Home » 2015 (Page 21)

Yearly Archives: 2015

Zydus Cadila Healthcare Ltd, WO 2015102017, lorcaserin

July 13, 2015 9:19 am / Leave a comment

Processes for the preparation of lorcaserin

Zydus Cadila Healthcare Ltd

WO 2015102017, 09 July2015

Applicants:	CADILA HEALTHCARE LIMITED [IN/IN]; Zydus Tower, Satellite Cross Roads Ahmedabad – 380 015 Gujarat (IN)
Inventors:	DWIVEDI, Shriprakash Dhar; (IN). SHAH, Alpeshkumar Pravinchandra; (IN). GAJJAR, Samir Rameshbhai; (IN). KHERA, Brij; (IN)

On 10 May 2012, after a new round of studies submitted by Arena, an FDA panel voted to recommend lorcaserin with certain restrictions and patient monitoring. The restrictions include patients with a BMI of over 30, or with a BMI over 27 and a comorbidity such as high blood pressure or type 2 diabetes.

On 27 June 2012, the FDA officially approved lorcaserin for use in the treatment of obesity for adults with a BMI equal to or greater than 30 or adults with a BMI of 27 or greater who “have at least one weight-related health condition, such as high blood pressure, type 2 diabetes, or high cholesterol

Useful for treating obesity.

The present invention relates to stable crystalline Form I of Iorcaserin hydrochloride of Formula (IA) and processes for its preparation. The invention also relates to processes for the preparation of lorcaserin and pharmaceutically acceptable salts, solvates and hydrates thereof.

Stable crystalline form I of lorcaserin hydrochloride and its process of preparation are claimed. Represents the first patenting from Cadila on lorcaserin, which was developed and launched by Arena Pharma and Eisai.

In July 2015, Newport Premium™ reported that Cadila is potentially interested in lorcaserin.

Lorcaserin hydrochloride is an agonist of the 5-HT_2c receptor and shows effectiveness at reducing obesity in animal models and humans developed by Arena Pharmaceuticals. It is chemically represented as (R)-8-chloro-l -methyl -2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride having Formula (I) as depicted herein below.

(IA)

U.S. Patent No. 6,953,787 B2 discloses compound of Formula (I) and pharmaceutically acceptable salt, solvates or hydrates thereof and process for preparation thereof.

U.S. Patent No. 8,168,624 B2 discloses (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride hemihydrate and process for its preparation. The patent also discloses crystalline Form I, Form II and Form III of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine hydrochloride. The crystalline Form

I and Form II are reported as anhydrous, non-solvated crystal forms. The crystalline Form III displays a dehydration feature calculated as a 3.7% weight loss which is consistent with the theoretical weight loss of 3.7% for a hemihydrate.

The patent discloses that anhydrous Form I and Form II readily converts to a hemihydrate, upon exposure to moisture. The dynamic vapor sorption (DVS) data for each of the three crystal forms reveals the hygroscopic nature of both Forms I and II, which readily adsorb moisture at relative humidity (RH) greater than about 40-60%. In addition, both Forms I and II were calculated to adsorb about 3.8% moisture between about 40 and about 80% RH which is consistent with conversion to the hemihydrate (Form III). X-ray powder diffraction (XRPD) carried out on both Forms I and II after the DVS cycle confirmed this conversion. In contrast, the DVS data in connection with Form III shows that it is substantially non-hygroscopic, adsorbing less than 0.5% water at 90% RH and the XRPD pattern showed no change in crystalline form after the DVS cycle.

International (PCT) Publication Nos. WO 2003/086306 Al, WO 2005/019179 Al, WO 2006/069363 Al, WO 2007/120517 Al, WO 2008/07011 1 Al and WO 2009/1 1 1004 Al disclose various synthetic approaches for the preparation of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine, its related salts, enantiomers, crystalline forms and intermediates.

International (PCT) Publication No. WO 2006/071740 Al discloses combination of (R)-8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine with other agents. International (PCT) Publication No. WO 2012/030938 Al discloses various salts of lorcaserin with optically active acids.

U.S. PG-Pub No. US 2014/0187538 Al discloses amorphous lorcaserin hydrochloride and amorphous solid dispersion comprising lorcaserin hydrochloride and one or more pharmaceutically acceptable carriers and processes for their preparation.

International (PCT) Publication No. WO 2014/135545 Al discloses solid dispersion comprising amorphous lorcaserin hydrochloride and one or more pharmaceutically acceptable water soluble polymers.

see…..https://patentscope.wipo.int/search/en/detail.jsf?docId=WO2015102017&recNum=1&maxRec=&office=&prevFilter=&sortOption=&queryString=&tab=PCTDescription

Example-7: Preparation of crystalline Form I of lorcaserin hydrochloride. In a round bottom flask, 560g of methyl ethyl ketone and 40 ml water were taken and 100 g of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine was added and stirred for 10 minutes. The reaction mass heated to 55 to 60°C and 19.3 g of. L-(+)-tartaric acid was added slowly and stirred for one to two hours. The reaction mass was further stirred at 10-15°C for an hour and the product was filtered and washed with a mixture of methyl ethyl ketone and water. The wet cake and 150 ml methyl ethyl ketone were taken in another flask and heated to 75-80°C. 20-25 ml water was, added and stirred for an hour. Further, the reaction mass was stirred for an hour at 0-5°C. The product was filtered and washed with methyl ethyl ketone.

100 g tartrate salt of 8-chloro-l-methyl-2,3,4,5-tetrahydro-lH-3-benzazepine and 300 mL water were taken in another round bottom flask. 200 mL methylene dichloride was added and the reaction mass was cooled to 10-20°C. 17.2 g sodium hydroxide dissolved in 89 ml water was added into the reaction mass at 10-20°C. The reaction mass was stirred for an hour at 25-30°C and the layers were separated. The solvent was removed from the organic layer under vacuum and then 100 mL ethyl acetate was added into that and distilled out. Further, 100 mL ethyl acetate was added and stirred for 15 minutes. The reaction mass was filtered through a hyflow bed and the filtrate was treated with dry HC1 gas till a pH of 1.5 to 2.5 was obtained at 0-10°C and it was stirred for about 30 minutes to an hour. The product was then filtered and washed with ethyl acetate and then dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride. Yield: 87.5-98.6 %.

Example-8: Preparation of crystalline Form I of lorcaserin hydrochloride

In a round bottom flask, 2.20 g lorcaserin, 30 mL methylene chloride, 17.4 mL of 1M HCI in ether were added and the mixture was stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give a white solid. This solid was again dissolved in 30 ml methylene chloride, 17.4 mL of 1M HCI solution and stirred for 5-15 minutes at room temperature. The solvent was removed under reduced pressure to give lorcaserin hydrochloride. The product was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Example-9: Preparation of crystalline Form I lorcaserin hydrochloride

50 g of lorcaserin hydrochloride hemihydrate and 50 g of hydroxypropylmethyl cellulose (HPMC) 3CPC were mixed in a blender at 25°C to 35°C. The mixture was mixed for 30 minutes and unloaded. The solid thus obtained was dried in a vacuum oven at 50°C to 55°C for 2 hours. The product was further dried at 90°C to 110°C for 20 hours to obtain crystalline Form I of lorcaserin hydrochloride.

Pankaj R. Patel (right), Chairman and Managing Director,

/////////

How flow chemistry can make processes greener.. Case study 1 Methylation with DMC.

July 13, 2015 4:35 am / 1 Comment on How flow chemistry can make processes greener.. Case study 1 Methylation with DMC.

Green Chemistry International

How flow chemistry can make processes greener

Case study 1 Methylation with DMC.

Increasing reaction efficiency through access to a wider range of reaction conditions

Efficient utilization of energy and time is fundamental to green chemistry and engineering. These factors are directly related to the rate of a chemical reaction, as a fast reaction will require less operating time. Economical use of space is also important, and fast reactions may allow for a smaller reactor to be utilized, particularly in continuous processes. The most straightforward way to increase reaction rate is with an increase in temperature; however, in a batch reactor, this is generally limited to the atmospheric boiling point of the solvent or reagents. In a flow reactor, pressure and temperature can be safely manipulated far beyond atmospheric conditions. Analogous to microwaves synthesis,¹ reactions done in flow are often faster than in the corresponding batch reactions, which gives…

View original post 426 more words

AXITINIB

July 9, 2015 12:08 pm / Leave a comment

Axitinib (AG013736; trade name Inlyta) is a small molecule tyrosine kinase inhibitor developed by Pfizer. It has been shown to significantly inhibit growth of breast cancer in animal (xenograft) models^[2] and has shown partial responses in clinical trials with renal cell carcinoma (RCC)^[3] and several other tumour types.^[4] It was approved by the U.S. Food and Drug Administration after showing a modest increase in progression-free survival,^[5] though there have been reports of fatal adverse effects.^[6]

Axitinib, a small-molecule indazole derivative chemically known as (E)-N-methyl-2-(3-(2-(pyridin-2-yl)-vinyl)-1H-indazol-6-ylthio)benzamide developed by Pfizer, was approved in January 2012 by the U.S. FDA with the trade name Inlyta. It selectively inhibits vascular endothelial growth factor receptors for the treatment of renal cell carcinoma

On January 27, 2012, axitinib was approved with the trade name INLYTA for treatment of patients in the United States with advanced renal cell carcinoma after failure of one prior systemic therapy.

It has received FDA (27 January 2012), EMA (13 September 2012), MHRA (3 September 2012) and TGA (26 July 2012) approval for use as a treatment for renal cell carcinoma.^[11]^[12]^[13]^[14]

A study published in 2015^[15] showed that axitinib effectively inhibits a mutated gene (BCR-ABL1[T315I]) that is common in chronic myeloid leukemias and adult acute lymphoblastic leukemias which have become resistant to other tyrosine kinase inhibitors likeimatinib. This is one of the first examples of a new indication for an existing drug being discovered by screening known drugs using a patient’s own cells.

Abstract Image

The discovery and development of an efficient synthesis route to axinitib is reported. The first-generation route researched by Pfizer implemented two Pd-catalyzed coupling reactions as key steps. In this work, the development of Heck-type and C–S coupling reactions catalyzed by CuI is briefly described, using an economial and practical protocol. Aspects of this route, such as selecting optimal ligands, solvent, and other conditions, are discussed in detail. The scale-up experiment was carried out to provide more than 300 g of active pharmaceutical ingredients of axitinib in Form XLI with 99.9% purity in 39% yield. In short, we provide a new choice of synthesis route to axitinib, through two copper-catalyzed coupling reactions with good yield.

Org. Process Res. Dev., Article ASAP

DOI: 10.1021/acs.oprd.5b00123

http://pubs.acs.org/doi/full/10.1021/acs.oprd.5b00123

(E)-N-Methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6-ylthiol)benzamide (Axitinib) Form XLI (326.4 g in 96% yield with purity 99.91%). Residual Cu content was determined to be 2.2 ppm by atomic absorption spectroscopy: mp 227.7 °C;

1H NMR (300 MHz, DMSO-d6) δ 13.27 (s, 1H), 8.60 (d, J = 4.8 Hz, 1H), 8.29 (d, J = 5.4 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 7.8 Hz, 1H), 7.63–7.44 (m, 3H), 7.29 (p, J = 7.4, 6.6 Hz, 3H), 7.19 (d, J = 8.5 Hz, 1H), 7.08 (d, J = 7.4 Hz, 1H), 2.78 (d, J = 4.6 Hz, 3H);

13C NMR (75 MHz, DMSO-d6) δ 167.89, 154.86, 149.54, 142.01, 141.86, 136.92, 136.88, 135.67, 132.52, 130.32, 129.99, 129.25, 127.80, 126.15, 125.59, 123.66, 122.68, 122.50, 121.79, 120.29, 114.76, 26.13.

………………………..

Axitinib (Axitinib, AG-013736, CAS: 319460-85-0) is a Pfizer research and development by the United States of new, mainly targeting VEGFR kinase GABA, inhibiting angiogenesis anticancer small molecule drug, trade name Inlyta, for other systems therapy for advanced renal cell carcinoma (Renal Cell Carcinoma, RCC), 2008 has been approved in the domestic clinical, and Pfizer’s cancer drug Sutent another similar imatinib (Sunitinib) , Axitinib also potent and selective multi-targeted tyrosine kinase inhibitor, can inhibit the vascular endothelial growth factor receptor (Vascular EndothelialGrowth Factor Rec India tor, VEGFR), including VEGFl receptor, VECF2 receptors and VECF3 receptor, can inhibit platelet-derived growth factor receptor (Platelet-derived growth factor receptor, PDGFR) and c_KIT. Axitinib is called sunitinib second generation, better than sunitinib adverse reactions.

Axitinib (II) chemical name 6- [2_ (methylcarbamoyl) phenylsulfanyl] -3-E- [2_ (Batch-2-yl) ethenyl] indazole structural formula as follows:

Axitinib (II)

Assi synthesis method for Nepal mainly in the following three ways:

(I) Patent US20060094881 (Agouron Pharmaceuticals), EP2163544 (Pfizer) reported the first synthesis method Axitinib to 3,6-diiodo-indazole as a starting material, first-iodo-6-position is substituted mercapto group, protection of the NH group, then the Heck reaction occurs (pyridine-2-yl) vinyl 3-position, after deprotection Axitinib whole synthesis route is as follows:

Axitinib Scheme I

This method although the synthesis route is shorter, but the catalyst and reagents used relatively expensive and require purified through the column, the total yield is low, is not conducive to industrial production.

[0004] (2) The second method of synthesis Axitinib e.g. W00102369 (Agouron Pharmaceuticals), US6531491 (Agouron Pharmaceuticals) reported in 6-nitro-indazole as a starting material, the 3-position first iodo, followed by the protecting group NH, Suzuki coupling reaction with boronic acid to give 3- styryl styryl-position, a nitro group reduced to an amino group, an amino diazotization reaction was iodo, the 3-position of the styrene-based ozone of the obtained aldehyde, followed by Wittig reaction to give the 3-position (pyridin-2-yl) ethenyl, 6-position is substituted mercapto iodine, alkaline hydrolysis then amidated, and finally deprotection Axitinib, the entire reaction formula as follows:

Axitinib Scheme 2

The method of synthesis route is long, harsh reaction conditions, complex process, the total yield is low, does not apply to industrial production.

[0005] (3) The third method is W02006048745 (Pfizer) discloses to 6-nitro-indazole as a starting material, the 3-position iodo first, followed by the protecting group NH, 3- bits Heck coupling reaction, a nitro group reduced to an amino group, an amino diazotization reaction was iodo, iodo-6-position is substituted mercapto group, and finally deprotected to give Axitinib, the entire reaction is as follows:

This method has an advantage over the first two methods, it is possible to enlarge the production, but the reaction was not complete in the reaction step, will generate new impurities through the column needs to be purified.

SYNTHESIS

aReagents and conditions: (a) I2, K2CO3, DMF; (b) CH2Cl2, CH3SO3H, dihydrofuran; (c) compound B, i-Pr2EtN, Pd(OAc)2, (o-Tol)3P, DMF; (d) iron, EtOH, NH4Cl; (e) AcOH, NaNO2, CH2Cl2, I2/KI; (f) compound C, Pd(dppf)Cl2, Cs2CO3, DMF; (h) 1, p-TsOH, MeOH; 2, NaHCO3; (i) AcOH, MeOH, Pd removal, recrystallization.

http://www.google.com/patents/WO2006048745A1?cl=en

Example 15: Final deprotectioπ step to produce 6-r2-(methylcarbamoyl)phenylsulfanyll-3-E-f2- (pyridine-2-yl)ethenyllindazole

N-1 THP 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole (355 g) was suspended in 2,485 ml_ of methanol, after which p-toluenesulfonic acid monohydrate (718 g) was added. The mixture was then heated to 65 ⁰C (hard reflux) for 4 hours under argon while the reaction was monitored by HPLC (gluco method). Heating continued until less than 1% of the N-1 THP protected starting material persisted. The heating was then removed and the reaction was cooled to room temperature. The solid was filtered and the wet cake was washed with methanol (2 volumes, 710 mL) then the solids were rinsed with ethyl acetate (2 volumes, 710 mL). The wet cake was transferred to a reactor containing sodium bicarbonate (126.84 g), deionized water (1800 mL), and ethyl acetate (975 mL), which was then stirred for 2 hours at 2O⁰C. The solids were filtered and washed with 5 volumes of deionized water (1800 mL), then with 2 volumes of ethyl acetate (760 mL), and then dried in a vacuum oven at 40⁰C for 16 hours. The isolated yield for the reaction was 92.5% (274 g). The isolated material was identified as crystalline Form III free base (0.5 ethyl acetate solvate). ¹H NMR, 300 MHz, (DMSO-D6), ppm; 13.35 (1 H, s), 8.60 (1 H, d, J=3.8 Hz), 8.39 (1 H, m), 8.23 (1 H, d, J=8.5 Hz), 7.95 (1 H, d, J=16.4 Hz), 7.82 (1 H, ddd, J=7.7, 7.6, 1.8 Hz), 7.67 (1 H, d, J=7.8 Hz), 7.60 (a H, s), 7.57 (1 H, d, J=16.4 Hz), 7.49 (1 H, dd, J=7.1 , 1.6 Hz), 7.35-7.26 (3 H, m), 7.19 (1 H, d, J=8.4 Hz), 7.04 (1 H, d, J=7.8 Hz), 2.77 (3 H, d, J=4.6 Hz). ¹³C NMR, 75 MHz, (DMSO-D6) ppm: 168.23, 155.18, 149.81 , 142.35, 142.22, 137.31 , 136.00, 132.89, 130.64, 130.36, 129.51 , 128.14, 126.50, 125.93, 124.08, 123.01 , 122.85, 122.12, 120.642, 115.08, 26.45.

Example 21 : Preparation of 6-F2-(methylcarbamovDphenylsulfanyll-3-Z-r2-(pyridine-2- vDethenyllindazole

To a 100 ml_ 3-neck flask containing a solution of 0.95 g of 6-[2- (methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole was added 2.5 g of phenyliodide diacetate followed by 1.0 mL of H₂NNH₂ H₂O. After the bubbling had settled, more phenyliodide diacetate and H₂NNH₂ H₂O were added in small portions, until LC/MS indicated the disappearance of 6-[2-(methylcarbamoyl)phenylsulfanyl]-3-[2-(pyridine-2-yl)ethynyl]indazole and the formation of 6-[2-(methylcarbamoyl)phenylsuIfanyl]-3-Z-[2-(pyridine-2-yl)ethenyl]indazole. Example 22: Palladium removal and polymorph control of 6-[2-(methylcarbamoyl)phenylsulfanvn- 3-E-r2-(pyridine-2-vDethenyllindazole

4) MeOH, reflux

Polymorph Form IV

5) HOAc/Xylenes

To a 12 L 3-neck flask, equipped with a mechanical stirrer, was added 160.20 g of 6-[2- (methylc’arbamoyl)phenylsulfanyl]-3-E-[2-(pyridine-2-yl)ethenyl]indazole and 1.6 L of DMA and 1.6 L of THF. After stirring for 20 minutes, the mixture became homogeneous. To the clear solution was added 800.99 g of 10% cysteine-silica and the resulting mixture was allowed to stir at room temperature overnight.

The mixture was filtered through a medium sintered glass fritted funnel, and the cake was washed with a solution of 500 mL of DMA and 500 mL of THF. The cake was further washed with 2.0 L of THF and the filtrate was collected into a separate flask. The volatile parts in the latter filtrate were removed in vacuo and the residue was combined with the main filtrate. The combined filtrate was recharged back into the 12 L flask, followed by 800 g of 10% cysteine-silica. The flask was equipped with a mechanical stirrer and stirred over the weekend at room temperature. The mixture was then filtered through a medium sintered glass fritted funnel and the silica was washed with a mixture of solvents of 500 ml. of DMA and 500 ml_ of THF, followed by 3.0 L of THF. The volatile parts in the filtrate were removed in vacuo and the remaining solution was transferred to a 22 L 3-neck flask and treated with 12 L of water (added over a 20 minute period of time), a thick precipitate formed at this stage. After stirring overnight, the mixture was filtered and the cake was washed with 2.0 L of water and sucked dry.

The cake was charged to a 5 L 3-neck flask, followed by 1.6 L of THF and 160 mL of DMF. The flask was equipped with a mechanical stirrer, a reflux condenser and the mixture was heated at reflux for 8 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry. The cake was charged to a 5 L 3-neck flask and 1.6 L of MeOH was added. The flask was equipped with a mechanical stirrer, a water condenser and the contents were heated at reflux for 6 hours. After cooling overnight, the mixture was filtered through sharkskin filter paper and sucked dry.

The cake was dissolved into 1.6 L of HOAc with the assistance of gentle heating in the water bath of a rotary evaporator. The solution was filtered through #3 filter paper and the total volume of the filtrate was reduced to ~500 mL in volume on the rotary evaporator at 60 °C/60 mmHg. At this stage, the bulk of the mixture remained a yellow solution and a small amount of precipitate formed. To the flask was charged 500 mL of xylenes (precipitate formed) and the total volume was reduced to -500 mL in volume on the rotary evaporator at 60°C/60 mmHg. The process was repeated two more times. After cooling, the mixture was filtered, the cake was washed with 500 mL of xylenes and sucked dry. The cake was transferred to a glass dish and further dried at 80°C/27 inch vacuum overnight.

The cake was off-white in color and weighed 108.38g. X-ray powder diffraction analysis indicated that a crystalline form was present, which was characterized as Form IV by a powder X- ray diffraction pattern comprising peaks at the following approximate diffraction angles (20): 8.9, 12.0, 14.6, 15.2, 15.7, 17.8, 19.2, 20.5, 21.6, 23.2, 24.2, 24.8, 26.2, and 27.5.

While the invention has been illustrated by reference to specific and preferred embodiments, those skilled in the art will recognize that variations and modifications may be made through routine experimentation and practice of the invention. Thus, the invention is intended not to be limited by the foregoing description, but to be defined by the appended claims and their equivalents.

………………………..

Chekal, B. P.; Guinness, S. M.; Lillie, B. M.; McLaughlin, R. W.; Palmer, C. W.; Post, R. J.; Sieser, J. E.; Singer, R. A.; Sluggett, G. W.; Vaidyanathan, R.; Withbroe, G. Org. Process Res. Dev. 2014, 18, 266 http://pubs.acs.org/doi/abs/10.1021/op400088k

The manufacturing process of axitinib (1) involves two Pd-catalyzed coupling reactions, a Migita coupling and a Heck reaction. Optimization of both of these pivotal bond-formation steps is discussed as well as the approach to control impurities in axitinib. Essential to the control strategy was the optimization of the Heck reaction to minimize formation of impurities, in addition to the development of an efficient isolation of crude axitinib to purge impurities.

Babu, S.; Dagnino, R., Jr.; Ouellette, M. A.; Shi, B.; Tian, Q.; Zook, S. E. PCT Int. Appl. WO/2006/048745, 2006.

…………………..

………………………………

http://www.google.com/patents/CN103570696A?cl=en

formula:

A Axitinib intermediate (1) production method, based on 6-nitro-indazole as a starting material, in the first catalyst is reacted with 3,4-dihydro -2H- pyran, bits of NH the protecting group tetrahydro -2H- pyran-2-yl, then the three iodide, to give the key intermediate in high yield 3-iodo-6-nitro-1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H- indazole (I), comprising the following synthetic steps:

(1) 6-nitro-indazole dissolved in an aprotic solvent, and 3,4-dihydro -2H- pyran catalyst, 6-nitro-indazole in the catalyst and the 3,4-dihydro -2H – pyran reaction, the protecting group NH-position, was prepared to give 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction equation is:

Wherein the 3,4-dihydro -2H- pyran an amount of 3 equivalents wide;

Aprotic solvent is acetonitrile, ethyl acetate, toluene or xylene;

The catalyst is 2,3-dichloro-5,6-dicyano-p-benzoquinone, p-toluenesulfonic acid or methanesulfonic acid;

The reaction temperature is 7 (T90 ° C, the reaction time is 1 to 4 hours;

(2) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole dissolved in a polar aprotic solvent, iodine was added and the acid-binding agent, an inorganic base, to afford 3- iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I), the reaction equation is:

Wherein the polar aprotic solvent is N, N- dimethylformamide (DMF), N, N- dimethylacetamide, N, N- diethylformamide, N, N- diethyl-acetamide ;

Inorganic base acid binding agent is potassium carbonate, sodium carbonate, potassium hydroxide, sodium hydroxide, potassium bicarbonate, sodium bicarbonate, cesium carbonate, lithium hydroxide;

The reaction temperature is 2 (T40 ° C, the reaction time is 8 to 20 hours.

[0009] A Axitinib intermediate (1) in preparation for the Nepalese Asif application, based on intermediate (1) and 2-vinyl pyridine Heck coupling reaction, followed sequentially nitro reduction and the diazotization reaction of iodine, and finally with a 2-mercapto–N- methylbenzamide was prepared by deprotection docking axitinib, including the following synthetic steps:

(I) Intermediate (1) and be given 2_ vinylpyridine Jie Heck coupling reaction to give (E) _6_ nitro _3- [2_ (P than-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, the reaction equation is:

(2) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- nitro indazole group reduction reaction, to give (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, The reaction equation is:

(3) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole diazo of the iodide to give (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole The reaction equation is:

(4) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole with 2- mercapto-methylbenzamide reaction -N-, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyrazol pyran-2-yl) -1H- indazol-6-yl] thio} benzamide, the reaction equation is:

(5) (E) -N- methyl-2- {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio} benzamide deprotected Axitinib (II), the reaction equation is:

Example 1

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (I) 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added acetonitrile (2L), followed by addition of 6-nitro-indazole (163.1g, 1.0mol), 3, 4- dihydro -2H- pyran (168.2g, 2.0mol), 2,3- dichloro-5,6-dicyano-p-benzoquinone (22.7g, 0.1mol), was heated to 820C under reflux for 2 hours to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirring I hour, delamination, the organic phase washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile, recrystallized from ethanol, 60 ° C and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 236.3 g, yield 95.6%, m.p. 110 ~ 120 ° C, 1Η NMR (CDCl3): δ 1.30-1.83 (m, 6Η, Η3, _Η5,), 3.82-3.93 (m, 2Η, Η6 ‘), 5.86 (m , 1Η, Η2 ‘), 8.10-8.12 (m, 2Η, Η3, Η5), 8.31 (m, 1Η; Η4), 8.55 (s, 1Η, Η7);

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, l.0eq) and potassium carbonate ( 251.6g, 1.82mol, 2.0eq), ice-cooled (10 ° C or less), followed by stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system, addition time 2 hours , the reaction system was stirred at 25 ° C for 16 hours to complete the reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the internal temperature 30 ° C Hereinafter, stirred for 30 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 30 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid (Ι), 326.5g, yield 96.2%, m.p. 135 ~ 137 ° C / H NMR (DMS0_d6): δ 1.60-1.61 (m, 2H, H4,, H5 ‘), 1.73-1.76 (m, 1H, H5’), 2.01-2.04 (m, 2H, H3 ‘, H4’), 2.35-2.38 (m, 1H, H3 ‘), 3.81-3.87 (m, 2H, H6’), 6.11-6.14 (dd, 1H, H2 ‘), 7.70-7.72 (d , 1H, H4),

8.05-8.07 (dd, 1H, H5), 8.79 (s, 1H, H7).

The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis of (I) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin-2 – yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5’), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3’, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6’), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole

5L reaction flask in ethanol HOOmLdjC 1000mL and ammonium chloride (300.0g, 5.61mol), was dissolved with stirring, followed by addition of (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (255.0g, 0.73mol), was added iron powder (162.6g, 2.91mol), heated to 50 ° C the reaction was stirred for 2 hours to completion of the reaction, was cooled to 22 ° C, tetrahydrofuran 2L, stirred for I hour at room temperature, filtered through Celite, the filter cake washed with tetrahydrofuran and the filtrate was rotary evaporated to dryness, cooled to room temperature, water was added 2L, stirred for I hour at room temperature, pumping filtered, the filter cake washed with petroleum ether, 50 ° C and dried under vacuum for 12 hours to give a pale yellow solid 206.5g, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole, yield 88.6%, m.p. 162 ~ 164 ° C / H NMR (CDCl3): δ 1.63-1.77 (m, 2H, H4 ‘, H5 ‘), 2.02-2.06 (m, 1H, H5’), 2.17-2.18 (m, 1H, H4 ‘), 2.55-2.60 (m, 1H, H3’) 3.70-3.72 (m, 2H, H3 ‘, H6 ‘), 3.91 (s, 2H, NH2), 4.04-4.07 (m, 1H, H6’), 5.57-5.60 (dd, 1H, H2 ‘), 6.64-6.66 (dd, 1H, H5), 6.74-6.75 (d, 1H, H7), 7.13-7.16 (dd, 1H, pyridine H5), 7.48-7.50 (d, 1H, pyridine H4), 7.49-7.53 (d, 1H, J = 16Hz, vinyl H2), 7.64 -7.68 (m, 1H, pyridine H3), 7.78-7.82 (d, 1H, J = 16Hz, vinyl Hl), 7.82-7.83 (d, 1H, H4), 8.60-8.61 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

A 5L reaction flask was added 600mL of water and sodium nitrite (70.2g, 1.02mol), stirred and dissolved, and cooled to (TC, (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl ] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I h, a solution process maintain an internal temperature of 0 ° C, the same temperature for I hour, dropping HCl solution (concentrated hydrochloric acid 112mL, water 200mL) at O ° C, the dropping time of 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). dropwise 800mL dichloromethane between 0 ° C, the dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) was dissolved water 600mL, in (TC dropwise added to the system at the same temperature for 2 hours to complete the reaction. The reaction mixture was poured into the system to 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layered , the aqueous phase was extracted with dichloromethane frozen (2x800mL), dichloromethane phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes , separated and the aqueous phase was extracted with dichloromethane (2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl ) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58- 1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,) , 3.79-3.81 (m, 1H, H6,), 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,), 7.29-7.31 (m, 1H, pyridine H5), 7.56 -7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4 ), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7), 8.61-8.62 (d, 1H, pyridine H6) ;

The reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

A 5L reaction flask was added DMF (1750mL) and (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1H- indazole (175.0g, 0.41mol), nitrogen, was added [1, I, – bis (diphenylphosphino) ferrocene] dichloropalladium dichloromethane complex (14.9g, 0.018mmol ), cesium carbonate (198.3g, 0.61mol) and dichloromethane 20mL, was added 2-mercapto -N- methylbenzamide (84.9g, 0.5Imol), heated to 80 ° C for 16 hours to complete the reaction, spin distilled was removed DMF, cooled to room temperature, ethyl acetate was added 3L, water 4L, stirred for 40 minutes, the organic phase was separated, washed with brine, layered, dried over sodium sulfate, filtered, and rotary evaporated to dryness, to give (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) -1- (tetrahydro -2H- pyran-2-yl) -1H- indazol-6-yl] thio } benzamide, 165.6g, a yield of 86.7%, the melting point of 142 ~ 143 ° C;

The reaction equation is as follows:

(5) Synthesis of axitinib

In a 2L reaction flask was added (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H – indazol-6-yl] thio} benzamide (150.0g, 0.32mol), p-toluenesulfonic acid monohydrate (303.2g, 1.59mol), methanol (800mL) and water (150mL), nitrogen, heated to 65 ° C for 4 hours, spin evaporated to dryness and ethanol (800mL), 65 ° C was stirred for I hour, the ethanol was removed by rotary evaporation, then repeated three times, TLC spot plate tracking reaction (petroleum ether: ethyl acetate = 1: 1). Completion of the reaction, cooled to room temperature, rotary evaporated to dryness, water was added 500mL, stirred for I h, filtered, and the filter cake was washed with methanol and ice, and then added to the reaction vessel, ethyl acetate was added 450mL, stirred at 65 ° C 30 minutes. cooled to room temperature, suction filtered, the filter cake washed with ethyl acetate and freeze paint, water paint, 50 ° C and dried under vacuum for 12 hours to give a white solid 117.5g, Axitinib (II), yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

Example 2

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added ethyl acetate (2L), followed by addition of 6-nitro-indazole (163.14g, 1.0mol), 3, 4- dihydro -2H- pyran (210.3g, 2.5mol), toluene acid (20.7g, 0.12mol), heated to 78 ° C under reflux for 3 hours to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirred for I hour, stratification, the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile, recrystallized from ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid 223.3g, 6- nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, yield 90.3%, m.p. 110 ^ 11 TC;

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (200.0g, 0.81mol, l.0eq) and sodium hydroxide (64.7g, 1.62mol, 2.0eq), ice-cooled (10 ° C or less), followed by stirring, iodine (369.6g, 1.46mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system, addition time 2 hours, the reaction system was stirred at 25 ° C for 12 hours to complete the reaction, sodium thiosulfate was added (198.2g, 1.25mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the temperature of 30 ° C or less, and stirred for 30 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 30 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid

(1), 294.3g, 97.5% yield, m.p. 136 ~ 137. . .

[0014] The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2Η-) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5’), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3’, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6’), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

The reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

The reaction equation is as follows:

(5) Synthesis of axitinib

The reaction equation is as follows:

Example 3

A Assi intermediates for preparing Nigeria, comprising the steps of:

Synthesis of (1) 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

5L reaction flask in toluene (2L), followed by addition of 6-nitro-indazole (163.lg, 1.0mol), 3,4- dihydro -2H- pyran (193.5g, 2.3mol), methanesulfonic acid (14.4g, 0.15mol), heated to 85 ° C under reflux for 3.5 hours, to complete the reaction, cooled to room temperature, rotary evaporated to dryness, added water and dichloromethane 2L 2L, stirred for I hour, stratification, the organic phase was washed with brine wash, dried over anhydrous sodium sulfate, filtered, and rotary evaporated to dryness, and then dissolved in acetonitrile and 2L, stirring ice-salt bath chilled to _5 ° C for 2 hours, suction filtered, the filter cake washed with a small amount of cold acetonitrile and paint, and recrystallized from ethanol , 60 ° C and dried in vacuo 12 hours to give an off-white solid, 6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 234.4g, 94.8% yield, m.p. 111 ~ 112.. ;

The reaction equation is as follows:

(2) 3-iodo-6-nitro-1- (tetrahydro -2H- pyran-2-yl) -1H- indazole (I),

5L reaction flask in DMF 700mL, followed by addition of 6-nitro-_1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole (225.0g, 0.91mol, 1.0eq) and potassium hydroxide ( 102.lg, 1.82mol, 2.0eq), ice-cooled below 10 ° C, with stirring, iodine (415.8g, 1.64mol, 1.8eq) was dissolved in DMF 300mL, was added dropwise to the reaction system dropwise over 2 hours, The reaction system was stirred at 30 ° C for 10 hours to complete the reaction, sodium thiosulfate was added (223.0g, 1.41mol, 1.55eq) and 1.50g of potassium carbonate aqueous solution (1.5L), while maintaining the internal temperature below 30 ° C , stirred for 45 minutes at room temperature, water was added with stirring 2L, solid precipitated, stirred for 45 minutes at room temperature, suction filtered, the filter cake was washed with water, 60 ° C and dried in vacuo 12 hours to give a pale yellow solid

(1), 317.2g, 93.4% yield, m.p. 135 ~ 136 ° C.

The reaction equation is as follows:

A Axitinib intermediate (1) in the preparation for the Nepalese Asif applications, including the following synthetic steps:

Synthesis (1) (E) -6- nitro-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

A 5L reaction flask was added DMF (2L), followed by addition of the intermediate (1) (312.0g, 0.84mol), 2- vinylpyridine (127.5g, 1.21mol), N, N- diisopropylethylamine ( 205.3g, 1.59mol), tri-o-tolylphosphine (22.3g, 0.073mol) and palladium chloride (4.9g, 0.028mol), nitrogen, and heated to 100 ° C for 12 hours to complete the reaction, cooled to 45 ° C, isopropanol was added 1L, stirring at 45 ° C for 30 minutes, diluted with water and 5L, stirring at room temperature for I h, suction filtered, washed with water, isopropanol was added to the filter cake 1.2L, stirred at 55 ° C for 30 minutes, then stirred at room temperature for 30 minutes, suction filtered, the filter cake washed with cold isopropanol, 50 ° C and dried under vacuum for 12 hours to give (E) -6- nitro-3- [2- (pyridin _2 _-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole, 275.3g, 94.0% yield, m.p. 175 ~ 176 ^, ¾ NMR (DMSO-Cl6): δ 1.63-1.64 (m, 2H, H4 ‘, H5’), 1.79-1.81 (m, 1H, H5 ‘), 2.05-2.07 (m, 2H, H3’, H4 ‘), 2.44-2.50 (m, 1H , H3 ‘), 3.86-3.90 (m, 2H, H6’), 6.15-6.18 (dd, 1H, H2 ‘), 7.30-7.33 (dd, 1H, pyridine H5), 7.65-7.69 (d, 1H, J = 16Hz, vinyl H2), 7.72-7.74 (d, 1H, pyridine H4), 7.82-7.86 (m, 1H, pyridine H3), 7.96-8.00 (d, 1H, J = 16Hz, vinyl HI), 8.07 -8.10 (dd, 1H, H4), 8.44-8.46 (d, 1H, H5), 8.63-8.64 (d, 1H, pyridine H6), 8.77-8.78 (d, 1H, H7);

The reaction equation is as follows:

Synthesis of (2) (E) -6- amino-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H- pyran-2-yl) -1H- indazole

The reaction equation is as follows:

Synthesis of (3) (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro-pyran-2-yl -2H-) -1Η- indazole

0.62mol) was dissolved in glacial acetic acid 1.3L, dropwise added to the system dropwise over I hour, added dropwise to maintain the internal temperature process 0 ° C, the same temperature for I h, HCl solution was added dropwise at O ° C (112mL of concentrated hydrochloric acid , water 200mL), was added dropwise for 10 minutes, with the temperature for I h, TLC plate tracking point diazonium salt formation reaction (PE: EA = 1: 1). Solution of methylene chloride at 0 ° C and 800mL, dropping time of 5 minutes, potassium iodide (207.3g, l.25mol) and iodine (79.2g, 0.31mol) dissolved in water 600mL, at (TC dropwise added to the system, same temperature for 2 hours to complete the reaction. The reaction system was poured into a mixture of 20% sodium thiosulfate solution (2L) and dichloromethane SOOmL and stirred, layers were separated, the aqueous phase was extracted with dichloromethane frozen (2x800mL ), methylene chloride phases were combined burning, 3M sodium hydroxide solution was added dropwise 3.5L, adjust the aqueous phase pH = 9 ~ 12, and water was added ammonia 200mL 400mL, stirred for 30 minutes, separated and the aqueous phase extracted with dichloromethane ( 2×1.2L), the organic phases were combined, rotary evaporated to dryness, and purified through silica gel to give (E) -6- iodo-3- [2- (pyridin-2-yl) ethenyl] -1- (tetrahydro -2H – pyran-2-yl) -1H- indazole, 176.0g, 65.4% yield, m.p. 142 ~ 143 ° C, 1H NMR (DMS0_d6): δ 1.58-1.61 (m, 2H, H4 ‘, H5,) 1.72-1.78 (m, 1H, H5,), 1.97-2.04 (m, 2H, H3,, H4,), 2.38-2.44 (m, 1H, H3,), 3.79-3.81 (m, 1H, H6,) , 3.88-3.90 (m, 1H, H6,), 5.91-5.94 (dd, 1H, H2,),

7.29-7.31 (m, 1H, pyridine H5), 7.56-7.60 (d, 1H ,, J = 16Hz, vinyl H2), 7.57-7.59 (m, 1H, pyridine H4), 7.69-7.71 (d, 1H, pyridine H3), 7.80-7.84 (m, 1H, H4), 7.89-7.93 (d, 1H, J = 16Hz, vinyl HI), 8.01-8.03 (d, 1H, H5), 8.25 (s, 1H, H7 ), 8.61-8.62 (d, 1H, pyridine H6); reaction equation is as follows:

(4) (E) -N- methyl-2 – {[3- (2- (pyridin-2-yl) ethenyl) _1_ (tetrahydro -2H- pyran-2-yl) -1H- indazole 6-ylthio} benzamide]

The reaction equation is as follows:

(5) Synthesis of axitinib

yield 95.4%, HPLC purity 98.8 % / H NMR (DMS0_d6): δ 2.78 (d, 3H, CH3), 7.05 (dd, 1H), 7.19 (dd, 1H), 7.36-7.23 (m, 3H), 7.50 (dd, 1H), 7.58 ( d, 1H), 7.61 (s, 1H), 7.66 (d, 1H), 7.85-7.76 (m, 1H), 7.96 (d, 1H, J = 16Hz), 8.21 (d, 1H), 8.39 (q, 1H), 8.61 (d, 1H), 13.35 (s, 1H).

The reaction equation is as follows:

…………………….

http://www.scielo.br/scielo.php?pid=S0103-50532014001202186&script=sci_arttext&tlng=en

………………………

http://emuch.net/html/201202/4061970.html

SEE NMR……….

http://orgspectroscopyint.blogspot.in/2015/07/axitinib.html

………..

NMR source apexbt

http://dmd.aspetjournals.org/content/suppl/2014/03/07/dmd.113.056531.DC1/Supplemental__Data_Figures_56531.pdf

NMR..SEE……..http://www.abmole.com/download/axitinib-hnmr.pdf

MASS

References

“Inlyta (axitinib) dosing, indications, interactions, adverse effects, and more”. Medscape Reference. WebMD. Retrieved 25 January 2014.
Wilmes, LJ; Pallavicini, MG; Fleming, LM; Gibbs, J; Wang, D; Li, KL; Partridge, SC; Henry, RG; Shalinsky, DR; Hu-Lowe, D; Park, JW; McShane, TM; Lu, Y; Brasch, RC; Hylton, NM (April 2007). “AG-013736, a novel inhibitor of VEGF receptor tyrosine kinases, inhibits breast cancer growth and decreases vascular permeability as detected by dynamic contrast-enhanced magnetic resonance imaging”. Magnetic Resonance Imaging 25 (3): 319–27. doi:10.1016/j.mri.2006.09.041. PMID 17371720.
Rini, B; Rixe, O; Bukowski, R; Michaelson, MD; Wilding, G; Hudes, G; Bolte, O; Steinfeldt, H; Reich, SD; Motzer, R (June 2005). “AG-013736, a multi-target tyrosine kinase receptor inhibitor, demonstrates anti-tumor activity in a Phase 2 study of cytokine-refractory, metastatic renal cell cancer (RCC)”. Journal of Clinical Oncology ASCO Annual Meeting Proceedings 23 (16S): 4509.
Rugo, HS; Herbst, RS; Liu, G; Park, JW; Kies, MS; Steinfeldt, HM; Pithavala, YK; Reich, SD; Freddo, JL; Wilding, G (August 2005). “Phase I trial of the oral antiangiogenesis agent AG-013736 in patients with advanced solid tumors: pharmacokinetic and clinical results”(PDF). Journal of Clinical Oncology 23 (24): 5474–83. doi:10.1200/JCO.2005.04.192.PMID 16027439.
“FDA Approves Inlyta for Advanced Renal Cell Carcinoma”. Drugs.com. January 27, 2012.
John Fauber, Elbert Chu (Oct 27, 2014). “The Slippery Slope: Is a Surrogate Endpoint Evidence of Efficacy?”. Milwaukee Journal Sentinel/MedPage Today.
Spano, JP; Chodkiewicz, C; Maurel, J; Wong, R; Wasan, H; Barone, C; Létourneau, R; Bajetta, E; Pithavala, Y; Bycott, P; Trask, P; Liau, K; Ricart, AD; Kim, S; Rixe, O (June 2008). “Efficacy of gemcitabine plus axitinib compared with gemcitabine alone in patients with advanced pancreatic cancer: an open-label randomised phase II study”. Lancet 371(9630): 2101–2108. doi:10.1016/S0140-6736(08)60661-3. PMID 18514303.
“Pfizer pancreatic cancer drug fails, trial halted”. Reuters. January 30, 2009.
“Pfizer’s Phase III Trial in mRCC Turns Up Positive Results”. 19 Nov 2010.
“ODAC Unanimously Supports Axitinib for Renal Cell Carcinoma”. 7 Dec 2011.
“INLYTA (axitinib) tablet, film coated [Pfizer Laboratories Div Pfizer Inc]”. DailyMed. Pfizer Laboratories Div Pfizer Inc. September 2013. Retrieved 25 January 2014.
“Inlyta : EPAR – Product Information” (PDF). European Medicines Agency. Pfizer Ltd. 17 December 2013. Retrieved 25 January 2014.
“Inlyta 1 mg 3mg, 5 mg & 7mg film-coated tablets – Summary of Product Characteristics (SPC)”. electronic Medicines Compendium. Pfizer Limited. 5 December 2013. Retrieved25 January 2014.
“PRODUCT INFORMATION INLYTA (axitinib)” (PDF). TGA eBusiness Services. Pfizer Australia Pty Ltd. 5 July 2013. Retrieved 25 January 2014.
Tea Pemovska,Eric Johnson,Mika Kontro,Gretchen A. Repasky,Jeffrey Chen,Peter Wells,Ciarán N. Cronin,Michele McTigue,Olli Kallioniemi,Kimmo Porkka,Brion W. Murray & Krister Wennerberg. “Axitinib effectively inhibits BCR-ABL1(T315I) with a distinct binding conformation”. Nature. doi:10.1038/nature14119.
“FDA Prescribing Information” (PDF). 30 Jan 2012.
Escudier, B; Gore, M. “Axitinib for the Management of Metastatic Renal Cell Carcinoma” (PDF). Drugs in R&d 11 (2): 113–126. doi:10.2165/11591240-000000000-00000. PMC 3585900. PMID 21679004.
Zhang Y (Jan 2014). “Screening of kinase inhibitors targeting BRAF for regulating autophagy based on kinase pathways.”. J Mol Med Rep 9 (1): 83–90.doi:10.3892/mmr.2013.1781. PMID 24213221.
[1]  http://www.cancer.gov/cancertopics/druginfo/axitinib[2]  http://www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm289439.htm[3] Kosugi M, Shimizu T, T. Migita, Chemistry Letters , 1978 , pp 13-14.[4] Organic Process Research & Development 2008 , 12, 869? 876.[5] Furstner A.  Chem. Commun ., 2008 , 2873? 2875.[6] Thorarensen A. ,  Synlett ,    2010  , 2 pp 219 – 222.
[7]  http://en.wikipedia.org/wiki/Heck_reaction  – where you can find the reaction mechanism and many other useful information.
[8] Aoyama, T.,  Synthesis ,    2004  , 8 pp 1183-1186.

http://www.cosmoscience.org/blog/wp-content/uploads/2014/08/GSluggett-Application-of-Topochemical-Principles-and-Solid-State-Photoreactivity.pdf

Raw Material Variation into QbD Risk Assessment

July 9, 2015 10:22 am / 2 Comments on Raw Material Variation into QbD Risk Assessment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Areas of discussion included how expectations for raw material control are evolving within changing regulatory and business paradigms including quality by design (QbD), counterfeiting, complex supply chains, and sourcing changes. discussed risk assessment and mitigation strategies along with supplier risk management plans.

Regulatory Considerations

the lack of a consistent definition of raw materials in regulations pertaining to the pharmaceutical industry. In its Q7 guideline, the International Conference on Harmonisation of Technical Requirements for the Registration of Pharmaceuticals for Human Use (ICH) defines raw materials as “starting materials, reagents, and solvents intended for use in the production of intermediates or APIs.” However, the term as defined by different speakers could cover a wide range of materials including the following:

• starting or source materials (cell lines, viral or bacterial stocks, media components, chemicals, tissues, serum, water)

• in-process materials (resins, buffers, filters, column housings, tubing, reagents)

• excipients

• packaging components, both…

View original post 3,002 more words

FDA Warning Letter on Data Integrity

July 9, 2015 4:13 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

The integrity of data is currently in the focus of international authorities In particular the US FDA issued serious violations in Warning Letters to the companies concerned. Read more about the current complaints in a Warning Letter issued to the API manufacturer VUAB Pharma.

http://www.gmp-compliance.org/enews_04898_FDA-Warning-Letter-on-Data-Integrity_9363,9267,Z-COVM_n.html

For authorities the integrity of data is an essential quality attribute in the manufacture of pharmaceutical products. After some serious deviations international authorities have moved the topic into the centre of their interest. In particular the US FDA issued serious violations in Warning Letters to the companies concerned.

In a current letter to the API manufacturer VUAB Pharma in the Czech Republic the inspector and the authority criticised multiple aspects with regard to “failure to prevent unauthorized access or change to data and to provide controls preventing data omissions”:

‘The firm did not retain complete raw data from testing performed to assure the quality…

View original post 408 more words

Development of monographs for Indian pharmacopoeia

July 8, 2015 1:28 am / Leave a comment

DRUG REGULATORY AFFAIRS INTERNATIONAL

Development of monographs for Indian pharmacopoeia

http://www.ipapharma.org/events/speakerpresentation/8-%20Dr%20S%20C%20Mathur.pdf

View original post

ALOGLIPTIN

July 6, 2015 10:19 am / Leave a comment

ALOGLIPTIN

Alogliptin is a potent, selective inhibitor of DPP-4 with IC50 of <10 nM, exhibits greater than 10,000-fold selectivity over DPP-8 and DPP-9.

Alogliptin (trade name Nesina in the US^[1] and Vipidia in Europe^[2]) is an orally administered anti-diabetic drug in the DPP-4 inhibitor class,^[3] developed by Syrrx, a company which was acquired by Takeda Pharmaceutical Company in 2005. Like other medications for the treatment of Type 2 diabetes, alogliptin does not decrease the risk of heart attack and stroke. Like other members of the gliptin class, it causes little or no weight gain, exhibits relatively little risk of causing hypoglycemia, and exhibits relatively modest glucose-lowering activity. Alogliptin and other gliptins are commonly used in combination with metformin in patients whose diabetes cannot adequately be controlled with metformin alone.^[4]

Clinical study

Alogliptin is a dipeptidyl peptidase-4 inhibitor (DPP-4i) that is designed to slow the inactivation of incretin hormones GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic peptide). ^[5]

A randomized clinical trial reporting in 2011 aimed to determine the efficacy and safety of alogliptin versus placebo and vogliboseamong newly diagnosed Type 2 diabetes patients in Japan. The main outcome indicated that alogliptin was statistically superior to both comparitors.^[6]

A randomized clinical trial reporting in 2012 aimed to demonstrate that alogliptin was “non-inferior” to a “very low fat/calorie traditional Japanese diet” among newly diagnosed Type 2 diabetes patients in Japan. The outcome indicated that both the drug and dietary treatments comparably impacted indicators of the diabetic condition, such as HbA1c levels and glycemic efficacy. The drug treatment had its impact without changing body mass index (BMI), but the dietary treatment was accompanied by a significant reduction in the BMI.^[7]

A randomized clinical trial reporting in 2011 aimed to demonstrate the efficacy of alogliptin as an add-on agent in combination withmetformin and pioglitazone versus simply increasing the dosage of pioglitazone in combination with metformin; in other words, this was a study to look at a three-agent therapy versus a two-agent therapy. The outcome of this study suggested that the addition of alogliptin to metformin and pioglitazone provided superior impact on diabetes biomarkers (e.g. HbA1c) than increasing the dose of pioglitazone in a two agent therapy with metformin.^[8]

Reported adverse events

Adverse events appear to be restricted to mild hypoglycemia based on clinical studies.^[6]^[7]^[8]

Alogliptin is not associated with increased weight, increased risk of cardiovasular events, or heart failure.^[9]^[10]

Market access

In December 2007, Takeda submitted a New Drug Application (NDA) for alogliptin to the United States Food and Drug Adminiistration (USFDA),^[11] after positive results from Phase III clinical trials.^[1] In September of 2008, the company also filed for approval in Japan,^[12] winning approval in April 2010.^[11] The company also filed a Marketing Authorization Application (MAA) elsewhere outside the United States, which was withdrawn in June 2009 needing more data.^[12] The first USFDA NDA failed to gain approval and was followed by a pair of NDAs (one for alogliptin and a second for a combination of alogliptin and pioglitazone) in July 2011.^[11] In 2012, Takeda received a negative response from the USFDA on both of these NDAs, citing a need for additional data.^[11]

In 2013 the FDA approved the drug in three formulations: As a stand-alone with the brand-name Nesina. Combined with metforminusing the name Kazano, and when combined with pioglitazone as Oseni.

Diabetes affects millions of people worldwide and is considered one of the main threats to human health in the 21^st century. In 2006, the World Health Organization (WHO) estimated that over 180 million people worldwide had diabetes, and the number is projected to double by 2030. Over time, uncontrolled diabetes can damage body systems, including the heart, blood vessels, eyes, kidneys and nerves. According to the WHO, approximately 1.1 million people died from diabetes in 2005, and it is estimated that diabetes-related deaths will increase by more than 50% in the next decade. Globally, the socioeconomic burden of diabetes is substantial.

There are two main types of diabetes, designated type 1 and type 2, with type 2 diabetes accounting for over 90% of all diabetes cases globally. Type 1 diabetes is characterized by insulin deficiency, primarily caused by autoimmune-mediated destruction of pancreatic islet β-cells, and type 2 diabetes is characterized by abnormal insulin secretion and concomitant insulin resistance. To prevent the development of ketoacidosis, people with type 1 diabetes must take exogenous insulin for survival. Although those with type 2 diabetes are not dependent on exogenous insulin as much as subjects with type 1 diabetes, they may require exogenous insulin to control blood glucose levels.

As diabetes has become a global health concern, research interest in the condition has rapidly increased. In addition to studies on prevention, many studies with the aim of developing new interventions for the treatment of diabetes, especially type 2 diabetes, have been conducted. Currently available medications for the treatment and management of type 2 diabetes include metformin, sulfonylureas, thiazolidinediones and insulin. However, these therapies are commonly associated with secondary failure and may cause hypoglycemia. Insulin resistance and progressively worsening hyperglycemia caused by reduced β-cell function are major challenges in managing type 2 diabetes. Evidence suggests that patients with insulin resistance do not develop hyperglycemia until their β-cells are unable to produce enough insulin. New agents that can enhance insulin secretion from islet β-cells in a sustained glucose-dependent manner could therefore hold promise for the treatment of type 2 diabetes.

One promising approach is based on inhibition of the serine protease dipeptidyl- peptidase IV (DPP IV), a postproline dipeptidyl aminopeptidase that belongs to the S9b peptidase family of proteolytic enzymes. It is known that DPP IV plays a key role in maintaining glucose homeostasis by controlling the incretin activity of glucagon-like peptide 1 (GLP-I) and glucose-dependent insulinotropic polypeptide (GIP, also known as gastric inhibitory polypeptide). Inhibition of DPP IV is therefore recognized as a novel therapeutic approach for the treatment of type 2 diabetes.

Recently, a series of DPP IV inhibitors were developed. Among these highly potent compounds, alogliptin benzoate (SYR-322) and its analogs demonstrated encouraging antidiabetic efficacy (EP 1586571 (WO 2005/095381); WO 2008/067465; WO 2007/035379, and US 2004/097510).

Alogliptin benzoate can be prepared as described in EP 1586571 (WO 2005/095381) according to the process set forth in Scheme 1 :

Scheme 1

In accordance with this process, 6-Chlorouracil (1) is alkylated with 2- (bromomethyl)benzonitrile in the presence of NaH and LiBr in a mixture of DMF- DMSO to produce the TV-benzyluracil derivative (2) in 54% yield. Compound (2) is further alkylated with iodomethane and NaH in DMF/THF to give the 1 ,3 disubstituted uracil (3) in 72% yield. Subsequent displacement of chlorouracil (IV) with 3(R)- aminopiperidine dihydrochloride in the presence of either NaHCO₃ in hot methanol or K₂CO₃ in aqueous isopropanol provides alogliptin (4), which is isolated as the corresponding benzoate salt by treatment with benzoic acid in ethanol. The overall yield of this three-stage process is -20-25%. One of the disadvantages of above described process is the difficulty to separate and purify mixtures of solvents with high boiling point (for example, DMF/DMSO) for recycling. Another disadvantage is the usage of hazardous materials such as sodium hydride, which requires anhydrous solvents as a reaction media.

Intermediate 2-((6-chloro-3-methyl-2,4-dioxo-3 ,4-dihydropyrimidin- 1 (2H)-yl)methyl) benzonitrile (3) is alternatively obtained by alkylation of 6-chloro-3 methyluracil with 2-(bromomethyl)benzonitrile by means of diisopropylethylamine in hot NMP (WO 2007/035629). Although this process is more technological than the previously described process (EP 1586571), the overall yield is still moderate (50-55%). The problem of mixed solvents (toluene, NMP, diisopropylethylamine) separation persists for this process as well.

………….

http://www.google.com/patents/EP2410855A1?cl=en

EXAMPLE 1

Preparation of (R)-2-((6-(3 -aminopiperidin-l-yl)-3 -methyl-2,4-dioxo-3 ,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 3):

Scheme 3

Preparation of l-(2-isocyanobenzyl)-3-methylurea

2-cyanobenzylamine hydrochloride (90 g) and Dichloromethane (800 ml) were taken into a round bottomed (RB) flask. Methyl isocyanate (45.6 g) was added at 5°C. Triethylamine (81 g) in Dichloromethane (300 ml) was added at the same temperature and stirred at room temperature for 16h. Water (1 L) was added and stirred for 30 min. The obtained solid was collected by filtration and dried in oven at 50°C for 12h. The yield is 85% and the purity 99.8%.

Preparation of l-(2-isocyanobenzyl)-3-methyIpyrimidine-2,4,6(lH,3H,5H)-trione

a). To a stirred solution of 0.11 mol of sodium ethanolate in 80 ml of ethanol abs. was added 0.1 mol of l-(2-isocyanobenzyl)-3-methylurea and 0.1 mol diethyl malonate. The mixture was refluxed for 3-5 h. The cooled residue was acidified with 0.1 M hydrochloric acid (60 ml). The solid which separated was filtered off and recrystallized from ethanol or any suitable solvent. The yield is 78-85% and purity >95%.

b). In an alternate embodiment, l-(2-isocyanobenzyl)-3-methylurea (30 g), acetic acid (105 ml) and malonic acid (18 g) were mixed and heated to 60°C. Acetic anhydride (60 ml) was added at 60°C and heating was continued for two hours at 80°C. The reaction mixture was poured over ice water (300 ml) and the obtained solid was filtered, washed with water (1×500 ml) and methyl-tert-butylether (100 ml). The yield is 60% with 93.4% purity.

The compound thus prepared can be used for the next step without purification or purified by crystallization or column chromatography.

Preparation of 6-chloro-l-(2-isocyanobenzyl)-3-methylpyriinidine-2,4(lH,3H)- dione

a). l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4,6(lH,3H,5H)-trione (30 g) was mixed with phosphorus oxychloride (300 ml) and cooled to 0°C. Water (9 ml) was added slowly, stirred for 10 min. and heated to reflux at 110°C for 5h. Progress of the reaction was monitored by TLC (50% Ethyl acetate/Hexane). On completion of the reaction, phosphorus oxychloride was distilled off. The crude compound was dissolved in dichloromethane (500 ml) and poured into ice water (500 ml) by small portions. The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. The mixture of two isomers (4-chloro and 6-chloro derivatives = 1:1) was isolated and separated by column chromatography using neutral alumina and eluent – 25-50% of ethylacetate and hexane). The off-white solid was obtained, yield – 37%, purity – 99.8%. ¹H NMR corresponds to literature data (J. Med. Chem. 2007, 50, 2297-2300).

b). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (18 mmol), phosphorus oxychloride (85 ml), benzyltriethylammonium chloride (16.5 g, 72 mmol) and phosphorus pentachloride (3.8 g, 18 mol) in acetonitrile (80 ml) was refluxed for 4-5 h with stirring. After evaporation under reduced pressure, the resulting oily residue was mixed with methylene chloride (or chloroform) and the mixture was poured into water and ice (50 ml). The layers were separated and the aqueous layer was extracted with dichloromethane (200 ml). The combined organic extracts were washed with water and brine, dried over sodium sulphate and concentrated under reduced pressure. Crude product was crystallized from THF-hexanes to give desired compound in 70.5% yield.

c). In an alternate embodiment, a solution of l-(2-isocyanobenzyl)-3-methylpyrimidine- 2,4,6(1 H,3H,5H)-trione (13.1 mmol) in POCl₃ (30 ml) was refluxed for 1-3 h. The solvent was concentrated and then partitioned with CH₂Cl₂ (100 ml) and water (100 ml). The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give 6-chloro compound as a solid (-95%). Compound can be also precipitated from concentrated methylene chloride solution by hexanes and used as a crude for the next step or purified by reslurring in isopropanol, filtered off, washed with isopropanol, and dried under vacuum at 55-60° C.

Preparation of (R)-tert-butyl l-(3-(2-isocyanobenzyI)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate

a). 6-chloro- l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (13 g), Dimethylformamide (130 ml), Potassium carbonate (13 g) and tert-butyl (R)-piperidin- 3-ylcarbamate (10.4 g) were heated to 80°C for 7 hrs. The mixture was then allowed to come to room temperature and poured over ice water (500 ml). The obtained solid was filtered and washed with cold water (500 ml). The solid thus obtained was taken in Methyl-tert-butylether (50 ml) stirred for 10 min. filtered and washed with Hexane (50 ml), to give the N-tert-butyloxycarbonyl protected compound in -75% yield. b). In an alternate embodiment, a flask charged with a stir bar, 6-chloro-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (4.10 mmol), (Λ)-3- terrtnityloxycarbonylaminopiperidine (4.64 mmol), K₂CO3 (1.15 g, 8.32 mmol) and DMF (12 mL) was stirred at 75 °C for 6 h. Then, water was added and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give the N-ter/butyloxycarbonyl protected compound in -93-96% yield.

Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile salts

a). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile hydrochloride

The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from previous procedure was dissolved in THF and acidified with 6M hydrochloric acid while maintaining the temperature below 15° C. The resultant slurry was cooled to 0-5° C, stirred at this temperature for 3-5 h and then filtered. The filter cake was washed twice with isopropanol and dried in vacuum at 45-5O⁰C to provide hydrochloride as a white crystalline solid.

b). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile trifluoroacetate

TFA (ImL) was added into the methylene chloride solution of (R)-tert-butyl l-(3-(2- isocyanobenzyl)- 1 -methyl-2,6-dioxo- 1 ,2,3,6-tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate from the above-mentioned procedure. The solution was stirred at room temperature for 1 h and then the mixture was concentrated in vacuo. The residue was dissolved in a small amount of MeOH or isopropanol and the desired salt was precipitated by addition of diisopropyl ether. The solids were filtered off, washed with diisopropyl ether and dried in vacuum at 45-5O⁰C to provide trifluoroacetate as an off- white powder. c). Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile benzoate (Alogliptin)

The crude (R)-tert-butyl l-(3-(2-isocyanobenzyl)-l-methyl-2,6-dioxo-l,2,3,6- tetrahydropyrimidin-4-yl)piperidin-3-yl carbamate was dissolved in ethanol. A solution of benzoic acid in ethanol was added and the mixture was slowly heated to 65-70°C. The solution was stirred at this temperature for Ih and was then crystallized by cooling to 0-5° C and stirring for 12 hrs. The solution was filtered, washed with alcohol. The wet cake was then conditioned under nitrogen for 2 hours. The cake was dried for 8 hrs at 40-50° C to provide the benzoic acid salt of alogliptin as a white crystalline solid.

EXAMPLE 2:

Preparation of (R)-2-((6-(3-aminopiperidin-l-yl)-3-methyl-2,4-dioxo-3,4- dihydropyrimidin-1 (2H)-yl) methyl)benzonitrile (alogliptin) via 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (Scheme 4)

Scheme 4 Preparation of 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)- dione

a). l-(2-isocyanobenzyl)-3-methylurea (0.2 mol) and cyanoacetic acid (0.22 mol) were dissolved in acetic anhydride (400 ml), and the mixture was heated at 80°C for 2 hours. Acetic anhydride was distilled off under reduced pressure and water (200 ml) was added. The mixture was cooled to 0-5 ⁰C and 2N NaOH solution (220 ml) was added and stirring was continued for 2 hours. The obtained solids were filtered off, washed with cold methanol and dried under vacuum. The yield of 6-amino-l-(2- isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione was 72 %.

b). Under nitrogen atmosphere, l-(2-isocyanobenzyl)-3-methylurea (98.4 g) and cyanoacetic acid (80.0 g) was added to N,N-dimethylformamide (836 ml). The mixture was stirred at room temperature and methanesulfonyl chloride (72.8 ml) was added dropwise with stirring at this temperature. The mixture was stirred at room temperature for 4 hrs, cooled with water, and water-isopropanol [2:1 (volume ratio), 1670 ml] was added drop wise. The mixture was stirred under water-cooling for 1 hr, and the precipitated crystals were collected by filtration and dried to give 3-(2-cyano-acetyl)-3- methyl-l-(2-isocyanobenzyl)-urea with 68% yield.

To 3-(2-cyano-acetyl)-3-methyl-l-(2-isocyanobenzyl)-urea (120 g) were added water (962 ml) and 2N aqueous sodium hydroxide solution (24.9 ml), and the mixture was stirred with heating at 80° C for 1 hr. After allowing to cool to room temperature, the crystals were collected by filtration and dried to give 6-amino-l-(2-isocyanobenzyl)-3- methylpyrimidine-2,4(lH,3H)-dione in 76% yield.

c). 6-amino-l-(2-isocyanobenzyl)-3-methylpyrimidine-2,4(lH,3H)-dione (0.1 mol) was mixed with (R)-piperidin-3-yl-carbamic acid tert.-butyl ester hydrochloride (0.1 mol) of the appropriate amine hydrochloride and (R)-piperidin-3-yl-carbamic acid tert.-butyl ester (0.1 mol). The mixture was heated at 100°C and bubbling continued for 3 hr. Water was added to the cooled mixture and the mixture was extracted with methylene chloride. The organic layer was washed with brine, dried over Na₂SO₄, and concentrated to give N-tert-butyloxycarbonyl protected compound in ~93-96% yield.

d). Benzoate salt of alogliptin was prepared as described above. While certain embodiments of the invention have been illustrated and described, it will be clear that the invention is not limited to the embodiments described herein. Numerous modifications, changes, variations, substitutions and equivalents will be apparent to those skilled in the art without departing from the spirit and scope of the present invention as described by the claims, which follow.

………………

Patent EP2410855A1

http://www.google.com/patents/EP2410855A1?cl=en

…………..

http://photo.blog.sina.com.cn/list/blogpic.php?pid=53891ebegd4e8671b28dc&bid=53891ebe0101grmv&uid=1401495230

NMR

SOURCE APEXBT

References

“Takeda Submits New Drug Application for Alogliptin (SYR-322) in the U.S.” (Press release). Takeda Pharmaceutical Company. January 4, 2008. Retrieved January 9, 2008.
Vipidia: EPAR summary for the public (European Medicines Agency)
Feng, Jun; Zhang, Zhiyuan; Wallace, Michael B.; Stafford, Jeffrey A.; Kaldor, Stephen W.; Kassell, Daniel B.; Navre, Marc; Shi, Lihong; Skene, Robert J.; Asakawa, Tomoko; Takeuchi, Koji; Xu, Rongda; Webb, David R.; Gwaltney II, Stephen L. (2007). “Discovery of alogliptin: a potent, selective, bioavailable, and efficacious inhibitor of dipeptidyl peptidase IV”. J. Med. Chem.50 (10): 2297–2300.doi:10.1021/jm070104l.PMID 17441705.
“www.aace.com” (PDF).
http://www.takeda.com/news/2013/20130618_5841.html
Seino, Yutaka; Fujita, Tetsuya; Hiroi, Shinzo; Hirayama, Masashi; Kaku, Kohei (September 2011), “Efficacy and safety of alogliptin in Japanese patients with type 2 diabetes mellitus: a randomized, double-blind, dose-ranging comparison with placebo, followed by a long-term extension study (abstract only)”, Current Medical Research and Opinion 27 (9): 1781–1792,doi:10.1185/03007995.2011.599371,PMID 21806314, retrieved April 26,2012
Kutoh, Eiji; Ukai, Yasuhiro (2012),“Alogliptin as an initial therapy in patients with newly diagnosed, drug naïve type 2 diabetes: a randomized, control trial (abstract only)”, Endocrine(January 17, 2012), doi:10.1007/s12020-012-9596-0, PMID 22249941, retrieved April 26, 2012
Bosi, Emanuele; Ellis, G.C.; Wilson, C.A.; Fleck, P.R. (October 2011), “Alogliptin as a third oral antidiabetic drug in patients with type 2 diabetes and inadequate glycaemic control on metformin and pioglitazone: a 52-week, randomized, double-blind, active-controlled, parallel-group study”, Diabetes, Obesity and Metabolism (October 27, 2011) 13 (12): 1088–1096, doi:10.1111/j.1463-1326.2011.01463.x, retrieved April 26,2012
White WB, Cannon CP, Heller SR et al. (October 2013). “Alogliptin after acute coronary syndrome in patients with type 2 diabetes”. N. Engl. J. Med. 369(14): 1327–35.doi:10.1056/NEJMoa1305889.PMID 23992602.
White WB, Zannad F (January 2014). “Saxagliptin, alogliptin, and cardiovascular outcomes”. N. Engl. J. Med. 370 (5): 484.doi:10.1056/NEJMc1313880.PMID 24482824.
Grogan, Kevin (April 26, 2012),“FDA wants yet more data on Takeda diabetes drug alogliptin”,PharmaTimes (PharmaTimes), PharmaTimes online, retrieved April 26,2012
“GEN News Highlights: Takeda Pulls MAA for Type 2 Diabetes Therapy”. Genetic Engineering & Biotechnology News. June 4, 2009.

EP1083172A1 *	May 26, 1998	Mar 14, 2001	Rimma Iliinichna Ashkinazi	N-substituted derivatives of 5-oxyiminobarbituric acid
US2598936 *	Apr 13, 1950	Jun 3, 1952	Searle & Co	Disubstituted cyanoalkanoylureas and thioureas and methods for their production
US6066641 *	Dec 12, 1995	May 23, 2000	Euro-Celtique S.A.	Aryl thioxanthines
US6248746 *	Jan 7, 1999	Jun 19, 2001	Euro-Celtique S.A.	3-(arylalkyl) xanthines
US20080194593 *	Jan 11, 2008	Aug 14, 2008	Rao Kalla	A2b adenosine receptor antagonists
WO1994003456A1 *	Aug 5, 1993	Feb 17, 1994	Boehringer Ingelheim Kg	Asymmetrically substituted xanthine with adenosine-antagonistic properties
WO2001029010A1 *	Oct 18, 2000	Apr 26, 2001	Amjad Ali	Gram-positive selective antibacterial compounds, compositions containing such compounds and methods of treatment
WO2007035629A2 *	Sep 15, 2006	Mar 29, 2007	Takeda Pharmaceutical	Process for the preparation of pyrimidinedione derivatives
WO2007150011A2 *	Jun 22, 2007	Dec 27, 2007	Smithkline Beecham Corp	Prolyl hydroxylase inhibitors

Alogliptin
Systematic (IUPAC) name

2-({6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl}methyl)benzonitrile
Clinical data
Trade names	Nesina, Vipidia Kazano, Vipidomet (withmetformin) Oseni, Incresync (withpioglitazone)
Pregnancy category	US: B (No risk in non-human studies)
Legal status	℞ (Prescription only)
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	100%
Protein binding	20%
Metabolism	Limited, hepatic (CYP2D6– and3A4-mediated)
Biological half-life	12–21 hours
Excretion	Renal (major) and fecal (minor)
Identifiers
CAS Registry Number	850649-62-6^BENZOATE850649-61-5 FREE BASE
ATC code	A10BH04
PubChem	CID: 11450633
IUPHAR/BPS	6319
ChemSpider	9625485
UNII	JHC049LO86
KEGG	D06553
ChEBI	CHEBI:72323
ChEMBL	CHEMBL376359
Synonyms	SYR-322
Chemical data
Formula	C₁₈H₂₁N₅O₂
Molecular mass	339.39 g/mol

Alogliptin benzoate

MF:	C18H21N5O2.C7H6O2
MW:	461.519

Melting Point:	185-188°C
Optical Rotation:	-56.3° (c=1, MeOH)

Solubility:Soluble in MeOH; Insoluble in ACN

850649-62-6^CAS

Alogliptin

- Synonyms:SYR-322
- ATC:A10BH04
Use:antidiabetic, DPP-4 inhibitor
Chemical name:2-[[5-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-2H-pyrimidin-1(2H)-yl]methyl]benzonitrile
Formula:C₁₈H₂₁N₅O₂

MW:339.40 g/mol
CAS-RN:850649-61-5

Derivatives

benzoate

Formula:C₁₉H₁₉NO₂
MW:293.37 g/mol
CAS-RN:850649-62-6

Synthesis Path

Substances Referenced in Synthesis Path

CAS-RN	Formula	Chemical Name	CAS Index Name
22115-41-9	C₈H₆BrN	2-(bromomethyl)benzonitril
	C₁₂H₈ClN₃O₂	2-[[6-chloro-3,4-dihydro-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile
	C₁₃H₁₀ClN₃O₂	2-[[6-chloro-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]benzonitrile
4270-27-3	C₄H₃ClN₂O₂	6-chloro-2,4(1H,3H)-pyrimidinedione
74-88-4	CH₃I	methyl iodide	Methane, iodo-
127294-73-9	C₅H₁₂N₂	(3R)-3-piperidinamine

Trade Names

Country	Trade Name	Vendor	Annotation
J	Nesina	Takeda ,2010

Formulations

tabl. 12.5 and 25 mg

References

- Feng, J. et al.: J. Med. Chem. (JMCMAR) 50, 2297-2300 (2007).
- WO 2 005 095 381 (SYRRX; 13.10.2005; appl. 15.12.2004; USA-prior. 15.3.2004).
- WO 2 010 109 468 (MAPI Pharma; 30.9.2010; appl. 25.3.2010; USA-prior. 26.3.2009).

solid preparation comprising Alogliptin and Pioglitazone:
- US 20 100 092 551 (Takeda Pharm.; 15.4.2010; appl. 30.1.2008; J-prior. 1.2.2007).

solid preparation comprising Alogliptin and Metformin:
- US 20 200 136 127 (Takeda Pharm.; 3.6.2010; appl. 16.7.2008; J-prior. 19.7.2007).

09b37-misc2b027 LIONEL MY SON

He was only in first standard in school when I was hit by a deadly one in a million spine stroke called acute transverse mylitis, it made me 90% paralysed and bound to a wheel chair, Now I keep him as my source of inspiration and helping millions, thanks to millions of my readers who keep me going and help me to keep my son happy

GEMIGLIPTIN

July 6, 2015 4:50 am / Leave a comment

GEMIGLIPTIN

1-[2(S)-Amino-4-[2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]-4-oxobutyl]-5,5-difluoropiperidin-2-one

PHASE 3, DPP-IV inhibitor, Lg Life Sciences Ltd.

CAS 911637-19-9

Mol. Formula: C18H19F8N5O2

Mol. Weight:489.36

Gemigliptin (rINN), previously identified as LC15-0444, is an oral anti-hyperglycemic agent (anti-diabetic drug) of the new dipeptidyl peptidase-4 (DPP-4) inhibitor class of drugs.^[1] It is well known that glucose lowering effects of DPP-4 inhibitors are mainly mediated by GLP-1 and gastric inhibitory polypeptide (GIP) incretin hormones which are inactivated by DPP-4.

Gemigliptin was initially developed solely by LG Life Sciences. In 2010, Double-Crane Pharmaceutical Co. (DCPC) joined with LGLS to co-develop the final compound and collaborate on the marketing of the drug in China. LGLS also announced on Nov., 2010 that NOBEL Ilac has been granted rights to develop and commercialize gemigliptin in Turkey.

Gemigliptin, a dipeptidyl peptidase IV (CD26; DPP-IV; DP-IV) inhibitor, is currently undergoing phase III clinical trials at LG Life Sciences as an oral treatment for type II diabetes. The company is also testing the compound in phase II/III clinical studies for the treatment of patients with cisplatin-induced acute kidney injury.

DPP IV inhibitors have glucose-lowering effects mediated by GLP-1 incretin hormone which is inactivated by DPP IV. In 2010, gemigliptin was licensed to Beijing Double-Crane Pharmaceutical by LG Life Sciences for distribution and supply in China for the treatment of type 2 diabetes.

A New Drug Application (NDA) for gemigliptin in the treatment of type 2 diabetes was submitted to the Korea Food & Drug Administration (KFDA) in July 2011. Then on June 27, 2012, the KFDA has approved the manufacture and distribution of LG Life Sciences’ diabetes treatment, Zemiglo, the main substance of which is gemigliptin. Clinical trials for evaluating the safety and efficacy of gemigliptin in combination with metformin have been completed.

…………

Efficient synthesis of gemigliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus, has been developed. Gemigliptin were prepared from two key API starting materials, DP18 and DP57, in 75~80% yield and >99% purity over three steps under the GMP control: coupling, deprotection of N-Boc group, and final crystallization with L-tartaric acid. All steps were conducted in the same solvent system and the intermediates were isolated by simple filtration without distillation of solvent. The established process was validated obviously through the three consecutive batches for a commercial production.

………..IN CASE IMAGES NOT VISIBLE …….SEE THIS AT ………http://www.allfordrugs.com/2015/07/06/gemigliptin/

GO TO MY OTHER SITE FOR SYNTHESIS

Clinical data
(3S)-3-amino-4-(5,5-difluoro-2-oxopiperidino)-1-[2,4-di(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-7-yl]butan-1-one
Routes of administration	Oral
Pharmacokinetic data
Bioavailability	94% (rat), 73% (dog), 26% (monkey)
Biological half-life	3.6 h (rat), 5.2 h (dog), 5.4 h (monkey)
Identifiers
CAS Registry Number	911637-19-9
ATC code	A10 BH06
PubChem	CID: 11953153
ChemSpider	10127461
UNII	5DHU18M5D6
Synonyms	LC15-0444
Chemical data
Formula	C₁₈H₁₉F₈N₅O₂
Molecular mass	489.36 g/mol

……………….

History

The NDA for gemigliptin was submitted to KFDA in July, 2011 and it was approved on June 27, 2012. By the end of 2012, gemigliptin will be marketed in Korea as Zemiglo which is the fifth new DPP-4 inhibitor diabetes treatment in the world.

Mechanism of action

DPP-4 is a serine protease located on the cell surfaces throughout the body. In plasma, DPP-4 enzyme rapidly inactivates incretins including GLP-1 and GIP which are produced in the intestine depending on the blood glucose level and contribute to the physiological regulation of glucose homeostatis. Active GLP-1 and GIP increase the production and release of insulin by pancreatinc beta cells. GLP-1 also reduces the scretion of glucacon by pancreatic alpha cells, thereby resulting in a decreased hepatic glucose production. However these incretins are rapidly cleaved by DPP-4 and their effects last only for a few minutes. DPP-4 inhibitors block the cleavage of the gliptins and thus lead to an increasee insulin level and a reduced glucagon level in a glucose-dependent way. This results in a decrease of fasting and postprandial glycemia, as well as HbA1c levels.^[2]

Preclinical studies

Gemigliptin is a competitive, reversible DPP-4 inhibitor (IC50 = 16 nM) with excellent selectivity over other critical human proteases such as DPP-2, DPP-8, DPP-9, elastase,trypsin, urokinase and cathepsin G. Gemigliptin was rapidly absorbed after single oral dosing and the compound was eliminated with a half-life of 3.6 h, 5.2 h, and 5.4 h in the rat, dog, and monkey, respectively.

The bioavailability of gemigliptin in the rat, dog, and monkey was species-dependent with the values of 94%, 73%, and 26%, respectively. Following the oral administration of gemigliptin in the rat, dog and monkey, about 80% inhibition of plasma DPP-4 activity were observed at the plasma levels of 18 nM, 14 nM and 4 nM, respectively.

In the diet-induced obese (DIO) mice, gemigliptin reduced glucose excursion during OGTT in a dose dependent manner with the minimum effective dose of 0.3 mg/kg and enhanced glucose-stimulated plasma GLP-1 increase in a dose dependent manner reaching the maximum effect at the dose of 1 mg/kg.

Following 4 week oral repeat dosing in the DIO mice, gemigliptin reduced significantly HbA1c with the minimum effective dose of 3 mg/kg. In the beagle dog, gemigliptin significantly enhanced active GLP-1, decreased glucagon, and reduced glucose excursion during OGTT following a single dosing.

Studies on animals suggest its positive effect on hepatic and renal fibrosis .^[3]^[4] Data on human patients are still inconclusive .^[5]

Clinical studies

The dose-range finding phase 2 study was performed and 145 patients (91men and 54 women) with type 2 diabetes mellitus were enrolled. All three doses (50,100 and 200 mg groups) of gemigliptin significantly reduced the HbA_1c from baseline compared to the placebo group without a significant difference between the doses.

Subjects with a higher baseline HbA_1c (≥8.5%) had a greater reduction in HbA_1c. Insulin secretory function, as assessed using homeostasis model assessment-beta cell, C-peptide and the insulinogenic index, improved significantly with gemigliptin treatment. Insulin sensitivity, as assessed using homeostasis model assessment-insulin resistance, also improved significantly after 12 weeks of treatment.

The 50 and 200 mg groups had significantly reduced total cholesterol and low-density lipoprotein cholesterol levels at 12 weeks compared to the placebo group.

The incidences of adverse events were similar in all study subjects. Gemigliptin monotherapy (50 mg for 12 weeks) improved the HbA_1c, FPG level, oral glucose tolerance testresults, β-cell function and insulin sensitivity measures, and was well tolerated in subjects with type 2 diabetes.

Results of Phase 3 clinical trials which have been finished recently will be updated near future.

…………..

WO 2006104356

http://www.google.co.in/patents/WO2006104356A1?cl=en

EXAMPLE 83: Synthesis of l-(f2SV2-amino-4-r2.4-bisftrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7f6H^‘)

-yl1-4-oxobutyll-5.5-difluoropiperidin-2-one [1960]

[1961] 21 mg of the title compound was obtained in a yield of 56% at the same manner as in EXAMPLE 1, except that 42 mg (0.071 mmol) of t-butyl

{(lS)-3-[2,4-bis(trifluoromethyl)-5,8-dihydropyrido[3,4-d]pyrimidin-7(6H)-yl]-l-[(5,5

-difluoro-2-oxpiperidin-l-yl)methyl]-3-oxpropyl}carbamate obtained in

PREPARATION 143 was used. [1962] ¹K NMR (CD₃OD) δ 5.05-4.92 (2H, m), 3.98-3.91 (2H, m), 3.85-3.79 (2H, m),

3.70-3.59 (2H, m), 3.54-3.48 (IH, m), 3.36-3.33 (2H, m), 3.24 (IH, bra), 3.14 (IH, bra), 2.83-2.76 (IH, m), 2.72-2.53 (3H, m), 2.43-2.34 (2H, m) [1963] Mass (m/e) 490 (M+l)

[1964]

[1965] PREPARATION 144: Synthesis of t-butyl

(riSV3-r2.4-bisrtrifluoromethylV5.8-dihvdropyridor3.4-d]pyrimidin-7r6HVyl]-l-(rr2 S)-2-methyl-5-oxomorpholin-4-yl1methyl 1 -3-oxpropyl 1 carbamate

[1966] 14 mg of the title compound was obtained in a yield of 17% at the same manner as in PREPARATION 45, except that 43.7 mg (0.138 mmol) of (3S)-3-[(t-butoxycarbonyl)amino]-4-[2(S)-2-methyl-5-oxomoφholin-4-yl]-butanoic acid obtained in PREPARATION 55 and 42.5 mg (0.138 mmol) of 2,4-bis(trifluoromethyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidine hydrochloric acid salt (product of PREPARATION 127) were used.

[1967] ¹K NMR (CDCl₃) δ 5.85-5.83 (IH, m), 5.09-4.92 (IH, m), 4.95-4.78 (IH, m),

4.23-4.08 (3H, m), 4.04-3.76 (3H, m), 3.73-3.66 (IH, m), 3.46-3.38 (IH, m), 3.36-3.21 (2H, m), 3.18-3.10 (2H, m), 2.96-2.81 (IH, m), 2.61-2.50 (IH, m), 1.43-1.41 (9H, m), 1.28-1.24 (3H, m)

[1968] Mass (m/e) 470 (M+l-Boc)

…………..

WO 2012030106

https://www.google.com/patents/WO2012030106A2?cl=en

Reaction Scheme 1

PREPARATION 1: Synthesis of diethyl 2,2-difluoropentanedioate

To a solution of ethyl bromodifluoroacetate (33.2 g) in tetrahydrofuran (94.0 g) was added ethyl acrylate (8.2 g) and copper powder (10.9 g). After heating to 50℃, TMEDA (9.5 g) was added dropwise and the reaction mixture was then stirred for 3 hours at the same temperature. Upon disappearance of ethyl acrylate as the starting material, to the reaction solution was added methyl t-butyl ether (MTBE, 73.7 g) followed by addition of 10% aqueous ammonium chloride solution (49.8 g) dropwise, and the mixture was then stirred for 30 minutes. The remaining copper residue was removed by filtration through a celite, and methyl t-butyl ether (MTBE, 66.3 g) was added to separate the layers. The separated organic layer was washed successively with 10% aqueous NH₄Cl solution (66.3 g) and 3 N aqueous hydrochloric acid solution (99.6 g) in order and then distilled under reduced pressure to obtain 55.0 g of the desired title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.26 (t, J=7.2 Hz, 3H), 1.37 (t, J=7.2 Hz, 3H), 2.37-2.49 (m, 2H), 2.55 (t, J=7.2 Hz, 2H), 4.16 (q, J=7.2 Hz, 2H), 4.29 (q, J=7.2 Hz, 2H).

PREPARATION 2: Synthesis of ethyl 4,4-difluoro-5-hydroxypentanoate

14.8 g of the compound obtained from the above Preparation 1 was diluted with ethanol (20.4 g) and tetrahydrofuran (69.1 g) and then cooled to 0℃. To this solution was slowly added sodium borohydride (NaBH₄, 3.5 g) stepwise while keeping the internal temperature below 30℃. After confirming completion of the reaction by ¹H NMR, the reaction solution was cooled to the temperature of 10℃ and 10% aqueous ammonium chloride solution (77.7 g) was slowly added. The remaining boron compound was filtered through celite, and the filtrate was distilled under reduced pressure to remove tetrahydrofuran. Then, ethyl acetate (105.2 g) was added to separate the layers, and the organic layer was distilled under reduced pressure to obtain 10.8 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.23 (t, J=7.2 Hz, 3H), 2.15-2.29 (m, 2H), 2.49 (t, J=7.2 Hz, 2H), 3.69 (t, J=12.0 Hz, 2H), 4.12 (q, J=4.0 Hz, 2H).

EXAMPLE 1: Synthesis of ethyl 4,4-difluoro-5-{[(trifluoromethyl)sulfonyl]oxy}- pentanoate

To the solution of 10.8 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (100.2 g) was added pyridine (7.0 g), and then the mixture was cooled to -5.0℃. After completion of cooling, trifluoromethane sulfonic acid anhydride (20.1 g) was slowly added dropwise while keeping the reaction temperature below 6.3℃. After stirring the reaction solution for 30 minutes, 1.5 N hydrochloric acid solution was added dropwise at 0℃ to separate the layers. The aqueous layer as separated was back-extracted twice with dichloromethane (33.4 g), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 19.7 g of the title compound as a yellow oil.

¹H NMR (500 MHz, CDCl₃) δ 1.27 (t, J=7.2 Hz, 3H), 2.29-2.39 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 4.55 (t, J=11.6 Hz, 2H).

EXAMPLE 2-1: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 100.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (300.0 ml) was added pyridine (65.7 g), and the mixture was then cooled to -10.0℃. After completion of cooling, nonafluorobutanesulfonic anhydride (477.4 g) was slowly added dropwise. After stirring the reaction solution for 3 hours, 1.0 N hydrochloric acid solution (300.0 ml) was added dropwise to separate the layers. The aqueous layer as separated was back extracted once with dichloromethane (500.0 ml), and the extracts were combined with the organic layer separated from the above and then distilled under reduced pressure to obtain 177.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.26 (t, 3H, J=7.3 Hz), 2.30-2.36 (m, 2H), 2.58 (t, 2H, J=7.4 Hz), 4.16 (q, 2H, J=7.3 Hz), 4.57 (t, 2H, J=11 Hz).

EXAMPLE 2-2: Synthesis of ethyl 4,4-difluoro-5-{[(nonafluorobutyl)sulfonyl]- oxy}pentanoate

To the solution of 500.0 g of the compound, as obtained from the above Preparation 2, dissolved in dichloromethane (1000.0 ml) was added triethylamine (389.0 g), and the mixture was then cooled to 0℃. After completion of cooling, perfluorobutanesulfonyl chloride (948.80 g) was slowly added dropwise. The reaction solution was stirred for 3 hours at room temperature, distilled under reduced pressure, dissolved in methyl t-butyl ether (MTBE, 3000.0 ml) and then washed three times with water. The organic layer thus obtained was dehydrated with magnesium sulfate, filtered through a celite and then distilled under reduced pressure to obtain 960.0 g of the title compound.

EXAMPLE 3: Synthesis of methyl (2S)-2-[(tert-butoxycarbonyl)amino]-4-oxo- pentanoate

To 25.0 g of the starting material, (3S)-3-[(t-butoxycarbonyl)amino]-4-oxo- pentanoic acid, was added t-butanol (96.9 g) followed by the addition of Boc₂O (25.4 g) and dimethylaminopyridine (DMAP, 62.0 g, 0.5 mol%) at room temperature, and the reaction mixture was then stirred for 23 hours at 40℃. Upon completion of the reaction, ethylene dichloride (62.3 g) in t-butanol was added, and the mixture was then distilled under reduced pressure to obtain 30.7 g of the title compound.

¹H NMR (400 MHz, CDCl₃) δ 1.45 (s, 9H), 1.47 (s, 9H), 2.71 (dd, J=4.8, 16.4 Hz, 1H), 2.88 (dd, J=4.4, 16.4 Hz, 1H), 3.75 (s, 3H), 4.53 (m, 1H), 5.44 (br d, J=8.0 Hz, 1H).

EXAMPLE 4: Synthesis of tert-butyl (3S)-3-[(tert-butoxycarbonyl)amino]-4-hydroxy- butanoate

30.7 g of the compound obtained from the above Example 3 was dissolved in ethanol (112.3 g) and, after lowering the internal temperature to 10.5℃ sodium borohydride (NaBH₄, 5.7 g) was slowly added dropwise. This reaction solution was stirred while maintaining the temperature below 22℃. After confirming completion of the reaction by ¹H NMR and TLC, to the reaction solution was slowly added 3.0 N hydrochloric acid solution (30.7 g) dropwise at the internal temperature of 10℃ followed by addition of diluted 0.2% hydrochloric acid solution (100.0 g). The reaction solution was adjusted to pH 3~4 with addition of 9.0% aqueous hydrochloric acid solution, and then back-extracted twice with ethyl acetate (100.0 g) and toluene (44.0 g). The organic layer thus obtained was distilled under reduced pressure to obtain 25.1 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.48-2.57 (m, 2H), 3.69 (d, J=4.9 Hz, 1H), 3.97 (m, 1H), 5.22 (bs, 1H).

EXAMPLE 5: tert-butyl (3S)-[(tert-butoxycarbonyl)amino]-4-[(methylsulfonyl)oxy]- butanoate

To 25.1 g of the compound obtained from the above Example 4 was added dichloromethane (133.0 g) and triethylamine (148.0 g), and the mixture was then cooled to 0℃. To this reaction solution was slowly added methanesulfonyl chloride (11.8 g) diluted with dichloromethane (39.9 g) dropwise for 50 minutes while maintaining the internal temperature below 12℃. After completion of the reaction, the reaction solution was washed with 0.5 N aqueous hydrochloric acid solution (120.0 g) and water (100.4 g), and then distilled under reduced pressure to obtain 31.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.46 (s, 9H), 2.62 (d, J=6.0 Hz, 2H), 3.04 (s, 3H), 4.21 (m, 1H), 4.30 (d, J=5.2 Hz, 2H), 5.16 (br d, J=7.2 Hz, 1H).

EXAMPLE 6: Synthesis of tert-butyl (3S)-4-azido-3-[(tert-butoxycarbonyl)amino]- butanoate

Sodium azide (NaN₃, 11.6 g) was diluted with dimethylacetamide (DMAc, 260.0 g). After elevating the internal temperature to 80℃, a solution of 31.5 g of the compound, as obtained from the above Example 5, diluted with dimethylacetamide (DMAc, 45.0 g) was added thereto. The reaction proceeded at 80℃ for 2 hours. To the reaction solution were added toluene (251.0 g) and water (320.0 g) to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 24.0 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ 1.47 (s, 9H), 1.49 (s, 9H), 2.49 (d, J=6.0 Hz, 2H), 3.44-3.55 (m, 2H), 4.09 (br s, 1H), 5.14 (br s, 1H).

EXAMPLE 7: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

To 21.0 g of the compound obtained from the above Example 6 was added tetrahydrofuran (93.3 g) followed by the addition of triphenylphosphine (PPh₃, 21.0 g) at 40℃, the mixture was stirred for 2 hours at the same temperature, and water (3.8 g) was then added thereto. The reaction solution was distilled under reduced pressure, and the resulting triphenylphosphine oxide solid was diluted with toluene (26.0 g) and n-hexane (41.0 g), and then filtered off. The filtrate was adjusted to pH 2~3 with 1.0 N aqueous hydrochloric acid solution (110.0 g) and then subjected to separation of the layers. To remove any residual triphenylphosphine oxide solid, the aqueous layer obtained above was washed with dichloromethane (100.0 g) and then adjusted to pH 8~9 with 28% aqueous ammonia solution (7.6 g). The aqueous solution thus obtained was extracted with dichloromethane (100.0 g) and distilled under reduced pressure to obtain 8.5 g of the title compound as a white solid.

¹H NMR (500 MHz, CDCl₃) δ 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 8: Synthesis of N,N-dibenzyl-L-N(Boc)-aspartamide 4-tert-butyl ester

N-Boc-L-aspartic acid 4-t-butyl ester (29.0 g, 0.10 mol) was added to THF (200 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (13.0 ml, 0.10 mol) followed by addition of N-methyl morpholine (12.0 ml, 0.10 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise dibenzylamine (21.1 ml, 0.11 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (300.0 mL) and 1 N hydrochloric acid to separate the layers, and distilled under reduced pressure to precipitate a solid. The solid was filtered and washed with ethyl acetate (100 ml), and then the washings were concentrated by distillation again under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (41.7 g, 0.89 mol).

¹H NMR (400 MHz, CDCl₃) δ: 7.32 (m, 5H), 7.20 (m, 5H), 5.39 (d, J=7.2 Hz, 1H), 5.30 (m, 1H), 4.87-4.77 (m, 2H), 4.48-4.39 (m, 2H), 2.72 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.56 (dd, J=15.8 Hz, J=6.4 Hz, 1H), 1.43 (s, 9H), 1.37 (s, 9H).

Mass (ESI, m/z): 491 (M+Na), 469 (M+H), 413 (M-55).

EXAMPLE 9: Synthesis of N, N-diallyl-L-N(Boc)-aspartamide 4-tert-butyl ester

L-N(Boc)-aspartic acid 4-t-butyl ester (5.00 g, 17.3 mol) was added to THF (50 ml). After cooling to temperature below -5℃, to the reaction solution was added isobutylchloroformate (2.26 ml, 17.3 mol) followed by addition of N-methyl morpholine (1.90 ml, 17.3 mol) dropwise, and the reaction mixture was stirred for over 30 minutes. To the reaction mixture was added dropwise diallylamine (2.35 ml, 19.0 mol), and the mixture was then stirred for over 3 hours and monitored for the reaction progress by TLC (EtOAc: Hexane=1:4). Upon completion of the reaction, the reaction solution was stirred with addition of ethyl acetate (60 ml) and 1 N hydrochloric acid and, after separating the layers, concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (6.0 g, 16.3 mol).

¹H NMR (400 MHz, CDCl₃) δ: 5.78 (m, 2H), 5.30 (m, 1H), 5.23-5.11 (m, 1H), 5.30 (m, 1H), 4.93 (m, 1H), 4.11-3.84 (m, 4H), 2.68 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 2.51 (dd, J=15.8 Hz, J=8.0 Hz, 1H), 1.44 (s, 9H), 1.42 (s, 9H).

Mass (ESI, m/z): 391 (M+Na), 369 (M+H), 313 (M-55).

EXAMPLE 10: Synthesis of N,N-dibenzyl-4-amino-3(S)-N(Boc)-aminobutanoic acid 4-tert-butyl ester

10.0 g of the compound obtained from the above Example 8, Ru₃(CO)₁₂ (136 mg, 1mol%), and diphenylsilane (19.7 ml, 106.7 mmol) were added to tetrahydrofuran (50 ml), and the reaction solution was stirred under reflux for over 40 hours. The reaction solution was extracted with ethyl acetate (200 ml) and concentrated by distillation under reduced pressure. The residue was then subjected to silica gel column to obtain the purified desired product (4.7 g, 10.5 mmol).

¹H NMR (400 MHz, CDCl₃) δ: 7.31-7.20 (m, 10H), 5.12 (bs, 1H), 3.90 (bs, 1H), 3.63 (d, J=12.0 Hz, 2H), 3.48 (d, J=12.0 Hz, 2H), 3.24 (m, 1H), 3.16 (bs, 1H), 2.42 (m, 2H), 1.81 (m, 1H), 1.59 (m, 9H), 1.46 (s, 9H), 1.06 (s, 9H).

Mass (ESI, m/z): 455 (M+H), 441 (M-13).

EXAMPLE 11: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- 4-oxobutanoate

360.0 g of the starting material, N-Boc-Asp(O-t-Bu)OH, together with Boc₂O (353.0 g) and ammonium bicarbonate (NH₄HCO₃, 123.9 g) was added to dimethylformamide (1174.6 g), and pyridine (61.0 g) was added dropwise thereto at room temperature, and the reaction mixture was then stirred for about 3 hours. Upon completion of the reaction, water (1440 ml) and toluene (1800 ml) were added to the reaction solution and stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to remove t-butanol and toluene to obtain the title compound, which was directly used in the next reaction.

EXAMPLE 12: Synthesis of (S)-tert-butyl 3-(tert-butoxycarbonylamino)-3-cyanopropanoate

To the compound obtained from Example 11 was added dimethylformamide (1019.5 g) followed by addition of cyanuric chloride (112.0 g) dropwise for 1.5 hours at temperature below 25℃. The reaction solution was stirred for one hour at room temperature, and then 0.1 N aqueous sodium hydroxide solution (1850.0 g) and toluene (1860 ml) were added thereto to separate the layers. The organic layer thus obtained was washed once again with water (700 ml) and then distilled under reduced pressure to obtain 318.3 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.44 (s, 9H), 1.45 (s, 9H), 2.45 (d, J=6.1 Hz, 2H), 2.77 (d, J=5.5 Hz, 2H), 3.87 (br s, 1H), 5.22 (br s, 1H).

EXAMPLE 13: Synthesis of tert-butyl (3S)-4-amino-3-[(tert-butoxycarbonyl)amino]- butanoate

To 212.1 g of the compound obtained from the above Example 12 was added acetic acid (4000 ml) followed by addition of 20 wt% Pd(OH)₂ (1.1 g) at 40℃. The mixture was stirred for 8 hours while keeping the internal temperature below 45℃ and 3 atmospheric pressure of hydrogen. Upon completion of the reaction, the reaction solution was distilled under reduced pressure to remove acetic acid, diluted with toluene (640 L) and then filtered through a celite. To the filtrate was added 0.25 N aqueous hydrochloric acid solution (1060 ml) to separate the layers. The aqueous layer thus obtained was basified with aqueous ammonia solution (543.1 g) and then extracted with methyl t-butyl ether (MTBE, 1000 ml). The organic layer thus obtained was distilled under reduced pressure to obtain 185.0 g of the title compound.

EXAMPLE 14: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid t-butyl ester

Triethylamine (13.2 g) was added to 16.0 g of the compound obtained from the above Example 1 or 2-1 or 2-2, and 14.1 g of the compound obtained from the above Example 7 or 13, and the mixture was then stirred for 21 hours at 40℃. Then, dichloromethane (154.8 g) and acetic acid (18.3 g) were added, and the mixture was stirred for 5 hours at room temperature. To the resulting reaction solution was added 0.5 N aqueous hydrochloric acid solution (116.8 g) and then, the mixture was stirred for 30 minutes to separate the layers. The organic layer thus obtained was distilled under reduced pressure to obtain 23.6 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.42 (s, 9H), 1.46 (s, 9H), 2.27 (m, 2H), 2.40-2.64 (m, 4H), 3.20 (dd, J=4.3, 13.5 Hz, 1H), 3.56-3.70 (m, 2H), 3.76-3.91 (m, 2H), 4.16 (m, 1H), 5.20 (d, J=8.6 Hz, 1H).

EXAMPLE 15: Synthesis of 3-t-butoxycarbonylamino-4-(5,5-difluoro-2-oxo- piperidin-1-yl)-butyric acid

23.6 g of the compound obtained from the above Example 14 was added to dichloromethane (20.0 g) followed by addition of H₃PO₄ (30.0 g), and the mixture was stirred for 16 hours at room temperature. After confirming the detachment of all of t-butyl group and t-butyloxycarbonyl group, the reaction solution was adjusted to pH 7.0~8.0 with 10 N aqueous hydrogen peroxide, and Boc₂O (16.0 g) was added thereto. After completion of the addition, 10 N aqueous hydrogen peroxide was used to maintain the pH of the reaction solution at 8.0~9.0. After stirring for 3 hours, the resulting sodium phosphate was filtered off, and the filtrate was then adjusted to pH 2.0~3.0 with 3.0 N aqueous hydrochloric acid solution. The resulting solid was filtered and dried under nitrogen to obtain 14.5 g of the title compound.

¹H NMR (500 MHz, CDCl₃) δ: 1.32 (s, 9H), 2.20-2.43 (m, 6H), 3.26-3.31 (m, 2H), 3.61 (m, 1H), 3.81 (m, 1H), 4.02 (m, 1H), 6.73 (d, J=8.6 Hz, 1H), 12.16 (s, 1H).

For the title compound resulting from the above, its enantiomeric isomers―i.e. S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess of the enantiomeric isomers (S vs. R form) (enantiomeric excess; ee) was then calculated as being ee > 99%. On the other hand, in case of the Comparative Example prepared according to the prior method based on WO 06/104356, as described below, the excess (ee) of enantiomeric isomers (S vs. R form) was 80%. From this, it can be identified that the compound of formula (2) having an optically high purity could be obtained according to the method of the present invention.

COMPARATIVE EXAMPLE 1: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

COMPARATIVE EXAMPLE 1-1: Synthesis of methyl 5-amino-4,4-difluoro- pentanoate HCl

To 10.0 g of the compound obtained from Example 1 was added 40 ml of anhydrous ammonia solution (7 M solution in methanol), and the mixture was stirred for 3 hours. The reaction solution was distilled and 30 ml of hydrochloric acid solution saturated with methanol was added dropwise thereto. The reaction mixture was stirred at room temperature and then distilled to obtain 7.2 g of the title compound as a white solid.

¹H NMR (500 MHz, CD₃OD) δ: 2.35 (m, 2H), 2.59 (t, J=7.6 Hz, 2H), 3.49 (t, J=15.3 Hz, 2H), 3.68 (s, 3H).

COMPARATIVE EXAMPLE 1-2: Synthesis of 3-t-butoxycarbonylamino-4-(5,5- difluoro-2-oxo-piperidin-1-yl)-butyric acid t-butyl ester

To the solution of the compound (1.93 g), as obtained from the above Example 4, dissolved in dichloromethane (20.0 g) and H₂O (4.0 g) were added NaBr (0.8 g) and TEMPO (11 mg, 1 mol%). To this reaction solution was slowly added a solution of 5% NaOCl (11.5 g) and NaHCO₃ (1.7 g) dissolved in H₂O (12.0 g) dropwise for about 2 hours while maintaining the temperature below 5℃. Upon completion of dropwise addition, the reaction solution was stirred for 30 minutes to separate the layers. To the organic layer thus obtained was added the compound (1.6 g) obtained from the above Comparative Example 1-1. After stirring for 15 minutes at room temperature, NaBH(OAc)₃ (2.23 g) was added to the reaction solution. After stirring for about 19 hours, 10% aqueous NaHCO₃ solution (20.0 g) and 0.5 N aqueous hydrochloric acid solution (20.0 g) were added dropwise to the reaction solution to separate the layers. The organic layer thus obtained was dehydrated under anhydrous MgSO₄ to obtain 2.0 g (yield 73%) of the same title compound as Example 14, as a yellow solid. For the title compound resulting from the above, its enantiomeric isomers―i.e., S-form and R-form―were measured by HPLC (high-performance liquid chromatography), and an excess (ee) of the enantiomeric isomers (S vs. R form) was then calculated as being ee = 80%.

WO2006104356A1	Mar 30, 2006	Oct 5, 2006	Seong Cheol Bu	Dipeptidyl peptidase-iv inhibiting compounds, methods of preparing the same, and pharmaceutical compositions containing the same as an active agent
EP0279435A2 *	Feb 18, 1988	Aug 24, 1988	BASF Aktiengesellschaft	Process for the reduction of mono- and dicarboxylic acids
US5556982 *	Jul 12, 1993	Sep 17, 1996	Neorx Corporation	Metal radionuclide labeled proteins for diagnosis and therapy
US20080039517 *	Aug 7, 2007	Feb 14, 2008	Washburn David G	Pyrrolidinone anilines as progesterone receptor modulators

Footnotes

Lim KS, Kim JR, Choi YJ, Shin KH, Kim KP, Hong JH, Cho JY, Shin HS, Yu KS, Shin SG, Kwon OH, Hwang DM, Kim JA, Jang IJ (October 2008). “Pharmacokinetics, pharmacodynamics, and tolerability of the dipeptidyl peptidase IV inhibitor LC15-0444 in healthy Korean men: a dose-block-randomized, double-blind, placebo-controlled, ascending single-dose, Phase I study”. Clin Ther 30 (10): 1817–30. doi:10.1016/j.clinthera.2008.10.013. PMID 19014837.
Ábel T. “A New Therapy of Type 2 Diabetes: DPP-4 Inhibitors”. In Rigobelo EC. Hypoglycemia – Causes and Occurrences. Croatia: InTech. pp. 3–52. doi:10.5772/23604. ISBN 978-953-307-657-7.
Kaji K (Mar 2014). “Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats.”. J Gastroenterol.. 49 (3): 481–91.doi:10.1007/s00535-013-0783-4. PMID 23475323.
Min HS (Jun 2014). “Dipeptidyl peptidase IV inhibitor protects against renal interstitial fibrosis in a mouse model of ureteral obstruction.”. Lab Invest. 94 (5): 598–607.doi:10.1038/labinvest.2014.50. PMID 24687121.
Gouni-Berthold I (2014). “The role of oral antidiabetic agents and incretin mimetics in type 2 diabetic patients with non-alcoholic Fatty liver disease.”. Curr Pharm Des. 20 (5): 3705–15.PMID 24040873.

External links

Official site

DAVID G. WASHBURN ET AL.: ‘Discovery or orally active, pyrrolidinone-based progesterone receptor partial agonist‘ BIOORGANIC & MEDICINAL CHEMISTRY LETTERS vol. 19, no. 16, 2009, pages 4664 – 4667, XP026419052
2	*	MONICA LOPEZ-GARCIA ET AL.: ‘Synthesis of (R)-3,4- diaminobutanoic acid by desymmetrization of dimethyl 3-(benzylamino)-glutarate through enzymatic ammonolysis‘ JOURNAL OF ORGANIC CHEMISTRY vol. 68, no. 2, 2003, pages 648 – 651, XP055105976

09b37-misc2b027 LIONEL MY SON

TRELAGLIPTIN

July 3, 2015 2:17 pm / Leave a comment

1 TRELAGLIPTIN

Trelagliptin succinate (SYR-472)

2-[[6-[(3R)-3-aminopiperidin-1-yl]-3-methyl-2, 4-dioxopyrimidin-1-yl]methyl]-4-fluorobenzonitrile; butanedioic acid

2-[6-[3(R)-Aminopiperidin-1-yl]-3-methyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-1-ylmethyl]-4-fluorobenzonitrile

2- [ [6- [ (3R) -3-amino-l-piperidinyl] -3, 4-dihydro-3- methyl-2, 4-dioxo-l (2H) -pyrimidinyl]methyl] -4-fluorobenzonitrile

succinic acid salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile

Sponsor/Developer: Takeda Pharmaceuticals and Furiex Pharmaceuticals

Mechanism of action: DPP-4 inhibitor

865759-25-7 cas FREE BASE

1029877-94-8 succinate

SYR 111472 succinate
SYR 472
Syr-472
Syr111472 succinate
Trelagliptin succinate
UNII-4118932Z90

clinical trials….http://clinicaltrials.gov/search/intervention=SYR+472

Trelagliptin-succinate M. Wt: 475.47

Trelagliptin-succinate Formula: C22H26FN5O6

SYR-472 is an oral dipeptidyl peptidase IV inhibitor originated by Takeda. It is in phase III clinical trials for the treatment of type 2 diabetes.

Diabetes affects 25.8 million people of all ages, or roughly 8.3 percent of the U.S. population.
The World Health Organization predicts that there will be 366 million people worldwide affected by diabetes by the year 2030.
The advent of trelagliptin succinate, a unique once weekly medication for patients with type 2 Diabetes is now the focus of clinical trials and exciting research and development.
Phase III clinical trials of trelagliptin succinate commenced in September 2011, and are estimated to be complete by the second half of 2013.

TRELAGLIPTIN (SYR-472)

Trelagliptin is a novel DPP-4 inhibitor that is being developed by Takeda. In contrast to alogliplitin, which is once a day, trelagliptin is a once-weekly oral agent which should provide patients with a convenient therapeutic alternative and has the potential to improve compliance. Takeda has commenced Phase III trials of trelagliptin in Japan for the treatment of Type 2 diabetes.

http://www.amstock.com/proxyservices/Files/AR26348.pdf

https://www.takeda.com/investor-information/annual/files/ar2013_10_en.pdf

Indication (Phase): Japan—Once-weekly oral treatment for type 2 diabetes (Phase III; study expected to be completed in second half of 2013)

trelagliptin succinate

Compound I, A, TRELAGLIPTIN which has the formula:

is a DPP-IV inhibitor that is described in U.S. patent application Ser. No. 11/080,992 filed Mar. 15, 2005 (see Compound 34). Its dosing, administration and biological activities are described in U.S. patent application Ser. No. 11/531,671 filed Sep. 13, 2006. U.S. patent application Ser. No. 11/080,992 and Ser. No. 11/531,671 are incorporated herein by reference in their entirety.

Dipeptidyl peptidase IV (IUBMB Enzyme Nomenclature EC.3.4.14.5) (referred herein as “DPP-IV”) is a type II membrane protein and a non-classical serine aminodipeptidase that removes Xaa-Pro dipeptides from the amino terminus (N-terminus) of polypeptides and proteins. DPP-IV is constitutively expressed on epithelial and endothelial cells of a variety of different tissues (e.g., intestine, liver, lung, kidney and placenta), and is also found in body fluids. DPP-IV is also expressed on circulating T-lymphocytes and has been shown to be synonymous with the cell-surface antigen, CD-26. DPP-IV has been implicated in a number of human disease states, including, but are not limit to, diabetes, particularly type II diabetes mellitus, diabetic dislipidemia, conditions of impaired glucose tolerance (IGT), conditions of impaired fasting plasma glucose (IFG), metabolic acidosis, ketosis, appetite regulation and obesity; autoimmune diseases such as inflammatory bowel disease, multiple sclerosis and rheumatoid arthritis; AIDS; and cancers.

DPP-IV inhibitors are believed to be useful agents for the prevention, delay of progression, and/or treatment of conditions mediated by DPP-IV.

Compound (A) or a salt thereof has been reported as an inhibitor of dipeptidyl peptidase (DPP-IV) , which is an enzyme that decomposes glucagon-like peptide-1 (GLP-1) , a hormone increasing insulin secretion (patent document 1) .

In addition, a method including administering 1 – 250 mg of compound (A) or a salt thereof to a patient once per week (patent documents 2, 3), crystal polymorphs of compound (A) (patent documents 4, 5) , and a preparation of compound (A)

(patent documents 6, 7) have also been reported. Compound (A) and a salt thereof are recommended for oral administration in view of the easiness of self-administration, and a tablet, particularly a tablet in the dosage form for administration once per week, is desired. [0006]

The dosage form of once per week is expected to improve drug compliance of patients, whereas it requires supply of compound (A) or a salt thereof to patients in a high dose as compared to, for example, the dosage form of once per day. Since a solid preparation containing compound (A) or a salt thereof in a high dose increases its size, it may conversely degrade the drug compliance for patients, particularly infants and elderly patients having difficulty in swallowing

……………………..

SYNTHESIS

US20090275750

Compound 34 IS TRELAGLIPTIN

4-Fluoro-2-methylbenzonitrile (31).

A mixture of 2-bromo-5-fluorotoluene (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was refluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄and the solvent removed to give product 31 (yield 60%). 1H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

2-Bromomethyl-4-fluorobenzonitrile (32).

A mixture of 4-fluoro-2-methylbenzonitrile (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl₄was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

Alternatively, 32 was made as follows.

4-Fluoro-2-methylbenzonitrile (1 kg) in DCE (2 L) was treated with AIBN (122 g) and heated to 75° C. A suspension of DBH (353 g) in DCE (500 mL) was added at 75° C. portionwise over 20 minutes. This operation was repeated 5 more times over 2.5 hours. The mixture was then stirred for one additional hour and optionally monitored for completion by, for example, measuring the amount of residual benzonitrile using HPLC. Additional AIBN (e.g., 12.5 g) was optionally added to move the reaction toward completion. Heating was stopped and the mixture was allowed to cool overnight. N,N-diisopropylethylamine (1.3 L) was added (at <10° C. over 1.5 hours) and then diethyl phosphite (1.9 L) was added (at <20° C. over 30 min). The mixture was then stirred for 30 minutes or until completion. The mixture was then washed with 1% sodium metabisulfite solution (5 L) and purified with water (5 L). The organic phase was concentrated under vacuum to afford 32 as a dark brown oil (3328 g), which was used without further purification (purity was 97% (AUC)).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (33).

A mixture of crude 3-methyl-6-chlorouracil (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃(0.5 g, 4 mmol) in DMSO (10 mL) was stirred at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

Alternatively, 33 was made as follows.

To a solution of 6-chloro-3-methyluracil (750 g) and N,N-diisopropylethylamine (998 mL) in NMP (3 L) was added (at <30° C. over 25 min) a solution of 32 (2963 g crude material containing 1300 g of 32 in 3 L of toluene). The mixture was then heated at 60° C. for 2 hours or until completion (as determined, for example, by HPLC). Heating was then stopped and the mixture was allowed to cool overnight. Purified water (3.8 L) was added, and the resultant slurry was stirred at ambient temperature for 1 hour and at <5° C. for one hour. The mixture was then filtered under vacuum and the wet cake was washed with IPA (2×2.25 L). The material was then dried in a vacuum oven at 40±5° C. for 16 or more hours to afford 33 as a tan solid (>85% yield; purity was >99% (AUC)).

TFAsalt OF TRELAGLIPTIN

2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (34).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

FREE BASE OF TRELAGLIPTIN

Alternatively, the free base of 34 was prepared as follows. A mixture of 33 (1212 g), IPA (10.8 L), (R)-3-amino-piperidine dihydrochloride (785 g), purified water (78 mL) and potassium carbonate (2.5 kg, powder, 325 mesh) was heated at 60° C. until completion (e.g., for >20 hours) as determined, for example, by HPLC. Acetonitrile (3.6 L) was then added at 60° C. and the mixture was allowed to cool to <25° C. The resultant slurry was filtered under vacuum and the filter cake was washed with acetonitrile (2×3.6 L). The filtrate was concentrated at 45° C. under vacuum (for >3 hours) to afford 2.6 kg of the free base of 34.

HCL salt OF TRELAGLIPTIN

The HCl salt of 34 was prepared from the TFA salt as follows. The TFA salt (34) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0° C. The HCl salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

Alternatively, the HCl salt was prepared from the free base as follows. To a solution of free base in CH₂Cl₂(12 L) was added (at <35° C. over 18 minutes) 2 M hydrochloric acid (3.1 L). The slurry was stirred for 1 hour and then filtered. The wet cake was washed with CH₂Cl₂(3.6 L) and then THF (4.8 L). The wet cake was then slurried in THF (4.8 L) for one hour and then filtered. The filter cake was again washed with THF (4.8 L). The material was then dried in a vacuum oven at 50° C. (with a nitrogen bleed) until a constant weight (e.g., >26 hours) to afford 34 as the HCl salt as a white solid (1423 g, >85% yield).

Succinate salt OF TRELAGLIPTIN

Figure US20080227798A1-20080918-C00001

The succinate salt of 34 was prepared from the HCl salt as follows. To a mixture of the HCl salt of 34 (1414 g), CH₂Cl₂(7 L) and purified water (14 L) was added 50% NaOH solution (212 mL) until the pH of the mixture was >12. The biphasic mixture was stirred for 30 min and the organic layer was separated. The aqueous layer was extracted with CH₂Cl₂(5.7 L) and the combined organic layers were washed with purified water (6 L). The organic layer was then passed through an in-line filter and concentrated under vacuum at 30° C. over three hours to afford the free base as an off-white solid. The free base was slurried in prefiltered THF (15 L) and prefiltered IPA (5.5 L). The mixture was then heated at 60° C. until complete dissolution of the free base was observed. A prefiltered solution of succinic acid (446 g) in THF (7 L) was added (over 23 min) while maintaining the mixture temperature at >57° C. After stirring at 60° C. for 15 min, the heat was turned off, the material was allowed to cool, and the slurry was stirred for 12 hours at 25±5° C. The material was filtered under vacuum and the wet cake was washed with prefiltered IPA (2×4.2 L). The material was then dried in a vacuum oven at 70±5° C. (with a nitrogen bleed) for >80 hours to afford the succinate salt of 34 as a white solid (1546 g, >90% yield).

The product was also converted to a variety of corresponding acid addition salts. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of 34 were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(−)-Mandelic and benzenesulfonic. The succinate was found to be crystalline as determined by x-ray powder diffraction analysis.

Methanesulfonate salt

In addition, the methanesulfonate salt was prepared as follows. A 10.5 g aliquot of the benzonitrile product was mixed with 400 mL of isopropylacetate. The slurry was heated to 75° C. and filtered through #3 Whatman filter paper. The solution was heated back to 75° C. and a 1M solution of methanesulfonic acid (30.84 mL) was added slowly over 10 minutes while stirring. The suspension was cooled to room temperature at a rate of about 20° C./hr. After 1 hr at room temperature, the solid was filtered and dried in an oven overnight to obtain the methanesulfonate salt.

…………………………

FORMULATION

WO2008114800A2

COMPD A IS TRELAGLIPTIN

Examples (Comparative Example IA)

Succinate of compound (A) (26.6 mg) was weighed in a glass bottle and used as Comparative Example IA. (Comparative Example 2A)

The succinate of compound (A) and microcrystalline cellulose were uniformly mixed in a mortar at a ratio of 1:10, and the mixture (226.6 mg) was weighed in a glass bottle and used as Comparative Example 2A. (Comparative Example 3A)

The succinate of compound (A) and corn starch were uniformly mixed in a mortar at a ratio of 1:5, and the mixture (126.6 mg) was weighed in a glass bottle and used as Comparative Example 3A. (Example IA) Succinate of compound (A) , mannitol and corn starch according to the formulation of Table IA were uniformly mixed in a fluid bed granulator (LAB-I, POWREX CORPORATION) , and the mixture was granulated by spraying an aqueous solution of dissolved hypromellose 2910, and dried therein. The obtained granules were passed through a sieve -(16M) to give milled granules. To the milled granules were added croscarmellose sodium, microcrystalline cellulose and magnesium stearate, and they were mixed in a bag to give granules for tableting. The granules were punched by a rotary tableting machine (Correct 19K, Kikusui Seisakusho, Ltd.) with a 6.5 mmφ punch to give a plain tablet weighting 121 mg. On the other hand, titanium oxide, yellow ferric oxide and talc were dispersed in a hypromellose 2910 aqueous solution to prepare a film coating liquid. The aforementioned coating liquid was sprayed onto the above-mentioned plain tablet in a film coating machine (Hicoater HCP-75, Freund Corporation), to give 2500 film- coated tablets containing 3.125 mg of compound (A) (free form) per tablet. Table IA

………………………..

POLYMORPHS AND SYNTHESIS

WO2008067465A1

FORM A

Form A may be prepared by crystallization from the various solvents and under the various crystallization conditions used during the polymorph screen (e.g., fast and slow evaporation, cooling of saturated solutions, slurries, and solvent/antisolvent additions). Tables B and C of Example 3 summarize the procedures by which Form A was prepared. For example, Form A was obtained by room temperature slurry of an excess amount of Compound I in acetone, acetonitrile, dichloromethane, 1,4-dioxane, diethyl ether, hexane, methanol, isopropanol, water, ethylacetate, tetrahydrofuran, toluene, or other like solvents on a rotating wheel for approximately 5 or 7 days. The solids were collected by vacuum filtration, and air dried in the hood. Also, Form A was precipitated from a methanol solution of Compound I by slow evaporation (SE).

[0091] Form A was characterized by XRPD, TGA, hot stage microscopy, IR, Raman spectroscopy, solution ¹H-NMR, and solid state ¹³C-NMR.

[0092] Figure 1 shows a characteristic XRPD spectrum (CuKa, λ=1.5418A) of Form A. The XRPD pattern confirmed that Form A was crystalline. Major X-Ray diffraction lines expressed in °2Θ and their relative intensities are summarized in Table 1.

Table 1. Characteristic XRPD Peaks (CuKa) of Form A

Characterization Data of Form A of Compound I

8. Amorphous Form

[0137] The Amorphous Form of Compound I was prepared by lyophilization of an aqueous solution of Compound I (Example 10). The residue material was characterized by XRPD and the resulting XRPD spectrum displayed in Figure 26. The XRPD spectrum shows a broad halo with no specific peaks present, which confirms that the material is amorphous. The material was further characterized by TGA, DSC, hot stage microscopy, and moisture sorption analysis.

Table A. Approximate Solubilities of Compound I

Compound I having the formula

POLYMORPH SCREEN

Crystallization Experiments of Compound I from Solvents

a) FE = fast evaporation; SE = slow evaporation; RT = room temperature; SC = slow cool;CC = crash cool, MB = moisture sorption/desorption analysis b) qty = quantity; PO = preferred orientation

…………………………

SYNTHESIS

WO2008033851A2

EXAMPLES

1. Preparation of 2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro- 2H-pyrimidin-l-ylmethyl]-4-fluoro-benzonitrile and pharmaceutically acceptable salts

4-Fluoro-2-methylbenzonitrile (3)

[0166] A mixture of 2-bromo-5fluorotoluene ( 2) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) was re fluxed for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄ and the solvent removed to give product 3 (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, IH), 6.93-7.06 (m, 2H), 2.55 (s, 3H). 2-Bromomethyl-4-fluorobenzonitrile (4)

[0167] A mixture of 4-fluoro-2-methylbenzonitrile (3) (2 g, 14.8 mmol), NBS (2.64 g, 15 mmol) and AIBN (100 mg) in CCl₄ was refluxed under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give crude product as an oil, which was used in the next step without further purification.¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J= 5.2, 8.4 Hz, IH), 7.28 (dd, J= 2.4, 8.8 Hz, IH), 7.12 (m, IH), 4.6 (s, 2H).

2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4-fluoro- benzonitrile (6)

[0168] A mixture of crude 3-methyl-6-chlorouracil (5) (0.6 g, 3.8 mmol), 2- Bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃ (0.5 g, 4 mmol) in DMSO

(10 mL) was stirred at 60 C for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄ and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, 1=12, 8.4Hz, IH), 7.26 (d, J- 4.0Hz, IH), 7.11-7.17 (m, IH), 6.94 (dd, J=2.0, 9.0 Hz, IH), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for Ci₃H₉ClFN₃O₂, 293.68; found 293.68.

2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, TFA salt (1) (TFA salt of Compound I)

[0169] 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l-ylmethyl)-4- fluoro-benzonitrile (5) (300 mg, 1.0 mmol), (i?)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) were stirred in a sealed tube in EtOH (3 mL) at 100 ⁰C for 2 hrs. The final compound was obtained as a TFA salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.16-7.27 (m, 2H), 5.46 (s, IH), 5.17-5.34 (ABq, 2H, J = 35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, IH), 2.67-2.92 (m, 2H), 2.07-2.17 (m, IH), 1.82-1.92 (m, IH), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for Ci₈H₂₀FN₅O₂, 357.38; found, 357.38.

2-[6-(3-Amino-piperidin-l-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-l- ylmethyl]-4-fluoro-benzonitrile, HCl salt

[0170] The TFA salt of Compound I was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The residue was dissolved in acetonitrile and HCl in dioxane (1.5 eq.) was added at 0 C. The HCl salt was obtained after removing the solvent. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, IH), 7.12-7.26 (m, 2H), 5.47 (s, IH), 5.21-5.32 (ABq, 2H, J = 32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, IH), 2.69-2.93 (m, 2H), 2.07-2.17 (m, IH), 1.83-1.93 (m, IH), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for Ci₈H₂₀FN₅O₂, 357.38; found, 357.38.

General procedure for the preparation of salts of Compound I.

[0171] The benzonitrile product may be isolated as the free base if desired, but preferably, the product may be further converted to a corresponding acid addition salt. Specifically, the benzonitrile product (approximately 10 mg) in a solution of MeOH (1 mL) was treated with various acids (1.05 equivalents). The solutions were allowed to stand for three days open to the air. If a precipitate formed, the mixture was filtered and the salt dried. If no solid formed, the mixture was concentrated in vacuo and the residue isolated. In this way, salts of Compound I were prepared from the following acids: benzoic, p-toluenesulfonic, succinic, R-(-)-Mandelic and benzenesulfonic. [0172] The isolation and/or purification steps of the intermediate compounds in the above described process may optionally be avoided if the intermediates from the reaction mixture are obtained as relatively pure compounds and the by-products or impurities of the reaction mixture do not interfere with the subsequent reaction steps. Where feasible, one or more isolation steps may be eliminated to provide shorter processing times, and the elimination of further processing may also afford higher overall reaction yields.

…………………..

TABLET

US20070060530

2. Exemplary formulations comprising succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile

Provided are examples of tablet formulations that may be used to administer succinate salt of 2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile (Succinate salt of Compound I) according to the present invention. It is noted that the formulations provided herein may be varied as is known in the art.

The exemplary tablet formulations are as follows:



12.5 mg of Compound I (weight of free base form) per tablet

Core Tablet Formulation
	(1)	2-[6-(3-Amino-piperidin-1-yl)-3-methyl-2,4-	17.0	mg
		dioxo-3,4-dihydro-2H-pyrimidin-1-
		ylmethyl]-4-fluoro-benzonitrile (succinate salt)
	(2)	Lactose Monohydrate, NF, Ph, Eur	224.6	mg
		(FOREMOST 316 FAST FLO)
	(3)	Microcrystalline Cellulose, NF, Ph, Eur	120.1	mg
		(AVICEL PH 102)
	(4)	Croscarmellose Sodium, NF, Ph, Eur	32.0	mg
		(AC-DO-SOL)
	(5)	Colloidal Silicon Dioxide, NF, Ph, Eur	3.2	mg
		(CAB-O-SIL M-5P)
	(6)	Magnesium Stearate, NF, Ph, Eur	3.2	mg
		(MALLINCKRODT, Non-bovine Hyqual)
	TOTAL	400.0	mg
	(per tablet)

…………..

US20080227798 AND US20120197018

POLYMORPHS AND SYNTHESIS

EXAMPLES Example 1 Preparation of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl]-4-fluoro-benzonitrile succinate (Compound I)

Compound I may be prepared by the follow synthetic route (Scheme 1)

A. Preparation of 4-fluoro-2-methylbenzonitrile (Compound B)

Compound B was prepared by refluxing a mixture of 2-bromo-5-fluoro-toluene (Compound A) (3.5 g, 18.5 mmol) and CuCN (2 g, 22 mmol) in DMF (100 mL) for 24 hours. The reaction was diluted with water and extracted with hexane. The organics were dried over MgSO₄and the solvent removed to give product B (yield 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.60 (dd, J=5.6, 8.8 Hz, 1H), 6.93-7.06 (m, 2H), 2.55 (s, 3H).

B. Preparation of 2-bromomethyl-4-fluorobenzonitrile (Compound C)

Compound C was prepared by refluxing a mixture of 4-fluoro-2-methylbenzonitrile (Compound B) (2 g, 14.8 mmol), N-bromosuccinimide (NBS) (2.64 g, 15 mmol) and azo-bis-isobutyronitrile (AIBN) (100 mg) in CCl₄under nitrogen for 2 hours. The reaction was cooled to room temperature. The solid was removed by filtration. The organic solution was concentrated to give the crude product the form of an oil, which was used in the next step without further purification. ¹H-NMR (400 MHz, CDCl₃): δ 7.68 (dd, J=5.2, 8.4 Hz, 1H), 7.28 (dd, J=2.4, 8.8 Hz, 1H), 7.12 (m, 1H), 4.6 (s, 2H).

C. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound D)

Compound E was prepared by stirring a mixture of crude 3-methyl-6-chlorouracil D (0.6 g, 3.8 mmol), 2-bromomethyl-4-fluorobenzonitrile (0.86 g, 4 mmol) and K₂CO₃(0.5 g, 4 mmol) in DMSO (10 mL) at 60° C. for 2 hours. The reaction was diluted with water and extracted with EtOAc. The organics were dried over MgSO₄and the solvent removed. The residue was purified by column chromatography. 0.66 g of the product was obtained (yield: 60%). ¹H-NMR (400 MHz, CDCl₃): δ 7.73 (dd, J=7.2, 8.4 Hz, 1H), 7.26 (d, J=4.0 Hz, 1H), 7.11-7.17 (m, 1H), 6.94 (dd, J=2.0, 9.0 Hz, 1H), 6.034 (s, 2H), 3.39 (s, 3H). MS (ES) [m+H] calc’d for C₁₃H₉ClFN₃O₂, 293.68; found 293.68.

D. Preparation of 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound F)

Compound F was prepared by mixing and stirring 2-(6-chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile (Compound E) (300 mg, 1.0 mmol), (R)-3-amino-piperidine dihydrochloride (266 mg, 1.5 mmol) and sodium bicarbonate (500 mg, 5.4 mmol) in a sealed tube in EtOH (3 mL) at 100° C. for 2 hrs. The final compound was obtained as trifluoroacetate (TFA) salt after HPLC purification. ¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.16-7.27 (m, 2H), 5.46 (s, 1H), 5.17-5.34 (ABq, 2H, J=35.2, 15.6 Hz), 3.33-3.47 (m, 2H), 3.22 (s, 3H), 2.98-3.08 (m, 1H), 2.67-2.92 (m, 2H), 2.07-2.17 (m, 1H), 1.82-1.92 (m, 1H), 1.51-1.79 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

E. Preparation of Compound I: the succinic acid salt of 2-(6-Chloro-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethyl)-4-fluoro-benzonitrile

The TFA salt prepared in the above step (Example 1, Step D) was suspended in DCM, and then washed with saturated Na₂CO₃. The organic layer was dried and removed in vacuo. The benzonitrile product (approximately 10 mg) was dissolved in MeOH (1 mL) and to which succinic acid in THF (1.05 equivalents) was added. The solutions were allowed to stand for three days open to the air. If a precipitate formed, the solid was collected by filtration. If no solid formed, the mixture was concentrated in vacuo, and the succinate salt was obtained after removing the solvent.

SUCCINATE SALT OF TRELAGLIPTIN

¹H-NMR (400 MHz, CD₃OD): δ. 7.77-7.84 (m, 1H), 7.12-7.26 (m, 2H), 5.47 (s, 1H), 5.21-5.32 (ABq, 2H, J=32.0, 16.0 Hz), 3.35-3.5 (m, 2H), 3.22 (s, 3H), 3.01-3.1 (m, 1H), 2.69-2.93 (m, 2H), 2.07-2.17 (m, 1H), 1.83-1.93 (m, 1H), 1.55-1.80 (m, 2H). MS (ES) [m+H] calc’d for C₁₈H₂₀FN₅O₂, 357.38; found, 357.38.

Compound I such prepared was found to be crystalline as determined by x-ray powder diffraction analysis (FIG. 1). The crystal material was designated Form A.

……………

patents

1. US 2013172377

2. WO 2011013639

3. WO 2009099172

4.WO 2009099171

5. WO 2008114807

6.WO 2008114800

7. WO 2008033851

8. WO 2007074884

9WO 2007035629

patent document 1: US2005/0261271

patent document 2: US2007/0060530

patent document 3: US2008/0287476

patent document 4: US2008/0227798

patent document 5: US2008/0280931

patent document 6: WO2008/114800

patent document 7: WO2011/013639

US7906523 *	Oct 30, 2007	Mar 15, 2011	Takeda Pharmaceutical Company Limited	Dipeptidyl peptidase inhibitors
US8084605 *	Nov 29, 2007	Dec 27, 2011	Kelly Ron C	Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US8188275 *	Oct 30, 2007	May 29, 2012	Takeda Pharmaceutical Company Limited	Dipeptidyl peptidase inhibitors
US8222411 *	Sep 15, 2006	Jul 17, 2012	Takeda Pharmaceutical Company Limited	Dipeptidyl peptidase inhibitors
US20090275750 *	Sep 15, 2006	Nov 5, 2009	Jun Feng	Dipeptidyl peptidase inhibitors

WO2013183784A1

Jun 4, 2013

Dec 12, 2013

Takeda Pharmaceutical Company Limited

Solid preparation

US20080227798 *	Nov 29, 2007	Sep 18, 2008	Kelly Ron C	Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor
US20120197018 *	Feb 15, 2012	Aug 2, 2012	Kelly Ron C	Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2h-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor

WO2007033265A1 *	Sep 13, 2006	Mar 22, 2007	Takeda Pharmaceutical	Dipeptidyl peptidase inhibitors for treating diabetis
WO2007033266A2 *	Sep 13, 2006	Mar 22, 2007	Takeda Pharmaceutical	Dipeptidyl peptidase inhibitors for treating diabetis
WO2007033350A1 *	Sep 13, 2006	Mar 22, 2007	Takeda Pharmaceutical	Dipeptidyl peptidase inhibitors for treating diabetes
EP1586571A1 *	Dec 21, 2004	Oct 19, 2005	Takeda San Diego, Inc.	Dipeptidyl peptidase inhibitors

EVOGLIPTIN

July 3, 2015 3:46 am / Leave a comment

ChemSpider 2D Image | Evogliptin | C19H26F3N3O3

EVOGLIPTIN
CAS: 1222102-29-5 FREE

HCL……1246960-27-9

tartare.. 1222102 -51-3

Dong-A Pharmaceutical. Co., Ltd, 동아제약 주식회사
2-Piperazinone, 4-((3R)-3-amino-1-oxo-4-(2,4,5-trifluorophenyl)butyl)-3-((1,1-dimethylethoxy)methyl)-, (3R)-
R)-4-((R)-3-Amino-4-(2,4,5-trifluorophenyl)-butanoyl)-3-(t-butoxymethyl)-piperazin-2-one

4-[3(R)-Amino-4-(2,4,5-trifluorophenyl)butyryl]-3(R)-(tert-butoxymethyl)piperazin-2-one hydrochloride

DA-1229

see…http://www.allfordrugs.com/2015/07/03/evogliptin/

DA-1229 is a dipeptidyl peptidase IV (CD26) inhibitor currently being developed in phase III clinical studies at Dong-A for the treatment of type 2 diabetes.

In 2014, Eurofarma aquired rights for product development and commercialization in Brazil.

Evogliptin Tartrate

If above image is not clear then see at…….http://www.allfordrugs.com/2015/07/03/evogliptin/

86…………H. J. Kim, W. Y. Kwak, J. P. Min, J. Y. Lee, T. H. Yoon, H. D. Kim, C. Y. Shin, M. K.
Kim, S. H. Choi, H. S. Kim, E. K. Yang, Y. H. Cheong, Y. N. Chae, K. J. Park, J. M.
Jang, S. J. Choi, M. H. Son, S. H. Kim, M. Yoo and B. J. Lee, Bioorg. Med. Chem. Lett.,
2011, 21 (12), 3809-3812.
[87] …………K. S. Lim, J. Y. Cho, B. H. Kim, J. R. Kim, H. S. Kim, D. K. Kim, S. H. Kim, H. J. Yim,
S. H. Lee, S. G. Shin, I. J. Jang and K. S. Yu, Br. J. Clin. Pharmacol., 2009, 68 (6), 883-
890.

Originator Dong-A Pharmaceutical
Developer Dong-A ST
Class Amides; Antihyperglycaemics; Fluorobenzenes; Piperazines; Small molecules
Mechanism of Action CD26 antigen inhibitors

Orphan Drug Status No
On Fast track No
New Molecular Entity Yes
Available For Licensing Yes – Type 2 diabetes mellitus

Highest Development Phases

Phase III Type 2 diabetes mellitus

Most Recent Events

01 Sep 2014 Phase-I clinical trials in Type-2 diabetes mellitus (In volunteers) in United Kingdom (PO)
31 Jul 2014 Phase-III clinical trials in Type-2 diabetes mellitus in South Korea (PO)
31 Jul 2014 Dong-A ST initiates enrolment in a phase I trial in patients with renal impairment in South Korea (NCT02214693)

Evogliptin Tartrate

…………………………………..

WO 2010114291

http://www.google.co.in/patents/WO2010114291A2?cl=en

Formula 1

Korea Patent Publication No. 2008-0094604 the call to the scheme, as indicated by A Ⅰ) of formula (II) beta-compound of formula 3 is already substituted heterocyclic compound having 1-hydroxy-benzotriazole group (HOBT) 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide (EDC) and reacting with a tertiary amine to prepare a compound of formula (4) connected by peptide bonds; Ⅱ) beta comprises the step of reacting under acidic conditions a compound of the formula (4) – a method of manufacturing the heterocyclic compounds of the formula I having an amino group is disclosed.

– Scheme A]

(Wherein, PG is a protecting group.)

In this case, the beta of the formula (2) of Scheme A – a compound having an amino group is prepared in addition to the DPP-IV inhibitor International Publication represented by Formula 1 WO03 / 000181, WO03 / 004498, WO03 / 082817, WO04 / 007468, WO04 / 032836, WO05 / 011581, WO06 / 097175, WO07 / 077508, WO07 / 063928, WO08 / 028662 WO08 / it may be used for the production of different DPP-IV inhibitors according 087,560 and can be prepared in a number of ways.

To, the compound of Formula 2 is an example as shown in Scheme J. Med.Chem. 2005; 141, and Synthesis 1997; it can be produced by the known method described in 873.

Specifically, (2S) – (+) – 2,5- dihydro-3,6-dimethoxy-2-isopropyl-pyrazine 2,4,5-trifluoro-react with benzyl bromide and acid treatment, and then the amine an ester compound obtained by the protection reaction. Ester compounds are hydrolyzed to re-3- (2,4,5-trifluoro-phenyl) -2-amino-propionic acid tert such as isobutyl chloroformate, triethylamine or diisopropylethylamine to give the amine, and then using diazomethane to form a diazo ketone, and then may be prepared by reaction with silver benzoate. However, the reaction can be performed at low temperature (-78 ℃) or high alpha-amino acid to purchase and use, and may have a risk of problems such as the need to use large diazomethane.

To a different process for preparing a compound of Formula 2 as shown in scheme Tetrahedron: Asymmetry 2006; It is known in 2622; 205 or similarly Bioorganic & Medicinal Chemistry Letters 2007.

That is, a 1,1′-carbonyl-2,4,5 which the phenyl trifluoroacetic acid activated using the following imidazole mono-methyl words potassium carbonate is reacted with the beta-keto ester compound is prepared. This produced an enamine ester using ammonium acetate and ammonium solution, the ester compound chloro (1,5-cyclooctadiene) rhodium (I) dimer using a chiral ferrocenyl ligands I the reaction of the high-pressure hydrogen with a chiral primary amine with a beta-amino ester compound after production and can lead to hydrolysis to prepare a compound of formula (2). However, use of expensive metal catalyst has a problem that must be performed in high pressure hydrogenation.

The method for preparing a compound of Formula 2 is disclosed in International Publication No. WO 04/87650.

Specifically, 2,4,5-fluorophenyl reagent is oxalyl chloride, the acid activated acid with 2,2-dimethyl-1,3-dioxane-4,6-dione, and after the reaction of methanol and the resulting material at reflux to prepare a corresponding compound. With a selective reducing reagents which enantiomers (S) -BINAP-RuCl ₂ and hydrogen through a reaction (S) – producing a compound having coordinated to each other, it again after the decomposition, and the singer O- benzyl hydroxyl amine and the coupling reaction and the intermediate is prepared. To do this, the resulting intermediate tree azodicarboxylate and diisopropyl azodicarboxylate presence ring condensation reaction, treated with an aqueous solution of lithium hydroxide to (R) – while having the formula (II) coordinated to the amine group protected with a benzyl-O- the compound can be produced. However, the method has a problem as a whole to be prepared by the reaction yield to be low and a long processing time to perform the reaction.

Thus, the conventional known method for producing a compound of the general formula (2) has the disadvantage of using expensive reagents, or not suitable for commercial mass-production method by a long synthesis time yield is also low.

In addition, the compound represented by General Formula (3), as described in Korea Patent Publication No. 2008-0094604 call, can be prepared by way of reaction schemes.

Specifically, the starting material D- serine methyl ester is substituted by a hydroxy group when reflux again substituted by trityl chloride as methoxy groups converted to the aziridine compound.

[Scheme 3]

<Example 3> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) Preparation of the hydrochloride

Step 1: t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소 – 1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트(화학식 Preparation of 4)

2 L flask, prepared in Example 1 (R) -3-t- butoxycarbonyl-4- (2,4,5-trifluoro-phenyl) butanoate acid (Formula 2) 10.0 g of toluene was dissolved in 450 mL of bis (2,2′-benzothiazolyl) disulfide 13.0 g, was cooled and then 10.2 g triphenylphosphine was added to the reaction solution at 0 ℃. While stirring the reaction mixture was added to a solution of 0.8 mL of triethylamine in 20 mL of toluene was stirred at room temperature for 5 hours. The reaction mixture was cooled to 0 ℃ and prepared in Example 2 (R) -3- (t- butoxymethyl) piperazin-2-one (Formula 3) was dissolved in 5.6 g of toluene and 40 mL pyridine a 2.4 mL was added slowly. After 30 minutes the reaction mixture was heated to room temperature and stirred for 1 hour. Saturated sheet to be the aqueous acid solution to a pH of 2.5 and then diluted with ethyl acetate 400 mL. Washed twice with brine and the organic layer was dehydrated with magnesium sulfate and concentrated. The residue was purified by column chromatography to give the title compound 838 mg.

¹ H NMR (400 MHz, CDCl ₃₎ δ 7.03 (m, 1H), 6.88 (m, 1H), 5.97 (m, 1H), 5.48 (m, 1H), 4.16 ~ 4.07 (m, 1H), 4.02 ~ 3.91 (m, 1H), 3.74 (m, 2H) 3.37 (m, 2H), 3.24 (m, 1H), 2.92 (m, 2H), 2.80 (m, 1H), 2.59 (m, 2H), 1.34 ( d, 9H), 1.13 (s, 9H)

Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- on the production of (I) hydrochloride

Prepared in Step 1 t- butyl (R)-4-[(R)-2-(t-부톡시메틸)-3-옥소피페라진-1-일]-4-옥소-1-(2,4,5-트리플루오로페닐)부탄-2-일카르바메이트 97 mg was dissolved in methanol was added 3 mL 2N- hydrochloric acid / diethyl ether 2 mL was stirred at room temperature for 3 hours. The reaction mixture was concentrated and dried under reduced pressure to give 64 mg of the title compound as a foaming solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.37 (m, 1H), 7.23 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H), 1.18 (s, 3H ), 1.11 (s, 6H)

Mass (M + 1): 402

<Example 4> (R)-4-[(R)-3-아미노-4-(2,4,5-트리플루오로페닐)부타노일]-3-(t-부톡시메틸)피페라진-2-온(화학식 1) tartaric acid salts

Step 1: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluoro-phenyl) butane five days] -3- (t- butoxymethyl) piperazin-2- Preparation of one (I)

Example 3 to give a compound of formula I in hydrochloride 60 mg 5% sodium hydrogen carbonate in dichloromethane was added to 10 mL of an aqueous solution / 2-propanol (4/1 (v / v)) was added to the mixed solution and extracted two times 10 mL The organic layer was dried under reduced pressure to give 55 mg of the title compound as a solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.27 (m, 1H), 7.14 (m, 1H), 4.56 ~ 4.39 (m, 1H), 3.96 ~ 3.81 (m, 3H), 3.70 (m, 1H) , 3.46 (m, 1H), 3.43 ~ 3.32 (m, 1H), 2.83 ~ 2.65 (m, 3H), 2.58 ~ 2.40 (m, 2H), 1.16 (s, 3H), 1.11 (s, 6H)

Mass (M + 1): 402

Step 2: (R) -4 – [(R) -3- amino-4- (2,4,5-trifluorophenyl) butanoyl] -3- (t- butoxymethyl) piperazin-2- one (I) tartaric acid salt [

Was dissolved 55 mg of the compound of step 1 in 0.56 mL of acetone, L- tartrate 26 mg ethanol / water (9/1 (v / v)) was added slowly to a solution of 0.35 mL was stirred for 30 minutes. Here was added 0.56 mL of 2-propanol was stirred for 10 minutes and re-filtered to give 77 mg of the title compound as a solid.

¹ H NMR (400 MHz, CD ₃ OD) δ 7.38 (m, 1H), 7.22 (m, 1H), 4.80 (m, 1H), 4.59 ~ 4.40 (m, 1H), 4.40 (s, 2H), 3.93 (m, 1H), 3.90 ~ 3.83 (m, 2H), 3.70 (m, 1H), 3.38 (m, 2H), 3.27 (m, 1H), 3.07 (m, 2H), 2.89 ~ 2.66 (m, 2H ), 1.15 (s, 3H), 1.11 (s, 6H)

Mass (M + 1): 402

………………………………

WO 2010114292

http://www.google.com/patents/WO2010114292A2?cl=en

…………………………………

Discovery of DA-1229: a potent, long acting dipeptidyl peptidase-4 inhibitor for the treatment of type 2 diabetes
Bioorg Med Chem Lett 2011, 21(12): 3809

http://www.sciencedirect.com/science/article/pii/S0960894X11004859

A series of β-amino amide containing substituted piperazine-2-one derivatives was synthesized and evaluated as inhibitors of dipeptidyl pepdidase-4 (DPP-4) for the treatment of type 2 diabetes. As results of intensive SAR study of the series, (R)-4-[(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl]-3-(t-butoxymethyl)-piperazin-2-one (DA-1229) displayed potent DPP-4 inhibition pattern in several animal models, was selected for clinical development.

About evogliptin tartrate tablets

Evogliptin tartrate tablets is a dipeptidyl peptidase IV inhibitor, in tablet form. Evogliptin tartrate

tablets is expected to be approved for the treatment of type 2 diabetes mellitus. The Group holds

an exclusive intellectual property licence from Dong-A Pharmaceutical Co. Ltd. to develop

and commercialise evogliptin tartrate tablets in China, including the exclusive right to develop

evogliptin tartrate tablets for manufacturing and sale in the Group’s name. The new drug certificate

to be issued by the CFDA will be approved and registered under the Group’s name.

Evogliptin is a patented new molecular entity in the United States and other international markets.

Evogliptin tartrate tablets is being concurrently developed by Dong-A Pharmaceutical Co. Ltd.

for the Korean market. Based on information released from a multi-centre, phase II, randomised,

double-blind, placebo-controlled, therapeutic exploratory clinical trial conducted in Korea by

Dong-A Pharmaceutical Co. Ltd. to investigate the efficacy and safety of evogliptin, evogliptin

was proven to be effective in significantly lowering blood glucose levels in patients with type

2 diabetes. Data also show that the body weights of patients remain stable over the treatment

period. In addition, evogliptin was proven to be safe and well tolerated with no severe adverse

drug reactions observed during those phase II clinical trials. The Company believes evogliptin

tartrate tablets will help reduce the burden of patients with moderate-to-severe renal impairment

as pharmacokinetic study in animal model and healthy human volunteers showed low renal

elimination.

According to the statistics of IMS Health Incorporated, the market size of products for the

treatment of diabetes in China in 2013 was approximately RMB7.8 billion, and grew at a

compound annual growth rate of 23.4% from 2011 to 2013.

http://www.luye.cn/en/uploads//2014-07/21/_1405936452_zr21xh.pdf

Dong-A ST

SEOUL, SOUTH KOREA

14 April 2015 – 5:45pm

Oh Seung-mock

Dong-A ST has licensed its new diabetes drug Evogliptin to 17 Latin American countries including Mexico, Venezuela, Argentina, Chile, Colombia, Ecuador, Peru, the Dominican Republic, and Uruguay, Jung Jae-wook, Dong-A ST’s PR manager, told Business Korea.

Dong-A ST and Eurofarma, a Brazilian pharmaceutical company, concluded the licensing contract at Dong-A ST’s headquarters on April 13 in Seoul.

Eurofarma will be responsible for Evogliptin’s product development and sales in the 17 Latin American countries, Dong-A ST said. Dong-A ST will receive royalties from Eurofarma, and export the raw material of the medicine.

Dong-A ST has been developing Evogliptin with the support of the Ministry of Health & Welfare of South Korea as an innovative new medicine research project since May 2008. Evogliptin is a DPP-4 remedy based on the inhibition mechanism which is “excellent” at reducing blood sugar, whilst “less likely” to cause weight increases and hypoglycemia, the company said.

Park Chan-il, president of Dong-A ST, said that Dong-A ST will pursue further out-licensing “over the globe,” through continuous investment in research and development.

Maurizio Billi, Eurofarma’s president, wished to expand both companies’ partnership in the innovative new remedy development sector, according to Dong-A ST.

Last July, Dong-A ST and Eurofarma concluded a contract out-licensing Evogliptin to Brazil itself, the company said.

– See more at: http://www.businesskorea.co.kr/article/10115/southern-strategy-dong-st-licenses-new-diabetes-drug-evogliptin-17-latin-american#sthash.liqwFTWU.dpuf

http://www.koreaittimes.com/story/47669/%EB%8F%99%EC%95%84st-evogliptin-%EC%B6%94%EA%B0%80-%EB%9D%BC%EC%9D%B4%EC%84%BC%EC%8B%B1-%EC%95%84%EC%9B%83-%EA%B3%84%EC%95%BD-%EC%B2%B4%EA%B2%B0

//////////

see gliptins at…..http://drugsynthesisint.blogspot.in/p/gliptin-series.html

Dong-A Pharm. Co., Ltd, Yongin-si, Gyeonggi-do, Republic of Korea.

	shivkr2 on SPSR Excellence Award 2025 – S…
	Bonkasaurus on Infigratinib phosphate
	PALOVAROTENE \| ORGAN… on Palovarotene
	Pfizer just purchase… on Temanogrel
	Pfizer To Cash In On… on Temanogrel

Yearly Archives: 2015

SEARCH THIS BLOG

Blog Stats

Flag and hits

Follow Blog via Email

Pages

Archives

Categories

Recent Posts

ORGANIC SPECTROSCOPY

SUBSCRIBE

Follow Blog via Email

Verified Services

Pages

Archives

Categories

Recent Comments

SEARCH THIS BLOG

Share this:

How flow chemistry can make processes greener

Increasing reaction efficiency through access to a wider range of reaction conditions

Share this:

SEE NMR……….

………..

MASS

References

Share this:

Share this:

Share this:

Share this:

Clinical study

Reported adverse events

Market access

Alogliptin

Derivatives

benzoate

Substance Classes

Synthesis Path

Substances Referenced in Synthesis Path

Trade Names

Formulations

References

solid preparation comprising Alogliptin and Pioglitazone:

solid preparation comprising Alogliptin and Metformin:

Share this:

History

Mechanism of action

Preclinical studies

Clinical studies

…………..

Footnotes

Further reading

External links

Google+

Share this:

Trelagliptin succinate (SYR-472)

Share this:

Highest Development Phases

Most Recent Events

Share this:

Post navigation

SEARCH THIS BLOG

FLAGS AND HITS

Follow Blog via Email