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Tofacitinib Synthesis Essay


We have surprisingly found that tofacitinib and the pharmaceutically acceptable salts thereof, in particular tofacitinib monocitrate, can be obtained with high purity and high yields by an efficient, innovative process by using intermediates not resolved up to the level of intermediate V. On the basis of the literature cited above, it was not foreseeable that excellent purity, an excellent enantiomeric excess, and simultaneously crystalline intermediates could be obtained with high yields, thus eliminating the need for chromatography.

Said process also presents numerous advantages, including a limited number of synthesis steps, isolation of products not requiring purification by silica-gel column chromatography, a high global molar yield and the use of raw materials and reagents which are readily commercially available and inexpensive.

The process according to the invention (Scheme 4) can be summarised as follows:

1. Condensation between intermediates VII and VIII to give intermediate VI

2. Hydrogenation of intermediate VI to give intermediate V

3. Resolution of intermediate V with 2,3-dibenzoyl-D-tartaric acid or 2,3-di-(p-toluoyl)-D-tartaric acid to give intermediate IV, wherein R is hydrogen or methyl, with enantiomeric purity exceeding 99%

4. Treatment of intermediate IV with bases to give intermediate III

5. N-acylation reaction of intermediate III to give intermediate II (tofacitinib)

6. Optional salification of intermediate II to give tofacitinib monocitrate (I)


Both starting substrates of the synthesis process claimed, namely 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (VII) and (3,4)-N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine bis-hydrochloride (VIII), are commercially available.

Step 1: Condensation of 4-chloro-7H-pyrrolo[2,3-d]pyrimidine(VII) and N,4-dimethyl-1-(phenylmethyl)-3-piperidinamine bis-hydrochloride(VIII)

The condensation reaction is carried out in polar solvent in the presence of a hydrogen acceptor. The condensation is effected at reflux temperature.

The reaction can be conducted using dioxane, n-butanol, water or isopropanol as solvent, preferably water.

The hydrogen acceptor can be selected from organic or inorganic bases, preferably inorganic. Of the inorganic bases, sodium carbonate or potassium carbonate is preferably used.

The reaction is carried out with a stoichiometric ratio of intermediate VII to intermediate VIII ranging between 1 and 2, preferably between 1.1 and 1.5, more preferably between 1.1 and 1.2.

The reaction time is between 36 and 72 hours, preferably between 48 and 60 hours.

To isolate intermediate VI, the reaction mixture is left to cool to below boiling point, a precipitate being obtained after suitable addition of a co-solvent such as acetone, methanol or isopropanol, preferably methanol.

The crude product obtained can be recrystallised from a suitable alcohol- or water/alcohol-based solvent such as methanol, ethanol or isopropanol, preferably isopropanol and ethanol, and even more preferably a mixture consisting of ethanol and water.

Step 2: Hydrogenation of Intermediate VI

V is prepared by metal-catalysed hydrogenation in an acid medium, wherein various operating conditions known from the literature can be used.

Pd/C, Pt/C, Pd(OH)2/C or other similar catalysts can be used.

The reaction can be conducted using methanol, ethanol, water or isopropanol as solvent, preferably isopropanol and water.

The product is isolated by extraction with organic solvent after removing the catalyst and restoring the pH to alkaline conditions with a suitable base.

Step 3: Resolution of Intermediate V to give Intermediate IV Having an Enantiomeric purity >99%

Intermediate V can form a wide variety of salts with numerous organic and inorganic acids.

Intermediate IV is prepared with enantiomeric purity exceeding 99% by treatment with a suitable resolving agent, in particular one belonging to the series of benzoyl-functionalised acids of D-tartaric acid, such as 2,3-di-p-toluoyl D-tartaric acid and 2,3-dibenzoyl D-tartaric acid.

The use of functionalised derivatives of tartaric acid belonging to series D promotes the selective precipitation of intermediate IV with the 3R,4R configuration, which is a further object of the invention.

The use of functionalised derivatives of tartaric acid belonging to series L promotes the selective precipitation of intermediate IV with the 3S,4S configuration, which also represents a further object of the invention.

The resolving agent can be anhydrous, hydrated, solvated or co-solvated.

The resolving agent can be used in a stoichiometric ratio ranging between 1 and 5 molar equivalents per molar equivalent of V, preferably in a stoichiometric ratio ranging between 1 and 2 molar equivalents per molar equivalent of V, more preferably in a stoichiometric ratio ranging between 1 and 1.2 molar equivalents per molar equivalent of V.

The amount of solvent to be used ranges between 5 and 20 volumetric equivalents compared with the amount of V, preferably between 8 and 15 volumetric equivalents compared with the amount of V.

Product IV deriving from the resolution process possesses enantiomeric purity exceeding 99%.

Intermediate IV, wherein R═H and which has the 3R,4R configuration, exists in a crystalline form obtainable by crystallisation from methanol and having an IR spectrum, DSC pattern and XRPD diffractogram as shown in FIGS. 2, 3 and 4 respectively.

In particular, said crystalline form of intermediate IV presents:

an IR spectrum comprising absorption peaks at 1723, 1564, 1492, 1414, 1348, 1259, 1177, 1097, 903 and 716±1.5 cm−1;

a DSC pattern comprising an endothermic peak at 156.7° C.;

an XRPD diffractogram comprising peaks with the following 2θ angle values and intensities: 7.18 (100); 9.03 (96.4); 9.45 (62.5); 12.35 (61); 15.44 (70.1); 16.57 (58.5); 18.09 (72.6); 20.91 (56.7).

Intermediate IV also exists in an amorphous form, obtainable by dissolving intermediate IV in MeOH at reflux followed by evaporation of the methanol solution until dry. Intermediate IV is obtained in amorphous form having an IR spectrum, DSC pattern and XRPD diffractogram as shown in FIGS. 6, 7 and 8 respectively.

In particular, the amorphous form of intermediate IV presents an IR spectrum having absorption peaks at 2930, 1585, 1557, 1509, 1370, 1224, 1054, 1010, 921, 838 and 650±1.5 cm−1.

Said forms of intermediate IV represent a further object of the invention.

Step 4: Treatment of IV with Bases

IV is treated with a sodium hydroxide solution of the solution of IV dissolved in organic solvent to give III.

Sodium hydroxide can be used in a concentration ranging between 0.1M and 2M, preferably between 0.3M and 1M, and more preferably between 0.4M and 0.6M.

Intermediate III is isolated by precipitation by adding an anti-solvent after concentrating the phase consisting of the organic solvent to a small volume.

Intermediate III exists in a crystalline form obtainable by crystallisation from cyclohexane having an IR spectrum, DSC pattern and XRPD diffractogram as shown in FIGS. 9, 10 and 11 respectively, which represents a further object of the invention.

In particular, said crystalline form of intermediate III presents:

an IR spectrum comprising characteristic absorption peaks at 3100, 2853, 1568, 1487, 1416, 1343, 1313, 1252, 1126, 1054, 924, 821, 730 and 608±1.5 cm−1;

a DSC pattern comprising an endothermic peak at 159.5° C.;

an XRPD diffractogram comprising peaks with the following 2θ angle values and intensities: 4.73 (100); 9.49 (25.9); 10.73 (6.9); 15.66 (18.4); 16.94 (40.5); 18.95 (28.9); 21.64 (23.7).

Step 5: N-acylation of III and Consecutive Salification of II

The piperidine nitrogen of the compound of formula III can be derivatised with an acylating agent such as cyanoacetic acid or derivatives thereof.

The N-acylation reaction takes place in the presence of an organic base such as triethylamine, DBU or DIPEA.

The reaction is conducted in polar protic solvent to give the compound of formula II (tofacitinib) in a time ranging between 18 and 72 hours, preferably between 24 and 48 hours.

Compound II can be converted to a pharmaceutically acceptable salt by adding an organic acid such as citric acid to the reaction mixture.

The invention will now be further illustrated by the following examples.


The IR spectra were recorded with a Perkin Elmer spectrum 1000 IR instrument. The sample is prepared as a KBr pellet. The spectrum is recorded by performing 16 scans at a resolution of 4 cm−1.

The DSC patterns were recorded with a Perkin Elmer Pyris 1 instrument, and 3-5 mg of material were used to prepare the samples. The scans are conducted at the speed of 10° C. a minute.

The NMR spectra were recorded with a Varian Mercury 300 instrument in DMSO at 25° C., 16 scans being performed.

The XRPD spectra were recorded with a Bruker D2 instrument which uses the following parameters: Wavelength CuKα (λ=15419 A)—Energy 30 KV—Step size: 0.02°-2θ Range: 2.6°-40°.

Example 1

81.4 g of VII and 42.92 g of VIII are added to a 21% aqueous solution by weight of K2CO3.

The mixture is maintained at reflux for 48 h, and 270 ml of methanol is then loaded. The mixture is cooled to room temperature. The mixture is filtered through a Büchner funnel. Intermediate VI (87.5 g) is dissolved at reflux in 2.2 lt of isopropanol, decolourised with activated carbon and recovered after cooling and filtration following partial removal of the solvent by evaporation under vacuum.

Example 2

101 ml of glacial acetic acid is added to a 4:1 mixture of isopropanol/water (925 ml). 185.2 g of intermediate VI is loaded, and the mixture is heated to 50° C. 18.5 g of 5% Pd/C is then loaded, and a hydrogen atmosphere is applied. The mixture is maintained under stirring for 24 h at 50° C. The mixture is filtered through a Büchner funnel. The pH is corrected to a value of 10-12 with 241 g of 30% NaOH solution, and the mixture is then concentrated at low pressure to a residual volume of 420 ml. The mixture is extracted with 500 ml of n-butanol.

The organic phase is concentrated at low pressure to a small volume, and product V is isolated by precipitation with cyclohexane.

Example b 3

Intermediate V (126.7 g) is dissolved in 760 ml of methanol. A solution of 2,3-dibenzoyl-D-tartaric acid monohydrate in methanol (187.5 g in 760 ml) is added by dripping. 20 minutes after the end of pouring, the mixture is seeded with a small amount of compound IV, wherein R is hydrogen.

The mixture is maintained under stirring for 2 h at room temperature, then for 2 h at 10° C. and 1 h at room temperature. The mixture is filtered through a Büchner funnel to obtain 139.9 g of IV, wherein R is hydrogen, with enantiomeric purity exceeding 99%. The product presents an IR spectrum, DSC pattern, XRPD diffractogram and 1H-NMR spectrum as shown in FIGS. 2-5 respectively.

The amorphous form of IV, wherein R is hydrogen, is obtained by dissolving intermediate IV in methanol at reflux and then concentrating the resulting solution to residue; said form presents an IR spectrum, DSC pattern and XRPD diffractogram as shown in FIGS. 6-8 respectively.

Example 4

Intermediate IV, wherein R is hydrogen (128 g), is suspended in n-butanol to which an 0.3N solution of NaOH is added by dripping. The mixture is maintained under stirring for 3 h, after which the phases are separated and the organic phase is washed with 300 ml of water.

The organic phase is concentrated at low pressure to a small volume. Product III (45 g) is obtained by precipitation from cyclohexane. The product presents an IR spectrum, DSC pattern, XRPD diffractogram and 1H-NMR spectrum as shown in FIGS. 9-12 respectively.

Example 5

Intermediate III (44.0 g) is dissolved in n-butanol (132 ml), after which ethyl cyanoacetate (36.8 ml) and DBU (12.9 ml) are added.

The solution is heated to T=50° C. and left under stirring for 24 h.

Citric acid monohydrate (72.7 g), water (66 ml) and n-butanol (176 ml) are added; the mixture is then heated to T =80° C. and maintained under stirring for 1 h, and then under stirring at room temperature for 1 h.

The mixture is further cooled to T=5° C. and maintained under stirring at that temperature for 2 h. The mixture is filtered through a Büchner funnel and finally washed with n-butanol (2×88 mL) and water (44 ml), to give tofacitinib citrate.

This article needs to be updated. Please update this article to reflect recent events or newly available information.(February 2017)

Clinical data
Trade namesXeljanz, Jakvinus
License data
  • US:C (Risk not ruled out)
Routes of
By mouth (tablets)
ATC code
Legal status
Legal status
Pharmacokinetic data
Protein binding40%
MetabolismHepatic (via CYP3A4 and CYP2C19)
Biological half-life3 hours

IUPAC name

  • 3-[(3R,4R)-4-Methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
CAS Number
ECHA InfoCard100.215.928
Chemical and physical data
Molar mass312.369 g/mol
3D model (JSmol)


  • CC2CCN(C(=O)CC#N)CC2N(C)c3ncnc1nccc13


  • InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1


  • InChI=1S/C16H20N6O/c1-11-5-8-22(14(23)3-6-17)9-13(11)21(2)16-12-4-7-18-15(12)19-10-20-16/h4,7,10-11,13H,3,5,8-9H2,1-2H3,(H,18,19,20)/t11-,13+/m1/s1


Tofacitinib (INN) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by the National Institutes of Health and Pfizer. Tofacitinib citrate is marketed as Xeljanz and Jakvinus.

It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States and other countries.

It has demonstrated effectiveness in the treatment of psoriasis in Phase 3 studies. It is being studied for treatment of inflammatory bowel disease,[1][2] and other immunological diseases, as well as for the prevention of organ transplant rejection.[3][4][5][6]

Approvals and indications[edit]

Rheumatoid arthritis[edit]

In November 2012, the U.S. FDA approved tofacitinib citrate "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate."[7] It was later approved in Japan, Switzerland and others (but not the EU). It is marketed as Xeljanz in all regions except for Russia where it will be marketed as Jakvinus or Jaquinus.[8]


It is an inhibitor of the enzyme janus kinase 1 (JAK1) and janus kinase 3 (JAK 3), which means that it interferes with the JAK-STAT signaling pathway, which transmits extracellular information into the cell nucleus, influencing DNA transcription.[9]

In a mouse model of established arthritis, tofacitinib rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. This efficacy in this disease model correlated with the inhibition of both JAK1 and 3 signaling pathways, suggesting that tofacitinib may exert therapeutic benefit via pathways that are not exclusive to inhibition of JAK3.[10]

Research history[edit]

The potential significance of JAK3 inhibition was first discovered in the laboratory of John O'Shea, an immunologist at the National Institute of Arthritis and Musculoskeletal and Skin Diseases of the National Institutes of Health (NIH).[11] In 1994, Pfizer was approached by the NIH to form a public-private partnership in order to evaluate and bring to market experimental compounds based on this research.[11] Pfizer initially declined the partnership but agreed in 1996, after the elimination of an NIH policy dictating that the market price of a product resulting from such a partnership would need to be commensurate with the investment of public taxpayer revenue and the "health and safety needs of the public."[11] Pfizer worked with O'Shea's laboratory to define the structure and function of JAK3 and its receptors, and then handled the drug discovery, preclinical development, and clinical development of tofacitinib in-house.[12]

The drug was coded as CP-690,550[13] during development. Its original recommended INN (rINN) was tasocitinib,[14] but that was overruled during the INN approval process as being inoptimally differentiable from other existing INNs, so the name tofacitinib was proposed and became the INN.

In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Two rheumatologists interviewed by the magazine Nature Biotechnology complained that they were "shocked" and "disappointed" at the $2,055 a month wholesale price.[12]

A 2014 study showed that tofacitinib treatment was able to convert white fat tissues into more metabolically active brown fat, suggesting it may have potential applications in the treatment of obesity.[15]

Clinical trials[edit]

Rheumatoid arthritis[edit]

Phase II clinical trials tested the drug in rheumatoid arthritis patients that had not responded to DMARD therapy. In a tofacitinib monotherapy study, the ACR score improved by at least 20% (ACR-20) in 67% of patients versus 25% who received placebo; and a study that combined the drug with methotrexate achieved ACR-20 in 59% of patients versus 35% who received methotrexate alone.

The most important side effects in Phase II studies were increased blood cholesterol levels (12 to 25 mg/dl LDL and 8 to 10 mg/dl HDL at medium dosage levels) and neutropenia.[16] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.[17]

In April 2011, four patients died after beginning clinical trials with tofacitinib. According to Pfizer, only one of the four deaths was related to tofacitinib.[18]

By April 2011, three phase III trials for RA had reported positive results.[19]

In November 2012, the U.S. FDA approved tofacitinib "to treat adults with moderately to severely active rheumatoid arthritis who have had an inadequate response to, or who are intolerant of, methotrexate."[7] FDA approved only the 5 mg twice-daily dose on the grounds that a higher dose was not considered to have an adequate risk-to-benefit ratio.[20]


Tofacitinib is a current investigational drug in psoriasis. Tofacitinib has demonstrated its effectiveness for plaque psoriasis in Phase 3 randomized, controlled trials in comparison to placebo and to etanercept.[20][21][22] In particular, a 10 mg twice-daily dose of tofacitinib was shown to be noninferior to etanercept 50 mg subcutaneously twice weekly.[22]

Ulcerative colitis[edit]

The phase 3 OCTAVE study of Tofacitinib in ulcerative colitis started in 2012 and completed in 2015.[23]

Alopecia areata[edit]

Based on preclinical studies in a mouse model of the disease,[24] tofacitinib has been investigated for the treatment of alopecia areata. Early case reports[25][26] suggested potential efficacy, as did a phase II open-label clinical trial,[27] published in tandem with a phase II clinical trial showing the same for ruxolitinib.[28]


In a June 2015 case report, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[29]

Atopic dermatitis[edit]

The results of using Tofacitinib in 6 patients with recalcitrant atopic dermatitis was published in the September 2015. All saw improvement in their atopic dermatitis without any adverse events.[30]

Ankylosing spondylitis[edit]

As of 2016[update] it is undergoing a phase II trial for ankylosing spondylitis.[31]

Safety and side effects[edit]

Tofacitinib was not approved by European regulatory agencies because of concerns over efficacy and safety.[32] Animal studies with tofacitinib conducted prior to human trials showed some carcinogenesis, mutagenesis, and impairment of fertility.[33]

Warnings and precautions[edit]

Tofacitinib is required by US FDA to have a boxed warning on its label about possible injury and death due to problems such as infections, Lymphoma and other malignancies which can arise from use of this drug.[7] Serious infections leading to hospitalization or death, including tuberculosis and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving tofacitinib. Epstein Barr Virus-associated post-transplantlymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with tofacitinib while on immunosuppressive medications. Patients are warned to avoid use of tofacitinib citrate during an "active serious infection, including localized infections." Doctors are advised to use it with caution in patients that may be at increased risk of gastrointestinal perforations. Laboratory Monitoring is recommended due to potential changes in lymphocytes, neutrophils, hemoglobin, liver enzymes and lipids. Tofacitinib claims to have no contraindications, however doctors are advised to reduce the patient's dosage when combined with "potent inhibitors of Cytochrome P450 3A4 (CYP3A4)," such as ketoconazole), or one or more combined medications that result in both moderate inhibition of CYP3A4 and potent inhibition of CYP2C19 such as fluconazole. Furthermore, immunizations with live vaccines should be avoided by tofacitinib users.[33]

Adverse reactions[edit]

The most commonly reported adverse reactions during the first three months in controlled clinical trials (occurring in greater than or equal to 2% of patients treated with tofacitinib citrate monotherapy or in combination with DMARDs) were upper respiratory tract infections, headache, diarrhea, and nasopharyngitis (the "common cold").[33]


  1. ^Vuitton, Lucine; Koch, Stéphane; Peyrin-Biroulet, Laurent (31 October 2013). "Janus Kinase Inhibition with Tofacitinib: Changing the Face of Inflammatory Bowel Disease Treatment". Current Drug Targets. 14 (12): 1385–1391. doi:10.2174/13894501113149990160. PMID 23627915. 
  2. ^Zand, Martin S. (July 2013). "Tofacitinab in Renal Transplantation". Transplantation Reviews. 27 (3): 85–89. doi:10.1016/j.trre.2013.04.001. PMC 3713609. PMID 23849222. 
  3. ^Allan D. Kirk; Stuart J. Knechtle; Christian P. Larsen; Joren C. Madsen; Thomas C. Pearson; Steven A. Webber (21 July 2014). Textbook of Organ Transplantation Set. John Wiley & Sons. pp. 245–. ISBN 978-1-118-88962-6. 
  4. ^Wojciechowski, D; Vincenti, F (September 2013). "Tofacitinib in kidney transplantation". Expert Opinion on Investigational Drugs. 22 (9): 1193–9. doi:10.1517/13543784.2013.811231. PMID 23841583. 
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  6. ^Kalluri, Hari Varun (2012). "Current state of renal transplant immunosuppression: Present and future". World Journal of Transplantation. 2 (4): 51–68. doi:10.5500/WJT.v2.i4.51. PMC 3782235. PMID 24175197. 
  7. ^ abc"FDA approves Xeljanz for rheumatoid arthritis". 6 Nov 2012. [dead link]
  8. ^Pfizer Provides Update on Global Regulatory Approvals and Launches of XELJANZ® (tofacitinib citrate) for the Treatment of Rheumatoid Arthritis. July 2013
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  11. ^ abc"Seeking Profit for Taxpayers in Potential of New Drug", Jonathan Weisman, New York Times, 18 March 2013 (subscription firewall)
  12. ^ abKen Garber (9 January 2013). "Pfizer's first-in-class JAK inhibitor pricey for rheumatoid arthritis market". Nature Biotechnology. 31 (1): 3–4. doi:10.1038/nbt0113-3. PMID 23302910. 
  13. ^Kremer, J. M.; Bloom, B. J.; Breedveld, F. C.; Coombs, J. H.; Fletcher, M. P.; Gruben, D.; Krishnaswami, S.; Burgos-Vargas, R. N.; Wilkinson, B.; Zerbini, C. A. F.; Zwillich, S. H. (2009). "The safety and efficacy of a JAK inhibitor in patients with active rheumatoid arthritis: Results of a double-blind, placebo-controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo". Arthritis & Rheumatism. 60 (7): 1895–1905. doi:10.1002/art.24567. PMID 19565475. 
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  15. ^Moisan A, et al. White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nature Cell Biology, 8 December 2014. doi:10.1038/ncb3075
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  17. ^Clinical trial number NCT00413699 for "Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis" at
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  19. ^"Two Phase III Studies Confirm Benefits of Pfizer's Tofacitinib Against Active RA". 28 Apr 2011. 
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  22. ^ abBachelez H, van de Kerkhof PC, Strohal R, et al. for the OPT Compare Investigators. (Aug 8, 2015). "Tofacitinib versus etanercept or placebo in moderate-to-severe chronic plaque psoriasis: a phase 3 randomised non-inferiority trial". Lancet. 386 (9993): 552–61. doi:10.1016/S0140-6736(14)62113-9. PMID 26051365. 
  23. ^A Multicentre, Randomized, Double-blind, Placebo-controlled, Parallel-group Study Of Oral Cp-690,550 As An Induction Therapy In Subjects With Moderate To Severe Ulcerative Colitis
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  26. ^Jabbari, Ali; Nguyen, Nhan; Cerise, Jane E.; Ulerio, Grace; de Jong, Annemieke; Clynes, Raphael; Christiano, Angela M.; Mackay-Wiggan, Julian (2016-08-01). "Treatment of an alopecia areata patient with tofacitinib results in regrowth of hair and changes in serum and skin biomarkers". Experimental Dermatology. 25 (8): 642–643. doi:10.1111/exd.13060. ISSN 1600-0625. PMC 4963264. PMID 27119625. 
  27. ^Kennedy Crispin, Milène; Ko, Justin M.; Craiglow, Brittany G.; Li, Shufeng; Shankar, Gautam; Urban, Jennifer R.; Chen, James C.; Cerise, Jane E.; Jabbari, Ali (2016-09-22). "Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata". JCI insight. 1 (15): e89776. doi:10.1172/jci.insight.89776. PMC 5033755. PMID 27699252. 
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  29. ^"Tofacitinib Citrate for the Treatment of Vitiligo: A Pathogenesis-Directed Therapy". JAMA Dermatol. 151: 1110–2. Oct 2015. doi:10.1001/jamadermatol.2015.1520. PMID 26107994. 
  30. ^Levy LL, Urban J, King BA (2015). "Treatment of recalcitrant atopic dermatitis with the oral Janus kinase inhibitor tofacitinib citrate". Journal of the American Academy of Dermatology. 73 (3): 395–399. doi:10.1016/j.jaad.2015.06.045. PMID 26194706. 
  31. ^AS: Is Tofacitinib the Next Big Thing? Nov 2016
  32. ^Nordqvist, Christian (27 April 2013). "Pfizer's Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe". Medical News Today. Retrieved 2 August 2013.