nitrogen inlet, a condenser, a thermocouple and a heating mantle was added 1 M aqueous sodium hydroxide (63.7 ml, 66.3 g, 63.7 mmol). The reaction mixture was heated at 75 °C for 18 h. LCMS showed the reaction was complete. Water (100 mL, 100 g) was added to give a thick suspension. This slurry was stirred at room temperature for 1 h and filtered. The cake was washed with water (3 x 10 mL, 3 x 10 g) and heptane (2 x 10 mL, 2 x 6.84 g). The cake was dried overnight by pulling a vacuum through the filter cake and then dried in an oven at 50 °C under vacuum overnight to give 3-(2,6-difluoro-3,5-dimethoxyphenyl)-l-ethyl-8-(morpholin-4-ylmethyl)-l,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5, 6]pyrido[4,3-d]pyrimidin-2-one (6.8 g, 87.6% yield): LCMS calculated for C24H28F2N5O4 [M+H]+: 488.20; Found: 488.2.

PATENT

US 20130338134

https://patents.google.com/patent/US20130338134A1/en

  • [0831]

Step 1: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

  • [0832]
  • [0833]
    To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (Example 49, Step 3: 900 mg, 2.32 mmol) in N,N-dimethylformamide (20 mL) cooled to 0° C. was added sodium hydride (185 mg, 4.63 mmol, 60 wt % in mineral oil). The resulting mixture was stirred at 0° C. for 30 min then benzenesulfonyl chloride (0.444 mL, 3.48 mmol) was added. The reaction mixture was stirred at 0° C. for 1.5 h at which time LC-MS showed the reaction completed to the desired product. The reaction was quenched with saturated NH4Cl solution and diluted with water. The white precipitate was collected via filtration then washed with water and hexanes, dried to afford the desired product (1.2 g, 98%) as a white solid which was used in the next step without further purification. LC-MS calculated for C25H23F2N4O5S [M+H]+ m/z: 529.1; found: 529.1.

Step 2: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde

  • [0834]
  • [0835]
    To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.75 g, 3.31 mmol) in tetrahydrofuran (80 mL) at −78° C. was added freshly prepared lithium diisopropylamide (1M in tetrahydrofuran (THF), 3.48 mL, 3.48 mmol). The resulting mixture was stirred at −78° C. for 30 min then N,N-dimethylformamide (1.4 mL, 18 mmol) was added slowly. The reaction mixture was stirred at −78° C. for 30 min then quenched with water and extracted with EtOAc. The organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SOand concentrated. The residue was purified by flash chromatography eluted with 0 to 20% EtOAc in DCM to give the desired product as a white solid (1.68 g, 91%). LC-MS calculated for C26H23F2N4O6S (M+H)+ m/z: 557.1; found: 556.9.

Step 3: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

  • [0836]
  • [0837]
    To a solution 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-2-oxo-7-(phenylsulfonyl)-2,3,4,7-tetrahydro-1H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidine-8-carbaldehyde (1.73 g, 3.11 mmol) in dichloromethane (50 mL) was added morpholine (0.95 mL, 11 mmol), followed by acetic acid (2 mL, 30 mmol). The resulting yellow solution was stirred at room temperature overnight then sodium triacetoxyborohydride (2.3 g, 11 mmol) was added. The mixture was stirred at room temperature for 3 h at which time LC-MS showed the reaction went to completion to the desired product. The reaction was quenched with saturated NaHCOthen extracted with ethyl acetate (EtOAc). The organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SOand concentrated. The residue was purified by flash chromatography eluted with 0 to 40% EtOAc in DCM to give the desired product as a yellow solid (1.85 g, 95%). LC-MS calculated for C30H32F2N5O6S (M+H)+ m/z: 628.2; found: 628.0.

Step 4: 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one

  • [0838]
    To a solution of 3-(2,6-difluoro-3,5-dimethoxyphenyl)-1-ethyl-8-(morpholin-4-ylmethyl)-7-(phenylsulfonyl)-1,3,4,7-tetrahydro-2H-pyrrolo[3′,2′:5,6]pyrido[4,3-d]pyrimidin-2-one (1.5 g, 2.4 mmol) in tetrahydrofuran (40 mL) was added tetra-n-butylammonium fluoride (1M in THF, 7.2 mL, 7.2 mmol). The resulting solution was stirred at 50° C. for 1.5 h then cooled to room temperature and quenched with water. The mixture was extracted with dichloromethane (DCM) and the organic extracts were combined then washed with water and brine. The organic layer was dried over Na2SOand concentrated. The residue was purified by flash chromatography eluted with 0 to 10% MeOH in DCM to give the desired product as a white solid, which was further purified by prep HPLC (pH=2, acetonitrile/H2O). LC-MS calculated for C24H28F2N5O(M+H)+ m/z: 488.2; found: 488.0. 1H NMR (500 MHz, DMSO) δ 12.09 (s, 1H), 8.06 (s, 1H), 7.05 (t, J=8.1 Hz, 1H), 6.87 (s, 1H), 4.78 (s, 2H), 4.50 (s, 2H), 4.17 (q, J=6.8 Hz, 2H), 3.97 (br, 2H), 3.89 (s, 6H), 3.65 (br, 2H), 3.37 (br, 2H), 3.15 (br, 2H), 1.37 (t, J=6.8 Hz, 3H).

PATENTS

Publication Number TitlePriority Date Grant Date
US-2013338134-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
US-2017137424-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
US-2019127376-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
US-9611267-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132017-04-04
WO-2014007951-A2Substituted tricyclic compounds as fgfr inhibitors2012-06-13
Publication Number TitlePriority Date Grant Date
JP-6336665-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-06-06
JP-6545863-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132019-07-17
JP-6711946-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132020-06-17
TW-201402574-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
US-10131667-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-11-20
Publication Number TitlePriority Date Grant Date
JP-2015521600-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-2017222709-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-2018135377-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-2019178156-ASubstituted tricyclic compounds as FGFR inhibitors2012-06-13 
JP-6301321-B2Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-03-28
Publication Number TitlePriority Date Grant Date
EP-3176170-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
EP-3176170-B1Substituted tricyclic compounds as fgfr inhibitors2012-06-132018-11-14
EP-3495367-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
ES-2704744-T3Substituted tricyclic compounds as FGFR inhibitors2012-06-132019-03-19
HU-E031916-T2Substituted tricyclic compounds as fgfr inhibitors2012-06-13
Publication Number TitlePriority Date Grant Date
DK-2861595-T5Substituted tricyclic compounds as FGFR inhibitors2012-06-132018-01-15
DK-3176170-T3Substituted tricyclic relations as fgfr inhibitors2012-06-132019-01-28
EP-2861595-A2Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
EP-2861595-B1Substituted tricyclic compounds as fgfr inhibitors2012-06-132016-12-21
EP-2861595-B9Substituted tricyclic compounds as fgfr inhibitors2012-06-132017-06-21
Publication Number TitlePriority Date Grant Date
WO-2019191707-A1Heterocyclic compounds as immunomodulators2018-03-30 
AU-2013287176-A1Substituted tricyclic compounds as FGFR inhibitors2012-06-13 
CA-2876689-A1Substituted tricyclic compounds as fgfr inhibitors2012-06-13 
CN-107383009-BSubstituted tricyclic compounds as FGFR inhibitors2012-06-132020-06-09
DK-2861595-T3Substituted tricyclic compounds as fgfr inhibitors2012-06-132017-02-13
Publication Number TitlePriority Date Grant Date
WO-2019213544-A2Solid forms of an fgfr inhibitor and processes for preparing the same2018-05-04 
WO-2019213544-A3Solid forms of an fgfr inhibitor and processes for preparing the same2018-05-04 
TW-202003511-AHeterocyclic compounds as immunomodulators2018-03-30 
US-10669271-B2Heterocyclic compounds as immunomodulators2018-03-302020-06-02
US-2019300524-A1Heterocyclic compounds as immunomodulators2018-03-30
Publication Number TitlePriority Date Grant Date
TW-201946630-ASalts of an FGFR inhibitor2018-05-04 
TW-202003516-ASolid forms of an FGFR inhibitor and processes for preparing the same2018-05-04 
US-2019337948-A1Solid forms of an fgfr inhibitor and processes for preparing the same2018-05-04 
US-2020002338-A1Salts of an fgfr inhibitor2018-05-04 
WO-2019213506-A1Salts of an fgfr inhibitor2018-05-04
Publication Number TitlePriority Date Grant Date
WO-2019227007-A1Tricyclic heterocyclic compounds as sting activators2018-05-25 
TW-201946626-AHeterocyclic compounds as immunomodulators2018-05-11 
US-10618916-B2Heterocyclic compounds as immunomodulators2018-05-112020-04-14
US-2019345170-A1Heterocyclic compounds as immunomodulators2018-05-11 
WO-2019217821-A1Tetrahydro-imidazo[4,5-c]pyridine derivatives as pd-l1 immunomodulators2018-05-11
Publication Number TitlePriority Date Grant Date
US-2020040009-A1Tricyclic heteraryl compounds as sting activators2018-07-31 
WO-2020028565-A1Tricyclic heteraryl compounds as sting activators2018-07-31 
WO-2020028566-A1Heteroaryl amide compounds as sting activators2018-07-31 
WO-2019238873-A1A method of precision cancer therapy2018-06-13 
US-2019359608-A1Tricyclic heterocyclic compounds as sting activators2018-05-25
TitlePriority Date Grant Date
WO-2020131627-A1Substituted pyrazolo[1,5-a]pyridine compounds as inhibitors of fgfr tyrosine kinases2018-12-19 
WO-2020131674-A17-((3,5-dimethoxyphenyl)amino)quinoxaline derivatives as fgfr inhibitors for treating cancer2018-12-19 
WO-2020081898-A1Non-invasive urinary biomarkers for the detection of urothelial carcinoma of the bladder2018-10-20 
US-2020115378-A1Dihydropyrido[2,3-d]pyrimidinone compounds as cdk2 inhibitors2018-10-11 
US-2020039994-A1Heteroaryl amide compounds as sting activators2018-07-31

References

  1. ^ “Pemigatinib (Pemazyre) Use During Pregnancy”Drugs.com. 11 August 2020. Retrieved 24 September 2020.
  2. ^ World Health Organization (2018). “International nonproprietary names for pharmaceutical substances (INN): recommended INN: list 80”. WHO Drug Information32 (3): 479. hdl:10665/330907.
  3. Jump up to:a b c d e f g h i j k l m n o “FDA Approves First Targeted Treatment for Patients with Cholangiocarcinoma, a Cancer of Bile Ducts”U.S. Food and Drug Administration (FDA) (Press release). 17 April 2020. Retrieved 17 April 2020.  This article incorporates text from this source, which is in the public domain.
  4. Jump up to:a b c d e f g h “FDA grants accelerated approval to pemigatinib for cholangiocarcinoma”U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
  5. Jump up to:a b c d e “EU/3/18/2066”European Medicines Agency (EMA). 19 December 2018. Retrieved 20 April 2020.  This article incorporates text from this source, which is in the public domain.
  6. Jump up to:a b c d “Drug Trials Snapshot: Pemazyre”U.S. Food and Drug Administration (FDA). 17 April 2020. Retrieved 5 May 2020.  This article incorporates text from this source, which is in the public domain.
  7. ^ “Pemazyre: FDA-Approved Drugs”U.S. Food and Drug Administration (FDA). Retrieved 21 April 2020.
  8. ^ “Pemigatinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
  9. ^ “Pemigatinib Orphan Drug Designation and Approval”U.S. Food and Drug Administration (FDA). Retrieved 19 April 2020.
  10. ^ “EU/3/19/2216”European Medicines Agency (EMA). 23 January 2020. Retrieved 19 April 2020.  This article incorporates text from this source, which is in the public domain.

Further reading

External links

  • “Pemigatinib”Drug Information Portal. U.S. National Library of Medicine.
  • “Pemigatinib”National Cancer Institute.
  • Clinical trial number NCT02924376 for “Efficacy and Safety of Pemigatinib in Subjects With Advanced/Metastatic or Surgically Unresectable Cholangiocarcinoma Who Failed Previous Therapy – (FIGHT-202)” at ClinicalTrials.gov
Clinical data
Trade namesPemazyre
Other namesINCB054828
AHFS/Drugs.comMonograph
MedlinePlusa620028
License dataUS DailyMedPemigatinib
Pregnancy
category
US: N (Not classified yet)[1]
Routes of
administration
By mouth
ATC codeNone
Legal status
Legal statusUS: ℞-only
Identifiers
IUPAC name[show]
CAS Number1513857-77-6
PubChem CID86705695
DrugBankDB15102
ChemSpider68007304
UNIIY6BX7BL23K
KEGGD11417
ChEMBLChEMBL4297522
Chemical and physical data
FormulaC24H27F2N5O4
Molar mass487.508 g·mol−1
3D model (JSmol)Interactive image
SMILES[hide]CCN1C2=C3C=C(NC3=NC=C2CN(C1=O)C4=C(C(=CC(=C4F)OC)OC)F)CN5CCOCC5
InChI[hide]InChI=1S/C24H27F2N5O4/c1-4-30-21-14(11-27-23-16(21)9-15(28-23)13-29-5-7-35-8-6-29)12-31(24(30)32)22-19(25)17(33-2)10-18(34-3)20(22)26/h9-11H,4-8,12-13H2,1-3H3,(H,27,28)Key:HCDMJFOHIXMBOV-UHFFFAOYSA-N

/////////Pemigatinib, 佩米替尼 , PEMAZYRE, FDA 2020, 2020 APPROVALS, INCB054828, INCB 054828, Orphan Drug Status, Myeloproliferative disorders, Lymphoma,  Cholangiocarcinoma, INCYTE

O=C1N(CC)C2=C3C(NC(CN4CCOCC4)=C3)=NC=C2CN1C5=C(F)C(OC)=CC(OC)=C5F.[H]Cl

INCB-039110, Janus kinase-1 (JAK-1) inhibitor……..for the treatment of rheumatoid arthritis, myelofibrosis, rheumatoid arthritis and plaque psoriasis.


Figure imgf000005_0001 INCB-39110,

CAS 1334298-90-6

INCB-039110, Jak1 tyrosine kinase inhibitor

3-​Azetidineacetonitril​e, 1-​[1-​[[3-​fluoro-​2-​(trifluoromethyl)​-​4-​pyridinyl]​carbonyl]​-​4-​piperidinyl]​-​3-​[4-​(7H-​pyrrolo[2,​3-​d]​pyrimidin-​4-​yl)​-​1H-​pyrazol-​1-​yl]​-

 C26H23F4N9O (MW, 553.51)

{ l- { l-[3-fluoro-2- (trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4- yl)-lH-pyrazol-l-yl]azetidin-3-yl}acetonitrile

2-(3-(4-(7H-pyrrolo[2,3-( Jpyrimidin-4-yl)-lH- pyrazol- 1 -yl)- 1 -( 1 -(3 -fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin- 3-yl)acetonitrile

2-(3-(4-(7H- Pyrrolo[2,3 -i/]pyrimidin-4-yl)- lH-pyrazol- 1 -yl)- 1 -(1 -(3 -fluoro-2- (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate MAY BE THE DRUG… HAS CAS 1334302-63-4

Figure imgf000005_0001Adipic acidADIPATE OF INCB-39110

ALSO/OR

 

Figure US20130060026A1-20130307-C00027

3-​Azetidineacetonitril​e, 1-​[1-​(3-​fluorobenzoyl)​-​4-​methyl-​4-​piperidinyl]​-​3-​[4-​(7H-​pyrrolo[2,​3-​d]​pyrimidin-​4-​yl)​-​1H-​pyrazol-​1-​yl]​-​, 2,​2,​2-​trifluoroacetateMAY BE THE DRUG ????…  HAS CAS  1334300-52-5

US 2011/0224190 is the pdt patent

 

 

Incyte Corporation

 

Clinical trials

 

IN PHASE 2 for the treatment of rheumatoid arthritis, myelofibrosis, rheumatoid arthritis and plaque psoriasis.

SEE

http://clinicaltrials.gov/show/NCT01633372

 

 

Jak2 tyrosine kinase inhibitor; Jak1 tyrosine kinase inhibitor

Breast tumor; Chronic obstructive pulmonary disease; Crohns disease; Inflammatory bowel disease; Influenza virus infection; Insulin dependent diabetes; Liver tumor; Multiple sclerosis; Prostate tumor; Rheumatoid arthritis; SARS coronavirus infection

Used for treating cancers (eg prostate cancer, hepatic cancer and pancreatic cancer) and autoimmune diseases. Follows on from WO2013036611, claiming the process for preparing the same JAK inhibitor. Incyte is developing INCB-39110 (phase II, September 2014), for the oral treatment of myelofibrosis, hematological neoplasm and non-small cell lung cancer.

INCB-039110 is a Jak1 inhibitor in phase II clinical studies at Incyte for the treatment of rheumatoid arthritis, myelofibrosis, rheumatoid arthritis and plaque psoriasis. The company is also conducting a phase I clinical study for the treatment of advanced or metastatic solid tumors.

Protein kinases (PKs) regulate divINCB-039110 is a Jak1 inhibitor in phase II clinical studies at Incyte for the treatment of rheumatoid arthritis, myelofibrosis, rheumatoid arthritis and plaque psoriasis. The company is also conducting a phase I clinical study for the treatment of advanced or metastatic solid tumors.erse biological processes including cell growth, survival, differentiation, organ formation, morphogenesis, neovascularization, tissue repair, and regeneration, among others. Protein kinases also play specialized roles in a host of human diseases including cancer. Cytokines, low-molecular weight polypeptides or glycoproteins, regulate many pathways involved in the host

inflammatory response to sepsis. Cytokines influence cell differentiation,

proliferation and activation, and can modulate both pro-inflammatory and antiinflammatory responses to allow the host to react appropriately to pathogens.

Signaling of a wide range of cytokines involves the Janus kinase family (JAKs) of protein tyrosine kinases and Signal Transducers and Activators of Transcription

(STATs). There are four known mammalian JAKs: JAK1 (Janus kinase-1), JAK2, JAK3 (also known as Janus kinase, leukocyte; JAKL; and L-JAK), and TYK2

(protein-tyros ine kinase 2).

Cytokine-stimulated immune and inflammatory responses contribute to pathogenesis of diseases: pathologies such as severe combined immunodeficiency (SCID) arise from suppression of the immune system, while a hyperactive or inappropriate immune/inflammatory response contributes to the pathology of autoimmune diseases (e.g., asthma, systemic lupus erythematosus, thyroiditis, 20443-0253WO1 (INCY0124-WO1) PATENT myocarditis), and illnesses such as scleroderma and osteoarthritis (Ortmann, R. A., T. Cheng, et al. (2000) Arthritis Res 2(1): 16-32).

Deficiencies in expression of JAKs are associated with many disease states. For example, Jakl-/- mice are runted at birth, fail to nurse, and die perinatally (Rodig, S. J., M. A. Meraz, et al. (1998) Cell 93(3): 373-83). Jak2-/- mouse embryos are anemic and die around day 12.5 postcoitum due to the absence of definitive

erythropoiesis.

The JAK/STAT pathway, and in particular all four JAKs, are believed to play a role in the pathogenesis of asthmatic response, chronic obstructive pulmonary disease, bronchitis, and other related inflammatory diseases of the lower respiratory tract. Multiple cytokines that signal through JAKs have been linked to inflammatory diseases/conditions of the upper respiratory tract, such as those affecting the nose and sinuses (e.g., rhinitis and sinusitis) whether classically allergic reactions or not. The JAK/STAT pathway has also been implicated in inflammatory diseases/conditions of the eye and chronic allergic responses.

Activation of JAK/STAT in cancers may occur by cytokine stimulation (e.g. IL-6 or GM-CSF) or by a reduction in the endogenous suppressors of JAK signaling such as SOCS (suppressor or cytokine signaling) or PIAS (protein inhibitor of activated STAT) (Boudny, V., and Kovarik, J., Neoplasm. 49:349-355, 2002).

Activation of STAT signaling, as well as other pathways downstream of JAKs (e.g., Akt), has been correlated with poor prognosis in many cancer types (Bowman, T., et al. Oncogene 19:2474-2488, 2000). Elevated levels of circulating cytokines that signal through JAK/STAT play a causal role in cachexia and/or chronic fatigue. As such, JAK inhibition may be beneficial to cancer patients for reasons that extend beyond potential anti-tumor activity.

JAK2 tyrosine kinase can be beneficial for patients with myeloproliferative disorders, e.g., polycythemia vera (PV), essential thrombocythemia (ET), myeloid metaplasia with myelofibrosis (MMM) (Levin, et al, Cancer Cell, vol. 7, 2005: 387- 397). Inhibition of the JAK2V617F kinase decreases proliferation of hematopoietic cells, suggesting JAK2 as a potential target for pharmacologic inhibition in patients with PV, ET, and MMM. 20443-0253WO1 (INCY0124-WO1) PATENT

Inhibition of the JAKs may benefit patients suffering from skin immune disorders such as psoriasis, and skin sensitization. The maintenance of psoriasis is believed to depend on a number of inflammatory cytokines in addition to various chemokines and growth factors (JCI, 1 13 : 1664-1675), many of which signal through JAKs (Adv Pharmacol. 2000;47: 113-74).

JAKl plays a central role in a number of cytokine and growth factor signaling pathways that, when dysregulated, can result in or contribute to disease states. For example, IL-6 levels are elevated in rheumatoid arthritis, a disease in which it has been suggested to have detrimental effects (Fonesca, J.E. et al, Autoimmunity

Reviews, 8:538-42, 2009). Because IL-6 signals, at least in part, through JAKl, antagonizing IL-6 directly or indirectly through JAKl inhibition is expected to provide clinical benefit (Guschin, D., N., et al Embo J 14: 1421, 1995; Smolen, J. S., et al. Lancet 371 :987, 2008). Moreover, in some cancers JAKl is mutated resulting in constitutive undesirable tumor cell growth and survival (Mullighan CG, Proc Natl Acad Sci U S A.106:9414-8, 2009; Flex E., et al.J Exp Med. 205:751-8, 2008). In other autoimmune diseases and cancers elevated systemic levels of inflammatory cytokines that activate JAKl may also contribute to the disease and/or associated symptoms. Therefore, patients with such diseases may benefit from JAKl inhibition. Selective inhibitors of JAKl may be efficacious while avoiding unnecessary and potentially undesirable effects of inhibiting other JAK kinases.

Selective inhibitors of JAKl, relative to other JAK kinases, may have multiple therapeutic advantages over less selective inhibitors. With respect to selectivity against JAK2, a number of important cytokines and growth factors signal through JAK2 including, for example, erythropoietin (Epo) and thrombopoietin (Tpo)

(Parganas E, et al. Cell. 93:385-95, 1998). Epo is a key growth factor for red blood cells production; hence a paucity of Epo-dependent signaling can result in reduced numbers of red blood cells and anemia (Kaushansky K, NEJM 354:2034-45, 2006). Tpo, another example of a JAK2-dependent growth factor, plays a central role in controlling the proliferation and maturation of megakaryocytes – the cells from which platelets are produced (Kaushansky K, NEJM 354:2034-45, 2006). As such, reduced Tpo signaling would decrease megakaryocyte numbers (megakaryocytopenia) and lower circulating platelet counts (thrombocytopenia). This can result in undesirable 20443-0253WO1 (INCY0124-WO1) PATENT and/or uncontrollable bleeding. Reduced inhibition of other JAKs, such as JAK3 and Tyk2, may also be desirable as humans lacking functional version of these kinases have been shown to suffer from numerous maladies such as severe-combined immunodeficiency or hyperimmunoglobulin E syndrome (Minegishi, Y, et al.

Immunity 25:745-55, 2006; Macchi P, et al. Nature. 377:65-8, 1995). Therefore a JAK1 inhibitor with reduced affinity for other JAKs would have significant

advantages over a less-selective inhibitor with respect to reduced side effects involving immune suppression, anemia and thrombocytopenia.

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http://www.google.com/patents/US20110224190

 

EXAMPLESThe example compounds below containing one or more chiral centers were obtained in enantiomerically pure form or as scalemic mixtures, unless otherwise specified.Unless otherwise indicated, the example compounds were purified by preparativeHPLC using acidic conditions (method A) and were obtained as a TFA salt or using basic conditions (method B) and were obtained as a free base.Method A:Column: Waters Sun Fire C18, 5 μm particle size, 30×100 mm;
Mobile phase: water (0.1% TFA)/acetonitrile
Flow rate: 60 mL/min
Gradient: 5 min or 12 min from 5% acetonitrile/95% water to 100% acetonitrileMethod B:Column: Waters X Bridge C18, 5 μm particle size, 30×100 mm;
Mobile phase: water (0.15% NH4OH)/acetonitrileMethod C:Column: C18 column, 5 μm OBD
Mobile phase: water+0.05% NH4OH (A), CH3CN+0.05% NH4OH (B)Gradient: 5% B to 100% B in 15 minFlow rate: 60 mL/minExample 1
{1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

Step A: tert-Butyl 3-Oxoazetidine-1-carboxylate

To a mixture of tert-butyl 3-hydroxyazetidine-1-carboxylate (10.0 g, 57.7 mmol), dimethyl sulfoxide (24.0 mL, 338 mmol), triethylamine (40 mL, 300 mmol) and methylene chloride (2.0 mL) was added sulfur trioxide-pyridine complex (40 g, 200 mmol) portionwise at 0° C. The mixture was stirred for 3 hours, quenched with brine, and extracted with methylene chloride. The combined extracts were dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column (0-6% ethyl acetate (EtOAc) in hexanes) to give tert-butyl 3-oxoazetidine-1-carboxylate (5.1 g, 52% yield).

Step B: tert-Butyl 3-(Cyanomethylene)azetidine-1-carboxylate

An oven-dried 1 L 4-neck round bottom flask fitted with stir bar, septa, nitrogen inlet, 250 ml addition funnel and thermocouple was charged with sodium hydride (5.6 g, 0.14 mol) and tetrahydrofuran (THF) (140 mL) under a nitrogen atmosphere. The mixture was chilled to 3° C., and then charged with diethyl cyanomethylphosphonate (22.4 mL, 0.138 mol) dropwise via a syringe over 20 minutes. The solution became a light yellow slurry. The reaction was then stirred for 75 minutes while warming to 18.2° C. A solution of tert-butyl 3-oxoazetidine-1-carboxylate (20 g, 0.1 mol) in tetrahydrofuran (280 mL) was prepared in an oven-dried round bottom, charged to the addition funnel via canula, then added to the reaction mixture dropwise over 25 minutes. The reaction solution became red in color. The reaction was allowed to stir overnight. The reaction was checked after 24 hours by TLC (70% hexane/EtOAc) and found to be complete. The reaction was diluted with 200 mL of 20% brine and 250 mL of EtOAc. The solution was partitioned and the aqueous phase was extracted with 250 mL of EtOAc. The combined organic phase was dried over MgSO4 and filtered, evaporated under reduced pressure, and purified by flash chromatography (0% to 20% EtOAc/hexanes, 150 g flash column) to give the desired product, tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (15 g, 66.1% yield).

Step C: 4-Chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

To a suspension of sodium hydride (36.141 g, 903.62 mmol) in N,N-dimethylacetamide (118 mL) at −5° C. (ice/salt bath) was added a dark solution of 4-chloropyrrolo[2,3-d]pyrimidine (119.37 g, 777.30 mmol) in N,N-dimethylacetamide (237 mL) slowly. The flask and addition funnel were rinsed with N,N-dimethylacetamide (30 mL). A large amount of gas was evolved immediately. The mixture became a slightly cloudy orange mixture. The mixture was stirred at 0° C. for 60 min to give a light brown turbid mixture. To the mixture was slowly added [2-(trimethylsilyl)ethoxy]methyl chloride (152.40 g, 914.11 mmol) and the reaction was stirred at 0° C. for 1 h. The reaction was quenched by addition of 12 mL of H2O slowly. More water (120 mL) was added followed by methyl tert-butyl ether (MTBE) (120 mL). The mixture was stirred for 10 min. The organic layer was separated. The aqueous layer was extracted with another portion of MTBE (120 mL). The organic extracts were combined, washed with brine (120 mL×2) and concentrated under reduced pressure to give the crude product 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine as a dark oil. Yield: 85.07 g (97%); LC-MS: 284.1 (M+H)+. It was carried to the next reaction without purification.

Step D: 4-(1H-Pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

A 1000 mL round bottom flask was charged with 4-chloro-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (10.00 g, 35.23 mmol), 1-butanol (25.0 mL), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (15.66 g, 52.85 mmol), water (25.0 mL) and potassium carbonate (12.17 g, 88.08 mmol). This solution was degased 4 times, filling with nitrogen each time. To the solution was added tetrakis(triphenylphosphine)palladium(0) (4.071 g, 3.523 mmol). The solution was degased 4 times, filling with nitrogen each time. The mixture was stirred overnight at 100° C. After being cooled to room temperature, the mixture was filtered through a bed of celite and the celite was rinsed with ethyl acetate (42 mL). The filtrate was combined, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The organic extracts were combined and concentrated under vacuum with a bath temperature of 30-70° C. to give the final compound 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine. Yield: 78%. LC-MS: 316.2 (M+H)+.

Step E: tert-Butyl 3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate

A 2 L round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (9.17 g, 0.0472 mol), 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (14.9 g, 0.0472 mol) and acetonitrile (300 mL). The resulting solution was heterogeneous. To the solution was added 1,8-diazabicyclo[5.4.0]undec-7-ene (8.48 mL, 0.0567 mol) portionwise via syringe over 3 min at room temperature. The solution slowly became homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 h. The reaction was complete by HPLC and LC/MS and was concentrated by rotary evaporation to remove acetonitrile (˜150 mL). EtOAc (100 mL) was added followed by 100 ml of 20% brine. The two phases were partitioned. The aqueous phase was extracted with 150 mL of EtOAC. The combine organic phases were dried over MgSO4, filtered and concentrated to yield an orange oil. Purification by flash chromatography (150 grams silica, 60% EtOAc/hexanes, loaded with CH2Cl2) yielded the title compound tert-butyl 3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate as a yellow oil (21.1 g, 88% yield). LC-MS: [M+H]+=510.3.

Step F: {3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride

To a solution of tert-butyl 3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidine-1-carboxylate (2 g, 3.9 mmol) in 10 mL of THF was added 10 mL of 4 N HCl in dioxane. The solution was stirred at room temperature for 1 hour and concentrated in vacuo to provide 1.9 g (99%) of the title compound as a white powder solid, which was used for the next reaction without purification. LC-MS: [M+H]+=410.3.

Step G: tert-Butyl 4-{3-(Cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate

Into the solution of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (2.6 g, 6.3 mmol), tert-butyl 4-oxo-1-piperidinecarboxylate (1.3 g, 6.3 mmol) in THF (30 mL) were added N,N-diisopropylethylamine (4.4 mL, 25 mmol) and sodium triacetoxyborohydride (2.2 g, 10 mmol). The mixture was stirred at room temperature overnight. After adding 20 mL of brine, the solution was extracted with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated. The residue was purified by combiflash column eluting with 30-80% EtOAc in hexanes to give the desired product, tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate. Yield: 3.2 g (86%); LC-MS: [M+H]+=593.3.

Step H: {1-Piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride

To a solution of tert-butyl 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}piperidine-1-carboxylate (3.2 g, 5.4 mmol) in 10 mL of THF was added 10 mL of 4 N HCl in dioxane. The reaction mixture was stirred at room temperature for 2 hours. Removing solvents under reduced pressure yielded 3.25 g (100%) of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride as a white powder solid, which was used directly in the next reaction. LC-MS: [M+H]+=493.3. 1H NMR (400 MHz, DMSO-d6): δ 9.42 (s 1H), 9.21 (s, 1H), 8.89 (s, 1H), 8.69 (s, 1H), 7.97 (s, 1H), 7.39 (d, 1H), 5.68 (s, 2H), 4.96 (d, 2H), 4.56 (m, 2H), 4.02-3.63 (m, 2H), 3.55 (s, 2H), 3.53 (t, 2H), 3.49-3.31 (3, 3H), 2.81 (m, 2H), 2.12 (d, 2H), 1.79 (m, 2H), 0.83 (t, 2H), −0.10 (s, 9H).

Step I: {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

A mixture of {1-piperidin-4-yl-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile trihydrochloride (1.22 g, 2.03 mmol), 3-fluoro-2-(trifluoromethyl)isonicotinic acid (460 mg, 2.2 mmol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (1.07 g, 2.42 mmol), and triethylamine (2.0 mL, 14 mmol) in dimethylformamide (DMF) (20.0 mL) was stirred at room temperature overnight. LS-MS showed the reaction was complete. EtOAc (60 mL) and saturated NaHCO3 aqueous solution (60 mL) were added to the reaction mixture. After stirring at room temperature for 10 minutes, the organic phase was separated and the aqueous layer was extracted with EtOAc three times. The combined organic phase was washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. Purification by flash chromatography provided the desired product {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile. LC-MS: 684.3 (M+H)+.

Step J: {1-{1-[3-Fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

Into a solution of {1-{1-[3-fluoro-2-(trifluoromethyl)isonicotinoyl]piperidin-4-yl}-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile (56 mg, 0.1 mmol) in methylene chloride (1.5 mL) was added trifluoroacetic acid (1.5 mL). The mixture was stirred at room temperature for 2 hours. After removing the solvents in vacuum, the residue was dissolved in a methanol solution containing 20% ethylenediamine. After being stirred at room temperature for 1 hour, the solution was purified by HPLC (method B) to give the title compound. LC-MS: 554.3 (M+H)+; 1H NMR (400 MHz, CDCl3): 9.71 (s, 1H), 8.82 (s, 1H), 8.55 (d, J=4.6 Hz, 1H), 8.39 (s, 1H), 8.30 (s, 1H), 7.52 (t, J=4.6 Hz, 1H), 7.39 (dd, J1=3.4 Hz, J2=1.5 Hz, 1H), 6.77 (dd, J1=3.6 Hz, J2=0.7 Hz, 1H), 4.18 (m, 1H), 3.75 (m, 2H), 3.63 (dd, J1=7.8 Hz, J2=3.7 Hz, 2H), 3.45 (m, 2H), 3.38 (s, 2H), 3.11 (m, 1H), 2.57 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H), 1.40 (m, 1H).

 

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http://www.google.com/patents/US20130060026

Example 1Synthesis of 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5)

Step 1. 4-Chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3)

To a flask equipped with a nitrogen inlet, an addition funnel, a thermowell, and the mechanical stirrer was added 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (1, 600 g, 3.91 mol) and N,N-dimethylacetimide (DMAC, 9.6 L) at room temperature. The mixture was cooled to 0-5° C. in an ice/brine bath before solid sodium hydride (NaH, 60 wt %, 174 g, 4.35 mol, 1.1 equiv) was added in portions at 0-5° C. The reaction mixture turned into a dark solution after 15 minutes. Trimethylsilylethoxymethyl chloride (2, SEM-Cl, 763 mL, 4.31 mol, 1.1 equiv) was then added slowly via an addition funnel at a rate that the internal reaction temperature did not exceed 5° C. The reaction mixture was then stirred at 0-5° C. for 30 minutes. When the reaction was deemed complete determined by TLC and HPLC, the reaction mixture was quenched by water (1 L). The mixture was then diluted with water (12 L) and methyl tert-butyl ether (MTBE) (8 L). The two layers were separated and the aqueous layer was extracted with MTBE (8 L). The combined organic layers were washed with water (2×4 L) and brine (4 L) and solvent switched to 1-butanol. The solution of crude product (3) in 1-butanol was used in the subsequent Suzuki coupling reaction without further purification. Alternatively, the organic solution of the crude product (3) in MTBE was dried over sodium sulfate (Na2SO4). The solvents were removed under reduced pressure. The residue was then dissolved in heptane (2 L), filtered and loaded onto a silica gel (SiO2, 3.5 Kg) column eluting with heptane (6 L), 95% heptane/ethyl acetate (12 L), 90% heptane/ethyl acetate (10 L), and finally 80% heptane/ethyl acetate (10 L). The fractions containing the pure desired product were combined and concentrated under reduced pressure to give 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3, 987 g, 1109.8 g theoretical, 88.9% yield) as a pale yellow oil which partially solidified to an oily solid on standing at room temperature. For 3: 1H NMR (DMSO-d6, 300 MHz) δ 8.67 (s, 1H), 7.87 (d, 1H, J=3.8 Hz), 6.71 (d, 1H, J=3.6 Hz), 5.63 (s, 2H), 3.50 (t, 2H, J=7.9 Hz), 0.80 (t, 2H, J=8.1 Hz), 1.24 (s, 9H) ppm; 13C NMR (DMSO-d6, 100 MHz) δ 151.3, 150.8, 150.7, 131.5, 116.9, 99.3, 72.9, 65.8, 17.1, −1.48 ppm; C12H18ClN3OSi (MW 283.83), LCMS (EI) m/e 284/286 (M++H).

Step 2. 4-(1H-Pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5)

To a reactor equipped with the overhead stirrer, a condenser, a thermowell, and a nitrogen inlet was charged water (H2O, 9.0 L), solid potassium carbonate (K2CO3, 4461 g, 32.28 mol, 2.42 equiv), 4-chloro-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (3, 3597 g, 12.67 mol), 1-(1-ethoxyethyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (4, 3550 g, 13.34 mol, 1.05 equiv), and 1-butanol (27 L) at room temperature. The resulting reaction mixture was degassed three timed backfilling with nitrogen each time before being treated with tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4, 46 g, 0.040 mol, 0.003 equiv) at room temperature. The resulting reaction mixture was heated to gentle reflux (about 90° C.) for 1-4 hours. When the reaction was deemed complete determined by HPLC, the reaction mixture was gradually cooled down to room temperature before being filtered through a Celite bed. The Celite bed was washed with ethyl acetate (2×2 L) before the filtrates and washing solution were combined. The two layers were separated, and the aqueous layer was extracted with ethyl acetate (12 L). The combined organic layers were concentrated under reduced pressure to remove solvents, and the crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (6) was directly charged back to the reactor with tetrahydrofuran (THF, 4.2 L) for the subsequent acid-promoted de-protection reaction without further purification.

To a suspension of crude 4-(1-(1-ethoxyethyl)-1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (6), made as described above, in tetrahydrofuran (THF, 4.2 L) in the reactor was charged water (H2O, 20.8 L), and a 10% aqueous HCl solution (16.2 L, 45.89 mol, 3.44 equiv) at room temperature. The resulting reaction mixture was stirred at 16-30° C. for 2-5 hours. When the reaction was deemed complete by HPLC analysis, the reaction mixture was treated with a 30% aqueous sodium hydroxide (NaOH) solution (4 L, 50.42 mol, 3.78 equiv) at room temperature. The resulting reaction mixture was stirred at room temperature for 1-2 hours. The solids were collected by filtration and washed with water (2×5 L). The wet cake was charged back to the reactor with acetonitrile (21.6 L), and resulting suspension was heated to gentle reflux for 1-2 hours. The clear solution was then gradually cooled down to room temperature with stirring, and solids were precipitated out from the solution with cooling. The mixture was stirred at room temperature for an additional 1-2 hours. The solids were collected by filtration, washed with acetonitrile (2×3.5 L), and dried in oven under reduced pressure at 45-55° C. to constant weight to afford 4-(1H-pyrazol-4-yl)-7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 3281.7 g, 3996.8 g theoretical, 82.1% yield) as white crystalline solids (99.5 area % by HPLC). For 5: 1H NMR (DMSO-d6, 400 MHz) δ 13.41 (br. s, 1H), 8.74 (s, 1H), 8.67 (br. s, 1H), 8.35 (br. s, 1H), 7.72 (d, 1H, J=3.7 Hz), 7.10 (d, 1H, J=3.7 Hz), 5.61 (s, 2H), 3.51 (t, 2H, J=8.2 Hz), 0.81 (t, 2H, J=8.2 Hz), 0.13 (s, 9H) ppm; C15H21N5OSi (MW, 315.45), LCMS (EI) m/e 316 (M++H).

Example 2tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (13)

Step 1. 1-Benzhydrylazetidin-3-ol hydrochloride (9)

A solution of diphenylmethanamine (7, 2737 g, 15.0 mol, 1.04 equiv) in methanol (MeOH, 6 L) was treated with 2-(chloromethyl)oxirane (8, 1330 g, 14.5 mol) from an addition funnel at room temperature. During the initial addition a slight endotherm was noticed. The resulting reaction mixture was stirred at room temperature for 3 days before being warmed to reflux for an additional 3 days. When TLC showed that the reaction was deemed complete, the reaction mixture was first cooled down to room temperature and then to 0-5° C. in an ice bath. The solids were collected by filtration and washed with acetone (4 L) to give the first crop of the crude desired product (9, 1516 g). The filtrate was concentrated under reduced pressure and the resulting semisolid was diluted with acetone (1 L). This solid was then collected by filtration to give the second crop of the crude desired product (9, 221 g). The crude product, 1-benzhydrylazetidin-3-ol hydrochloride (9, 1737 g, 3998.7 g theoretical, 43.4% yield), was found to be sufficiently pure to be used in the subsequent reaction without further purification. For 9: 1H NMR (DMSO-d6, 300 MHz), δ 12.28 (br. d, 1H), 7.7 (m, 5H), 7.49 (m, 5H), 6.38 (d, 1H), 4.72 (br. s, 1H), 4.46 (m, 1H), 4.12 (m, 2H), 3.85 (m, 2H) ppm; C16H18ClNO (free base of 9, C16K7NO MW, 239.31), LCMS (EI) m/e 240 (M++H).

Step 2. tert-Butyl 3-hydroxyazetidine-1-carboxylate (10)

A suspension of 1-benzhydrylazetidin-3-ol hydrochloride (9, 625 g, 2.27 mol) in a 10% solution of aqueous sodium carbonate (Na2CO3, 5 L) and dichloromethane (CH2Cl2, 5 L) was stirred at room temperature until all solids were dissolved. The two layers were separated, and the aqueous layer was extracted with dichloromethane (CH2Cl2, 2 L). The combined organics extracts were dried over sodium sulfate (Na2SO4) and concentrated under reduced pressure. This resulting crude free base of 9 was then dissolved in THF (6 L) and the solution was placed into a large Parr bomb. Di-tert-butyl dicarbonate (BOC2O, 545 g, 2.5 mol, 1.1 equiv) and 20% palladium (Pd) on carbon (125 g, 50% wet) were added to the Parr bomb. The vessel was charged to 30 psi with hydrogen gas (H2) and stirred under steady hydrogen atmosphere (vessel was recharged three times to maintain the pressure at 30 psi) at room temperature for 18 h. When HPLC showed that the reaction was complete (when no more hydrogen was taken up), the reaction mixture was filtered through a Celite pad and the Celite pad was washed with THF (4 L). The filtrates were concentrated under reduced pressure to remove the solvent and the residue was loaded onto a Biotage 150 column with a minimum amount of dichloromethane (CH2Cl2). The column was eluted with 20-50% ethyl acetate in heptane and the fractions containing the pure desired product (10) were collected and combined. The solvents were removed under reduced pressure to afford tert-butyl 3-hydroxyazetidine-1-carboxylate (10, 357 g, 393.2 g theoretical, 90.8% yield) as colorless oil, which solidified upon standing at room temperature in vacuum. For 10: 1HNMR (CDCl3, 300 MHz), δ 4.56 (m 1H), 4.13 (m, 2H), 3.81 (m, 2H), 1.43 (s, 9H) ppm.

Step 3. tert-Butyl 3-oxoazetidine-1-carboxylate (11)

A solution of tert-butyl 3-hydroxyazetidine-1-carboxylate (10, 50 g, 289 mmol) in ethyl acetate (400 mL) was cooled to 0° C. The resulting solution was then treated with solid TEMPO (0.5 g, 3.2 mmol, 0.011 equiv) and a solution of potassium bromide (KBr, 3.9 g, 33.2 mmol, 0.115 equiv) in water (60 mL) at 0-5° C. While keeping the reaction temperature between 0-5° C. a solution of saturated aqueous sodium bicarbonate (NaHCO3, 450 mL) and an aqueous sodium hypochlorite solution (NaClO, 10-13% available chlorine, 450 mL) were added. Once the solution of sodium hypochlorite was added, the color of the reaction mixture was changed immediately. When additional amount of sodium hypochlorite solution was added, the color of the reaction mixture was gradually faded. When TLC showed that all of the starting material was consumed, the color of the reaction mixture was no longer changed. The reaction mixture was then diluted with ethyl acetate (EtOAc, 500 mL) and two layers were separated. The organic layer was washed with water (500 mL) and the saturated aqueous sodium chloride solution (500 mL) and dried over sodium sulfate (Na2SO4). The solvent was then removed under reduced pressure to give the crude product, tert-butyl 3-oxoazetidine-1-carboxylate (11, 48 g, 49.47 g theoretical, 97% yield), which was found to be sufficiently pure and was used directly in the subsequent reaction without further purification. For crude 11: 1HNMR (CDCl3, 300 MHz), δ 4.65 (s, 4H), 1.42 (s, 9H) ppm.

Step 4. tert-Butyl 3-(cyanomethylene)azetidine-1-carboxylate (13)

Diethyl cyanomethyl phosphate (12, 745 g, 4.20 mol, 1.20 equiv) and anhydrous tetrahydrofuran (THF, 9 L) was added to a four-neck flask equipped with a thermowell, an addition funnel and the nitrogen protection tube at room temperature. The solution was cooled with an ice-methanol bath to −14° C. and a 1.0 M solution of potassium tert-butoxide (t-BuOK) in anhydrous tetrahydrofuran (THF, 3.85 L, 3.85 mol, 1.1 equiv) was added over 20 minutes keeping the reaction temperature below −5° C. The resulting reaction mixture was stirred for 3 hours at −10° C. and a solution of 1-tert-butoxycarbonyl-3-azetidinone (11, 600 g, 3.50 mol) in anhydrous tetrahydrofuran (THF, 2 L) was added over 2 h keeping the internal temperature below −5° C. The reaction mixture was stirred at −5 to −10° C. over 1 hour and then slowly warmed up to room temperature and stirred at room temperature for overnight. The reaction mixture was then diluted with water (4.5 L) and saturated aqueous sodium chloride solution (NaCl, 4.5 L) and extracted with ethyl acetate (EtOAc, 2×9 L). The combined organic layers were washed with brine (6 L) and dried over anhydrous sodium sulfate (Na2SO4). The organic solvent was removed under reduced pressure and the residue was diluted with dichloromethane (CH2Cl2, 4 L) before being absorbed onto silica gel (SiO2, 1.5 Kg). The crude product, which was absorbed on silica gel, was purified by flash column chromatography (SiO2, 3.5 Kg, 0-25% EtOAc/hexanes gradient elution) to afford tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (13, 414.7 g, 679.8 g theoretical, 61% yield) as white solid. For 13: 1H NMR (CDCl3, 300 MHz), δ 5.40 (m, 1H), 4.70 (m, 2H), 4.61 (m, 2H), 1.46 (s, 9H) ppm; C10H14N2O2 (MW, 194.23), LCMS (EI) m/e 217 (M′+Na).

Example 3(3-Fluoro-2-(trifluoromethyl)pyridin-4-yl)(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)methanone (17)

Step 1. 1,4-Dioxa-8-azaspiro[4.5]decane (15)

To a 30 L reactor equipped with a mechanic stirrer, an addition funnel and a septum was charged sodium hydroxide (NaOH, 1.4 kg, 35 mol) and water (7 L, 3.13 kg, 17.43 mol). To the solution thus obtained was added 1,4-dioxa-8-azaspiro[4.5]decane hydrochloric acid (14, 3.13 kg, 17.43 mol). The mixture was stirred at 25° C. for 30 minutes. Then the solution was saturated with sodium chloride (1.3 kg) and extracted with 2-methyl-tetrahydrofuran (3×7 L). The combined organic layer was dried with anhydrous sodium sulfate (1.3 kg), filtered and concentrated under reduced pressure (70 mmHg) at 50° C. The yellow oil thus obtained was distilled under reduced pressure (80 mmHg, bp: 115° C. to 120° C.) to give compound 15 (2.34 kg, 16.36 mol, 93.8%) as a clear oil, which was used directly in the subsequent coupling reaction.

Step 2. (3-Fluoro-2-(trifluoromethyl)pyridin-4-yl)(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)methanone (17)

To a dried 100 L reactor equipped with a mechanic stirrer, an addition funnel, a thermometer and a vacuum outlet were placed 3-fluoro-2-(trifluoromethyl)isonicotinic acid (16, 3.0 kg, 14.35 mol), benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP reagent, 7.6 kg, 17.2 mol, 1.20 equiv) in dimethylformamide (DMF, 18 L). To the resulting solution was added 1,4-dioxa-8-azaspiro[4.5]decane (15, 2.34 kg, 16.36 mol, 1.14 equiv) with stirring over 20 minutes. Triethylamine (Et3N, 4 L, 28.67 mol, 2.00 equiv) was then added over 1 hour. The temperature was kept between 5° C. and 10° C. during the additions. The dark brown solution thus obtained was stirred for 12 hours at 20° C. and then chilled to 10° C. With vigorous stirring, 18 L of saturated sodium bicarbonate solution and 36 L of water were sequentially added and the temperature was kept under 15° C. The precipitation (filter cake) thus obtained was collected by filtration. The aqueous phase was then saturated with 12 kg of solid sodium chloride and extracted with EtOAc (2×18 L). The combined organic layer was washed with saturated sodium bicarbonate solution (18 L), and water (2×18 L) in sequence. The filter cake from the previous filtration was dissolved back in the organic phase. The dark brown solution thus obtained was washed twice with 18 L of water each and then concentrated under reduced pressure (40-50° C., 30 mm Hg) to give 5.0 kg of the crude product as viscous brown oil. The crude product 17 obtained above was dissolved in EtOH (8.15 L) at 50° C. Water (16.3 L) was added over 30 minutes. The brown solution was seeded, cooled to 20° C. over 3 hours with stirring and stirred at 20° C. for 12 h. The precipitate formed was filtered, washed with a mixture of EtOH and water (EtOH:H2O=1:20, 2 L) and dried under reduced pressure (50 mmHg) at 60° C. for 24 hours to afford (3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)methanone (17, 3.98 kg, 11.92 mol, 83.1%) as a white powder. For 17: 1H NMR (300 MHz, (CD3)2SO) δ 8.64 (d, 3JHH=4.68 Hz, 1H, NCH in pyridine), 7.92 (dd, 3JHH=4.68 Hz, 4JHF=4.68 Hz, 1H, NCCH in pyridine), 3.87-3.91 (m, 4H, OCH2CH2O), 3.70 (br s, 2H, one of NCH2 in piperidine rine, one of another NCH2 in piperidine ring, both in axial position), 3.26 (t, 3JHH=5.86 Hz, 2H, one of NCH2 in piperidine rine, one of another NCH2 in piperidine ring, both in equatorial position), 1.67 (d, 3JHH=5.86 Hz, 2H, one of NCCH2 in piperidine ring, one of another NCCH2 in piperidine ring, both in equatorial position), 1.58 (br s, 2H, one of NCCH2 in piperidine ring, one of another NCCH2 in piperidine ring, both in axial position) ppm; 13C NMR (75 MHz, (CD3)2SO) δ 161.03 (N—C═O), 151.16 (d, 1JCF=266.03 Hz, C—F), 146.85 (d, 4JCF=4.32 Hz, NCH in pyridine), 135.24 (d, 2JCF=11.51 Hz, C—C═O), 135.02 (quartet, 2JCF=34.57 Hz, NCCF3), 128.24 (d, 4JCF=7.48 Hz, NCCH in pyridine), 119.43 (d×quartet, 1JCF=274.38 Hz, 3JCF=4.89 Hz, CF3), 106.74 (OCO), 64.60 (OCCO), 45.34 (NC in piperidine ring), 39.62 (NC in piperidine ring), 34.79 (NCC in piperidine ring), 34.10 (NCC in piperidine ring) ppm; 19F NMR (282 MHz, (CD3)2SO) δ-64.69 (d, 4JFF=15.85 Hz, F3C), −129.26 (d×quartet, 4JFF=15.85 Hz, 4JFH=3.96 Hz, FC) ppm; C14H14F4N2O3 (MW, 334.27), LCMS (EI) m/e 335.1 (M++H).

Example 4(3-Fluoro-2-(trifluoromethyl)pyridin-4-yl) (1,4-dioxa-8-azaspiro[4,5]decan-8-yl)methanone (18)

In a 5 L 4-necked round bottom flask equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was placed (3-fluoro-2-(trifluoromethyl)pyridin-4-yl)(1,4-dioxa-8-azaspiro[4,5]decan-8-yl)methanone (17, 100 g, 0.299 mol) in acetonitrile (ACN, 400 mL) at room temperature. The resultant solution was cooled to below 10° C. To the reaction mixture was added 6.0 N aqueous hydrochloric acid (HCl, 450 mL, 2.70 mol, 9.0 equiv), while the internal temperature was kept below 10° C. The resulting reaction mixture was then warmed to room temperature and an additional amount of 6.0 N aqueous hydrochloric acid (HCl, 1050 mL, 6.30 mol, 21.0 equiv) was slowly introduced to the reaction mixture at room temperature in 8 hours via the addition funnel. The reaction mixture was then cooled to 0° C. before being treated with 30% aqueous sodium hydroxide (NaOH, 860 mL, 8.57 mmol, 28.6 equiv) while the internal temperature was kept at below 10° C. The resulting reaction mixture was subsequently warmed to room temperature prior to addition of solid sodium bicarbonate (NaHCO3, 85.0 g, 1.01 mol, 3.37 equiv) in 1 hour. The mixture was then extracted with EtOAc (2×1.2 L), and the combined organic phase was washed with 16% aqueous sodium chloride solution (2×800 mL) and concentrated to approximately 1.0 L by vacuum distillation. Heptane (2.1 L) was added to the residue, and the resulting mixture was concentrated to 1.0 L by vacuum distillation. To the concentrated mixture was added heptane (2.1 L). The resulting white slurry was then concentrated to 1.0 L by vacuum distillation. To the white slurry was then added methyl tert-butyl ether (MTBE, 1.94 L). The white turbid was heated to 40° C. to obtain a clear solution. The resulting solution was concentrated to about 1.0 L by vacuum distillation. The mixture was stirred at room temperature for 1 hour. The white precipitate was collected by filtration with pulling vacuum. The filter cake was washed with heptane (400 mL) and dried on the filter under nitrogen with pulling vacuum to provide compound 18 (78.3 g, 90.1%) as an off-white solid. For 18: 1H NMR (300 MHz, (CD3)2SO) δ 8.68 (d, 3JHH=4.69 Hz, 1H, NCH in pyridine), 7.97 (dd, 3JHH=4.69 Hz, 4JHF=4.69 Hz, 1H, NCCH in pyridine), 3.92 (br s, 2H, one of NCH2 in piperidine rine, one of another NCH2 in piperidine ring, both in axial position), 3.54 (t, 3JHH=6.15 Hz, 2H, one of NCH2 in piperidine rine, one of another NCH2 in piperidine ring, both in equatorial position), 2.48 (t, 3JHH=6.44 Hz, 2H, NCCH2), 2.34 (t, 3JHE=6.15 Hz, 2H, NCCH2) ppm; 13C NMR (75 MHz, (CD3)2SO) δ 207.17 (C═O), 161.66 (N—C═O), 151.26 (d, 1JCF=266.89 Hz, C—F), 146.90 (d, 4JCF=6.05 Hz, NCH in pyridine), 135.56 (C—C═O), 134.78-135.56 (m, NCCF3), 128.27 (d, 3JCF=7.19 Hz, NCCH in pyridine), 119.52 (d×quartet, 1JCF=274.38 Hz, 3JCF=4.89 Hz, CF3), 45.10 (NC in piperidine ring) ppm, one carbon (NCC in piperidine ring) missing due to overlap with (CD3)2SO; 19F NMR (282 MHz, (CD3)2SO) δ-64.58 (d, 4JFF=15.85 Hz, F3C), −128.90 (d×quartet, 4JFF=15.85 Hz, 4JFH=4.05 Hz, FC) ppm; C12H10F4N2O2 (MW, 290.21), LCMS (EI) m/e 291.1 (M++H).

Example 53-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (20)

Step 1. tent-Butyl 3-(cyanomethyl)-3-(4-(7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidine-1-carboxylate (19)

In a dried 30 L reactor equipped with a mechanic stirrer, a thermometer, an addition funnel and a vacuum outlet were placed 4-(1H-pyrazol-4-yl)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (5, 4.50 kg, 14.28 mol), tert-butyl 3-(cyanomethylene)azetidine-1-carboxylate (13, 3.12 kg, 16.08 mol, 1.126 equiv) in acetonitrile (9 L) at 20±5° C. To the resultant pink suspension was added 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 225 mL, 1.48 mol, 0.10 equiv) over 40 minutes. The batch temperature was kept between 10° C. and 20° C. during addition. The brown solution obtained was stirred at 20° C. for 3 hours. After the reaction was complete, water (18 L) was added with stirring over 80 minutes at 20° C. The mixture was seeded and the seeded mixture was stirred at room temperature for 12 hours. The solids were collected by filtration and the filter cake was washed with a mixture of acetonitrile and water (1:2, 9 L) and dried in a vacuum oven with nitrogen purge for 12 hours at 60° C. to provide the crude product (19, 7.34 kg) as a light yellow powder. The crude product obtained above was dissolved in methyl tert-butyl ether (MTBE, 22 L) at 60° C. in a 50 L reactor equipped with a mechanic stirrer, a thermometer, an addition funnel and a septum. Hexanes (22 L) was added over 1 hour at 60° C. The solution was then seeded, cooled to 20° C. over 3 hours and stirred at 20° C. for 12 hours. The precipitation was collected by filtration. The resultant cake was washed with a mixture of MTBE and hexane (1:15, 3 L) and dried in a vacuum oven for 10 hours at 50° C. to provide the compound 19 (6.83 kg, 13.42 mol, 94.0%) as a white powder. For 19: 1H NMR (400 MHz, CDCl3) δ 8.87 (s, 1H), 8.46 (d, J=0.6 Hz, 1H), 8.36 (d, J=0.7 Hz, 1H), 7.44 (d, J=3.7 Hz, 1H), 6.82 (d, J=3.7 Hz, 1H), 5.69 (s, 2H), 4.57 (d, J=9.6 Hz, 2H), 4.32 (d, J=9.5 Hz, 2H), 3.59-3.49 (m, 2H), 3.35 (s, 2H), 1.49 (s, 9H), 0.96-0.87 (m, 2H), −0.03-−0.10 (s, 9H) ppm; 13C NMR (101 MHz, CDCl3) δ 157.22, 153.67, 153.24, 151.62, 142.13, 130.16, 129.67, 124.47, 116.72, 115.79, 102.12, 82.54, 74.23, 68.01, 60.25, 58.23, 29.65, 29.52, 19.15, −0.26 ppm; C25H35N7O3Si (MW, 509.68), LCMS (EI) m/e 510.1 (M++H).

Step 2. 3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (20)

In a 2 L 4-necked round bottom flask equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 19 (55.0 g, 0.108 mol) and methanol (MeOH, 440 mL) at 20±5° C. The resulting white turbid was stirred for 20 minutes at room temperature to provide a light yellow solution. A solution of hydrochloric acid (HCl) in isopropanol (5.25 M, 165 mL, 0.866 mol, 8.02 equiv) was then added to the reaction mixture via the addition funnel in 5 minutes. The resulting reaction mixture was then heated to 40° C. by a heating mantle. After 2 hours at 40° C., water (165 mL, 9.17 mol, 84.8 equiv) was added to the reaction mixture via the addition funnel to provide a light green solution at 40° C. Methyl tert-butyl ether (MTBE, 440 mL) was added to the resulting mixture via the addition funnel at 40° C. The resulting mixture was slowly cooled to 10° C. The solids were collected by filtration and washed with MTBE (2×220 mL). The white solids were dried in the filter under nitrogen with a pulling vacuum for 18 hours to afford compound 20 (52.2 g, KF water content 5.42%, yield 94.9%). For 20: 1H NMR (400 MHz, (CD3)2SO) δ 10.39 (brs, 1H), 10.16 (brs, 1H), 9.61 (s, 1H), 9.12 (s, 1H), 9.02 (s, 1H), 8.27-8.21 (d, J=3.8 Hz, 1H), 7.72-7.66 (d, J=3.8 Hz, 1H), 5.82 (s, 2H), 4.88-4.77 (m, 2H), 4.53-4.44 (m, 2H), 4.12 (s, 2H), 3.69-3.60 (m, 2H), 0.98-0.89 (m, 2H), 0.01 (s, 9H) ppm; 13C NMR (101 MHz, (CD3)2SO) δ 151.25, 146.45, 145.09, 140.75, 133.38, 132.44, 116.20, 116.09, 112.79, 102.88, 73.07, 66.14, 59.16, 53.69, 26.44, 17.15, −1.36 ppm; C20H29Cl2N7OSi (free base of 20, C20H27N7OSi, MW 409.56), LCMS (EI) m/e 410.2 (M++H).

Example 62-(1-(1-(3-Fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(7-(2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)azetidin-3-yl)acetonitrile (21)

In a 100 L dried reactor equipped with a mechanical stirrer, a thermocouple, a condenser, and a nitrogen inlet was added (20, 3.24 kg, 6.715 mol) and dichloromethane (32 L) at 20±5° C. The mixture was stirred at room temperature for 10 minutes before being treated with triethylamine (TEA, 1.36 kg, 13.44 mol, 2.00 equiv) at an addition rate which keeping the internal temperature at 15-30° C. Compound 18 (2.01 kg, 6.926 mol, 1.03 equiv) was then added to the reactor at room temperature. After 10 minutes, sodium triacetoxyborohydride (NaBH(OAc)3, 2.28 kg, 10.75 mol, 1.60 equiv) was added portion wise to the reactor in 1 hour while the internal temperature was kept at 15-30° C. The resulting reaction mixture was stirred at 15-30° C. for an additional one hour. Once the reductive amination reaction is deemed complete, the reaction mixture was treated with a 4% aqueous sodium bicarbonate solution (NaHCO3, 32 L) to adjust the pH to 7-8. After stirring for 30 minutes at room temperature, the two phases were separated. The aqueous phase was extracted with dichloromethane (29 L). The combined organic phase was sequentially washed with 0.1 N aqueous hydrochloric acid solution (16 L), 4% aqueous sodium bicarbonate solution (16 L), 8% aqueous sodium chloride solution (2×16 L). The resultant organic phase was partially concentrated and filtered. The filtrate was subjected to solvent exchange by gradually adding acetonitrile (65 L) under vacuum. The white solids were collected by filtration, washed with acetonitrile (10 L) and dried at 40-50° C. in a vacuum oven with nitrogen purge to afford compound 21 (4.26 kg, 6.23 mol, 92.9%). For 21: 1H NMR (500 MHz, (CD3)2SO) δ 8.84 (s, 1H), 8.76 (s, 1H), 8.66 (d, J=4.7 Hz, 1H), 8.43 (s, 1H), 7.90 (t, J=4.7 Hz, 1H), 7.78 (d, J=3.7 Hz, 1H), 7.17 (d, J=3.7 Hz, 1H), 5.63 (s, 2H), 4.07 (dt, J=11.1, 4.9 Hz, 1H), 3.75 (d, J=7.8 Hz, 2H), 3.57 (dd, J=10.2, 7.8 Hz, 2H), 3.55 (s, 2h), 3.52 (dd, J=8.5, 7.4 Hz, 2H), 3.41 (dq, J=13.3, 4.3 Hz, 1H), 3.26 (t, J=10.0 Hz, 1H), 3.07 (ddd, J=13.1, 9.4, 3.2 Hz, 1H), 2.56 (dt, J=8.5, 4.7 Hz, 1H), 1.81-1.73 (m, 1H), 1.63 (m, 1H), 1.29 (m, 1H), 1.21 (m, 1H), 0.82 (dd, J=8.5, 7.4 Hz, 2H), −0.12 (s, 9H) ppm; 13C NMR (101 MHz, (CD3)2SO) δ 161.68, (154.91, 152.27), 153.08, 152.69, 151.53, 147.69, 140.96, (136.19, 136.02), (136.48, 136.36, 136.13, 136.0, 135.78, 135.66, 135.43, 135.32), 131.43, 130.84, 129.03, (126.17, 123.42, 120.69), 117.99, 122.77, 118.78, 114.71, 102.02, 73.73, 67.04, 62.86, 61.88, 58.51, 45.63, 30.03, 29.30, 28.60, 18.52, 0.00 ppm; C32H37F4N9O2Si (MW, 683.77), LCMS (EI) m/e 684.2 (M++H).

Example 72-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (22)

Figure US20130060026A1-20130307-C00025 BASE OF INCB 39110

To a 250 mL 4-necked round bottom flask equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 21 (9.25 g, 13.52 mmol, KF water content 3.50%) and acetonitrile (74 mL) at 20±5° C. The resulting white slurry was cooled to below 5° C. Boron trifluoride diethyl etherate (BF3.OEt2, 6.46 mL, 51.37 mmol, 3.80 equiv) was then added at a rate while the internal temperature was kept at below 5.0° C. The reaction mixture was then warmed to 20±5° C. After stirring at 20±5° C. for 18 hours, the reaction mixture was cooled to 0-5° C. and an additional amount of BF3.OEt2 (0.34 mL, 2.70 mmol, 0.2 equiv) was introduced to the reaction mixture at below 5.0° C. The resulting reaction mixture was warmed to 20±5° C., and kept stirring at room temperature for an additional 5 hours. The reaction mixture was then cooled to 0-5° C. before water (12.17 mL, 0.676 mol, 50 equiv) was added. The internal temperature was kept at below 5.0° C. during addition of water. The resultant mixture was warmed to 20±5° C. and kept stirring at room temperature for 2 hours. The reaction mixture was then cooled to 0-5° C. and aqueous ammonium hydroxide (NH4OH, 5 N, 121.7 mmol, 9.0 equiv) was added. During addition of aqueous ammonium hydroxide solution, the internal temperature was kept at below 5.0° C. The resulting reaction mixture was warmed to 20±5° C. and stirred at room temperature for 20 hours. Once the SEM-deprotection was deemed complete, the reaction mixture was filtered, and the solids were washed with EtOAc (9.25 mL). The filtrates were combined and diluted with EtOAc (74 mL). The diluted organic solution was washed with 13% aqueous sodium chloride solution (46.2 mL). The organic phase was then diluted with EtOAc (55.5 mL) before being concentrated to a minimum volume under reduced pressure. EtOAc (120 mL) was added to the residue, and the resulting solution was stirred at 20±5° C. for 30 minutes. The solution was then washed with 7% aqueous sodium bicarbonate solution (2×46 mL) and 13% aqueous sodium bicarbonate solution (46 mL). The resultant organic phase was diluted with EtOAc (46 mL) and treated with water (64 mL) at 50±5° C. for 30 minutes. The mixture was cooled to 20±5° C. and the two phases were separated. The organic phase was treated with water (64 mL) at 50±5° C. for 30 minutes for the second time. The mixture was cooled to 20±5° C. and the two phases were separated. The resultant organic phase was concentrated to afford crude compound 22 (free base), which was further purified by column chromatography (SiO2, 330 g, gradient elution with 0-10% of MeOH in EtOAc) to afford analytically pure free base (22, 7.00 g, 93.5%) as an off-white solid. For 22:

 

1H NMR (400 MHz, (CD3)2SO) δ 12.17 (d, J=2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J=7.9 Hz, 2H), 3.61 (t, J=7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J=10.5 Hz, 1H), 3.09 (ddd, J=13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83-1.75 (m, 1H), 1.70-1.63 (m, 1H), 1.35-1.21 (m, 2H) ppm;

13C NMR (101 MHz, (CD3)2SO) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 119.19, 116.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm;

C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.1 (M′+H).

ADIPATE

Example 8

2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (25)

Step 1. 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate crude salt (24)

The process of making compound 22 in Example 7 was followed, except that the final organic phase was concentrated by vacuum distillation to the minimum volume to afford crude compound 22, which was not isolated but was directly used in subsequent adipate salt formation process. To the concentrated residue which containing crude compound 22 was added methanol (200 mL) at room temperature. The mixture was the concentrated by vacuum distillation to a minimum volume. The residue was then added methanol (75 mL) and the resulting solution was heated to reflux for 2 hours. Methyl isobutyl ketone (MIBK, 75 mL) was added to the solution and the resulting mixture was distilled under vacuum to about 30 mL while the internal temperature was kept at 40-50° C. Methanol (75 mL) was added and the resulting mixture was heated to reflux for 2 hours. To the solution was added MIBK (75 mL). The mixture was distilled again under vacuum to about 30 mL while the internal temperature was kept at 40-50° C. To the solution was added a solution of adipic acid (23, 2.15 g, 14.77 mmol) in methanol (75 mL). The resultant solution was then heated to reflux for 2 hours. MIBK (75 mL) was added. The mixture was distilled under vacuum to about 60 mL while the internal temperature was kept at 40-50° C. Heating was stopped and heptane (52.5 mL) was added over 1-2 hours. The resultant mixture was stirred at 20±5° C. for 3-4 hours. The white precipitates were collected by filtration, and the filter cake was washed with heptane (2×15 mL). The solid was dried on the filter under nitrogen with a pulling vacuum at 20±5° C. for 12 hours to provide compound 24 (crude adipate salt, 8.98 g, 12.84 mmol., 95.0%). For 24: 1H NMR (400 MHz, (CD3)2SO) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm; 13C NMR (101 MHz, (CD3)2SO) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm; C32H33F4N9O5 (Mol. Wt: 699.66; 24: C26H23F4N9O, MW 553.51), LCMS (EI) m/e 554.0 (M++H).

Step 2.

2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl)-1-(1-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (25)

In a 100 L dried reactor equipped with a mechanical stirrer, a thermocouple, an addition funnel and a nitrogen inlet was added compound 24 (3.40 kg, 4.86 mol) and acetone (23.8 L). The resulting white turbid was heated to 55-60° C. to provide a clear solution. The resultant solution was filtered through an in-line filter to another 100 L reactor. Heptane (23.8 L) was filtered through an in-line filter to a separated 50 L reactor. The filtered heptane was then charged to the acetone solution in the 100 L reactor at a rate while the internal temperature was kept at 55-60° C. The reaction mixture in the 100 L reactor was then cooled to 20±5° C. and stirred at 20±5° C. for 16 hours. The white precipitates were collected by filtration and the cake was washed with heptane (2×5.1 L) and dried on the filter under nitrogen with a pulling vacuum. The solid was further dried in a vacuum oven at 55-65° C. with nitrogen purge to provide compound 25 (3.11 kg, 92.2%) as white to off-white powder. For 25:

ADIPATE OF INCB 39110

1H NMR (400 MHz, (CD3)2SO) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J=4.7 Hz, 1H), 8.45 (s, 1H), 7.93 (t, J=4.7 Hz, 1H), 7.63 (dd, J=3.6, 2.3 Hz, 1H), 7.09 (dd, J=3.6, 1.7 Hz, 1H), δ 4.11 (dt, J=11.0, 4.4 Hz, 1H), 3.77 (d, J=7.8 Hz, 2H), 3.60 (t, J=7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J=14.4, 4.6 Hz, 1H), 3.28 (t, J=10.4 Hz, 1H), 3.09 (ddd, J=13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J=8.6, 3.5 Hz, 1H), 2.28-2.17 (m, 4H), 1.83-1.74 (m, 1H), 1.67 (d, J=11.0 Hz, 1H), 1.59-1.46 (m, 4H), 1.37-1.21 (m, 2H) ppm;

 

13C NMR (101 MHz, (CD3)2SO) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 119.29, 116.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm;

 

C32H33F4N9O5 (Mol. Wt: 699.66; free base: C26H23F4N9O (MW, 553.51), LCMS (EI) m/e 554.0 (M++H).

 

…………………………

WO-2014138168

 http://www.google.com/patents/WO2014138168A1?cl=en

Processes for preparing JAK inhibitor (preferably INCB-39110) comprising the reaction of a substituted 1H-pyrazole compound with 4-chloro-7H-pyrrolo[2,3-d]pyrimidine in the presence of a base (eg cesium fluoride) and a solvent under Suzuki coupling conditions ([1,1′- bis(dicyclohexylphosphino)ferrocene]dichloropalladium (II)), followed by deprotection and then reaction with a piperidine derivative, and salt synthesis are claimed. Also claimed are novel intermediates and processes for their preparation. The compound is disclosed to be useful for treating disease mediated by JAK activity (targeting JAK-1 and 2), such as multiple sclerosis, rheumatoid arthritis, type I diabetes, inflammatory bowel disease, Crohn’s disease, COPD, prostate cancer, hepatic cancer, breast cancer, influenza, and SARS.

Example 1. Synthesis of 2-(3-(4-(7H-Pyrrolo[2,3-< ]pyrimidin-4-yl)-lH-pyrazol-l- yl)-l-(l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3- yl)acetonitrile Adipate (9)20443-0253WO1 (INCY0124-WO1) PATENT

tert-Butyl 3-(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)azetidine-l-carboxylate (3). To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were sequentially added isopropanol (IP A, 200 mL), l,8-diazabicyclo[5,4,0]undec-ene (DBU, 9.8 g, 64.4 mmol, 0.125 equiv), 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1, 101 g, 520.51 mmol, 1.01 equiv) and tert-butyl 3-(cyanomethylene)azetidine-l-carboxylate (2, 100 g, 514.85 mmol) at ambient temperature to generate a reaction mixture as a

suspension. The resulting reaction mixture was heated to reflux in 30 minutes to provide a homogenous solution and the mixture was maintained at reflux for an additional 2 – 3 hours. After the reaction was complete as monitored by HPLC, n- heptane (400 mL) was gradually added to the reaction mixture in 45 minutes while maintaining the mixture at reflux. Solids were precipitated out during the w-heptane addition. Once w-heptane addition was complete, the mixture was gradually cooled to ambient temperature and stirred at ambient temperature for an additional 1 hour. The solids were collected by filtration, washed with w-heptane (200 mL), and dried under vacuum at 50 °C with nitrogen sweeping to constant weight to afford tert-butyl 3- 20443-0253WO1 (INCY0124-WO1) PATENT

(cyanomethyl)-3-(4-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- IH-pyrazol- 1 – yl)azetidine-l -carboxylate (3, 181 g, 199.9 g theoretical, 90.5%) as a white to pale yellow solid. For 3: XH NMR (400 MHz, DMSO-i¾) δ 8.31 (s, 1H), 7.74 (s, 1H), 4.45 – 4.23 (m, 2H), 4.23 – 4.03 (m, 2H), 3.56 (s, 2H), 1.38 (s, 9H), 1.25 (s, 12H) ppm; 13C NMR (101 MHz, DMSO-i/6) δ 155.34, 145.50, 135.88, 1 16.88, 107.08 (br), 83.15, 79.36, 58.74 (br), 56.28, 27.96, 26.59, 24.63 ppm; Ci9H29B 404 (MW 388.27),

LCMS (EI) mle 389 (M+ + H). teri-Butyl 3-(4-(7H-pyrrolo[2,3-< |pyrimidin-4-yl)-lH-pyrazol-l-yl)-3- (cyanomethyl)-azetidine-l-carboxylate (5). To a 1-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added 4-chloro-7H-pyrrolo[2,3- i/]pyrimidine (4, 39.6 g, 257.6 mmol), tert-butyl 3-(cyanomethyl)-3-(4-(4,4,5,5- tetramethyl- 1 ,3 ,2-dioxaborolan-2-yl)- IH-pyrazol- 1 -yl)azetidine- 1 -carboxylate (3, 100 g, 257.6 mmol, 1.0 equiv), cesium fluoride (136.9 g, 901.4 mmol, 3.5 equiv), tert- butanol (250 mL), water (250 mL), and [l, l’-bis(di- cyclohexylphosphino)ferrocene]dichloropalladium(II) (Pd-127, 351.4 mg, 0.46 mmol, 0.0018 equiv) at ambient temperature. The resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to reflux and maintained at reflux under nitrogen for 20 – 24 hours. When HPLC showed the reaction was complete, the reaction mixture was cooled to 45 – 55 °C in 30 minutes, the two phases were separated, and the aqueous phase was discarded. To the organic phase was added w-heptane (125 mL) in 30 minutes at 45 – 55 °C. The resulting mixture was slowly cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 2 hours. The solids were collected by filtration, washed with n- heptane (100 mL), and dried under vacuum at 50 °C with nitrogen sweeping to constant weight to afford tert-butyl 3-(4-(7H-pyrrolo[2,3-<i]pyrimidin-4-yl)-lH- pyrazol-l-yl)-3-(cyanomethyl)-azetidine-l -carboxylate (5, 96.8 g, 97.7 g theoretical, 99%) as a pale yellow solid. For 5: XH NMR (400 MHz, DMSO-i¾) δ 8.89 (s, 1H), 8.68 (s, 1H), 8.44 (s, 1H), 7.60 (d, J= 3.5 Hz, 1H), 7.06 (d, J= 3.6 Hz, 1H), 4.62 – 4.41 (m, 2H), 4.31 – 4.12 (m, 2H), 3.67 (s, 2H), 1.39 (s, 9H) ppm; 13C NMR (101 MHz, DMSO-i¾) δ 155.40, 152.60, 150.63, 149.15, 139.76, 129.53, 127.65, 122.25, 20443-0253WO1 (INCY0124-WO1) PATENT

116.92, 113.21, 99.71, 79.45, 58.34 (br), 56.80, 27.99, 26.83 ppm; Ci9H21 702 (MW 379.4), LCMS (EI) mle 380 (M+ + H).

2- (3-(4-(7H-Pyrrolo[2,3-< |pyrimidin-4-yl)-lH-pyrazol-l-yl)azetidin-3- yl)acetonitrile dihydrochloride salt (6). To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added tert- butyl 3 -(4-(7H-pyrrolo [2,3 -<i]pyrimidin-4-yl)- lH-pyrazol- 1 -yl)-3 – (cyanomethyl)azetidine-l-carboxylate (5, 15 g, 39.5 mmol), water (7.5 mL, 416 mmol) and dichloromethane (75 mL) at room temperature. The mixture was stirred at room temperature to generate a suspension. To the suspension was added a solution of 5 M hydrogen chloride (HQ) in isopropanol (55 mL, 275 mmol, 7.0 equiv) in 5 minutes. The resulting reaction mixture was then heated to gentle reflux and

maitained at reflux for 3-4 hours. After the reaction was completed as mornitored by HPLC, tert-butyl methyl ether (TBME, 45 mL) was added to the reaction suspension. The mixture was gradually cooled to room temperature, and stirred for an additional one hour. The solids were collected by filtration, washed with tert-butyl methyl ether (TBME, 45 mL) and dried under vacuum at 50 °C with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H-pyrrolo[2,3-i/]pyrimidin-4-yl)-lH-pyrazol-l-yl)azetidin-

3- yl)acetonitrile dihydrochloride salt (6, 13.6 g, 13.9 g theoretical, 98%) as an off- white to light yellow solid. For 6: XH NMR (400 MHz, D20) δ 8.96 (s, 1H), 8.81 (s, 1H), 8.49 (s, 1H), 7.78 (d, J= 3.8 Hz, 1H), 7.09 (d, J= 3.7 Hz, 1H), 4.93 (d, J= 12.8 Hz, 2H), 4.74 (d, J= 12.5 Hz, 2H), 3.74 (s, 2H) ppm; 13C NMR (101 MHz, D20) δ 151.35, 143.75, 143.33, 141.33, 132.03, 131.97, 115.90, 114.54, 113.85, 103.18, 59.72, 54.45 (2C), 27.02 ppm; Ci4H15Cl2N7 (Ci4H13N7 for free base, MW 279.30), LCMS (EI) mle 280 (M+ + H).

2-(3-(4-(7H-Pyrrolo[2,3-< |pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3-fluoro-2- (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8, Free Base). To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a mechanical stirrer were added 2-(3-(4-(7H-pyrrolo[2,3-<i]pyrimidin-4- yl)-lH-pyrazol-l-yl)azetidin-3-yl)acetonitrile dihydrochloride salt (6, 20 g, 56.78 mmol), dichloromethane (200 mL) and triethylamine (TEA, 16.62 mL, 119.2 mmol, 20443-0253WO1 (INCY0124-WO1) PATENT

2.1 equiv) at ambient temperature. The mixture was stired at ambient temperature for 30 minutes before l-(3-fluoro-2-(trifluoromethyl)-isonicotinoyl)piperidin-4-one (7, 17.15 g, 57.91 mmol, 1.02 equiv) was added to the mixture. The mixture was then treated with sodium triacetoxyborohydride (25.34 g, 1 13.6 mmol, 2.0 equiv) in 5 minutes at ambient temperature (below 26 °C). The resulting reaction mixture was stirred at ambient temperature for 2 hours. After the reaction was complete as mornitored by HPLC, the reaction mixture was quenched with saturated aHC03 aqueous solution (200 mL). The two phases were separated and the aqueous phase was extracted with methylene chloride (200 mL). The combined organic phase was washed with 4% brine (100 mL) followed by solvent switch of methylene chloride to acetone by distillation. The resulting solution of the desired crude product (8) in acetone was directly used for the subsequent adipate salt formation. A small portion of solution was purified by column chromatography (S1O2, 0 – 10% of MeOH in EtOAc gradient elution) to afford the analytically pure 2-(3-(4-(7H-pyrrolo[2,3- i/]pyrimidin-4-yl)- lH-pyrazol- 1 -yl)- 1 -( 1 -(3 -fluoro-2-

(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base) as an off-white solid. For 8: ¾ NMR (400 MHz, DMSO-i¾) δ 12.17 (d, J= 2.8 Hz, 1H), 8.85 (s, 1H), 8.70 (m, 2H), 8.45 (s, 1H), 7.93 (t, J= A J Hz, 1H), 7.63 (dd, J= 3.6, 2.3 Hz, 1H), 7.09 (dd, J= 3.6, 1.7 Hz, 1H), 4.10 (m, 1H), 3.78 (d, J= 7.9 Hz, 2H), 3.61 (t, J= 7.9 Hz, 1H), 3.58 (s, 2H), 3.46 (m, 1H), 3.28 (t, J= 10.5 Hz, 1H), 3.09 (ddd, J = 13.2, 9.5, 3.1 Hz, 1H), 2.58 (m, 1H), 1.83 – 1.75 (m, 1H), 1.70 – 1.63 (m, 1H), 1.35 – 1.21 (m, 2H) ppm; 13C MR (101 MHz, DMSO-i/6) δ 160.28, (153.51, 150.86), 152.20, 150.94, 149.62, (146.30, 146.25), 139.48, (134.78, 134.61), (135.04, 134.92, 134.72, 134.60, 134.38, 134.26, 134.03, 133.92), 129.22, 127.62, 126.84, 121.99, 122.04, (124.77, 122.02, 1 19.19, 1 16.52), 117.39, 113.00, 99.99, 61.47, 60.49, 57.05, 44.23, 28.62, 27.88, 27.19 ppm;

(MW, 553.51), LCMS (EI) mle 554.1 (M+ + H).

2-(3-(4-(7H-Pyrrolo[2,3-< |pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3-fluoro-2- (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile Adipate (9). To a 0.5-L flask equipped with a mechanical stirrer, a thermocouple, an addition funnel, and a nitrogen inlet was added a solution of crude 2-(3-(4-(7H-pyrrolo[2,3- 20443-0253WO1 (INCY0124-WO1) PATENT i/]pyrimidin-4-yl)- lH-pyrazol- 1 -yl)- 1 -( 1 -(3 -fluoro-2-

(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8 free base, 31.38 g, 56.7 mmol) in acetone (220 mL) and adipic acid (8.7 g, 59.53 mmol, 1.05 equiv) at ambient temperature. The reaction mixture was then heated to reflux to give a solution. w-Heptane (220 mL) was gradually added to the reaction mixture at 40 – 50 °C in one hour. The resulting mixture was gradually cooled to ambient temperature in one hour and stirred at ambient temperature for an additional 16 hours. The solids were collected by filtration, washed with w-heptane (2 X 60 mL), and dried under vacuum at 50 °C with nitrogen sweeping to constant weight to afford 2-(3-(4-(7H- Pyrrolo[2,3 -i/]pyrimidin-4-yl)- lH-pyrazol- 1 -yl)- 1 -(1 -(3 -fluoro-2- (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile adipate (9,34.0 g, 39.7 g theoretical, 85.6% for two steps) as a white to off-white solid. 9:

XH NMR (400 MHz, DMSO-i/6) δ 12.16 (s, 1H), 12.05 (brs, 2H), 8.85 (s, 1H), 8.72 (s, 1H), 8.69 (d, J= A J Hz, 1H), 8.45 (s, 1H), 7.93 (t, J= A J Hz, 1H), 7.63 (dd, J= 3.6, 2.3 Hz, 1H), 7.09 (dd, J= 3.6, 1.7 Hz, 1H), 5 4.1 1 (dt, J= 1 1.0, 4.4 Hz, 1H), 3.77 (d, J= 7.8 Hz, 2H), 3.60 (t, J= 7.8 Hz, 2H), 3.58 (s, 2H), 3.44 (dt, J= 14.4, 4.6 Hz, 1H), 3.28 (t, J= 10.4 Hz, 1H), 3.09 (ddd, J= 13.2, 9.6, 3.2 Hz, 1H), 2.58 (tt, J= 8.6, 3.5 Hz, lH), 2.28 – 2.17 (m, 4H), 1.83 – 1.74 (m, 1H), 1.67 (d, J= 11.0 Hz, 1H), 1.59 – 1.46 (m, 4H), 1.37 – 1.21 (m, 2H) ppm;

 

13C MR (101 MHz, DMSO-i/6) δ 174.38, 160.29, (153.52, 150.87), 152.20, 150.94, 149.63, (146.30, 146.25), 139.48, (134.79, 134.62), (135.08, 134.97, 134.74, 134.62, 134.38, 134.28, 134.04, 133.93), 129.21, 127.62, 126.84, 122.05, (124.75, 122.02, 1 19.29, 1 16.54), 117.39, 113.01, 99.99, 61.47, 60.50, 57.06, 44.24, 33.42, 30.70, 28.63, 27.89, 27.20, 24.07 ppm;

C32H33F4N9O5 ( MW 699.66;Figure imgf000043_0001 for free base, MW, 553.51), LCMS (EI) mle 554.0 (M+ + H).

 

 

Example 2: Alternative Synthesis of 2-(3-(4-(7H-Pyrrolo[2,3-d]pyrimidin-4-yl)- lH-pyrazol-l-yl)-l-(l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4- yl)azetidin-3-yl)acetonitrile 20443-0253WO1 (INCY0124-WO1) PATENT

Scheme II

………………………………..COMPD11……………………………………………………………………………………………………..COMPD  8 BASE

C26H3i BF4N603 C26H23F4N9O Mol. Wt: 562.37 Mol. Wt: 553.51

2- (Azetidin-3-ylidene)acetonitrile hydrochloride (2a). To a 0.5-L flask equipped with a nitrogen inlet, a thermocouple, and a mechanical stirrer were added tert-butyl

3- (cyanomethylene)azetidine-l-carboxylate (2, 30 g, 154.46 mmol) and

methylenechloride (300 mL) at ambient temperature. The solution was then treated with a solution of 5 M hydrogen chloride (HQ) in isopropanol solution (294.2 mL, 1.54 mol, 10 equiv) at ambient temperature and the resulting reaction mixture was stirred at ambient temperature for 18 hours. After the reaction was complete as monitored by HPLC, the suspension was added tert-butyl methyl ether (TBME, 150 mL), and the mixture was stirred at ambient temperature for 2 hours. The solids was collected by filtration, washed with w-heptane (2 X 100 mL), and dried on the filtration funnel at ambient temperature for 3 hours to afford 2-(azetidin-3- ylidene)acetonitrile hydrochloride (2a, 13.7 g, 20.2 g theoretical, 67.8 %) as a white solid. For 2a: XH NMR (500 MHz, DMSO-i¾) δ 9.99 (s, 2H), 5.94 (p, J= 2.5 Hz, 1H), 20443-0253WO1 (INCY0124-WO1) PATENT

4.85 – 4.80 (m, 2H), 4.77 – 4.71 (m, 2H) ppm; C NMR (126 MHz, DMSO-i¾) δ 155.65, 114.54, 94.78, 55.26, 54.63 ppm; C5H7C1N2 (MW 130.58; C5H6N2 for free base, MW 94.11), LCMS (EI) mle 95 (M+ + H).

2-(l-(l-(3-Fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3- ylidene)acetonitrile (10). To a 0.25-L flask equipped with a nitrogen inlet, a thermocouple, and a magnetic stirrer were added 2-(azetidin-3-ylidene)acetonitrile hydrochloride (2a, 4.5 g, 34.46 mmol), l-(3-fluoro-2-

(trifluoromethyl)isonicotinoyl)piperidin-4-one (7, 10 g, 34.46 mmol, 1.0 equiv), and methylenechloride (100 mL) at ambient temperqature and the resulting mixture was then treated with sodium triacetoxyborohydride (14.6 g, 68.93 mmol, 2.0 equiv) at ambient temperature. The reaction mixture was stirred at ambient temperature for 2 hours before being quenched with saturated sodium bicarbonate (NaHCOs) aqueous solution (50 mL). The two phases were separated and the aqueous phase was extracted with dichloromethane (200 mL). The combined organic phase was washed with water (50 mL) and brine (50 mL) and concentrated under reduced pressure to afford the crude desired product (10), which was purified by column chromatography (S1O2, 0 – 10 % of ethyl acetate in hexane gradient elution) to afford 2-(l-(l-(3- fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-ylidene)acetonitrile (10, 9.5 g, 12.7 g theoretical, 74.8 %) as a white solid. For 10: XH NMR (400 MHz, CDCI3) δ 8.57 (d, J= A J Hz, 1H), 7.54 (t, J= 4.6 Hz, 1H), 5.29 (p, J= 2.4 Hz, 1H), 4.18 – 4.08 (m, 1H), 4.08 – 4.03 (m, 2H), 3.98 – 3.94 (m, 2H), 3.57 – 3.39 (m, 2H), 3.17 – 3.04 (m, 1H), 2.56 (tt, J= 7.4, 3.5 Hz, 1H), 1.86 – 1.77 (m, 1H), 1.75 – 1.64 (m, 1H), 1.54 – 1.43 (m, 1H), 1.43 – 1.31 (m, lH) ppm; 13C MR (101 MHz, CDC13) δ 161.34, 160.73, 152.62 (d, J= 269.1 Hz), 145.75 (d, J= 6.1 Hz), 136.73 (qd, J = 36.1, 12.0 Hz), 134.56 (d, J= 16.9 Hz), 126.89, 120.58 (qd, J= 275.0, 4.9 Hz),

115.11, 92.04, 62.05, 60.57 (2C), 44.47, 39.42, 29.38, 28.47 ppm; Ci7H16F4N40 (MW 368.33), LCMS (EI) mle 369 (M++ H).

2-(l-(l-(3-Fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)azetidin-3-yl)acetonitrile (11). To a 25 mL flask equipped with a nitrogen inlet, a thermocouple, and a magnetic 20443-0253WO1 (INCY0124-WO1) PATENT stirrer were added 4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazole (1, 210 mg, 1.08 mmol, 1.08 equiv), 2-(l-(l-(3-fluoro-2-

(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3 -ylidene)acetonitrile (10, 370 mg, 1.0 mmol) and acetonitrile (3 mL) at ambient temperature. The solution was then treated with l,8-diazabicyclo[5,4,0]undec-ene (DBU, 173 mg, 0.17 mL, 1.12 mmol, 1.12 equiv) at ambient temperature and the resulting reaction mixture was warmed to 50 °C and stirred at 50 °C for overnight. When the reaction was complete as

monitored by HPLC, the reaction mixture was directly load on a solica gel (S1O2) column for chromatographic purification (0 – 2.5 % MeOH in ethyl acetate gradient elution) to afford 2-(l-(l-(3-fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)-3- (4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH-pyrazol-l-yl)azetidin-3- yl)acetonitrile

Figure imgf000010_0003COMPD 11

(11, 263 mg, 562.4 mg theoretical, 46.7 %) as a white solid.

For 11: ΧΗ NMR (400 MHz, DMSO-i/6) δ 8.64 (d, J= 4.7 Hz, 1H), 8.22 (d, J= 0.6 Hz, 1H), 7.88 (dd, J= A J Hz, 1H), 7.69 (s, 1H), 4.10 – 3.99 (m, 1H), 3.58 (d, J= 7.8 Hz, 2H), 3.52 – 3.42 (m, 2H), 3.44 (s, 2H), 3.41 – 3.33 (m, 1H), 3.28 – 3.15 (m, 1H), 3.03 (ddd, J= 12.9, 9.2, 3.2 Hz, 1H), 2.51 – 2.44 (m, 1H), 1.77 – 1.66 (m, 1H), 1.64 – 1.54 (m, 1H), 1.28 – 1.17 (m, 2H), 1.24 (s, 12H) ppm;

 

13C MR (101 MHz, DMSO-i/6) δ 160.22, 152.13 (d, J= 265.8 Hz), 146.23 (d, J= 5.7 Hz), 145.12, 135.41, 134.66 (d, J= 16.9 Hz), 134.43 (qd, J= 35.0, 1 1.7 Hz), 127.58, 120.61 (qd, J= 274.4, 4.6 Hz), 117.35, 106.59 (br), 83.10, 61.40, 60.53 (2C), 56.49, 44.17, 38.99, 28.55, 27.82, 27.02, 24.63 ppm; C26H3iBF4 603 (MW 562.37), LCMS (EI) mle 563 (M+ + H).

 

2-(3-(4-(7H-Pyrrolo[2,3-< |pyrimidin-4-yl)-lH-pyrazol-l-yl)-l-(l-(3-fluoro-2- (trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin-3-yl)acetonitrile (8). To a

25-mL flask equipped with a nitrogen inlet, a thermocouple, an additional funnel, and a magnetic stirrer were added 2-(l-(l-(3-fluoro-2-(trifluoromethyl)- isonicotinoyl)piperidin-4-yl)-3-(4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)-lH- pyrazol-l-yl)azetidin-3-yl)acetonitrile (11, 307 mg, 0.546 mmol), 4-chloro-7H- pyrrolo[2,3-if|pyrimidine (4, 84.8 mg, 0.548 mmol, 1.0 equiv), sodium bicarbonate (NaHC03, 229 mg, 2.72 mmol, 5.0 equiv), water (1.6 mL), and 1,4-dioxane (1.6 mL) at ambient temperature. The mixture was then teated with

tetrakis(triphenylphosphine)palladium(0) (12.8 mg, 0.011 mmol, 0.02 equiv) at 20443-0253WO1 (INCY0124-WO1) PATENT ambient temperature and the resulting reaction mixture was de-gassed and refilled with nitrogen for 3 times before being heated to 85 °C. The reaction mixture was stired at 85 °C under nitrogen for overnight. When the reaction was complete as monitored by HPLC, the reaction mixture was concentrated to dryness under reduced pressure and the desired product, 2-(3-(4-(7H-pyrrolo[2,3-( Jpyrimidin-4-yl)-lH- pyrazol- 1 -yl)- 1 -( 1 -(3 -fluoro-2-(trifluoromethyl)isonicotinoyl)piperidin-4-yl)azetidin- 3-yl)acetonitrile (8 free base, 135 mg, 302.2 mg theoretical, 44.6 %), was obtained as off- white solids by direct silica gel (S1O2) cloumn chromatography (0 – 10% of ethyl acetate in hexane gradient elution) purification of the dried reaction mixture. The compound obtained by this synthetic approach is identical in every comparable aspect to the compound 8 manufactured by the synthetic method as described above inExample 1.

……………………………………………….

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