(S)-Atenolol

(S)-Atenolol

• Selective β1 adrenoceptor antagonist
• Biological descriptionSelective β1 adrenoceptor antagonist. Orally active. Limited ability to cross the blood-brain barrier. Antihypertensive activity in vivo.

Properties

• Chemical name(S)-(-)-4-[2-Hydroxy-3-[(1-methylethyl)amino]propoxy]benzeneacetamide
• Molecular Weight 266.34
• Molecular formula C14H22N2O3
• CAS Number 93379-54-5

US6982349

Emcure Pharmaceuticals Limited

http://www.google.com/patents/US6982349

Satish Ramanlal Mehta, Baburao Manikroa Bhawal, Vishnu Hari Deshpande,Mukund Keshav Gurjar

m.p. 152–153° C.

[α]D 25: −17.2 (c=1.0, 1N HCl).

IR: νmax 3352, 3168, 1635, 1242 cm−1.

1H NMR (DMSO-d6): δ 0.99 (d, J=7 Hz, 6H, 2×CH3), 2.60 (m, 1H, CH), 2.74 (m, 2H, CH2), 3.27 (s, 2H, CH2), 3.88 (m, 4H, CH2, CH, NH), 6.83 (d, J=8 Hz, 2H, Ar—H), 7.14 (d, J=8 Hz, 2H, Ar—H), 7.40 (bs, 1H).

13C NMR (DMSO-d6):
22.01, 22.09,
41.26, 48.39, 49.38, 67.73, 70.58, 114.16, 128.41, 129.93, 157.17, 172.59 ppm.

COBICISTAT

Cobicistat, GS-9350

1004316-88-4

C 40 H 53 N 7 O 5 S 2

N-[1(R)-Benzyl-4(R)-[2(S)-[3-(2-isopropylthiazol-4-ylmethyl)-3-methyl]ureido]-4-(4-morpholinyl)butyramido]-5-phenylpentyl]carbamic acid thiazol-5-ylmethyl ester

(1,3-thiazol-5-yl) methyl (5S, 8R, 11R) -8,11-dibenzyl-2-methyl-5-[2 - (morpholin-4-yl) ethyl] -1 – [2 - (propan-2-yl) -1,3-thiazol-4-yl] -3,6-dioxo-2 ,4,7,12-tetraazatridecan-13-oate

cytochrome P450 3A4 (CYP3A4) inhibitor

Gilead Sciences, Inc.

SEE SYNTHESIS AT
http://newdrugapprovals.org/2014/09/26/fda-approves-tybost-cobicistat-for-use-in-the-treatment-of-hiv-1-infection/http://newdrugapprovals.org/2014/09/26/fda-approves-tybost-cobicistat-for-use-in-the-treatment-of-hiv-1-infection/

Cobicistat (GS-9350): A potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer
ACS Med Chem Lett 2010, 1(5): 209

http://pubs.acs.org/doi/abs/10.1021/ml1000257

http://pubs.acs.org/doi/suppl/10.1021/ml1000257/suppl_file/ml1000257_si_001.pdf

1-Benzyl-4-{2-[3-(2-isopropyl-thiazol-4-ylmethyl)-3-methyl-ureido]-4-morpholin-4-yl-butyrylamino}-5-phenyl-pentyl)-carbamic acid thiazol-5-ylmethyl ester (GS-9350)

HPLC (Chiral CelROD-H, Chiral Technologies Inc;heptane/iPrOH = 70/30).

1H NMR (CD3OD)

δ8.98 (1 H, s), 7.82 (1 H, s), 7.25-7.05

(11 H, m), 5.25-5.10 (2 H, m), 4.60-4.50 (2 H, m), 4.21-4.03 (2 H, m), 3.82-3.72 (1

H, m), 3.65-3.65 (4 H, m), 3.35-3.25 (1 H, m), 2.98 (3 H, s), 2.8-2.6 (4 H, m), 2.4-2.2

(6 H, m), 1.95-1.8 (1 H, m), 1.8-1.6 (1 H, m), 1.6-1.4 (4 H, m), 1.42-1.32 (6 H, m).

MS (ESI) m/z: 776.2 (M+H)+.

HRMS calc. for C40H53N7O5S2: 775.355, found: 775.353.

US 2014088304

http://www.google.com/patents/US20140088304

The product I was isolated as the stock solution in ethanol (35.0 kg product, 76.1% yield).

¹H NMR (^dDMSO) δ□ 9.05 (s, 1H), 7.85 (s, 1H), 7.52 (d, 1H), 7.25-7.02 (m, 12H), 6.60 (d, 1H), 5.16 (s, 2H), 4.45 (s, 2H), 4.12-4.05 (m, 1H), 3.97-3.85 (m, 1H), 3.68-3.59 (m, 1H), 3.57-3.45 (m, 4H), 3.22 (septets, 1H), 2.88 (s, 3H), 2.70-2.55 (m, 4H), 2.35-2.10 (m, 6H), 1.75 (m, 1H), 1.62 (m, 1H), 1.50-1.30 (m, 4H), 1.32 (d, 6H).

¹³C NMR (CD₃OD) δ 180.54, 174., 160.1, 157.7, 156.9, 153.8, 143.8, 140.1, 140.0, 136.0, 130.53, 130.49, 129.4, 127.4, 127.3, 115.5, 67.7, 58.8, 56.9, 55.9, 54.9, 53.9, 51.6, 49.8, 42.7, 42.0, 35.4, 34.5, 32.4, 32.1, 29.1, 23.7.

MAKE IN INDIA
http://makeinindia.com/
http://makeinindia.com/sector/pharmaceuticals/

Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

COMPD HAS  cas no 1616882-93-9

MF……….C18 H11 F3 N2 O2

[1]​Benzopyrano[4,​3-​c]​pyrazol-​4(1H)​-​one, 3-​methyl-​1-​[4-​(trifluoromethyl)​phenyl]​-

 3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one

Synthesis, biological evaluation and docking analysis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones as potential cyclooxygenase-2 (COX-2) inhibitors

Bioorganic & Medicinal Chemistry Letters,Volume 24, Issue 19, 1 October 2014, Pages 4638–4642

DOI: 10.1016/j.bmcl.2014.08.050

Jagdeep Grover, Vivek Kumar, M. Elizabeth Sobhia, Sanjay M. Jachak

http://www.sciencedirect.com/science/article/pii/S0960894X14008944

 Abstract

As a part of our continued efforts to discover new COX inhibitors, a series of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones were synthesized and evaluated for in vitro COX inhibitory potential. Within this series, seven compounds (3a–d, 3h, 3k and 3q) were identified as potential and selective COX-2 inhibitors (COX-2 IC50’s in 1.79–4.35 μM range; COX-2 selectivity index (SI) = 6.8–16.7 range). Compound 3b emerged as most potent (COX-2 IC50 = 1.79 μM; COX-1 IC50 >30 μM) and selective COX-2 inhibitor (SI >16.7). Further, compound 3b displayed superior anti-inflammatory activity (59.86% inhibition of edema at 5 h) in comparison to celecoxib (51.44% inhibition of edema at 5 h) in carrageenan-induced rat paw edema assay. Structure–activity relationship studies suggested that N-phenyl ring substituted with p-CF3 substituent (3b, 3k and 3q) leads to more selective inhibition of COX-2. To corroborate obtained experimental biological data, molecular docking study was carried out which revealed that compound 3b showed stronger binding interaction with COX-2 as compared to COX-1.

Authors

• Jagdeep Grovera,
• Vivek Kumarb,
• M. Elizabeth Sobhiab,
• Sanjay M. Jachaka, , ,

• a Department of Natural Products, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar (Mohali) 160062, Punjab, India
• b Department of Pharmacoinformatics, National Institute of Pharmaceutical Education and Research, Sector-67, S.A.S. Nagar 160062, Punjab, India

Sanjay Corresponding author. Tel.: +91 172 2214683; fax: +91 172 2214692.

 CLICK……….

• Supplementary data

Cyclooxygenase (COX) or prostaglandin endoperoxide synthase (PGHS), catalyzes the conversion of arachidonic acid to inflammatory mediators such as prostaglandins (PGs), prostacyclins and thromboxanes. COX exists in mainly two isoforms: COX-1 and COX-2.Nonsteroidal anti-inflammatory drugs (NSAIDs), widely used for relief of fever, pain and inflammation, act by inhibiting COX catalyzed biosynthesis of inflammatory mediators.

However, the therapeutic use of classical NSAIDs is associated with well-known side effects at the gastrointestinal level (mucosal damage, bleeding) and, less frequently, at the renal level.

Two decades after the discovery of COX isoforms, it was recognized that selective inhibition of COX-2 might be endowed with improved anti-inflammatory properties and reduced gastrointestinal toxicity profiles than classical NSAIDs.

Overall, these selective COX-2 inhibitors (coxibs) have fulfilled the hope of possessing reduced risk in gastrointestinal events, but unfortunately cardiovascular concerns regarding the use of these agents have emerged that led to the withdrawal of rofecoxib (Vioxx) and valdecoxib (Bextra) from the market in 2004 and 2005, respectively.

Ongoing safety concerns pertaining to the use of non-selective NSAIDs have spurred development of coxibs with improved safety profile.

……………………………………………………………………………………………..

cas no 1616882-93-9

mf……….C18 H11 F3 N2 O2

[1]​Benzopyrano[4,​3-​c]​pyrazol-​4(1H)​-​one, 3-​methyl-​1-​[4-​(trifluoromethyl)​phenyl]​-

 3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one

Scheme 1.

Reagent and conditions: (a) Piperidine, rt, 20 min; (b) ArNHNH2, EtOH, reflux, 5 h; (c) K2CO3, acetone, reflux, 24 h.

COMPD IS

3b

R1=H

R2= H

4-CF3-C6H4

90

3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one (3b):

White solid; yield 90%; mp: 224–225 °C;

1H NMR (CDCl3, 400 MHz): δ ppm 7.89 (d, 2H, J = 8.32 Hz, Ar-H), 7.73 (d, 2H, J = 8.24 Hz, Ar-H), 7.45–7.52 (m, 2H, H-6, H-7), 7.16 (dd, 1H, J = 1.4, 8.2 Hz, H-9), 7.10 (td, 1H, J = 1.56, 7.38 Hz, H-8), 2.69 (s, 3H, CH3);

13C NMR (CDCl3, 100 MHz): δ ppm 157.7, 153.3, 151.5, 142.3, 141.8, 131.9, 127.2, 127.1, 127.0, 124.0, 122.2, 118.3, 111.5, 107.1, 12.8;

HRMS (ESI) m/z: Calcd for C18H11F3N2O2Na [M + Na]+ 367.0670; found 367.0676.

Synthetic Communications (2014), 44(13), 1914-1923

DOI:

10.1080/00397911.2013.879184

Jagdeep Grovera, Somendu Kumar Roya & Sanjay Madhukar Jachaka*

pages 1914-1923

http://www.tandfonline.com/doi/abs/10.1080/00397911.2013.879184#.VCI5f0DgXXM

http://www.tandfonline.com/doi/suppl/10.1080/00397911.2013.879184/suppl_file/lsyc_a_879184_sm8537.pdf

Abstract

Unprecedented cyclization was observed during N-sulfonylation of 3-[1-(phenylhydrazono)-ethyl]-chromen-2-one in pyridine, affording 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones. To avoid use of noxious pyridine, reaction was tried in different basic conditions and the best results were obtained with potassium carbonate in acetone. A wide range of substrates bearing either electron-donating or electron-withdrawing substituents on phenylhydrazine ring were compatible with the developed methodology. Rapid access of starting material, 3-acetylcoumarin, excellent yields of products, and use of environmentally benign base and solvent for the cyclization make this strategy an efficient and convenient method for synthesis of 3-methyl-1-phenylchromeno[4,3-c]pyrazol-4(1H)-ones.

Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one (4b):

Whitesolid;

yield 90%; mp: 224–225 °C;

1H NMR (CDCl3, 400 MHz):δppm 
2.69 (s, 3H, CH3),

7.10(td, 1H,J= 1.56, 7.38 Hz, H-8),

7.16 (dd, 1H,J= 1.4, 8.2 Hz, H-9),

7.45–7.52 (m, 2H, H-6, H-7),

7.73 (d, 2H,J= 8.24 Hz, Ar-H),

7.89 (d, 2H,J= 8.32 Hz, Ar-H);

13C NMR (CDCl3, 100MHz):

δppm
12.8, 
107.1, 
111.5, 
118.3, 
122.2, 
124.0,

127.0, 
127.1, 
127.2, 
131.9, 
141.8, 
142.3,

151.5, 
153.3, 
157.7;

HRMS (ESI)m/z: Calcd for C18H11F3N2O2Na [M + Na]+367.0670; found367.0676.

 3-Methyl-1-(4-(trifluoromethyl)phenylchromeno[4,3-c]pyrazol-4(1H)-one

SEE BELOW  1H NMR, 13CNMR, AND MASS SPEC

13C NMR




MASS

References
1. Jones, G.; Willett, P.; Glen, R. C.; Leach, A. R.; Taylor, R. J. Mol. Biol. 1997, 267, 727.
2. Bernstein, F. C.; Koetzle, T. F.; Williams, G. J. B.; Meyer, E. F.; Brice, M. D.; Rodgers, J. R.; Kennard, O.; Shimanouchi, T.; Tasumi, M. J. Mol. Biol. 1977, 112, 535.

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Your sister will teach you spectroscopy..3 ACETYL COUMARIN

 

3 ACETYL COUMARIN

CAS 3949-36-8

Synonym Name:	3-Acetyl-2H-chromen-2-one; 2H-1-benzopyran-2-one, 3-acetyl-; 3-acetyl-chromen-2-one
Synthesis Reference:	Monatshefte fur Chemie, 121, p. 85, 1990

H1 NMR Spectrum

Predict NMR spectrum

Liu, Jinbing; Wu, Fengyan; Chen, Lingjuan; Zhao, Liangzhong; Zhao, Zibing; Wang, Min; Lei, Sulan
Food Chemistry, 2012 ,  vol. 135,  4  pg. 2872 - 2878

 http://www.sciencedirect.com/science/article/pii/S0308814612011697

1H NMR, 400 MHZ

chloroform-d1

¹H NMR (400 MHz, CDCl₃):

δ 8.49 (s, 1H, C=CH),

7.65-7.63 (m, 2H, Ph-H),

7.37-7.32 (m, 2H, Ph-H),

2.71 (s, 3H, CH₃)

13 C NMR

(100 MHz, CDCl₃)

δ 195.41 (1C),  C=O OF ACETYL

159.17 (1C), C=O OF COUMARIN

155.27 (1C), ARC-O-C=O

147.39 (1C),

134.33 (1C),
130.17 (1C),

124.92 (1C),

124.48 (1C),

118.20 (1C),

116.63 (1C),

30.49 (1C)    -CH3

IR (KBr): 3078, 3026,

1723,  C=O

1675, 1598, 1556, 1441, 1406, 1351, 1297, 1220, 1198, 1162, 1098, 967, 762 cm^-1

4-fluoro-N-((3R,4S)-3-hydroxy-6-(piperazin-1-yl)chroman-4-yl)benzamide

4-fluoro-N-((3R,4S)-3-hydroxy-6-(piperazin-1-yl)chroman-4-yl)benzamide



HPLC purity = 97.3% (tR = 5.7 min) by HPLC method 2. ee = 100% at 4.68 min by Chiral HPLC method 2.

Specific rotation: [α]D20 = 23.02 (c = 10, 95% EtOH-5% H2O).

1H NMR (400 MHz, DMSO-d6) δ 8.75 (d, J = 8.2 Hz, 1H), 8.02–7.92 (m, 2H), 7.33–7.22 (m, 2H), 6.80 (dd, J = 8.9, 2.9 Hz, 1H), 6.71–6.60 (m, 2H), 5.36 (d, J = 3.9 Hz, 1H), 4.95 (dd, J = 8.2, 5.2 Hz, 1H), 4.12 (dd, J = 10.4, 1.8 Hz, 1H), 3.95–3.83 (m, 2H), 2.84–2.71 (m, 8H), 2.17 (s, 1H).


13C NMR (DMSO-d6, 100 MHz): δ 165.6, 163.1, 148.3, 146.7, 131.3, 130.7, 122.2, 118.2, 117.3, 116.8, 115.4, 67.5, 66.2, 51.5, 46.1, 40.8.


HRMS (ESI+): calcd. for C20H22FN3O3 (M+1): 372.1718, found 372.1712.
S6

INCB-039110, Janus kinase-1 (JAK-1) inhibitor

 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 adipateMAY BE THE DRUG… HAS CAS 1334302-63-4

ADIPATE OF INCB-39110

ALSO/OR

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

base

smilesN#CCC6(n3cc(c1ncnc2[n]ccc12)cn3)CN(C5CCN(C(=O)c4ccnc(C(F)(F)F)c4F)CC5)C6

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

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).