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ORGANIC SPECTROSCOPY

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DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO Ph.D

DR ANTHONY MELVIN CRASTO, Born in Mumbai in 1964 and graduated from Mumbai University, Completed his Ph.D from ICT, 1991,Matunga, Mumbai, India, in Organic Chemistry, The thesis topic was Synthesis of Novel Pyrethroid Analogues, Currently he is working with GLENMARK 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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Icosapent ethyl, イコサペント酸エチル


DB08887.png

Ethyl eicosapentaenoate.png

Icosapent ethyl

330.5042 , C22H34O2

cas 86227-47-6 / 73310-10-8

ethyl (5Z,8Z,11Z,14Z,17Z)-icosa-5,8,11,14,17-pentaenoate

Ethyl eicosapentaenoic acid

イコサペント酸エチル

(5Z,8Z,11Z,14Z,17Z)-Eicosapetaenoic acid ethyl ester
(all-Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester
5,8,11,14,17-Eicosapentaenoic acid, ethyl ester, (5Z,8Z,11Z,14Z,17Z)- [ACD/Index Name]
5,8,11,14,17-Eicosapentaenoic acid, ethyl ester, (all-Z)-
6GC8A4PAYH
86227-47-6 [RN]
all-cis-5,8,11,14,17-Eicosapentaenoic Acid Ethyl Ester
Timnodonic acid ethyl ester
Vascepa
  • 5,8,11,14,17-Eicosapentaenoic acid, ethyl ester, (all-Z)-
  • (5Z,8Z,11Z,14Z,17Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester
  • (all-Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester
  • AMR 101
  • C20:5 n-3 Ethyl ester
  • Epadel
  • Epadel S 300
  • Ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate
  • Ethyl all-Z-5,8,11,14,17-eicosapentanenoate
  • Ethyl all-cis-5,8,11,14,17-eicosapentaenoate
  • Ethyl eicosapentaenoate
  • Ethyl icosapentate
  • Icosapent ethyl
  • Incromega EPA
  • Timnodonic acid ethyl ester
  • Vascepa
  • cis-Eicosapentaenoic acid ethyl ester

(all-Z)-5,8,11,14,17-Eicosapentaenoic acid ethyl ester; Ethyl all-cis-5,8,11,14,17-eicosapentaenoate;Timnodonic acid ethyl ester; cis-Eicosapentaenoic acid ethyl ester; Ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate; Epadel; Icosapent; EPA ethyl ester; E-EPA; Ethyl eicosapentaenoate; OMEGA-3 ACIDS ETHYL ESTER; EPA-E;

AMARIN PHARMACEUTICALS IRELAND LTD

AMR 101 / AMR-101 / AMR101

Icosapent ethyl or ethyl eicosapentaenoic acid is a synthetic derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA). It is used as adjunct therapy for severe hypertriglyceridemia (TG levels > 500 mg/dL). FDA approved on July 26, 2012.

In 2000, Amarin licensed exclusive U.S. rights to icosapent ethyl ester from the Scottish company Laxdale, and acquired the company in July 2004. In 2015, the product was licensed to Eddingpharm by Amarin for the development and commercialization in China, Hong Kong and Taiwan. Fast-track status has been granted in the U.S. for the treatment of HD. Orphan drug designation was assigned to the compound for this indication in both the U.S. and E.U.

fda

IND 107616 was submitted on 25 March 2010 for the indication of severe hypertriglyceridemia; Epanova had been previously investigated for the treatment of Crohn’s Disease under IND in the Division of Gastroenterology Products. An end-of-phase 2 (EOP2) meeting was held on 02 June 2010. Regarding the indication under consideration at this time, a special protocol assessment (SPA) for the single phase 3 trial OM-EPA-003 (also known as “EVOLVE”) was submitted 02 July 2010 and ultimately agreed upon, after amendments, on 22 October 2010. On 25 April 2012, the applicant proposed an alternative to conducting a thorough QTc study by assessing ECGs recorded during OM-EPA-003; this was found acceptable. A clinical pre-NDA meeting was held on 14 November 2012. The nonclinical development strategy was found reasonable. A clinical package containing OM-EPA-003 (pivotal) and OMEPA-004 (a 6-week phase 3 trial , with long-term safety supported by data from the former Crohn’s disease program (“EPIC” trials), was found adequate for submission. Agreement was reached regarding the clinical pharmacology portion of the submission. Details regarding data pooling for the Integrated Summary of Safety (ISS) were found acceptable

from the former Crohn’s disease program (“EPIC” trials), was found adequate for submission. Agreement was reached regarding the clinical pharmacology portion of the submission. Details regarding data pooling for the Integrated Summary of Safety (ISS) were found acceptable

CMC Drug Substance & Drug Product Chemistry, manufacturing, and controls data related to both the drug substance (omega-3- carboxylic acids) and drug product (Epanova Capsules 1 g) are detailed in the review by Martin Haber, PhD, and Xavier Ysern, PhD. They recommend the NDA for approval. There are no pending CMC issues. The drug substance at sites in Nova Scotia and Prince Edward Island, Canada, from crude fish oil obtained from fish It is a complex mixture of PUFAs, predominantly the omega-3 acids EPA (55%), DHA (20%), and docosapentaenoic acid %). It consistently contains omega-3 and omega-6 PUFA components: total omega-3 fatty acids are limited to not less than % and total omega-6 fatty acids are limited to not more than %. The drug substance also contains 0.3% (m/m) α-tocopherol as . During purification, . Environmental pollutants (heavy metals, pesticides, are controlled by specific tests on the drug substance . Drug substance specifications include tests for acid value, saponification value, ester value, peroxide value, p-anisidine value, total oxidation value, cholesterol, oligomers, , fatty acid composition (PUFAs, EPA, DHA, DPA, total omega-3 fatty acids, total omega-6 fatty acids, other polyunsaturated fatty acids, As described in the review by Drs. Haber and Ysern, the qualitative identify of the drug substance was developed by examining consistencies of peak patterns across 21 discrete lots: there are omega-3 and omega-6 PUFA peaks consistently present in the GC chromatograms (although not necessarily always above the limit of quantitation), which can be used to establish the fingerprint identity of omega-3-carboxylic acids . The quantitative fatty acid composition is given in the table below, excerpted from p. 25 of their review:

Ethyl eicosapentaenoic acid (E-EPAicosapent ethyl) is a derivative of the omega-3 fatty acid eicosapentaenoic acid (EPA) that is used in combination with changes in diet to lower triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia. This was the second class of fish oil-based drug to be approved for use as a drug and was approved by the FDA in 2012. These fish oil drugs are similar to fish oil dietary supplements but the ingredients are better controlled and have been tested in clinical trials.

The company that developed this drug, Amarin Corporation, challenged the FDA’s ability to limit its ability to market the drug for off-label use and won its case on appeal in 2012, changing the way the FDA regulates pharmaceutical marketing.

Medical use

E-EPA is used in addition to changes in diet to reduce triglyceride levels in adults with severe (≥ 500 mg/dL) hypertriglyceridemia.[1]

Intake of large doses (2.0 to 4.0 g/day) of long-chain omega-3 fatty acids as prescription drugs or dietary supplements are generally required to achieve significant (> 15%) lowering of triglycerides, and at those doses the effects can be significant (from 20% to 35% and even up to 45% in individuals with levels greater that 500 mg/dL). It appears that both eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) lower triglycerides, however, DHA alone appears to raise low-density lipoprotein (the variant which drives atherosclerosis; sometimes very inaccurately called: “bad cholesterol”) and LDL-C values (always only a calculated estimate; not measured by labs from person’s blood sample for technical and cost reasons), whilst EPA alone, does not and instead lowers the parameters aforementioned.[2]

Other fish-oil based drugs

There are other omega-3 fish oil based drugs on the market that have similar uses and mechanisms of action.[3]

Dietary supplements

There are many fish oil dietary supplements on the market.[8] There appears to be little difference in effect between dietary supplements and prescription forms of omega-3 fatty acids, but EPA and DHA ethyl esters (prescription forms) work less well when taken on an empty stomach or with a low-fat meal.[2] The ingredients of dietary supplements are not as carefully controlled as prescription products and have not been fixed and tested in clinical trials, as prescription drugs have,[9] and the prescription forms are more concentrated, requiring fewer capsules to be taken and increasing the likelihood of compliance.[8]

Side effects

Special caution should be taken with people who have with fish and shellfish allergies.[1] In addition, as with other omega-3 fatty acids, taking E-EPA puts people who are on anticoagulants at risk for prolonged bleeding time.[1][2] The most commonly reported side effect in clinical trials has been joint pain; some people also reported pain in their mouth or throat.[1] E-EPA has not been tested in pregnant women is rated pregnancy category C; it is excreted in breast milk and the effects on infants are not known.[1]

Pharmacology

After ingestion, E-EPA is metabolized to EPA. EPA is absorbed in the small intestine and enters circulation. Peak plasma concentration occurs about 5 hours after ingestion and the half-life is about 89 hours. EPA is metabolized mostly in the liver like other dietary fatty acids.[1]

Mechanism of action

EPA, the active metabolite of E-EPA, like other omega-3 fatty acid based drugs, appears to reduce production of triglycerides in the liver, and to enhance clearance of triglycerides from circulating very low-density lipoprotein (VLDL) particles; the way it does that is not clear, but potential mechanisms include increased breakdown of fatty acids; inhibition of diglyceride acyltransferase which is involved in biosynthesis of triglycerides in the liver; and increased activity of lipoprotein lipase in blood.[1][3]

Physical and chemical properties[edit]

E-EPA is an ethyl ester of eicosapentaenoic acid, which is an omega-3 fatty acid.[1]

History

In July 2012, the US Food and Drug Administration approved E-EPA for severe hypertriglyceridemia as an adjunct to dietary measures; Amarin Corporation had developed the drug.[10]

E-EPA was the second fish-oil drug to be approved, after omega-3 acid ethyl esters (GlaxoSmithKline‘s Lovaza which was approved in 2004[11]) and sales were not as robust as Amarin had hoped. The labels for the two drugs were similar, but doctors prescribed Lovaza for people who had triglycerides lower than 500 mg/dL based on some clinical evidence. Amarin wanted to actively market E-EPA for that population as well which would have greatly expanded its revenue, and applied to the FDA for permission to do so in 2013, which the FDA denied.[12] In response, in May 2015 Amarin sued the FDA for infringing its First Amendment rights,[13] and in August 2015 a judge ruled that the FDA could not “prohibit the truthful promotion of a drug for unapproved uses because doing so would violate the protection of free speech.”[14] The ruling left open the question of what the FDA would allow Amarin to say about E-EPA, and in March 2016 the FDA and Amarin agreed that Amarin would submit specific marketing material to the FDA for the FDA to review, and if the parties disagreed on whether the material was truthful, they would seek a judge to mediate.[15]

PAPER

https://link.springer.com/article/10.1023%2FB%3ACONC.0000039128.78645.a8

Synthesis of Fatty-Acid Ethanolamides from Linum catharticum Oils and Cololabis saira Fats
Chemistry of Natural Compounds (Translation of Khimiya Prirodnykh Soedinenii) (2004), 40, (3), 222-226

PAPER

Journal of Molecular Catalysis B: Enzymatic, 84, 173-176; 2012

https://www.sciencedirect.com/science/article/pii/S1381117712000896?via%3Dihub

STARTING MATERIAL CAS 10417-94-4

  • (all-Z)-Δ5,8,11,14,17-Eicosapentaenoic acid
  • (all-cis)-5,8,11,14,17-Eicosapentaenoic acid

PATENT

CN 104846023

https://patents.google.com/patent/CN104846023A/en

Example 1

[0041] A method for preparing a concentrated fish oil fatty acid glycerides, the process steps shown in Figure 1, comprising the steps of:

[0042] S11 using crude enzyme preparation of deep sea fish art: the ratio: (m m) of deep-sea fish through the machine crushed bone formation minced, weighed 600g yue meat, meat by:: water = 0 5.1 water was added seal, in the dark, under nitrogen flow, at 75 ° C cooking lh. Using NaOH to adjust pH to 8.0. Mass fraction of 2% trypsin (trypsin: food grade, Zhengzhou Hong Cheng Chemical Products Limited), in the dark, enzyme 17h at 20 ° C. After 20min by centrifugation 3000r / min, the upper layer was enzymolysis, namely crude fish oil;

[0043] S12 is prepared refined fish oil: Crude fish oil prepared in Step S11 is added a volume ratio of 0.5% phosphoric acid: degummed (crude phosphoric acid fish oil), a concentration of 70% phosphoric acid, followed by centrifugation speed of 3000 rpm / min, and then add a volume ratio of 1% deacidification NaOH, the NaOH concentration is 20%, after centrifugation, the rotational speed of 3000- rpm / min, to obtain refined fish oil;

. [0044] S13 of the refined fish oil fatty acid ethyl ester prepared by esterification process: step S12 is added to the fish oil refining prepared in mass ratio of 0.5% of sodium ethoxide, and a mass ratio of 0.5 in ethanol (ethanol: fish oil refining ), 40 ° C water bath for 1 hour, 1% (by mass) citric acid (citric acid: fish oil refining), standing layer, the upper layer and the liquid was washed with hot deionized water, standing layered repeated three times to give fatty acid ethyl ester.

. [0045] S14 of the fatty acid ethyl ester was extracted Separation: fatty acid ethyl ester obtained in step S13 is subjected to supercritical fluid extraction (extraction process of separation vessel as a rectification column I – separation kettle II), extraction conditions: a rectification column temperature 25-30-35-40 ° C, a pressure of 6 MPa rectification column, separation kettle I temperature 25 ° C, pressure in the separator tank I is 6 MPa, the temperature in the separation tank II 30-45 ° C, C0 2 flow rate of 151,711;

. [0046] S15 of the fatty acid ethyl ester after enzymatic extraction separation processing: The fatty acid ethyl ester obtained in step S14 using Penicillium expansum lipase enzyme, 4% of the amount of enzyme added,, reaction temperature 40 ° C , reaction pH of 10, speed 150 revolutions / min, hydrolysis time 4h, to obtain fatty acid glycerides.

[0047] Example 2

[0048] A process for preparing concentrated fish oil fatty acid glycerides, comprising the steps of:

. [0049] S21 using crude enzyme preparation of deep sea fish art: The procedure of Example 1 with reference to embodiment 11, wherein the cooking temperature is 85 ° C, hydrolysis temperature 25 ° C, centrifuge speed is 4000r / min;

. [0050] S22 refined fish oil preparation: The procedure of Example 1 with reference to embodiment 12; wherein, phosphate: the crude fish oil volume ratio is 1.5%, the phosphoric acid concentration of 75%; K0H: crude fish oil volume ratio of 3%, K0H the concentration of 30%, a centrifugal speed of 4000r / min;

. [0051] S23 of the refined fish oil fatty acid ethyl ester prepared by esterification process: The procedure of Example 1 with reference to embodiment 13; wherein, potassium ethoxide: refined fish oil mass ratio of 1 billion% ethanol: refined fish oil mass ratio of 2.0 , heat the water bath 60 ° C for 3 hours, and acetic acid is acetic acid: refined fish oil mass ratio of 3.0%;

. [0052] S24 was extracted to separate fatty acid ethyl ester: The procedure of Example 1 with reference to embodiment 14; wherein the extraction conditions: temperature rectification column 30-35-40-45 ° C, a pressure rectification column is 15 megabytes Pa, temperature of separation vessel I 35 ° C, pressure in the separator tank I is 8 MPa, the temperature in the separation tank II was 40 ° C, C0 2 flow rate of 171,711;

. [0053] S25 of the fatty acid ethyl ester after enzymatic extraction is carried out the separation treatment: The procedure of Example 1 with reference to embodiment 15; wherein 10% of the amount of enzyme added, reaction temperature 50 ° C, pH 8 hydrolysis, speed 300 rpm / min, hydrolysis time 12h, to obtain fatty acid glycerides.

[0054] Example 3

[0055] – Preparation Method Species of concentrated fish oil fatty acid glycerides, comprising the steps of:

. [0056] S31 using crude enzyme preparation of deep sea fish art: The procedure of Example 1 with reference to embodiment 11, wherein the cooking temperature is 90 ° C, hydrolysis temperature 35 ° C, centrifuge speed is 5000r / min;

. [0057] S32 prepared fine fish oil: The procedure of Example 1 with reference to embodiment 12; wherein, phosphate: the crude fish oil volume ratio of 3% phosphoric acid concentration of 85%; NaOH: crude fish oil volume ratio of 6% and the concentration of NaOH 50%, a centrifugal speed of 5000r / min;

. [0058] S33 of the refined fish oil fatty acid ethyl ester prepared by esterification process: The procedure of Example 1 with reference to embodiment 13; wherein, potassium ethoxide: refined fish oil mass ratio of 1.5%, ethanol: refined fish oil mass ratio of 4.0 heat treatment is 80 ° C water bath for 5 hours, citric acid and citric acid are added: refined fish oil mass ratio of 5.0%;

. [0059] S34 was extracted to separate fatty acid ethyl ester: The procedure of Example 1 with reference to embodiment 14; wherein the extraction conditions: temperature rectification column 30-35-40-45 ° C, pressure column 17 trillion Pa, I of separation vessel temperature 40 ° C, pressure in the separator tank I is 10 MPa, the temperature in the separation tank II is 45 ° C, C0 2 flow rate is? L / h;

. [0060] S35 of the fatty acid ethyl ester after enzymatic extraction separation processing: The procedure of Example 1 with reference to embodiment 15; wherein 20% of the amount of enzyme added, reaction temperature 60 ° C, a pH of 6.5 hydrolysis, speed 300 rpm / min, hydrolysis time 24h, to obtain fatty acid glycerides.

[0061] Comparative Example

[0062] S1 • obtaining crude fish: The procedure of Example 1 with reference to embodiment 11;

. [0063] S2 refined fish oil preparation: see Example 1, Step 12;

. [0064] S3 of refined fish oil fatty acid ethyl ester prepared by esterification process: Step 1, Example 13 process embodiment with reference, to obtain fatty acid ethyl ester.

PATENT

https://patents.google.com/patent/WO2014054435A1

WO 2014054435

 In recent years, highly unsaturated fatty acids such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been clarified for their pharmacological effects and are used as raw materials for pharmaceuticals and health foods. Since these polyunsaturated fatty acids have a plurality of double bonds, it is not easy to obtain them by chemical synthesis. Therefore, most of industrially used highly unsaturated fatty acids are produced by extraction or purification from marine organism-derived materials rich in polyunsaturated fatty acids, such as fish oil, etc. However, the content of highly unsaturated fatty acid is not necessarily high, because the biological material is a mixture of various kinds of fatty acids having different numbers of carbon atoms, number and position of double bonds, constitutional ratio of stereoisomers, and the like. For this reason, conventionally, it has been required to selectively purify a target highly unsaturated fatty acid from a biological raw material.
 Patent Document 1 discloses a supercritical gas extraction method after a thin film distillation method when a raw material containing a highly unsaturated fatty acid or an alkyl ester thereof is treated by a thin film distillation method, a supercritical gas extraction method and a urea addition method A method for purifying a highly unsaturated fatty acid or an alkyl ester thereof is described.
 In Patent Document 2, a raw material containing a highly unsaturated fatty acid such as EPA is subjected to vacuum precision distillation treatment, and the resulting EPA or a fraction containing a lower alcohol ester thereof is mixed with an aqueous silver nitrate solution, whereby a high purity eicosapentaene A method of purifying an acid or a lower alcohol ester thereof is described. It is described that the condition of the vacuum precision distillation is a pressure of 5 mmHg (665 Pa) or less, preferably 1 mmHg (133 Pa) or less, 215 ° C. or less, preferably 210 ° C. or less.
 Further, Patent Document 3 discloses a process for producing eicosapentaenoic acid or an ester thereof having a concentration of 80% or more by gradually distilling a raw material containing a highly unsaturated fatty acid or an alkyl ester thereof using a distillation tower having three or more stages Is described. It is described that the condition of the distillation is 10 Torr (1330 Pa) or less, preferably 0.1 Torr (13.3 Pa) or less, 210 ° C. or less, preferably 195 ° C. or less.
 However, highly unsaturated fatty acids having higher concentrations and purities than those obtained by the above-mentioned conventional methods are required as raw materials for pharmaceuticals and health foods.
There are cis and trans isomers in highly unsaturated fatty acids. Most of the highly unsaturated fatty acids in vivo are cis, however, they may be converted from cis form to trans form by heating or the like at the stage of purification from biological origin materials (Non-Patent Document 1). Therefore, polyunsaturated fatty acids conventionally purified industrially from biologically derived raw materials contain a certain amount of trans isomer. However, trans fatty acids have been reported to increase health risks, especially LDL cholesterol levels, and increase the risk of cardiovascular disease. In the United States and Canada, foods are obliged to indicate the content of trans fatty acids.
 Therefore, there is a need for a highly unsaturated fatty acid-containing composition which not only contains the targeted highly unsaturated fatty acid at a high concentration as a raw material for pharmaceuticals and health foods but also contains a trans fatty acid content as low as possible . However, conventionally, purification of highly unsaturated fatty acids has not been conducted focusing on the stereoisomer ratio.
Patent Document 1: Japanese Patent Application Laid-Open No. 10-95744
Patent Document 2: Japanese Patent Application Laid-Open No. 7-242895
Patent Document 3: Japanese Patent No. 3005638

Non-patent literature

[0010]
Non-patent document 1: Journal of the American Oil Chemists’ Society, 1989, 66 (12): 1822-1830

Example 

[0035]
 Hereinafter, the present invention will be described in more detail by way of examples, but the present invention is not limited to only these examples.

[0036]
 In the following examples, the method of composition analysis of highly unsaturated fatty acids and the method of quantitating stereoisomers are as follows.
9 μL of the measurement sample was diluted to 1.5 mL of n-hexane, and the content ratio of each fatty acid and the content ratio of isomers were analyzed using a gas chromatography analyzer (Type 6890 GC, manufactured by Agilent Technologies) under the following conditions did. The results are expressed as mass% converted from the area of the chromatogram.
<Column condition>
Column: DB-WAX 0.25 mm × 30 m manufactured by J & W Co., column temperature: 210 ° C.
He flow rate: 1.0 ml / min, He pressure: 134 kPa
<Detection condition>
2 flow rate: 30 ml / min, Air flow rate : 400 ml / min
He flow rate: 10 ml / min, DET temperature: 260 ° C.
The isomer ratio in the target highly unsaturated fatty acid was obtained by the following formula.

[0037]
[Expression 1]

[0038]
(Example 1)
Raw material: 1000 mL of anhydrous ethanol solution in which 50 g of sodium hydroxide was dissolved was added to 1 kg of sardine oil, mixed and stirred at 70 to 80 ° C. for 1 hour, then 500 mL of water was added and mixed well, 1 It was left standing for a while. The separated aqueous phase was removed and the oil phase was washed several times with water to neutralize the washings to give 820 g of ethyl esterified sardine oil.
As shown in Table 1, the composition of the sardine oil was 44.09% (mass%, hereinafter the same) of eicosapentaenoic acid (EPA), 1.52% of eicosatetraenoic acid (ETA), 1.52% of arachidonic acid (AA) 1.77%, docosahexaenoic acid (DHA) 6.92%. Also, the trans isomer ratio in EPA was 1.23%.
Step (1) 160 ml of n-hexane was added to 300 g of the ethyl esterified sardine oil prepared above, and the mixture was stirred well and dissolved. To this was added 500 mL of an aqueous solution containing 50% by weight of silver nitrate, and the mixture was stirred under conditions of 5 to 30 ° C. After standing, the separated n-hexane phase was removed, and the aqueous phase was recovered.
Step (2): 2000 mL of fresh n-hexane was added to the aqueous phase obtained in the step (1), and the mixture was sufficiently stirred at 50 to 69 ° C. to extract the fatty acid ethyl ester into n-hexane. After standing, the separated aqueous phase was removed and the n-hexane phase was concentrated. The crude fatty acid ethyl ester crude product contained in this n-hexane phase contained 74.54% EPA, 0.32% ETA, 0.17% AA and 14.87% DHA in total fatty acids as shown in Table 1 It was. Also, the trans isomer ratio in EPA was 0.19%.
Step (3): The n-hexane phase containing the fatty acid ethyl ester obtained in the step (2) was maintained under conditions of a top vacuum degree of 1 Pa or less and a distillation temperature of 170 to 190 ° C. using a packed tower precision distillation apparatus While performing vacuum distillation to obtain a highly purified EPA ethyl ester-containing composition in a yield of about 60%. As shown in Table 1, this EPA ethyl ester-containing composition contained 98.25% of EPA, 0.43% of ETA, 0.21% of AA, and 0.05% of DHA in total fatty acids. Also, the trans isomer ratio in EPA was 0.45%.
The yield of EPA in this example in which the steps were performed in the order of (1), (2), (3) was about 53%.

[0039]
Example 2 The
steps (1), (2) and (3) were carried out in the same manner as in Example 1 except that the step (3) was carried out while maintaining the distillation temperature of 180 to 185 ° C., EPA ethyl ester-containing composition was obtained in a yield of about 58%. As shown in Table 1, this EPA ethyl ester-containing composition contained 98.29% of EPA, 0.40% of ETA, 0.32% of AA, and 0.05% of DHA in total fatty acids. Also, the trans isomer ratio in EPA was 0.28%, and the trans isomer was extremely small.
Comparative Example 1 An
EPA ethyl ester-containing composition was obtained in the same manner as in Example 1, except that the top vacuum degree was set to 13.3 Pa (0.1 Torr) in the step (3). As shown in Table 1, the composition contained EPA content ratio as high as 97.44% in the total fatty acid, but the trans isomer ratio in EPA was high (1.37%).

[0040]
Comparative Example 2 The
EPA ethyl ester-containing composition was obtained by performing vacuum distillation (step (3)) of ethyl esterified sardine oil and then steps (1) and (2). The conditions of each step were the same as in Example 1. As shown in Table 1, this composition contained 95.05% EPA, 0.72% ETA, 0.50% AA, 0.21% DHA in total fatty acids, the trans isomer ratio in EPA was 1.55% Met. The yield of EPA in this comparative example in which the steps were carried out in the order of (3), (1) and (2) was about 31%, and the EPA yield greatly decreased as compared with Example 1.
By changing the condition of the vacuum distillation in this Comparative Example (0.5 Pa, 185 to 195 ° C.), it was possible to raise the content of EPA in the total fatty acids in the composition to 98.12%, however, The rate further declined and the trans isomer ratio in EPA was 2.01%, further increased.

[0041]
[table 1]

[0042]
Examples 3 to 4 and Comparative Example 3 In the
step (3), the distillation temperature was 180 ° C. (Example 3), 190 ° C. (Example 4), 200 ° C. (Comparative Example 3), and the vacuum distillation time was A highly purified EPA ethyl ester-containing composition was obtained in the same manner as in Example 1 except that various changes were made and the trans isomer ratio of EPA in the composition was determined. The results are shown in Fig. 1. 1, in Examples 3 to 4 having a distillation temperature of 190 ° C. or less, the trans isomer ratio was less than 1% by mass, but in Comparative Example 3 having a distillation temperature of 200 ° C., the trans isomer The ratio exceeds 1% by mass.

References

  1. Jump up to:a b c d e f g h Icosapent ethyl Label Last revised June 2015. Check for updates at FDA label index page here
  2. Jump up to:a b c Jacobson TA, et al, NLA Expert Panel. National Lipid Association Recommendations for Patient-Centered Management of Dyslipidemia: Part 2. J Clin Lipidol. 2015 Nov-Dec;9(6 Suppl):S1-S122.e1. PMID 26699442 Free full text
  3. Jump up to:a b Weintraub, HS (2014). “Overview of prescription omega-3 fatty acid products for hypertriglyceridemia”Postgrad Med126: 7–18. doi:10.3810/pgm.2014.11.2828PMID 25387209. Retrieved 20 April 2015.
  4. Jump up^ University of Utah Pharmacy Services (15 August 2007) “Omega-3-acid Ethyl Esters Brand Name Changed from Omacor to Lovaza”
  5. Jump up^ Omtryg Label Revised April 2014
  6. Jump up^ FDA Omega-3 acid ethyl esters products Page accessed 31 March 2016
  7. Jump up^ “Epanova (omega-3-carboxylic acids)”CenterWatch. Retrieved 15 December 2014.
  8. Jump up to:a b Ito MK. A Comparative Overview of Prescription Omega-3 Fatty Acid Products. P T. 2015 Dec;40(12):826-57. PMID 26681905 Free PMC Article PMC 4671468
  9. Jump up^ Sweeney MET. Hypertriglyceridemia Pharmacologic Therapy for Medscape Drugs & Diseases, Ed. Khardori R. Updated: 14 April 2015, page accessed 1 April 2016
  10. Jump up^ CenterWatch Vascepa (icosapent ethyl) Page accessed 31 March 2016
  11. Jump up^ VHA Pharmacy Benefits Management Strategic Healthcare Group and the Medical Advisory Panel. October 2005 National PBM Drug Monograph Omega-3-acid ethyl esters (Lovaza, formerly Omacor)
  12. Jump up^ Matthew Herper for Forbes. 17 October 2013 Why The FDA Is Right To Block Amarin’s Push To Market Fish Oil To Millions
  13. Jump up^ Thomas, Katie (7 May 2015). “Drugmaker Sues F.D.A. Over Right to Discuss Off-Label Uses”New York Times. Retrieved 17 May 2017.
  14. Jump up^ Andrew Pollack for the New York Times. 7 August 2015 Court Forbids F.D.A. From Blocking Truthful Promotion of Drug
  15. Jump up^ Katie Thomas for the New York Times. 8 March 2016 F.D.A. Deal Allows Amarin to Promote Drug for Off-Label Use
CN1288732A *2000-07-122001-03-28刘玉Soft concentrated fish oil capsule and its supercritical CO2 extraction and rectification process
CN101255380A *2007-03-032008-09-03苑洪德Triglyceride type fish oil and method for making same
CN101818176A *2010-04-092010-09-01浙江兴业集团有限公司;华南理工大学Method for transforming fatty acid ethyl ester into glyceride
CN102964249A *2012-11-162013-03-13成都圆大生物科技有限公司Process capable of simultaneously producing and separating high-purity EPA (eicosapentaenoic acid) ethyl ester and high-purity DHA (docosahexaenoic acid) ethyl ester
CN102994236A *2012-12-112013-03-27成都圆大生物科技有限公司Method for preparing fatty acid ethyl ester with Omega-3 content of more than 90 percent
Ethyl eicosapentaenoic acid
Ethyl eicosapentaenoate.png
Names
IUPAC name

Ethyl (5Z,8Z,11Z,14Z,17Z)-eicosa-5,8,11,14,17-pentaenoate
Other names

Eicosapentaenoic acid ethyl ester; Ethyl eicosapentaenoate; Eicosapent; Icosapent ethyl; EPA ethyl ester; E-EPA
Identifiers
3D model (JSmol)
ChEBI
ChemSpider
PubChem CID
Properties
C22H34O2
Molar mass 330.51 g·mol−1
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).

////////////Icosapent ethyl, fda 2012, Timnodonic acid ethyl ester, Vascepa, AMR 101, AMR-101, E-EPA, Ethyl eicosapentaenoic acid , Fast-track status, Orphan drug designation 

CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC

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Bedaquiline fumarate, ベダキリンフマル酸塩


Bedaquiline fumarate.png

Bedaquiline fumarate; Bedaquiline (fumarate); Cas 845533-86-0; UNII-P04QX2C1A5; P04QX2C1A5;

Bedaquiline fumarate

(1R,2S)-1-(6-bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-2-naphthalen-1-yl-1-phenylbutan-2-ol;(E)-but-2-enedioic acid

  • R 207910
  • TMC 207
Molecular Formula: C36H35BrN2O6
Molecular Weight: 671.588 g/mol
Product
Formula
C32H31BrN2O2. C4H4O4
CAS

845533-86-0 FUMARATE
FREE FORM 843663-66-1
Mol weight
671.5769
2018/1/19  PMDA

JAPAN

APPROVED

Bedaquiline fumarate Sirturo Janssen Pharmaceutical

ベダキリンフマル酸塩
Bedaquiline Fumarate

C32H31BrN2O2▪C4H4O4 : 671.58
[845533-86-0]

FREE FORM

  1.  Saga, Yutaka; Journal of the American Chemical Society 2010, Vol132(23), Pg 7905-7907 , -168.0 ° Conc: 0.8 g/100mL; Solv:DMF; Wavlenght: 589.3 nm; Temp: 25 °C
  2.  Chandrasekhar, Srivari; European Journal of Organic Chemistry 2011, (11), PG 2057-2061, S2057/1-S2057/18  -165.2 °       Conc: 0.8 g/100mL; Solv: DMF ; Wavlenght: 589.3 nm; Temp: 25 °, MP 104 °C

EMA

http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002614/WC500163215.pdf

The applicant Janssen-Cilag International N.V. submitted on 28 August 2012 an application for Marketing Authorisation to the European Medicines Agency (EMA) for SIRTURO, through the centralised procedure falling within the Article 3(1) and point 4 of Annex of Regulation (EC) No 726/2004. The eligibility to the centralised procedure was agreed upon by the EMA/CHMP on 21 July 2011. SIRTURO was designated as an orphan medicinal product EU/3/05/314 on 26 August 2005. SIRTURO was designated as an orphan medicinal product in the following indication: treatment of tuberculosis. The applicant applied for the following indication: SIRTURO is indicated in adults (≥ 18 years) as part of combination therapy of pulmonary tuberculosis due to multi-drug resistant Mycobacterium tuberculosis.

Disease to be treated About a third of the global population, more than 2 billion people, is infected with M. tuberculosis, of which the majority is latent. The life time risk to fall ill in overt TB is around 10% in general, but many times higher (around 10% annual risk) in untreated HIV-positive individuals. Tuberculosis is the leading cause of death in the latter population. It was estimated that a total of 8.8 million new TB cases occurred in 2010, including 1.1 million people co infected with HIV, and that about 1.45 million people died due to TB. During more recent years the burden of TB resistant to first line therapy has increased rapidly. Such multidrug resistant tuberculosis (defined later in this assessment report) has been reported in all regions of the world. Presently around 500.000 of new MDR cases are estimated to emerge every year, which is close to 5% of all new TB cases. China and India carried nearly 50% of the total burden of incident MDR-TB cases in 2008, followed by the Russian Federation (9%). The incidence of MDR-TB in US and EU was reported to be 1.1% and 2.4%, respectively. Within the EU, the incidence is much higher in certain Eastern European countries, with the largest burden in Romania, Latvia and Lithuania. MDR TB is an orphan disease in the EU, US and in Japan.

Current TB therapy and definitions Treatment of pulmonary drug susceptible TB typically takes 6 months resulting in cure rates in well over 90% of cases with good treatment adherence. The two most important drugs in this treatment are isoniazid (INH) and rifampicin (RIF). TB with resistance to at least both INH and RIF is called multidrug resistant (MDR) TB. The two most important “classes” of second-line TB drugs to be used in such cases are injectable drugs (the aminoglycosides amikacin and kanamycin, and the related agent capreomycin) and fluoroquinolones. Apart from these agents a number of miscellaneous drugs are used in addition, as part of combination therapy. The effectiveness of these latter miscellaneous drugs is generally lower, the tolerability is problematic and established breakpoints for resistance determination are lacking.

The term pre-XDR (pre-extensively drug resistant) TB is used when resistance is present also to one of the two main second-line class agents (injectables or any of the fluoroquinolones), and XDR-TB when resistance is present to INH+RIF + injectables + fluoroquinolones. The WHO standard treatment for MDR-TB is commonly divided into 2 phases: • a 4 to 6-month intensive treatment phase in which an injectable drug plus 3-4 other drugs, including a fluoroquinolone, • a continuation phase without the injectable drug and often without pyrazinamide (PZA) for a total duration of 18-24 months. Using this approach, cure rates in MDR-TB are much lower than those seen in DS-TB (ranging from less than 50% to around 75%), despite the higher number of agents and longer treatment duration. Hence, MDR TB is associated with a high mortality and is considered an important major threat to public health. More recent approaches to evaluate various MDR TB regimens have yielded somewhat more optimistic outcomes, despite shorter treatment durations. In these non-randomised studies (with low number of patients) cure rates in the range of 90% were achieved by including a fourth generation fluoroquinolone and by increasing the number of agents even further, to include up to 7 agents in the intensive phase, and still 4-5 agents in a second phase.

About the product SIRTURO (bedaquiline, formerly known as TMC 207) is a new agent of a unique class, specific for mycobacteria, and seemingly without cross-resistance to available TB agents. A large number of pre-clinical studies showed promising results for bedaquiline. For example, in animal models bedaquiline + pyrazinamide cured TB at a higher rate than the traditional first line combination, even when therapy was shortened for the former combination. The clinical program for bedaquiline has been aimed at treating MDR-TB, and data is now available from phase 2b studies of moderate size, both placebo-controlled and non-controlled studies. The treatments given in these studies were similar to those recommended by the WHO, although the number of agents used was slightly higher (five agents in the preferred background regimens). Bedaquiline (versus placebo in the controlled study) was added during the first (intensive) treatment phase, while the background regimens were generally unchanged throughout the complete course of therapy (18-24 months). On the basis of these studies, the applicant submitted an application for a conditional approval for bedaquiline, with the proposed indication: treatment of adult patients infected with pulmonary tuberculosis due to MDR M. tuberculosis, as part of combination therapy. In line with the approach in the phase 2 studies, Sirturo is only to be used during the first 6 months of therapy. However the planned pivotal study (as a specific obligation) will test for 40 weeks of bedaquiline treatment.

In 2009, the drug candidate was licensed to Global Alliance TB Drug Development by Tibotec worldwide for the treatment of tuberculosis.

Bedaquiline (INN) is chemically designated as (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol with fumaric acid (1:1), and has the following structure:

str4

Bedaquiline fumarate is a white to almost white powder. It contains two asymmetric carbon atoms, C-1 (R), C-2 (S) and exhibits ability to rotate the orientation of linearly polarized light (optical rotation). The substance is non-hygroscopic. It is practically insoluble in aqueous media over a wide pH range and very slightly soluble in 0.01 N HCl. The substance is soluble in a variety of organic solvents. Due to the low solubility Log KD (log P) could not be determined experimentally. In Biopharmaceutics Classification System (BCS) bedaquiline is classified as a Class 2 compound (expressing low solubility and high permeability). Bedaquiline exists in only one non-solvated crystalline form: Form A. In addition 2 pseudopoly-morphs were found: Form B and Form C. The substance can also be made amorphous. Sufficient evidence was provided to demonstrate that Form A is obtained by the employed manufacturing process of the active substance. Particle size was considered a critical quality attribute of the active substance as bedaquiline is not dissolved in the dosage form. Therefore an appropriate test on particle size determination was included in the active substance specification. The acceptance criteria are based upon the capabilities of the milling process, batch and stability data, and the known impact of the particle size on manufacturability, in-vitro release, and in-vivo performance

Bedaquiline is a bactericidal antimycobacterial drug. Chemically it is a diarylquinoline. FDA approved on December 28, 2012.

Image result for Bedaquiline fumarate

Bedaquiline is indicated as part of combination therapy in adults (≥ 18 years) with pulmonary multi-drug resistant tuberculosis (MDR-TB).

Bedaquiline, sold under the brand name Sirturo, is a medication used to treat active tuberculosis.[1] It is specifically used to treat multi-drug-resistant tuberculosis(MDR-TB) when other treatment cannot be used.[1][5] It should be used along with at least three other medications for tuberculosis.[1][5] It is used by mouth.[5]

Common side effects include nausea, joint pains, headaches, and chest pain.[1] Serious side effects include QT prolongation, liver dysfunction, and an increased risk of death.[1] While harm during pregnancy has not been found, it has not been well studied in this population.[6] It is in the diarylquinoline antimycobacterialclass of medications.[1] It works by blocking the ability of M. tuberculosis to make adenosine 5′-triphosphate (ATP).[1]

Bedaquiline was approved for medical use in the United States in 2012.[1] It is on the World Health Organization’s List of Essential Medicines, the most effective and safe medicines needed in a health system.[7] The cost for six months is approximately $900 USD in low income countries, $3,000 USD in middle income countries, and $30,000 USD in high income countries.[5]

SIRTURO (bedaquiline) for oral administration is available as 100 mg strength tablets. Each tablet contains 120.89 mg of bedaquiline fumarate drug substance, which is equivalent to 100 mg of bedaquiline. Bedaquiline is a diarylquinoline antimycobacterial drug.

Bedaquiline fumarate is a white to almost white powder and is practically insoluble in aqueous media. The chemical name of bedaquiline fumarate is (1R, 2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4- (dimethylamino)-2-(1-naphthalenyl)-1-phenyl-2-butanol compound with fumaric acid (1:1). It has a molecular formula of C32H31BrN2O2 · C4H4O4 and a molecular weight of 671.58 (555.50 + 116.07). The molecular structure of bedaquiline fumarate is the following:

SIRTURO (bedaquiline) Structural Formula Illustration

SIRTURO (bedaquiline) contains the following inactive ingredients: colloidal silicon dioxide, corn starch, croscarmellose sodium, hypromellose 2910 15 mPa.s, lactose monohydrate, magnesium stearate, microcrystalline cellulose, polysorbate 20, purified water (removed during processing).

Medical uses

Its use was formally approved (Dec 2012) by the U.S. Food and Drug Administration (FDA) for use in tuberculosis (TB) treatment, as part of a Fast-Trackaccelerated approval, for use only in cases of multidrug-resistant tuberculosis, and the more resistant extensively drug resistant tuberculosis.[8]

As of 2013 Both the World Health Organization (WHO) and US Centers for Disease Control (CDC) have recommended (provisionally) that bedaquiline be reserved for patients with multidrug-resistant tuberculosis when an otherwise recommended regimen cannot be designed.[9][10]

Clinical trials

Bedaquiline has been studied in phase IIb studies for the treatment of multidrug-resistant tuberculosis while phase III studies are currently underway.[11] It has been shown to improve cure rates of smear-positive multidrug-resistant tuberculosis, though with some concern for increased rates of death (further detailed in the Adverse effects section).[12]

Small studies have also examined its use as salvage therapy for non-tuberculous mycobacterial infections.[11]

It is a component of the experimental BPaMZ combination treatment (bedaquiline + pretomanid + moxifloxacin + pyrazinamide).[13][14]

Side effects

The most common side effects of bedaquiline in studies were nausea, joint and chest pain, and headache. The drug also has a black-box warning for increased risk of death and arrhythmias, as it may prolong the QT interval by blocking the hERG channel.[15] All patients on bedaquiline should have monitoring with a baseline and repeated ECGs.[16] If a patient has a QTcF of > 500ms or a significant ventricular arrythmia, bedaquiline and other QT prolonging drugs should be stopped.

There is considerable controversy over the approval for the drug, as one of the largest studies to date had more deaths in the group receiving bedaquiline that those receiving placebo.[17] 10 deaths occurred in the bedaquiline group out of 79, while 2 occurred in the placebo group, out of 81.[12] Of the 10 deaths on bedaquiline, 1 was due to a motor vehicle accident, 5 were judged as due to progression of the underlying tuberculosis and 3 were well after the patient had stopped receiving bedaquiline.[17] However, there is still significant concern for the higher mortality in patients treated with bedaquiline, leading to the recommendation to limit its use to situations where a 4 drug regimen cannot otherwise be constructed, limit use with other medications that prolong the QT interval and the placement of a prominent black box warning.[17][11]

Drug interactions

Bedaquiline should not be co-administered with other drugs that are strong inducers or inhibitors of CYP3A4, the hepatic enzyme responsible for oxidative metabolism of the drug.[16] Co-administration with rifampin, a strong CYP3A4 inducer, results in a 52% decrease in the AUC of the drug. This reduces the exposure of the body to the drug and decreases the antibacterial effect. Co-administration with ketoconazole, a strong CYP3A4 inhibitor, results in a 22% increase in the AUC, and potentially an increase in the rate of adverse effects experienced[16]

Since bedaquiline can also prolong the QT interval, use of other QT prolonging drugs should be avoided.[9] Other medications for tuberculosis that can prolong the QT interval include fluoroquinolones and clofazimine.

Mode of action

Bedaquiline blocks the proton pump for ATP synthase of mycobacteria. ATP production is required for cellular energy production and its loss leads to cell death, even in dormant or nonreplicating mycobacteria.[18] It is the first member of a new class of drugs called the diarylquinolines.[18] Bedaquiline is bactericidal.[18]

Resistance

The specific part of ATP synthase affected by bedaquiline is subunit c which is encoded by the gene atpE. Mutations in atpE can lead to resistance. Mutations in drug efflux pumps have also been linked to resistance.[19]

History

Bedaquiline was described for the first time in 2004 at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) meeting, after the drug had been in development for over seven years.[20] It was discovered by a team led by Koen Andries at Janssen Pharmaceutica.[21]

Bedaquiline was approved for medical use in the United States in 2012.[1]

It is manufactured by Johnson & Johnson (J&J), who sought accelerated approval of the drug, a type of temporary approval for diseases lacking other viable treatment options.[22] By gaining approval for a drug that treats a neglected disease, J&J is now able to request expedited FDA review of a future drug.[23]

When it was approved by the FDA on the 28th December 2012, it was the first new medicine for TB in more than forty years.[24][25]

Bedaquiline, formally called (1R, 2S)-1-(6-Bromo-2-methoxy-3-quinolinyl)-4-(dimethylamino)-2-(1-naphthyl)-1-phenyl-2-butanol in chemistry and known as Sirturo in commercial, is a new anti-mycobacterial medicine of diarylquinolines. It impinges on the
ATP synthesis of Mycobacterium tuberculosis by inhibiting the activity of proton pump on the cell’s ATP synthetase, and thereby eliminates M. tuberculosis (TB). It’s used for adult multi-drug resistant tuberculosis (MDR-PTB).

Image result for Bedaquiline fumarate

PATENT

US 20050148581

WO 2005117875

WO 2006125769

CA 2529265

WO 2006131519

JP 2011168519

CN 105017147

CN 105085395

CN 105198808

CN 105085396

WO 2016116076

WO 2016058564

WO 2016116075

WO 2016116073

WO 2016198031

CN 106866525

CN 106279017

CN 107602464

PATENT

WO 2017015793

The chemical name of beidaquinoline is (1R,2S)-1-(6-bromo-2-methoxy-3-quinolinyl)-4-dimethylamino-2-(1-naphthyl)-1 -Phenyl-2-butanol, the first drug developed by Johnson & Johnson in the United States to inhibit mycobacterium adenosine triphosphate (ATP) synthetase, was first introduced in the United States in December 2012 for the treatment of adult multidrug-resistant tuberculosis. The trade name is Sirturo. Beidaquinoline shows strong selectivity for Mycobacterium tuberculosis ATP synthase. Its novel mechanism of action makes it not cross-resistance with other anti-tuberculosis drugs, which will greatly reduce the drug resistance of Mycobacterium tuberculosis. It shows good activity against MDR-TB in macrophages, suggesting that it has the effect of shortening treatment time.

The synthesis of beidaquinoline has been reported in the literature. The specific synthesis route is as follows:

The patent WO2004011436 mentions the use of column chromatography to separate and purify the crude product, but this method is not conducive to industrialization; in addition, a method for isolating and purifying beraquinoline diastereomer A is disclosed in Step C of the Example of WO2006125769. . However, although the purity of the diastereomer A obtained by the separation and purification method disclosed in this patent is 82%, it is actually only possible to achieve the reaction conversion rate of more than 80%. The actual study found that due to the difficult control of the reaction conditions for the preparation of bedaquino, the control conditions for water, temperature, and drip rate are harsh and the reaction is unstable, and it cannot be ensured that the conversion rate reaches more than 80% per batch, and the conversion is usually When the rate is between 60-80%, the ratio of diastereomer B to diastereomer A obtained by this method is between 1:1 and 1:3, and the next step is chiral separation. It has an impact; even the conversion rate is sometimes as low as about 50%. When the conversion rate is as low as 50%, since the amount of the product in the reaction liquid is small, as in the method using patent WO 2006125769, the isolated product can hardly be purified even if the product is separated and purified by the purification method disclosed in this patent. The resulting diastereomer A is also of low purity.

Example 1
Reaction material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA (20g) reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 56%. After quenching the reaction, n-heptane (40 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 0° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 50% acetic acid aqueous solution to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 15% hydrochloric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by layering the filtrate, adjusted to alkaline with aqueous ammonia, extracted with toluene and free, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure to obtain a product that is not correct. Enantiomer A (4.9 g), purity 89%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (40 ml), DMSO (4.9 ml), and R-binaphthol phosphate (2.62 g) were added to diastereomer A (4.9 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitates are separated out; at room temperature, the filter cake is washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.07 g);
Split salt (2.07g), toluene (37ml), potassium carbonate (1.51g) and water (13ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, at this time organic layer TLC monitoring; washed with purified water to neutral pH (20ml × 3 times); organic layer was concentrated under reduced pressure to give a colorless oil (1.5g); add toluene (1ml) to heat the whole Dissolve, add ethanol (12ml) and stir at room temperature for 0.5h. Precipitate the solid, and stir in ice water bath for 1h. Filter and wash the filter cake with ethanol. Dry it in vacuo at 50-60°C to give bedaquinoline (1.07g). The HPLC purity is >99%. .
Example 2
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 65%. After quenching the reaction, diisopropyl ether (160 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 5° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 10% aqueous formic acid to remove 3-dimethylamino-1-(naphthalene-5-yl)acetone as a raw material, and 5% aqueous sulfuric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. Filtration, filtration of the filtrate, the product was transferred to the aqueous layer, the raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer, and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. The product was diastereoisomer A (5.7 g), purity 92%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.7 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. Cooling, precipitated salt precipitation; filtered at room temperature, washed with acetone cake, 50-60 ° C vacuum drying salt (2.6g);
The resolved salt (2.41 g), toluene (39 ml), potassium carbonate (1.58 g) and water (14 ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% aqueous potassium carbonate solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.6g); toluene was added (1ml) to heat the solution and ethanol was added (12ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.19 g) with an HPLC purity of >99%.
Example 3
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one-step reaction to obtain a racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 75%. After quenching the reaction, diisopropyl ether (400 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 2° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 60% aqueous solution of propionic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as a raw material, and 40% methanesulfonic acid aqueous solution was added to the organic layer for stirring to make the product salified. Precipitated in the water layer. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.0 g), purity 94%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.0 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomeric A (6.0 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolved salt (2.59 g).
The resolved salt (2.59g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml × 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.7 g); toluene (1 ml) was added and heated to complete dissolution, and ethanol (12 ml) was added. The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedaquinoline (1.20 g) with an HPLC purity of >99%.
Example 4
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction by HPLC analysis was 70%. After quenching the reaction, petroleum ether (16 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 3° C. and filtered to remove diastereoisomer B. The obtained filtrate was washed with 30% acetic acid aqueous solution to remove 3-methylamino-1-(naphthalen-5-yl)acetone as a raw material, and 25% phosphoric acid aqueous solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be slightly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, and then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (5.72 g), purity 88%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetylene (45 ml), DMSO (5.7 ml), and R-binaphthol phosphate (3.04 g) were added to diastereomer A (5.72 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give a resolution salt (2.43 g);
Split salt (2.43g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved. While hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5 ml) was washed once, washed with purified water until the pH was neutral (20 ml x 3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.5 g); toluene (1 ml) was added for heating and ethanol was added (12 ml) The precipitated solid was stirred at room temperature for 0.5 h, stirred in an ice-water bath for 1 h, filtered, and the filter cake was washed with ethanol. Drying in vacuo at 50-60° C. gave bedaquinoline (1.16 g) with an HPLC purity of >99%.
Example 5
Starting material 3-benzyl-6-bromo-2-methoxyquinoline (10 g) and 3-dimethylamino-1-(naphthalene-5-yl)propanone (10 g) in tetrahydrofuran (80 ml) with LDA ( 20g) Reaction, one step reaction to obtain the racemic bedaquiline reaction solution. The conversion of this reaction was 80% by HPLC analysis. After quenching the reaction, n-hexane (80 ml) was added to the reaction solution. Undesired diastereomer B was precipitated in an ice-water bath at 1° C. and filtered to remove diastereoisomer B. The resulting filtrate was washed with 40% aqueous acetic acid to remove 3-dimethylamino-1-(naphthalen-5-yl)acetone as starting material, and 20% aqueous hydrochloric acid solution was added to the organic layer for stirring to make the product salified in the aqueous layer. In the middle. After filtration, the filtrate was separated and the product was transferred to the aqueous layer. The raw material 3-benzyl-6-bromo-2-methoxyquinoline was left in the organic layer and the organic layer was discarded. The filtered product salt solid is combined with the aqueous layer obtained by the layering of the filtrate, adjusted to be weakly alkaline with sodium hydroxide, extracted with dichloromethane, and washed, then the organic layer is washed with water to neutrality, and the organic layer is concentrated under reduced pressure. Obtained product diastereomer A (6.1 g), purity 96%.
With reference to the method of patent WO2006125769, the obtained diastereoisomer A is resolved to obtain the desired bedaquiline, the specific method is as follows:
Acetate (48 ml), DMSO (6.1 ml), and R-binaphthol phosphate (3.09 g) were added to diastereomer A (6.1 g) of the obtained bedaquinoline, and the mixture was heated under reflux for 2 hours. After cooling, precipitated salt precipitated out; it was filtered at room temperature, and the filter cake was washed with acetone and dried under vacuum at 50-60° C. to give the resolution salt (2.69 g).
The resolved salt (2.69g), toluene (40ml), potassium carbonate (1.60g) and water (14ml) were mixed, heated to 90°C and stirred until completely dissolved; while hot stratified, the organic layer was treated with 10% potassium carbonate aqueous solution ( (5ml) was washed once, washed with purified water until the pH was neutral (20ml×3 times); the organic layer was concentrated under reduced pressure to give a colorless oil (1.8g); toluene (1ml) was added to heat to dissolve and ethanol (12ml) was added. The precipitated solid was stirred for 0.5 h at room temperature, stirred in an ice-water bath for 1 h, filtered, washed with ethanol, and dried in vacuo at 50-60° C. to give bedalquinoline (1.28 g) with an HPLC purity of >99%.

PAPER

ACS Medicinal Chemistry Letters (2017), 8(10), 1019-1024

6-Cyano Analogues of Bedaquiline as Less Lipophilic and Potentially Safer Diarylquinolines for Tuberculosis

 Auckland Cancer Society Research Centre, School of Medical Sciences, The University of Auckland, Private Bag 92019, Auckland 1142, New Zealand
 Medicinal Chemistry Department (Infectious Diseases), Janssen Pharmaceuticals, Campus de Maigremont, BP315, 27106 Val de Reuil Cedex, France
§ Global Alliance for TB Drug Development, 40 Wall Street, New York, New York 10005, United States
 Infectious Diseases BVBA, Janssen Pharmaceuticals, Beerse, Belgium
 Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, Illinois 60612, United States
ACS Med. Chem. Lett.20178 (10), pp 1019–1024
DOI: 10.1021/acsmedchemlett.7b00196
Publication Date (Web): September 22, 2017
Copyright © 2017 American Chemical Society

Abstract

Abstract Image

Bedaquiline (1) is a new drug for tuberculosis and the first of the diarylquinoline class. It demonstrates excellent efficacy against TB but induces phospholipidosis at high doses, has a long terminal elimination half-life (due to its high lipophilicity), and exhibits potent hERG channel inhibition, resulting in clinical QTc interval prolongation. A number of structural ring A analogues of bedaquiline have been prepared and evaluated for their anti-M.tb activity (MIC90), with a view to their possible application as less lipophilic second generation compounds. It was previously observed that a range of 6-substituted analogues of 1 demonstrated a positive correlation between potency (MIC90) toward M.tb and drug lipophilicity. Contrary to this trend, we discovered, by virtue of a clogP/M.tb score, that a 6-cyano (CN) substituent provides a substantial reduction in lipophilicity with only modest effects on MIC values, suggesting this substituent as a useful tool in the search for effective and safer analogues of 1.

PAPER

Chinese Chemical Letters (2015), 26(6), 790-792

PAPER

Organic & Biomolecular Chemistry (2016), 14(40), 9622-9628.

http://pubs.rsc.org/en/content/articlelanding/2016/ob/c6ob01893a/unauth#!divAbstract

New synthetic approaches towards analogues of bedaquiline

Abstract

Multi-drug resistant tuberculosis (MDR-TB) is of growing global concern and threatens to undermine increasing efforts to control the worldwide spread of tuberculosis (TB). Bedaquiline has recently emerged as a new drug developed to specifically treat MDR-TB. Despite being highly effective as a result of its unique mode of action, bedaquiline has been associated with significant toxicities and as such, safety concerns are limiting its clinical use. In order to access pharmaceutical agents that exhibit an improved safety profile for the treatment of MDR-TB, new synthetic pathways to facilitate the preparation of bedaquiline and analogues thereof have been discovered.

Graphical abstract: New synthetic approaches towards analogues of bedaquiline
http://www.rsc.org/suppdata/c6/ob/c6ob01893a/c6ob01893a1.pdf

PAPER

 Topics in Organometallic Chemistry (2011), 37(Bifunctional Molecular Catalysis), 1-30

PAPER

Saga, Yutaka; Journal of the American Chemical Society 2010, Vol132(23), Pg 7905-7907

Catalytic Asymmetric Synthesis of R207910

Graduate School of Pharmaceutical Sciences, The University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
J. Am. Chem. Soc.2010132 (23), pp 7905–7907
DOI: 10.1021/ja103183r
Publication Date (Web): May 20, 2010
Copyright © 2010 American Chemical Society

Abstract

Abstract Image

The first asymmetric synthesis of a very promising antituberculosis drug candidate, R207910, was achieved by developing two novel catalytic transformations; a catalytic enantioselective proton migration and a catalytic diastereoselective allylation of an intermediate α-chiral ketone. Using 2.5 mol % of a Y-catalyst derived from Y(HMDS)3 and the new chiral ligand 9, 1.25 mol % of p-methoxypyridine N-oxide (MEPO), and 0.5 mol % of Bu4NCl, α-chiral ketone 3 was produced from enone 4 with 88% ee. This reaction proceeded through a catalytic chiral Y-dienolate generation via deprotonation at the γ-position of 4, followed by regio- and enantioselective protonation at the α-position of the resulting dienolate. Preliminary mechanistic studies suggested that a Y: 9: MEPO = 2: 3: 1 ternary complex was the active catalyst. Bu4NCl markedly accelerated the reaction without affecting enantioselectivity. Enantiomerically pure 3 was obtained through a single recrystallization. The second key catalytic allylation of ketone 3 was promoted by CuF•3PPh3•2EtOH (10 mol %) in the presence of KOtBu (15 mol %), ZnCl2 (1 equiv), and Bu4PBF4 (1 equiv), giving the desired diastereomer 2 in quantitative yield with a 14: 1 ratio without any epimerization at the α-stereocenter. It is noteworthy that conventional organometallic addition reactions did not produce the desired products due to the high steric demand and a fairly acidic α-proton in substrate ketone 3. This first catalytic asymmetric synthesis of R207910 includes 12 longest linear steps from commercially available compounds with an overall yield of 5%.

https://pubs.acs.org/doi/suppl/10.1021/ja103183r/suppl_file/ja103183r_si_001.pdf

1 in 62 % yield (6.5 mg, 0.012 mmol ). 1H NMR (500 MHz, CDCl3) : 1.91-1.95 (m, 1H), 1.98 (s, 6H), 1.99-2.10 (m, 2H), 2.52 (d, J = 14.1 Hz, 1H), 4.21 (s, 3H), 5.89 (s, 1H), 6.87-6.89 (m, 3H), 7.10-7.15 (m, 2H), 7.31 (t, J = 7.6 Hz, 2H), 7.48 (t, J = 8.5 Hz, 1H), 7.61 (t, J = 8.5 Hz, 1H), 7.63-7.67 (m, 2H), 7.72 (d, J = 8.9 Hz, 1H), 7.87 (d, J = 8.5 Hz, 1H), 7.91 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 2.2 Hz, 1H), 8.60 (d, J = 8.5 Hz, 1H), 8.89 (s, 1H); 13C NMR (126 MHz, CDCl3) : 29.7, 33.5, 44.7, 49.5, 54.2, 56.4, 82.6, 117.0, 124.5, 125.0, 125.1, 125.3, 125.8, 126.9, 127.1, 127.4, 127.9, 128.0, 128.1, 128.5, 129.8, 129.9, 131.9, 132.7, 133.3, 134.7, 138.8, 140.6, 141.8, 143.8, 161.4; IR (KBr, cm-1 ):  3443; MS (ESI) m/z 555 (M+H) + ; HRMS (FAB) calcd for C32H32N2O2Br (M+H) + 555.1647. Found 555.1644; [] 26 D – (c = 0.3, DMF).

PAPER

Gaurrand, Sandrine; Chemical Biology & Drug Design 2006, VOL 68(2), PG 77-84 

http://web.a.ebscohost.com/ehost/pdfviewer/pdfviewer?vid=1&sid=fac0fcc3-2a10-4f5f-8e20-d057adf71ce9%40sessionmgr4006

str1 str2

PAPER

Chandrasekhar, Srivari; European Journal of Organic Chemistry 2011, (11), PG 2057-2061, S2057/1-S2057/18

Srivari Chandrasekhar

Dr.Chandrasekhar S
Director 
CSIR-Indian Institute of Chemical Technology                              
(Council of Scientific and Industrial Research)
Ministry of Science & Technology, Government of India
Tarnaka, Hyderabad-500007, Telangana, INDIA

Landline 27193030
Mobile 9440802787
Fax
Email ID director@iict.res.in
Alternate Email ID srivaric@iict.res.in
Alternate URL http://www.iictindia.org/staffprofiles/staffProfile.aspx?emp_id=iict1372

READ

http://www.iictindia.org/staffprofiles/staffprofile.aspx?qry=1372

(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)- 2-(naphthalen-1-yl)-1-phenylbut-an-2-ol (3a): A solution of 16a and 16b (6.0 g, 10.2 mmol) in Me2NH (200 mL, 8.0 m in THF) was stirred at 45 °C for 24 h. The solution was filtered and the filtrate concentrated under reduced pressure to afford the crude product which on purification by silica gel column chromatography (eluent: ethyl acetate/hexane = 1:6) furnished 3a and 3b as white solids (4.8 g, 90%) (1:1 w/w).

3a: M.p. 104 °C. [α]D 25 = –165.2 (c = 0.8, DMF). (2S)- R207910 (3a)

1 H NMR (300 MHz, CDCl3): δ = 8.89 (s, 1 H, H4), 8.61 (d, J = 8.6 Hz, 1 H, H20), 7.96 (d, J = 2.0 Hz, 1 H, H5), 7.92 (d, J = 7.4 Hz, 1 H, H14), 7.87 (d, J = 8.1 Hz, 1 H, H17), 7.72 (d, J = 8.8 Hz, 1 H, H8), 7.68–7.56 (m, 3 H, H7, H16, H19), 7.48 (t, J = 7.6 Hz, 1 H, H18), 7.30 (t, J = 7.7 Hz, 1 H, H15), 7.17–7.10 (m, 2 H, H24), 6.93–6.83 (m, 3 H, H25, H26), 5.89 (s, 1 H, H11), 4.21 (s, 3 H, H30), 2.60–2.51 (m, 1 H, H27), 2.18–2.02 (m, 2 H, H27, H28), 1.99 (s, 6 H, H29), 1.95–1.85 (m, 1 H, H28) ppm.

13C NMR (75 MHz, CDCl3): δ = 161.3, 143.7, 141.6, 140.5, 138.7, 134.6, 131.9, 129.9, 129.8, 129.7, 128.4, 128.1, 127.8, 127.3, 127.1, 126.8, 125.7, 125.2, 125.1, 125.0, 124.4, 116.9, 82.4, 56.2, 54.1, 49.5, 44.6, 33.4, 29.6 ppm.

IR (KBr): ν˜ = 3441 cm–1.

HRMS (ESI) calcd. for C32H32BrN2O2 [M + H]+ 555.1642; found 555.1671.

(2R)-R207910

References[

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Bedaquiline
Bedaquiline.svg
Clinical data
Trade names Sirturo
Synonyms Bedaquiline fumarate,[1]TMC207,[2] R207910, AIDS222089
AHFS/Drugs.com Monograph
License data
Pregnancy
category
  • US: B (No risk in non-human studies)
Routes of
administration
by mouth
ATC code
Legal status
Legal status
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Protein binding >99.9% [4]
Metabolism Liver, by CYP3A4[3]
Biological half-life 5.5 months [3]
Excretion fecal[3]
Identifiers
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
Chemical and physical data
Formula C32H31BrN2O2
Molar mass 555.5 g/mol
3D model (JSmol)

FDA Orange Book Patents

FDA Orange Book Patents: 1 of 2 (FDA Orange Book Patent ID)
Patent 8546428
Expiration Mar 19, 2029
Applicant JANSSEN THERAP
Drug Application N204384 (Prescription Drug: SIRTURO. Ingredients: BEDAQUILINE FUMARATE)
FDA Orange Book Patents: 2 of 2 (FDA Orange Book Patent ID)
Patent 7498343
Expiration Oct 2, 2024
Applicant JANSSEN THERAP
Drug Application N204384 (Prescription Drug: SIRTURO. Ingredients: BEDAQUILINE FUMARATE)
Patent ID

Patent Title

Submitted Date

Granted Date

US7498343 Mycobacterial inhibitors
2005-07-07
2009-03-03
US8546428 FUMARATE SALT OF (ALPHA S, BETA R)-6-BROMO-ALPHA-[2-(DIMETHYLAMINO)ETHYL]-2-METHOXY-ALPHA-1-NAPHTHALENYL-BETA-PHENYL-3-QUINOLINEETHANOL
2010-02-04

//////////////Bedaquiline, JAPAN 2018, R 207910, Sirturo, TMC 207, FDA 2012, EMA 2014, ベダキリンフマル酸塩

CN(C)CCC(C1=CC=CC2=CC=CC=C21)(C(C3=CC=CC=C3)C4=C(N=C5C=CC(=CC5=C4)Br)OC)O.C(=CC(=O)O)C(=O)O

Vismodegib


Vismodegib3Dan.gif

Vismodegib2DACS.svg

 

 

Vismodegib

2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide

Vismodegib; 879085-55-9; GDC-0449; 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide; Erivedge; HhAntag691; CUR-691
GDC-449
Hh-Antag691
HhAntag
R-3616
RG-3616

421.29706 g/mol

C19H14Cl2N2O3S

LAUNCHED 2012

Vismodegib is a Hedgehog Pathway Inhibitor. The mechanism of action of vismodegib is as a Smoothened Receptor Antagonist.

Hedgehog Antagonist GDC-0449 is an orally bioavailable small molecule with potential antineoplastic activity. Hedgehog antagonist GDC-0449 targets the Hedgehog signaling pathway, blocking the activities of the Hedgehog-ligand cell surface receptors PTCH and/or SMO and suppressing Hedgehog signaling. The Hedgehog signaling pathway plays an important role in tissue growth and repair; aberrant constitutive activation of Hedgehog pathway signaling and uncontrolled cellular proliferation may be associated with mutations in the Hedgehog-ligand cell surface receptors PTCH and SMO.

NMR from net

 

 

Vismodegib.png

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

Vismodegib (trade name Erivedge) is a drug for the treatment of basal-cell carcinoma (BCC). The approval of vismodegib on January 30, 2012, represents the first Hedgehog signaling pathway targeting agent to gain U.S. Food and Drug Administration (FDA) approval.[1] The drug is also undergoing clinical trials for metastatic colorectal cancer, small-cell lung cancer, advanced stomach cancer, pancreatic cancer, medulloblastoma and chondrosarcoma as of June 2011.[2] The drug was developed by thebiotechnology/pharmaceutical company Genentech, which is headquartered at South San Francisco, California, USA.

Indication

Vismodegib is indicated for patients with basal cell carcinoma (BCC) which has metastasized to other parts of the body, relapsed after surgery, or cannot be treated with surgery or radiation.[3] [4]

Mechanism of action

The substance acts as a cyclopamine-competitive antagonist of the smoothened receptor (SMO) which is part of the hedgehog signaling pathway.[2] SMO inhibition causes the transcription factors GLI1 and GLI2 to remain inactive, which prevents the expression of tumor mediating genes within the hedgehog pathway.[5] This pathway is pathogenetically relevant in more than 90% of basal-cell carcinomas.[6]

 

PAPER

Bioorg Med Chem Lett 2009, 19(19): 5576

http://www.sciencedirect.com/science/article/pii/S0960894X10012709

Schematic for the discovery of 2 (GDC-0449) from 1, and the inspiration for ...

Figure 1.

Schematic for the discovery of 2 (GDC-0449) from 1, and the inspiration for further analogs 3 and 4

 

CN 103910671

http://www.google.com/patents/CN103910671A?cl=en

In embryonic development, Hedgehog signaling in cell differentiation, tissue development and organogenesis play an important role. In the adult body, Hedgehog signaling pathway is mainly in slumber, but when abnormal tissue growth and self-healing, Hedgehog pathway may be activated. With the in-depth study of the tumor, the presence of numerous evidence of abnormal tumor occurrence and the close relationship between Hedgehog signaling pathway, such as sporadic basal cell carcinoma, medulloblastoma, small cell lung cancer and gastrointestinal cancer and other diseases, therefore Hedgehog signaling pathway targeted anti-cancer therapy inhibitors become hot.

 Vismodegib chemical name 2_ chlorine -N_ (4_ chlorine _3_ (_2_ pyridyl) phenyl) _4_ (methylsulfonyl) benzamide, is by Roche’s Genentech (Genentech) Hedgehog pathway inhibitors developed, and can be inhibited by binding seven transmembrane protein Smoothened (Smo), thereby preventing signal transduction. Vismodegib capsule in January 2012 I was approved and listed by the US Food and Drug Administration, under the trade name Erivedge, for the treatment of adults with the most common type of skin cancer – basal cell carcinoma. This medicine is not intended for surgery or radiotherapy of cancer and basal cell skin cancer locally advanced patients have been transferred. This was the first drug approved for the treatment of basal cell carcinoma.

 

Figure CN103910671AD00051

W02006028958 Vismodegib disclose the following synthesis route:

 Route One Negishi coupling reactions

 

Figure CN103910671AD00052

wherein, X1 is chloro, bromo or iodo; X2 is bromo, iodo or tosylate. The route to the 2-halo-pyridine as starting material an organic zinc compound, and then prepared by Negishi coupling reaction to give 2- (2-chloro-5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine in turn through a reduction reaction with acylation reaction, to give the final product Vismodegib. The key coupling step of the route using an organic zinc reagent required to react under strict anhydrous, anaerobic conditions.

 The second route Suzuki coupling reaction [0010]

Figure CN103910671AD00061

 wherein, X2 is bromo, iodo or tosylate. The route from 3-halo-4-chloro-nitrobenzene as raw material, and 2-chloro-5-nitrophenyl boronic acid pinacol ester, and then reacted with a 2-halo-pyridine was prepared to give 2- (2-chloro 5-nitrophenyl) pyridine. 2- (2-chloro-5-nitrophenyl) pyridine then after reduction and acylation reaction, to give the final product Vismodegib. The key coupling step of the route using the Suzuki coupling reaction, organic boron reagent price to use expensive, high production costs.

 The route three Suzuki coupling reaction

 

Figure CN103910671AD00062

wherein, X2 is bromo, iodo or tosylate. Similar to the second route, the route is still critical coupling step using a Suzuki coupling reaction, the same need to use expensive organic boron reagents, higher production costs.

 route four Stille coupling reaction

 

Figure CN103910671AD00063

 The route to 2-p-toluenesulfonyl pyridine as starting material, is reacted with an organotin reagent, prepared to give pyridin-2-yl trimethyltin, then by Stille coupling reaction, was prepared to give 2- (2-chloro – 5- nitrophenyl) pyridine, followed by reduction reaction, acylation prepared to give Vismodegib. The key step of the route using the Stille coupling reaction, this step need to use expensive and toxic organotin reagents, and the need to carry out the reaction under strict anhydrous, anaerobic conditions.

A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising: a compound of formula III was prepared as a compound of Formula II;

Figure CN103910671AC00021

Then, the compound of formula II with a compound of formula I, to give 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide;

Figure CN103910671AC00022

Wherein, R1 is halogen or hydroxy, preferably chlorine, or a hydroxyl group.

2. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Figure CN103910671AC00023

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

3. A process for preparing 2-chloro -N- (4- chloro-3- (pyridin-2-yl) phenyl) -4- (methylsulfonyl) benzamide, comprising:

Figure CN103910671AC00031

Wherein, X is halogen, preferably bromo or iodo condition is halo or hydroxy, preferably chlorine, or a hydroxyl group.

Method 2 or claim 3,

Example 1: N–oxo-2- (2-chloro-5-nitrophenyl) pyridine

 

Figure CN103910671AD00121

[0108] To a 100mL three-necked flask were added 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol potassium carbonate, 0.05mmol tri-butyl acetate button and 0.15mmol phosphorus tetrafluoroborate salt, 40ml of toluene, IS gas exchange three times, under argon at reflux for 2 days, then the reaction mixture was poured into 100mL of ethyl acetate, filtered, and the filtrate was washed with saturated brine, dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50), fractions were collected and the solvent was distilled off under reduced pressure to give a pale yellow solid, yield 60%.

 1HMffi (500Hz, DMS0_d6): 8.35 (m, 3H), 7.90 (d, 1Η), 7.62 (q, 1Η), 7.55 (m, 1Η), 7.48 (m, 1Η);

 MS: 251.1,253.1 ([Μ + Η] +).

2  Example: Ν–oxo-2- (2-chloro-5-nitrophenyl) pyridine

 

Figure CN103910671AD00131

 To a 100mL three-necked flask 30mmoll- oxopyrido, 10mmol2- bromo-1-chloro-4-nitrobenzene, 12mmol of potassium carbonate, 0.05mmol iodide and 0.1Ommoll, 10- Fei Luo Jie morpholine, 40ml of xylene, an argon gas exchange three times, under argon at reflux for 2 days, cooled to room temperature and then the reaction system was poured into 100mL methylene chloride, filtered and the filtrate washed with saturated brine, dried, filtered, The filtrate solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: methanol / dichloromethane = 1/50) to give a pale yellow solid, yield 42%. .

3  Example: 2- (2-chloro-5-nitrophenyl) pyridine

 

Figure CN103910671AD00132

After 3.0mmol N- oxo added to 100mL of Lord vial _2_ (2_ chloro _5_ nitrophenyl) pyrazole 唳, 15mmol phosphorus trichloride and 30ml of chloroform was heated at reflux for 12h, the reaction It was poured into 100mL of water and extracted with ethyl acetate (50ml X 2), and the combined organic phase was dried and the solvent was distilled off under reduced pressure, column chromatography (mobile phase V / V: petroleum ether / ethyl acetate = 20/1) , fractions were collected, the solvent was distilled off under reduced pressure to give a white solid, yield 95%.

 1Hnmr (SooHzJDCI3): 8.78 (d, 1H), 8.51 (d, 1H), 8.20 (m, 1H), 7.85 (m, 1H), 7.72 (d, 1H), 7.65 (d, 1H), 7.40 (m, 1H);

MS: 235.1,237.1 ([M + H] +).

4 Example 2: Preparation 4_ chlorine _3_ (topiramate 唳 _2_ yl) aniline

 

Figure CN103910671AD00133

 To a vial was added 100mL of Lord 20mmol2- (2- chloro-5-nitrophenyl) pyridine 唳, 50ml of acetic acid, heated to 80 ° C and stirred, and then slowly added IOOmmol iron, reaction 0.5h The reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X 3), the combined organic phases, the organic phase was washed with saturated sodium carbonate solution (50ml X 3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a pale yellow solid, yield 75%.

1HMflUSOOHz, DMS0_d6): 8.63 (m, 1H), 7.84 (m, 1H), 7.56 (d, 1H), 7.37 (m, 1H),

7.13 (d, 1H), 6.76 (d, 1H), 6.61 (q, 1H), 5.32 (s, 2H);

 MS: 205.1,207.1 ([M + H] +).

5 Example: 4-chloro-3- (pyridin 唳-2-yl) aniline

 

Figure CN103910671AD00141

to 100mL of God-shaped flask 20mmol2_ (2_ chlorine _5_ nitrophenyl) pyridine Jie set, 50ml of methanol, Ig activated carbon, 2mmol FeOOH and 60mmol85% of hydrazine hydrate, heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, the organic phase was washed with saturated sodium bicarbonate solution (20ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product was recrystallized from n-propanol to give a pale yellow solid, yield 96%.

6 Example 2: Preparation 4_-chloro-3- (2-yl) aniline

 

Figure CN103910671AD00142

 20mmol N- oxo added to 100mL eggplant-shaped flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of acetic acid, heated to 80 ° C and stirred, and then iron powder was slowly added IOOmmol After 0.5h the reaction the reaction solution was poured into 200ml water and extracted with dichloromethane (150ml X3), the combined organic phases were washed with saturated sodium carbonate solution (50ml X3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propanol recrystallized to give a white solid, yield 70%.

Preparation 7.Α ~ chlorine -3_ (topiramate 唳 2-yl) aniline [0130] Example

 

Figure CN103910671AD00143

 20mmol N- oxo added to 100mL eggplant type flask _2_ (2_ chloro _5_ nitrophenyl) pyridine, 50ml of methanol, Ig active carbon, 2mmol FeOOH 60mmol85% hydrazine hydrate and heated to reflux and stirred for 6 ~ 8h, after the completion of the reaction, was filtered, spin-dry the solvent, dissolved in 150ml of dichloromethane, washed with saturated aqueous sodium bicarbonate solution, the organic phase (20mlX3), the organic phase was dried, evaporated under reduced pressure to give the crude product, n-propyl alcohol weight crystallized to give a white solid, yield 82%.

Vismodegib Preparation: 8 Example

 

Figure CN103910671AD00144

In the Lord 50ml vial, the 1.50mmol2- chloro-4-methanesulfonyl-chloride in 15ml of dry tetrahydrofuran, cooled to ice bath O ~ 10 ° C, a solution of 4-chloro-3 – (pyridin-2-yl) aniline in anhydrous tetrahydrofuran (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction system was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

1HNMR (500Hz, DMS0_d6): 10.90 (s, 1H), 8.70 (d, 1H), 8.12 (d, 1H), 8.01 (t, 2H), 7.92 (m, 2H), 7.74 (q, 1H ), 7.69 (d, 1H), 7.58 (d, 1H), 7.44 (m, 1H), 3.34 (s, 3H).

 MS: 421.1,423.1 ([M + H] +).

Vismodegib Preparation: 9  Example

 

Figure CN103910671AD00151

 In 50ml vial of God, will 1.50mmol2_ chlorine _4_ methylsulfonyl benzoic acid, 1.47mmol4_ chlorine _3_ (batch 唳 2-yl) aniline and triethylamine were dissolved in 25ml 2.5mmol anhydrous tetrahydrofuran in an ice bath to cool to O ~ 10 ° C, was added in portions N, N ‘- dicyclohexyl carbodiimide (DCC) 1.50mmol, After the addition, the reaction at room temperature 6h, after the reaction, white solid was removed by filtration, the filtrate was poured into 50ml water and stirred, precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 84%.

Vismodegib Preparation: 10 [0141] Example

 

Figure CN103910671AD00152

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

 

PATENT

CN 103910672

http://www.google.com/patents/CN103910672A?cl=en

Vismodegib PreparatioN

Figure CN103910672AD00192

 In 50ml eggplant-shaped flask, 1.50mmol2- chloro-4-methanesulfonyl-benzoic acid was dissolved in 15ml of dichloromethane, cooled to ice bath O ~ 5 ° C, thionyl chloride was added dropwise 3.0mmol After stirring at room temperature 30min, removed by rotary evaporation dichloromethane and excess thionyl chloride, 15ml of anhydrous tetrahydrofuran was added, the ice bath was cooled to O ~ 10 ° C, solution of 4-chloro-3- (pyridin-2- yl) aniline in anhydrous THF (1.47mmol / 10ml), triethylamine was added dropwise and then finished 2.5mmol of dropwise addition, the reaction at room temperature 4h, the reaction was completed, the reaction was poured into 50ml water system and stirring, the precipitated solid was filtered, washed with water, and dried to give a white solid product, yield 88%.

PATENT

WO2006028958

https://www.google.co.in/patents/WO2006028958A2?cl=en

Example 1 General Procedure

Compounds of examples 2-51 were prepared according to the following general procedures.

A: Suzuki Coupling Procedure

Figure imgf000069_0001

2 M aq. Potassium carbonate (5.0 eq) and 4:1 toluene :ethanol mixture (2.5 mL) were added to a microwave vial charged with the appropriate boronate ester (2.6 eq), aryl halide (0.35 mmol, 1.0 eq), and Pd(PPh3)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 160 0C for ten minutes. The solution was poured onto 2 M aq. Sodium hydroxide (20 mL), extracted with ethyl acetate (2 x 20 mL), dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

B: Negishi Coupling Procedure

Figure imgf000070_0001

X = I or Br R = H, 3-Me, 4-Me5 5-Me, 6-Me

Aryl zinc bromide (0.5 M in THF, 2.5 eq) was added to an oven-dried microwave vial charged with the appropriate aryl halide (1.0 eq) and Pd(PPh3)4 (0.04 eq). The vial was sealed and heated with stirring in the microwave to 140 0C for 10 minutes. The crude reaction mixture was concentrated and purified by chromatography on silica gel (conditions given below) to afford the desired product.

C: Iron Reduction of Aryl Nitro Group

Figure imgf000070_0002

R = I or pyridin-2-yl

The appropriate nitro aryl (1 mmol, 1 eq) in AcOH/EtOH (1:1, 0.42 M) was added slowly to a solution of Iron powder (6.0 eq) in AcOH/EtOH (1:2, 2 M) at 60 °C. The solution was stirred at 70 0C for 30-60 minutes. The reaction mixture was cooled to 23 0C, filtered through celite, washed with ethyl acetate, and concentrated. The oily residue was dissolved in ethyl acetate (30 mL), washed with saturated aq. NaHCO3 (2 x 15 rnL) and water (2 x 10 niL), dried (MgSO4), and concentrated. The oily residue was used with out further purification.

D: Amide Bond Formation

Figure imgf000071_0001

R = I or pyridin-2-yI

Acid chloride (1.05-1.1 eq) was added to a solution of aniline (1.0 eq) and TEA (1.1-1.5 eq) in methylene chloride at the indicated temperature. The solution was stirred for 0.5-3 hours, poured onto saturated aq. NaHCO3, extracted twice with methylene chloride, dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product.

E: EDC Amide Bond Formation

Figure imgf000071_0002

R = I or pyridin-2-yl

Carboxylic acid (1.1 eq) was added to a solution of aniline (1.0 eq) and EDC (1.4 eq) in methylene chloride (0.7 M in aniline). The solution was stirred at 23 0C for 2 hours, poured onto a 1 :1 mixture of saturated aq. NH4Cl and water, extracted twice with methylene chloride, dried (MgSO4), and concentrated. Purification of the crude product by chromatography on silica gel (conditions given below) afforded the desired product. F: addition of amines to 2-chloropyridine

Figure imgf000072_0001

NHRR’ = ethanolamine, analine, benzylamine, 2-methylpropylamine, N-methylpiperazine, morpholine, 2-morpholinoethylamine

Primary or secondary amine (5 eq) in either BuOH or a mixture of BuOH/ethylene gylcol was heated to 170 to 220 0C for 20 min in a sealed tube. The BuOH was removed under reduced pressure. In cases where ethylene glycol was used, the reaction was diluted with water, and the product was extracted into ethyl acetate, dried (MgSO^, and concentrated. The crude residue was purified by reverse phase HPLC to afford the desired product.

G: Amide bond coupling with HATU

HATU, DIPEA, DMF NaOH or NaHCO3

Figure imgf000072_0002

ethyl acetate extraction

Figure imgf000072_0003

Aniline (1.0 eq) was added to a mixture of carboxylic acid (1.1 eq), HATU (1.1 eq) and DIPEA (2 eq) in DMF (0.1 – 0.2 M). After stirring overnight, the reaction mixture was diluted with 0.1 N sodium hydroxide or saturated NaHCθ3, extracted into ethyl acetate and the combined organic layers were washed with brine. The organic layer was dried (MgSO4), concentrated and the crude mixture was purified by reverse phase HPLC. H: Preparation of sulfonamide benzoic acids

Figure imgf000073_0001

Chlororsulfonylbenzoic acid (1.0 eq) was added to a solution of amine (1.1 eq) in 10-20% DEPEA/methanol (1 M) at 4 0C. After 1 h, the reaction mixture was concentrated, and the crude residue was purified by reverse phase HPLC.

I : Stannylation of 2-pyridyl triflates

Figure imgf000073_0002

A solution of tetrakis-triphenylphosphinepalladium (0.04 eq.) in toluene (1 mL) was added to degassed solution of aryltriflate (1 eq), bis-trialkyltin (1.05 eq), and lithium chloride (3 eq) in dioxane. Heated to reflux for 2 hours, cooled to 23 0C, diluted with ethyl acetate, washed with 10% NH4θH(aq) and brine, dried (MgSO4) and concentrated. The crude material was used without further purification.

J: Stannylation of substituted pyridines

Figure imgf000073_0003

ιMmβco3 n-Butyl lithium (6 eq, 2.5 M in hexanes) was added dropwise to a solution of dimethylaminoethanol (3 eq) in hexane at 0 0C. The solution was stirred at 0 0C for thirty minutes before dropwise addition of the substituted pyridine (1 eq). The solution was stirred at 0 0C for an additional hour, then cooled to -78 0C. A solution of trialkyltin in hexane was added dropwise. The solution was stirred at -78 0C for thirty minutes, warmed to 0 0C, quenched with water, extracted twice with ether, dried (MgSO4), and concentrated. K: Stille Coupling

Figure imgf000074_0001

Palladium catalyst (0.02 eq) was added to a degassed solution of aryliodide (1 eq), arylstannane (2 eq), and triphenylphosphine (0.16 eq) in NMP. Heated in the microwave to 130 0C for 15 minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH4θH(aq) and brine, dried (MgSC>4), concentrated and purified by silica gel chromatography.

L: Synthesis of alky lethers

Figure imgf000074_0002

A solution of hydroxypyridine (1 eq), alkyliodide (excess), and cesium carbonate in NMP was heated in the microwave to 1000C for ten minutes. The reaction mixture was diluted with ethylacetate, washed with 10% NH4θH(aq) and brine, dried (MgSC^), concentrated and purified by silica gel chromatography.

M: Methyl Ester Saponification

Figure imgf000074_0003

The methyl ester (leq) was hydrolyzed with LiOH (2eq) in 50/50 THF/water mix. Upon completion of the reaction the THF was evaporated under reduced pressure and the solution is acidified with HCl to pH 2. The resultant solid was filtered and dried to give the pure acid.

N: Bromination in the presence of a free acid functionality

Figure imgf000075_0001

The paramethylbenzoic acid (leq) was combined with Benzoyl Peroxide (O.leq) and N- Bromosuccinimde (0.9eq) in a solution of 5%AcOH in Benzene and heated in the microwave at 120°C for 5-15minutes. The product was separated from the starting material and di-bromo product via ISCO flash chromatography with an ethyl acetate (with 1% AcOH) and hexanes solvent system.

O: Sodium Methanesulfinate displacement of Bromine

Figure imgf000075_0002

To the bromine starting material (leq) was added sodium methanesulfinate (2eq) in DMF and heated to 120°C in the microwave for 5 minutes. Alternatively, the reaction was heated to 60°C in an oil bath for several hours until completed. Reaction mixture was concentrated under reduced pressure and extracted in ethyl acetate and water. The organic layer was dried over Magnesium Sulfate, filtered and concentrated in vacuo to yield generic methylsulfone.

P: Amine displacement of Bromine

Figure imgf000076_0001

To the bromo starting material (leq) was added appropriate amine (3eq) in either DMSO or BuOH and stirred at room temperature until complete. For less nucleophilic amines or anilines, the reactions were forced to completion using microwave conditions ranging from 150°-170°C for 15 minutes. Crude reactions were concentrated to dryness and either extracted with ethyl acetate and saturated bicarbonate if the reaction resulted in an intermediate or purified via HPLC if the reaction resulted in a final product.

Q: Thiol displacement of halogen

Figure imgf000076_0002

The paramethylbromo benzoate (leq) was treated with Potassium (or Cesium) Carbonate (1.5eq) and appropriate thiol derivative (l,leq) in DMF (or CH3CN) and stirred overnight at room temperature. The DMF was evaporated in vacuo and the reaction was extracted with ethyl acetate and water. The organic layer was dried over Magnesium Sulfate , filtered and concentrated to yield the thiol or derivatized thiol compound.

R: Oxone Oxidation

oxone 2:1 MeOHTH2O

Figure imgf000076_0004
Figure imgf000076_0003

Derivatized thiol (leq) was dissolved in MeOH while Oxone (2eq) was seperately dissolved in half the amount of water. Once all the oxone was dissolved, the solution was added to the thiol in MeOH solution at once and stirred until complete. The MeOH was evaporated in vacuo and the remaining water was extracted twice with Ethyl Acetate. The organic layer was dried over Magnesium Sulfate and concentrated to yield the sulfone.

S: Thio lysis of epoxides at alumina surfaces

Figure imgf000077_0001

A mixture of epoxides (1.0 eq), thiophenol (1.5 eq) and neutral aluminum oxide (~70 eq) in diethyl ether was stirred for 3 h at room temperature while being monitored by TLC. The reaction mixture was filtered through Celite, washed with ethyl acetate and concentrated. Purified by silica gel chromatography (0-40% ethyl acetate/hexane) to yield β -hydroxysulfide product.

T: Conversion of nitrile group to carboxylic acid

Figure imgf000077_0002

R

A solution of benzonitrile (1.0 eq) and sodium hydroxide (2.0 eq) in H2O was heated to 120 ° C for 2h. The reaction mixture was cooled to room temperature and acidified with HCl to pH 2. The resulting solid was filtered to afford the pure acid product.

U. Alkylation of phenols

Figure imgf000078_0001

The phenol was dissolved in DMF (1.0 ml). Cesium carbonate (1.0 eq.) and an alkyl bromide or alkyl iodide (1.0 to 2.0 eq.) were added, and the reaction was stirred at room temperature for 18 hrs or 5O0C for 1 to 24 hours. The reaction was quenched in water, and extracted with ethyl acetate twice. The organic extracts were washed with water once, brine once, dried with MgSC>4, and evaporated to a crude oil which was purified on reverse phase HPLC.

V. Amide bond formation with an acid chloride and an aniline

Figure imgf000078_0002

The aniline was dissolved in THF (1.5 ml) and dichloromethane (1.5 ml). MP-Carbonate (1.5 eq.) and an acid chloride (1.1 eq.) were added, and the solution was stirred at room temperature for 18 hours. The reaction was diluted with methanol and dichloromethane, and filtered to remove the MP-Carbonate. The mother liquors were evaporated to a solid and purified by reverse phase HPLC.

W. Amidine formation from an imidate

Figure imgf000078_0003

A solution of freshly formed imidate in methanol was treated with a primary or secondary amine (1.5 eq.) at room temperature for 18 hours. The methanol was removed on a rotary evaporator and the residue purified by reverse phase HPLC.

 

Example 37 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide

Figure imgf000097_0002

Procedure G was used to couple 4-chloro-3-(pyridin-2-yl)aniline (50 mg) and 2-chloro-4- methylsulfonylbenzoic acid to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4- (methylsulfonyl)benzamide. MS (Ql) 421.0 (M)+. The product was then dissolved in 1 Ν HCI solution followed by freebasing with 0.5 Ν NaOH solution (pH to 11). The resulting precipitate was filtered and vacuum-dry.

Procedure D may also be used to couple 4-chloro-3-(pyridin-2-yl)aniline and 2-chloro-4- (methylsulfonyl)benzoyl chloride to produce 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-

(methylsulfonyl)benzamide which is collected by suction filtration and the HCl salt is washed with

Et2O (or alternatively with MTBE). This material is freebased using EtOAc/aq NaHCO3 and the organics are dried and concentrated to the solid freebase. This material is then crystallized from acetone :EtOAc (80:20, approx lOmL/g) which is then finally recrystallized from hot slurry of iPrOAc. 2-chloro-N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(methylsulfonyl)benzamide HCl salt may also be dissolved in distilled water followed by freebasing with 0.5 N NaOH solution (pH to 11) and filtering and vacuum drying the precipitate.

Patent

 

 

 

WO 2016020324, BASF AG, vismodegib , new patent

WO2016020324,  MULTI-COMPONENT CRYSTALS OF VISMODEGIB AND SELECTED CO-CRYSTAL FORMERS OR SOLVENTS

BASF SE [DE/DE]; 67056 Ludwigshafen (DE)

VIERTELHAUS, Martin; (DE).
CHIODO, Tiziana; (DE).
SALVADOR, Beate; (DE).
VOSSEN, Marcus; (DE).
HAFNER, Andreas; (CH).
HINTERMANN, Tobias; (CH).
WEISHAAR, Walter; (DE).
HELLMANN, Rolf; (DE)

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 and a second compound selected from the group consisting of co-crystal formers and sol-vents. The invention is further related to pharmaceutical compositions comprising such multi-component crystals. Furthermore, the invention relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease.front page image

Developed and launched by Roche and its subsidiary Genentech, under license from Curis. Family members of the product Patent of vismodegib (WO2006028958),

Vismodegib was first disclosed in WO Patent Publication No. 06/028959. Vismodegib, chem-ically 2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide, is represented by the following structure:

formula 1

Vismodegib is an active pharmaceutical ingredient produced by Genentech (Roche) and sold under the trade name Erivedge® (which contains crystalline Vismodegib as the active ingre-dient). Erivedge® is an oral Hedgehog signaling pathway inhibitor approved for the treatment of basal-cell carcinoma (BCC).

The present invention primarily relates to multi-component crystals comprising a compound of formula 1 (cf. above) and a second compound selected from the group consisting of co-crystal formers and solvents.

The invention is further related to pharmaceutical compositions comprising said multi-component crystals. Furthermore, the invention also relates to processes for preparing said multi-component crystals. The invention also relates to several aspects of using said multi-component crystals or pharmaceutical compositions to treat a disease. Further details as well as further aspects of the present invention will be described herein below.

Vismodegib is a BCS class II compound with a high permeability but a low solubility where enhanced solubility or dissolution rates can lead to a significant advantage in respect to bio-availability.

Vismodegib is known to exist as crystalline free base. Salts of Vismodegib are men-tioned in US 7,888,364 B2 but not specified. In particular, the HCI salt is mentioned as intermediate but not characterized. Co-crystals or solvates are not reported at all.

The solubility of Vismodegib is reported to be 0.1 μg/mL at pH 7 and 0.99 mg/mL at pH 1 for Erivedge®. The absolute bio-availability after single dose is reported to be 31.8 % and the ex-posure is not linear at single doses higher than 270 mg. Erivedge® capsules do not have a food label. The estimated elimination half-life (t1/2) after continuous once-daily dosing is 4 days and 12 days after a single dose treatment (Highlights of Prescribing Information: ERIVEDGE® (vismodegib) capsule for oral use; Revised: 01/2012).

The discovery and preparation of new co-crystals or solvates offer an opportunity to improve the performance profile of a pharmaceutical product. It widens the reservoir of techniques/materials that a formulation scientist can use for designing a new dosage form of an active pharmaceutical ingredient (API) with improved characteristics. One of the most important characteristics of an API such as Vismodegib is the bio-availability which is often determined by the aqueous solubility.

A compound like Vismodegib may give rise to a variety of crystalline forms having dis-tinct crystal structures and physical characteristics like melting point, X-ray diffraction pattern, infrared spectrum, Raman spectrum and solid state NMR spectrum. One crystalline form may give rise to thermal behavior different from that of another crystalline form. Thermal behavior can be measured in the laboratory by such techniques as capillary melting point, thermogravimetry (TG), and differential scanning calorimetry (DSC) as well as content of sol-vent in the crystalline form, which have been used to distinguish polymorphic forms.

Multi-component crystals comprising Vismodegib and selected co-crystal formers or solvents may improve the dissolution kinetic profile and allow to control the hygrosco-picity of Vismodegib.

Therefore, there is a need for multi-component crystals comprising Vismodegib that avoid the above disadvantages. In particular, it is an object of the present invention to provide multi-component crystals of Vismodegib with optimized manufacture, formula-tion, stability and/or biological efficacy

.

Example 1 :

314 mg Vismodegib and 86 mg maleic acid are suspended in toluene saturated with maleic acid for 2 d, filtered and dried.

TG data shows a mass loss of about 2.3 wt % between 100 and 1 18 °C which is attributed to rest solvent. DSC data shows a single endothermal peak with an onset of about 1 15 °C (99 J/g).

H-NMR spectroscopy indicates a molar ratio of Vismodegib to maleic acid of about 1 :1 .3. However single crystal X-ray data confirms a ratio of 1 :2 (Table 1 ).

 

update……………

Vismodegib Synthesis

WO2009126863A2: also see Ref. 1. It all started from here.


Identification:

1H NMR (Estimated) for Vismodegib

Experimental: 1H NMR (400MHz, CDCl3) δ (ppm): 9.58 (bs, 1H), 8.43 (d, J = 4.7Hz, 1H), 8.03 (dd, J = 2.6, 8.7Hz, 1H), 7.90 (d, J = 1.6Hz, 1H), 7.67-7.78 (m, 4H), 7.60 (d, J = 8.0Hz, 1H), 7. 51 (d, J = 8.8Hz, 1H), 7.23-7.24 (m, 1H), 3.01 (s, 3H).

UPDATES…….

Manufacturing Development and Genotoxic Impurity Control Strategy of the Hedgehog Pathway Inhibitor Vismodegib

Small Molecule Process Chemistry, Small Molecule Analytical Chemistry, Genentech, A Member of the Roche Group, 1 DNA Way, South San Francisco, California 94080, United States
§ Siegfried AG, Untere Brühlstrasse 4, CH-4800 Zofingen, Switzerland
Org. Process Res. Dev., Article ASAP
Abstract Image

The development work toward the robust and efficient manufacturing process to vismodegib, the active pharmaceutical ingredient (API) in Erivedge, is described. The optimization of the four-stage manufacturing process was designed to produce the API with the required critical quality attributes: (1) the selective catalytic hydrogenation reduction of the nitro compound 3 to the corresponding aniline 4 while minimizing the formation of potential genotoxic (mutagenic) impurities; (2) the control of the polymorphic phase and multipoint specification for particle size distribution.

Vismodegib2DACS.svg

Vismodegib

 

1H

 

13C

 

 

////////////////

References

External links

PatentSubmittedGranted

Pyridyl inhibitors of hedgehog signalling [US7888364]2006-03-232011-02-15

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2009281089]2009-11-12

ANTI-HEDGEHOG ANTIBODIES [US8030454]2010-01-072011-10-04

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2011092461]2011-04-21

PYRIDYL INHIBITORS OF HEDGEHOG SIGNALLING [US2012094980]2011-10-142012-04-19

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2013045240]2010-08-252013-02-21

COMBINATION THERAPY WITH NANOPARTICLE COMPOSITIONS OF TAXANE AND HEDGEHOG INHIBITORS [US2014072630]2013-02-282014-03-13

Acyl guanidine derivatives modulating the hedgehog protein signaling pathway [US8889678]2010-07-192014-11-18

COMBINATION THERAPY [US2012184529]2012-01-032012-07-19

METHOD OF INHIBITING DYRK1B [US2014371251]2014-06-182014-12-18

USE OF SUBSTITUTED HEXITOLS INCLUDING DIANHYDROGALACTITOL AND ANALOGS TO TREAT NEOPLASTIC DISEASE AND CANCER STEM AND CANCER STEM CELLS INCLUDING GLIOBLASTOMA MULTIFORME AND MEDULLOBLASTOMA [US2014377336]2013-01-222014-12-25

SHH Regulation and Methods Thereof [US2012082623]2011-09-302012-04-05

NOVEL 2-PIPERIDIN-1-YL-ACETAMIDE COMPOUNDS FOR USE AS TANKYRASE INHIBITORS [US2015025070]2012-07-132015-01-22

Compositions and Methods for Modulating Neuron Degeneration and Neuron Guidance [US2011065645]2010-09-102011-03-17

SMOOTHENED ANTAGONISM FOR THE TREATMENT OF HEDGEHOG PATHWAY-RELATED DISORDERS [US2014200217]2014-01-242014-07-17

 

CN101072755A * Sep 2, 2005 Nov 14, 2007 遗传技术研究公司 Pyridyl inhibitors of hedgehog signalling
CN102731373A * Jul 19, 2012 Oct 17, 2012 南京药石药物研发有限公司 Preparation method of intermediate of antitumor drug GDC-0449 (vismodegib)
US20080132698 * Nov 30, 2006 Jun 5, 2008 University Of Ottawa Use of N-oxide compounds in coupling reactions
US20090076266 * Sep 10, 2008 Mar 19, 2009 The University Of Houston System Copper-catalyzed c-h bond arylation

NON-PATENT CITATIONS

Reference
1 * GEORGETTE M. CASTANEDO,等: “Second generation 2-pyridyl biphenyl amide inhibitors of the hedgehog pathway“, 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 20, 15 September 2010 (2010-09-15), pages 6748 – 6753
2 * 曹萌,等: “Vismodegib 的合成“, 《第十一届全国青年药学工作者最新科研成果交流会论文集》, 21 June 2012 (2012-06-21)
3 * 耿一丁: “Vismodegib“, 《中国药物化学杂志》, vol. 22, no. 3, 20 June 2012 (2012-06-20)
4 * 邢其毅,等: “《基础有机化学》”, 31 December 2005, article “201310019450.0“, pages: 896-897
Vismodegib
Vismodegib2DACS.svg
Vismodegib3Dan.gif
Systematic (IUPAC) name
2-Chloro-N-(4-chloro-3-pyridin-2-ylphenyl)-4-methylsulfonylbenzamide
Clinical data
Trade names Erivedge
AHFS/Drugs.com monograph
Licence data EMA:Link, US FDA:link
Pregnancy
category
  • AU: X (High risk)
  • US: D (Evidence of risk)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 31.8%
Protein binding >99%
Metabolism <2% metabolised byCYP2C9, CYP3A4, CYP3A5
Biological half-life 4 days (continuous use),
12 days (single dose)
Excretion Faeces (82%), urine (4.4%)
Identifiers
CAS Number 879085-55-9
ATC code L01XX43
PubChem CID 24776445
IUPHAR/BPS 6975
DrugBank DB08828
ChemSpider 23337846
UNII 25X868M3DS
ChEBI CHEBI:66903 Yes
ChEMBL CHEMBL473417
Synonyms GDC-0449, RG-3616
Chemical data
Formula C19H14Cl2N2O3S
Molar mass 421.30 g/mol

SEE…http://apisynthesisint.blogspot.in/2016/02/vismodegib.html

/////

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

CS(=O)(=O)C1=CC(=C(C=C1)C(=O)NC2=CC(=C(C=C2)Cl)C3=CC=CC=N3)Cl

MIRABEGRON


ChemSpider 2D Image | Mirabegron | C21H24N4O2SMIRABEGRON
  • Betanis
  • Myrbetriq
  • UNII-MVR3JL3B2V
  • YM 178
  • YM178
Мирабегрон ميرابيغرون 米拉贝隆
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
MF: C21H24N4O2S =396.5
Mirabegron (YM-178, Astellas Pharma), is an orally active, first-in-class selective β₃-adrenoceptor agonist for the symptomatic treatment of overactive bladder (OAB), and has been approved for urinary frequency and urinary incontinence associated with OAB

Mirabegron (YM-178) is the first β3-adrenoceptor agonist that is clinically effective for overactive bladder. Mirabegron (0.3 and 1 mg/kg) inhibits mechanosensitive single-unit afferent activities (SAAs) of Aδ fibers in response to bladder filling. Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity. Mirabegron (YM-178) acts partly as an irreversible or quasi-irreversible metabolism-dependent inhibitor of CYP2D6. Mirabegron at a dose of 3 mg/kg i.v. decreased the frequency of rhythmic bladder contraction induced by intravesical filling with saline without suppressing its amplitude in anesthetized rats. Mirabegron decreases primary bladder afferent activity and bladder microcontractions in rats. Mirabegron (YM-178) also reduced non-micturition bladder contractions in an awake rat model of bladder outlet obstruction.

Mirabegron is a white crystalline powder, not hygroscopic and freely soluble in dimethyl sulfoxide, soluble in methanol and soluble in water between neutral to acidic pH. The chemical name is 2-(2- Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2- phenylethyl]amino}ethyl)phenyl]acetamide., Mirabegron exhibits stereoisomerism due to the presence of one chiral centre. The R enantiomer has been used in the manufacture of the finished product. The enantiomeric purity is controlled routinely by chiral HPLC-UV. Polymorphism has been observed for the active substance. The polymorphic form α is routinely and consistently produced by the synthetic process and it is used in the manufacture of the finished product…….http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002388/WC500137308.pdf

Mirabegron (formerly YM-178, trade name MyrbetriqBetmiga in Spain) is a drug for the treatment of overactive bladder.[2] It was developed by Astellas Pharma and was approved in the United States in July 2012.[3]
Mirabegron activates the β3 adrenergic receptor in the detrusor muscle in the bladder, which leads to muscle relaxation and an increase in bladder capacity.[4]\
NMR PREDICT
NMR CHEMDOODLE
PAPER
Journal of Chemical and Pharmaceutical Research, 2015, 7(4):1473-1478
In the first approach, the introduction of the chiral hydroxyl group was planned at the later stage (Scheme 1). Accordingly, 2-(4-nitrophenyl)ethyl amine 4 was protected as the Boc-derivative 5, followed by the reduction of the nitro group using stannous chloride to furnish corresponding aniline 6. Alternate reducing conditions such as hydrogenation in the presence of 10% Pd-C were also provided the desired 6 in good yield. Amide coupling of the aniline 6 with 2-(2-aminothiazol-4-yl) acetic acid 7 in the presence of EDC, HOBt/DIPEA furnished the desired amide 8. Interestingly, lower reactivity of 2-aminothiazole precluded any self-coupling of 7.
MIRA SYN 1
Removal of Boc-group in 8, set the stage for the critical step of introducing the chiral hydroxyl by means of stereocontrolled ring opening of the chiral (R)-styrene epoxide 10. Epoxide opening reaction of 10 was initially attempted with amine 9 in the presence of Et3N in MeOH as the solvent. Alternatively, epoxy opening was also performed under simple isopropanol reflux condition to get the desired 1. The desired product 1 was isolated in 27% yield after purification by column chromatography. This is due to the formation of N-alkylated derivatives of 1 by undesired reaction of 10 with amino functionalities of 1. However, the inefficiency of the epoxide opening reaction precluded a high purity of final product, Mirabegron 1. Since it is not practical to embark on repeated purifications at the last stage (which leads to poor yields), this route was not pursued for further optimization.
13C NMR PREDICT
C-NMR MOLBASE
1H NMR PREDICT
H-NMR MOLBASE
………………
1H NMR PREDICT
H EXPLODED H-NMR NMRDB GRAPHH-NMR NMRDB VAL
13C NMR PREDICT
C-NMR NMRDB GRAPH C-NMR NMRDB VAL
COSY PREDICT
COSY NMR prediction (24)CN 103896872
http://www.google.com/patents/CN103896872A?cl=en

Figure CN103896872AD00082
Figure CN103896872AD00091

Third, Mira Veron synthesis:
reaction:

Figure CN103896872AD00092

in 500mL three-necked flask, 2- (2-aminothiazol-4-yl) acetic acid 17.42g (0.086mol), N, N- dimethylformamide 180mL, then added H0BT15.12g (0.104 mol), was added (R) _2 _ ((4- aminophenyl) amino) phenyl-ethan-l-ol -1_ 20g (0.078mol), was added triethylamine 13.04g (0.13mol), was added portionwise EDCI21. 46g (0.104mol), under magnetic stirring, room temperature for 5h, TLC until the reaction was complete tracking.
After treatment: After the completion of the reaction, the reaction solution was poured into 900mL saturated saline water, and then extracted with 400mL of dichloromethane each time, and extracted three times, each time the organic phase is then washed with 200mL of saturated aqueous sodium carbonate solution, washed three times, each time with distilled water and then 200mL of water, washed three times, the organic phase was dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid in methylene chloride was distilled off Mira Veron crude, the crude product was recrystallized from methanol solution, wherein the methanol solution of methanol and water, the volume ratio of 10: 4, and recrystallized to give 25.08g, yield 81.0%.
The present embodiment Mira Veron synthesized for testing and structural identification:
mp138 ~ 140 ° C (137 ~ 139 ° C)
[α] 20-18. ~ -22. (CH3OH)
chemical purity HPLC: 99.96%
Optical purity: 97.55ee%
HRMS (ES1-MS, m / z) calcd: for C21H25N4O2S [M + H] + 397.16.Found:. 397.16
1H Mffi (400MHz, DMS0) Sl0.00 (s, lH), 7.50 ( d, J = 8.5Hz, 2H), 7.30 (dd, J = 9.5,5.1Hz, 4H), 7.23 (dd, J = 6.0, 2.7Hz, 1H), 7.12 (d, J = 8.5Hz, 2H), 6.90 (s, 2H), 6.30 (s, 1H), 5.24 (s, 1H), 4.60 (s, 1H), 3.45 (s, 2H), 2.74 (dd, J = 9.8, 3.5Hz, 2H), 2.64 (m, 4H).
13C NMR (101MHz, DMSO) δ 168.69 (s), 168.26 (s), 146.35 (s), 145.03 (s), 137.66 (s), 135.51 (s), 129.24 (s ), 128.38 (s), 127.22 (s), 126.33 (s), 119.46 (s), 103.03 (s), 71.88 (s), 57.94 (s), 51.20 (s), 40.40 (s), 40.20 (s ), 39.99 (s), 39.78 (s), 39.57 (s), 35.77 (s)

1H NMR FIG2…SEE…….http://orgspectroscopyint.blogspot.in/2015/08/mirabegron.html

1H NMR

13C NMR FIG3

 13C NMR

………….

CN 103193730
http://www.google.com/patents/CN103193730A?cl=en
Figure CN103193730AD00081

By and O ° C under nitrogen protection temperature conditions, 7.3g (R) -2- amino _1_ benzeneethanol added 250mL three-necked flask, the stirring was dissolved in 50mL of dichloromethane Mira Veron Intermediate C was added dropwise to the reaction solution to form three-necked flask. Stirred for I hour under nitrogen, with stirring 4.12g of sodium borohydride was added to the reaction mixture. The reaction mixture was stirred (under TC 3 hours to TLC the reaction was complete. The reaction is complete the reaction mixture was added dropwise a saturated aqueous ammonium chloride solution IOmL quenched reaction was washed twice with 40mL of water, the organic phase was separated. The The organic phase at the conditions at 0 ° C was added concentrated sulfuric acid was stirred IOmL until TLC after 0.5 hours the reaction was complete, then was added 20mL of 20% aqueous sodium hydroxide solution to complete the reaction of the organic phase was adjusted to pH 10 and stirred for 15 minutes minutes solution. The organic phase first with 50mL saturated brine I times with IOg anhydrous sodium sulfate and concentrated to give crude product was recrystallized from methanol and water to give 18.7g of the final product Mira Veron purity of 99.33%, chiral purity of 99.01%, a yield of 88.12%.
Mira Veron use randomly selected samples prepared by the synthesis method of the present invention is detected by liquid chromatography.
Test conditions: Instrument: Agilent 1100 HPLC;
Column: Luna C18, 4.6mmX 250mm, 5 μ m;
Column temperature: 25 ° C;
flow rate: 1.0mL / min;
The detection wavelength: 2IOnm;
Injection volume: 5ul;
Mobile phase A: acetonitrile;
Mobile phase B: 0.1% phosphoric acid aqueous solution;
Running time: 40min.
FIG liquid chromatography after detection of the sample shown in Figure 1; results are shown in Table I.
Table 1: The Mira Veron chromatographic analysis sample preparation method of the present invention

Figure CN103193730AD00121

……….

http://www.google.co.in/patents/EP1440969A1?cl=en

Figure 00090001

      Example 4 (Production of the α-form crystal from wet cake of the β-form crystal) :
  • The same procedures as in Example 2 were followed to obtain 23.42 kg of a wet cake of the β-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide from 6.66 kg of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride. This cake was added with and dissolved in 92 L of water and 76 L of ethanol by heating at about 80°C, and the solution was cooled at a rate of about 10°C per hour, to which was then added 8.4 g of the α-form crystal at 55°C. Thereafter, the mixture was cooled to 20°C. A crystal was filtered and dried to obtain 6.56 kg of the α-form crystal of (R)-2-(2-aminothiazol-4-yl)-4′-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide.
  • Powder X-ray diffraction diagram and thermal analysis diagram of the α-form crystal are shown in Fig. 4 and Fig. 5, respectively.
    1H-NMR (DMSO-d 6, 500 MHz) δ (ppm) = 1.60 (1H, s), 2.59 to 2.66 (4H, m), 2.68 to 2.80 (2H, m), 3.45 (2H, s), 4.59 (1H, br), 5.21 (1H, br), 6.30 (1H, s), 6.89 (2H, s), 7.11 (2H, d, J = 8.5 Hz), 7.19 to 7.23 (1H, m), 7.27 to 7.33 (4H, m), 7.49 (2H, d, J = 8.5 Hz), 9.99 (1H,s). FAB-MS m/z: 397 (M+H)+.

References

  1.  “mirabegron (Rx) – Myrbetriq”Medscape Reference. WebMD. Retrieved 17 November 2013.
  2.  Gras, J (2012). “Mirabegron for the treatment of overactive bladder”. Drugs of today (Barcelona, Spain : 1998) 48 (1): 25–32. doi:10.1358/dot.2012.48.1.1738056PMID 22384458.
  3.  Sacco, E; Bientinesi, R et al. (Apr 2014). “Discovery history and clinical development of mirabegron for the treatment of overactive bladder and urinary incontinence”. Expert Opin Drug Discov9 (4): 433–48. doi:10.1517/17460441.2014.892923PMID 2455903.
  4.  “New Drug Approvals 2012 – Pt. XIV – Mirabegron (MyrbetriqTM)”ChEMBL. 5 July 2012. Retrieved 28 September 2012.
  5.  “MYRBETRIQ (mirabegron) tablet, film coated, extended release [Astellas Pharma US, Inc.]“DailyMed. Astellas Pharma US, Inc. September 2012. Retrieved 17 November 2013.
  6.  “Betmiga 25mg & 50mg prolonged-release tablets”electronic Medicines Compendium. Astellas Pharma Ltd. 22 February 2013. Retrieved 17 November 2013.
  7.  Cypess, Aaron; Weiner, Lauren; Roberts-Toler, Carla; Elía, Elisa; Kessler, Skyler; Kahn, Peter; English, Jeffrey; Chatman, Kelly; Trauger, Sunia; Doria, Alessandro; Kolodny, Gerald (6 January 2015). “Activation of Human Brown Adipose Tissue by a β3-Adrenergic Receptor Agonist”Cell Metabolism 21 (1): 33–38. doi:10.1016/j.cmet.2014.12.009PMID 25565203. Retrieved 26 January 2015.

External links

Mirabegron
Mirabegron2DACS2.svg
Systematic (IUPAC) name
2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide
Clinical data
Trade names Myrbetriq (US), Betanis (Japan), Betmiga (EU)
Licence data EMA:LinkUS FDA:link
Pregnancy
category
  • US: C (Risk not ruled out)
Legal status
Routes of
administration
Oral
Pharmacokinetic data
Bioavailability 29-35%[1]
Protein binding 71%[1]
Metabolism Hepatic via (direct) glucuronidation, amide hydrolysis, and minimal oxidative metabolism in vivo byCYP2D6 and CYP3A4. Some involvement of butylcholinesterase[1]
Biological half-life 50 hours[1]
Excretion Urine (55%), faeces (34%)[1]
Identifiers
CAS Registry Number 223673-61-8
ATC code G04BD12
PubChem CID: 9865528
ChemSpider 8041219
Synonyms YM-178
Chemical data
Formula C21H24N4O2S
Molecular mass 396.506 g/mol
Patent Submitted Granted
Alpha-form or beta-form crystal of acetanilide derivative [US7342117] 2005-01-06 2008-03-11
Pharmaceutical composition for treating stress incontinence and/or mixed incontinence [US2006004105] 2006-01-05
Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor Pharmaceutical composition comprising a beta-3-adrenoceptor agonist and a serotonin and/or norepinephrine reuptake inhibitor [US2009012161] 2005-11-24
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and alpha-agonist [US2005154041] 2005-07-14
Pharmaceutical composition consisting of a beta-3-adrenoceptor agonist and an active substance which influences prostaglandin metabolism [US2005119239] 2005-06-02
Pharmaceutical Composition For Treating Stress Incontinence And/Or Mixed Incontinence [US2007129435] 2007-06-07
Remedy for overactive bladder comprising acetic acid anilide derivative as the active ingredient [US7750029] 2006-06-01 2010-07-06
[alpha]-form or [beta]-form crystal of acetanilide derivative [US7982049] 2008-09-04 2011-07-19
BETA ADRENERGIC RECEPTOR AGONISTS FOR THE TREATMENT OF B-CELL PROLIFERATIVE DISORDERS [US2010009934] 2010-01-14
PHARMACEUTICAL COMPOSITION FOR IMPROVING LOWER URINARY TRACT SYMPTOMS [US2010261770] 2010-10-14
11 to 16 of 16
Patent Submitted Granted
PHARMACEUTICAL COMPOSITION FOR MODIFIED RELEASE [US2010144807] 2010-06-10
BENZYLAMINE DERIVATIVE OR PHARMACEUTICALLY ACCEPTABLE ACID ADDITION SALT THEREOF, AND USE THEREOF FOR MEDICAL PURPOSES [US8148427] 2010-04-22 2012-04-03
Pharmaceutical composition containing a beta-3-adrenoceptor agonist and an alpha antagonist and/or a 5-alpha reductase inhibitor [US2005101607] 2005-05-12
REMEDY FOR OVERACTIVE BLADDER COMPRISING ACETIC ACID ANILIDE DERIVATIVE AS THE ACTIVE INGREDIENT [US2009093529] 2009-04-09
PHARMACEUTICAL COMPOSITION FOR TREATING OVERACTIVE BLADDER [US2010240697] 2010-09-23
Pharmaceutical composition comprising beta-3-adrenoceptor-agonists and antimuscarinic agents [US2005261328] 2005-11-24
US Patent No Patent Expiry patent use
6346532 Oct 15, 2018
6562375 Aug 1, 2020
6699503 Sep 10, 2013
7342117 Nov 4, 2023
7750029 Dec 18, 2023 U-913
7982049 Nov 4, 2023
Exclusivity Code Exclusivity Date
NCE Jun 28, 2017

U-913……….TREATMENT OF OVERACTIVE BLADDER WITH SYMPTOMS OF URGE URINARY INCONTINENCE, URGENCY, AND FREQUENCY

//////Mirabegron, Overactive bladder, FDA 2012, ASTELLAS PHARMA, YM-178, MyrbetriqBetmiga

Updates…….

Figure

Overactive bladder (OAB) is characterized by symptoms of urinary urgency, with or without urgency incontinence, usually with increased daytime frequency and nocturia.(1-3) Current guidelines recommend oral antimuscarinics drugs as the first-line pharmacologic therapy in the management of OAB despite the companion adverse effects.(4, 5) Mirabegron is an orally active β3 adrenoceptor agonist approved by the FDA for treatment of OAB in 2012, which is an important step toward the better treatment options for the management of OAB.(6)

(R)-Styrene oxide 1 and 4-nitrophenethylamine 2 were exploited as starting materials in the first synthesis of mirabegron (Scheme 1). Heating 1 and 2 in i-propanol afforded amino alcohol 3, and then the amino group was protected by di-tert-butyl dicarbonate (Boc2O), followed by a condensation with 2-aminothiazol-4-acetic acid. Deprotection of the condensation product 7 finally afforded mirabegron.(7-10) Although reactions in the whole process were all conventional reactions, optically pure 1 was not industrially available, which restricted its application in industry.

(R)-Mandelic 8 and 4-nitrophenethylamine hydrochloride 9 were exploited as starting materials in an alternate route (Scheme 2). Condensation of 8 and 9 in the presence of 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide hydrochloride (EDCI), 1-hydroxybenzotriazole (HOBt), and triethylamine in N,N-dimethylformamide (DMF) furnished the corresponding amide 10, which was further reduced in the presence of borane-tetrahydrofuran complex in a mixed solution of 1,3-dimethyl-2-imidazolidinone (DMI) and tetrahydrofuran (THF), affording amine 11. The nitro group of 11 was then reduced by hydrogenation affording aniline 12 which was further amidated by an aqueous EDCI coupling affording mirabegron. This route was rather concise with only four steps, in which the sole stereogenic center was introduced via a bulk starting material 8.(11-13) However, usage of the costly EDCI twice, especially in the first step, led to a high cost and more impurities.

Figure

mail: chm_zhenggx@ujn.edu.cn,  chm_zhenggx@ujn.edu.cn

  1. 1   AbramsP.CardozoL.FallM.GriffithsD.RosierP.UlmstenU.Van KerrebroeckP.VictorA.Wein,A. UROLOGY 20036137DOI: 10.1016/S0090-4295(02)02243-4

  2. 2.AbramsP.ChappleC.KhouryS.RoehrbornC.de la RosetteJ. J. Urol. 20091811779DOI: 10.1016/j.juro.2008.11.127

  3. 3.JaiprakashH.BenglorkarG. M. RJPBCS 20145 ( 3213

  4. 4.LucasM. G.RuudJ. L.BoschR. J. L.BurkhardF. C.CruzF.MaddenT. B.NambiarA. K.Neisius,A.de RidderD. J. M. K.TubaroA.TurnerW.PickardR. Eur. Urol. 2012621130DOI: 10.1016/j.eururo.2012.08.047

  5. 5.GormleyE. A.LightnerD. J.BurgioK. L.ChaiT. C.ClemensJ. Q.CulkinD. J.DasA. K.FosterH. E.ScarperoH. M.TessierC. D.VasavadaS. P. J. Urol. 20121882455DOI: 10.1016/j.juro.2012.09.079

  6. 6.SaccoE.BientinesiR. World J. Obstet Gynecol 20132 ( 465DOI: 10.5317/wjog.v2.i4.65

  7. 7.MaruyamaT.SuzukiT.OndaK.HayakawaM.MoritomoH.KimizukaT.MatsuiT. US6346532,2002.

  8. 8.KawazoeS.SakamotoK.AwamuraY.MaruyamaT.SuzukiT.OndaK.TakasuT. EP144096A1,2004.

  9. 9.TakasuT.SatoS.UkaiM.MaruyamaT. EP1559427A1, 2005.

  10. 10ZhangH.LiY.ChenS.ShenM.WangX. CN103896872A, 2014

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TOFACITINIB 的合成, トファシチニブ, Тофацитиниб, توفاسيتين يب SPECTRAL VISIT


Tofacitinib Citrate, 的合成

托法替布,  トファシチニブクエン酸塩, Тофацитиниба Цитрат

 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt

CAS : 540737-29-9

ROTATION +

Tofacitinib; Tasocitinib;

477600-75-2 base ; CP-690550;

3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile;

3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt

CP 690550 Tofacitinib; CP-690550; CP-690550-10; Xeljanz; Jakvinus; Tofacitinib citrate

Trademarks: Xeljanz; Jakvinus

MF: C16H20N6O

CAS : 477600-75-2 BASE ; 540737-29-9(citrate) 3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile

Molecular Weight: 312.369

SMILES: C[C@@H]1CCN(C[C@@H]1N(C)C2=NC=NC3=C2C=CN3)C(=O)CC#N

Activity: Treatment of Rheumatoid Arthritis; RA Treatment, JAK Inhibitor; Protein Kinase Inhibitor; JAK3 Inhibitor; Janus Kinase 3 Inhibitor; JAK-STAT Signaling Pathway; JAK1 Kinase Inhibitor; Selective Immunosuppressants

Status: Launched 2012

Originator: Pfizer
Pfizer Inc’s oral JAK inhibitor tofacitinib was approved on November 6, 2012 by US FDA for the treatment of rheumatoid arthritis.
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Tofacitinib (trade names Xeljanz and Jakvinus, formerly tasocitinib,[1] CP-690550[2]) is a drug of the janus kinase (JAK) inhibitor class, discovered and developed by Pfizer. It is currently approved for the treatment of rheumatoid arthritis (RA) in the United States,Russia, Japan and many other countries, is being studied for treatment of psoriasis, inflammatory bowel disease, and other immunological diseases, as well as for the prevention of organ transplant rejection.

An Improved and Efficient Process for the Preparation of Tofacitinib Citrate

Publication Date (Web): November 17, 2014 (Article)
DOI: 10.1021/op500274j
 
MS m/z 313 (M+ + 1);
mp 201–202 °C;  
1H NMR (CDCl3) δ 8.34 (s, 1H), δ 7.38 (d, 1H, J = 2.4 Hz), δ 6.93 (d, 1H, J = 2.4 Hz), δ 4.97 (m, 1H), δ 3.93–4.03 (m, 4H), δ 3.66 (m, 1H), δ 3.50 (m, 4H), δ 2.91 (d, 2H, J = 15.6 Hz), δ 2.80 (t, 2H, J = 12.8 Hz), δ 2.55 (m, 1H), δ 1.99 (m, 1H), δ 1.77 (m, 1H), δ 1.13–1.18 (m, 3H).
Print
09338-acsnews1-pfizercxd
TEAMWORK
Part of the Pfizer group responsible for Xeljanz: Front row, from left: Sally Gut Ruggeri, Chakrapani Subramanyam, Eileen Elliott Mueller, and Frank Busch. Second row, from left: Matthew Brown, Mark Flanagan, and Robert Dugger. Back row, from left: Elizabeth Kudlacz and Douglas Ball.
Credit: Pfizer
Mark Flanagan, who was on the team at Pfizer that discovered Xeljanz, (tofacitinib citrate), an oral treatment for rheumatoid arthritis, remembers testing the drug in a rat model and seeing the drug decrease the level of inflammation in the rats’ footpads. “What we look for is physical measurements of the size of the joint. In the control animals, there was quite a bit of inflammation in the joints, whereas animals treated with different doses of the drug showed a dose-dependent decrease in the size of the joint. “Tofacitinib showed robust efficacy in the first such study run. I can remember the excitement that this data generated on the team,” he says.

Tofacitinib, chemically known as (3R,4R)-4-methyl-3-(methyl-7H-pyrrolo [2,3- d]pyrimidin-4-ylamino)-B-oxo-l -piperidinepi panenitrile, is represented Formula I. Tofacitinib citrate, a janus kinase inhibitor, is approved as XELJANZ® tablets for treatment .of rheumatoid arthritis.

Figure imgf000002_0001

Various intermediates and processes for preparation of tofacitinib are disclosed in patents like US7301 023 and US8232394.

Figure imgf000020_0001

Formula I or isomers or a mixture of isomers thereof by following any method provided in the prior art, for example, by following Example 14 of U.S. Patent No. RE41,783 or by following Example 6 of U.S. Patent No. 7,301,023. Tofacitinib of Formula I or isomers of tofacitinib or a mixture of isomers thereof may be converted into a salt by following any method provided in the prior art, for example, by following Example 1 of U.S. Patent No. 6,965,027 or by following Example 1 or Example 8 of PCT Publication No. WO 2012/135338. 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).[5] 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.[5] 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.”[5] The drug discovery, preclinical development, and clinical development of tofacitinib took place exclusively at Pfizer.[6] In November 2012, the U.S. Food and Drug Administration (FDA) approved tofacitinib for treatment of rheumatoid arthritis. Once on the market, rheumatologists complained that the $2,055 a month wholesale price was too expensive, though the price is 7% less than related treatments.[6] 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.[7] 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.[3] Recently it has been shown in a murine model of established arthritis that 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.[4]

Preparation of 3-{(3R,4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile citrate salt (Tofacitinib citrate, Xeljanz, CP-690550-10)
To a round-bottomed flask fitted with a temperature probe, condenser, nitrogen source, and heating mantle, methyl-[(3R,4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (5.0 g, 20.4 mmol) was added followed by 1-butanol (15 mL), ethyl cyanoacetate (4.6 g, 40.8 mmol), and DBU (1.6 g, 10.2 mmol). The resulting amber solution was stirred at 40 °C for 20 h. Upon reaction completion, citric acid monohydrate (8.57 g, 40.8 mmol) was added followed by water (7.5 mL) and 1-butanol (39.5 mL). The mixture was heated to 81 °C and held at that temperature for 30 min. The mixture was then cooled slowly to 22 ºC and stirred for 2 h. The slurry was filtered and washed with 1-butanol (20 mL). The filter cake was dried in a vacuum oven at 80 °C to afford 9.6 g (93%) of tofacitinib citrate as an off-white solid.
1H NMR (500 MHz, d6-DMSO): δ 8.14 (s, 1H), 7.11 (d, J=3.6 Hz, 1H), 6.57 (d, J=3.6 Hz, 1H), 4.96 (q, J=6.0 Hz, 1H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1H), 2.45-2.41 (m, 1H), 1.81 (m, 1H), 1.69-1.65 (m, 1H), 1.04 (d, J=6.9 Hz, 3H).
सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.
PAPER
3-((3R,4R)-4-Methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)piperidin-1-yl)-3-oxopropanenitrile (1) Monocitrate
J. Med. Chem., 2010, 53 (24), pp 8468–8484
DOI: 10.1021/jm1004286
1monocitrate as a white crystalline solid (mp = 201 dec).
LRMS: m/z 313.2 (MH+).
1H NMR (400 MHz) (D2O) δ HOD: 0.92 (2 H, d, J = 7.2 Hz), 0.96 (1 H, d, J = 7.6 Hz), 1.66 (1 H, m), 1.80 (1 H, m), 2.37 (1 H, m), 2.58 (2 H, 1/2 ABq, J = 15.4 Hz), 2.70 (2 H, 1/2 ABq, J = 15.4 Hz), 3.23 (2 H, s), 3.25 (1 H, s), 3.33 (1 H, m), 3.46 (1 H, m), 3.81 (4 H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).
Anal. Calcd for C22H28N6O8: C, 52.38; H, 5.59; N, 16.66. Found: C, 52.32; H, 5.83; N, 16.30. For additional characterization of the monocitrate salt of 1 see WO 03/048162.
NMR PREDICT
References:
Weiling Cai, James L. Colony,Heather Frost, James P. Hudspeth, Peter M. Kendall, Ashwin M. Krishnan,Teresa Makowski, Duane J. Mazur, James Phillips, David H. Brown Ripin, Sally Gut Ruggeri, Jay F. Stearns, and Timothy D. White; Investigation of Practical Routes for the Kilogram-Scale Production of cis-3-Methylamino-4-methylpiperidinesOrganic Process Research & Development 2005, 9, 51−56
Ripin, D. H.B.; 3-amino-piperidine derivatives and methods of manufacture, US patent application publication, US 2004/0102627 A1
Ruggeri, Sally, Gut;Hawkins, Joel, Michael; Makowski, Teresa, Margaret; Rutherford, Jennifer, Lea; Urban,Frank,John;Pyrrolo[2,3-d]pyrimidine derivatives: their intermediates and synthesis, PCT pub. No. WO 2007/012953 A 2, US20120259115 A1, United States Patent US8232393. Patent Issue Date: July 31, 2012
Kristin E. Price, Claude Larrive´e-Aboussafy, Brett M. Lillie, Robert W. McLaughlin, Jason Mustakis, Kevin W. Hettenbach, Joel M. Hawkins, and Rajappa Vaidyanathan; Mild and Efficient DBU-Catalyzed Amidation of Cyanoacetates, Organic Letters, 2009, vol.11, No.9, 2003-2006
MORE NMR PREDICT

tofacitinib Molbase str

Tofacitinib TOFA  1H proton NMR spectra

tofacitinib 1h values

13C NMR PREDICT  TOFA  13C NMR spectra

 

 

SEE…….https://newdrugapprovals.org/2015/07/24/tofacitinib-%E7%9A%84%E5%90%88%E6%88%90-spectral-visit/

 

 

COSY PREDICT COSY NMR prediction सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

 

NMR PICTURE FROM THE NET

tofacitinib ABMOLE NMR BASE

 

PAPER

Volume 54, Issue 37, 11 September 2013, Pages 5096–5098

Asymmetric total synthesis of Tofacitinib

  • a Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources, University of Talca, P.O. Box 747, Talca, Chile
  • b Laboratory of Natural Products, Department of Chemistry, University of Antofagasta, P.O. Box 170, Antofagasta, Chile

http://dx.doi.org/10.1016/j.tetlet.2013.07.042

Abstract

A novel stereoselective synthesis of Tofacitinib (CP-690,550), a Janus tyrosine kinase (JAK3) specific inhibitor, has been achieved starting from (5S)-5-hydroxypiperidin-2-one in 10 steps from 2 with a 9.5% overall yield. The potentiality of this synthetic route is the obtention of tert-butyl-(3S,4R)-3-hydroxy-4-methylpiperidine-1-carboxylate (6b) as a new chiral precursor involved in the synthesis of CP690,550, in a three-step reaction, without epimerizations, rather than the 5 or more steps used in described reactions to achieve this compound from analogues of 6b.


Graphical abstract

Image for unlabelled figure

…………………. Tofacitinib synthesis: US2001053782A1

Tofacitinib synthesis: WO2002096909A1
 
Tofacitinib synthesis: Org Process Res Dev 2014, 18(12), 1714-1720 (also from a chinese publication, same procedure just slight changes in reagents/conditions)
 
References:
1. Blumenkopf, T. A.; et. al. Pyrrolo[2,3-d]pyrimidine compounds. US2001053782A1
2. Flanagan, M. E.; et. al. Optical resolution of (1-benzyl-4-methylpiperidin-3-yl) -methylamine and the use thereof for the preparation of pyrrolo 2,3-pyrimidine derivatives as protein kinases inhibitors. WO2002096909A1
3. Das, A.; et. al. An Improved and Efficient Process for the Preparation of Tofacitinib Citrate. Org Process Res Dev2014, 18(12), 1714-1720.

 

PATENT https://www.google.co.in/patents/WO2003048162A1?cl=en The crystalline form of the compound of this invention 3-{4-methyl-3-[methyl- (7H-pyrrolot2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo-propionitrile mono citrate salt is prepared as described below. Scheme 1

Figure imgf000005_0001
Figure imgf000005_0002

Scheme 2

Figure imgf000006_0001
Figure imgf000006_0002
Figure imgf000006_0003
Figure imgf000006_0004

Example 1 3-{(3R,4R)-4-methyl-3-rmethyl-(7H-pyrrolor2,3-dlpyrimidin-4-yl)-amino1- piperidin-1-yl}-3-oxo-propionitrile mono citrate salt Ethanol (13 liters), (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H-pyrrolo[2,3- d]pyrimidin-4-yl)-amine (1.3 kg), cyano-acetic acid 2,5-dioxo-pyrrolidin-1-yl ester (1.5 kg), and triethylamine (1.5 liters) were combined and stirred at ambient temperature. Upon reaction completion (determined by High Pressure Liquid Chromotography (HPLC) analysis, approximately 30 minutes), the solution was filtered, concentrated and azeotroped with 15 liters of methylene chloride. The reaction mixture was washed sequentially with 12 liters of 0.5 N sodium hydroxide solution, 12 liters of brine and 12 liters of water. The organic layer was concentrated and azeotroped with 3 liters of acetone (final pot temperature was 42°C). The resulting solution was cooled to 20°C to 25°C followed by addition of 10 liters of acetone. This solution was filtered and then aqueous citric acid (0.8 kg in 4 liters of water) added via in-line filter. The reaction mixture was allowed to granulate. The slurry was cooled before collecting the solids by filtration. The solids were dried to yield 1.9 kg (71 %) (3R, 4R)- 3-{4-Methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile mono citrate. This material was then combined with 15 liters of a 1:1 ratio of ethanol/water and the slurry was agitated overnight. The solids were filtered and dried to afford 1.7 kg (63% from (3R, 4R)-methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine) of the title compound as a white crystalline solid. 1H NMR (400 MH2)(D20) δ HOD: 0.92 (2H, d, J = 7.2 Hz), 0.96 (1H, d, J = 7.6 Hz), 1.66 (1H, m), 1.80 (1H, m), 2.37 (1H, m), 2.58 (2H, 1/2 ABq, J = 15.4 Hz), 2.70 (2H, 3 ABq, J = 154 Hz), 3.23 (2H, s), 3.25 (1H, s), 3.33 (1H, m), 3.46 (1H, m), 3.81 (4H, m), 4.55 (1 H, m), 6.65 (1 H, d, J = 3.2 Hz), 7.20 (1 H, t, J = 3.2 Hz), 8.09 (1 H, m).

 

Patent

http://www.google.co.in/patents/EP1913000A2?cl=en Example 10 Preparation of methyl-[(3R, 4R)-4-methyl-piperidin-3-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine:

KEY INTERMEDIATE

To a clean, dry, nitrogen-purged 2 L hydrogenation reactor were charged 20 wt% Pd(OH)2/C (24.0 g, 50% water wet), water (160 ml), isopropanol (640 ml), (1-benzyl-4-methyl-piperidin-3-yI)-methyi- (7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine (160.0 g, 0.48 mol), and acetic acid (28.65 g, 0.48 mol). The reactor was purged with three times at 50 psi with nitrogen and three times at 50 psi with hydrogen. Once purging was complete, the reactor was heated to 45-55°C and pressurized to 50 psi with hydrogen through a continuous feed. The hydrogen uptake was monitored until no hydrogen was consumed for 1 hour. The reactor was cooled to 20-300C and purged three times at 50 psi with nitrogen. The reaction mixture was filtered through wet Celite and the filtrate was sent to a clean, dry, nitrogen-purged vessel. A solution of sodium hydroxide (39.33 g) in water (290 ml) was charged and the mixture was stirred for a minimum of 1 hour then heated to 75-900C. The isopropanol was removed by distillation. The reaction mixture was cooled to 20-30°C and 2-methyltetrahydrofuran (1.6 L) was added. The aqueous layer was drained off and the 2-methyltetrahydrofuran was displaced with toluene (1.6 L). The distillation was continued until the final volume was 800 ml. The slurry was cooled to 20-30°C and held for a minimum of 7 hours. The resulting solids were isolated by filtration and washed with toluene (480 ml). After drying under vacuum between 40-50DC for a minimum of 24 hours with a slight nitrogen bleed 102.3 g (87.3%) of the title compound were isolated. Mp 158.6-159.8°C. 1H NMR (400 MHz, CDCI3): δ 11.38 (bs, 1H), 8.30 (s, 1H), 7.05 (d, J=3.5 Hz, 1H), 6.54 (d, J=3.5 Hz, 1H), 4.89-4.87 (m, 1H), 3.39 (s, 3H), 3.27 (dd, J=12.0, 9.3 Hz, 1 H), 3.04 (dd, J=12.0, 3.9 Hz, 1H), 2.94 (td, J=12.6, 3.1 Hz, 1H0, 2.84 (dt, J=12.6, 4.3 Hz, 1H), 2.51-2.48 (m, 1H), 2.12 (bs, 2H), 1.89 (ddt, J=13.7, 10.6, 4 Hz, 1 H), 1.62 (dq, J=13.7, 4Hz, 1 H), 1.07 (d, J=7.3 Hz, 3H). 13C NMR (400 MHz, CDCI3): δ 157.9, 152.0, 151.0, 120.0, 103.0, 102.5, 56.3, 46.2, 42.4, 34.7, 33.4, 32.4, 14.3. KEY INT

 

Example 11 Preparation of 3-{(3R, 4R)-4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3- oxo-propionitrile….TOFACITINIB BASE

 

To a clean, dry, nitrogen-purged 1.0 L reactor were charged methyl-(4-methyl-piperidin-3-yI)-(7H- pyrroIo[2,3-d]pyrimidin-4-yl)-amine (32.0 g, 0.130 mol), toluene (160 ml), ethyl cyanoacetate (88.53 g, 0.783 mol) and triethyl amine (26.4 g, 0.261 mol). The reaction was heated to 1000C and held for 24 hours. The reaction was washed with water (160 ml). The organic layer concentrated to a volume of 10 ml and water (20 ml) was added. The residual toluene was removed by distillation and the mixture was cooled to room temperature. Acetone (224 ml) was added followed by citric acid (27.57 g, 0.144 mol) in water (76 ml). The resulting slurry was stirred for 7 hours. The solids were isolate by filtration, washed with acetone (96 ml), and dried under vacuum to afford 42.85 g (65.3%) of the title compound. Example 13 Preparation of 3-{(3R, 4R)~4-methyl-3-[methyl-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amino]-piperidin-1-yl}-3-oxo- propionitrile citrate salt:…………..TOFACITINIB CITRATE To a clean, dry, nitrogen-purged 500 ml reactor were charged methyl-(4-methyl-piperidin-3-yl)-(7H- pyrrolo[2,3-d]pyrimidin-4-yl)-amine (25.0 g, 0.102 mol) and methylene chloride (250 ml). The mixture was stirred at room temperature for a minimum of 2.5 hours. To a clean, dry, nitrogen-purged 1 L reactor were charged cyanoacetic acid (18.2 g, 0.214 mol), methylene chloride (375 ml), and triethyl amine (30.1 ml, 0.214 mol). The mixture was cooled to -15.0— 5.00C over one hour and trimethylacetyl chloride (25.6 ml, 0.204 mol) was added at a rate to maintain the temperature below O0C. The reaction was held for a minimum of 2.5 hours, then the solution of the amine was added at a rate that maintained the temperature below O0C. After stirring for 1 hour, the mixture was warmed to room temperature and 1 M sodium hydroxide (125 ml) was added. The organic layer was washed with water (125 ml) The methylene chloride solution.was displaced with acetone until a volume of 500 ml and a temperature of 55-650C had been achieved. Water (75 ml) was charged to the mixture while maintaining the temperature at 55-65°C. A solution of citric acid (20.76 g, 0.107 mol) in water (25.0) was charged and the mixture was cooled to room temperature. The reactor was stirred for a minimum of 5 hours and then the resulting solids were isolated by filtration and washed with acetone (2×75 ml), which was sent to the filter. The salt was charged into a clean, dry, nitrogen-purged 1L reactor with 2B ethanol (190 ml) and water (190 ml). The slurry was heated to 75-850C for a minimum of 4 hours. The mixture was cooled to 20-300C and stirred for an additional 4 hours. The solids were isolated by filtration and washed with 2B ethanol (190 ml). After drying in a vacuum oven at 500C with a slight nitrogen bleed, 34.6 g (67.3%) of the title compound were isolated. 1H NMR (500 MHz, CZ6-DMSO): δ 8.14 (s, 1 H), 7.11 (d, J=3.6 Hz, 1 H), 6.57 (d, J=3.6 Hz, 1 H), 4.96 (q, J=6.0 Hz, 1 H), 4.00-3.90 (m, 2H), 3.80 (m, 2H), 3.51 (m, 1 H), 3.32 (s, 3H), 2.80 (Abq, J=15.6 Hz, 2H), 2.71 (Abq, J=15.6 Hz, 2H), 2.52-2.50 (m, 1 H), 2.45-2.41 (m, 1 H), 1.81 (m, 1 H), 1.69-1.65 (m, 1 H), 1.04 (d, J=6.9 Hz, 3H)

 

 

PAPER

Org. Lett., 2009, 11 (9), pp 2003–2006
DOI: 10.1021/ol900435t

http://pubs.acs.org/doi/full/10.1021/ol900435t Figure

 

PATENT

http://www.omicsonline.org/open-access/advances-in-the-inhibitors-of-janus-kinase-2161-0444.1000540.php?aid=29799   …………….. सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

Clinical trials

Rheumatoid arthritis

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. In a psoriasis study, the PASI score improved by at least 75% in between 25 and 67% of patients, depending on the dose, versus 2% in the placebo group.[8] 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) andneutropenia.[8] Phase III trials testing the drug in rheumatoid arthritis started in 2007 and are scheduled to run until January 2015.[9] 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.[10] By April 2011, three phase III trials for RA had reported positive results.[11] 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.”[12]

Psoriasis

As of April 2011 a phase III trial for psoriasis is under way.[11]

Alopecia

In June 2014, scientists at Yale successfully treated a male patient afflicted with alopecia universalis. The patient was able to grow a full head of hair, eyebrows, eyelashes, facial, armpit, genitalia and other hair. No side effects were reported in the study.[13]

Ulcerative colitis

The OCTAVE study of Tofacitinib in Ulcerative Colitis started in 2012. It is currently enrolling patients, though the NIH trials page states that they expect the trial to close in June 2015.[14]

Vitiligo

In a June 2015 study, a 53-year-old woman with vitiligo showed noticeable improvement after taking tofacitinib for five months.[15]

Development of Safe, Robust, Environmentally Responsible Processes for New Chemical Entities

– Dr. V. Rajappa, Director & Head-Process R&D, Bristol-Myers Squibb, India

A PRESENTATION

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  1. Herper, Matthew (2 March 2011). “Why Pfizer’s Biggest Experimental Drug Got A Name Change”. Forbes. Retrieved 3 March 2011.
  2.  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. edit
  3.  “Tasocitinib”. Drugs in R&D 10 (4): 271–284. 2010. doi:10.2165/11588080-000000000-00000. PMC 3585773. PMID 21171673. edit
  4.  Ghoreschi, K.; Jesson, M. I.; Li, X.; Lee, J. L.; Ghosh, S.; Alsup, J. W.; Warner, J. D.; Tanaka, M.; Steward-Tharp, S. M.; Gadina, M.; Thomas, C. J.; Minnerly, J. C.; Storer, C. E.; Labranche, T. P.; Radi, Z. A.; Dowty, M. E.; Head, R. D.; Meyer, D. M.; Kishore, N.; O’Shea, J. J. (2011). “Modulation of Innate and Adaptive Immune Responses by Tofacitinib (CP-690,550)”. J Immunol. 186 (7): 4234–4243. doi:10.4049/jimmunol.1003668. PMC 3108067. PMID 21383241. edit
  5. ^ Jump up to:a b c “Seeking Profit for Taxpayers in Potential of New Drug”, Jonathan Weisman, New York Times, March 18, 2013
  6. Ken 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.
  7. Jump up^ 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
  8.  “EULAR: JAK Inhibitor Effective in RA But Safety Worries Remain”. MedPage Today. June 2009. Retrieved 9 February 2011.
  9.  Clinical trial number NCT00413699 for “Long-Term Effectiveness And Safety Of CP-690,550 For The Treatment Of Rheumatoid Arthritis” at ClinicalTrials.gov
  10.  Matthew Herper. “Pfizer’s Key Drug Walks A Tightrope”. Forbes.
  11.  “Two Phase III Studies Confirm Benefits of Pfizer’s Tofacitinib Against Active RA”. 28 Apr 2011.
  12.  “FDA approves Xeljanz for rheumatoid arthritis”. 6 Nov 2012.
  13.  “Hairless man grows full head of hair in yale arthritis drug trial”. 19 Jun 2014.
  14.  https://clinicaltrials.gov/ct2/show/NCT01465763?term=A3921094&rank=1
  15. “This Drug Brought Pigment Back for Woman with Vitiligo”. TIME. June 27, 2015. Retrieved June 29, 2015.
  16. Nordqvist, Christian (27 April 2013). “Pfizer’s Arthritis Drug Xeljanz (tofacitinib) Receives A Negative Opinion In Europe”. Medical News Today. Retrieved 2 August 2013.
  17. “”XALEJANZ PRESCRIBING INFORMATION @ Labeling.Pfizer.com””.

SEE………http://orgspectroscopyint.blogspot.in/2014/12/tofacitinib-citrate.html

Tofacitinib
Tofacitinib2DACS.svg
Systematic (IUPAC) name
3-[(3R,4R)-4-methyl-3-[methyl(7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]piperidin-1-yl]-3-oxopropanenitrile
Clinical data
Trade names Xeljanz, Jakvinus
AHFS/Drugs.com entry
Licence data US FDA:link
Pregnancy category
  • US: C (Risk not ruled out)
Legal status
Routes of administration Oral
Pharmacokinetic data
Bioavailability 74%
Protein binding 40%
Metabolism Hepatic (via CYP3A4 andCYP2C19)
Biological half-life 3 hours
Excretion Urine
Identifiers
CAS Registry Number 477600-75-2
ATC code L04AA29
PubChem CID: 9926791
IUPHAR/BPS 5677
DrugBank DB08183
ChemSpider 8102425
UNII 87LA6FU830
ChEBI CHEBI:71200 Yes
ChEMBL CHEMBL221959
Synonyms CP-690550
Chemical data
Formula C16H20N6O
Molecular mass 312.369 g/mol

सुकून उतना ही देना प्रभू, जितने से जिंदगी चल जाये।औकात बस इतनी देना,कि औरों का भला हो जाये।………..P.S. : The views expressed are my personal and in no-way suggest the views of the professional body or the company that I represent.

 

 

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He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy
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European Commission Approves Genzyme’s Once-Daily, Oral Multiple Sclerosis Treatment Aubagio® (teriflunomide)


Teriflunomide,

Teriflunomide, HMR-1726, 1726, A-771726, RS-61980, SU-0020,
(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
108605-62-5, 282716-73-8 (monosodium salt)
C12-H9-F3-N2-O2
270.2091
Aventis Pharma (Originator), Sanofi-Aventis U.S. Llc
Sugen (Licensee)
Antiarthritic Drugs, Disease-Modifying Drugs, Immunologic Neuromuscular Disorders, Treatment of, IMMUNOMODULATING AGENTS, Immunosuppressants, Multiple Sclerosis, Agents for, NEUROLOGIC DRUGS, TREATMENT OF MUSCULOSKELETAL & CONNECTIVE TISSUE DISEASES, Dihydroorotate Dehydrogenase Inhibitors

CAMBRIDGE, Mass.–Aug. 30, 2013–(BUSINESS WIRE)–Genzyme, a Sanofi company (EURONEXT: SAN and NYSE: SNY), announced today that the European Commission has granted marketing authorization for Aubagio® (teriflunomide) 14 mg, a once-daily, oral therapy indicated for the treatment of adult patients with relapsing remitting multiple sclerosis (RRMS).

read all at

http://www.pharmalive.com/ec-approves-genzyme-s-aubagio-for-ms

Teriflunomide (trade name Aubagio, marketed by Sanofi, also known as A77 1726) is the active metabolite of leflunomide.[1]Teriflunomide was investigated in the Phase III clinical trial TEMSO as a medication for multiple sclerosis (MS). The study was completed in July 2010.[2] 2-year results were positive.[3] However, the subsequent TENERE head-to-head superiority trial reported that “although permanent discontinuations [of therapy] were substantially less common among MS patients who received teriflunomide compared with interferon beta-1a, relapses were more common with teriflunomide.”[4] The drug was approved by the FDA on September 13, 2012.[5]

Mechanisms of action

Teriflunomide is an immunomodulatory drug inhibiting pyrimidine de novo synthesis by blocking the enzyme dihydroorotate dehydrogenase. It is uncertain whether this explains its effect on MS lesions.[6]

Teriflunomide inhibits rapidly dividing cells, including activated T cells, which are thought to drive the disease process in MS. Teriflunomide may decrease the risk of infections compared to chemotherapy-like drugs because of its more-limited effects on the immune system.[7]

It has been found that teriflunomide blocks the transcription factor NF-κB. It also inhibits tyrosine kinase enzymes, but only in high doses not clinically used.[8]

Activation of leflunomide to teriflunomide

Leflunomide.svgE-Teriflunomide structure.svgTeriflunomide structure.svg

The structure which results from ring opening can interconvert between the E and Z enolic forms (and the corresponding keto-amide), with the Z enol being the most stable and therefore most predominant form.

Space filling model of the E isomer of teriflunomide


  1. ^
     Magne D, Mézin F, Palmer G, Guerne PA (2006). “The active metabolite of leflunomide, A77 1726, increases proliferation of human synovial fibroblasts in presence of IL-1beta and TNF-alpha”. Inflamm. Res. 55 (11): 469–75. doi:10.1007/s00011-006-5196-xPMID 17122964.
  2. ^ ClinicalTrials.gov Phase III Study of Teriflunomide in Reducing the Frequency of Relapses and Accumulation of Disability in Patients With Multiple Sclerosis (TEMSO)
  3.  “Sanofi-Aventis’ Teriflunomide Comes Up Trumps in Two-Year Phase III MS Trial”. 15 Oct 2010.
  4.  Gever, John (June 4, 2012). “Teriflunomide Modest Help but Safe for MS”medpage. Retrieved June 04, 2012. Unknown parameter |source= ignored (help)
  5. ^ “FDA approves new multiple sclerosis treatment Aubagio” (Press release). US FDA. Retrieved 2012-09-14.
  6. ^ H. Spreitzer (March 13, 2006). “Neue Wirkstoffe – Teriflunomid”. Österreichische Apothekerzeitung (in German) (6/2006).
  7.  Dr. Timothy Vollmer (May 28, 2009). “MS Therapies in the Pipeline: Teriflunomide”. EMS News (in English) (May 28, 2009).
  8. ^ Breedveld, FC; Dayer, J-M (November 2000). “Leflunomide: mode of action in the treatment of rheumatoid arthritis”Ann Rheum Dis 59 (11): 841–849. doi:10.1136/ard.59.11.841.PMC 1753034PMID 11053058.

SYNTHESIS

………………………

http://www.google.com/patents/WO2014177978A3?cl=en

Formula i

Teriflunomide is an immunosuppressant, acting as a tyrosine kinase inhibitor. It is also evaluated in the treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis. An oral film coated tablet containing teriflunomide as the active ingredient is marked in the United States by Sanofi Aventis US using brand AUBAGIO™. AUBAGIO is indicated for the treatment of patients with relapsing forms of multiple sclerosis.

U.S. Patent No. 5,679,709 appears to claim teriflunomide and its pharmaceutically acceptable salts, the same patent also further covers pharmaceutical composition and method of administering top a patients suffering from autoimmune disease.

U.S. Patent No. 5,494,91 I disclosesthe process for the preparation of teriflunomide by reacting 5-methylisoxazole-4-carbonyl chloride with trifluoromethyl aniline in the presence of acetonitrile to yield Leflunomide with on further hydrolysis with aqueous sodium hydroxide solution in methanol gives teriflunomide of formula I.

U.S. Patent No. 5,990,141 discloses the process for the preparation of teriflunomide by reacting 4-trifluoromethyl aniline with cyano acetic acid ethyl ester to yield cyanoaceto-(4-trifluromethyl)-aniline, with on further reacted with acetyl chloride in the presence of sodium hydride base and THF and acetonitrile solvent to give teriflunomide of formula I.

U.S. patent No. 6,365,626 discloses the process for the preparation of teriflunomide by reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetyl chloride in the presence of sodium hydride to give teriflunomide of formula I.

U.S. Patent No. 6,894,184 discloses the process for the preparation of teriflunomide involves reacting 4-trifluromethylaniline with cyanoacetic acid to give cyanoacet-(4- trifluoromethyl)anilide which on further reacted with acetic anhydride in the presence of base to give teriflunomide of formula I.

International PCT application No. WO 2009/147624 discloses the process for the preparation of teriflunomide involves condensation of ethyl-2-cyano-3-hydroxybut-2-enoate and 4-(trifluoromethyl) aniline in presence of xylene solvent at reflux temperatures for 16 hours to give teriflunomide of formula I.

preparation of teriflunomide (I) comprises steps of;

1 ) condensation of cyanoacetic acid of formula (II) with 4-trifluoromethyl aniline of formula (III) in the presence of chlorinating agent to give 2-cyano-N-[4-(trifluromethyl)phenyl]acetamide of formula (IV);

(II I) (IV)

2) acetylation of 2-cyano-N-[4-(trifluromethyl)phenyl] acetamide of

formula (IV) with an acetylating agent in the presence of base and suitable solvents to yield teriflunomide of formula (I).

EXAMPLE 1 : Preparation of 2-cvano-N-f4-(trifluoromethyl> phenyl! acetamide (IV)

A round bottom flask is charged with cyanoacetic acid (100 g) and phosphorous pentachloride and tetrahydrofuran (300 ml) and the reaction mixture is stirred at room temperature for 4 hours. 4-trifluoromethyl aniline (161 g) dissolved in tetrahydrofuran (100 ml) is slowly added to the reaction mixture and stirred for completion of reaction. The resultant reaction mass is cooled and separated solid is filtered and washed with slurry of Isoproapnol and cyclohexane and dried under reduced pressure to afford the title compound. Weight: 196 gm.

Purity by HPLC: 98%

EXAMPLE 2: preparation of 2-cyano-3-hvdroxy-N-f4-( trifluoromethyl) phenyl] but-2-enamide (Teriflunomide crude)

A round bottom flask is charged with 2-cyano-N-[4-{trifluromethyl} phenyl] acetamide (100g), sodium hydroxide (70 gm) and dimethyl formamide is added and the reaction mixture is stirred for 30 minutes. Isopropenyl acetate (60 ml) is added slowly and the resultant mixture is stirred for about 4-5 hours at room temperature. After completion of the reaction, the resulting reaction mixture is diluted with water and acidified with Cone. HCI solution and stirred for solid separation. The separated solid is filtered and washed with water and dried under reduced pressure to afford Teriflunomide.

The obtained teriflunomide is charged in round bottom flask and aqueous solution of sodium hydroxide solution (29.6 g in 300 ml water) is added slowly at 25-35°C and stirred for 1 to 2 hours. The mixture is brought to 5 to 10°C and dichloromethane is added, the mixture is stirred for 15 minutes. The organic and the aqueous layer are separated, and the resultant aqueous layer is acidified with aq. Hcl and stirred. The separated solid is filtered and washed with water and dried under vacuum at 65-70°C for 10-12 hours to afford teriflunomide.

Weight: 101 gm

Purity by HPLC: 95%

EXAMPLE 3; Purification of Teriflunomide:

Teriflunomide (5 g) is charged into a flask followed by addition of acetonitrile (125 ml) and heated to reflux and stirred for 2 hours. The resultant reaction solution is filtered through highflow bed to obtain a clear solution and cooled to room temperature and stirred for solid separation. The separated solid is filtered, washed with Isopropanol (50 ml) and dried under vacuum to afford pure teriflunomide.

Weight: 3.8 gm

Purity by HPLC: 99.7%

…………………………………………………………………………………………………………

EP 0527736; JP 1993506425; JP 1999322700; JP 1999343285; US 5494911; US 5532259; WO 9117748

5-Methylisoxazole-4-carboxylic acid (I) was converted to the corresponding acid chloride (II) upon refluxing with SOCl2. Coupling of acid chloride (II) with 4-(trifluoromethyl)aniline (III) produced anilide (IV). Finally, isoxazole ring opening in the presence of NaOH gave rise to the title cyano amide.

Teriflunomide, a dihydroorotate dehydrogenase (DHODH) inhibitor, is the active metabolite of leflunomide a synthetic, low-molecular-weight drug currently used in the treatment of rheumatoid arthritis. The mechanisms by which teriflunomide exerts its antiinflammatory, antiproliferative and immunosuppressive effects are not yet completely understood, although inhibition of pyrimidine biosynthesis (via suppression of DHODH) and interference with tyrosine kinase activity both appear to be involved. Based on its efficacy shown in animal models of experimental allergic encephalomyelitis, teriflunomide was tested in a phase II study in patients with multiple sclerosis with relapses. Recruitment is ongoing for a phase III study to determine the efficacy of teriflunomide in reducing the frequency of relapses and accumulation of disability in multiple sclerosis patients.

The chemical name of Teriflunomide is 2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is C12H9F3N2O2 and molecular weight is 270.207.

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in U.S. Pat. No. 5,679,709 but this patent does not mention any process of preparation for salt formation.

U.S. Pat. No. 5,494,911, U.S. Pat. No. 5,990,141 disclose various processes for preparing Teriflunomide. These patents do not disclose process for preparation Teriflunomide salts or mention any its polymorphic form.

EP 2280938 A2

HISTORY OF SYNTHESIS

The chemical name of Teriflunomide is

2-cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide and formula is Ci2H9 F3N2O2 and molecular weight is 270.207.

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.

US patent no. 5,494,911 discloses a process for preparation of Teriflunomide as shown in given below

Figure imgf000002_0002

4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below

Figure imgf000003_0001

Teriflunomide (I)

The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).

US patent no. 6,365,626 discloses a process for preparation of Teriflunomide  which is as given in below

Figure imgf000003_0002

Teriflunomide

ONE MORE

Graphical abstract: Mechanosynthesis of amides in the total absence of organic solvent from reaction to product recovery

http://pubs.rsc.org/en/content/articlelanding/2012/cc/c2cc36352f GET ABOVE DETAILS HERE

Teriflunomide is used as Immunosupressant. It acts as tyrosine kinase inhibitor. It is used in treatment of rheumatoid arthritis, autoimmune disease and multiple sclerosis.

Teriflunomide was first disclosed and claimed in US patent no. 5,679,709 but this application does not mention the process of preparation.

[H] US patent no. 5,494,911 discloses a process for preparation of Teriflunomide in Example-4 as shown in given below scheme-I

(V) (IV) (VI) (D

Scheme-I

The proces; 5 involves re acting 5-metlr

4-trifluoromethylaniline (IV) in acetonitrile to give leflunomide (VI). The subsequent hydrolysis with aqueous sodium hydroxide solution in methanol gives Teriflunomide (I). US patent 5,990,141 discloses a process for preparation of Teriflunomide as shown in given below scheme-II.

Teriflunomide (I)

Scheme-II  The process involves reacting 4-trifluorometyl aniline (IV) with cyanoacetic acid ethyl ester (II) to give cyanoacet-(4-trifluoromethyl)-anilide (VII). This compound is further reacted first with sodium hydride in acetonitrile and then with acetylchloride in THF to give Teriflunomide (I).

US patent no. 6,365,626 discloses a process for preparation of Teriflunomide in Fig. 19 which is as given in below scheme-Ill.

Teriflunomide

(I)

Scheme-Ill  The process involves reacting 4-trifluoromethyl aniline (IV) with cyanoacetic acid (Ha) to give compound of formula (VII). This compound is further reacted first with sodium hydride and then with acetylchloride to give Teriflunomide (I)

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Example-1  Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).

Yield: 84.6%Example-2 ] Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.

Yield: 71.0%

Purity: 99.4%

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.

13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,

187.8 ppm.

MS(FD) : m/e 269(M”, 100). [88] IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,

842, 684 cm-1.

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see

http://pubs.rsc.org/en/Content/ArticleLanding/2004/OB/b312682j#!divAbstract

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http://www.google.com/patents/CN103848756A?cl=en

Currently, for the preparation of teriflunomide mainly in the following three categories:

The first synthetic methods: mainly 5-methyl-isoxazole-4-carboxylic acid starting materials or by Synthesis of 5-methyl-isoxazole-4-carboxylic acid intermediate, then reacted with 4- trifluoromethyl base – aniline was synthesized teriflunomide, specific synthetic route is as follows:

[0007]

Figure CN103848756AD00042

The general reaction step above normal class methods, not easy to intermediate purification, total yield is low, and the synthesis process using a large number of chloride corrosion of equipment can easily produce large amounts of acid mist and acidic water, thus polluting the environment .

  The second class of methods: 2-cyano-acetic acid derivatives and 4-trifluoromethyl aniline. Such methods will be first prepared as a 2-cyano acetic acid chloride, and then 4-trifluoromethyl-aniline to give the corresponding amide, and then acetyl chloride for

With, the condensation reaction between the molecules to give the desired product, the synthesis route is as follows:

Figure CN103848756AD00051

This class methods used in the reaction process large amounts of chloride reagent for large equipment and environmental damage.

The third method: This method is quite similar to the second type of method, mainly in the 2-cyano-acetic acid derivatives and 4-trifluoromethyl-aniline; The method of the second type is different, In the last step with 1-methyl-2-chloro-propylene oxide as raw materials to build α, β-unsaturated nitrile of the enol structure, i.e., to give the desired product, the synthesis route is as follows:

Figure CN103848756AD00052

Teriflunomide Preparation Example 18 [0185] Implementation

Example 17 was obtained as a pale yellow solid of 61.2g crude compound was used directly in the synthesis of teriflunomide. In a 2L round bottom flask was added compound 27.2g (0.32mol) having the structure shown in formula IV, dry dioxane (620mL), sodium hydride 4g (0.16mol, in g / mL count, mass volume ratio 60% saving in kerosene), calcium hydride

6.7g (0.16mol), 15 ° C was stirred for I h, then slowly added dropwise in Example 17 was obtained as a pale yellow solid compound 61.2g (0.32mol) embodiment of dioxane 200mL, approximately I hour addition was complete, After the addition was complete the reaction was heated to reflux, the reaction at 80 ° C for 24 hours, the reaction process using a nitrogen blanket. After completion of the reaction was added 500mL of ice water to quench the reaction, with 2mol / L of HCl (aq.) And the reaction solution was adjusted to neutral pH, and extracted with EtOAc three times each in an amount of 500mL, and the combined organic phase was washed with saturated aqueous NaCl solution 800mL, dried over anhydrous Na2SO4, concentrated under reduced pressure, the mixed solution was twice recrystallized from methanol i_PrOH, the volume ratio of 1-PrOH and methanol is 2: 1, by volume of each recrystallized with a mixed solution of methanol with i_PrOH for 600mL, the crystallization temperature of 10 ° C, to give 58.8g of white solid compound in a yield of 66%, the total yield of 54% ο

Figure CN103848756AD00221

using mass spectrometry, nuclear magnetic resonance spectroscopy and NMR spectra of the resulting white solid carbon compound structures were identified. MS data [M-H +] = 269.1, H NMR data = 1H-NMR (DMSO-Cie) δ the white solid compound: 10.88 (s, 1Η), 10.07 (br, s, 1H), 7.79 ( d, 2H), 7.66 (d, 2H), 2.26 (s, 3H), carbon NMR spectral data for: 13C-NMR (DMS0-d6) δ: 23.5,80.2,119.1,119.9,120.3,122.4,122.0, 123.5,125.3,126.2,141.8,166.2,186.0. Structural analysis by a white solid compound obtained in the present embodiment example for teriflunomide. Cases detected by HPLC obtained teriflunomide the embodiment of purity, calculated based on the peak area normalization method available, the present embodiment obtained teriflunomide a purity of 99.9%.

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Scheme-A

Scheme-A

Pure Teriflunomide ………………………………………….Crude Teriflunomide

xamples

Example- 1: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (Formula-2)

Methylene chloride (125 ml) and dimethyl formamide (2.87 gms) were added to 5-methylisoxazole-4-carboxylic acid (25 gms) at 25-30°C. Heated the reaction mixture to 35-40°C and thionyl chloride (47.59 gms) was slowly added and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. To the obtained compound, dichloromethane was added at 25-30°C. Distilled off the solvent completely from the reaction mixture. Acetonitrile (50 ml) was added to the obtained compound at 25-30°C and slowly added to a mixture of acetonitrile (300 ml) and 4-(trifluoromethyl)aniline (64.45 gms) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. Filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (225 ml), followed by activated carbon (2.5 gms) were added to the obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (250 ml) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 39.8 gms; Melting point: 165-168°C. Purity by HPLC: 99.63%.

Example-2: Preparation of N-(4′-trifluoromethylphenyl)-5-methylisoxazoIe-4-carboxamide (FormuIa-2)

Methylene chloride (15 Its) and dimethyl formamide (40 ml) were added to 5-methylisoxazole-4-carboxylic acid (3 kgs) at 25-30°C. Thionyl chloride (5.70 kgs) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 4 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dichloromethane was added at the same temperature. Distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C and dissolved the obtained compound in acetonitrile (6.0 Its) at the same temperature. Slowly added to a mixture of acetonitrile (36 Its) and 4-(trifluoromethyl)aniline (7.70 kgs) at 25-30°C and stirred the reaction mixture for 5 hours at the same temperature. After completion of the reaction, filtered the reaction mixture and distilled off the solvent completely from the filtrate. Methanol (27 Its), followed by activated carbon (30 gms) was added to obtained compound at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hyflow bed and washed with methanol. Water (30 Its) was slowly added to the obtained filtrate at 25-30°C and stirred the reaction mixture for 2 hours. Filtered the precipitated solid, washed with water. To the obtained wet compound, toluene (9 Its) was added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the solid, washed with toluene and dried to get the title compound. Yield: 4.7 kg.

Example-3: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-l)

Methanol (150 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (50 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 2 hours at 0-5°C. Water was added to the reaction mixture. Adjust the pH of the reaction mixture to 7.5 by using dilute hydrochloric acid at 25-30°C. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 46.0 gms;

Example-4: Preparation of crystalline form-M of (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethyl phenyl)-amide (Formula-1)

Dimethylformamide (300 ml) was added to (Z)-2-cyano-3-hydroxy-but-2-enoic acid-(4-trifluoromethylphenyl)-amide (50 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with dimethyl formamide. To the obtained filtrate, methanol (350 ml) was added at 25-30°C. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 41 gms;

Melting point: 228-231°C; Water content: 0.06% w/w; Phenyl isoxazole impurity: 0.004%; Purity by HPLC: 99.97%.

Particle size distribution before micronisation: D10: 6.71 μιτι; D50: 34.4 μπι; D90: 109.8 μηι; Particle size distribution after micronisation: DIO: 1.35 μητ, D50: 4.52 μητ, D90: 10.26 μιη.

The P-XRD of the obtained compound is shown in figure- 1.

The DSC thermogram of the obtained compound is shown in figure-2.

Reference Example- 1: Preparation of (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethylphenyl)-amide according to US5494911 (Formula-1)

Methanol (74 ml) was added to N-(4′-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide (20 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C and aqueous sodium hydroxide solution {prepared by dissolving sodium hydroxide (3.26 gms) in water (74 ml)} was slowly added to the reaction mixture at the same temperature. Stirred the reaction mixture for 1 hour at 0-5°C. After completion of the reaction, 20% aqueous hydrochloric acid solution was added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 8.7 gms.

The P-XRD pattern of the obtained compound is shown in figure-3.

The DSC thermogram of the obtained compound is shown in figure-4.

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TERIFLUNOMIDE SPECTRAL DATA


Teriflunomide,
HMR-1726, 1726, A-771726, RS-61980, SU-0020,
(Z)-2-Cyano-3-hydroxy-N-[4-(trifluoromethyl)phenyl]-2-butenamide
108605-62-5, 282716-73-8 (monosodium salt)
C12-H9-F3-N2-O2 270.2091

17= US2011/0105795A1

NMR DASTA

1H NMR AND 13C NMR

1H NMR 13C NMR

above 13C NMR

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.
 
13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3, 122.2, 126.5, 126.9, 142.1, 167.4,
187.8 ppm.
MS(FD) : m/e 269(M”, 100).
 IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,
842, 684 cm-1.

REF EP 2280938 A2

Example-1  Preparation of Ethyl-2-cyano-3-hydroxy-but-2-enoate (III) [77] Potassium carbonate (73.3 g) was added to the well stirred solution of Ethylcy- anoacetate (50 g) in Dimethylformamide (250 ml) and stirred for 15 minute at ambient temperature. Acetic anhydride (90.25 g) was added drop wise to the above well stirred solution during 2 to 3 hours at ambient temperature. Reaction mixture was stirred at ambient temperature for 15 to 20 hours. Reaction mixture was diluted with water (500 ml) and extracted with dichloromethane (3 xlOO ml). Combined organic layer was washed with saturated sodium carbonate solution (3x100ml). Aqueous carbonate layer was separated and acidified with 50% HCl solution and extracted with dichloromethane (3x100ml). Combined organic layer was washed with brine solution (100 ml), dried over sodium sulfate and evaporated to yield Ethyl 2-cyano-3-hydroxy-but-2-enoate (58 g).

Yield: 84.6% Example-2 Preparation of Teriflunomide (I) [82] Ethyl 2-cyano-3-hydroxybut-2-enoate (III) (50 g) and 4-(trifluoromethyl) aniline (51.9 g) in xylene (1000 ml) was refluxed for 48 hours. The reaction mixture was allowed to cool at room temperature. Separated solid was filtered and washed with xylene (2×100 ml). Solid was dried under vacuum at 700C to yield (62 g) of Teri- flunomide.

Yield: 71.0%

Purity: 99.4%

! HNMR (DMSO, 300MHz) :δ 2.24(s, 3H); 5.36(bs, IH); 7.65(d, J=8.7Hz, 2H);

7.76(d, J=8.6Hz, 2H); 10.89(s, IH) ppm.

13 CNMR (DMSO, 75MHz) :δ 23.5, 82.1, 118.3,

122.2, 126.5,

126.9, 142.1, 167.4,

187.8 ppm.

MS(FD) : m/e 269(M”, 100).

IR : 3305, 2220, 1633, 1596, 1554, 1418, 1405, 1325, 1247, 1114, 1157, 1073, 971,

842, 684 cm-1.

1H NMR PREDICT

2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide NMR spectra analysis, Chemical CAS NO. 108605-62-5 NMR spectral analysis, 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide H-NMR spectrum

2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide NMR spectra analysis, Chemical CAS NO. 108605-62-5 NMR spectral analysis, 2-Cyano-3-hydroxy-N-(4-(trifluoromethyl)phenyl)but-2-enamide,teriflunomide C-NMR spectrum

COSY

COSY

HPLC

HPLC method of analysis:

N-(4′-trifluoromethylphenyI)-5-methylisoxazole-4-carboxamide of formula-2:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Cosmicsil APT CI 8, 100 x 4.6 mm, 3 μιη (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 210 nm; Column Temperature: 25°C; Injection volume: 20 μί; Run time: 40 min; Diluent: Mobile phase; Needle wash: Tetrahydrofuran; Elution: Isocratic; Mobile phase: 5 ml of triethyl amine into a 650 ml of water. Adjusted the pH to 3.4 with dil. Orthophosphoric acid and filter this solution through 0.22 μπι nylon membrane filter paper and sonicate to degas it. (Z)-2-cyano-3-hydroxy-but-2-enoicacid-(4-trifluoromethyl phenyl)-amide compound of formula- 1:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV- detector; Column: Kromasil 100 C18, 250 x 4.6 mm, 5 μηι (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 35°C; Injection volume: 5 μί; Run time: 37 min; Diluent: 0.01 M dipotassium hydrogen orthophosphate in 1000 ml of water; Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Buffer (70:30 v/v); Buffer: 1 ml of ortho phosphoric acid into a 1000 ml of water and 3.0 grams of 1 -octane sulfonic acid sodium salt anhydrous. Adjust pH to 6.0 with potassium hydroxide solution and filtered through 0.22μηι Nylon membrane filter paper and sonicate to degas it……..http://www.google.com/patents/WO2015029063A2?cl=en

WO2009147624A2 * 3 Jun 2009 10 Dec 2009 Alembic Limited A process for preparing teriflunomide
WO2011004282A2 * 22 Jun 2010 13 Jan 2011 Alembic Limited Novel polymorphic form of teriflunomide salts
US5494911 24 Oct 1990 27 Feb 1996 Hoechst Aktiengesellschaft Isoxazole-4-carboxamides and hydroxyalkylidenecyanoacetamides, pharmaceuticals containing these compounds and their use
US5679709 7 Jun 1995 21 Oct 1997 Hoechst Aktiengesellschaft N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide or salts, used for reduction of b-cell produced self-antibodies
US5990141 6 Jan 1995 23 Nov 1999 Sugen Inc. Administering 5-methyl-isoxazole-4-carboxylic acid-n-(4-trifluoromethyl)anilide or 2-cyano-3-hydroxy-n-(4-trifluoro-methyl)phenyl-2-butenamide; antitumor,-carcinogenic and proliferative agents; kinase inhibitors
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