CAS OF FREE BASE      1314944-07-4

C₂₁ H₂₄ N₆ O

Benzonitrile, 2-​[[7-​[(3R)​-​3-​amino-​1-​piperidinyl]​-​2,​3-​dihydro-​3,​5-​dimethyl-​2-​oxo-​1H-​imidazo[4,​5-​b]​pyridin-​1-​yl]​methyl]​-

http://www.google.com/patents/EP2524917A1?cl=en

(R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile AS TFA SALT

1314944-08-5  CAS

C₂₁ H₂₄ N₆ O . C₂ H F₃ O₂

Benzonitrile, 2-​[[7-​[(3R)​-​3-​amino-​1-​piperidinyl]​-​2,​3-​dihydro-​3,​5-​dimethyl-​2-​oxo-​1H-​imidazo[4,​5-​b]​pyridin-​1-​yl]​methyl]​-​, 2,​2,​2-​trifluoroacetate (1:1)

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• C₁₉ H₁₉ N₅ O₂
• Benzonitrile, 2-​[[7-​[(3R)​-​3-​amino-​1-​piperidinyl]​-​2-​oxooxazolo[5,​4-​b]​pyridin-​1(2H)​-​yl]​methyl]​-

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SEE  POLYMORPHS

EP2730575A1, WO2013007167A1

CN 102863440

http://www.google.com/patents/CN102863440A?cl=en

Dipeptidyl peptidase-IV (DPP-IV) inhibitors are a new generation of oral treatment of type 2 diabetes by enhancing the role of incretin activity, a non-insulin therapy. With conventional medicine for treating diabetes compared, DPP-IV inhibitors have not weight gain and edema and other adverse reactions. [0003] The compound shown in formula ⑴ (R) -2 – [[7 - (3 - amino-piperidine-I-yl) -3,5 - dimethyl-2 - oxo-2 ,3 - dihydro- -IH-imidazo [4,5-b] pyridin-I-yl] methyl] benzonitrile (referred to as the specification of compound A, in the patent application CN201010291056. 9 already described) is a DPP-IV inhibitor compounds , the DPP-IV has a strong inhibitory effect and high selectivity.

V

[0004] formula ⑴

[0005] In the crystalline drug development research is very important, compound crystal form, will result in its stability, solubility and other properties are different. Therefore, the inventors of the compound or its salt polymorph A lot of research carried out, whereby it was confirmed, and the invention of the compound A crystalline salt.

3, Invention

[0006] The object of the present invention is to solve the above problems and to provide better stability, better maneuverability, good bioavailability and solubility of the compound A or a salt thereof and method for preparing the crystalline form.

[0007] The present invention provides formula (I), the compound A dihydrochloride salt polymorph I: using Cu-K α radiation, to angle 2 Θ (°) represents an X-ray powder diffraction at 8. 7 ± 0. 2 °, 19.4 ± 0.2 °, 23. 5 ± 0. 2 °, 27. 2 ± 0. 2 ° at a characteristic peaks.

Butterfly NC N

[0008] formula ⑴

[0009] A compound of the dihydrochloride salt polymorph I, with Cu-Ka radiation, to angle 2 Θ (°) represents an X-ray powder diffraction peaks in addition to the features described above, it also at 12. 5 ± 0. 2 °, 22. 5 ± 0. 2 °, 25. 5 ± 0.2 ° at a characteristic peaks.

[0010] A compound of the dihydrochloride salt polymorph I, with Cu-κα exposed to radiation angle 2 Θ (°) represents an X-ray powder diffraction peaks in addition to the features described above, it also at 11.7 ± 0.2 °, 14.6 ± 0.2 °,

26. O ± 0.2 ° at a characteristic peak.

[0011] The present invention also provides the compound A dihydrochloride Preparation of polymorph I.

[0012] Compound A was dissolved in an organic solvent, and temperature, was added dropwise a stoichiometric ratio of hydrochloric acid, after the addition was complete stirring, filtered and dried to give the dihydrochloride salt of Compound A crystalline form I.

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http://www.google.com/patents/EP2524917A1?cl=en

0r

WO 2011085643

• Diabetes mellitus is a systemic chronic metabolic disease caused by a blood glucose level higher than normal level due to loss of blood glucose control. It is basically classified into four categories, including: type I (insulin-dependent) and type II (non-insulin-dependent), the other type and gestational diabetes. Type I and type II diabetes are primary diabetes, which are the two most common forms caused by the interaction of genetic and environmental factors. The cause of diabetes is very complicated, but in the final analysis, is due to absolute or relative insulin deficiency, or insulin resistance. It is characterized by the metabolic disorder of carbohydrate, protein, fat, electrolytes and water caused by absolute or relative insulin deficiency and the reduced sensitivity of target cells to insulin.
• In recent years, because of the improvement of living level, changes in the diet structure, the increasingly intense pace of life and lifestyle of less exercise and many other factors, the global incidence of diabetes is rapidly increasing, so that diabetes has become the third chronic disease which has a serious threat to human health next to tumor and cardiovascular diseases. Presently, the number of the patients suffering from diabetes has exceeded 120 million in the world, and the number in our country is the second largest in the world. According to statistics, up to 40 million people have been diagnosed as diabetes in China, and the number of the patients is increasing at a rate of 1 million per year. Among them, patients having type I and type II diabetes accounted for 10% and 90% respectively. Diabetes has become the increasingly concerned public health issue.
• The main drugs currently used for the treatment of type I diabetes are insulin preparations and their substitutes; for the treatment of type II diabetes, the main drugs are oral hypoglycemic agents, generally divided into sulfonylureas, biguanides, traditional Chinese medicine preparations, other hypoglycemic agents, and auxiliary medication. Although these drugs have good effects, they can not maintain long-term efficacy in reducing the high blood glucose, and can not effectively alleviate the condition against the cause of diabetes. Many of the anti-diabetic drugs can well control the blood glucose at the beginning, but their efficacy can not be maintained when the treatment using such drugs are continuously used. It is one of the main reasons why combination therapies or drugs in different classes are used. However, the existing anti-diabetic drugs is lack of long-term efficacy mainly because their mechanism of action is to increase the sensitivity of target tissues to insulin action or improve insulin-producing activity of pancreas, but these drugs have no targeted effect to the reduced function of the pancreatic β cell, which is the fundamental cause of diabetes.
• Dipeptidyl peptidase-IV (DPP-IV) is widely present in the body, and is a cell surface protein involved in a variety of biological functions. It can degrade many active enzymes in vivo, such as glucagon like peptide-1 (GLP-1), glucose-dependent insulinotropic polypeptide (GIP), neuropeptide, substance P, and chemokines and the like. The deficiency of GLP-1 and GIP is the main cause resulting in type II diabetes (i.e., non-insulin-dependent diabetes). DPP-IV inhibitor is a new generation of anti-diabetic drug. It protects the activity of GLP-1, GIP and the like, stimulates the secretion of insulin, lowers blood glucose level by inhibiting the activity of DPP-IV, and does not cause hypoglycemia, weight gain, edema and other side effects. Its effect for lowering blood glucose level stops when a normal blood glucose level has been reached, and hypoglycemia will not occur. It can be used for a long term, and can repair the function of β-cells.
• Sitagliptin is the first marketed DPP-IV inhibitor. It rapidly became a “blockbuster” drug after marketed in 2006 by Merck. The FDA approved the saxagliptin developed by AstraZeneca and Bristol-Myers Squibb on July 31, 2009. SYR-322 developed by Takeda has an activity and selectivity better than that of sitagliptin and saxagliptin, and is currently in the phase of pre-registration. In addition, there are three drugs in clinical phase III: BI-1356 (linagliptin) developed by Boehringer Ingelheim, PF-734200 (gosogliptin) developed by Pfizer Inc, and PHX1149 (dutogliptin) developed by Phenomix Inc. Nine drugs are in the clinical phase II, and seven drugs are in clinical phase I.
• However, the limited varieties of drugs can not satisfy the clinical requirements. Accordingly, there is an urgent need for development of many DPP-IV inhibitor drugs to satisfy the clinical use.

Example 17 The preparation of (R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dihydro-1

-imidazo[4,5-b]pyridin-1-yl]methyl]benzonitrile (Compound 17) trifluoroacetate

(1)2,4-dichloro-6-methyl-3-nitropyridine

• 6-methyl-3-nitropyridin-2,4-diol (1.7 g, 10 mmol) was dissolved in 10 mL POCl₃, heated to 95°C, and stirred for 1.5 h. The excess POCl₃ was removed through centrifugation. 100 mL ice water was carefully added. The reaction solution was extracted with ethyl acetate (80 mL×3). The organic phase was combined, washed with saturated brine, dried with anhydrous Na₂SO₄ and spinned to dryness to afford 1.773 g yellow powder with a yield of 85.7 %.

(2) (R)-1-(2-chloro-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate

• [0216]
  The specific operation referred to the step (1) described in Example 1 for details. 0.96 g 2,4-dichloro-6-methyl-3-nitropyridin (4.64 mmol), and 0.933 g R-tert-butylpiperidin-3-yl-carbamate (4.66 mmol) were charged to afford 1.1 g titled product with a yield of 63.9 %.

(3) (R)-1-(2-methylamino-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate

• The specific operation referred to the step (2) described in Example 1 for details, 1.1 g (R)-1-(2-chloro-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate (2.97 mmol), and 5 mL 27 % solution of methylamine in alcohol were charged to afford 1.0 g titled product with a yield of 92.1 %.

(4) (R)-1-(2-methylamino-3-amino-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate

• The specific operation referred to the step (3) described in Example 1 for details. 1.0 g (R)-1-(2-methylamino-3-nitro-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate (2.74 mmol), and 0.1 g 10% Pd-C were charged to afford 0.873 g titled product with a yield of 95 %.

(5)(R)-1-(3,5-dimethyl-2-oxo-2,3-dihydro-1

H

-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl tert-butyl carbamate
• The specific operation referred to the step (4) described in Example 1 for details. 873 mg (R)-1-(2-methytamino-3-amino-6-methylpyridin-4-yl)piperidin-3-yl tert-butyl carbamate (2.60 mmol), 849 mg triphosgene (2.86 mmol), and 1.39 mL triethylamine (10.4 mmol) were charged to afford 0.813 g titled product with a yield of 86.5 %.

(6)(R)-1-[1-(2-cyanobenzyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1

H

-imidazo[4,5-b] pyridin-7-yl]piperidin-3-yl tert-butyl carbamate
• The specific operation referred to the step (5) described in Example 1 for details.813 mg (R)-1-(3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin-7-yl)piperidin-3-yl tert-butyl carbamate (2.25 mmol), 441 mg 2-(bromomethyl)benzonitrile (2.25 mmol), and 621 mg potassium carbonate (4.50 mmol) were charged to afford 0.757 g titled product with a yield of 70.5%.

(7)(R)-2-[[7-(3-aminopiperidin-1-yl)-3,5-dimethyl-2-oxo-2,3-dibydro-1-imidazo [4,5-b]pyridin-1-yl]methyl]benzonitrile trifluoroacetate

• The specific operation referred to the step (6) described in Example 1 for details. 750 mg (R)-1-[1-(2-cyanobenzyl)-3,5-dimethyl-2-oxo-2,3-dihydro-1H-imidazo[4,5-b]pyridin -7-yl]piperidin-3-yl tert-butyl carbamate (1.57 mmol), and 8.5 mL trifluoroacetic acid were charged to afford 0.680 g titled product with a yield of 88.3%.
  Molecular formula: C₂₁H₂₄N₆O Molecular weight: 376.45 Mass spectrum (M+H): 377.2
  ¹H-NMR(D₂O, 400 MHz): δ 7.64 (d, 1H), 7.42 (t, 1H), 7.29 (d, 1H), 6.93(d, 1H), 6.76(s, 1H), 5.39(d, 1H), 5.25(d, 1H), 3.27(s, 3H), 3.04(m, 1H), 2.90(m, 2H), 2.80-2.60 (m, 2H), 2.48 (m, 1H), 2.32 (s, 3H), 1.90 (m, 1H), 1.54 (m, 1H), 1.32 (m, 1H).

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PAPER

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-Λ/²-methylpyridine-2- carboxamide is commonly known as sorafenib (I). Sorafenib is prepared as its tosylate salt. Sorafenib blocks the enzyme RAF kinase, a critical component of the RAF/MEK/ERK signaling pathway that controls cell division and proliferation; in addition, sorafenib inhibits the VEGFR-2/PDGFR-beta signaling cascade, thereby blocking tumor angiogenesis.

Sorafenib, marketed as Nexavar by Bayer, is a drug approved for the treatment of advanced renal cell carcinoma (primary kidney cancer). It has also received “Fast Track” designation by the FDA for the treatment of advanced hepatocellular carcinoma (primary liver cancer). It is a small molecular inhibitor of Raf kinase, PDGF (platelet-derived growth factor), VEGF receptor 2 & 3 kinases and c Kit the receptor for Stem cell factor.

Sorafenib and pharmaceutically acceptable salts thereof is disclosed in WO0042012. Sorafenib is also disclosed in WO0041698. Both these patents disclose processes for the preparation of sorafenib.

WO0042012 and WO0041698 describe the process as given in scheme I which comprises reacting picolinic acid (II) with thionyl chloride in dimethyl formamide (DMF) to form acid chloride salt (III). This salt is then reacted with methylamine dissolved in tetrahydrofuran (THF) to give carboxamide (IV). This carboxamide when further reacted with 4- aminophenol in anhydrous DMF and potassium tert-butoxide 4-(2-(N-methylcarbamoyl)-4- pyridyloxy)aniline (V) is formed. Subsequent reaction of this aniline with 4-chloro-3- (trifluoromethyl) phenyl isocyanate (Vl) in methylene chloride yields sorafenib (I). The reaction is represented by Scheme I as given below.

Scheme I

Picolini

Sorafenib (I)

WO2006034796 also discloses a process for the preparation of sorafenib and its tosylate salt. The process comprises reacting 2-picolinic acid (II) with thionyl chloride in a solvent inert toward thionyl chloride without using dimethyl formamide to form acid chloride salt (III). This acid salt on further reaction with aqueous solution methylamine or gaseous methylamine gives compound (IV). Compound (IV) is then reacted with 4-aminophenol with addition of a carbonate salt in the presence of a base to yield compound (V).

Compound (V) can also be obtained by reacting compound (IV) with 4-aminophenol in the presence of water with addition of a phase transfer catalyst. Compound (V) when reacted with 4-chloro-3-(trifluoromethyl) phenyl isocyanate (Vl) in a non-chlorinated organic solvent, inert towards isocyanate gives sorafenib (I). Sorafenib by admixing with p- toluenesulfonic acid in a polar solvent gives sorafenib tosylate (VII). The reaction is represented by Scheme Il as given below.

Scheme Il

P

A key step in the synthesis of sorafenib is the formation of the urea bond. The processes disclosed in the prior art involve reactions of an isocyanate with an amine. These isocyanate compounds though commercially available are very expensive. Further synthesis of isocyanate is very difficult which requires careful and skillful handling of reagents.

Isocyanate is prepared by reaction of an amine with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) or trichloromethyl chloroformate (diphosgene). Isocyanate can also be prepared by using a hazardous reagent such as an azide. Also, the process for preparation of an isocyanate requires harsh reaction conditions such as strong acid, higher temperature etc. Further, this isocyanate is reacted with an amine to give urea.

Reactions of isocyanates suffer from one or more disadvantages. For example phosgene or phosgene equivalents are hazardous and dangerous to use and handle on a large scale. These reagents are also not environment friendly. Isocyanates themselves are thermally unstable compounds and undergo decomposition on storage and they are incompatible with a number of organic compounds. Thus, the use of isocyanate is not well suited for industrial scale application.

Sorafenib and its pharmaceutically acceptable salts and solvates are reported for the first time in WO0041698 (corresponding US 03139605) by Bayer. In the literature only one route is disclosed for the preparation of sorafenib. According to this route (Scheme-I), picolinic acid of formula III is reacted with thionyl chloride to give the 4-chloro derivative which on treatment

VII

Scheme-I with methanol gave the methyl ester of formula V. Compound of formula V is reacted with methylamine to get the corresponding amide of formula VL Compound of formula VI is reacted with 4-aminophenol to get the ether derivative of formula VII. Compound of formula VII is reacted with 4-chloro-3-trifluoromethylphenylisocyante to get sorafenib base of formula I. Overall yield of sorafenib in this process is 10% from commercially available 2-picolinic acid of formula II. Main drawback in this process is chromatographic purification of the intermediates involved in the process and low yield at every step.

Donald Bankston’s (Org. Proc. Res. Dev., 2002, 6, 777-781) development of an improved synthesis of the above basic route afforded sorafenib in an overall yield of 63% without involving any chromatographic purification. Process improvements like reduction of time in thionyl chloride reaction; avoid the isolation of intermediates of formulae IV and V₅ reduction of base quantity in p-aminophenol reaction, etc lead to the simplification of process and improvement in yield of final compound of formula I.

Above mentioned improvements could not reduce the number of steps in making sorafenib of formula-I. In the first step all the raw materials are charged and heated to target temperature (72°C). Such a process on commercial scale will lead to sudden evolution of gas emissions such as sulfur dioxide and hydrogen chloride. Also, in the aminophenol reaction two bases (potassium carbonate and potassium t-butoxide) were used in large excess to accomplish the required transformation.

A scalable process for the preparation of sorafenib is disclosed in WO2006034796. In this process also above mentioned chemistry is used in making sorafenib of formula I. In the first step, catalytic quantity. of DMF used in the prior art process is replaced with reagents like hydrogen bromide, thionyl bromide and sodium bromide. Yield of required product remained same without any advantages from newly introduced corrosive reagents. Process improvements like change of solvents, reagents, etc were applied in subsequent steps making the process scalable. Overall yield of sorafenib is increased to 74% from the prior art 63% yield. Purity of sorafenib is only 95% and was obtained as light brown colored solid.

Main drawbacks in this process are production of low quality sorafenib and requirement of corrosive and difficult to handle reagents such as thionyl bromide and hydrogen bromide. Also, there is no major improvement in the yield of sorafenib.

Sorafenib tosylate ( Brand name: Nexavar ®, BAY 43-9006 other name, Chinese name: Nexavar, sorafenib, Leisha Wa) was Approved by U.S. FDA for the treatment of advanced kidney cancer in 2005 and liver cancer in 2007 .

Sorafenib, co-Developed and co-marketed by Germany-based Bayer AG and South San Francisco-based Onyx Pharmaceuticals , is an Oral Multi-kinase inhibitor for VEGFR1, VEGFR2, VEGFR3, PDGFRbeta, Kit, RET and Raf-1.

In March 2012 Indian drugmaker Natco Pharma received the first compulsory license ever from Indian Patent Office to make a generic Version of Bayer’s Nexavar despite the FACT that Nexavar is still on Patent. This Decision was based on the Bayer Drug being too expensive to most patients. The Nexavar price is expected to drop from $ 5,500 per person each month to $ 175, a 97 percent decline. The drug generated $ 934 million in global sales in 2010, according to India’s Patent Office.

Sorafenib tosylate

Chemical Name: 4-Methyl-3-((4 – (3-pyridinyl)-2-pyrimidinyl) amino)-N-(5 – (4-methyl-1H-imidazol-1-yl) -3 – (trifluoromethyl) phenyl) benzamide monomethanesulfonate, Sorafenib tosylate

CAS Number 475207-59-1 (Sorafenib tosylate ) , 284461-73-0 (Sorafenib)

References for the Preparation of Sorafenib References

1) Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl Substituted diphenyl Ureas as RAF kinase inhibitors ; U.S. Patent numberUS7235576
2) Rossetto, Pierluigi; Macdonald, Peter, Lindsay; Canavesi, Augusto; Process for preparation of sorafenib and Intermediates thereof , PCT Int. Appl., WO2009111061
3) Lögers, Michael; gehring, Reinhold; Kuhn, Oliver; Matthäus, Mike; Mohrs, Klaus; müller-gliemann, Matthias; Stiehl, jürgen; berwe, Mathias; Lenz, Jana; Heilmann, Werner; Process for the preparation of 4 – {4 – [( {[4-chloro-3-(TRIFLUOROMETHYL) phenyl] amino} carbonyl) amino] phenoxy}-N-methylpyridine-2-carboxamide , PCT Int. Appl., WO2006034796
4) Shikai Xiang, Liu Qingwei, Xieyou Rong, sorafenib preparation methods, invention patent application Publication No. CN102311384 , Application No. CN201010212039
5) Zhao multiply there, Chenlin Jie, Xu Xu, MASS MEDIA Ji Yafei; sorafenib tosylate synthesis ,Chinese Journal of Pharmaceuticals , 2007 (9): 614 -616

Preparation of Sorafenib Tosylate (Nexavar) Nexavar, sorafenib Preparation of methyl sulfonate

Sorafenib (Sorafenib) chemical name 4 – {4 – [({[4 - chloro -3 - (trifluoromethyl) phenyl] amino} carbonyl) amino] phenoxy}-N-methyl-pyridine -2 – formamide by Bayer (Bayer) research and development, in 2005 the U.S. Food and Drug Administration (FDA) approval. Trade name Nexavar (Nexavar). This product is an oral multi-kinase inhibitor, for the treatment of liver cancer and kidney cancer.

Indian Patent Office in March this year for Bayer’s Nexavar in liver and kidney cancer drugs (Nexavar) has released a landmark “compulsory licensing” (compulsory license). Indian Patent Office that due to the high price Nexavar in India, the vast majority of patients can not afford the drug locally, thus requiring local Indian pharmaceutical company Natco cheap Nexavar sales. Nexavar in 2017 before patent expiry, Natco pay only Bayer’s pharmaceutical sales to 6% royalties. The move to make Nexavar patent drug prices, the supply price from $ 5,500 per month dropped to $ 175, the price reduction of 97%. Compulsory licensing in India for other life-saving drugs and patent medicines overpriced open a road, the Indian Patent Office through this decision made it clear that the patent monopoly does not guarantee that the price is too high. Nexavar is a fight against advanced renal cell carcinoma, liver cancer cure. In China, a box of 60 capsules of Nexavar price of more than 25,000 yuan. In accordance with the recommended dose, which barely enough to eat half of patients with advanced cancer. In September this year India a patent court rejected Bayer Group in India cheap drugmaker emergency appeal. Indian government to refuse patent medicine overpriced undo “compulsory licensing rules,” allowing the production of generic drugs Nexavar.

Sorafenat by Natco – Sorafenib – Nexavar – India natco Nexavar

Chemical Synthesis of  Sorafenib Tosylate (Nexavar)

Sorafenib tosylate (brand name :Nexavar®, other name BAY 43-9006, was approved by US FDA for the treatment of kidney cancer in 2005 and advanced liver cancer in 2007.

US Patent US7235576, WO2006034796, WO2009111061 and Faming Zhuanli Shenqing(CN102311384) disclosed processes for preparation of sorafenib base and its salt sorafenib tosylate.

References

1)Bernd Riedl, Jacques Dumas, Uday Khire, Timothy B. Lowinger, William J. Scott, Roger A. Smith, Jill E. Wood, Mary-Katherine Monahan, Reina Natero, Joel Renick, Robert N. Sibley; Omega-carboxyaryl substituted diphenyl ureas as raf kinase inhibitors; US patent numberUS7235576
2)Rossetto, pierluigi; Macdonald, peter, lindsay; Canavesi, augusto; Process for preparation of sorafenib and intermediates thereof, PCT Int. Appl., WO2009111061
3)Lögers, michael; gehring, reinhold; kuhn, oliver; matthäus, mike; mohrs, klaus; müller-gliemann, matthias; stiehl, jürgen; berwe, mathias; lenz, jana; heilmann, werner; Process for the preparation of 4-{4-[({[4-chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-n-methylpyridine-2-carboxamide, PCT Int. Appl., WO2006034796CN102311384, CN201010212039

Full Experimental Details for the preparation of Sorafenib Tosylate (Nexavar) 

Synthesis of 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline.

A solution of 4-aminophenol (9.60 g, 88.0 mmol) in anh. DMF (150 mL) was treated with potassium tert-butoxide (10.29 g, 91.7 mmol), and the reddish-brown mixture was stirred at room temp. for 2 h. The contents were treated with 4-chloro- N -methyl-2-pyridinecarboxamide (15.0 g, 87.9mmol) and K2CO3 (6.50 g, 47.0 mmol) and then heated at 80°C. for 8 h. The mixture was cooled to room temp. and separated between EtOAc (500 mL) and a saturated NaCl solution (500 mL). The aqueous phase was back-extracted with EtOAc (300 mL). The combined organic layers were washed with a saturated NaCl solution (4×1000 mL), dried (Na2SO4) and concentrated under reduced pressure. The resulting solids were dried under reduced pressure at 35°C. for 3 h to afford 4-(2-(N-methylcarbamoyl)-4-pyridyloxy)aniline as a light-brown solid 17.9 g, 84%):. 1H-NMR (DMSO-d6) δ 2.77 (d, J = 4.8 Hz, 3H), 5.17 (br s, 2H), 6.64, 6.86 (AA’BB’ quartet, J = 8.4 Hz, 4H), 7.06 (dd, J = 5.5, 2.5 Hz, 1H), 7.33 (d, J = 2.5 Hz, 1H), 8.44 (d, J = 5.5 Hz; 1H), 8.73 (br d, 1H); HPLC ES-MS m/z 244 ((M+H)+).

Synthesis of 4-{4-[({[4-Chloro-3-(trifluoromethyl)phenyl]amino}carbonyl)amino]phenoxy}-N-methylpyridine-2-carboxamide (sorafenib)

4-(4-Aminophenoxy)-N-methyl-2-pyridinecarboxamide (52.3 kg, 215 mol) is suspended in ethyl acetate (146 kg) and the suspension is heated to approx. 40° C. 4-Chloro-3-trifluoromethylphenyl isocyanate (50 kg, 226 mol), dissolved in ethyl acetate (58 kg), is then added to such a degree that the temperature is kept below 60° C. After cooling to 20° C. within 1 h, the mixture is stirred for a further 30 min and the product is filtered off. After washing with ethyl acetate (30 kg), the product is dried under reduced pressure (50° C., 80 mbar). 93 kg (93% of theory) of the title compound are obtained as colorless to slightly brownish crystals. m.p. 206-208° C. 1H-NMR (DMSO-d6, 500 MHz): δ =2.79 (d, J=4.4 Hz, 3H, NCH3); 7.16 (dd, J=2.5, 5.6 Hz, 1H, 5-H); 7.18 (d, J=8.8 Hz, 2H, 3′-H, 5′-H); 7.38 (d, J=2.4 Hz, 1H, 3-H); 7.60-7.68 (m, 4H, 2′-H, 6′-H, 5″-H, 6″-H); 8.13 (d, J=1.9 Hz, 1H, 2″-H); 8.51 (d, J=5.6 Hz, 1H, 6-H); 8.81 (d, J=4.5 Hz, 1H, NHCH3); 9.05 (br. s, 1H, NHCO); 9.25 (br. s, 1H, NHCO) MS (ESI, CH3CN/H2O): m/e=465 [M+H]+.

Synthesis of Sorafenib Tosylate (Nexavar)

4-(4-{3-[4-chloro-3-(trifluoromethyl)phenyl]ureido}phenoxy)-N2-methylpyridine-2-carboxamide (sorafenib) (50g, 0.1076 mol) is suspended in ethyl acetate (500 g) and water (10g). The mixture is heated to 69°C within 0.5 h, and a filtered solution of p-toluenesulfonic acid monohydrate (3.26 g, 0.017 mol) in a mixture of water (0.65 g) and ethyl acetate (7.2 g) is added. After filtration a filtered solution of p-toluenesulfonic acid monohydrate (22g, 0.11 mol) in a mixture of ethyl acetate (48 g) and water (4.34 g) is added. The mixture is cooled to 23°C within 2 h. The product is filtered off, washed twice with ethyl acetate (92.5 g each time) and dried under reduced pressure. The sorafenib tosylate (65.5 g, 96% of theory) is obtained as colorless to slightly brownish crystals.

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http://www.google.com/patents/EP2195286A2?cl=en

Example 22: Synthesis of Sorafenib

Phenyl 4-chloro-3-(trifluoromethyl)phenylcarbamate (100 g, 0.3174 mol) and 4-(4- aminophenoxy)-N-methylpicolinamide (77.14 g, 0.3174 mol) were dissolved in N₁N- dimethyl formamide (300 ml) to obtain a clear reaction mass. The reaction mass was agitated at 40-45⁰C for 2-3 hours, cooled to room temperature and diluted with ethyl acetate (1000 ml). The organic layer was washed with water (250 ml) followed by 1N HCI (250ml) and finally with brine (250 ml). The organic layer was separated, dried over sodium sulfate and degassed to obtain solid. This solid was stripped with ethyl acetate and finally slurried in ethyl acetate (1000 ml) at room temperature. It was then filtered and vacuum dried to give (118 g) of 4-(4-(3-(4-chloro-3- (trifluoromethyl)phenyl)ureido)phenoxy)-N-methylpicolinamide (sorafenib base).

Example 23: Synthesis of 1-(4-chloro-3-(trifluoromethyl)phenyl)urea (Compound 4)

Sodium cyanate (1.7 g, 0.02mol) was dissolved in water (17ml) at room temperature to obtain a clear solution. This solution was then charged drop wise to the clear solution of 3- trifluoromethyl-4-chloroaniline (5 g, 0.025 mol) in acetic acid (25 ml) at 40°C-45°C within 1- 2 hours. The reaction mass was agitated for whole day and cooled gradually to room temperature. The obtained solid was filtered washed with water and vacuum dried at 50⁰C to afford the desired product (5.8 g) i.e. 1-(4-chloro-3-(trifluoromethyl)phenyl)urea.

Example 24: Synthesis of Sorafenib

1-(4-chloro-3-(trifluoromethyl) phenyl)urea (15 g, 0.0628 mol), 1 ,8- diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N- methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120⁰C for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl) phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).

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http://www.google.com/patents/WO2009054004A2?cl=en

http://worldwide.espacenet.com/publicationDetails/biblio?CC=WO&NR=2009054004A2&KC=A2&FT=D&date=20090430&DB=EPODOC&locale=en_gb

EXAMPLES

Example 1

Preparation of l-(4-chloro-3-(trifluoromethyl)phenyI)-3-(4-hydroxyphenyl)urea Into a 250 ml, four-necked RB flask was charged 1O g of 4-aminophenol and 100 ml of toluene. A solution of 4-chloro-3-(trifluoromethyl)phenyl isocyante (20.4 g) in toluene (50 ml) was added to the reaction mass at 25-30⁰C. The reaction mass was stirred at room temperature for 16 h. The reaction mass was filtered and washed the. solid with 50 ml of toluene. The wet material was dried in the oven at 50-60°C to get 29.8 g of title compound as white solid. M.P. is 218-222°C. IR (KBr): 3306, 1673, 1625, 1590, 1560, 1517, 1482, 1435, 1404, 1328, 1261, 1182, 1160, 1146, 1125, 1095, 1032, 884, 849, 832, 812, 766, 746, 724, 683, 539 and 434 cm^“1.

Example 2 Preparation of sorafenib tosylate

Into a 100 ml, three-necked RB flask was charged 2.0 g of l-(4-chloro-3- (trifluoromethyl)-phenyl)-3-(4-hydroxyphenyl)urea and 10 ml of DMF. Potassium tert- butoxide (2.3 g) was added to the reaction mass and stirred for 45 min at RT. 4-Chlro-N- methylpicolinamide (1.14 g) and potassium carbonate (0.42 g) were added to the reaction mass and heated to 80°C. The reaction mass was maintained at 80-85°C for 8 h and cooled to 30°C. The reaction mass was poured into water and extracted with ethyl acetate. Ethyl acetate layer was washed with water, brine and dried over sodium sulphate. Solvent was distilled of under reduced pressure.

The crude compound (4.7 g) was dissolved in 10 ml of IPA and added 1.9 g of p- toluenesulfonic acid. The reaction mass was stirred at RT for 15 h and filtered. The wet solid was washed with 10 ml of IPA and dried at 50-60°C to get 3.4 g of title compound as off-white crystalline solid.

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A Scaleable Synthesis of BAY 43-9006:  A Potent Raf Kinase Inhibitor for the Treatment of Cancer

http://pubs.acs.org/doi/abs/10.1021/op020205n

Urea 3 (BAY 43-9006), a potent Raf kinase inhibitor, was prepared in four steps with an overall yield of 63%. Significant process research enabled isolation of each intermediate and target without chromatographic purification, and overall yield increases >50% were observed compared to those from previous methods. This report focuses on improved synthetic strategies for production of scaled quantities of 3 for preclinical, toxicological studies. These improvements may be useful to assemble other urea targets as potential therapeutic agents to combat cancer.

References

External links

• Nexavar.com – Manufacturer’s website
• Prescribing Information – includes data from the key studies justifying the use of sorafenib for the treatment of kidney cancer (particularly clear cell renal cell carcinoma, which is associated with the von Hippel-Lindau gene)
• Patient Information from FDA
• Sorafenib in Treating Patients With Soft Tissue Sarcomas
• Sorafenib Sunitinib differences – diagram
• ClinicalTrials.gov NCT00217399  – Sorafenib and Anastrozole in Treating Postmenopausal Women With Metastatic Breast Cancer
• Cipla launches Nexavar generic at 1/10 of Bayer’s price