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ORGANIC SPECTROSCOPY

Read all about Organic Spectroscopy on ORGANIC SPECTROSCOPY INTERNATIONAL 

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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 PHARMACEUTICALS 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 year tenure till date Dec 2017, 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, 50 Lakh plus views on dozen plus blogs, 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 19 lakh plus views on New Drug Approvals Blog in 216 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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Imipenem, イミペネム水和物


Imipenem.svg

ChemSpider 2D Image | Imipenem hydrate | C12H19N3O5S

74431-23-5.png

Imipenem

イミペネム水和物

Cas 74431-23-5

  • Molecular FormulaC12H19N3O5S
  • Average mass317.361 Da

(5R,6S)-3-((2-(Formimidoylamino)ethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo(3.2.0)hept-2-ene-2-carboxylic acid monohydrate

1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid, 6-[(1R)-1-hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-, (5R,6S)-, monohydrate
264-734-5 [EINECS]
74431-23-5 [RN]
N-Formimidoylthienamycin Monohydrate
Primaxin monohydrate
Tienam monohydrate
(5R,6S)-3-((2-Formimidamidoethyl)thio)-6-((R)-1-hydroxyethyl)-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid hydrate
(5R,6S)-3-[2-(aminomethylideneamino)ethylsulfanyl]-6-[(1R)-1-hydroxyethyl]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid and hydrate
8174596 [Beilstein]
imipemide monohydrate

Antibacterial, Cell wall biosynthesis inhibitor

Imipenem
CAS Registry Number: 74431-23-5; 64221-86-9 (anhydrous)
CAS Name: (5R,6S)-6-[(1R)-1-Hydroxyethyl]-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monohydrate
Additional Names: N-formimidoylthienamycin monohydrate; imipemide
Manufacturers’ Codes: MK-787
Molecular Formula: C12H17N3O4S.H2O
Molecular Weight: 317.36
Percent Composition: C 45.41%, H 6.03%, N 13.24%, O 25.21%, S 10.10%
Literature References: Extremely broad-spectrum semi-synthetic antibiotic; first stable derivative of thienamycin, q.v. Prepn: W. J. Leanza et al., J. Med. Chem. 22, 1435 (1979); T. W. Miller, EP 6639 (1980 to Merck & Co.), C.A. 93, 155845y (1980); B. G. Christensen et al., US 4194047 (1980 to Merck & Co.). Totally synthetic prepn without formation of thienamycin: I. Shinkai et al.,Tetrahedron Lett. 23, 4903 (1982). HPLC determn in serum: C. M. Myers, J. L. Blumer, Antimicrob. Agents Chemother. 26, 78 (1984). Series of articles on in vitro activity, pharmacokinetics, clinical efficacy of combination with cilastatin sodium, q.v., a renal dehydropeptidase I inhibitor: J. Antimicrob. Chemother. 12, Suppl. D, 1-155 (1983); Rev. Infect. Dis. 7, Suppl. 3, S389-S536 (1985); Am. J. Med. 78, Suppl. 6A, 1-167 (1985); Infection 14, Suppl. 2, S111-S180 (1986). Comprehensive description: E. R. Oberholtzer, Anal. Profiles Drug Subs. 17, 73-114 (1988).
Properties: Crystals from water-ethanol. [a]D25 +86.8° (c = 0.05 in 0.1M phosphate, pH 7). pKa1 ~3.2, pKa2 ~9.9. uv max (water): 299 nm (e 9670, 98% NH2OH ext). Soly (mg/ml): water 10, methanol 5, ethanol 0.2, acetone <0.1, dimethylformamide <0.1, dimethylsulfoxide 0.3.
pKa: pKa1 ~3.2, pKa2 ~9.9
Optical Rotation: [a]D25 +86.8° (c = 0.05 in 0.1M phosphate, pH 7)
Absorption maximum: uv max (water): 299 nm (e 9670, 98% NH2OH ext)
Derivative Type: Combination with cilastatin sodium
CAS Registry Number: 85960-17-4
Trademarks: Imipem (Neopharmed); Primaxin (Merck & Co.); Tenacid (Sigma-Tau); Tienam (Merck & Co.); Zienam (Merck & Co.)
Therap-Cat: Antibacterial.
Keywords: Antibacterial (Antibiotics); ?Lactams; Carbapenems.

Imipenem (Primaxin among others) is an intravenous β-lactam antibiotic discovered by Merck scientists Burton Christensen, William Leanza, and Kenneth Wildonger in the mid-1970s.[1] Carbapenems are highly resistant to the β-lactamase enzymes produced by many multiple drug-resistant Gram-negative bacteria,[2] thus play a key role in the treatment of infections not readily treated with other antibiotics.[3]

Imipenem was patented in 1975 and approved for medical use in 1985.[4] It was discovered via a lengthy trial-and-error search for a more stable version of the natural product thienamycin, which is produced by the bacterium Streptomyces cattleya. Thienamycin has antibacterial activity, but is unstable in aqueous solution, so impractical to administer to patients.[5] Imipenem has a broad spectrum of activity against aerobic and anaerobicGram-positive and Gram-negative bacteria.[6] It is particularly important for its activity against Pseudomonas aeruginosa and the Enterococcus species. It is not active against MRSA, however.

Medical uses

Spectrum of bacterial susceptibility and resistance

Acinetobacter anitratusAcinetobacter calcoaceticusActinomyces odontolyticusAeromonas hydrophilaBacteroides distasonisBacteroides uniformis, and Clostridium perfringens are generally susceptible to imipenem, while Acinetobacter baumannii, some Acinetobacter spp., Bacteroides fragilis, and Enterococcus faecalis have developed resistance to imipenem to varying degrees. Not many species are resistant to imipenem except Pseudomonas aeruginosa (Oman) and Stenotrophomonas maltophilia.[7]

Coadministration with cilastatin

Imipenem is rapidly degraded by the renal enzyme dehydropeptidase 1 when administered alone, and is almost always coadministered with cilastatin to prevent this inactivation[8]

Adverse effects

Common adverse drug reactions are nausea and vomiting. People who are allergic to penicillin and other β-lactam antibiotics should take caution if taking imipenem, as cross-reactivity rates are high. At high doses, imipenem is seizurogenic.[9]

Mechanism of action

Imipenem acts as an antimicrobial through inhibiting cell wall synthesis of various Gram-positive and Gram-negative bacteria. It remains very stable in the presence of β-lactamase (both penicillinase and cephalosporinase) produced by some bacteria, and is a strong inhibitor of β-lactamases from some Gram-negative bacteria that are resistant to most β-lactam antibiotics.

SYM

By reaction of thienamycin (I) with methyl formimidate (II) by means of NaOH in water.

DE 2652679; FR 2332012; GB 1570990; NL 7612939

SYN 2

WO 0294828

The reaction of (3R,5R,6S)-6-(1(R)-hydroxyethyl)-2-oxo-1-carbapenem-3-carboxylic acid p-nitrobenzyl ester (I) with diphenyl chlorophosphate by (II) means of DMAP and DIEA in DMA/dichloromethane gives the enol phosphate (III), which is condensed with 2-aminoethanethiol (IV) in DMA to yield the 2-aminoethylsulfanyl derivative (V). The reaction of (V) with benzyl formimidate (VI) by means of DIEA in DMA affords the intermediate p-nitrobenzyl ester (VII), which is finally hydrogenated with H2 over Pd/C in water/isopropanol/N-methylmorpholine to provide the target Imipemide.

SYN 3

Tetrahedron Lett 1982,23(47),4903

The condensation of 7-oxo-6-(1-hydroxyethyl)-3-(diphenoxyphosphate)-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid p-nitrophenyl ester (I) with the bis(trimethylsilyl) derivative of 2-(iminomethylamino)ethanethiol (II) in the presence of base gives p-nitrophenyl ester of MK-0787, protected with a trimethylsilyl group (III), which is finally deprotected by hydrogenolysis.

CLIP

Image result for imipenem synthesis

Synthesis Path

References

  1. ^ U.S. Patent 4,194,047
  2. ^ Clissold, SP; Todd, PA; Campoli-Richards, DM (Mar 1987). “Imipenem/cilastatin. A review of its antibacterial activity, pharmacokinetic properties and therapeutic efficacy”. Drugs33 (3): 183–241. doi:10.2165/00003495-198733030-00001PMID 3552595.
  3. ^ Vardakas, KZ; Tansarli, GS; Rafailidis, PI; Falagas, ME (Dec 2012). “Carbapenems versus alternative antibiotics for the treatment of bacteraemia due to Enterobacteriaceae producing extended-spectrum β-lactamases: a systematic review and meta-analysis”. The Journal of Antimicrobial Chemotherapy67 (12): 2793–803. doi:10.1093/jac/dks301PMID 22915465.
  4. ^ Fischer, Janos; Ganellin, C. Robin (2006). Analogue-based Drug Discovery. John Wiley & Sons. p. 497. ISBN 9783527607495.
  5. ^ Kahan, FM; Kropp, H; Sundelof, JG; Birnbaum, J (Dec 1983). “Thienamycin: development of imipenen-cilastatin”. The Journal of Antimicrobial Chemotherapy. 12 Suppl D: 1–35. doi:10.1093/jac/12.suppl_d.1PMID 6365872.
  6. ^ Kesado, Tadataka; Hashizume, Terutaka; Asahi, Yoshinari (1980). “Antibacterial activities of a new stabilized thienamycin, N-formimidoyl thienamycin, in comparison with other antibiotics”Antimicrobial Agents and Chemotherapy17 (6): 912–7. doi:10.1128/aac.17.6.912PMC 283902PMID 6931548.
  7. ^ “Imipenem spectrum of bacterial susceptibility and Resistance” (PDF). Retrieved 4 May 2012.
  8. ^ “IMIPENEM/CILASTATIN”livertox.nih.gov. Retrieved 2019-03-08.
  9. ^ Cannon, Joan P.; Lee, Todd A.; Clark, Nina M.; Setlak, Paul; Grim, Shellee A. (2014-08-01). “The risk of seizures among the carbapenems: a meta-analysis”Journal of Antimicrobial Chemotherapy69 (8): 2043–2055. doi:10.1093/jac/dku111ISSN 0305-7453.

Further reading

External links

Imipenem
Imipenem.svg
Imipenem ball-and-stick.png
Clinical data
Trade names Primaxin
AHFS/Drugs.com International Drug Names
MedlinePlus a686013
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
Routes of
administration
IMIV
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding 20%
Metabolism Renal
Elimination half-life 38 minutes (children), 60 minutes (adults)
Excretion Urine (70%)
Identifiers
CAS Number
PubChem CID
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.058.831 Edit this at Wikidata
Chemical and physical data
Formula C12H17N3O4S
Molar mass 299.347 g/mol g·mol−1
3D model (JSmol)
    • Synonyms:Imipemide
    • ATC:J01DH51
  • Use:carbapenem antibiotic
  • Chemical name:[5R-[5α,6α(R*)]]-6-(1-hydroxyethyl)-3-[[2-[(iminomethyl)amino]ethyl]thio]-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid
  • Formula:C12H17N3O4S
  • MW:299.35 g/mol
  • CAS-RN:64221-86-9
  • InChI Key:ZSKVGTPCRGIANV-ZXFLCMHBSA-N
  • InChI:InChI=1S/C12H17N3O4S/c1-6(16)9-7-4-8(20-3-2-14-5-13)10(12(18)19)15(7)11(9)17/h5-7,9,16H,2-4H2,1H3,(H2,13,14)(H,18,19)/t6-,7-,9-/m1/s1
  • EINECS:264-734-5
  • LD50:1660 mg/kg (M, i.v.); >5 g/kg (M, p.o.);
    1972 mg/kg (R, i.v.); >5 g/kg (R, p.o.)

Derivatives, monohydrate

  • Formula:C12H17N3O4S • H2O
  • MW:317.37 g/mol
  • CAS-RN:74431-23-5
References
    • Leanza, W.J. et al.: J. Med. Chem. (JMCMAR) 22, 1435 (1979).
    • a Salzmann, T.L. et al.: J. Am. Chem. Soc. (JACSAT) 102, 6161-6163 (1980).
    •  Reider, P.J.; Grabowski, E.J.J.: Tetrahedron Lett. (TELEAY) 23, 2293-2296 (1982).
    •  Grabowski, E.J.J.: Chirality (CHRLEP) 17, 249-259 (2005).
    • US 4 194 047 (Merck & Co.; 18.3.1980; prior. 21.11.1975).
    • DOS 2 652 679 (Merck & Co.; appl. 19.11.1976; USA-prior. 21.11.1975).
    • b US 5 998 612 (Merck & Co.; 7.12.1999; appl. 12.6.1992; prior. 23.10.1981).
    • c US 4 981 992 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).
    •  US 5 204 460 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).
    •  US 5 204 462 (Takasago; 20.4.1993; appl. 8.11.1991; J-prior. 8.11.1990).
    •  US 5 712 388 (Takasago; 27.1.1998; appl. 13.5.1996; J-prior. 11.5.1995).
    •  US 5 081 239 (Takasago; 14.1.1992; appl. 29.11.1989; J-prior. 29.11.1988).
  • Acetoxylation of 2-azetidinones in 4-position:
    • Noyori, R. et al.: J. Am. Chem. Soc. (JACSAT) 111, 9134-9135 (1989).
    • Noyori, R. et al.: Angew. Chem. (ANCEAD) 114, 2108-2123 (2002).
    • US 5 288 862 (Takasago; 22.2.1994; appl. 16.4.1992; J-prior. 18.4.1991).
    • US 5 606 052 (Takasago; 25.2.1997; appl. 16.4.1992; J-prior. 18.4.1991).
  • Noyori-catalyst:
    • US 4 739 084 (Takasago; 19.4.1988; appl. 15.4.1987; J-prior. 13.5.1986).
  • d process of Nippon Soda (Nisso):
    • US 5 026 844 (Suntory & Nippon Soda; 25.6.1991; appl. 13.10.1989; J-prior. 19.10.1988).
    • US 5 792 861 (Tanabe Seiyaku & Nippon Soda; 11.8.1998; appl. 29.6.1994, 4.11.1996; J-prior. 30.6.1993).
    • US 5 808 055 (Suntory & Nippon Soda; 15.9.1998; appl. 30.3.1993, 5.7.1995; J-prior. 30.3.1993).
    • e US 4 791 198 (Kanegafuchi; 13.12.1988; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1986).
    •  US 4 861 877 (Kanegafuchi; 29.8.1989; appl. 1.7.1985, 6.1.1987; J-prior. 5.7.1984, 14.1.1985, 14.1.1986).
    •  US 5 061 817 (Kanegafuchi; 29.10.1991; appl. 1.7.1985, 6.1.1987, 31.5.1988; J-prior. 5.7.1984, 14.1.1986).
    •  US 4 914 200 (Kanegafuchi; 3.4.1990; appl. 28.4.1987, 14.2.1989; J-prior. 30.4.1986, 13.11.1986, 9.2.1987).
  • Enzymatic reduction of alkyl-2-(N-benzoylamino)methyl-3-oxobutyrates with bakers yeast:
    • US 5 463 047 (Ciba-Geigy; 31.10.1995; appl. 15.9.1994; CH-prior. 4.5.1987).
  • Further synthesis processes of Merck & Co. for thienamycin:
    • Johnston, D.B.R. et al.: J. Am. Chem. Soc. (JACSAT) 100, 313-315 (1978).
    • Mellilo, D.G. et al.: Tetrahedron Lett. (TELEAY) 21, 2783 (1980).
    • Melillo, D.G. et al.: J. Org. Chem. (JOCEAH) 51, 1498-1504 (1986).
    • Karady, S. et al.: J. Am. Chem. Soc. (JACSAT) 103, 6765-6767 (1981).
    • US 4 269 772 (Merck & Co.; 26.5.1981; appl. 14.1.1980).
    • US 4 282 148 (Merck & Co.; 4.8.1981; appl. 14.1.1980).
    • US 4 287 123 (Merck & Co.; 1.9.1981; appl. 14.1.1980).
    • US 4 290 947 (Merck & Co.; 22.9.1981; appl. 29.5.1980).
    • US 4 360 684 (Merck & Co.; 23.11.1982; appl. 8.4.1981).
    • US 4 206 219 (Merck & Co.; 3.6.1980; appl. 24.10.1978).
    • US 4 348 320 (Merck & Co.; 7.9.1982; appl. 20.8.1980; USA-prior. 19.11.1976).
    • US 4 460 507 (Merck & Co.; 17.7.1984; appl. 29.4.1982; USA-prior. 10.10.1980).
    • US 5 055 573 (Merck & Co.; 8.10.1991, appl. 24.8.1990; USA-prior. 19.11.1976).
    • US 5 037 974 (Merck & Co.; 6.8.1991; appl. 14.8.1990; prior. 23.5.1988, 10.4.1990).
  • Review of thienamycin syntheses:
    • Nicolaou, K.C.; Sorensen, E.J.: Classics in Total Synthesis, VCH 1996, Weinheim & New York, chapter 16, p. 249-263.
    • Berks, A.H.: Tetrahedron (TETRAB) 52, 331-375 (1996).
  • Alternative 2-azetidinone ring closure with chlorosulfonyl isocyanate:
    • US 4 350 631 (Merck & Co.; 21.9.1982; appl. 18.3.1981; prior. 18.12.1980).
  • Thienamycin (by fermentation of S. cattleya):
    • US 3 950 357 (Merck & Co.; 13.4.1976; appl. 25.11.1974).
    • DOS 2 552 638 (Merck & Co.; appl. 24.11.1975; USA-prior. 25.11.1974).
  • Combination with cilastatin:
    • EP 48 301 (Merck & Co.; appl. 24.9.1980).

/////////////Imipenem, イミペネム水和物  , MK-787,

SK1-I , BML 258


BML-EI411

img

SK1-I , BML 258

Sphingosine kinase 1 (SphK1) inhibitor; antiproliferative

  • (1E)-1,2,4-Trideoxy-4-(methylamino)-1-(4-pentylphenyl)-D-erythro-pent-1-enitol
  • (E,2R,3S)-2-(Methylamino)-5-(4-pentylphenyl)pent-4-ene-1,3-diol
  • D-erythro-Pent-1-enitol, 1,2,4-trideoxy-4-(methylamino)-1-(4-pentylphenyl)-, (1E)-
Name: (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol . HCl
Formula: C17H27NO. HCl
MW: 313.9
CAS: 1072443-89-0

 

  • Originator Enzo Biochem; Virginia Commonwealth University
  • Developer Enzo Biochem
  • Class Antineoplastics; Small molecules
  • Mechanism of Action Sphingosine kinase inhibitors
  • Preclinical Autoimmune hepatitis; Haematological malignancies; Liver cancer; Solid tumours
  • 07 May 2019 Preclinical trials in Liver cancer in USA (unspecified route)
  • 03 Dec 2018 SK1 I is available for licensing as of 03 Dec 2018. http://www.enzo.com/
  • 03 Dec 2018 Enzo Biochem has patent pending for SK1 I worldwide

SK1 I, a small molecule that specifically inhibits sphingosine kinase 1, is being developed by Enzo Biochem for the treatment of cancer and autoimmune diseases. Preclinical development is underway for the treatment of solid tumours, liver cancer, haematological malignancies and autoimmune hepatitis in the US.

As at December 2018, Enzo Biochem seeks partners for the development of SK1

SK1-I is a sphingosine analog and a sphingosine competitive inhibitor specific for sphingosine kinase 1 (SK1), with ki~10µM and excellent water solubility. It is not to be confused with SKI-I, 5-naphthalen-2-yl-2H-pyrazole-3-carboxylic acid (2-hydroxy-naphthalen-1-ylmethylene)-hydrazide, CAS 306301-68-8, a noncompetitive inhibitor of both SK1 and SK2 with poor water solubility (K.J. French, et al., 2006; N.J. Pyne and S. Pyne, 2010). SK1-I does not inhibit SK2, PKCα, PKCδ, PKA, AKT1, ERK1, EGFR, CDK2, IKKβ or CamK2β. Not only does it decrease sphingosine-1-phosphate levels, it also causes an accumulation of its proapoptotic precursor ceremide. Inhibits tumor cell growth in vitro and in vivo.

PATENTS

US 20100035959

WO 2010127093

US 20100278741

WO 2011025545

Patent

US-10364211

https://patentscope.wipo.int/search/en/detail.jsf?docId=US249091462&tab=PCTDESCRIPTION&_cid=P10-JZ0Q22-89420-1

This patent was granted in July 30, 2019 and set to expire on October 24, 2038. Claims methods for synthesizing the compound (2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol (also known as SK1-I and BML-258 (as HCl salt)) and its intermediates.

(2R,3S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I and BML-258 (as HCl salt), is a pharmaceutical inhibitor of sphingosine kinase 1 initially described in Paugh et al., Blood. 2008 Aug. 15; 112(4): 1382-1391. An existing method for synthesizing SK1-I is disclosed in U.S. Pat. No. 8,314,151.


and

    The invention provides methods and intermediate compounds for synthesizing the compound (2R,3 S,4E)-N-methyl-5-(4′-pentylphenyl)-2-aminopent-4-ene-1,3-diol, also known as SK1-I, and related compounds. The structure of SK1-I is shown below.
      A step-wise synthesis of SK1-I according to the invention is exemplified as follows.

N-Boc-(D)-Serine Methyl Ester

      To an ice-cooled suspension of the (D)-Serine methyl ester hydrochloride (62.24 g, 0.4 mol) in dichloromethane (600.0 mL), triethylamine (40.4 g, 0.4 mol) was added. After the mixture was stirred for 30 min, Boc anhydride (96.0 g, 0.44 mol) in dichloromethane (100 mL) was added dropwise with vigorous stirring over 30 min. The reaction mixture was stirred for 16 hours at room temperature. Water (600 mL) was added. The organic layer was separated. The aqueous layer was extracted with 2×200 mL of dichloromethane. The combined organic layer was washed with water (2×400 mL) and dried (Na 2SO 4). The solution was filtered, concentrated under reduced pressure to give an oil 93.36 g (˜100% yield), which was used directly in the next step without further purification.

Protection of N-Boc-(D)-Serine Methyl Ester

      Boc-Serine methyl ester from above (93.0 g, 0.42 mol) and catalyst p-toluenesulfonic acid (9.3 g) were dissolved in dichloromethane (500 mL) and 2,2-dimethoxypropane (500 mL). The mixture was stirred at room temperature for 20 hours with a drying tube. Saturated sodium bicarbonate (600.0 mL) was added. The mixture was then stirred vigorously for 30 min. The organic layer was separated, washed with bicarbonate (2×400.0 mL), water (400.0 mL), saturated NaCl (400.0 mL) and dried (Na 2SO 4). The solution was filtered and concentrated under vacuum to give 87.22 g oil (84% yield for two steps), which was used directly in the next step without further purification.

(R)—Garner Aldehyde

      To a cooled solution of the ester (87.0 g, 0.336 mol) in anhydrous toluene (690.0 mL, −78° C., acetone/dry ice bath), DIBAL in toluene (1.49 M in toluene, 392 mL, 585.0 mmol) was added dropwise under argon in such a way that the internal temperature did not rise above −70° C. After the addition, the reaction mixture was stirred for an additional 4 hours at −78° C. Methanol (128 mL) was added to the mixture to quench the reaction. The mixture was poured slowly into an aqueous solution of Rochelle salt (potassium sodium tartrate tetrahydrate; 1.2 M, 660 g/1949 mL water) with vigorous stirring. The mixture was stirred at room temperature until clear separation into two layers. The aqueous layer was extracted with diethyl ether (2×300.0 mL). The combined organic layer was washed with water (2×800 mL) and brine (800 mL), then dried with anhydrous Na 2SO 4. The solvent was evaporated under vacuum to give aldehyde as a pale yellow oil (68.59 g, 89%), which was used without further purification.

Addition of 4-Pentylphenyl Acetylene to the Above Aldehyde

      To a cooled (−20° C.) solution of 4-n-pentylphenylacetylene (51.68 g, 300 mmol) in dry THF (400 mL), n-BuLi solution (2.5 M in hexane, 120 mL, 300 mmol) was added dropwise under argon. After 2 hours, the mixture was cooled to −78° C., followed by the addition of HMPA (hexmethylphosphoramide, 64.5 g, 360 mmol). After the mixture was stirred at −78° C. for an additional 30 mins, methyl (R)-(+)-3-(t-butoxycarbonyl)-2,2-dimethyl-4-oxazolidinecarboxaldehyde (58.0 g, 248.3 mmol) in anhydrous THF (tetrahydrofuran; 100 mL) was added dropwise (maintaining the temperature below −60° C.). The mixture was stirred for an additional 5 hours at −78° C., then quenched by saturated ammonium chloride solution (1000 mL). The aqueous layer was extracted with ethyl ether (3×400 mL). The combined organic layer was washed with 0.5 N HCl (2×400 mL) and brine (400 mL), then dried with anhydrous sodium sulfate. The solvent was removed under vacuum to give a yellow oil (104.04 g, ˜100% yield), which was used without further purification.

Deprotection of the Above Oxazolidine


      To an ice cooled solution of Boc-oxazolidine (103.0 g, 257.0 mmol) in methanol (1000 mL), was added conc. HCl (43.5 mL, pre-cooled to 0° C.). The mixture was stirred at room temperature overnight and then extracted with hexane (3×400 mL). The pH of the methanol solution was adjusted with solid sodium bicarbonate to 8.0. Boc anhydride (53.94 g, 245.92 mmol) was added and the mixture was stirred at room temperature for 1-4 hours until the disappearance of formed intermediate free amine. The solvent was removed under vacuum. The residue was redissolved in water (300 mL) and diethyl ether (300 mL). The ethyl ether layer was dried with anhydrous sodium sulfate and then evaporated to give a brown oil (87.54 g, 94%), which was used without further purification.

Reduction of the Above Alcohol


      To an ice-cooled solution of the above acetylene (87.0 g, 241.0 mmol) in THF (800 mL), Red-Al (Sodium bis(2-methoxyethoxy)aluminum dihydride; 60% w/w in toluene, 392 mL; 1.205 mol) was added dropwise over 1 hour under argon with stirring. The solution was then stirred at room temperature for 36 hours. The reaction mixture was cooled in an ice bath and then poured carefully into a pre-cooled solution of Rochelle salt in water (700 g in 2200 mL of water). The mixture was vigorously stirred until two layers were visible and well separated. The aqueous layer was extracted with 2×600 mL of toluene. The combined toluene layer was washed with water (2×800 mL) and saturated sodium chloride (800 mL) and dried (Na 2SO 4). The solvent was removed under vacuum to give a yellowish semi solid, which was recrystallized with hexane (200 mL) to give a white solid 43.3 g (purity: >98%; yield: 49%)

Deprotection to SK1-I (BML-258)


      To a solution of Boc protected amine (15 g, 41.3 mmol) in anhydrous THF (300 mL), DIBAL (25% w/w in toluene, 1.49 M, 278 mL, 413 mmol) was added at room temperature under argon. The mixture was refluxed until the starting material disappeared. The mixture was cooled to room temperature and poured into Rochelle salt (340 g/1000 mL water) containing sodium hydroxide (50 g, ˜5%). The mixture was stirred vigorously for 1 hour. The aqueous layer was extracted with ethyl acetate (2×500 mL). The combined organic layer was washed with water (1000 mL) and brine (1000 mL) and dried with anhydrous sodium sulfate. The solvent was removed under vacuum to afford yellowish oil, which turned into a pale solid after storing at −20° C. overnight. To a cold solution (ice bath) of this solid in ethyl ether (400 mL), was added 1M HCl in ethyl ether (50 mL). The white precipitate was collected by filtration and washed with ethyl ether (2×50 mL), and then dried under vacuum to give product as a white solid (8.11 g, 63% yield).

PATENT

WO2018237379 ,

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2018237379

claiming sphingosine pathway modulating compounds for the treatment of cancers, assigned to Enzo Biochem Inc , naming different team

Sphingosine- 1 -phosphate (SIP) was discovered to be a bioactive signaling molecule over 20 years ago. Studies have since identified two related kinases, sphingosine kinase 1 and 2 (a/k/a sphingosine kinase “type I” and “type II” respectively, and SphKl and SphK2 respectively), which catalyze the phosphorylation of sphingosine to SIP. Extracellular SIP can bind to and activate each of five S IP-specific, G protein-coupled receptors (designated S IPR1-5) to regulate cellular and physiological processes in an autocrine or paracrine manner. Selective inhibitors of each of sphingosine kinase 1 and 2, as well as both nonselective and selective agonists of SlPRs, have been developed and are known in the art.

Product Literature References

Sphingosine kinase 1 activation by estrogen receptor α36 contributes to tamoxifen resistance in breast cancer: M.A. Maczis, et al.; J. Lipid Res. 59, 2297 (2018), AbstractFull Text
TP53 is required for BECN1- and ATG5-dependent cell death induced by sphingosine kinase 1 inhibition: S. Lima, et al.; Autophagy 11, 1 (2018), Abstract;
A novel E2F/Sphingosine kinase 1 axis regulates anthracycline response in squamous cell carcinoma: M. Hazar-Rethinam, et al.; Clin. Cancer Res. 21, 417 (2015), Application(s): Inhibition of Sphingosine kinase 1 in doxorubicin-treated SCC cells and in vivo., Abstract;
Inhibition of Sphingosine Kinase 1 Ameliorates Angiotensin II-induced Hypertension and Inhibits Transmembrane Calcium Entry via Store-Operated Calcium Channel: P. C. Wilson, et al.; Mol. Endocrinol. 29, 896 (2015), Application(s): Cell Culture, AbstractFull Text
Sphingosine Kinases Signalling in Carcinogenesis: G. Marfe, et al.; Mini Rev. Med. Chem. 15, 300 (2015), Application(s):Inhibition of Sphingosine kinase 1, Abstract;
K63-linked polyubiquitination of transcription factor IRF1 is essential for IL-1-induced production of chemokines CXCL10 and CCL5.: K. B. Harikumar, et al.; Nat. Immunol. 15, 231 (2014), Application(s): Inhibition of Sphingosine kinase 1 in primary human astrocytes and mice, AbstractFull Text
LRIG1 modulates aggressiveness of head and neck cancers by regulating EGFR-MAPK-SPHK1 signaling and extracellular matrix remodeling: J. J. C. Sheu, et al.; Oncogene 33, 1375 (2014), Application(s): Inhibition of Sphingosine kinase 1 in head and neck cancer TW06 cells, Abstract;
Role of sphingosine kinase 1 and sphingosine-1-phosphate in CD40 signaling and IgE class switching: E. Y. Kim, et al.; FASEB J. 28, 4347 (2014), Application(s): Inhibition of Sphingosine kinase 1 in human tonsil B cells, mouse splenic B cells and in mice, Abstract;
Sphingosine kinase-1 enhances resistance to apoptosis through activation of PI3K/Akt/NF-κB pathway in human non–small cell lung cancer: L. Song et al.; Clin. Cancer Res. 17, 1839 (2011), Abstract;
Targeting sphingosine kinase 1 inhibits Akt signaling, induces apoptosis, and suppresses growth of human glioblastoma cells and xenografts: D. Kapitonov et al.; Cancer Res. 69, 6915 (2009), Abstract;
A selective sphingosine kinase 1 inhibitor integrates multiple molecular therapeutic targets in human leukemia: S.W. Paugh et al.; Blood 112, 1382 (2008), Abstract;

General Literature References

Sphingosine-1-phosphate and cancer: N.J. Pyne & S. Pyne; Nat. Rev. Cancer 10, 489 (2010), Abstract;
Antitumor Activity of Sphingosine Kinase Inhibitors: K.J. French, et al.; J. Pharmacol. Exp. Ther. 318, 596 (2006), AbstractFull Text

/////////SK1-I , SK1I , SK1 I , BML 258, Enzo Biochem,  Virginia Commonwealth, Preclinical, solid tumours, liver cancer, haematological malignancies, autoimmune hepatitis, 

CCCCCC1=CC=C(/C=C/[C@H](O)[C@H](NC)CO)C=C1.Cl

PF 04965842, Abrocitinib


PF-04965842, >=98% (HPLC).png

img

2D chemical structure of 1622902-68-4

PF-04965842

PF 04965842, Abrocitinib

UNII: 73SM5SF3OR

CAS Number 1622902-68-4, Empirical Formula  C14H21N5O2S, Molecular Weight 323.41

N-[cis-3-(Methyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)cyclobutyl]-1-propanesulfonamide,

N-((1s,3s)-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)cyclobutyl)propane-1-sulfonamide

1-Propanesulfonamide, N-(cis-3-(methyl-7H-pyrrolo(2,3-d)pyrimidin-4-ylamino)cyclobutyl)-

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide

PHASE 3, for the potential oral treatment of moderate-to-severe atopic dermatitis (AD)

Jak1 tyrosine kinase inhibitor

THE US

In February 2018, the FDA granted Breakthrough Therapy designation for the treatment of patients with moderate-to-severe AD

PHASEIII

In December 2017, a randomized, double-blind, placebo-controlled, parallel-group, phase III trial (NCT03349060; JADE Mono-1; JADE; B7451012; 2017-003651-29) of PF-04965842 began in patients aged 12 years and older (expected n = 375) with moderate-to-severe AD

PRODUCT PATENT

Pub. No.: WO/2014/128591 International Application No.: PCT/IB2014/058889
Publication Date: 28.08.2014 International Filing Date: 11.02.2014

EXPIRY  Roughly 2034

form powder
color white to beige
solubility DMSO: 10 mg/mL, clear
storage temp. room temp
    Biochem/physiol Actions
    • PF-04965842 is a Janus Kinase (JAK) inhibitor selective for JAK1 with an IC50value of 29 nM for JAK1 compared to 803 nM for JAK2, >10000 nM for JAK3 and 1250 nM for Tyk2. JAKs mediate cytokine signaling, and are involved in cell proliferation and differentiation. PF-04965842 has been investigated as a possible treatment for psoriasis.
  • Originator Pfizer
  • Class Skin disorder therapies; Small molecules
  • Mechanism of Action Janus kinase 1 inhibitors

Highest Development Phases

  • Phase IIIAtopic dermatitis
  • DiscontinuedLupus vulgaris; Plaque psoriasis

Most Recent Events

  • 08 Mar 2018Phase-III clinical trials in Atopic dermatitis (In children, In adults, In adolescents) in USA (PO) (NCT03422822)
  • 14 Feb 2018PF 4965842 receives Breakthrough Therapy status for Atopic dermatitis in USA
  • 06 Feb 2018Pfizer plans the phase III JADE EXTEND trial for Atopic Dermatitis (In children, In adults, In adolescents) in March 2018 (PO) (NCT03422822)

This compound was developed by Pfizer for Kinase Phosphatase Biology research. To learn more about Sigma′s partnership with Pfizer and view other authentic, high-quality Pfizer compounds,

Image result for PF-04965842

PF-04965842 is an oral Janus Kinase 1 inhibitor being investigated for treatment of plaque psoriasis.

Protein kinases are families of enzymes that catalyze the phosphorylation of specific residues in proteins, broadly classified into tyrosine and serine/threonine kinases. Inappropriate kinase activity, arising from mutation, over-expression, or inappropriate regulation, dys-regulation or de-regulation, as well as over- or under-production of growth factors or cytokines has been i mplicated in many diseases, including but not limited to cancer, cardiovascular diseases, allergies, asthma and other respiratory diseases, autoimmune d iseases, inflammatory diseases, bone diseases, metabolic disorders, and neurological and neurodegenerative disorders such as Alzheimer’s disease. Inappropriate kinase activity triggers a variety of biological cellular responses relating to cell growth, cell differentiation , survival, apoptosis, mitogenesis, cell cycle control, and cel l mobility implicated in the aforementioned and related diseases.

Thus, protein kinases have emerged as an important class of enzymes as targets for therapeutic intervention. In particular, the JAK family of cellular protein tyrosine kinases (JAK1, JAK2, JAK3, and Tyk2) play a central role in cytoki ne signaling (Kisseleva et al., Gene, 2002, 285 , 1; Yamaoka et al. Genome Biology 2004, 5, 253)). Upon binding to their receptors, cytokines activate JAK which then phosphorylate the cytokine receptor, thereby creating docking sites for signaling molecules, notably, members of the signal transducer and activator of transcription (STAT) family that ultimately lead to gene expression. Numerous cytokines are known to activate the JAK family. These cytokines include, the IFN family (IFN-alpha, IFN-beta, IFN-omega, Limitin, IFN-gamma, IL- 10, IL- 19, IL-20, IL-22), the gp 130 family (IL-6, IL- 11, OSM, LIF, CNTF, NNT- 1//SF-3, G-CSF, CT- 1, Leptin, IL- 12 , I L-23), gamma C family (IL-2 , I L-7, TSLP, IL-9, IL- 15 , IL-21, IL-4, I L- 13), IL-3 family (IL-3 , IL-5 , GM-CSF), single chain family (EPO, GH, PRL, TPO), receptor tyrosine kinases (EGF, PDGF, CSF- 1, HGF), and G-protein coupled receptors (ATI).

There remains a need for new compounds that effectively and selectively inhibit specific JAK enzymes, and JAK1 in particular, vs. JAK2. JAK1 is a member of the Janus family of protein kinases composed of JAK1, JAK2, JAK3 and TYK2. JAK1 is expressed to various levels in all tissues. Many cytokine receptors signal through pairs of JAK kinases in the following combinations: JAK1/JAK2, JAK1/JAK3, JAK1/TYK2 , JAK2/TYK2 or JAK2/JAK2. JAK1 is the most broadly

paired JAK kinase in this context and is required for signaling by γ-common (IL-2Rγ) cytokine receptors, IL—6 receptor family, Type I, II and III receptor families and IL- 10 receptor family. Animal studies have shown that JAK1 is required for the development, function and homeostasis of the immune system. Modulation of immune activity through inhibition of JAK1 kinase activity can prove useful in the treatment of various immune disorders (Murray, P.J.

J. Immunol., 178, 2623-2629 (2007); Kisseleva, T., et al., Gene, 285 , 1-24 (2002); O’Shea, J . J., et al., Ceil , 109, (suppl .) S121-S131 (2002)) while avoiding JAK2 dependent erythropoietin (EPO) and thrombopoietin (TPO) signaling (Neubauer H., et al., Cell, 93(3), 397-409 (1998);

Parganas E., et al., Cell, 93(3), 385-95 (1998)).

Figure

Tofacitinib (1), baricitinib (2), and ruxolitinib (3)

SYNTHESIS 5+1 =6 steps

Main synthesis

Journal of Medicinal Chemistry, 61(3), 1130-1152; 2018

INTERMEDIATE

CN 105732637

ONE STEP

CAS 479633-63-1,  7H-Pyrrolo[2,3-d]pyrimidine, 4-chloro-7-[(4- methylphenyl)sulfonyl]-

Image result for PF-04965842

Pfizer Receives Breakthrough Therapy Designation from FDA for PF-04965842, an oral JAK1 Inhibitor, for the Treatment of Patients with Moderate-to-Severe Atopic Dermatitis

Wednesday, February 14, 2018 8:30 am EST

Dateline:

NEW YORK

Public Company Information:

NYSE:
PFE
US7170811035
“We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

NEW YORK–(BUSINESS WIRE)–Pfizer Inc. (NYSE:PFE) today announced its once-daily oral Janus kinase 1 (JAK1) inhibitor PF-04965842 received Breakthrough Therapy designation from the U.S. Food and Drug Administration (FDA) for the treatment of patients with moderate-to-severe atopic dermatitis (AD). The Phase 3 program for PF-04965842 initiated in December and is the first trial in the J AK1 A topic D ermatitis E fficacy and Safety (JADE) global development program.

“Achieving Breakthrough Therapy Designation is an important milestone not only for Pfizer but also for patients living with the often devastating impact of moderate-to-severe atopic dermatitis, their providers and caregivers,” said Michael Corbo, Chief Development Officer, Inflammation & Immunology, Pfizer Global Product Development. “We look forward to working closely with the FDA throughout our ongoing Phase 3 development program with the hope of ultimately bringing this important new treatment option to these patients.”

Breakthrough Therapy Designation was initiated as part of the Food and Drug Administration Safety and Innovation Act (FDASIA) signed in 2012. As defined by the FDA, a breakthrough therapy is a drug intended to be used alone or in combination with one or more other drugs to treat a serious or life-threatening disease or condition and preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development. If a drug is designated as a breakthrough therapy, the FDA will expedite the development and review of such drug.1

About PF-04965842 and Pfizer’s Kinase Inhibitor Leadership

PF-04965842 is an oral small molecule that selectively inhibits Janus kinase (JAK) 1. Inhibition of JAK1 is thought to modulate multiple cytokines involved in pathophysiology of AD including interleukin (IL)-4, IL-13, IL-31 and interferon gamma.

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitor therapies in development. As a pioneer in JAK science, the Company is advancing several investigational programs with novel selectivity profiles, which, if successful, could potentially deliver transformative therapies for patients. Pfizer has three additional kinase inhibitors in Phase 2 development across multiple indications:

  • PF-06651600: A JAK3 inhibitor under investigation for the treatment of rheumatoid arthritis, ulcerative colitis and alopecia areata
  • PF-06700841: A tyrosine kinase 2 (TYK2)/JAK1 inhibitor under investigation for the treatment of psoriasis, ulcerative colitis and alopecia areata
  • PF-06650833: An interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitor under investigation for the treatment of rheumatoid arthritis

Working together for a healthier world®

At Pfizer, we apply science and our global resources to bring therapies to people that extend and significantly improve their lives. We strive to set the standard for quality, safety and value in the discovery, development and manufacture of health care products. Our global portfolio includes medicines and vaccines as well as many of the world’s best-known consumer health care products. Every day, Pfizer colleagues work across developed and emerging markets to advance wellness, prevention, treatments and cures that challenge the most feared diseases of our time. Consistent with our responsibility as one of the world’s premier innovative biopharmaceutical companies, we collaborate with health care providers, governments and local communities to support and expand access to reliable, affordable health care around the world. For more than 150 years, we have worked to make a difference for all who rely on us. We routinely post information that may be important to investors on our website at www.pfizer.com. In addition, to learn more, please visit us on www.pfizer.com and follow us on Twitter at @Pfizer and @Pfizer_NewsLinkedInYouTube and like us on Facebook at Facebook.com/Pfizer.

DISCLOSURE NOTICE: The information contained in this release is as of February 14, 2018. Pfizer assumes no obligation to update forward-looking statements contained in this release as the result of new information or future events or developments.

This release contains forward-looking information about PF-04965842 and Pfizer’s ongoing investigational programs in kinase inhibitor therapies, including their potential benefits, that involves substantial risks and uncertainties that could cause actual results to differ materially from those expressed or implied by such statements. Risks and uncertainties include, among other things, the uncertainties inherent in research and development, including the ability to meet anticipated clinical trial commencement and completion dates and regulatory submission dates, as well as the possibility of unfavorable clinical trial results, including unfavorable new clinical data and additional analyses of existing data; risks associated with preliminary data; the risk that clinical trial data are subject to differing interpretations, and, even when we view data as sufficient to support the safety and/or effectiveness of a product candidate, regulatory authorities may not share our views and may require additional data or may deny approval altogether; whether regulatory authorities will be satisfied with the design of and results from our clinical studies; whether and when drug applications may be filed in any jurisdictions for any potential indication for PF-04965842 or any other investigational kinase inhibitor therapies; whether and when any such applications may be approved by regulatory authorities, which will depend on the assessment by such regulatory authorities of the benefit-risk profile suggested by the totality of the efficacy and safety information submitted, and, if approved, whether PF-04965842 or any such other investigational kinase inhibitor therapies will be commercially successful; decisions by regulatory authorities regarding labeling, safety and other matters that could affect the availability or commercial potential of PF-04965842 or any other investigational kinase inhibitor therapies; and competitive developments.

A further description of risks and uncertainties can be found in Pfizer’s Annual Report on Form 10-K for the fiscal year ended December 31, 2016 and in its subsequent reports on Form 10-Q, including in the sections thereof captioned “Risk Factors” and “Forward-Looking Information and Factors That May Affect Future Results”, as well as in its subsequent reports on Form 8-K, all of which are filed with the U.S. Securities and Exchange Commission and available at www.sec.gov  and www.pfizer.com .

Image result for PF-04965842

# # # # #

1 Food and Drug Administration Fact Sheet Breakthrough Therapies at https://www.fda.gov/RegulatoryInformation/LawsEnforcedbyFDA/SignificantAmendmentstotheFDCAct/FDASIA/ucm329491.htmaccessed on January 25, 2018

PATENT

CA 2899888

PATENT

WO 2014128591

https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=6767BBB5964A985E88C9251B6DF3182B.wapp2nB?docId=WO2014128591&recNum=233&maxRec=8235&office=&prevFilter=&sortOption=&queryString=EN_ALL%3Anmr+AND+PA%3Apfizer&tab=PCTDescription

PFIZER INC. [US/US]; 235 East 42nd Street New York, New York 10017 (US)

BROWN, Matthew Frank; (US).
FENWICK, Ashley Edward; (US).
FLANAGAN, Mark Edward; (US).
GONZALES, Andrea; (US).
JOHNSON, Timothy Allan; (US).
KAILA, Neelu; (US).
MITTON-FRY, Mark J.; (US).
STROHBACH, Joseph Walter; (US).
TENBRINK, Ruth E.; (US).
TRZUPEK, John David; (US).
UNWALLA, Rayomand Jal; (US).
VAZQUEZ, Michael L.; (US).
PARIKH, Mihir, D.; (US)

COMPD 2

str1

Example 2 : N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane- l -sulƒonamide

This compound was prepared using 1-propanesulfonyl chloride. The crude compound was purified by chromatography on silica gel eluting with a mixture of dichloromethane and methanol (93 : 7) to afford the title compound as a tan sol id (78% yield). 1NMR (400 MHz, DMSO-d6): δ 11.60 (br s, 1 H), 8.08 (s, 1 H), 7.46 (d, 1 H), 7.12 (d, 1 H), 6.61 (d, 1 H), 4.81-4.94 (m, 1 H), 3.47-3.62 (m, 1 H), 3.23 (s, 3 H), 2.87-2.96 (m, 2 H), 2.52-2.63 (m, 2 H), 2.14-2.27 (m, 2 H) 1.60- 1.73 (m, 2 H) 0.96 (t, 3 H). LC/MS (exact mass) calculated for C14H21N5O2S;

323.142, found (M + H+); 324.1.

PAPER

 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

Abstract Image

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.7b01598

N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}propane-1-sulfonamide (25)

Compound 48a·2HBr …………..was collected by filtration, washed with 2:1 EtOH/H2O (100 mL), and again dried overnight in a vacuum oven at 40 °C.
1H NMR (400 MHz, DMSO-d6): 11.64 (br s, 1H), 8.12 (s, 1 H), 7.50 (d, J = 9.4 Hz, 1H), 7.10–7.22 (m, 1H), 6.65 (dd, J= 1.8, 3.3 Hz, 1H), 4.87–4.96 (m, 1H), 3.53–3.64 (m, 1H), 3.27 (s, 3H), 2.93–2.97 (m, 2H), 2.57–2.64 (m, 2H), 2.20–2.28 (m, 2H), 1.65–1.74 (m, 2H), 0.99 (t, J = 7.4 Hz, 3H).
LC/MS m/z (M + H+) calcd for C14H22N5O2S: 324. Found: 324. Anal. Calcd for C14H21N5O2S: C, 51.99; H, 6.54; N, 21.65; O, 9.89; S, 9.91. Found: C, 52.06; H, 6.60; N, 21.48; O, 10.08; S, 9.97.

SchmiederG.DraelosZ.PariserD.BanfieldC.CoxL.HodgeM.KierasE.Parsons-RichD.MenonS.SalganikM.PageK.PeevaE. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study Br. J. Dermatol. 2017DOI: 10.1111/bjd.16004

Compound 25N-{cis-3-[Methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]cyclobutyl}-propane-1-sulfonamide is available through MilliporeSigma (cat. no. PZ0304).

REFERENCES

1: Schmieder GJ, Draelos ZD, Pariser DM, Banfield C, Cox L, Hodge M, Kieras E, Parsons-Rich D, Menon S, Salganik M, Page K, Peeva E. Efficacy and safety of the Janus Kinase 1 inhibitor PF-04965842 in patients with moderate to severe psoriasis: phase 2, randomized, double-blind, placebo-controlled study. Br J Dermatol. 2017 Sep 26. doi: 10.1111/bjd.16004. [Epub ahead of print] PubMed PMID: 28949012

 2 Journal of Medicinal Chemistry (2018), 61(3), 1130-1152.

  • Originator Pfizer
  • Class Anti-inflammatories; Antipsoriatics; Pyrimidines; Pyrroles; Skin disorder therapies; Small molecules; Sulfonamides
  • Mechanism of Action Janus kinase 1 inhibitors
  • Phase III Atopic dermatitis
  • Discontinued Lupus vulgaris; Plaque psoriasis
  • 21 May 2019Pfizer initiates enrolment in a phase I trial in Healthy volunteers in USA (PO) (NCT03937258)
  • 09 May 2019 Pfizer plans a phase I pharmacokinetic and drug-drug interaction trial in healthy volunteers in May 2019 (NCT03937258)
  • 30 Apr 2019 Pfizer completes a phase I trial (In volunteers) in USA (PO) (NCT03626415)

/////////PF 04965842, Abrocitinib, Phase III,  Atopic dermatitis, pfizer

CCCS(=O)(N[C@H]1C[C@@H](N(C)C2=C3C(NC=C3)=NC=N2)C1)=O

CCCS(=O)(=O)N[C@@H]1C[C@@H](C1)N(C)c2ncnc3[nH]ccc23

Ritlectinib, PF 06651600


Image result for PF-06651600

Image result for PF-06651600

Ritlectinib

PF-06651600

CAS 1792180-81-4

C₁₅H₁₉N₅O, 285.34, UNII-2OYE00PC25

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one

Image result for PF-06651600

 1-[(2S,5R)-2-Methyl-5-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-1-piperidinyl]-2-propen-1-one malonate

PF-06651600 malonate
CAS: 2140301-97-7 (malonate)
Chemical Formula: C18H23N5O5

Molecular Weight: 389.412

PHASE 2  alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis.

PF-06651600 is a potent and selective JAK3 inhibitor. PF-06651600 is a potent and low clearance compound with demonstrated in vivo efficacy. The favorable efficacy and safety profile of this JAK3-specific inhibitor PF-06651600 led to its evaluation in several human clinical studies. JAK3 was among the first of the JAKs targeted for therapeutic intervention due to the strong validation provided by human SCID patients displaying JAK3 deficiencies

Pfizer has established a leading kinase research capability with multiple unique kinase inhibitors in development as potential medicines. PF-06651600 is a highly selective and orally bioavailable Janus Kinase 3 (JAK3) inhibitor that represents a potential immunomodulatory therapy. With the favorable efficacy, safety profile, and ADME properties, this JAK3-specific covalent inhibitor has been under clinical investigation for the treatment of alopecia areata, rheumatoid arthritis, Crohn’s disease, and ulcerative colitis. Supported by positive results from a Phase 2 study, 1 was granted Breakthrough Therapy designation by the FDA on Sept. 5, 2018 for treatment of alopecia areata.

SYN

PAPER

J. Med. Chem. 201760 (5), 19711993DOI: 10.1021/acs.jmedchem.6b01694

https://pubs.acs.org/doi/abs/10.1021/acs.jmedchem.6b01694

Paper

Process Development and Scale Up of a Selective JAK3 Covalent Inhibitor PF-06651600, 

Yong Tao*

Cite This:Org. Process Res. Dev.2019XXXXXXXXXX-XXX

Publication Date:July 19, 2019

https://doi.org/10.1021/acs.oprd.9b00198

A scalable process for PF-06651600 (1) has been developed through successful enabling of the first generation syntheis. The synthesis highlights include the following: (1) replacement of costly PtO2 with a less expensive 5% Rh/C catalyst for a pyridine hydrogenation, (2) identification of a diasteroemeric salt crystallization to isolate the enantiomerically pure cis-isomer directly from a racemic mixture of cis/trans isomers, (3) a high yielding amidation via Schotten–Baumann conditions, and (4) critical development of a reproducible crystallization procedure for a stable crystalline salt (1·TsOH), which is suitable for long-term storage and tablet formulation. All chromatographic purifications, including two chiral SFC chromatographic separations, were eliminated. Combined with other improvements in each step of the synthesis, the overall yield was increased from 5% to 14%. Several multikilogram batches of the API have been delivered to support clinical studies.

https://pubs.acs.org/doi/10.1021/acs.oprd.9b00198

1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop-2-en-1-one p-Toluenesulfonate (1·TsOH)

1·TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. Mp 199 °C. Rotomers observed for NMR spectroscopies. 1H NMR (400 MHz, DMSO-d6): δ ppm 12.68 (brs, 1H), 9.22 (brs, 1H), 8.40 (s, 1H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1.2 Hz, 1H), 6.84 (m, 1H), 6.13 (m, 1H), 5.70 (m, 1H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1.91–1.72 (m, 4H), 1.24–1.17 (m, 3H). 13C NMR (100 MHz, DMSO-d6): δ ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51, 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41, 25.22, 21.28, 16.97, 15.51. HRMS (ESI) m/z: calculated for C15H20N5O [M + H]+286.1668; observed 286.1692.

PAPER

Telliez JB, et al. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451.

PATENT

WO 2015083028

https://patents.google.com/patent/WO2015083028A1

PATENT

WO 2020084435

https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2020084435&tab=PCTDESCRIPTION&_cid=P12-KIL68Y-23557-1

1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one has the structural formula:

The synthesis of 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one is described in WO2015/083028, commonly assigned to the assignee of the present invention and which is incorporated herein by reference in its entirety. 1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one is useful as an inhibitor of protein kinases, such as the enzyme Janus Kinase (JAK) and as such is useful therapy as an immunosuppressive agent for organ transplants, xeno transplantation, lupus, multiple sclerosis, rheumatoid arthritis, psoriasis, Type I diabetes and complications from diabetes, cancer, asthma, atopic dermatitis, autoimmune thyroid disorders, ulcerative colitis, Crohn’s disease, alopecia, vitiligo, Alzheimer’s disease, leukemia and other indications where immunosuppression would be desirable. See ACS Chem. Biol. , 2016, 11 (12), pp 3442-3451 . The present invention relates to a novel p-toluenesulfonic acid salt and crystalline solid form of the said salt of 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one that demonstrate improved properties for use in a pharmaceutical dosage form, particularly for oral dosage forms.

Preparations

Scheme 1. Synthesis of 1

Scheme 2. Alternate Synthesis of Intermediates 7 and 10

1. K2C03, MIBK/water 1. H2, H2O

2. EtOAc, aq. NaCI Pd(OH)2/C (wet)

3. MeOH, H20 2. NaOH, MeOH

7 + 8 –  9 – – 10 . H2O

89% 89%

Scheme 3. First Alternate Preparation of 1

Scheme 4. Second Alternate Preparation of 1

Preparation 1

ferf-Butyl (6-methylpyridin-3-yl)carbamate (3). To a 3000L reactor was charged 2 (72.00 kg, 665.8 mol) and THF (660 kg). A solution of NH4CI (1 .07 kg , 20 mol) in water (72 kg, 4000 mol) was added. The mixture was heated to 57 °C and Di-f-butyl dicarbonate (220.0 kg, 1003 mol) was added slowly with rinse of THF (45 kg) while maintaining the temperature between 55 – 60 °C. The mixture was stirred at 55 – 60 °C for 10 h. Upon reaction completion, the slurry was cooled to 20 °C and ethyl acetate (654 kg) and water (367 kg) were added. The organic phase was separated, washed by water (2 x 360 kg) and stirred with active carbon (22 kg) for 5 h. The mixture was filtered through a layer of diatomaceous earth (22 kg) with THF rinse and the filtrates were concentrated under vacuum at <40 °C to a residual volume of ~370 L. n-Heptane (500 kg) was added slowly over 1 h and the resulting slurry was cooled to 20 °C and stirred for 2 h. The solid was collected by centrifuge with an n-heptane wash (420 kg), then dried at 45 °C under vacuum for 20 h to give 3 (131 .15 kg, 629.7 mol) as a white powder in 94.5% yield. HPLC purity: 99.9%. 1H NMR (400 MHz, DMSO-c/6): d ppm 9.42 (brs, 1 H), 8.48 (d, J = 1 .9 Hz, 1 H), 7.75 (d, J = 8.6 Hz, 1 H), 7.13 (d, J = 8.6 Hz, 1 H), 2.38 (s, 3H), 1 .49 (s, 9H). 13C NMR (100 MHz, DMSO-d6y d ppm 153.34, 151 .56, 139.75, 134.13, 126.10, 123.09, 79.87, 28.56, 23.70. HRMS (ESI) m/z: calculated for C11H17N2O2 [M + H]+ 209.1290; observed 209.1285.

Preparation 2

ferf-Butyl (6-methylpiperidin-3-yl)carbamate (rac-4). To a 3000L reactor was charged 3 (137.0 kg, 667.8 mol), ethanol (988 kg) and acetic acid (139 kg). The reactor was purged with nitrogen three times and 5 wt% Rhodium on carbon (wet, 27.4 kg, 20 wt% loading relative to 3) was added. The reactor was purged with nitrogen three times and then with hydrogen three times. The hydrogen pressure was adjusted to 0.34 – 0.38 MPa and the reactor temperature was adjusted to 47 °C. The mixture was stirred at 45 – 60 °C under hydrogen pressure at 0.34 – 0.38 MPa for 10 h. Upon reaction completion, the reactor was cooled to 20 °C and flushed with nitrogen. The mixture was filtered through a layer of diatomaceous earth (20 kg) with an ethanol rinse (1320 kg) and the filtrates were concentrated under vacuum at <50 °C to a residual volume of ~350 L. n-Heptane (571 kg) was added and the mixture was concentrated under vacuum at <50 °C to a residual volume of~350 L. This operation was repeated twice until the residual acetic acid <8.0%. Ethanol (672 kg) was added and the mixture was concentrated under vacuum at <50 °C to a residual volume of ~350 L. This operation was repeated twice until the residual n-heptane was <0.2% and water was <0.2%. Ethanol (889 kg) was added and the solution (1254 kg) was transferred to drums for use in the subsequent classical resolution step. Achiral HPLC assay indicated that the solution contained 10.8 wt% of the total reduced product (rac-4) in 96% mass recovery and chiral SFC showed that the solution contained 36.3% of the desired stereoisomer cis-4.

Preparation 3

ferf-Butyl ((3R,6S)-6-methylpiperidin-3-yl)carbamate (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid salt (15). To a 2000L reactor (R1 ) was charged rac-4 as a 10.8 wt% solution in ethanol (620.5 kg, ~312.7 mol. of all 4 isomers). The solution was concentrated under vacuum at <45 °C to a residual volume of ~210 L and then cooled to 20 °C. To a 3000 L reactor (R2) was charged (R)-2-(3,5-dinitrobenzamido)-2-phenylacetic acid 14 (47.0 kg, 136.1 mol) and ethanol (1 125 kg). With high speed agitation, reactor R2 was heated to 70 °C, stirred at 68 – 70 °C for ~2 h to dissolve all solid 14, and then seeded with crystalline 15 (1 1 g). The solution containing 4 in reactor R1 was slowly transferred to reactor R2 over 30 min with ethanol rinse (160 kg). Reactor R2 was stirred at ~74 °C for 3 h and then cooled to 22 °C with a linear cooling rate over a period of 5 h and stirred for 16 h. The solid was collected by centrifuge with ethanol wash (2 x 200 kg). The wet cake (with 97.1 % e.e.) was charged back to reactor R2. The slurry was heated to 74 °C and the mixture was stirred for 17 h. The mixture was then cooled to 22 °C with a linear cooling rate over a period of 5 h and stirred for 4 h. The solid was collected by centrifuge with ethanol wash (2 x 200 kg) and dried at 35 °C under vacuum for 25 h to give 15 (56.05 kg, 100.2 mol) as a white powder in 30.7% yield over 2 steps. Chiral HPLC purity: 99.1 %. 1H NMR (400 MHz, DMSO-d6): d ppm 9.46 (d, J = 7.0 Hz, 1 H), 9.07 (d, J = 2.2 Hz, 2H), 8.96 (t, J = 2.2 Hz, 1 H), 7.49 (d, J = 7.3 Hz, 2H), 7.30 (t, J = 7.3 Hz, 2H), 7.23 (t, J = 7.3, 1 H), 7.1 1 (m, 1 H), 5.31 (d, J = 7.0 Hz, 1 H), 3.66 (m, 1 H), 2.98 (m, 3H), 1 .63 (m, 2H), 1 .45 (m, 2H), 1 .40 (s, 9H), 1 .1 1 (d, J = 6.7 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 172.71 , 161 .71 , 155.42, 148.51 , 141 .27, 137.70, 128.29, 128.25, 128.02, 127.05, 121 .12, 78.49, 59.74, 50.66, 46.29, 43.34, 28.66, 26.88, 26.1 1 , 18.60.

Preparation 4

Benzyl (2S,5R)-5-amino-2-methylpiperidine-1 -carboxylate hydrochloride (7»HCI) -telescoped process. To a 2000L reactor was charged 15 (70.0 kg, 125 mol) and MTBE (500 kg). The mixture was cooled to 12 °C and 6.9 wt% aqueous NaOH solution (378 kg, 652 mol) was added slowly while maintaining the temperature between 10 – 25 °C. The mixture was stirred at 18 °C for 1 h . The organic phase was separated and washed with 3.8 wt% aqueous NaOH solution (2 x 221 kg) and then 25 wt% aqueous NaCI solution (2 x 220 kg). The organic layer (containing the free base cis-4) was concentrated under vacuum at <40 °C to a residual volume of ~300 L and then cooled to 20 °C. NaHCOs (53 kg, 632 mol) and water (200 kg) were added and the mixture was cooled to 7 °C. Benzyl chloroformate (32.30 kg, 189.3 mol) was added slowly while maintaining the temperature between 5 – 20 °C. The mixture was stirred at 17 °C for 20 h. Upon reaction completion, the mixture was cooled to 12 °C, 25 wt% aqueous ammonium hydroxide solution (79 kg, 1 160 mol) was added slowly while maintaining the temperature between 10 – 20 °C, and the mixture was stirred at 15 °C for 1 h. The organic phase was separated and washed with 25 wt% aqueous NaCI solution (3 x 90 kg). The organic layer (containing 5) was concentrated under vacuum at <45 °C to a residual volume of ~150 L. Isopropyl acetate (310 kg) was added and the mixture was concentrated under vacuum at <45 °C to a residual volume of ~150 L. This operation was repeated twice to meetthe criteria of water <0.1 % (by KF). Isopropyl acetate (130 kg) was then added and the mixture was cooled to -3 °C. 4-5N HCI in methanol (181 kg, ~730 mol) was added slowly while maintaining the temperature between -5 to 5 °C, and the mixture was stirred at 3 °C for 12 h. Upon reaction completion, the mixture was cooled to -3 °C and MTBE (940 kg) was added slowly while maintaining the temperature between -5 to 5 °C. The resulting slurry was stirred at 3 °C for 3 h. The solid was collected by centrifuge with MTBE washes (4 x 70 kg), and then dried at 45 °C under vacuum for 20 h to give 7»HCI (28.60 kg, 100.4 mol) as a white powder in 80.3% yield. Achiral HPLC purity: 100%. Chiral SFC purity: 99.8% e.e. 1H NMR (400 MHz, DMSO-d6): d ppm 8.36 (brs, 3H), 7.37 (m, 5H), 5.09 (s, 2H), 4.31 (m, 1 H), 4.16 (d, J = 8.2 Hz, 1 H), 3.00 (m, 2H), 1 .82 (m, 2H), 1 .59 (m, 2H), 1 .1 1 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 154.71 , 137.24, 128.92, 128.34, 128.00, 66.89, 47.20, 45.66, 40.68, 28.16, 23.02, 15.67. HRMS (ESI) m/z. calculated for C H N O [M + H]+ 249.1603; observed 249.1598.

Preparation 5

Benzyl (2S, 5R)-5-((2-chloro-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2 -methyl-piperidine-1 -carboxylate (9). To a 2000L reactor was charged 7»HCI (88.6 kg, 31 1 .12 mol), 8 (56.0 kg, 298 mol), K2C03 (133.0 kg, 962.3 mol), water (570 kg) and MIBK (101 kg). The mixture was heated to 90 °C and stirred at this temperature for 22 h. Upon reaction completion, the mixture was cooled to 56 °C and ethyl acetate (531 kg) was added. After cooling the mixture to 22 °C, the organic phase was separated, washed with water (570 kg) and concentrated under vacuum at <40 °C to a residual volume of ~220 L. Methanol (360 kg) was added slowly over a period of 1 h and the mixture concentrated under vacuum at <50 °C to a residual volume of ~220 L. This operation was repeated three times until residual MIBK reached <5 wt%. Methanol (270 kg) was added, followed by seeding with 9 (120 g). The mixture was stirred at 22 °C for >4 h and water (286 kg) was added slowly over 4 h. The slurry was stirred for 10 h and the solid was then collected by centrifuge. The wet cake (165.6 kg) was charged back to a clean reactor and water (896 kg) was added. The slurry was heated to 55 °C and stirred at this temperature for 7 h; and then cooled to 22 °C and stirred at this temperature for 2 h. The solid was collected by centrifuge with water wash (3 x 170 kg) and dried at 55 °C under vacuum for 20 h to give 9 (106.62 kg, 266.6 mol) as a white powder in 89.5% yield. Achiral HPLC purity: 99.7%. 1H NMR (400 MHz, DMSO-d6): d ppm 1 1 .71 (brs, 1 H), 7.72 (d, J = 7.9 Hz, 1 H), 7.38 (m, 5H), 7.10 (s, 1 H), 6.57 (d, J = 2.7 Hz, 1 H), 5.1 1 (m, 2H), 4.39 (m, 1 H), 4.17 (m, 1 H), 4.01 (m, 1 H), 3.36 (s, 2H), 2.77 (m, 1 H), 1 .73-1 .81 (m, 4H), 1 .16 (d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 156.65, 154.74, 153.04, 151 .31 , 137.43, 128.89, 128.27, 127.96, 122.13, 101 .65, 99.51 , 66.75, 49.10, 47.32, 45.64, 42.98, 29.05, 25.08. HRMS (ESI) m/z. calculated for C20H22CIN5O2 [M + H]+ 400.1540; observed 400.1535.

Preparation 6

N-((3R,6S)-6-methylpiperidin-3-yl)-7H-pyrrolo[2,3-dlpyrimidin-4-amine monohydrate (10·H2O) To a 1600L reactor was charged water (570 kg). The reactor was purged with nitrogen three times. 10% Pd(OH)2/C (wet, 3.2 kg) and 9 (53.34 kg, 133.2 mol) were added with water rinses (2 x 55 kg). The reactor was purged with nitrogen three times and then with hydrogen three times. The hydrogen pressure was adjusted to 0.34 – 0.38 MPa and the reactor temperature was adjusted to 77 °C. The mixture was stirred at 75 – 80 °C under a hydrogen pressure of 0.34 -0.38 MPa for 10 h. Upon reaction completion, the reactor was cooled to 20 °C and purged with nitrogen. The mixture was filtered through a layer of diatomaceous earth (8 kg) with a water rinse (460 kg), and the filtrates were transferred to a 3000L reactor. Methanol (260 kg) was added, followed by slow addition of 50 wt% aqueous sodium hydroxide (12.0 kg , 150 mol) while maintaining the temperature between 15 – 25 °C. The slurry was heated to 55 °C and stirred for 2 h; then cooled to 22 °C and stirred for 10 h. The solid was collected by centrifuge with a 10:1 water/methanol wash (3 x 1 10 kg) and then dried at 55 °C under vacuum for 20 h to give 10·H2O (30.90 kg, 266.6 mol) as a white powder in 89.1 % yield. Achiral HPLC purity: 99.7%. Chiral SFC

purity: 99.8% e.e. 1H NMR (400 MHz, DMSO-d6): d ppm 1 1 .48 (brs, 1 H), 8.08 (s, 1 H), 7.07 (s, 1 H), 6.85 (d, J = 7.3 Hz, 1 H), 6.64 (s, 1 H), 4.16 (m, 1 H), 3.35 (brs, 2H), 2.96 (d, J = 12.7 Hz, 1 H), 2.82 (d, J = 12.7 Hz, 1 H), 2.67 (m, 1 H), 2.04 (brs, 1 H), 1 .92 (m, 1 H), 1 .63 (m, 1 H), 1 .44 (m, 1 H), 1 .33 (m, 1 H), 1 .03 (d, J = 6.2 Hz, 3H). 13C NMR (100 MHz, DMSO-d6): d ppm 155.95, 151 .87, 150.74, 121 .20, 102.97, 99.20, 51 .27, 49.94, 44.78, 29.97, 28.69, 22.35. HRMS (ESI) m/z\ calculated for C12H17N5 [M + H]+ 232.1562; observed 232.1558.

Preparation 7

1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one (1 ). To a 100L reactor was charged water (18.0 L), 10·H2q (3.60 kg, 14.4 mol) and THF (36.0 L). The mixture was heated to 53 °C and stirred for 15 min to dissolve all the solids. The solution was then cooled to 18 °C and K3PO4 (6.38 kg, 30.1 mol) was added. The mixture was stirred at 18 °C for 10 min to dissolve all the solids, and then cooled to 10 °C. 3-Chloropropionyl chloride (2.20 kg, 17.3 mol) was added while maintaining the temperature <20 °C. The mixture was then stirred at 20 °C for 2 h. Upon reaction completion, 2 N aqueous NaOH solution (23.50 kg, 43.76 mol) was added while maintaining the temperature <25 °C. The mixture was stirred at 22 °C for >12 h until the elimination reaction was complete (11 <0.2%). KH2PO4 (10.32 kg, 75.8 mol) was added and the mixture was stirred at 20 °C for 10 min. The organic phase was separated and then washed with 23.5 wt% aqueous NaCI solution (2 x 8.5 kg). The isolated organic phase was concentrated under vacuum at <30 °C to a residual volume of ~10 L, whereupon MEK (39.6 L) was added. This operation was repeated once or twice until residual THF was <1 % and water was <2%. MgS04 (0.96 kg), Silica gel (4.90 kg) and Darco™ G-60 (0.48 kg) were added to the MEK solution, and the mixture was stirred at 20 °C for 1 h, then filtered through a layer of Diatomaceous Earth with a MEK rinse (76 L). The combined filtrates were concentrated under vacuum at <30 °C to a residual volume of ~8 L. The concentration of the residual solution was measured by qNMR, and the solution was transferred to a container with a rinse using the calculated amount of MEK to adjust the final concentration to 30 wt%. Thus, a 30 wt% solution of 1 in MEK (1 1 .09 kg, 1 1 .66 mol of 1) with 98.7% purity was obtained in 81 % yield, which was stored in a cold room (2 – 8 °C) for the next step.

Preparation 8

1 -((2S,5R)-5-((7H-pyrrolo[2,3-cdpyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one p-toluenesulfonate (1»TsOH). To a 20L reactor was charged a 30 wt% solution of 1 in MEK (9.80 kg, 10.30 mol of 1) and silica gel (0.74 kg). The mixture was stirred at 22 °C for 15 min and filtered through a 0.45 micron Teflon cartridge filter with a MEK rinse (7.89 kg, 9.8 L), collecting in a 100L reactor. Water (1 .27 L) was added, followed by a solution of p-toluenesulfonic acid monohydrate (2.18 kg, 1 1 .3 mol) in MEK (4.75 kg, 5.9 L) with a MEK rinse (3.14 kg, 3.9 L), followed by the addition of 1 »TsOH seed (188 g, 0.41 mol). The mixture was stirred at 22 °C for

4 h to form a slurry and MEK (31 .56 kg, 39.2 L) was added slowly over a period of 3 h. The slurry was stirred at 22 °C for an additional 2 h and then filtered. The cake was washed with MEK (4.02 kg, 5 L) and then dried at 50 °C under vacuum for 10 h to give 1 »TsOH (4.41 kg, 9.64 mol) as a white powder in 89.6% yield (accounting for the amount of seed charged). Achiral HPLC purity: 99.6% with 0.22% of dimer 15. Chiral SFC purity: >99.7%. m.p. 199 °C. Rotomers observed for NMR spectroscopies. Ή NMR (400 MHz, DMSO-d6): d ppm 12.68 (brs, 1 H), 9.22 (brs, 1 H), 8.40 (s, 1 H), 7.50 (d, J = 8.2 Hz, 2H), 7.45 (m, 1 H), 7.12 (d, J = 8.2 Hz, 2H), 6.94 (d, J = 1 .2 Hz, 1 H), 6.84 (m, 1 H), 6.13 (m, 1 H), 5.70 (m, 1 H), 4.81 (m, 0.5H), 4.54 (m, 0.5H), 4.41 (m, 0.5H), 4.12 (m, 0.5H), 3.99 (m, 1 H), 3.15 (m, 0.5H), 2.82 (m, 0.5H), 2.29 (s, 3H), 1 .91 -1 .72 (m, 4H), 1 .24-1 .17 (m, 3H). 13C NMR (100 MHz, DMSO-c/6): d ppm 165.52, 165.13, 150.50, 145.64, 143.06, 138.48, 129.51 , 129.24, 128.67, 127.99, 127.73, 125.97, 125.02, 102.30, 49.53, 48.92, 47.27, 43.83, 42.96, 29.37, 28.41 , 25.22, 21 .28, 16.97, 15.51 . HRMS (ESI) m/z: calculated for Ci5H2oN50 [M + H]+ 286.1668; observed 286.1692.

Comparative Example

Preparation of 1 -((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methyl-piperidin-1 -yl)prop-2-en-1 -one Malonic Acid Salt (Form 1 )

A 250 ml_ round bottom flask was charged with 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one (4.10 g, 14.4 mmol), MEK (Methyl Ethyl Ketone (15.0 ml_/g, 687 mmol, 49.5 g, 61 .5 ml_)). To the solution, malonic acid (0.950 equiv. 13.7 mmol, 1 .42 g) was added in one portion. The mixture was heated to 50 °C and stirred at 50 °C for 15min. The heating was turned off and the slurry was stirred for 16 hours. The resulting white slurry was filtered. The filter cake was washed with MEK (2 X 5 ml_) and dried in a vacuum oven (40 °C) for 2 hours give 1 -((2S,5R)-5-((7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1 -yl)prop-2-en-1 -one malonic acid salt (Form 1) (4.48 g, 1 1 .5 mmol, 4.48 g, 80.1 % Yield) as white powder.

REFERENCES

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2: Robinette ML, Cella M, Telliez JB, Ulland TK, Barrow AD, Capuder K, Gilfillan S, Lin LL, Notarangelo LD, Colonna M. Jak3 deficiency blocks innate lymphoid cell development. Mucosal Immunol. 2018 Jan;11(1):50-60. doi: 10.1038/mi.2017.38. Epub 2017 May 17. PubMed PMID: 28513593; PubMed Central PMCID: PMC5693788.

3: Thorarensen A, Dowty ME, Banker ME, Juba B, Jussif J, Lin T, Vincent F, Czerwinski RM, Casimiro-Garcia A, Unwalla R, Trujillo JI, Liang S, Balbo P, Che Y, Gilbert AM, Brown MF, Hayward M, Montgomery J, Leung L, Yang X, Soucy S, Hegen M, Coe J, Langille J, Vajdos F, Chrencik J, Telliez JB. Design of a Janus Kinase 3 (JAK3) Specific Inhibitor 1-((2S,5R)-5-((7H-Pyrrolo[2,3-d]pyrimidin-4-yl)amino)-2-methylpiperidin-1-yl)prop -2-en-1-one (PF-06651600) Allowing for the Interrogation of JAK3 Signaling in Humans. J Med Chem. 2017 Mar 9;60(5):1971-1993. doi: 10.1021/acs.jmedchem.6b01694. Epub 2017 Feb 16. PubMed PMID: 28139931.

4: Telliez JB, Dowty ME, Wang L, Jussif J, Lin T, Li L, Moy E, Balbo P, Li W, Zhao Y, Crouse K, Dickinson C, Symanowicz P, Hegen M, Banker ME, Vincent F, Unwalla R, Liang S, Gilbert AM, Brown MF, Hayward M, Montgomery J, Yang X, Bauman J, Trujillo JI, Casimiro-Garcia A, Vajdos FF, Leung L, Geoghegan KF, Quazi A, Xuan D, Jones L, Hett E, Wright K, Clark JD, Thorarensen A. Discovery of a JAK3-Selective Inhibitor: Functional Differentiation of JAK3-Selective Inhibition over pan-JAK or JAK1-Selective Inhibition. ACS Chem Biol. 2016 Dec 16;11(12):3442-3451. Epub 2016 Nov 10. PubMed PMID: 27791347.

5: Walker G, Croasdell G. The European League Against Rheumatism (EULAR) – 17th Annual European Congress of Rheumatology (June 8-11, 2016 – London, UK). Drugs Today (Barc). 2016 Jun;52(6):355-60. doi: 10.1358/dot.2016.52.6.2516435. PubMed PMID: 27458612.

////////////PF-06651600, PF 06651600, PF06651600, Breakthrough Therapy designation, PHASE 2,   alopecia areata, rheumatoid arthritis, Crohn’s disease,  ulcerative colitis, Ritlectinib

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