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VX-? , an Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication from Vertex

May 2, 2016 10:21 am / Leave a comment

VX-?

An Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication from Vertex

SYNTHESIS COMING……..

CAS 1259498-06-0

MF C₂₃ H₂₇ F₂ N₇ O, MW, 455.50

1-Piperidinecarboxamide, N-[(1R,3S)-3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-4-pyrimidinyl]amino]cyclohexyl]-

N-[(1R,3S)-3-[[5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide

N-[(1R,3S)-3-[[5-Fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide , (1R,3S)-cis-diaminocyclohexane.

Specific Rotation

[α]²¹_D = −165.7° (c = 1 in MeOH).

¹H NMR (300 MHz, d₆-DMSO) δ 12.23 (s, 1H), 8.42 (dd, J = 9.8, 2.9 Hz, 1H), 8.34–8.18 (m, 2H), 8.14 (d, J = 4.0 Hz, 1H), 7.49 (d, J = 7.5 Hz, 1H), 6.33 (d, J= 7.6 Hz, 1H), 4.24–4.00 (m, 1H), 3.75–3.57 (m, 1H), 3.57–3.42 (m, 4H), 3.28–3.09 (m, 4H), 2.15 (d, J = 11.4 Hz, 1H), 2.01 (d, J = 11.2 Hz, 1H), 1.83 (d, J = 9.7 Hz, 2H), 1.60–1.07 (m, 4H).¹⁹F NMR (282.4 MHz, d₆-DMSO) −138.10, −158.25 ppm.

HRMS (ESI) [M + H]⁺ calculated for C₂₂H₂₆F₂N₇O₂ 458.2111, found 458.2110.

Influenza spreads around the world in seasonal epidemics, resulting in the deaths of hundreds of thousands annually – millions in pandemic years. For example, three influenza pandemics occurred in the 20th century and killed tens of millions of people, with each of these pandemics being caused by the appearance of a new strain of the virus in humans. Often, these new strains result from the spread of an existing influenza virus to humans from other animal species.

Influenza is primarily transmitted from person to person via large virus-laden droplets that are generated when infected persons cough or sneeze; these large droplets can then settle on the mucosal surfaces of the upper respiratory tracts of susceptible individuals who are near (e.g. within about 6 feet) infected persons. Transmission might also occur through direct contact or indirect contact with respiratory secretions, such as touching surfaces contaminated with influenza virus and then touching the eyes, nose or mouth. Adults might be able to spread influenza to others from 1 day before getting symptoms to approximately 5 days after symptoms start. Young children and persons with weakened immune systems might be infectious for 10 or more days after onset of symptoms. [00103] Influenza viruses are RNA viruses of the family Orthomyxoviridae, which comprises five genera: Influenza virus A, Influenza virus B, Influenza virus C, Isavirus and Thogoto virus.

The Influenza virus A genus has one species, influenza A virus. Wild aquatic birds are the natural hosts for a large variety of influenza A. Occasionally, viruses are transmitted to other species and may then cause devastating outbreaks in domestic poultry or give rise to human influenza pandemics. The type A viruses are the most virulent human pathogens among the three influenza types and cause the most severe disease. The influenza A virus can be subdivided into different serotypes based on the antibody response to these viruses. The serotypes that have been confirmed in humans, ordered by the number of known human pandemic deaths, are: HlNl (which caused Spanish influenza in 1918), H2N2 (which caused Asian Influenza in 1957), H3N2 (which caused Hong Kong Flu in 1968), H5N1 (a pandemic threat in the 2007-08 influenza season), H7N7 (which has unusual zoonotic potential), H1N2 (endemic in humans and pigs), H9N2, H7N2 , H7N3 and H10N7. [00105] The Influenza virus B genus has one species, influenza B virus. Influenza B almost exclusively infects humans and is less common than influenza A. The only other animal known to be susceptible to influenza B infection is the seal. This type of influenza mutates at a rate 2-3 times slower than type A and consequently is less genetically diverse, with only one influenza B serotype. As a result of this lack of antigenic diversity, a degree of immunity to influenza B is usually acquired at an early age. However, influenza B mutates enough that lasting immunity is not possible. This reduced rate of antigenic change, combined with its limited host range (inhibiting cross species antigenic shift), ensures that pandemics of influenza B do not occur.

The Influenza virus C genus has one species, influenza C virus, which infects humans and pigs and can cause severe illness and local epidemics. However, influenza C is less common than the other types and usually seems to cause mild disease in children. [00107] Influenza A, B and C viruses are very similar in structure. The virus particle is 80-120 nanometers in diameter and usually roughly spherical, although filamentous forms can occur. Unusually for a virus, its genome is not a single piece of nucleic acid; instead, it contains seven or eight pieces of segmented negative-sense RNA. The Influenza A genome encodes 11 proteins: hemagglutinin (HA), neuraminidase (NA), nucleoprotein (NP), Ml, M2, NSl, NS2(NEP), PA, PBl, PB1-F2 and PB2.

HA and NA are large glycoproteins on the outside of the viral particles. HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles. Thus, these proteins have been targets for antiviral drugs. Furthermore, they are antigens to which antibodies can be raised. Influenza A viruses are classified into subtypes based on antibody responses to HA and NA, forming the basis of the H and N distinctions (vide supra) in, for example, H5N1. [00109] Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventative measures. In the United States, influenza is responsible for a total cost of over $10 billion per year, while it has been estimated that a future pandemic could cause hundreds of billions of dollars in direct and indirect costs. Preventative costs are also high. Governments worldwide have spent billions of U.S. dollars preparing and planning for a potential H5N1 avian influenza pandemic, with costs associated with purchasing drugs and vaccines as well as developing disaster drills and strategies for improved border controls.

Current treatment options for influenza include vaccination, and chemotherapy or chemoprophylaxis with anti-viral medications. Vaccination against influenza with an influenza vaccine is often recommended for high-risk groups, such as children and the elderly, or in people that have asthma, diabetes, or heart disease. However, it is possible to get vaccinated and still get influenza. The vaccine is reformulated each season for a few specific influenza strains but cannot possibly include all the strains actively infecting people in the world for that season. It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time and infects people although they have been vaccinated (as by the H3N2 Fujian flu in the 2003-2004 influenza season). It is also possible to get infected just before vaccination and get sick with the very strain that the vaccine is supposed to prevent, as the vaccine takes about two weeks to become effective. [00111] Further, the effectiveness of these influenza vaccines is variable. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years. A vaccine formulated for one year may be ineffective in the following year, since the influenza virus changes rapidly over time, and different strains become dominant.

Also, because of the absence of RNA proofreading enzymes, the RNA- dependent RNA polymerase of influenza vRNA makes a single nucleotide insertion error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA. Hence, nearly every newly-manufactured influenza virus is a mutant — antigenic drift. The separation of the genome into eight separate segments of vRNA allows mixing or reassortment of vRNAs if more than one viral line has infected a single cell. The resulting rapid change in viral genetics produces antigenic shifts and allows the virus to infect new host species and quickly overcome protective immunity.

Antiviral drugs can also be used to treat influenza, with neuraminidase inhibitors being particularly effective, but viruses can develop resistance to the standard antiviral drugs.

PAPER

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00063

Development of a Scalable Synthesis of an Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication

Jianglin Liang^*, John E. Cochran, Warren A. Dorsch, Ioana Davies, and Michael P. Clark

Vertex Pharmaceuticals Incorporated, 50 Northern Avenue, Boston, Massachusetts 02210, United States

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00063

Publication Date (Web): April 08, 2016

A scalable, asymmetric route for the synthesis of the influenza virus replication inhibitor 2 is presented. The key steps include an enzymatic desymmetrization of cis-1,3-cyclohexanediester in 99% yield and 96% ee, S_NAr displacement of a methanesulfinylpyrimidine, and a Curtius rearrangement to form a morpholinyl urea. This high-yielding route allowed us to rapidly synthesize hundreds of grams of 2 in 99% purity to support in vivo studies.

About Influenza

Often called “the flu,” seasonal influenza is caused by influenza viruses, which infect the respiratory tract.¹ The flu can result in seasonal epidemics² and can produce severe disease and high mortality in certain populations, such as the elderly.³ Each year, on average 5 to 20 percent of the U.S. population gets the flu⁴ resulting in more than 200,000 flu-related hospitalizations and 36,000 deaths.⁵The overall national economic burden of influenza-attributable illness for adults is $83.3 billion.⁵ Direct medical costs for influenza in adults totaled $8.7 billion including $4.5 billion for adult hospitalizations resulting from influenza-attributable illness.⁵ The treatment of the flu consists of antiviral medications that have been shown in clinical studies to shorten the disease and reduce the severity of symptoms if taken within two days of infection.⁶ There is a significant need for new medicines targeting flu that provide a wider treatment window, greater efficacy and faster onset of action.

About Vertex

Vertex is a global biotechnology company that aims to discover, develop and commercialize innovative medicines so people with serious diseases can lead better lives. In addition to our clinical development programs focused on cystic fibrosis, Vertex has more than a dozen ongoing research programs aimed at other serious and life-threatening diseases.

Founded in 1989 in Cambridge, Mass., Vertex today has research and development sites and commercial offices in the United States, Europe, Canada and Australia. For four years in a row, Science magazine has named Vertex one of its Top Employers in the life sciences. For additional information and the latest updates from the company, please visit www.vrtx.com.

Vertex’s press releases are available at www.vrtx.com.

SYNTHESIS COMING

WO-2010148197

http://www.google.co.in/patents/WO2010148197A1?cl=en

General Scheme 44 SIMILAR TO A POINT BUT NOT SAME

(a) Pd(PPh₃)₄ sodium carbonate, DME/water, reflux (b) meta-chloroperbenzoic acid, dichloromethane, rt. (c) 20a, tetrahydrofuran, 5O°C (d) trifluoroacetic acid, dichloromethane, rt.

SIMILAR NOT SAME

(e) morpholιne-4-carbonyl chloride, dimethylformamide, rt (f) sodium methoxide, methanol, rt.

Formation of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-lΗ- pyrrolo[2,3-b]pyridine (44b)

2-Chloro-5-fluoro-4-methylsulfanyl-pyrimidine (34.1 g, 191.0 mmol) , 5-fluoro-1-(p- tolylsulfonyl)-3-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (53.0 g, 127.3 mmol) and Na₂Cθ3 (40.5 g, 381.9 mmol) were dissolved in a mixture of DME (795 mL) and water (159 mL). The mixture was purged with nitrogen for 20 minutes and treated with Pd(PPh₃ )₄ (7.4 g, 6.6 mmol). After purging with nitrogen for another 20 minutes, the reaction was heated to reflux overnight, cooled to room temperature and diluted with water (60OmL). The resulting suspension was stirred at room temperature for 30 minutes and the precipitate was then collected by filtration, washed with water and acetonitrile and dried at 50 °C to afford 48.2 g of 5-fluoro-3-[5-fluoro-4-(methylthio)pyrimidin-2-yl]-1-tosyl-1H- pyrrolo[2,3-b]pyridine as a white solid.

¹H NMR (300 MHz, OMSO-d6) δ 8.70 – 8.58 (m, 2H), 8.54 – 8.41 (m, 2H), 8.09 (d, J = 8.4 Hz, 2H), 7.45 (d, J= 8.2 Hz, 2H), 2.76 (s, 3H), 2.36 (s, 3H).

Formation of 5-fluoro-3-[5-fluoro-4-(methylsulfinyl)pyrimidin-2-yl]-1- tosyl-1H-pyrrolo[2,3-b]pyridine (44c)

5-fluoro-3 – [5 -fluoro-4-(methylthio)pyrimidin-2-yl] – 1 -tosyl- 1 H-pyrrolo [2,3 – b]pyridine, 44b, (48.2 g, 111.5 mmol) was dissolved in dichloromethane (2.3 L) and treated portionwise with m-CPBA (27.5 g, 122.6 mmol) while keeping the temperature below 20 °C. After addition was complete, the reaction was stirred at room temperature for 2 hours, then treated with another portion of m-CPBA (1.9 g) and stirred for another hour. The reaction mixture was washed with 12% aqueuous K₂CO3 (2 x 1.0 L) and the organic layer was dried on Na₂SO₄ and concentrated in vacuo to provide 50 g of 5-fluoro-3-[5-fluoro-4- (methylsulfinyl)pyrimidin-2-yl]-1-tosyl-1H-pyrrolo[2,3-b]pyridine as a yellow solid.

¹H NMR (300 MHz, DMSO-rf<5) δ 9.11 (d, J= 1.5 Hz, 1H), 8.69 (s, 1H), 8.65 (dd, J = 9.0, 2.9 Hz, 1H), 8.52 (dd, J= 2.8, 1.2 Hz, 1H), 8.11 (d, J = 8.4 Hz, 2H), 7.46 (d, J = 8.3 Hz, 2H), 3.05 (s, 3H), 2.36 (s, 3H).

[001057] Formation of tert-butyl N-[(IR, 3S)-3-[[5-fluoro-2-[5-fluoro-1-(p- tolylsulfonyl)pyrrolo [2,3-b] pyridin-3-yl]pyrimidin-4-yl] amino] cyclohexyl] carbamate (44d)

5-fluoro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridine, 44c, (5.9 g, 10.5 mmol) and tert-butyl N-[(IR, 35^*)-3-aminocyclohexyl]carbamate (3 g, 12.60 mmol) were dissolved in THF (100 mL). The reaction mixture was heated to 50 °C for 6 hours, then cooled to room temperature. C₆ lite was added and the solvent was removed under reduced pressure. The C₆ lite-supported residue was purified by silica gel chromatography (20-80% EtOAc/hexanes gradient to provide 3.7 g of tert-butyl N-[(IR, 3S)- 3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4- yl]amino]cyclohexyl]carbamate.

¹H NMR (300 MHz, CDCl₃) δ 8.51 (s, 1H), 8.46 – 8.41 (m, 1H), 8.29 (d, J = 1.6 Hz, 1H), 8.11 (s, 1H), 8.08 (s, 1H), 8.06 (d, J= 3.2 Hz, 1H), 7.27 (d, J= 8.4 Hz, 2H), 4.91 (d, J = 8.0 Hz, 1H), 4.41 (s, 1H), 4.29 – 4.01 (m, 1H), 3.64 (s, 1H), 2.47 (d, J= 11.5 Hz, 1H), 2.36 (s, 3H), 2.24 (d, J = 13.1 Hz, 1H), 2.08 (d, J= 10.9 Hz, 1H), 1.91 (d, J= 13.8 Hz, 1H), 1.43 (s, 9H), 1.30 – 1.03 (m, 4H).

Formation of (IS, SΛHVHS-fluoro^-β-fluoro-1-Cp- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-1,3-diamine (44e) tert-Butyl N-[(IR, 3S>3-[[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3- b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]carbamate, 44d, (3.7 g, 6.2 mmol) was dissolved in dichloromethane (105 mL) and treated with trifluoroacetic acid (31 mL). After 5 minutes, the volatiles were evaporated under reduced pressure, and the resulting residue was treated with IN NaOH (75 mL). The resulting precipitate was collected by filtration, washed with water (3 x 30 mL) and vacuum dried to provide 2.7 g of (IS, 3R)-Nl -[5-fluoro-2-[5- fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]cyclohexane-l,3-diamine as a white solid.

¹H NMR (300 MHz, MeOD) d 8.56 (dd, J = 8.0, 3.9 Hz, 2H), 8.35 – 8.26 (m, 1H), 8.12 (dd, J= 10.3, 6.1 Hz, 3H), 7.43 (d, J= 8.4 Hz, 2H), 4.36 – 4.21 (m, 1H), 3.28 – 3.13 (m, 1H), 2.48 (d, J= 12.3 Hz, 1H), 2.46 (s, 3H), 2.25 – 1.97 (m, J= 17.3, 10.6, 4.1 Hz, 4H), 1.76 – 1.28 (m, 3H).

Formation of N-[(IR, 3S>3-[[5-fluoro-2-[5-fluoro-1-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl] morpholine- 4-carboxamide (44f)

(15, 3R)-M-[5-fluoro-2-[5-fluoro-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridin-3- yl]pyrimidin-4-yl]cyclohexane- 1,3 -diamine, 44e, (2.3 g, 4.6 mmol) was dissolved in DMF (5OmL) and treated with morpholine-4-carbonyl chloride (2.1 g, 13.8 mmol) and DIPEA (4.2 g, 5.6 mL, 32.3 mmol). After one hour, the resulting solution was diluted with water (400 mL) and stirred for an additional two hours. The resulting precipitate was collected by filtration, washed with water (3 x 50 mL) and dried to provide the crude product. This material was purified by flash chromatography on a 4Og column using EtOAc/DCM 20- 100%, to provide 2.0 g of N-[(1R, 35)-3-[[5-fluoro-2-[5-fluoro-1-(p- tolylsulfonyl)pyrrolo[2,3-b]pyridin-3-yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4- carboxamide as a white solid.

¹H NMR (300 MHz, DMSO-Λ5) δ 8.53 – 8.43 (m, J = 11.9, 2.7 Hz, 3H), 8.22 (d, J = 3.9 Hz, 1H), 8.07 (d, J= 8.4 Hz, 2H), 7.44 (d, J= 8.3 Hz, 2H), 6.32 (d, J= 7.5 Hz, 1H), 4.05 (s, J= 19.4 Hz, 1H), 3.62 (s, 1H), 3.58 – 3.45 (m, 4H), 3.27 – 3.18 (m, 4H), 2.36 (s, 3H), 2.12 (d, J= 11.7 Hz, 1H), 1.99 (d, J= 9.5 Hz, 1H), 1.83 (d, J= 10.3 Hz, 2H), 1.53 – 1.11 (m, J = 32.3, 22.8, 10.9 Hz, 4H).

ormation of N-[(IR, 3S>3-[[5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3- b]pyridin-3-yl)pyrimidin-4-yl] amino] cyclohexyl]morpholine-4-carboxamide (706)

N- [( IR, 35)-3 – [ [5 -fluoro-2- [5 -fluoro- 1 -(p-tolylsulfonyl)pyrrolo [2,3 -b]pyridin-3 – yl]pyrimidin-4-yl]amino]cyclohexyl]morpholine-4-carboxamide, 44f, (2.0 g, 3.2 mmol) was suspended in methanol (50 mL) and treated with 25% sodium methoxide in methanol (19.9 mL, 92.3 mmol) . After stirring for 1 hour, the solvent was evaporated under reduced pressure, and the residue was partitioned between water (100 mL) and ethyl acetate (100 mL). The organic layer was collected, dried on Νa₂SO₄ and concentrated to provide the crude product as a yellow solid. This material was purified by silica gel chromatography on a 4Og column, using DCM/MeOH 1-6%. The purified fractions were treated with 2N HCl in ether and concentrated to provide 1.5 g of N-[(1R, 35)-3-[[5-fluoro-2-(5-fluoro-1H- pyrrolo[2,3-b]pyridin-3-yl)pyrimidin-4-yl]amino]cyclohexyl]-morpholine-4-carboxamide as a white solid.

HCI D DCM

44e

Formation of (IS, S^-M-^-fluoro-S-CS-fluoro-1H-pyrrolo^S-^pyridin- 3-yl)phenyl)cyclohexane-1,3-diamine (44e)

To a solution of tert-butyl (IR, 35)-3-(2-fluoro-5-(5-fluoro-1-tosyl-lH-pyrrolo-[2,3- &]pyridin-3-yl)phenylamino)cyclohexylcarbamate, 44d, (0.65 g, 1.09 mmol) in methylene chloride (22 mL) was added hydrogen chloride (2.71 mL of 4M solution in 1,4-dioxane, 10.86 mmol). The reaction was heated to 50 °C and stirred for 6 hours. The mixture was cooled to room temperature and concentrated in vacuo, producing a yellow solid. The crude residue was purified via silica gel chromatography (25-50% Ethyl Acetate/hexanes gradient). Desired fractions were combined and concentrated in vacuo to produce 350 mg of 44e as a yellow powder.

General Scheme 67 SIMILAR TO A POINT BUT NOT SAME

(a) Pd/C (wet, Degussa), hydrogen, EtOH (b) 2,4-dichloro-5-fluoropyrimidine, ¹Pr₂NEt, THF, reflux (c) LiOH, THF/water, 5O°C

SIMILAR BUT NOT SAME

(d) DPPA, Et₃N, THF, 85 °C (e) 5-fluoro-3-(4,4,5,5-tetramethyl-1,3 ,2-dioxaborolan-2-yl)-1- tosyl-l//-pyrrolo[2,3-i]pyridine, XPhos, Pd₂(dba)₃, K₃PO₄, 2-methylTHF, water, 125 °C (f)

Formation (IR, 35)-ethyl 3-aminocyclohexanecarboxylate (67b)

To a solution of (IR, 35)-ethyl 3-(benzyloxycarbonylamino)cyclohexane-carboxylate, 18b, (14.0 g, 45.9 mmol) in ethanol (3 mL) was added Pd/C (wet, Degussa (2.4 g, 2.3 mmol). The mixture was evacuated and then stirred under atmosphere of nitrogen at room temperature overnight. The reaction mixture was filtered through a pad of celite and the resulting filtrate concentrated in vacuo to provide an oil that was used without further purification.

Formation (IR, SS^-ethyl 3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane- carboxylate (67c)

To a solution of (IR, 3«S)-ethyl S-aminocyclohexanecarboxylate, 67b, (5.1 g, 24.1 mmol) and 2,4-dichloro-5,-fluoropyrimidine (6.0 g, 36.0 mmol) in THF (60 mL) was added diisopropylethylamine (9.6 mL, 55.4 mmol). The mixture was heated to reflux overnight. The reaction was cooled to room temperature and concentrated in vacuo. The residue was diluted with water and extracted twice with ethyl acetate. The combined organic phases were dried (MgSO₄), filtered and concentrated in vacuo. The residue was purified by silica gel chromatography (0-40% EtOAc/hexanes gradient) to provide 6.7 g of (IR, 35^*)-ethyl 3-(2- chloro-5-fluoropyrimidin-4-ylamino)cyclohexane-carboxylate as a white solid: LCMS RT = 3.1 (M+H) 302.2.

Formation (IR, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexanecarboxylic acid (67d)

To a solution of (IR, 35^*)-ethyl 3-(2-chloro-5-fluoropyrimidin-4- ylamino)cyclohexane-carboxylate, 67c, (20.0 g, 66.3 mmol) in THF (150 mL) was added added a solution of LiOH hydrate (8.3 g, 198.8 mmol) in 100ml water. The reaction mixture was stirred at 50 °C overnight, To the reaction mixture was added HCl (16.6 mL of 12 M solution, 198.8 mmol) and EtOAc. The organic phase was washed with brine and dried over MgSO₄ and the solvent was removed under reduced pressure to afford 17.5 g of product that was used without further purification: ¹H NMR (300 MHz, CDC13) δ 7.91 (d, J = 2.7 Hz, 2H), 5.24 (d, J = 7.3 Hz, 2H), 4.19 – 4.03 (m, 3H), 3.84 – 3.68 (m, 3H), 2.59 (ddd, J= 11.5, 8.2, 3.6 Hz, 2H), 2.38 (d, J = 12.4 Hz, 2H), 2.08 (d, J = 9.6 Hz, 6H), 1.99 – 1.76 (m, 5H), 1.63 – 1.34 (m, 6H), 1.32 – 1.15 (m, 4H).

Formation N-((1R, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)- pyrrolidine-1-carboxamide (67e)

A solution of (IR, 35)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexane- carboxylic acid, 67d, (8.2 g, 30.0 mmol), (azido(phenoxy)phosphoryl)oxybenzene (9.7 mL, 45.0 mmol) and triethylamine (5.8 mL, 42.0 mmol) in THF (200 mL) was degassed under nitrogen for 15 minutes. The reaction mixture was heated at 85 °C for 30 minutes until LC/MS indicated complete consumption of carboxylic acid, 67d. To the reaction mixture was added pyrrolidine (7.5 mL, 90.0 mmol) and the reaction was heated at 85 °C for an additional 15 min. The mixture was diluted into brine and extracted with EtOAc. The organic phase was separated, dried over MgSO₄. The product was isolated (6.25 g) by filtration after partial removal of solvent in vacuo: ¹H NMR (300 MHz, CDC13) δ 7.87 (d, J = 2.8 Hz, 2H), 5.04 (d, J = 8.1 Hz, 2H), 4.09 (ddd, J = 26.9, 13.4, 5.6 Hz, 4H), 3.91 – 3.71 (m, 2H), 3.32 (t, J= 6.5 Hz, 7H), 2.45 (d, J= 11.5 Hz, 2H), 2.08 (dd, J= 22.1, 12.0 Hz, 4H), 1.96- 1.82 (m, 9H), 1.54 (dd, J= 18.6, 8.5 Hz, 2H), 1.22 – 1.01 (m, 6H).

Formation N-((IR, 3S>3-(5-fluoro-2-(5-fluoro-1-tosyl-1H-pyrrolo[2,3-b]pyridm-3- yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (67f)

A solution of N-((1R, 3«S)-3-(2-chloro-5-fluoropyrimidin-4-ylamino)cyclohexyl)- pyrrolidine-1-carboxamide, 67e, (6.8 g, 20.0 mmol), 5-fluoro-1-(p-tolylsulfonyl)-3-(4,4,5,5- tetramethyl-l,3,2-dioxaborolan-2-yl)pyrrolo[2,3-b]pyridine, 44a, (12.5 g, 30.0 mmol) and K₃PO₄ (17.0 g, 80.0 mmol) in 2-methyl TΗF (180 mL) and water (20 mL) was degassed under nitrogen for 30 min. To the mixture was added dicyclohexyl-[2-(2,4,6- triisopropylphenyl)phenyl]phosphane (XPhos) (1.1 g, 2.4 mmol) and Pd₂(dba)₃ (0.5 g, 0.5 mmol). The reaction mixture was heated in a pressure bottle at 125 °C for 2.5 hr. The reaction mixture was filtered through celite, the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (8%MeOΗ/CΗ₂Cl₂) to afford 11.5 g of the desired product: ¹H ΝMR (300 MHz, CDC13) δ 8.54 (s, 1H), 8.49 (dd, J= 9.0, 2.8 Hz, 1H), 8.32 (d, J= 2.1 Hz, 1H), 8.13 (d, J= 8.3 Hz, 2H), 8.07 (d, J= 3.2 Hz, 1H), 7.30 (d, J = 8.5 Hz, 2H), 4.98 (d, J = 6.3 Hz, 1H), 4.37 – 4.16 (m, 1H), 4.08 (d, J = 7.3 Hz, 1H), 3.99 – 3.80 (m, 1H), 3.33 (t, J= 6.5 Hz, 4H), 2.52 (d, J= 11.6 Hz, 1H), 2.39 (s, 3H), 2.29 (d, J= 11.3 Hz, 1H), 2.12 (d, J= 11.1 Hz, 1H), 1.99 – 1.81 (m, 5H), 1.70 – 1.55 (m, 1H), 1.22 – 1.08 (m, 2H).

Formation N-((IR, 3S>3-(5-fluoro-2-(5-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)- pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide (895)

A solution of N-((1R, 35)-3-(5-fluoro-2-(5-fluoro-1-tosyl-lH-pyrrolo[2,3-b]pyridin-3- yl)pyrimidin-4-ylamino)cyclohexyl)pyrrolidine-1-carboxamide, 67f, (11.5 g, 19.3 mmol) in TΗF (150 mL) was added sodium methoxide (4.173 g, 19.31 mmol). After stirring the reaction mixture for 2 minutes, the mixture was poured into an aqueous saturated solution of NaHCO₃. The organic phase was washed with brine, dried over MgSO₄ and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel chromatography (10%MeOH/CH₂Cl₂) to afford 6.5g of the desired product. The product was converted to an HCl salt by dissolving in MeOH (100 mL) and adding 2.4 mL of 12M HCl solution at room temperature. The solution was stirred at for lhour and the HCl salt precipitated out and filtered to provide 7.05g of the HCl salt: ¹H NMR (300 MHz, DMSO) δ 9.36 (s, 2H), 9.05 (d, J= 3.0 Hz, 2H), 8.49 (d, J= 5.6 Hz, 2H), 8.41 (dd, J= 2.6, 1.4 Hz, 2H), 8.31 (d, J= 9.5 Hz, 2H), 5.92 (s, 3H), 4.24 (s, 3H), 3.64 (s, 2H), 3.18 (t, J= 6.6 Hz, 7H), 2.07 (dt, J = 22.7, 11.5 Hz, 4H), 1.87 (t, J = 12.6 Hz, 4H), 1.77 (dd, J = 8.0, 5.3 Hz, 7H), 1.65 – 1.13 (m, 8H).

PATENT

US-20120171245-A1 / 2012-07-05

INHIBITORS OF INFLUENZA VIRUSES REPLICATION

Charifson, Paul S. [US] ET AL

/////////VX-? , an Azaindolyl-Pyrimidine Inhibitor, Influenza Virus Replication, Vertex, preclinical, 1259498-06-0

O=C(NC1CCC[C@@H](C1)Nc2nc(ncc2F)\C\4=C\N=C3\N\C=C(\F)/C=C3/4)N5CCCCC5

ASP 3026

May 2, 2016 10:19 am / Leave a comment

ASP3026

ASP3026;

CAS 1097917-15-1; ASP-3026; ASP 3026; UNII-HP4L6MXF10;

N2-[2-Methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl]phenyl]-N4-[2-[(1-methylethyl)sulfonyl]phenyl]-1,3,5-triazine-2,4-diamine;

2-N-[2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl]-4-N-(2-propan-2-ylsulfonylphenyl)-1,3,5-triazine-2,4-diamine

(N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel selective inhibitor of the fusion protein EML4-ALK.

¹H NMR (CDCl₃, 400 MHz) (ppm) = 1.31 (d, 6H, J = 6.8 Hz), 1.58–1.80 (m, 4H), 1.90–2.04 (m, 2H), 2.16–2.84 (m, 12H), 3.18–3.32 (m, 1H), 3.66–3.76 (m, 2H), 3.88 (s, 3H), 6.48–6.60 (m, 2H), 7.18–7.26 (m, 1H), 7.50–7.72 (m, 2H), 7.86–7.92 (dd, 1H, J = 1.2 Hz, J = 7.6 Hz), 8.06–8.16 (m, 1H), 8.28–8.48 (m, 1H), 8.48–8.62 (m, 1H), 9.28 (s, 1H).

Molecular Formula:	C₂₉H₄₀N₈O₃S
Molecular Weight:	580.7447 g/mol

ASP3026 is a novel and selective inhibitor for the ALK kinase. ASP3026 potently inhibited ALK kinase activity and was more selective than crizotinib in a Tyr-kinase panel. In an anchorage independent in vitro cell growth assay, ASP3026 inhibited the growth of NCI-H2228, a human NSCLC tumor cell line endogenously expressing EML4-ALK variant 3 and that of 3T3 cells expressing EML4-ALK variant 1, 2 and 3. The plasma and tumor concentrations of ASP3026 in mice xenografted with NCI-H2228 tumor were determined using high-performance liquid chromatography-tandem mass spectrometry. Significant tumor penetration was observed. The antitumor activities were evaluated using mice bearing subcutaneous NCI-H2228 tumor xenografts.

ASP-3026 was studied in P1 clinical trials at Astellas Pharma for the oral treatment of advanced solid tumors and advanced B-cell lymphoma. In 2014 the product was discontinued by Astellas due to strategic reasons

JP 2012153674

WO 2012102393

WO 2011145548

WO 2009008371

PATENT

WO2012102393

The compound of the formula (1) has an excellent EML4-ALK fusion protein and inhibitory activity of the kinase of the mutant EGFR protein, we are already reported to be useful as an active ingredient of a pharmaceutical composition for cancer treatment (Patent Document 1). Further, it is the compound of formula (1) there are five polymorphs shown as A01 ~ A05 type, among others A04 type crystal is in finding reported that the most stable type crystals (Japanese Patent Document 2).
[Formula 1] 　a compound of formula (1) described in Patent Document 1 production method of (Patent Document 1 of Example 23), referring to Production Examples and Examples described in this document, the reaction formula (I) It is shown in. That is, 2,4-dichloro-1,3,5-triazine (hereinafter, may be referred to as “compound of formula (15)”.), 2- (isopropylsulfonyl) aniline (hereinafter, “the formula (8) sometimes referred to compound “.) using, by reacting according to the method described in production example 7 of this document, to give compounds of formula (14) to (production example 22 of Patent Document 1), then , the resulting compound of formula (14), a known method (e.g., International Publication No. 2005/016894 pamphlet reference) was prepared by 2-methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] aniline (hereinafter, may be referred to as “formula (13) compounds of.”) is used to react according to the method described in example 1 of the document, and the target it is a method for producing a compound of formula (1) to.

[Formula 2]

Patent Document 1: International Publication No. 2009/008371 pamphlet
Patent Document 2: WO 2011/145548 pamphlet

Example 1
The first step 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (R ¹ and R ² Synthesis of methyl Any compound of formula (10))
　4,4 – N and dimethoxy piperidine monohydrochloride (35.9 g), N-dimethylformamide and (75 mL) were mixed, and the mixed solution of 1,8-diazabicyclo [5.4.0] undec-7-ene (57.5 mL) was added It was. It was separately prepared here 5-fluoro-2-nitroanisole (30.0 g) and N, N-dimethylformamide (30 mL) was stirred for 5 hours at room temperature. Water (120 mL) was added at room temperature to the reaction mixture, after stirring for 4 hours, the precipitated crystals were collected by filtration. The resulting crystals N, N-dimethylformamide and a mixed solution of water (1: 1) (60mL) , water (60 mL), was further washed sequentially with water (60 mL), and dried under reduced pressure at 40 ° C. to give 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (49.9 g, 96.1% yield) as crystals.
D2: 1.72-1.80 (4H, m) , 3.14 (6H, s), 3.44-3.50 (4H, m), 3.91 (3H, m), 6.52 (1H, d, J = 2.4Hz), 6.60 (1H, dd, J = 2.4,9.2Hz), 7.88 (1H, D, J = 9.2Hz)
ESI Tasu: 297

The second step 4- (R (4,4-dimethoxy-1-yl) -2-methoxyaniline ¹ and R ² is methyl none has the formula (Compound 6)) Synthesis of

　4,4-dimethoxy – 1- (3-methoxy-4-nitrophenyl) piperidine and (45.0 g) in tetrahydrofuran and a (225 mL) were mixed, 5% palladium carbon (about 50% wet product, 4.5 g) to this mixed solution was added at room temperature, under a hydrogen atmosphere (2.4821×10 ⁵ Pa), and the mixture was stirred for 5 hours and a half at room temperature. Then filtered off and palladium-carbon, washed with tetrahydrofuran (90mL), was concentrated under reduced pressure filtrate until total volume of about 90mL obtain a slurry. After the slurry was stirred for 1 hour at 40 ° C., n- heptane (135 mL) was added and after stirring for 1 hour at 40 ° C., cooled to 0 ° C., was added n- heptane (405 mL), precipitated crystals It was collected by filtration.The obtained crystals were washed with a mixed solution of tetrahydrofuran (9 mL) and n- heptane (54 mL), and dried in vacuo at 40 ℃, 4- (4,4- dimethoxy-1-yl) -2-methoxy to give aniline (37.9g, 93.7% yield) as crystals.
D2: 1.72-1.80 (4H, m) , 2.90-2.97 (4H, m), 3.11 (6H, s), 3.73 (3H, m), 4.21 (1H, br), 6.30 (1H, d, J = 2.4 , 8.4Hz), 6.46_6.56 (2H, M)
ESI Tasu: 267

The third step 4,6-dichloro-N- [2-(propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (Lv is Cl any, compounds of formula (7) synthesis of)

　cyanuric chloride (25.0 g), sodium bicarbonate (13.7 g), were mixed 2- (isopropylsulfonyl) aniline (29.7 g) and acetone (200 mL), and stirred at room temperature for 25 hours. After adding water (200 mL) at room temperature the reaction mixture was stirred for 19 hours, the precipitated crystals were collected by filtration. The resulting crystals acetone and a mixed solution of water (1: 1) was washed with (100 mL), and dried in vacuo at 40 ° C., 4,6-dichloro-N- [2-(propane-2-sulfonyl) to give phenyl] -1,3,5-triazin-2-amine (45.1g, 95.8% yield) as crystals.
D1: 1.32 (6H, d, J = 6.8Hz), 3.22 (1H, sept, J = 6.8Hz), 7.37 (1H, m), 7.74 (1H, m), 7.93 (1H, m), 8.44 (1H , M), 10.02 (1H, Br)
ESI-: 345, 347

Fourth step 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxy-phenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , (a Lv is Cl, R 5- triazine-2,4-diamine ¹and R ² none is methyl, the formula (compound 5)) synthesis of
4,6-dichloro-N- [2-( propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (40.0 g) was mixed with tetrahydrofuran (400 mL), to this mixed solution 4- (4,4-dimethoxy-piperidin-1 yl) -2-methoxyaniline (32.2 g) and N, N- diisopropylethylamine (16.38g) was stirred for 4 hours at room temperature.Thereafter, isopropyl acetate (40 mL), then extracted by adding a mixed solution of potassium carbonate (2.0 g) and water (40 mL). The obtained organic layer was concentrated under reduced pressure until the total volume of about 200 mL, as a seed crystal, 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- inoculated with [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (4 mg), to give a slurry and stirred for about 15 minutes. The slurry n- heptane (200 mL) was added and filtered off cooled to 18 hours with stirring to precipitate crystals to 0 ° C.. The resulting crystals were washed with a mixed solution of tetrahydrofuran (40 mL) and n- heptane (40 mL), and dried in vacuo at 40 ° C., 6- Chloro -N- [4- (4,4- dimethoxy-piperidine – 1-yl) -2-methoxyphenyl] -N ‘- [2- (the propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (61.4 g, 92.4% yield) It was obtained as a crystal.
D1: 1.30 (6H, d, J = 6.8Hz), 1.88-1.92 (4H, m), 3.18-3.26 (1H, m), 3.23 (3H, s), 3.87 (1H, br), 6.53 (2H, br), 7.21-7.23 (1H, m ), 7.62 (1H, br), 7.88 (1H, d, J = 7.9Hz), 8.05 (1H, br), 8.48 (1H, br), 9.41 (1H, br )
ESI-: 575,577

The fourth alternative process (e.g. without using a seed crystal) 6-Chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane 2-sulfonyl) phenyl] (a Lv is Cl, R-1,3,5-triazine-2,4-diamine ¹ and R ² none is methyl, the formula (5) synthesis of compound of)
4 , and mixed 6-dichloro -N- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (23.0 g) in tetrahydrofuran (230 mL), to this mixed solution 4- (4,4-dimethoxy-1-yl) -2-methoxyaniline (18.5 g) and N, N- diisopropylethylamine (12.7 mL) was stirred for 2 hours at room temperature. Thereafter, isopropyl acetate (57.5 mL), then extracted by adding potassium carbonate (5.75 g) and a mixed solution of water (115 mL). The resulting organic layer was concentrated under reduced pressure. The resulting residue is added and stirred in tetrahydrofuran (50mL) to obtain a slurry. After stirring for 1 hour at the slurry was added tetrahydrofuran (75 mL) and n- heptane (75mL) 40 ℃, cooled to 0 ° C., and stirred for a further 18 hours.Thereafter, n- heptane (50 mL) was added, and the precipitated crystals were collected by filtration. The resulting crystals tetrahydrofuran and n- heptane mixed solution (5: 7) After washing with (24 mL), and dried in vacuo at 40 ° C., 6- chloro-N- [4- (4,4-dimethoxy piperidin-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (30.6g, 80.0% yield ) was obtained as a crystal.

The fifth step and the sixth step (continuous process) 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino ) phenyl] piperidin-4-one synthesis of compound) (formula (3)
6-chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [ 2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (60.0 g), tetrahydrofuran (540 mL) and 10% palladium carbon (about 50% wet product, 10.7 g) and mixed, N to the mixture, added to N- diisopropylethylamine (16.11g) and 2-propanol (60 mL), under a hydrogen atmosphere (2.4131X10 ^{5 of 5} Pa), and stirred for 7 hours at 40 ° C.. Filtration of the palladium-carbon, and washed with tetrahydrofuran (120 mL), the resulting filtrate activated carbon (12.0 g) was added to, and stirred at room temperature overnight. Then filtered off and the activated carbon, and washed with tetrahydrofuran (120mL), N- [4- ( 4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane – to obtain a solution containing 2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine. To this solution was added a mixed solution of 35% hydrochloric acid (21.7 g) and water (120 mL), and stirred for 21 hours at room temperature. To the reaction mixture, it was added a mixed solution of potassium carbonate (35.9 g) and water (120 mL), and extracted. Activated carbon (12.0 g) was added to the obtained organic layer was stirred for 16 h, filtered, washed with activated carbon in tetrahydrofuran (120 mL). The filtrate obtained total amount was concentrated under reduced pressure to approximately 120 mL. After addition of acetone (180 mL) to the resulting mixture, as a seed crystal, 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5 after stirring for 1 hour and inoculated triazin-2-yl} amino) phenyl] piperidin-4-one crystals (60 mg), water (480 mL) was stirred for 20 hours was added, and the precipitated crystals were collected by filtration . The obtained crystals were washed with a mixed solution of acetone (36 mL) and water (96 mL), and dried in vacuo at 40 ℃, 1- [3- methoxy-4 – ({4- [2- (propane -2 – was obtained sulfonyl) anilino] -1,3,5-triazine-2-yl} amino) phenyl] piperidine-4-one (45.8g, 88.7% yield (yield in a continuous two steps)) as crystals .
D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Fifth Step N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine 2,4-diamine (R ¹ and R ² is methyl any formula (4) of compound) synthesis of
6-chloro-N- [4- (4,4-dimethoxy-1-yl) – 2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (5.0 g), tetrahydrofuran (45 mL), 2-propanol (5mL ), 10% palladium-carbon (about 50% wet product, 1.0 g) were mixed, added N, N- diisopropylethylamine (1.81 mL) to this mixed solution, under a hydrogen atmosphere (2.4821X10 ^{5 of 5} Pa), 40 ° C. in and the mixture was stirred for 5 hours and a half. Filtration of the palladium-carbon was washed with tetrahydrofuran (10 mL), and extraction was performed with 10% brine (20 mL). The resulting organic layer was concentrated under reduced pressure. Acetone to the concentrated residue (10 mL), was added diisopropyl ether (40 mL), it was collected by filtration stirred precipitated crystals 30 minutes. The obtained crystals were washed with diisopropyl ether (20 mL), and dried in vacuo at 40 ℃, N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl]-N’- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (4.31 g, 91.6% yield) as crystals.
D2,343K: 1.17 (6H, d, J = 6.8Hz), 1.80 (4H, dd, J = 5.5,5.7Hz), 3.15 (6H, s), 3.21 (4H, dd, J = 5.5,5.7Hz) , 3.77 (3H, s), 6.50 (1H, dd, J = 2.5,8.7Hz), 6.62 (1H, d, J = 2.5Hz), 7.25-7.28 (1H, m), 7.34 (1H, d, J 8.7 Hz =), 7.58 (1H, br), 7.77-7.79 (1H, yd), 8.28 (1H, s), 8.49 (1H, br), 8.63 (1H, br), 9.25 (1H, br)
ESI +: 543

Sixth Step 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (equation (3) a compound of) synthesis of
N- [4- (4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (4.0 g), and tetrahydrofuran (36 mL) and 2-propanol (4 mL) solution of 35% hydrochloric acid containing (1.44 g) a mixture of water (4 mL) was added on, and the mixture was stirred for 17 hours at room temperature. To the reaction mixture, it was added a mixed solution of potassium carbonate (2.4 g) and water (4 mL), and extracted.The resulting organic layer was concentrated under reduced pressure. After stirring for 30 minutes by addition of acetone (12 mL) and water (4 mL) to the concentrated residue, add water (28 mL) was stirred for 1 hour, the precipitated crystals were collected by filtration. The obtained crystals were washed with a mixed solution of acetone (8 mL) and tetrahydrofuran (3 mL), and dried in vacuo at 40 ℃, 1- [3- methoxy-4 – ({4- [2- (propane -2 – give sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (3.42g, 99.2% yield) as crystals.
D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Seventh Step N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (formula (1) compounds) synthesis
of 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1 , 3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (20.0 g), methyl piperazine (8.07 g), were mixed in toluene (200 mL) and acetic acid (9.0 mL), 1 hour at room temperature It stirred. To this mixture solution was added sodium triacetoxyborohydride (17.06 g), and stirred at room temperature for 20 hours. To the reaction mixture, water (60 mL) and methanol (20 mL) was added, extraction to give an organic layer and an aqueous layer 1. This organic layer, water (20 mL) and re-extracted to give a water layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (200 mL). Methanol (220 mL) to the resulting aqueous layer, a mixed solution of sodium hydroxide (9.68 g) and water (48 mL) was added, as a seed crystal, N-{2-methoxy-4- [4- (4-methylpiperazin- 1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystal of diamine (2.0mg) inoculated, after stirring at room temperature for 1.5 hours, add water (220 mL), further stirred for 2 hours at room temperature, the precipitated crystals were collected by filtration. The resulting crystals were washed with a mixed solution of methanol (40mL) and water (40mL), and then dried under reduced pressure at 50 ℃, N- {2- methoxy-4- [4- (4-methyl-piperazine -1 – yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (20.15g, 86.1% yield) It was obtained as A06-form crystals.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

Alternatively 1 (Example not using seed crystals) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N seventh step ‘- [ 2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (compound of formula (1))

　1- [3-methoxy-4 – ({4- [2 – (propane-2-sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (5.0 g), methyl piperazine (2.02 g), toluene (50 mL) and acetic acid (1.5 mL) were mixed and stirred at room temperature for 1 hour. To this mixture solution was added sodium triacetoxyborohydride (4.72 g), and stirred at room temperature for 18 hours. To the reaction mixture, water (15 mL) and methanol (5 mL) was added, extraction to give an organic layer and an aqueous layer 1. This organic layer, water (5 mL) and re-extracted to give a water layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (50 mL). The resulting aqueous layer methanol (55 mL), a mixed solution was added sodium hydroxide (2.0 g) and water (10 mL), was stirred for 62 hours at room temperature, add water (55 mL), at room temperature for a further 2 hours stirring, the formed crystals were separated by filtration. The obtained crystals were washed with a mixed solution of methanol (5 mL) and water (5 mL), and dried in vacuo at 40 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin–1 – yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (4.56g, 78.0% yield) It was obtained as A06-form crystals.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581
alternative seventh step 2 (example using reducing catalyst) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane -2 – sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine synthesis of compounds of formula (1)
1- [3-methoxy-4 – ({4- [2- (propan-2 sulfonyl) anilino] -1,3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (5.0 g), tetrahydrofuran (30 mL), methylpiperazine (1.81 g) and 10% palladium carbon (about 50 % wet product, were mixed 0.8 g), under a hydrogen atmosphere (2.4821X10 ^{5 of 5}Pa), and stirred for 7 hours at 40 ° C.. Filtration of the palladium-carbon, and washed with tetrahydrofuran (10 mL), the resulting filtrate was concentrated under reduced pressure. To the concentrated residue 2-butanone (9 mL) was added, followed by stirring at 60 ° C. 30 minutes, cooled slowly, at 30 ° C. n-heptane (9 mL) was added, and stirred for 19 hours at room temperature, the precipitated crystals were collected by filtration did.The resulting crystals of 2-butanone and (1 mL) was washed with a mixture of n- heptane (1 mL), and dried in vacuo at 40 ℃, N- {2- methoxy-4- [4- (4-methyl piperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (3.09 g, yield: 88.0%) was obtained.
D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

　N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , 5-triazine-2,4-diamine by recrystallization purification steps (formula (1 compound of))
(the a method) N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (8.80 g), 2-butanone (211 mL) after mixing and confirmation of dissolution and stirring at 65 ° C. 30 minutes for clarifying filtration. After filtrate was total volume concentrated normal pressure to approximately 70 mL, and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (0.9 mg), and stirred for about 10 minutes to obtain a slurry. After stirring for 3 hours at 70 ° C., cooled to 5 ℃ at a rate of 20 ° C. / h and stirred for 17 hours, the precipitated crystals were collected by filtration. The resulting crystals were washed with 2-butanone were cooled with ice water (35.2 mL), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (7.88 g, 89.5% yield, purity 99.4%) was obtained as a A04 type crystal (A04 type ratio 98.9%).

(B method): N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl ] -1,3,5-triazine-2,4-diamine (8.80g), was mixed activated carbon (0.88 g) and 2-butanone (211 mL), after stirring for 1 hour at 75 ° C., was subjected to activated carbon filtration .The filtrate activated carbon (0.88g) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. The filtrate activated carbon (0.88g) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. After filtrate was total volume concentrated normal pressure to approximately 70 mL, and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (0.9 mg), and stirred for about 10 minutes to obtain a slurry. After stirring for 3 hours at 70 ° C., cooled to 5 ℃ at a rate of 20 ° C. / h and stirred for 16 hours, the precipitated crystals were collected by filtration. The resulting crystals were washed with 2-butanone were cooled with ice water (35.2 mL), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (6.60 g, 75.0% yield, purity 99.3%) was obtained as A04 type crystal (A04 type ratio 100%).

Example 2
The first step 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (R ¹ and R ² is methyl Any formula (Compound 10)) Synthesis of
4,4 – dimethoxy piperidine monohydrochloride (69.9kg) and N, N-dimethylformamide (125.7kg) was mixed, to this mixed solution 1,8-diazabicyclo [5.4.0] undec-7-ene and (117.3kg) N It was added N- dimethylformamide (17.0kg). N of separately prepared here 5-fluoro-2-nitroanisole (60.0kg), the N- dimethylformamide (57.0kg) was added at room temperature, N, N- dimethylformamide (29.0 kg) solution was added 5 hours It stirred. At room temperature with a seed crystal of 4,4-dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (about 6 g) was added to the reaction mixture was stirred at room temperature for 14 hours. Water (240 kg) was added at room temperature to the reaction mixture, after stirring for 22 hours, the precipitated crystals were collected by filtration. The obtained crystals N, washed with a mixed solution of N- dimethylformamide (56.9kg) and water (60kg), washed twice with water (120 kg), and dried in vacuo at 50 ° C., 4, 4 – to give dimethoxy-1- (3-methoxy-4-nitrophenyl) piperidine (99.7kg, 96.0% yield) as crystals.

D2: 1.72-1.80 (4H, m) , 3.14 (6H, s), 3.44-3.50 (4H, m), 3.91 (3H, m), 6.52 (1H, d, J = 2.4Hz), 6.60 (1H, dd, J = 2.4,9.2Hz), 7.88 (1H, D, J = 9.2Hz)
ESI Tasu: 297

The second step 4- (R (4,4-dimethoxy-1-yl) -2-methoxyaniline ¹ and R ² is methyl none has the formula (Compound 6)) Synthesis of
4,4-dimethoxy – 1- (3-methoxy-4-nitrophenyl) piperidine (99.0kg), 5% palladium carbon (about 50% wet product, 10.5 kg), were mixed at room temperature in tetrahydrofuran (440 kg), under a hydrogen atmosphere (200 ~ 300 kPa ), and stirred at room temperature for 3 hours. Then filtered off and palladium-carbon, tetrahydrofuran and washed with (180.5Kg), the filtrate was concentrated under reduced pressure until the total volume of about 220L, as a seed crystal 4- (4,4-dimethoxy-1-yl) – crystals of 2-methoxyaniline was inoculated (approximately 10g). To the resulting slurry n- heptane (205.4kg) was added at 40 ° C., after stirring for 1 h, was stirred and cooled to 0 ° C. 16 hours. To this slurry was added n- heptane (613.5kg), After stirring for 2 hours, the crystals were collected by filtration. The obtained crystals were washed with a mixed solution of tetrahydrofuran (17.8 kg) and n- heptane (81.5kg), and dried in vacuo at 50 ℃, 4- (4,4- dimethoxy-1-yl) -2 – give methoxyaniline (84.1kg, 94.5% yield) as crystals.

D2: 1.72-1.80 (4H, m) , 2.90-2.97 (4H, m), 3.11 (6H, s), 3.73 (3H, m), 4.21 (1H, br), 6.30 (1H, d, J = 2.4 , 8.4Hz), 6.46_6.56 (2H, M)
ESI Tasu: 267

The third step 4,6-dichloro-N- [2-(propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (Lv is Cl any, compounds of formula (7) synthesis of)

　cyanuric acid chloride (40.0kg) and acetone (249.2kg) was mixed at a 17 ℃. Sodium hydrogen carbonate in the mixed solution (21.9 kg), 2-a (isopropylsulfonyl) aniline (47.5Kg) was added, and stirred at room temperature for 23 hours. After adding to the reaction mixture water (320 kg) at room temperature, and stirred for 3.5 hours, the precipitated crystals were collected by filtration. After washing the obtained crystals with a mixed solution of acetone (63.0kg) and water (80 kg), and dried in vacuo at 50 ° C., 4,6-dichloro -N- [2- (propane-2-sulfonyl) phenyl ] -1,3,5-triazin-2-amine (71.6kg, 95.1% yield) was obtained as crystals.

D1: 1.32 (6H, d, J = 6.8Hz), 3.22 (1H, sept, J = 6.8Hz), 7.37 (1H, m), 7.74 (1H, m), 7.93 (1H, m), 8.44 (1H , M), 10.02 (1H, Br)
ESI-: 345, 347

Fourth step 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2-methoxy-phenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , (a Lv is Cl, R 5- triazine-2,4-diamine ¹and R ² none is methyl, the formula (compound 5)) synthesis of
4,6-dichloro-N- [2-( propane-2-sulfonyl) phenyl] -1,3,5-triazin-2-amine (70.9 kg) in tetrahydrofuran (611.1kg) was mixed at room temperature, to this mixed solution 4- (4,4-dimethoxy-piperidine 1-yl) -2-methoxyaniline (57.1kg), N, N- diisopropylethylamine (29.1 kg) was stirred for 4 hours at room temperature. Thereafter, isopropyl acetate (61.0kg), then extracted by adding potassium carbonate (3.6 kg) and a mixed solution of water (71 kg).The resulting organic layer total amount was concentrated under reduced pressure at an external temperature of about 40 ° C. to approximately 360 L, as a seed crystal, 6-chloro -N- [4- (4,4- dimethoxy-1-yl) -2 – methoxyphenyl] -N ‘- [2- was inoculated with (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (approximately 7 g) to give a slurry. To this slurry of 2-propanol (111.0kg), n- heptane (243.1kg) was added and after cooling for 2 hours at room temperature, was collected by filtration stirred precipitated crystals were cooled to 0 ℃ 18 hours. The resulting crystals tetrahydrofuran (74.9kg), 2- propanol (44.6kg), was washed with a mixed solution of n- heptane (97.6kg), and then dried under reduced pressure at 50 ℃, 6- chloro -N- [ 4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine It was obtained (108.9kg, 92.4% yield) as crystals.

D1: 1.30 (6H, d, J = 6.8Hz), 1.88-1.92 (4H, m), 3.18-3.26 (1H, m), 3.23 (3H, s), 3.87 (1H, br), 6.53 (2H, br), 7.21-7.23 (1H, m ), 7.62 (1H, br), 7.88 (1H, d, J = 7.9Hz), 8.05 (1H, br), 8.48 (1H, br), 9.41 (1H, br )
ESI -: 575,577
fifth step and the sixth step (continuous process) 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1,3,5-triazine – 2-yl} amino) phenyl] piperidin-4-one synthesis of compound) (formula (3)
6-chloro-N- [4- (4,4-dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (108.2kg), tetrahydrofuran (866.0kg), 10% palladium carbon (about 50% wet goods, 23.3 kg) were mixed, N to this mixed solution was added to N- diisopropylethylamine (28.9 kg) and 2-propanol (85.5kg), under a hydrogen atmosphere (100 ~ 300kPa), 4 hours at 40 ° C. did. Filtration of the palladium-carbon was washed with tetrahydrofuran (193.3kg), N- [4- ( 4,4- dimethoxy-1-yl) -2-methoxyphenyl] -N ‘- [2- (propane -2 – to obtain a solution containing a sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine. To this solution was added 35% hydrochloric acid (39.1 kg) of mixed solution of water (217kg), and stirred for 15 hours at room temperature. To the reaction mixture, added potassium carbonate (64.8kg) and a mixed solution of water (217kg), and extracted. Activated carbon (10.8 kg) was added to the obtained organic layer and stirred for 17 hours at room temperature, filtered and washed activated carbon with tetrahydrofuran (96.0kg). The resulting filtrate was concentrated under reduced pressure until the total volume of about 380L at 40 ° C.. After the resultant mixture was added acetone (257.1Kg), as a seed crystal, 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] 1,3,5 – after stirring for 1 hour was inoculated triazin-2-yl} amino) phenyl] piperidin-4-one crystals (approximately 11g), the addition of water (865Kg) was stirred for 15 hours, the precipitated crystals were collected by filtration did. The obtained crystals were washed with a mixed solution of acetone (50.9kg) and Tsunemizu (173 kg), and dried in vacuo at 50 ℃, 1- [3- methoxy-4 – ({4- [2- (propane 2-sulfonyl) anilino] -1,3,5-triazine-2-yl} amino) phenyl] piperidine-4-one (82.9kg, 89.0% yield (yield in a continuous two steps)) as crystals Obtained.

D2,343K: 1.17 (6H, d, J = 6.8Hz), 2.46-2.50 (4H, m), 3.40 (1H, sept, J = 6.8Hz), 3.61 (4H, dd, J = 6.1,6.2Hz) , 3.79 (3H, s), 6.57 (1H, dd, J = 2.6,8.7Hz), 6.70 (1H, d, J = 2.6Hz), 7.25-7.29 (1H, m), 7.38 (1H, d, J 8.7 Hz =), 7.61 (1H, br), 7.77-7.80 (1H, yd), 8.28 (1H, s), 8.50 (1H, br), 8.66 (1H, br), 9.25 (1H, br)
ESI +: 497

Seventh Step N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] – 1,3,5-triazine-2,4-diamine (formula (1) compounds) synthesis
of 1- [3-methoxy-4 – ({4- [2- (propane-2-sulfonyl) anilino] -1 , 3,5-triazin-2-yl} amino) phenyl] piperidin-4-one (60.1kg), methylpiperazine (24.2kg), was mixed with toluene (500 kg) and acetic acid (28.4kg), 1 hour at room temperature It stirred. To this mixture solution was added sodium triacetoxyborohydride (51.4kg), and stirred at room temperature for 17 hours. To the reaction mixture, methanol (47.5kg) and water (180.1kg) was added, extraction to give an organic layer and an aqueous layer 1. The organic layer was re-extracted by adding water (60.0kg), to obtain an aqueous layer 2. After mixing the aqueous layer 1 and aqueous layer 2 was extracted by adding isopropyl acetate (523.4kg). The resulting aqueous layer methanol (522.3kg), a mixed solution of 48% sodium hydroxide (60.6kg) and water (112.7kg) was added, as a seed crystal N- {2- methoxy-4- [4- (4 – methyl-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystal of diamine (about 6 g) were inoculated, after stirring at room temperature for 2 hours, added water (660.2kg), further stirred for 3.5 hours at room temperature, the precipitated crystals were collected by filtration. The obtained crystals were washed with a mixed solution of methanol (104.4kg) and water (132.0kg), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin- 1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (54.2kg, yield: 77.1 %) was obtained as A06-form crystals.

D1: 1.31 (6H, d, J = 6.8Hz), 1.59-1.78 (2H, m), 1.90-2.01 (2H, m), 2.24-2.80 (11H, m), 2.30 (3H, s), 3.19- 3.32 (1H, m), 3.65-3.75 (2H, m), 3.88 (3H, s), 6.50-6.59 (2H, m), 7.18-7.30 (1H, m), 7.53-7.70 (2H, m), 7.88 (1H, dd, J = 1.5,8.3Hz), 8.10 (1H, br), 8.37 (1H, br), 8.53 (1H, br), 9.29 (1H, s)
ESI +: 581

　N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3 , purification step by recrystallization 5-triazine-2,4-diamine (compound of formula (1))
N-{2-methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (54.3kg), activated charcoal (5.4 kg), 2-butanone (1046.1 kg) were mixed, stirred for 1 hour at 75 ° C., was subjected to active carbon filtration. The filtrate activated carbon (5.4kg) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. The filtrate activated carbon (5.4kg) in addition to, and the mixture was stirred for 1 hour at 75 ℃, was activated carbon filtration. After filtrate was total volume approximately until 430L normal pressure concentrated and cooled to 70 ° C., as a seed crystal N- {2- methoxy-4- [4- (4-methylpiperazin-1-yl) piperidine-1 yl] phenyl} -N ‘- inoculated with [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-crystalline diamine (approximately 5 g), after stirring for 3 hours, It was cooled to 5 ℃ at a rate of 20 ℃ / h, and the precipitated crystals were collected by filtration. After washing with the resulting crystals were cooled in 5 of 5 ° C. 2-butanone (220L), and dried in vacuo at 50 ℃, N- {2- methoxy-4- [4- (4-methylpiperazin-1- yl) piperidin-1-yl] phenyl} -N ‘- [2- (propane-2-sulfonyl) phenyl] -1,3,5-triazine-2,4-diamine (42.6kg, 78.5% yield, purity 99.5%) was obtained as A04-form crystals (A04 type ratio 100%).

Ken Jones, president and chief executive officer, Astellas Pharma Europe

Paper

Organic Process Research & Development (2015), 19(12), 1966-1972

Strategy for Controlling Polymorphism of Di(Arylamino) Aryl Compound ASP3026 and Monitoring Solution Structures via Raman Spectroscopy

Kazuhiro Takeguchi^*^†^§, Kazuyoshi Obitsu^†, Shun Hirasawa^†, Ryoki Orii^†, Shigeru Ieda^‡, Minoru Okada^†, andHiroshi Takiyama^§

^† Technology Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001,Japan

^‡ Astellas Pharma Tech Co., Ltd., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan

^§ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Org. Process Res. Dev., 2015, 19 (12), pp 1966–1972

DOI: 10.1021/acs.oprd.5b00208

Publication Date (Web): October 23, 2015

*E-mail:kazuhiro.takeguchi@astellas.com. Tel.: +81-293-23-5459. Fax: +81-293-23-5993.

Abstract

ASP3026(N-{2-Methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date, and the most stable polymorph (A04) was selected for designing solid formulations. The influence of crystallization process parameters on nucleation of A03 and A04 was clarified for process development. A04 was obtained at relatively high temperatures and A03 at relatively low temperatures, regardless of the superaturation ratio. A03 and A04 were therefore able to be selectively obtained via temperature control, possibly due to temperature-dependent variations in the concentrations of conformers in solution. The relationship between polymorphs and solution structures before nucleation was investigated using in situ Raman spectroscopy. The relationship with the intensity ratios of nine Raman bands of both polymorphs and ASP3026 solution structures was investigated in detail. Our findings suggest that the solution structure shifted from a structure similar to that of A04 to one similar to that of A03 with decreasing temperature.

Chairman of Astellas Pharma Inc. Mr. Masafumi Nogimori is conferred with Netherlands Honor – ‘Officer in the Order of Oranje-Nassau’

PAPER

Effect of Temperature and Solvent of Solvent-Mediated Polymorph Transformation on ASP3026 Polymorphs and Scale-up

Kazuhiro Takeguchi^*^†^§, Kazuyoshi Obitsu^†, Shun Hirasawa^†, Ryoki Orii^†, Shigeru Ieda^‡, Minoru Okada^†, andHiroshi Takiyama^§

^† Technology Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi, Ibaraki 318-0001,Japan

^‡ Astellas Pharma Tech Co., Ltd., 160-2 Akahama, Takahagi, Ibaraki 318-0001, Japan

^§ Department of Chemical Engineering, Tokyo University of Agriculture and Technology, 2-24-16, Naka-cho, Koganei, Tokyo 184-8588, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.6b00068

Publication Date (Web): April 28, 2016

*Telephone: +81-293-23-5459. Fax: +81-293-23-5993; e-mail:kazuhiro.takeguchi@astellas.com.

Abstract

ASP3026 (N-{2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]phenyl}-N′-[2-(propane-2-sulfonyl)phenyl]-1,3,5-triazine-2,4-diamine) was developed as a novel and selective inhibitor of the fusion protein EML4-ALK. Five polymorphs of ASP3026 (A01, A02, A03, A04, and A05) as well as a hydrate have been identified to date. Process development was conducted for large-scale pilot plant manufacturing, and obtaining the desired polymorph A04 was key after a synthetic route of ASP3026 was selected for scale-up. The effects of temperature and solvent species on induction time of polymorph transformation were investigated using in situ Raman spectroscopy, and selective transformation conditions of A02 to A03 and A04 were examined in detail. A04 was obtained at high temperatures using highly polar non-hydrogen-bond-donating solvents, while A03 was obtained at low temperatures using low-polarity or hydrogen-bond-donating solvents. Further, the desired polymorph A04 was successfully obtained in high purity in first stage scale-up manufacturing. Given these findings, this method of solvent-mediated polymorph transformation may aid in process development for obtaining desired polymorphs.

http://pubs.acs.org/doi/full/10.1021/acs.oprd.6b00068

REFERENCES

1: Awad MM, Shaw AT. ALK Inhibitors in Non-Small Cell Lung Cancer: Crizotinib and Beyond. Clin Adv Hematol Oncol. 2014 Jul;12(7):429-39. PubMed PMID: 25322323.

2: George SK, Vishwamitra D, Manshouri R, Shi P, Amin HM. The ALK inhibitor ASP3026 eradicates NPM-ALK⁺ T-cell anaplastic large-cell lymphoma in vitro and in a systemic xenograft lymphoma model. Oncotarget. 2014 Jul 30;5(14):5750-63. PubMed PMID: 25026277; PubMed Central PMCID: PMC4170597.

3: Mori M, Ueno Y, Konagai S, Fushiki H, Shimada I, Kondoh Y, Saito R, Mori K, Shindou N, Soga T, Sakagami H, Furutani T, Doihara H, Kudoh M, Kuromitsu S. The selective anaplastic lymphoma receptor tyrosine kinase inhibitor ASP3026 induces tumor regression and prolongs survival in non-small cell lung cancer model mice. Mol Cancer Ther. 2014 Feb;13(2):329-40. doi: 10.1158/1535-7163.MCT-13-0395. Epub 2014 Jan 13. PubMed PMID: 24419060.

Patent ID	Date	Patent Title
US2015150850	2015-06-04	TREATING CANCER WITH HSP90 INHIBITORY COMPOUNDS
US8906885	2014-12-09	Treating cancer with HSP90 inhibitory compounds
US2013338358	2013-12-19	METHOD FOR PRODUCING DI(ARYLAMINO)ARYL COMPOUND AND SYNTHETIC INTERMEDIATE THEREFOR
US2013096100	2013-04-18	DI(ARYLAMINO)ARYL COMPOUND
US2013059855	2013-03-07	CRYSTAL OF DI(ARYLAMINO)ARYL COMPOUND
US2010099658	2010-04-22	DI(ARYLAMINO)ARYL COMPOUND

////ASP3026, EML4-ALK, ASP 3026, ASTELLAS

CC(C)S(=O)(=O)C1=CC=CC=C1NC2=NC=NC(=N2)NC3=C(C=C(C=C3)N4CCC(CC4)N5CCN(CC5)C)OC

Anaplastic lymphoma kinase (ALK) is a validated therapeutic target for treating echinoderm microtubule-associated protein-like 4 (EML4)-ALK positive non-small cell lung cancer (NSCLC). ASP3026 (1) is a potent and selective ALK inhibitor that Astellas designed and synthesized through detailed structure–activity relationship (SAR) studies

Our effort toward the process improvement of anaplastic lymphoma kinase (ALK) inhibitor ASP3026 (1) is described. A cost-effective and practical synthesis of 1 was accomplished as a result of the change of starting material from 2,4-dichloro-1,3,5-triazine (6) to cyanuric chloride (9) and late-stage introduction of a highly reactive N-methyl piperazine moiety by reductive amination of intermediate ketone 13. The modified process avoided the challenges with the original synthesis and furnished the several hundred kilograms of high-quality API with high economic efficiency, operability, and reproducibility. Furthermore, a sequence of investigation of polymorphic control in the second-generation synthetic route to obtain the thermodynamically desired, most stable polymorph Form A04 is also discussed.

Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

Yuji Takahama *

, Kazuyoshi Obitsu, Kazuhiro Takeguchi, Shun Hirasawa, Koji Kobayashi, Takahiro Akiba, Norihiro Ueda, Ryoki Orii, Atsushi Ohigashi, Takumi Takahashi, Minoru Okada, and Shigeru Ieda

Process Chemistry Laboratories, Astellas Pharma Inc., 160-2 Akahama, Takahagi-shi, Ibaraki 318-0001, Japan

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.8b00427

*E-mail: yuji.takahama@astellas.com.

This article is part of the Japanese Society for Process Chemistry special issue.

https://pubs.acs.org/doi/10.1021/acs.oprd.8b00427

crude 1 (25.0 kg, 43.0 mol, 48% yield) as a pale yellow solid in Form A02. HPLC purity: 97.9A%. ¹H NMR (600 MHz, chloroform-d) δ 9.28 (s, 1H), 8.47–8.61 (bs, 1H), 8.30–8.48 (m, 1H), 8.10 (bs, 1H), 7.88 (d, J = 8.2 Hz, 1H), 7.49–7.72 (m, 2H), 7.23 (t, J = 8.2 Hz, 1H), 6.45–6.60 (m, 2H), 3.88 (s, 3H), 3.63–3.75 (m, 2H), 3.18–3.32 (m, 1H), 2.31–2.78 (m, 11H), 2.30 (s, 3H), 1.92–2.01 (m, 2H), 1.65–1.79 (m, 2H), 1.31 (d, J = 6.9 Hz, 6H). ¹³C NMR (150 MHz, chloroform-d) δ (ppm) 166.3, 163.6, 149.6, 148.6, 138.4, 134.5, 131.1, 124.4, 123.6, 123.0, 122.1, 121.4, 119.6, 108.0, 100.4, 61.6, 55.6, 55.5, 55.4, 50.0, 49.0, 46.0, 28.1, 15.3. LC–MS (ESI): calcd for C₂₉H₄₁N₈O₃S ([M + H]⁺) 581.3; found 581.2.

/////////

New FDA Draft Guidance ‘Data Integrity and Compliance with cGMP’ published

April 29, 2016 1:46 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

In the last years, the topic “data integrity” has become a priority for the FDA. Recently, the Agency has published the draft of a Guidance for Industry on the topic which presents the comprehensive opinion of the FDA on data integrity. Read more about the draft of the Guidance for Industry “Data Integrity and Compliance with cGMP”.

http://www.gmp-compliance.org/enews_05311_New-FDA-Draft-Guidance–Data-Integrity-and-Compliance-with-cGMP–published_15555,15527,15062,15064,Z-COVM_n.html

In recent years, the topic “data integrity” has become a priority for European and American inspectors. At the beginning of 2015, the British authority MHRA published a first paper on that topic. Also in 2015, the World Health Organisation WHO issued another significant draft document on data integrity. Recently, the US American FDA has released the draft of a Guidance for Industry entitled “Data Integrity and Compliance with cGMP”. Although the FDA describes the Guidance as a non-binding recommendation, one may assume that the document presents the current thinking of the…

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Five new General Chapters in the European Pharmacopoeia on Genotoxic Impurities in Pharmaceutical APIs

April 29, 2016 1:42 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

During the manufacture of APIs as sulfonate salts, esters of sulfonic acid may develop in undesired chemical side reactions. Recently, five new General Monographs have been included in the European Pharmacopoeia which describe how to cope with these impurities. Read more about these genotoxic impurities and the possibility to control them thanks to risk assessments.

http://www.gmp-compliance.org/enews_05313_Five-new-General-Chapters-in-the-European-Pharmacopoeia-on-Genotoxic-Impurities-in-Pharmaceutical-APIs_15499,S-AYL_n.html

Sulfonic acids are often used for the manufacture of pharmaceutical APIs. They serve as counterions in crystallisation processes, as protective groups or acid catalysts in API syntheses. Here, if short-chain alcohols such as methanol, ethanol or isopropanol are present, the formation of esters of these sulfonic acids can occur, which may have a genotoxic potential (alkylation of DNA).

The Mesilate Working Party which has been appointed in 2008 by the European Pharmacopoeia Commission has elaborated five General Chapters on different sulfonates which have been published in the European Pharmacopoeia Supplement 8.7 that came into force on 1 April 2016. The…

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FDA releases draft guidance on the use of comparability protocols for post approval changes

April 29, 2016 1:40 pm / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The US FDA released a draft guidance for industry “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information”. The guidance replaces the draft guidance published in February 2003. It provides recommendations on implementing postapproval changes through the use of comparability protocols (CPs). Read more about FDA´s draft guidance for industry “Comparability Protocols for Human Drugs and Biologics”.

On April 19, 2016, the US Food & Drug Administration (FDA) released a draft guidance for industry “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information”. Comments and suggestions regarding the draft guideline should be submitted within 60 days of publication.

The guidance replaces the draft guidance published in February 2003. It provides recommendations on implementing postapproval changes through the use of comparability protocols (CPs). A CP is a comprehensive, prospectively written plan for assessing the effect of proposed CMC postapproval changes on the identity, strength…

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энкломифен Enclomiphene citrate إينكلوميفان

April 29, 2016 1:23 pm / Leave a comment

Enclomiphene citrate

An estrogen receptor (ER) antagonist potentially for treatment of hypogonadotropic hypogonadism.

ICI-46476; RMI-16289

CAS No.15690-57-0(free)

7599-79-3(Enclomiphene citrate)

Molecular Weight	598.08
Formula	C26H28ClNO▪C6H8O7

Ethanamine, 2-[4-[(1E)-2-chloro-1,2-diphenylethenyl]phenoxy]-N,N-diethyl-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)

Ethanamine, 2-[4-(2-chloro-1,2-diphenylethenyl)phenoxy]-N,N-diethyl-, (E)-, 2-hydroxy-1,2,3-propanetricarboxylate (1:1)
Triethylamine, 2-[p-(2-chloro-1,2-diphenylvinyl)phenoxy]-, citrate (1:1), (E)-
(E)-Clomiphene citrate
Androxal
Clomiphene B citrate

Enclomid
Enclomiphene citrate
trans-Clomiphene citrate

Clomifene is a mixture of two geometric isomers, enclomifene (E-clomifene) and zuclomifene (Z-clomifene). These two isomers have been found to contribute to the mixed estrogenic and anti-estrogenic properties of clomifene.

Enclomifene

Zuclomifene

PATENT

WO 2015138340

EXAMPLE 1

Preparation of trans-clomiphene citrate from

1- {4- [2-(Oiethylamino)ethoxy| phenylj-1 ,2-diphenylethanol

Dehydration

[0023] l-{4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) dissolved in ethanol containing an excess of hydrogen chloride was refluxed 3 hours at 50 °C. The solvent and excess hydrogen chloride were removed under vacuum and the residue was dissolved in dichloromethane. 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanaminium hydrogen chloride (7) was obtained.

Chlorination

The hydrochloride salt (7) solution obtained above was treated with 1.05 equivalents of N-chlorosuccinimide and stirred at room temperature for about 20 hours. Completion of the reaction was confirmed by HPLC. The hydrochloride salt was converted to the free base by addition of saturated aqueous bicarbonate solution. The mixture was stirred at room temperature for 30 minutes after which the phases were separated and the organic phase was evaporated in vacuo. 2-{4-[2-chloro-l,2- diphenylvinyl]phenoxy}-N,N-diethylethanamine (clomiphene -1.8:1 E:Z mixture) (8) was obtained.

Separation of clomiphene isomers

Clomiphene (8) obtained above is dissolved in methanol and racemic binaphthyl- phosphoric acid (BPA) is added under stirring. When the precipitate begins separating from the solution, stirring is stopped and the mixture is allowed to settle at room temperature for 2 hours. The precipitate is filtered, washed with methanol and ether and dried. Trans-clomiphene-BPA salt (3) is obtained.

The enclomiphene-BPA salt (3) obtained above is extracted with ethyl acetate and NH₃ solution. To the organic solution washed with water and dried, citric acid dissolved in ethanol is added. The solution is allowed to settle for about one hour at room temperature; the precipitate is then filtered and dried under vacuum. The obtained precipitate, trans-clomiphene citrate (1) is dissolved in 2-butanone for storage.

EXAMPLE 2

Synthesis of Clomiphene Using a Single Solvent

Step 1 – Dehydration of l-i4-r2-(Diethylamino)ethoxy1phenyl|-l,2- diphenylefhanol to form 2-{4-[(Z)-l,2-diphenylvinyllphenoxy}-N,N-diethylethanaminium hydrogen sulfate (7) [0030] The synthesis route described in Example 1 utilized HC1 for the dehydration step and utilized ethanol at 50 °C as the solvent. Sulfuric acid was investigated as an alternative to HC1 for the dehydration step (as described in Example 1) in part due to the more favorable corrosion profile of sulfuric acid. Dichloromethane (methylene chloride) was investigated as an alternative solvent for the dehydration step as this would render removal of the ethanol solvent prior to the chlorination step unnecessary.

A 100 mL 3-neck round bottom flask, fitted with a temperature probe and a stir bar, was charged with l- {4-[2-(Diethylamino)ethoxy]phenyl}-l,2-diphenylethanol (6) (6.60 g, 16.9 mmol) and 66 mL (lxlO³ mmol) of methylene chloride to give a yellow solution which was cooled in an ice bath to 0 °C. Concentrated sulfuric acid (H₂S0₄, 0.96 mL, 18.1 mmol) was added at a rate such that the internal temperature did not exceed 5 °C. Upon completion of the addition, the mixture was allowed to stir one hour at ambient temperature. Completion of the reaction was confirmed by high performance liquid chromatography (HPLC). The reaction resulted in 7.96 grams of 2- (4-[(Z)- 1 ,2- diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7), a yield of 100%. Thus, sulfuric acid was demonstrated to be a suitable acid for the dehydration step.

[0042] Using these HPLC conditions, starting material has a retention time of 3.30 min and product has a retention time of 4.05 min.

It was determined that removal of water produced by the dehydration reaction was important before performing the chlorination step. When ethanol is used as the solvent for this reaction, as in Example 1, the water is removed azeotropically upon removal of the ethanol. Several methods of drying the dichloromethane solution were attempted. Drying with MgS0₄ had a deleterious effect on the subsequent chlorination step, rendering the chlorination process very messy with a number of new impurities observed following HPLC analysis which were determined to be the corresponding chlorohydrins. On the other hand, a wash with brine was sufficient to remove enough water and had no deleterious effect on the chlorination step. Accordingly, the solution was stirred vigorously with brine (66 ml) for 30 minutes and then the phases were separated prior to chlorination step.

Step 2- Synthesis of 2-|4-r2-chloro-L2-diphenylvinyl1phenoxyl-N,N- diethylethanamine 8

The solution of 2-{4-[(Z)-l,2-diphenylvinyl]phenoxy}-N,N-diethylethanaminium hydrogen sulfate (7.94 grams) in methylene chloride obtained in step 1 is stirred at room temperature and treated with N-chlorosuccinimide (2.37 g, 17.7 mmol, 1.05 equivalents) in a single portion and left to stir at room temperature for 12 hours. The yellow solution became orange and then went back to yellow. After 12 hours, a sample was removed, concentrated and assayed by HPLC to confirm the extent of reaction. HPLC analysis revealed that the reaction had proceeded but not to completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred at room temperature for an additional 4 hours. The reaction was again assayed by HPLC which revealed that the reaction was near completion. Accordingly, an additional 0.09 equivalents of N-chlorosuccinimide (203 mg, 1.52 mmol) was added and the solution stirred for an additional 12 hours at room temperature. The reaction was again assayed by HPLC and an additional 0.058 equivalents of N-chlorosuccinimide (131 mg, 0.98 mmol) was added and the solution stirred for an additional 4 hours. HPLC indicated that the reaction was complete at that point. The reaction was carefully quenched by slow addition of 66 mL (600 mmol) of saturated aqueous sodium bicarbonate solution and the quenched mixture was stirred for 30 minutes at room temperature – the reaction mixture pH should be about 8-9 after addition of saturated aqueous sodium bicarbonate solution. The reaction yielded 6.86 grams of 2-{4-[2-chloro-l,2-diphenylvinyl]phenoxy}-N,N- diethylethanamine (8). The phases were separated and the organic phase was evaporated in vacuo. The resulting light brown oil was transferred to a tared amber bottle using a small volume of dichloromethane.

[0055] Using these HPLC conditions, the retention time of product is 15 minutes.

Chromatographic Separation of Clomiphene Isomers

Clomiphene (mixture of isomers) in free base form obtained by steps 1 and 2 is loaded onto a chromatographic column (e.g. batch high pressure chromatography or moving bed chromatography) using the same solvent as used in steps 1 and 2 (here DCM) in order to separate the cis- and trans-clomiphene isomers. Trans-clomiphene is preferably eluted using a solvent suitable for recrystallization.

PATENT

Indian (1978), IN 143841

http://worldwide.espacenet.com/publicationDetails/biblio?DB=EPODOC&II=0&ND=3&adjacent=true&locale=en_EP&FT=D&date=19780211&CC=IN&NR=143841B&KC=B

PAPER

Separation of E- and Z-isomers of clomiphene citrate by high-performance liquid chromatography using methenamine as mobile phase modifier
Journal of Chromatography (1984), 298, (1), 172-4.

http://www.sciencedirect.com/science/article/pii/S0021967301927074

PATENT

http://www.google.com/patents/CN103351304A?cl=en

SYTHESIS

Patent
US2914562https://www.google.co.in/patents/US2914562PATENTUS2914529

http://www.google.co.in/patents/US2914529

PAPER

J. Med. Chem.1967, 10, 84–86.

http://pubs.acs.org/doi/pdf/10.1021/jm00313a017

J. Org. Chem.1983, 48, 2782-2784.

http://pubs.acs.org/doi/pdf/10.1021/jo00164a036

PAPER

Chem Commun (London) 2015, 51(44): 9133

Chem. Commun., 2015, 51, 9133-9136
DOI: 10.1039/C5CC01968K

A transition-metal-free, ambient-pressure, and general methodology for carbonylative Suzuki coupling has been developed.

Graphical abstract: Transition-metal-free, ambient-pressure carbonylative cross-coupling reactions of aryl halides with potassium aryltrifluoroborates

CN103351304A *	Jul 1, 2013	Oct 16, 2013	暨明医药科技（苏州）有限公司	Synthesis method of clomiphene
US2914563 *	Aug 6, 1957	Nov 24, 1959	Wm S Merrell Co	Therapeutic composition
US3848030 *	Mar 10, 1972	Nov 12, 1974	Richardson Merrell Spa	Optical isomers of binaphthyl-phosphoric acids
US5681863 *	Dec 5, 1994	Oct 28, 1997	Merrell Pharmaceuticals Inc.	Non-metabolizable clomiphene analogs for treatment of tamoxifen-resistant tumors

Reference
1	*	RAO ET AL.: “Synthesis of carbon-14 labeled clomiphene.“, JOUMAL OF LABELLED COMPOUNDS AND RADIOPHARMACEUTICALS, vol. 22, no. 3, 1985, pages 245 – 255, XP055180053, Retrieved from the Internet <URL:http://onlinelibrary. wiley .com/doi/10.1002/jlcr.2580220306/abstract> [retrieved on 20150504]

//////////энкломифен, Enclomiphene citrate, إينكلوميفان , ICI-46476, RMI-16289, nda filed,

Cymipristone

April 29, 2016 1:19 pm / Leave a comment

ChemSpider 2D Image | Cymipristone | C34H43NO2

Cymipristone

(8S,11R,13S,14S,17S)-11-{4-[Cyclohexyl(méthyl)amino]phényl}-17-hydroxy-13-méthyl-17-(1-propyn-1-yl)-1,2,6,7,8,11,12,13,14,15,16,17-dodécahydro-3H-cyclopenta[a]phénanthrén-3-one

Estra-4,9-dien-3-one, 11-[4-(cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)-, (11β,17β)-

11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one

Estra-4,9-dien-3-one, 11-[4-(cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propynyl)-, (11β,17β)- (9CI)
(11β,17β)-11-[4-(Cyclohexylmethylamino)phenyl]-17-hydroxy-17-(1-propyn-1-yl)estra-4,9-dien-3-one
Saimisitong

Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,

A progesterone receptor antagonist potentially for termination of intrauterine pregnancy.

CAS No.329971-40-6

Molecular FormulaC₃₄H₄₃NO₂
Average mass497.711 Da
Steroid Compounds, a Method for Preparation thereof, Pharmaceutical Compositions Containing the Same and Use thereof

This invention relates to steroid compounds and pharmaceutical acceptable salts thereof, a method for preparation thereof, pharmaceutical compositions containing the same as active component, and their use in the preparation of medicines for treating diseases associated with progestogen dependence and for fertility control, abortion or contraception and for anticancer use.
Mifepristone (11β-[4-(N,N-dimethylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in French Patent No. 2,497,807 to Rousell-Uclaf, published May 31, 1983. It is the first progesterone receptor antagonist put into clinical application and is a new type of anti-progestin. It binds to progesterone receptor and glucocorticoid receptor, having an affinity with progesterone receptor in rabbit endometrium five-fold higher than that of progesterone and thereby having strong anti-progesterone effect. It causes degeneration of pregnant villus tissue and decidual tissue, endogenous prostaglandin (PG) release, luteinizing hormone decrease, corpus luteum dissolution, and necrosis of embryo sac whose development depends on corpus luteum, leading to abortion. Therefore, it can be used as a non-surgical medicine for stopping early pregnancy. It can also be used, inter alia, in contraception and as an antineoplastic. (The Antiprogestin Steroid Ru486 and Human Fertility Control, 1985, New York: Plenum Press) .
Onapristone (11β-[4-(N,N-diemthylamino)phenyl]-17α-hydroxy-17β-(3-hydroxypropyl)-13α-4,9-estradiene-3-one), is a steroid compound which is disclosed in German Patent No. 3,321,826 to Schering AG, published Dec. 20, 1984. It has a strong antiprogestin activity and can be used in abortion (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), anticancer (Breast Cancer Research and Treatment, 1989, 14:275-288), etc. It was reported that onapristone had toxicity to human liver (European Journal of Cancer, 1999, 35(2):214-218).
Lilopristone (11β-[4-(N,N-dimethylamino) phenyl]-17α-[3-hydroxy-1(Z)-propenyl]-17β-hydroxy-4,9-estradiene-3-one) is a steroid compound which is disclosed in German Patent No. 3,347,126 to Schering AG, published July 11, 1985. It has a strong antiprogestin activity and can be used in abortion, contraception (American Journal of Obstetrics and Gyencology, 1987, 157:1065-1074), etc. It was reported that the clinical effect of lilopristone in stopping early pregnancy was only equivalent to that of mifepristone (Human Reproduction, 1994, 9(1):57-63).
ZK112993 (11β-(4-acetylphenyl)-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one) is as steroid compound which is disclosed in German Patent No. 3,504,421 to Schering AG, published Aug. 7, 1986. It has a potent antiprogestin activity and can be used in, inter alia, anticancer (Anticancer Res., 1990, 10:683-688).
In European Patent No. 321,010 to Akzo NV, The Netherland published June 21, 1989 are disclosed “11-arylsteroid compounds” having a strong antiprogestin activity.

PATENT

WO 2001018026

http://www.google.com/patents/EP1219632A1?cl=en

The preparation method of the present invention includes the following single- or multi-step procedures:

1. Method for the preparation of 11β-[4-(N-methyl-N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (IV) which includes the following steps:

(1) Preparation of Grignard reagent (III)

4-bromo-N-methyl-N-cyclohexylaniline (II) is reacted with magnesium in tetrahydrofuran (THF) to obtain Grignard reagent of formula (III).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (III) prepared in step (1) are brought to an additive reaction to obtain compound of formula (V).

(3) Hydrolytic reaction

The compound of formula (V) prepared in step (2) is subjected to a hydrolytic reaction to obtain compound of form (VI).

2. Method for preparation of 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI) which includes the following steps:

(1) Preparation of Grignard reagent of formula (IX)

4-bromo-N-cyclohexylaniline (VII) is first protected by trimethylchlorosilane, then reacted with magnesium in THF to obtain Grignard reagent of formula (IX).

(2) C₁₁ additive reaction

Compound of formula (IV) and the Grignard reagent of formula (IX) prepared in step (1) are brought to an additive reaction to obtain compound of formula (X).

(3) Hydrolytic reaction

The compound of formula (X) prepared in step (2) is subjects to a hydrolytic reaction to obtain compound of formula (XI).

Example 2:

9g 4-bromo-N-cyclohexylaniline (VII) (CA registration number [113388-04-8], see Synthetic Communications, 1986, 16(13): 1641-1645 for its preparation) was placed into a four-necked flask and 15 ml (1.5 mol/L) n-BuLi solution in n-hexane. The mixture was stirred for 30 min at room temperature. Then 8 g trimethylsilyl chloride (Me₃SiCl) was added and the mixture was stirred for 1 hour. Solvent and excessive Me₃SiCl was evaporated under reduced pressure to yield 4-bromo-(N-cyclohexyl-N-trimethylsilylaniline) (VIII) which was formulated into a solution with 7.5 ml anhydrous tetrahydrofuran for further use.
1.3 g magnesium was placed into a four-necked flask and a small amount of the above solution was added dropwise and slowly at 40°C. After completion of addition, the temperature was kept for 1 hour to yield a solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenylmagnesium bromide (IX) in tetrahydrofuran for further use.

(2) Preparation of 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cylohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

5g 3,3-ethylenedioxy-5,10-epoxy-17α-(1-propinyl)-17β-hydroxy-9(11)-estrene (IV) was placed into a four-necked flask and 10 ml anhydrous tetrahydrofuran and a catalytic amount of cuprous chloride (Cu2Cl2) added. Then solution of 4-(N-cyclohexyl-N-trimethylsilylamino)phenyl magnesium bromide (IX) in tetrahydrofuran was added dropwise and slowly while controlling the temperature below 5°C. After completion of addition, the mixture was allowed to react for 2 hours at room temperature and to stand overnight. Saturated ammonium chloride aqueous solution was added and the tetrahydrofuran layer separated which was washed with saturated ammonium chloride solution. The solution in tetrahydrofuran was washed with saturated saline and dried over anhydrous sodium sulfate. Evaporation of tetrahydrofuran under reduced pressure yielded a residual which was chromatographed on silica gel column using cyclohexane: acetone (5:1) as developing agent to yield 3 g 3,3-ethylenedioxy-5α,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene(X).

IR (KBr) cm^-1: 3420 (C₅, C₁₇-OH), 1610, 1510 (benzene backbone), 840, 808 (ArH).
¹H NMR (CDCl₃) δ ppm: 0.52(3H, S, C₁₃-CH₃), 2.72(3H, S, N-CH₃), 3.92(4H, m, -O-CH₂CH₂-O-), 4.24(1H, m, C₁₁-H), 6.65-7.00 (4H, ArH).

(3) Preparation of 11β- [4- (N-cyclohexylamino)phenyl] -17α- (1-propinyl) -17β-hydroxy-4,9-estradiene-3-one (XI).

1.5g 3,3-ethylenedioxy-5,17β-dihydroxy-11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-9(10)-estrene (X) and 0.75 g para-toluenesulfonic acid (PTS) were dissolved in 15 ml 90 % ethanol (v/v). The mixture was stirred for 2 hours while controlling the temperature at 40°C-50°C. After completion of the reaction, the reactant was poured into diluted sodium hydroxide aqueous solution, extracted with dichloroethane, washed with water to neutrality, and dried over anhydrous sodium sulfate. Evaporation of the solvent and chromatography on silica gel column using cyclohexane: ethyl acetate (5:1) as developing agent yielded 0.9 g 11β-[4-(N-cyclohexylamino)phenyl]-17α-(1-propinyl)-17β-hydroxy-4,9-estradiene-3-one (XI).

IR (KBr) cm^-1: 3400 (C₁₇-OH), 1658 (unsaturated ketone), 1613, 1514 (benzene backbone), 865, 810 (ArH).
¹H NMR (CDCl₃) δ ppm: 0.50 (3H, S, C₁₃-CH₃), 1.76 (3H, S, C≡C-CH₃), 4.32(1H, S, C₁₁-H), 5.75(1H, S, C₄-H), 6.9-7.10 (4H, ArH).

PATENT

WO 2006063526

PATENT

WO 2007009397

Example 1

Race meters mifepristone synthetic routes:

Epoxy adduct match rice mifepristone

(N- hexylamino methylcyclohexyl) phenyl magnesium bromide (1) 4-

In the four-necked flask, 1.4 g of magnesium into pieces (Mg) and 10 ml of anhydrous tetrahydrofuran (THF), no iodine or add a little change, at about 50 ° C, a solution of 10.86 g of 4-bromo-methyl -N- cyclohexyl aniline (dissolved in 24 ml of anhydrous tetrahydrofuran) dropwise Bi, incubation was continued for 1 hour with stirring to give 4- (N- methyl-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran solution (to be used in the next step an addition reaction ).

(2) 3,3-ethylenedioxy -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propyl block-yl) -9 (10) – Preparation of estra-ene (adduct) of

In the four-necked flask, into 5 g of 3,3-ethylenedioxy-5,10-epoxy -17 α – (1- propynyl) – 17 (3 – hydroxy – 9 (11) – estra-ene (epoxy), 29.1 ml anhydrous tetrahydrofuran (THF) and 0.1 g cuprous chloride (of Cu ₂ of Cl ₂ ), a solution of 4- (N- methyl -N-cyclohexylamino) phenyl magnesium bromide tetrahydrofuran

Nan solution, temperature control 5. C, the drop was completed, the incubation was continued for 5 hours, the reaction was completed, the reaction solution was poured into saturated aqueous ammonium chloride solution, points to the water layer, the organic layer was washed with saturated ammonium chloride solution, the aqueous layer extracted with ethyl acetate number times, the organic layers combined, washed with saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, a silica gel column, eluent cyclohexane: acetone = (5: 1) to give 3,3-ethylene dioxo -5 α, 17 β – dihydroxy -11 β – [4- (- methyl -Ν- cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – female steroidal women (adduct) solid 6 grams.

IR. ‘KBi cm- ^ SlS OI ^ ^ -OH lS jSlS benzene backbone), 819 (aromatic hydrogen). NMR Ή: (CDC1 ₃ ) ppm by [delta]: 0.47 (3H, the S, the C _IR CH ₃ ), 1.88 (3H, the S, the C ≡ the C-CH ₃ ), 2.72 (3H, the S, the N-CH ₃ ), 6.65- 7.03 (4H, ArH) _O

(3) 11 β – [4- (N- methyl -N- cyclohexylamino) phenyl] -17 α – (1- propynyl) -17 β – hydroxy-estra-4,9-diene – Preparation of 3-one (match rice mifepristone) of

‘2.5 g of p-toluenesulfonic acid (PTS) and 5 grams of 3,3-ethylenedioxythiophene -5 α, 17 β – dihydroxy -11 β – [4- (Ν- methyl cyclohexylamino) phenyl] -17 α – (1- propynyl) -9 (10) – estra-ene (adduct) was dissolved in 50 ml of ethanol 90% (V / V), and at 5 ° C – 40 ° C the reaction was stirred 3 hours, the reaction solution was poured into dilute aqueous sodium hydroxide solution, the precipitated solid was suction filtered, washed with water until neutral, the filter cake was dissolved in 50 ml of ethyl acetate, then with saturated aqueous sodium chloride solution to the water layer was evaporated part of the solvent, the precipitated solid was suction filtered, and dried to give a pale yellow solid 11 β – [4- (Ν- -N- methyl-cyclohexylamino)] -17 α – (1- propynyl) -17 β – hydroxy estra-4,9-dien-3-one (match rice mifepristone) 3 grams.

^ Cm & lt IRCKB ¹ : 3447 (the C _{. 17} -OH), among 1655 (unsaturated ketone), 1607,1513 (benzene backbone), 865,819 (aromatic hydrogen).

NMR ¾: (CDC1 ₃ ) ppm by [delta]: 0.56 (3H, the S ₅ the C ₁₃ -CH ₃ ), 1.89 (3H, the S ₅ -C ≡ the C-the CH3), 2.74 (3H, the S, the N-the CH3), 4.34 ( lH, the S, the C _N -H), 5.75 (lH, the S, the C ₄ -H), 6.68-6.99 (4H, ArH).

PATENT

CN 102107007

PATENT

CN 102106805

PAPER

Journal of Chromatography B

Volume 878, Issues 7–8, 1 March 2010, Pages 719–723

Determination of cymipristone in human plasma by liquid chromatography–electrospray ionization-tandem mass spectrometry

doi:10.1016/j.jchromb.2010.01.027

Abstract

A rapid, specific and sensitive liquid chromatography–electrospray ionization-tandem mass spectrometry method was developed and validated for determination of cymipristone in human plasma. Mifepristone was used as the internal standard (IS). Plasma samples were deproteinized using methanol. The compounds were separated on a ZORBAX SB C₁₈ column (50 mm × 2.1 mm i.d., dp 1.8 μm) with gradient elution at a flow-rate of 0.3 ml/min. The mobile phase consisted of 10 mM ammonium acetate and acetonitrile. The detection was performed on a triple-quadruple tandem mass spectrometer by selective reaction monitoring (SRM) mode via electrospray ionization. Target ions were monitored at [M+H]⁺m/z 498 → 416 and 430 → 372 in positive electrospray ionization (ESI) mode for cymipristone and IS, respectively. Linearity was established for the range of concentrations 0.5–100 ng/ml with a coefficient correlation (r) of 0.9996. The lower limit of quantification (LLOQ) was identifiable and reproducible at 0.5 ng/ml. The validated method was successfully applied to study the pharmacokinetics of cymipristone in healthy Chinese female subjects.

CHEMICAL ABSTRACTS, vol. 115, no. 25, 23 December 1991 (1991-12-23) Columbus, Ohio, US; abstract no. 270851g, X. ZHAO ET AL.: “Synthesis and terminating early pregnancy effect of mifepristone derivatives” page 117; XP002219009 & ZHONGGUO YAOKE DAXUE XUEBAO, vol. 22, no. 3, 1991, pages 133-136,

//////////Cymipristone, Saimisitong, Shanghai Siniwest Pharmaceutical Chemical Technology Co., Ltd., Shanghai Zhongxi Pharmaceutical Co. Ltd., Xianju Pharmaceutical Co., Ltd,

New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd, Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467

April 28, 2016 9:50 am / Leave a comment

Tedizolid phosphate

Suzhou MiracPharma Technology Co Ltd; Zheren Pharmaceutical Nanjing Co Ltd

WO-2016058467 click for patent

SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1 Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN).
ZHEREN PHARMACEUTICAL NANJING CO., LTD [CN/CN]; Qiaolin Industry Park 32-71, Pukou District Nanjing, Jiangsu 211806 (CN)

Disclosed is a method for preparing tedizolid phosphate (I), and the preparation step thereof comprises producing the tedizolid phosphate (I) by means of a coupling reaction of a compound of formula II and a compound of formula III. The preparation method uses easily available raw materials and a simple process, is economical and environmentally friendly, and is suitable for industrial production.

Process for preparing tedizolid phosphate (TD-P), useful for treating bacterial infection. The present filing represents the first PCT and first filing to be seen from Suzhou Miracpharma and Zheren Pharmaceutical, respectively, that focuses on tedizolid; however this case was first seen as a Chinese national filing (assigned to Suzhou Miracpharma), published in February 2015. The drug was developed and launched by Dong-A ST and licensees Cubist Pharmaceuticals and Bayer, for treating acute bacterial skin and skin structure infections.

Tedizolid phosphate by Charpy Manchester (Cubist) pharmaceutical companies to develop a oxazolidinone antibiotics. Tedizolid phosphate in June 2014 to obtain FDA approval in the United States, the trade name Sivextro. The drug was first approved by the FDA in the second generation oxazolidinone antibiotics, and linezolid compared to the previous generation, Sivextro some bacteria in vitro inhibitory activity 2-8 times higher security to a certain extent also improved. Because compound Tedizolid not have standard Chinese translation, so the applicant where it is transliterated as “Thai to acetazolamide.”

Thailand phosphate to acetazolamide (Tedizolid phosphate) Chemical name: {(5R) -3- [3- fluoro-4- [6- (2-methyl–2H- tetrazol -5-yl) pyridine-3 yl] phenyl] -2-oxazolone -5-yl} methanol phosphate (I), having the formula:

Preparation of phosphate Thailand to acetazolamide has been reported, PCT Patent No. WO2005058886, No. WO2010042887 and “European Journal of Medicinal Chemistry” 2011 on 1027 – 1039 Section 46 were reported to temozolomide and phosphate Thai analog synthesis and related intermediates. Comparative summary of these methods, which are synthetic route from Intermediate A and Intermediate B (or intermediate B ‘) by an aryl coupling reaction to achieve.

Wherein 2- (2-methyl-tetrazol-5-yl) -5-bromopyridine (Intermediate A) is generated by a tetrazolium derivative azide reaction of 2-cyano-5-bromopyridine, and then the use of methyl iodide or dimethyl sulfate, etc. methylating reagent for tetrazole ring methylation reaction, to give 2- (2-methyl-tetrazol-5-yl) -5-bromopyridine (intermediate A ) and (1-methyl-tetrazol-5-yl) -5-bromo pyridine (by-product) in a mixture of 2, by column chromatography or recrystallization to give the intermediate separator A.

Intermediate B or B ‘by R-3- (3- fluoro-4-iodo-phenyl) -2-oxo-5-oxazolidinyl methanol formed organoboron reagent or an organotin reagent, the reagent is Stille or Suzuki coupling reactions, realize intermediate a coupling.

This shows that the existing preparation method has the steps for preparing long, difficult to obtain raw materials and high costs weaknesses; preparation and use of organotins on equipment and environmental requirements are high, there is environmental pollution risks. In addition, intermediate B or B ‘structure halogens fluorine and iodine exist, reducing the selective formation of organometallic reagents, so that an increase in side effects, product quality is difficult to be effectively controlled.

Example One:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid (II) (2.15g, 10.5mmol) , R-3- (3- fluoro – 4-iodo – phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (4.17g, 10mmol) , tetrakis (triphenylphosphine) palladium (0.23g, 0.2mmol), 1M phosphoric acid 15mL of toluene solution of potassium 30mL, warmed to reflux, maintained the reaction at reflux for 10-12 hours, TLC the reaction was complete. Ethyl acetate was added 30mL, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized, and dried in vacuo to give a white The solid phosphoric acid to Thailand acetazolamide (I) 3.82g, yield% 84.9, ¹ the H NMR (of DMSO-d6): D 8.92 (S, IH), 8.20 (m, 2H), 7.74 (T, IH), 7.66 ( dd, 1H), 7.50 (dd , 1H), 4.95 (m, 1H), 4.46 (s, 3H), 4.21 (t, 1H), 4.05 (m, 2H), 3.91 (m, 1H), FAB-MS m / Z: 451 [the m the H +] ⁺ .

Example Two:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester (II) (3.01g, 10.5mmol), R-3- (3 – fluoro-4-bromo – phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (3.69g, 10mmol), [1,1′- bis (diphenylphosphino) ferrocene Fe] dichloropalladium / dichloromethane complex (0.15g, 0.2mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 50mL, heated to 110 ℃, the reaction was stirred for 4-5 hours , TLC the reaction was complete. Ethyl acetate was added 50mL, successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized, and dried in vacuo to give a white Thai solid phosphoric acid to acetazolamide (I) 4.02g, yield 89.3%.

Example Three:

Under a nitrogen atmosphere, in a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) -5-bromo – pyridine (IV) (2.4g, 10mmol), alcohol-based dual which diborane ( 1.27g, 5mmol), 1,1′- bis (diphenylphosphino) ferrocene palladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 30mL , heated to 110 deg.] C, the reaction was stirred for 4 hours. Cooled to room temperature, still under nitrogen, was added to the system for R-3- (3- fluoro-4-bromo – phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) (3.69 g, 10mmol), 1,4- dioxane and 20mL 5M potassium phosphate 0.5mL, again heated to 100 ℃, the reaction was stirred for 4 hours, TLC the reaction was complete. Ethyl acetate was added 50mL, filtered and the filtrate was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure, the resulting oil was treated with n-hexane and ethyl acetate (1:1, V / V) was recrystallized vacuo Thai dried to give a white solid phosphoric acid to acetazolamide (I) 3.34g, yield 74.2%.

IV (Preparation of the intermediate II) Example:

In a three-necked reaction flask 2- (2-methyl-tetrazol-5-yl) -5-bromo – pyridine (IV) (2.4g, 10mmol) was dissolved in 25mL anhydrous tetrahydrofuran, cooled to -55 deg.] C, was added dropwise isopropylmagnesium chloride (1M, 15ml), dropwise after completion of the reaction was stirred for 30 minutes. To the reaction system was added trimethylborate (1.25g, 12mmol), stirring was continued for 4-5 hours the reaction. At low temperature with saturated ammonium chloride solution to quench the reaction, and the reaction solution was poured into dilute hydrochloric acid and 30mL 1N reaction at room temperature for 1 hour. Extracted three times with ethyl acetate, the combined organic phase was washed with water and saturated brine, dried over anhydrous sodium sulfate. Concentrated under reduced pressure, the resulting solid is washed with petroleum ether, and then recrystallized from water to give a white solid of 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid (II) 1.6g, 78.0% yield, m the MS-FAB / Z: 206 [the m the H +] ⁺ .

Embodiment 5 (preparation of intermediate II):

In a three-necked reaction flask was added 2- (2-methyl-tetrazol-5-yl) -5-bromo – pyridine (IV) (2.4g, 10mmol) , alcohol-based dual which diborane (1.27g, 5mmol ), 1,1′-bis (diphenylphosphino) ferrocene palladium dichloride (0.82g, 1mmol), potassium acetate (1.17g, 12mmol) and 1,4-dioxane 50mL, heated to 110 ℃, the reaction was stirred for 8-10 hours to complete the reaction by TLC. Extracted three times with ethyl acetate, the combined organic phases were washed with brine, dried over anhydrous sodium sulfate. Concentrated, ethyl acetate and n-hexane (1:4) recrystallized to give an off-white solid 2- (2-methyl-tetrazol-5-yl) pyridine-5-boronic acid pinacol ester (II) 2.48g, yield 86.4 %, the MS-FAB m / Z: 288 [the m the H +] ⁺ .

Six (preparation of intermediate III) Example:

Under nitrogen, in a three-necked reaction flask R- glycidyl tosylate (TG) (2.28g, 10mmol) and N, N- dimethylformamide 25mL, stirred and dissolved, was added cesium carbonate (0.33 g, 1mmol) and 3-fluoro-4-bromo – phenyl isocyanate (V) (2.15g, 10mmol) , was heated to 100 ℃, after 1 hour, TLC detection completion of the reaction. Recovery of the solvent under reduced pressure, the residue was dissolved with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted twice with methylene chloride, concentrated under reduced pressure to give an oil which was R-3- (3- fluoro-4-bromo – phenyl) -2-oxo-5-oxazolidinyl methanol p-toluenesulfonate (the VI), without further purification, 1N hydrochloric acid was added directly to the reaction at 50 ℃ 5 hours and extracted three times with dichloromethane The combined organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 30mL of triethyl phosphate was added at room temperature, phosphorus oxychloride (2.2mL, 24mmol), stirred for 2-3 hours. 30mL of ethyl acetate was added, stirred for half an hour, poured into 50g of ice-water, and stirring was continued for 2 hours at 0 deg.] C, and a solid white precipitate was filtered, the filter cake washed with acetone and dried to give an off-white solid R-3- (3-fluoro-4-bromo – phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) 2.45g, yield 66.4%, FAB-MS m / z: 369 [m + H ] ⁺ .

Six (preparation of intermediate III) Example:

Under nitrogen, in a three-necked reaction flask R- glycidyl tosylate (TG) (2.28g, 10mmol) and tetrahydrofuran 50mL, stirred and dissolved, was added lithium iodide (0.14g, 1mmol) and 3- fluoro-4 – phenyl isocyanate (V) (2.63g, 10mmol) , was heated to reflux. after 2 hours, TLC detection completion of the reaction. Recovery of the solvent under reduced pressure, the residue was dissolved with dichloromethane and water, the organic phase was separated, the aqueous phase was extracted twice with methylene chloride, concentrated under reduced pressure to give an oil which was R-3- (3- fluoro-4 – phenyl) -2-oxo-5-oxazolidinyl methanol p-toluenesulfonate (the VI), without further purification, 1N hydrochloric acid was added directly to the reaction at 50 ℃ 5 hours and extracted three times with dichloromethane The combined organic phase was successively washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The concentrate was dissolved in 30mL of triethyl phosphate was added at room temperature, phosphorus oxychloride (2.2mL, 24mmol), stirred for 2-3 hours. 30mL of ethyl acetate was added, stirred for half an hour, poured into 50g of ice-water, and stirring was continued for 2 hours at 0 deg.] C, and a solid white precipitate was filtered, the filter cake washed with acetone and dried to give an off-white solid R-3- (3-fluoro-4-iodo – phenyl) -2-oxo-5-oxazolidinyl methanol phosphate (III) 2.65g, yield 63.7%, FAB-MS m / z: 417 [m + H ] ⁺ .

//////New Patent, Tedizolid phosphate, Suzhou MiracPharma Technology Co Ltd, Zheren Pharmaceutical Nanjing Co Ltd, WO 2016058467

Lurasidone hydrochloride, Jubilant Generics Ltd, WO 2016059649, New patent

April 28, 2016 9:45 am / Leave a comment

Lurasidone

Lurasidone hydrochloride, Jubilant Life Sciences Ltd, WO 2016059649, New patent

An improved process for the preparation of lurasidone hydrochloride

Jubilant Life Sciences Ltd

WO 2016059649

JUBILANT GENERICS LIMITED (FORMERLY JUBILANT LIFE SCIENCES DIVISION) [IN/IN]; Plot 1A, Sector 16 A, NOIDA Uttar Pradesh 201301 (IN)

MISHRA, Vaibhav; (IN).
DUBEY, Shailendr; (IN).
SINGH, Kumber; (IN).
CHOUDHARY, Alka Srivastava; (IN).
VIR, Dharam; (IN)

Disclosed herein is an improved process for the preparation of Lurasidone and its pharmaceutically acceptable salts via novel intermediate and use thereof for the preparation of an antipsychotic agent useful for the treatment of schizophrenia and bipolar disorder. Further, present invention provides a cost effective and eco-friendly process for producing Lurasidone hydrochloride of formula (I) substantially free of residual solvent(s) at industrial scale.

Improved process for preparing lurasidone or its hydrochloride, substantially free of residual solvent, useful for treating schizopherenia and bipolar disorder. Also claims novel intermediate of lurasidone eg ((R,R)-cyclohexane-1,2-diyl)bis((1H-imidazol-1-yl)methanone) and its preparation method.

In April 2016, Newport Premium™ reported that Jubilant Life Sciences was capable of producing commercial quantities of lurasidone and lists the drug as a molecule available under research and development on the company’s website.

This is the first patenting to be seen from Jubilant Life Sciences that focuses on lurasidone – it having been developed and launched by Sumitomo Dainippon Pharma and EU licensee Takeda, for treating schizophrenia.

May 2, 2014

Neeraj Agrawal: Took charge of API business for Jubilant Life Sciences at the age of 31

Position: CEO Generics, Jubilant Life Sciences

Education: IIIM-C, MBA, 1998; IIT, Bombay, Electrical Engg., 1995.

Previous Jobs: Associate-Business Strategy, Operations Improvement, McKinsey & Co.

Claim to Fame: Took charge of the API business for Jubilant when he was just 31-years-old

Management mantra: It revolves around trust, freedom and teams. I like my team to think and act like an entrepreneur – assess business risks and rewards suitably and then take decisions.

Lurasidone and its pharmaceutically acceptable salts like lurasidone hydrochloride is chemically, (3a ?,45,7 ?,7a5)-2-{ (1 ?,2 ?)-2-[4-(l,2-benzisothiazol-3-yl)piperazin-lyl-methyl] cyclohexylmethyl }hexahydro-4,7-methano-2H-isoindole- 1 ,3 -dione hydrochloride and has the structure represented by the Formula (I):

Formula-I

Lurasidone hydrochloride is marketed in the United States under the trade name Latuda®. Lurasidone and its pharmaceutically acceptable salts as well as process for their preparation was first disclosed in US patent no. 5,532,372. The patent discloses the preparation of lurasidone hydrochloride using racemic trans 1,2-cyclohexane dicarboxylic acid. Racemic trans 1,2-cyclohexane dicarboxylic acid on reduction with lithium aluminium hydride in THF at reflux temperature forms l,2-bis(hydroxymethyl)cyclohexane which is converted into racemic iran5-l,2-bis(methanesulfonyloxymethyl)cyclohexane by reaction with methane sulfonyl halide. l-(l,2-benzisothiazol-3-yl)piperazine on reaction with trans-l, 2-b (methanesulfonyloxymethyl)cyclohexane in the presence of sodium carbonate and acetonitrile forms iran5-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazine methanesulfonate which on reaction with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in the presence of potassium carbonate, dibenzo-18-crown-6-ether and xylene on refluxing forms racemic lurasidone free base. The compound is obtained by column chromatography and then treated the resulting lurasidone free base with IPA.HCl in acetone to obtain racemic lurasidone hydrochloride. Resolution of racemic lurasidone hydrochloride is carried out using tartaric acid as resolving agent. The process involves use of lithium aluminium hydride which is highly pyrophoric reagent and is not to utilize the same on commercial scale due to its handling problems associated with its reactivity. Also, the use of the column chromatography for purification is not viable on commercial scale. Further the process involves the usage of dibenzo-18-crown-6-ether as a phase transfer catalyst which is costly material and in turn increases the cost of production. Carrying out the resolution in the last stages is difficult due to the presence of six chiral centres in lurasidone and is also not suitable for an industrial scale preparation as it affects the overall yield and cost of the manufacturing process.

Chinese patent application no. CN102731512 discloses a process for preparation of lurasidone which comprises reaction of racemic irans-l,2-bis(methanesulfonyloxymethyl) cyclohexane and l-(l,2-benzisothiazol-3-yl)piperazine in toluene in the presence of sodium carbonate or potassium carbonate having particle size less than 200 micron and tetrabutyl ammonium bromide to give the intermediate /rans-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazinemethanesulfonate which on reaction with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide in toluene using potassium carbonate having particle size less than 200 micron forms racemic lurasidone free base. The racemic free base is converted into racemic hydrochloride salt using acetone and cone, hydrochloric acid. Racemic lurasidone hydrochloride is resolved by following the method disclosed in US patent no. 5,532,372. The process involves resolution of product in the last stage which is not commercially viable as it affects the overall yield and cost of the manufacturing process.

Japanese patent no. JP4219696 discloses the resolution of trans 1,2-cycloheaxne dicarboxylic acid using (lS,2R)-(+)-norephedrine or (lR,2S)-(-)norephedrine to provide (R,R)-trans 1 ,2-cyclohexanedicarboxylic acid. The (R,R)-iran,sl,2-cyclohexane dicarboxylic acid obtained was esterified with ethanol and the obtained ester compound was reduced with vitride to provide (R,R)-l,2-bis(hydroxymethyl)cyclohexane followed by treatment with methane sulfonyl chloride to form (R,R)-1,2-bis(methanesulfonyloxymethyl)cyclohexane. The process requires large quantity of reducing agent viz., for reducing one lg of compound about 5g of reducing agent is required which is not conducive for industrial production.

Chinese patent application no. CN 102952001 discloses a process for the preparation of (lR,2R)cyclohexane-l,2-dimethanol by the reduction of (lR,2R)cyclohexane-l,2-

dicarboxylic acid using sodium borohydride or potassium borohydride and boron triflouoride diethyl ether in THF or diethyl ether as solvent. Boron triflouoride diethyl ether is used in large quantity and quite expensive which makes the process commercially unviable.

International publications no. WO 2012/131606 and WO 2014/037886 disclose a process for preparation of lurasidone which involves separating the racemic transl,2-cyclohexane dicarboxylic acid into its (R,R) trans and (S,S) trans isomers and then using the desired trans (R,R) isomer for the preparation of lurasidone hydrochloride using the chemistry disclosed in US patent no. 5,532,372 for preparation of racemic lurasidone hydrochloride. In these publications diisobutyl aluminium hydride (DIBAL) is used as the reducing agent for the preparation of (1R,2R) cyclohexane 1,2-dimethanol from (1R,2R) cyclohexane 1,2-dicarboxylic acid which is quite expensive. Further the process involves the usage of dibenzo-18-crown-6-ether as a phase transfer catalyst which is costly material and in turn increases the cost of production.

Some of the prior art processes disclose the process for the preparation of lurasidone hydrochloride from l,2-(lR,2R)-bis-(methanesulfonyloxymethyl)cyclohexane using different solvents and bases.

US patent no. 8,853,395 discloses a process for the preparation of lurasidone in which condensation of iran5-l,2-bis(methanesulfonyloxymethyl)cyclohexane with 1-(1,2-benz isothiazol-3-yl)piperazine and condensation of /rans-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)]piperazine methanesulfonate with bicyclo[2.2.1] heptane-2-exo-3-exo-dicarboximide is carried out using organic bases with a ρ¾ higher than 10 such as l,4-diazabicycloundec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diaza bicyclo[2.2.2] -octane (DABCO). These organic bases are comparatively expensive.

Indian patent application no. IN 2306/MUM/2014 and Chinese patent applications no. CN 102863437 and CN 103864774 disclose the use of dimethyl formamide (DMF), dimethyl sulphoxide (DMSO), dimethyl acetamide (DMA) and N-methyl pyrrolidine (NMP) for the condensation of iran5-3a,7a-octahydroisoindolium-2-spiro- -[4′-(l,2-benzisothiazol-3-yl)] piperazine methanesulfonate with bicyclo[2.2.1] heptane-2-exo-3-exo-dicarboximide to form lurasidone. These solvents have high boiling point so not preferred at commercial scale.

Some of the prior art processes are related to reduction of impurities or quality improvement of lurasidone hydrochloride.

International publication no. WO2011/136383 discloses a process for the preparation of lurasidone hydrochloride in which amount of by products are reduced by increasing the quantity of l-(l,2-benzisothiazol-3-yl)piperazine instead of sodium carbonate or potassium carbonate as base in the reaction mixture. Increasing the amount of l-(l,2-benzisothiazol-3-yl)piperazine causes an increase in cost of production and removal of excess compound makes the process less commercially viable.

International publication no. WO2011/136384 discloses a process for the preparation of lurasidone hydrochloride in which amount of by products are reduced by using dibasic potassium phosphate with a small amount of water as a base instead of sodium carbonate. Use of dibasic potassium phosphate as a base causes an increase in cost of production as dibasic potassium phosphate is expensive.

International publication no. WO2013/014665 discloses various processes for the preparation of lurasidone hydrochloride. In general the process is shown below:

Formula-(I)

In this process iran5-(lR,2R)-2-(aminomethyl)cyclohexyl)methanol of Formula (B) is first reacted with bicyclo[2.2.1]heptane-2-exo-3-exo-dicarboximide of Formula (A) to form (3aR,4S,7R,7aS)-2-(((lR,2R)-2-(hydroxymethyl)cyclohexyl)methyl)hexahydro-lH-4,7-methanoisoindole-l,3(2H)-dione of Formula (C) which on reaction with methane sulphonyl chloride followed by reaction with l-(l,2-benzisothiazol-3-yl)piperazine of Formula (D) forms lurasidone free base which was converted into lurasidone hydrochloride using acetone and cone, hydrochloric acid.

Some of the prior art processes disclose various combinations of hydrogen chloride and solvent for the preparation of lurasidone hydrochloride from lurasidone free base.

US 7,605,260 discloses use of acetone and aqueous HC1 having strength 1.8-14.4 % for preparing lurasidone hydrochloride. The yield of lurasidone hydrochloride is relatively low (85%) by this method. If the acid concentration during the salt formation is more than 5.0% then acetone quantity as the residual solvent in the reaction product is found to be greater than 0.5% in our hands which is above the ICH limits. If acid concentration during the salt formation is less than 1.8%, then yield is reduced drastically to 65%. Therefore, this method has limitations on the large-scale industrial production.

Chinese patent application no. CN102746289A discloses the process for the preparation of lurasidone hydrochloride by adding a mixture of acetone and aqueous HC1 to a solution of lurasidone free base in acetone. On reproducing this process in laboratory, it was observed that the XRPD of the product obtained does not match with XRPD of lurasidone hydrochloride.

Indian patent application IN 777/MUM/2013 discloses use of IPA, water and 35% Aqueous HC1 for the preparation of lurasidone hydrochloride. The IPA content in the product was found to be more than 5000ppm.

The methods described in the prior art are not suitable for large scale commercial production as the residual solvent is out of the ICH limits and thus the product obtained can’t be used as a drug. In order to keep the residual solvent(s) within ICH limits, repeated crystallization/purification are required which results in reduced yield and make the process quite expensive.

The prior art discloses various processes for the preparation of lurasidone hydrochloride and its intermediates. However, there still remains a need for alternative process for the preparation of lurasidone and its pharmaceutically acceptable salts substantially free of residual solvent(s) which can be used as a drug.

According to another embodiment of the present invention, novel process for the preparation of the compound of Formula (III), their isomers and pharmaceutically acceptable salts thereof, comprises condensing 1,2-cyclohexane dicarboxylic acid of Formula (II), their isomers with carbonyl diimidazole, optionally in a solvent.

(IV)

Formula (III)

NaBH₄ RT /H₂0

Formula (VII)

Scheme-1:

Example-1

Synthesis of trans(R,R)-l,2-cyclo exane dicarboxylic acid

A round bottom flask was charged with methanol (500 mL), IPA (500 mL) and trans (racemic)-l,2-cyclohexane dicarboxylic acid (100 g). In this reaction mass (R)-l-phenylethyl amine (74 mL) was added over a period of 30 minutes and stirred for 2-3 hrs at 30-40 °C. The solid obtained was filtered, washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure to obtain crude salt of iran5(R,R)-l,2-cyclohexane dicarboxylic acid. The obtained salt was stirred in a solution of methanol (500 mL) and IPA (500 mL) at 65-70 °C for 2-3 hours, cooled to room temperature and filtered. The solid was washed with methanol and IPA solution (50+50 mL) and dried under reduced pressure. The solid thus obtained was dissolved in about 2N hydrochloric acid and extracted two times with ethyl acetate (1000 mL+200 mL). Organic layers were combined and washed with brine solution (100 mL). Ethyl acetate was distilled off under vacuum at 50-55 °C and cyclohexane was added to the residue. The solid separated out was filtered and washed with cyclohexane and dried under vacuum at 45-50 °C for 8-10 hours. Yield = 29.4 g

Example-2

Synthesis of ((R,R)-cyclohexane-L2-diyl)bis((lH-imidazol-l-yl)methanone)

To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) is added and stirred for one hour at 25-30 °C . To the said solution of (R,R)2-(((lH-imidazole-lcarbonyl)oxy)carbonyl)cyclohexanecarboxylic acetic anhydride lH-imidazole (25.0 g) in THF (250 mL) is stirred for one hour at 45-50 °C. The compound obtained is isolated and is characterized by mass and NMR.

[m z = 272.75; 1H-NMR: 8.24 (s, 2H), 7.72 (d, 2H); 7.50 (d, 2H), 3.5 (m, 2H), 2.26-1.50 (m, 8H)]

Example-3

Synthesis of tra»,s(R,R)-l,2- bis(hydroxymethyl)cyclohexane

To a solution of ((R,R)-cyclohexane-l,2-diyl)bis((lH-imidazol-l-yl)methanone) (25 g) in THF (250 mL), sodium borohydride (22.0 g) followed by water (44.0 mL) are added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) are added, stirred and layers separated. The organic layer is washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass

dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) are added, stirred and layers obtained are separated. The dichloromethane is distilled off completely from organic layer at 40 °C to obtain oily mass (15.5 g).

Example-4

One pot process for synthesis of trans(R,R)-l,2- bis(hydroxymethyl)cyclohexane from trans(R,R)-l,2-cyclo exane dicarboxylic acid

To a solution of iran5(R,R)-l,2-cyclohexane dicarboxylic acid (25.0 g) in THF (250 mL), carbonyl diimidazole (60 g) was added and stirred for one hour at 25-30 °C. To the intermediate obtained sodium borohydride (22.0 g) and water (44.0 mL) were added and stirred for one hour. To this reaction mass, 10% solution of acetic acid (500 mL) and dichloromethane (500 mL) were added, stirred and layers separated. The aqueous layer was washed with dichloromethane (250 mL). The organic layer was washed with 10% sodium bicarbonate solution followed by water. The dichloromethane is distilled off from organic layer under vacuum to give an oily mass. To the oily mass dichloromethane (100 mL), water (100 mL) and 12.5mL cone, hydrochloric acid (35%) were added, stirred and layers obtained were separated. The dichloromethane was distilled off completely at 40 °C to obtain oily mass (15.5 g).

Example-5

Synthesis of m¾ns(R,R)- 2-bis(methanesulfonylmethyl) cyclohexane

To a suspension of irafts(R,R)-l,2-bis(hydroxymethyl)cyclohexane (15.0g) in dichloro methane (300 mL), triethyl amine (43.7 mL) followed by methane sulphonyl chloride (17.8 mL) were added over a period of 30-45 minutes. Reaction mass was stirred for 2-3 hrs. Reaction was monitored by HPLC (RI detector). After the completion of reaction, water was added, stirred and layers separated. The organic layer was washed with 10% sodium bicarbonate solution (150 mL) followed by water (150 mL). The dichloromethane was distilled off from organic layer under vacuum at 40-55 °C to give an oily mass. Methanol (30 mL) was added to the oily mass and strip off under vacuum at 40°C, added methanol (150 mL) and stirred for 1 h at 10-15°C and the solid obtained was filtered, washed with methanol (15 mL) and dried under vacuum to get the product (15.8g).

Example-6

Synthesis of ?ran (R,R)-3aJ(¾-octahvdroisoindolium-2-spiro- -r4-(L2-benzoisothiazole-3-yl)l piperazine methanesulfonate:

To a suspension of iran5(R,R)-l,2-bis(methanesulfonylmethyl)cyclohexane (15 g) in acetonitrile (150 mL) l-(l,2-benzisothiazol-3-yl)piperazine (10.95g) and sodium carbonate (7.8 g) were added, heated and stirred for 20 hrs at reflux temperature. Reaction was monitored by HPLC. After the completion of reaction, mass was cooled to 40-45 °C, filtered and washed with acetonitrile (20 mL). The acetonitrile was distilled off under vacuum at 45-50 °C. To the residue acetone (100 mL) was added, stirred for 1 hour, filtered, washed with acetone (10 mL), dried at 50-55°C for 6-8 hours to get the product (12.5 g).

Example-7

Synthesis of Lurasidone

To a suspension of iran5(R,R)-3<3,7(3-octahydroisoindolium-2-spiro- -[4-(l,2-benzo isothiazole-3-yl)]piperazinemethanesulfonate (10 g) in toluene (150 mL), bicycle[2.2.1] heptane-2-exo-3-exo-dicarboximide (5.9 g) and potassium carbonate (4.8 g) were added, heated to 110° C and stirred for 8-10 hours. Reaction was monitored by HPLC. After the completion of reaction, reaction mass was cooled to 20-30 °C, filtered and washed with toluene (10 mL). The toluene was distilled off at 55-60°C. To the residue IPA (100 mL) was added and stirred for 1-2 hours at room temperature. Lurasidone free base obtained was filtered and washed with IPA (10 mL). The solid was suck dried for 30 minutes to obtain lurasidone.

Example-8

Synthesis of Lurasidone hydrochloride

To lurasidone base (5g), acetone (75mL) and water (10 mL) were added. The mixture was heated to 55-60°C followed by the addition of IPA.HCl (10%) (lOmL) and stirred for 1-2 hours, reflux temperature. The clear solution obtained was stirred for 30 min and then 5ml IPA.HCl (10%) was added. The reaction mixture was stirred at reflux temperature for 30 min, cooled and stirred for 60 min. The solid obtained was filtered and washed with acetone (5ml) and dried under vacuum at 60°C for 8 hours.

Acetone: 542 ppm; IPA= 38ppm; Yield=93%

Example-9

Synthesis of Lurasidone hydrochloride

To lurasidone base (5g), acetone (75mL) and water (5 mL) were added. The mixture was heated to 55-60°C followed by the addition of IPA.HCl (10%) (5mL) and stirred for about 1-2 hours. The reaction mixture was stirred for 30 min. at 55-60°C, cooled and stirred for 60 min. The solid obtained was filtered and washed with acetone (5ml) and dried under vacuum at 70-80°C for 8 hours.

Jubilant Generics Limited

Pharmaceutical Company

Address: 18, 56, 57 and 58, KIADB Industrial Area, Nanjangud, Mysuru, Karnataka 571302

Chairman's Message

Chairman & Managing Director
Jubilant Bhartia Group Shyam, together with his brother Hari, is founder of Jubilant Bhartia Group (www.jubilantbhartia.com) headquartered in New Delhi, India. The Jubilant Bhartia Group, with 30,000 employees, has a strong presence in diverse sectors like Pharmaceuticals and Life Sciences, Oil and Gas (exploration and production), Agri products, Performance Polymers, Retail, Food and Consulting in Aerospace and Oilfield Services. Jubilant Bhartia Group has four flagships Companies- Jubilant Life Sciences Limited, Jubilant FoodWorks Limited and Jubilant Industries Limited, listed on Indian Stock Exchange and Jubilant Energy NV, listed at AIM market of London Exchange.Shyam, holds a bachelors’ degree in commerce from St. Xavier’s College, Calcutta University, and is a qualified cost and works accountant & a fellow member of the Institute of Cost and Works Accountants of India (ICWAI).Shyam has been associated with various institutions and has served as Member of Board of Governors, Indian Institute of Technology (IIT), Mumbai, and Indian Institute of Management (IIM), Ahmedabad. Shyam has also served as a Member of the Executive Committee of Federation of Indian Chamber of Commerce & Industry (FICCI) & Confederation of Indian Industry (CII) and was also a member of Task Force on Chemicals appointed by the Government of IndiaShyam’s immense contributions have been recognized by various awards. CHEMEXCIL has conferred Lifetime Achievement Award 2010-11 to him. He, along with his brother, was felicitated with the Entrepreneur of the Year Award at the prestigious AIMA Managing India Awards 2013, presented by the President of India. In 2010, the duo also shared the much-covetedErnst & Young Entrepreneur of the Year Award for Life Sciences & Consumer Products category.Shyam serves on the Board of several Public and Private and Foreign companies likes of Chambal Fertilizers and Chemicals Ltd, Putney Inc., CFCL Technologies Limited (Cayman Islands), Tower Promoters, BT Telecom India Pvt Ltd., American Orient Capital Partners India Pvt Ltd, IMACID, Morocco, Safe Food Corporation, etc. He was also a Director on the Board of Air India.Shyam is a regular participant at the World Economic Forum Annual Meeting in Davos and a member of the Chemical Governors Council of the World Economic Forum.Shyam is married to Shobhana, Former Member of Parliament & Chairperson, The Hindustan Times Media Ltd. They have two sons- Priyavrat and Shamit.

ISO Certification

ISO 9001:2008, 14001:2004 & OHSAS 18001:2007 certified

Code of Conduct

Code Of Conduct for Directors and Senior ManagementThis Code of Conduct highlights the standards of conduct expected from the Company’s Directors and Senior Management so as to align these with the Company’s Vision, Promise and Values.Jubilant Life Sciences Ltd. (Jubilant) has a well formulated Vision which drives the business and has the promise of Caring, Sharing, Growing to all the stakeholders–We will, with utmost care for the environment, continue to enhance value for our customers by providing innovative products and economically efficient solutions and for our shareholders through sales growth, cost effectiveness and wise investment of resources.

Director’s Desk

Co-Chairman & Managing Director
Jubilant Bhartia Group
Hari, together with his brother Shyam, is co-founder of Jubilant Bhartia Group (www.jubilantbhartia.com) headquartered in New Delhi, India.The Jubilant Bhartia Group, with 30,000 employees, has a strong presence in diverse sectors like Pharmaceuticals and Life Sciences, Oil and Gas (exploration and production), Agri products, Performance Polymers, Retail, Food and Consulting in Aerospace and Oilfield Services. Jubilant Bhartia Group has four flagships Companies- Jubilant Life Sciences Limited, Jubilant FoodWorksLimited and Jubilant Industries Limited, listed on Indian Stock Exchange and Jubilant Energy NV, listed at AIM market of London Exchange.A Chemical Engineering Graduate from the prestigious Indian Institute of Technology (IIT), Delhi, Hari was conferred the Distinguished Alumni award by his alma mater in 2000. He has been associated in various capacities with the IIT system and with the Ministry of Human Resource Development, Government of India.Hari is a past President of the Confederation of Indian Industry (CII) & a member of several educational, scientific and technological programmes of the Government of India. He is currently the Chairman of the Board of Governors of the Indian Institute of Management (IIM), Raipur and Member of the International Advisory Board of McGill University, Canada.Hari is the Co-Chairman of India-Canada CEO’s Forum appointed by the Prime Minister of India. He is also a member of CEO’s Forum for India-USA, India-France and India-Sri Lanka and Joint Task Force for India-Myanmar & India-UAE. He is a regular participant at the World Economic Forum Annual Meeting in Davos and is a member of the World Economic Forum’s International Business Council and the Health Governors.Hari’s immense contributions have been recognized by various awards. He, along with his brother, was felicitated with the Entrepreneur of the Year Award at the prestigious AIMA Managing India Awards 2013, presented by the President of India. In 2010, the duo also shared the much-coveted Ernst & Young Entrepreneur of the Year Award for Life Sciences & Consumer Products category.Hari serves on the board of several public and private companies like TV 18 Broadcast Ltd., Shriram Pistons & Rings Ltd., Export Credit Guarantee Corporation of India Ltd., BT Telecom India Pvt. Ltd & India Brand Equity Foundation.Hari is married to Kavita, a leading Fashion Designer and Retailer. They have a daughter, Aashti and a son, Arjun.

Executive Leadership Team

Shyam S Bhartia

Chairman
Hari S Bhartia

Co-Chairman & Managing Director
Shyamsundar Bang

Executive Director –Manufacturing & Supply Chain
R Sankaraiah

Executive Director – Finance
Pramod Yadav

Co-CEO
Life Science Ingredients
Rajesh Srivastava

Co-CEO
Life Science Ingredients
G. P. Singh

Fine Chemicals and CRAMS
CEO – Jubilant Pharma
Chandan Singh

President – Life Science Chemicals
Martyn Coombs

President – Jubilant DraxImage
Bryan Downey

President – Allergy Business
T. S. Parmar

President – India Branded Pharmaceuticals
Dr. Ashutosh Agarwal

Chief Scientific Officer –Chemicals and Life Science Ingredients
Ajay Khanna

Chief – Strategic & Public Affairs

read………http://www.jubl.com/uploads/downloads/93down_jll_sustainability_report_2014-15.pdf

///////Lurasidone hydrochloride, Jubilant Life Sciences Ltd, WO 2016059649, New patent

Albutrepenonacog alfa

April 27, 2016 12:25 pm / Leave a comment

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Albutrepenonacog alfa

recombinant factor IX

(Idelvion^®)

A recombinant albumin-human coagulation factor IX (FIX) fusion protein indicated for the treatment and prevention of bleeding in patients with hemophilia B.

Research Code CSL-654

CAS 1357448-54-4

Blood- coagulation factor IX (synthetic human) fusion protein with peptide (synthetic linker) fusion protein with serum albumin (synthetic human)

Type	Recombinant coagulation factor
Source	Human
Molecular Formula	C5077H7846N1367O1588S67
Molecular Weight	~125000

Other Names

Albutrepenonacog alfa

Protein Sequence

Sequence Length: 1018modified (modifications unspecified)

Originator CSL Behring
Class Albumins; Antihaemorrhagics; Blood coagulation factors; Recombinant fusion proteins
Mechanism of Action Blood coagulation factor replacements; Factor X stimulants

Orphan Drug Status Yes – Haemophilia B

Marketed Haemophilia B

Most Recent Events

21 Mar 2016 Launched for Haemophilia B (In adolescents, In children, In adults) in USA (IV) – First global launch
07 Mar 2016 Preregistration for Haemophilia B in Australia (IV) before March 2016
04 Mar 2016 Registered for Haemophilia B (In children, In adolescents, In adults) in USA (IV)

Company	CSL Ltd.
Description	Fusion protein linking recombinant coagulation Factor IX with recombinant albumin
Molecular Target	Factor IX
Mechanism of Action
Therapeutic Modality	Biologic: Fusion protein

Latest Stage of Development	Approved
Standard Indication	Hemophilia
Indication Details	Treat and prevent bleeding episodes in hemophilia B patients; Treat hemophilia B
Regulatory Designation	U.S. – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients); EU – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients); Switzerland – Orphan Drug (Treat and prevent bleeding episodes in hemophilia B patients)

BNF Category:	Antifibrinolytic drugs and haemostatics (02.11)
Pharmacology:	Albutrepenonacog alfa is a recombinant factor IX (rIX-FP) albumin fusion protein, designed to exhibit an extended half-life. Factor IX has a short half-life which necessitates multiple injections.
Epidemiology:	Haemophilia B is a genetic disorder caused by missing or defective factor IX, a clotting protein. It has a prevalence of around 1 in 50,000 live births in the UK and is more common in males. In 2012-13, there were 476 hospital admissions in England due to haemophilia B, accounting for 508 finished consultant episodes and 125 bed days.
Indication:	Haemophilia B

Albutrepenonacog alfa was approved by the U.S. Food and Drug Administration (FDA) on March 4, 2016. It was developed and marketed as Idelvion^® by CSL Behring.

Albutrepenonacog alfa is a recombinant albumin-human coagulation factor IX (FIX) fusion protein, which replaces the missing FIX needed for effective hemostasis. It is indicated for the treatment and prevention of bleeding in children and adults with hemophilia B.

Idelvion^® is available as injection (lyophilized powder) for intravenous use, containing 250 IU, 500 IU, 1000 IU or 2000 IU of albutrepenonacog alfa in single-use vials. In control and prevention of bleeding episodes and perioperative management, the required dosage is determined using the following formulas: Required Dose (IU) = Body Weight (kg) x Desired Factor IX rise (% of normal or IU/dL) x (reciprocal of recovery (IU/kg per IU/dL)). In routine prophylaxis, the recommended dose is 25-40 IU/kg (for patients ≥12 years of age) or 40-55 IU/kg (for patients <12 years of age) every 7 days.

EMA

On 25 February 2016, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive opinion, recommending the granting of a marketing authorisation for the medicinal product IDELVION, intended for treatment and prophylaxis of bleeding in patients with Haemophilia B. IDELVION was designated as an orphan medicinal producton 04 February 2010. The applicant for this medicinal product is CSL Behring GmbH.

IDELVION will be available as 250 IU, 500 IU, 1000 IU and 2000 IU Powder and solvent for solution for injection. The active substance of IDELVION is albutrepenonacog alfa, an antihaemorrhagic, blood coagulation factor IX, (ATC code: B02BD04). It works as replacement therapy and temporarily increases plasma levels of factor IX, helping to prevent and control bleeding.

The benefits with IDELVION are its ability to stop the bleeding when given on demand and prevent bleeding when used as routine prophylaxis or for surgical procedures. The most common side effects are injection site reaction and headache.

The full indication is: “the treatment and prophylaxis of bleeding in patients with Haemophilia B (congenital factor IX deficiency)”. Idelvion can be used in all age groups. It is proposed that IDELVION be prescribed by physicians experienced in the treatment of haemophilia B.

Detailed recommendations for the use of this product will be described in the summary of product characteristics (SmPC), which will be published in the European public assessment report (EPAR) and made available in all official European Union languages after the marketing authorisation has been granted by the European Commission.

Name	Idelvion
INN or common name	albutrepenonacog alfa
Therapeutic area	Hemophilia B
Active substance	albutrepenonacog alfa
Date opinion adopted	25/02/2016
Company name	CSL Behring GmbH
Status	Positive
Application type	Initial authorisation

//////Albutrepenonacog alfa, CSL-654, Idelvion; Recombinant factor IX – CSL Behring, Recombinant factor IX fusion protein linked with human albumin, rFIX-FP – CSL Behring; rIX-FP, Orphan Drug Status, Haemophilia B, recombinant factor IX , FDA 2016

update

Human medicines European public assessment report (EPAR): Idelvion, albutrepenonacog alfa, Hemophilia B, 11/05/2016,

, 9, Authorised

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Alizulatide vixocianine
Alizulatide vixocianine CAS 2924859-51-6 MF C115H145N17O25S, 2,197.55 L-Serine, N-[6-[2-[7-[1,3-dihydro-1,1-dimethyl-3-(4-sulfobutyl)-2H-benz[e]indol-2-ylidene]-1,3,5-heptatrien-1-yl]-1,1-dimethyl-1H-benz[e]indolio]-1-oxohexyl]-L-α-glutamyl-L-α-glutamyl-L-α-aspartyl-3-cyclohexyl-L-alanyl-L-phenylalanyl-D-seryl-D-arginyl-L-tyrosyl-L-leucyl-L-tryptophyl-, inner salt 4-[2-[7-[3-[6-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2R)-1-[[(2R)-5-carbamimidamido-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(1S)-1-carboxy-2-hydroxyethyl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-1-oxopentan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-cyclohexyl-1-oxopropan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-6-oxohexyl]-1,1-dimethylbenzo[e]indol-3-ium-2-yl]hepta-2,4,6-trienylidene]-1,1-dimethylbenzo[e]indol-3-yl]butane-1-sulfonate diagnostic imaging agent, 8M3Q8XZ6MJ Alizulatide vixocianine is a polypeptide that can be discovered…
Aleniglipron
Aleniglipron CAS 2685823-26-9 MF C49H55FN9O6P MW916.0 g/mol 3-[(1S,2S)-1-[2-[(4S)-3-[3-[4-diethylphosphoryl-3-(methylamino)phenyl]-2-oxoimidazol-1-yl]-2-(4-fluoro-3,5-dimethylphenyl)-4-methyl-6,7-dihydro-4H-pyrazolo[4,3-c]pyridine-5-carbonyl]-5-(oxan-4-yl)indol-1-yl]-2-methylcyclopropyl]-4H-1,2,4-oxadiazol-5-one glucagon-like peptide 1 (GLP-1) receptor agonist, GSBR-1290, GSBR 1290, Z6XCL6R9SX Aleniglipron (development code GSBR-1290) is a small-molecule GLP-1 agonist developed by Structure Therapeutics.[1] It…
Limnetrelvir
Limnetrelvir CAS 2923500-04-1 MF C27H23F4N5O4 MW 557.50 N-[(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl]-8-fluoro-2-oxo-1H-quinoline-4-carboxamide N-{(3R)-1-[4-cyano-2-(morpholine-4-carbonyl)-6-(trifluoromethyl)phenyl]pyrrolidin-3-yl}-8-fluoro-2-oxo1,2-dihydroquinoline-4-carboxamideantiviral, ABBV-903, ABBV 903, 4TPS988XGG Limnetrelvir (ABBV-903) is a MPro inhibitor. Limnetrelvir could be used in antiviral research. SYN https://patentscope.wipo.int/search/en/detail.jsf;jsessionid=4D458E543A941751578F87216FA39801.wapp1nA?docId=WO2024081351&_cid=P10-MJQJMM-46773-1#detailMainForm:MyTabViewId:PCTDESCRIPTION Example…
Aficamten
Aficamten C18H19N5O2, 337.4 g/mol FDA 2025, APPROVALS 2025, Myqorzo, 12/19/2025, To treat symptomatic obstructive hypertrophic cardiomyopathy CK-3773274, B1I77MH6K1, BAY-3723113; CK 3773274; CK 274; MYQORZO N-[(1R)-5-(5-ethyl-1,2,4-oxadiazol-3-yl)-2,3-dihydro-1H-inden-1-yl]-1-methylpyrazole-4-carboxamide Aficamten,…
Zoliflodacin
Zoliflodacin MF C22H22FN5O7 MW 487.4 g/mol FDA 2025, APPROVALS 2025, 12/12/2025, Nuzolvence (4′R,6′S,7′S)-17′-fluoro-4′,6′-dimethyl-13′-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]spiro[1,3-diazinane-5,8′-5,15-dioxa-2,14-diazatetracyclo[8.7.0.02,7.012,16]heptadeca-1(17),10,12(16),13-tetraene]-2,4,6-trione Spiro[isoxazolo[4,5-g][1,4]oxazino[4,3-a]quinoline-5(6H),5′(2′H)-pyrimidine]-2′,4′,6′(1′H,3′H)-trione, 11-fluoro-1,2,4,4a-tetrahydro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-3-oxazolidinyl]-, (2R,4S,4aS)- (2R,4S,4aS)-11-Fluoro-2,4-dimethyl-8-[(4S)-4-methyl-2-oxo-1,3-oxazolidin-3-yl]-1,2,4,4a-tetrahydro-2′H,6H-spiro[1,4-oxazino[4,3-a][1,2]oxazolo[4,5-g]quinoline-5,5′-pyrimidine]-2′,4′,6′(1′H,3′H)-trione To treat uncomplicated urogenital gonorrhea due to Neisseria gonorrhoeae…
Iscartrelvir
Iscartrelvir CAS 2921711-74-0 MF 2921711-74-0, 526.4 g/mol N-{(1S,2R)-2-[4-bromo-2-(methylcarbamoyl)-6-nitroanilino]cyclohexyl}isoquinoline-4-carboxamideantiviral, WU-04, WU 04, W2LTV65R5E Iscartrelvir is an investigational new drug developed by the Westlake University for the treatment of COVID-19. It targets the SARS-CoV-2 3CL…
Zoracopan
Zoracopan CAS 2243483-63-6 MF C31H31BrN6O3 MW 615.52 2-Azabicyclo[3.1.0]hexane-3-carboxamide, 2-[2-[3-acetyl-7-methyl-5-(2-methyl-5-pyrimidinyl)-1H-indol-1-yl]acetyl]-N-(6-bromo-3-methyl-2-pyridinyl)-5-methyl-, (1R,3S,5R)- (1R,3S,5R)-2-{[3-acetyl-7-methyl-5-(2-methylpyrimidin5-yl)-1H-indol-1-yl]acetyl}-N-(6-bromo-3-methylpyridin2-yl)-5-methyl-2-azabicyclo[3.1.0]hexane-3-carboxamidecomplement factor D inhibitor, ALXN-2080, ALXN 2080, E7799Y8LXY Zoracopan is a selective complement factor D (CFD) inhibitor.…
Zopocianine
Zopocianine CAS 2206660-94-6, NA SALT 2206660-95-7 MF C74H93N7O27S4, 1,640.83 L-Tyrosine, N-[[[(1S)-1,3-dicarboxypropyl]amino]carbonyl]-L-g-glutamyl-3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanyl-O-[6-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-2H-indol-2-ylidene]ethylidene]-2-[2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-3H-indolium-2-yl]ethenyl]-1-cyclohexen-1-yl]-, inner salt N-{[(1S)-1,3-dicarboxypropyl]carbamoyl}-L-γ-glutamyl3-[2-(2-aminoethoxy)ethoxy]propanoyl-L-phenylalanylO-[(6Ξ)-2-{(1Ξ)-2-[3,3-dimethyl-1-(4-sulfobutyl)-5-sulfonato-3H-indol-1-ium-2-yl]ethen-1-yl}-6-{(2Ξ)-2-[3,3-dimethyl-5-sulfo-1-(4-sulfobutyl)-1,3-dihydro-2Hindol-2-ylidene]ethylidene}cyclohex-1-en-1-yl]-Ltyrosinediagnostic imaging agent, UD9V5S9M7A, OTL 0078, OTL 78 AS ON OCT2025 4.511…
Zomiradomide
Zomiradomide CAS 2655656-99-6 MF C45H48F3N7O6S MW871.97 antineoplastic, IRAK degrader-1, AQ5UXV5646 Zomiradomide is an orally active PROTAC degrader for IRAK4 (DC50=6 nM), thereby inhibiting the NF-κB signaling pathway. Zomiradomide acts also as…
Zerencotrep
Zerencotrep CAS 1628287-16-0 MF C23H20ClF3N4O5, MW 524.88 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methyl-8-[3-(trifluoromethoxy)phenoxy]purine-2,6-dione 7-[(4-chlorophenyl)methyl]-1-(3-hydroxypropyl)-3-methyl-8-[3-(trifluoromethoxy)phenoxy]-3,7-dihydro1H-purine-2,6-dionetransient receptor potential channel 4 and 5 (TRPC4, TRPC5) inhibitor, Pico 145, HC 608, HMIMSYLCWQ Pico145 (HC-608)…

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Development of a Scalable Synthesis of an Azaindolyl-Pyrimidine Inhibitor of Influenza Virus Replication

INHIBITORS OF INFLUENZA VIRUSES REPLICATION

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Effect of Temperature and Solvent of Solvent-Mediated Polymorph Transformation on ASP3026 Polymorphs and Scale-up

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Improved Manufacturing Route and Polymorphic Control of a Potent and Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor ASP3026

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Determination of cymipristone in human plasma by liquid chromatography–electrospray ionization-tandem mass spectrometry

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