WO2016016279, NEW PATENT, DOLUTEGRAVIR SODIUM, LEK PHARMACEUTICALS D.D. , SANDOZ AG

WO2016016279, NOVEL HYDRATES OF DOLUTEGRAVIR SODIUM

LEK PHARMACEUTICALS D.D. [SI/SI]; Verovskova 57 1526 Ljubljana (SI).
SANDOZ AG [CH/CH]; Lichtstrasse 35 CH-4056 Basel (CH)

HOTTER, Andreas; (AT).
THALER, Andrea; (AT).
LEBAR, Andrija; (SI).
JANKOVIC, Biljana; (SI).
NAVERSNIK, Klemen; (SI).
KLANCAR, Uros; (SI).
ABRAMOVIC, Zrinka; (SI)

The present invention relates to novel hydrates of sodium dolutegravir and their methods of preparation. In addition, the invention relates to a novel crystalline form of sodium dolutegravir, which is a useful intermediate for the preparation of one of the new hydrates. The invention also relates to the use of the new hydrates for the production of pharmaceutical compositions.

Finally, the invention relates to pharmaceutical compositions comprising an effective amount of the novel hydrates, oral dosage forms comprising these pharmaceutical compositions, a process for preparing said oral dosage forms, and the use of such pharmaceutical compositions or dosage forms in the treatment of retroviral infections such as HIV infections -1.

Dolutegravir, chemically designated (4f?, 12aS)-/V-(2,4-difluorobenzyl)-7-hydroxy-4-methyl-6,8-dioxo-3,4,6,8, 12, 12a-hexahydro-2H-pyrido[1 ',2':4,5]pyrazino[2, 1- ?][1 ,3]oxazine-9-carboxamide, is a human immunodeficiency virus type 1 (HIV-1 ) integrase strand transfer inhibitor (INSTI) indicated in combination with other a nti retroviral agents for the treatment of HIV-1 infection. The marketed finished dosage form (TIVICAY™) contains dolutegravir as its sodium salt, chemically denominated sodium (4f?,12aS)-9-((2,4-difluorobenzyl)carbamoyl)-4-methyl-6,8-dioxo-3,4,6,8,12, 12a-hexahydro-2H-pyrido[1 ',2':4,5]pyrazino[2, 1- ?][1 ,3]oxazin-7-olate, which is represented by the following general chemical formula (I):

 

(I)

WO 2010/068253 A1 discloses a monohydrate and an anhydrous form of dolutegravir sodium as well as a crystalline form of the free compound. Processes for the preparation of said forms are also provided in the application.

WO 2013/038407 A1 discloses amorphous dolutegravir sodium and processes for preparing the same.

Hydrates of pharmaceutical drug substances are of particular interest as they provide new opportunities for preparing novel pharmaceutical compositions with improved quality, activity and/or compliance. This is due to the fact that hydrates have different physicochemical properties compared to their anhydrous counterparts such as melting point, density, habitus, chemical and physical stability, hygroscopicity, dissolution rate, solubility, bioavailability etc., which influence the formulation process and also impact the final drug product.

If an anhydrous form is selected, phase changes during the formulation process induced by hydrate formation must be avoided. This can be particularly difficult if for example wet granulation is used with a substance that is able to form hydrates like dolutegravir sodium.

Hence, a stable hydrate of dolutegravir sodium would allow to easily formulate dolutegravir sodium in a controlled manner and subsequently also facilitate storage and packaging.

However, the so far known dolutegravir sodium monohydrate disclosed in WO 2010/068253 A1 shows excessive water uptake when exposed to moisture and on the other hand already dehydrates below 30% relative humidity.

Therefore, there is a need for hydrates of dolutegravir sodium with improved physicochemical properties, e.g. for hydrates which are stable over a broad humidity range, in particular for hydrates absorbing only low amounts of water at elevated humidity and on the other hand preserving their crystal structure also at dry conditions. In addition, there is a need for pharmaceutical compositions comprising these hydrates, and thus also for hydrates that allow for improved formulation of dolutegravir sodium in pharmaceutical compositions.

SUMMARY OF THE INVENTION

The present invention relates to novel hydrates of dolutegravir sodium and to processes for their preparation. Specifically, the present invention provides crystalline forms of dolutegravir sodium of formula (I) according to respective claims 1 , 5 and 6, with preferred embodiments being set forth in sub-claim 2. The present invention also provides processes for their preparation according to respective claims 3, 7 and 8, with preferred process embodiments being set forth in sub-claim 4. The present invention further provides the uses according to claims 9 and 16, and a pharmaceutical composition according to claim 10, and preferred embodiments thereof according to sub-claims 1 1 and 12. The present invention also provides a process for the preparation of the pharmaceutical composition according to claim

13, and preferred embodiments thereof according to sub-claim 14. The pharmaceutical composition for therapeutic use is set forth in claim 15.

The novel hydrates are physically and chemically stable over a broad humidity range, show only low water uptakes when exposed to moisture and are even stable at dry conditions. Therefore, the novel hydrates are especially suitable for the preparation of pharmaceutical compositions, e.g. in terms of time and costs.

In particular, it has been found that crystal Form HxA exhibits improved properties which allow for improved formulation of Form HxA in pharmaceutical compositions.

In addition, the present invention relates to a novel crystalline form of dolutegravir sodium, which, for the first time, allows the preparation of one of the novel hydrates and is therefore a valuable intermediate.

///////////

WO2016016279, NEW PATENT,  DOLUTEGRAVIR SODIUM, LEK PHARMACEUTICALS D.D. , SANDOZ AG

WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, NEW PATENT

(S) – propylene glycol and water, 1: 1 crystalline complex

PATENT
WO2016018024, CRYSTALLINE COMPOSITE COMPRISING DAPAGLIFLOZIN AND METHOD FOR PREPARING SAME
HANMI FINE CHEMICAL CO., LTD. [KR/KR]; 59, Gyeongje-ro, Siheung-si, Gyeonggi-do 429-848 (KR)
KIM, Ki Lim; (KR).
PARK, Chulhyun; (KR).
LEE, Jaeheon; (KR).
CHANG, Young-kil; (KR)

The present invention relates to a crystalline composite comprising dapagliflozin and a method for preparing the same. More specifically, the present invention provides a novel crystalline composite comprising dapagliflozin, which is an SGLT2 inhibitor, and a preparing method capable of economically preparing the novel crystalline composite at high purity.

long period of time, there is a problem with secretion of insulin in diabetes is a problem with the function of insulin, or the two compounds problems of the disease that is to say maintaining a high blood sugar. Insulin helps the one that sends glucose into cells in order to replace the nutrients such as glucose that is in a hormone secreted by the beta cells of the pancreas blood into energy. However, if there is insufficient action of insulin, glucose accumulates in the blood does not enter the cell and cause the muscles and blood sugar, sugar in the urine is out. When these two long-standing high blood sugar will cause a number of microvascular complications. Not cut due to such complications, such as may result in blindness.

Worldwide diabetes has become one of the major causes of death in adults, an increasing number of diabetes patients may sharply with the increase of obesity population.

In diabetic patients SGLT2 (Sodium-Glucose linked transporter 2) selective inhibition of significant gastrointestinal side effects without increasing the emissions of glucose in the urine, thereby improving insulin sensitivity and delay the onset of diabetes complications by the normalization of plasma glucose can be there.

Bristol-to US Patent No. 6,515,117 of Myers Squibb Company of formula It discloses a binary) to dapa glyphs.

[Formula 1]

While preparing the material of Formula 1 in the above patent, the desired compound was obtained as an oil form, here was added to the chloroform under vacuum to reprocess getting the desired compound as a solid in a viscous that contains ethyl acetate. Compounds of the formula I obtained by the above method of production must be carried out the purification using a column, etc. because it can not remove the impurities of the desired compound, which is not suitable as an industrial method.

In addition, Bristol-to the US Patent 7,919,598 of Myers Squibb Company No. discloses a compound of formula 2.

[Formula 2]

Compounds of Formula 2 are the compounds of formula 1, (S) – propylene glycol and water, 1: 1 crystalline complex: 1. The compound of Formula 2 can be conveniently used in medicine to use by crystallizing the compound of formula 1 with low crystallinity and are also useful in the purification of the compounds of formula (I).

However, the compound of formula 2 is (S), the price is very expensive – and the use of propylene glycol, which results in increasing the production cost. This is very disadvantageous In the eyes of people with diabetes need to take the long-term.

In addition, European Patent No. 2597090 of Sandoz is disclosed of the formula monohydrate. Of the formula monohydrate is then stirred as a compound of the sugar alcohol and the formula of the glycol, glycerol, arabitol, xylitol, etc. in water obtained the seed (seed), by using this discloses a method for preparing the monohydrate in water, and have.

However, the European patent is described that the hydrate should be obtained stirred for three days at low temperature in order to obtain after obtaining the actual seed crystals, although not yield is mentioned is expected to be very low. For this reason, because of the situation in the research and development of novel crystalline complexes THE dapa glyphs are continually required.

Best Mode for Carrying out the Invention

Hereinafter, the present invention will be described in detail.

Crystalline complex according to the invention is for lowering the production cost by obtaining a product of high purity without the need for further purification, it has the structure of formula (3).

[Formula 3]

The crystalline complex is in the X- ray diffraction pattern of 9.7, 17.3, 20.0, 20.4, and may comprise a characteristic peak at a 2θ of 21.4 ± 0.2 °, preferably 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 43.9 ± 0.2 °, and can include a peak at 2θ of teukjeongjik, it may be most preferably having a powder X-ray diffraction pattern is shown in Fig.

It was confirmed that the heat-absorption peak appears at about 163 ℃, to refer to the thermal analysis by; (DSC differential scanning calorimetr) The crystalline complex is differential scanning calorimetry of FIG.

The crystalline complex is the measured moisture content in accordance with the Karl-Fischer method can be 2-5%, preferably be 2.1 ~ 3.5%.

In addition, the present invention includes a mixture of 1), mannitol and the solvent to prepare a mannitol solution; 2) preparing an alcohol solution by mixing the alcohol with the glyph dapa gin; 3) mixing the mannitol solution and the alcohol solution, heating to 50 ~ 100 ℃; And 4) cooling the heated solution to 0 ~ 15 ℃ provides a method for preparing the crystalline complex comprising the steps of obtaining a composite having a crystalline structure of Formula 3.

It describes a method for producing crystalline complex according to the present invention;

Step 1: Mannitol solution prepared

Step 1 of the manufacturing method according to the present invention is a step in which a mixture of mannitol and a solvent to prepare a mannitol solution.

The mannitol is suitable for the manufacture of a therapeutic agent for diabetes to be taking a long period of time as a material that is widely used like medicine, food, with high stability and low price. Furthermore, mannitol is used in reducing the edema by osmotic action, and thus the material to promote diuresis. This is mannitol is determined to be helpful to the action Qin dapa glyphs used as SGLT-2 inhibitors.

The mannitol is typically so long that can be purchased and / or synthesis is not particularly limited, preferably the D- mannitol, L- and D · mannitol may include one or more of the group consisting of L- mannitol , and it can be most preferably D- Magny-tolyl.

The solvent as long as it can dissolve the mannitol is not particularly limited, and may preferably be water.

The Mani mixing ratio of the toll and the solvent. If the amount that can be dissolve the mannitol, the solvent is not particularly restricted, the preferably mannitol and solvent 1: 8-20 weight ratio or 1: 1 may be mixed with 10 to 15 weight .

Step 2: Preparation of an alcohol solution

Step 2 of the manufacturing method according to the invention by mixing the alcohol with Jean dapa glyph is a step for preparing the alcoholic solution.

In the glyph binary dapa may be prepared by the method described in commercially available, and arc carried US Patent 6,515,117 example G.

The alcohol is long as it can dissolve the THE dapa glyph is not particularly limited, preferably the C ₁ ~ C ₄ alcohol may comprise at least one of (a lower alcohol), and most preferably ethanol .

The dapa If the mixing ratio of the pictures and alcohol as a glyph is content that can be dissolved in THE dapa glyph to alcohol is not particularly limited, preferably the gin alcohol dapa glyphs 1: 3-8 or 1: a volume ratio of 6-7 It may be mixed.

Step 3: heat-up phase

Step 3 of the manufacturing method according to the present invention is a step in which the mani mixing and heating the solution and the alcohol solution toll.

The step is a process for producing a crystalline complex containing THE dapa glyphs included in mannitol as an alcohol solution that is included in the mannitol solution, the mixing ratio of the mixed solution and the alcohol solution is mannitol and the pro pageul a binary 1: 0.5-2 or 1: it is preferable to mix in 1.0 to 1.5 molar ratio.

The heating may preferably be carried out at 50 ~ 100 70 ~ 90 ℃ or ℃.

Step 4: obtained crystalline complexes

Step 4 according to the present invention is by cooling the heated solution to obtain a crystalline complex having the structure of Formula 3.

The cooling is preferably at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃.

Further, according to the embodiment of the present invention, in order to improve the speed of determining the crystalline complex to be obtained, the cooling after seeding may further include a (seeding) and further comprising cooling. The further cooling can preferably be carried out at 0 ~ 15 ℃ ℃ or 3 ℃ ~ 12 ℃ for 5 to 24 hours, or 7 ~ 15 hours.

The production method of the present invention as described above, dapa glyphs to binary and mannitol for the crystalline complex has the advantage that can be produced in more than 99.0% pure without further purification, including, of high purity at a low manufacturing cost crystalline It has the advantage of producing the composite.

Mode for the Invention

Hereinafter the present invention will be described in more detail by examples. However, these examples are for the purpose of illustrating the invention by way of example, but the scope of the present invention is limited to these Examples.

Example 1. Preparation of the crystalline complex

The D- mannitol 0.98g (5.4mmol) was dissolved in purified water to prepare a mannitol 12㎖. On the other hand, amorphous THE dapa glyphs (purity:> 94%, U.S. Patent No. 6,515,117 prepared by the method described in of Example G) was dissolved in 2g (4.9mmol) in ethanol to give the alcohol 13 ㎖ solution. After the mannitol solution at room temperature to give the mixed solution is added to the alcohol solution. The mixed solution was heated under reflux for 3 hours so that the 80 ℃. After the cooling the solution obtained through the reflux slowly to 10 ℃ for 2 hours and then added to camp in the dapa glyph to 4 wt% solution total weight compared to the seeding (seeding) for 12 hours at 200 rpm at 4 ℃ cooling and stirring was added. After Buchner funnel (Buchner funnel) and filtered with a filter paper 55 ㎜ and dried for 8 hours under nitrogen and 20 ℃ to obtain a crystalline complex 1.3g (45%).

Experimental Example 1. Structural analysis

Nuclear magnetic resonance spectrum (NMR) (400MHz FT-NMR Spectrometer (Varian, 400-MR)) of a crystalline complex obtained in Example 1 by using ¹ yielded a H NMR spectrum, and the results, and in Fig. 1 It exhibited.

¹ H NMR (400㎒, DMSO-d ₆ ): δ 7.37-7.35 (d, 1H), 7.32-7.31 (d, 1H), 7.24-7.21 (dd, 1H), 7.10-7.08 (d, 2H), 6.83-6.81 (d, 2H), 4.97-4.95 (dd, 2H), 4.84-4.83 (d, 1H), 4.48-4.44 (t, 1H), 4.42-4.40 (d, 1H), 4.34-4.31 (t , 1H), 4.14-4.12 (d, 1H), 4.02-3.92 (m, 5H), 3.71-3.67 (m, 1H), 3.67-3.58 (m, 1H), 3.56-3.52 (t, 1H), 3.46 -3.35 (m, 3H), 3.28-3.07 (m, 4H), 1.31-1.27 (t, 3H)

The ^first through the results of 1 H NMR, and also, to the structure of a crystalline complex obtained in Example 1, it was confirmed that the formula (4).

[Formula 4]

Experimental Example 2. OK crystalline crystalline complexes

By performing an X-ray diffraction analysis and differential scanning calorimetry, it was confirmed that crystal form of the crystalline complex obtained in Example 1. More specifically, Diffraction Extensible Resource Descriptor (Brucker, USA) for use with X-ray diffraction (XRD) to perform, and differential scanning calorimetry (Differential scanning calorimeter; METTLER TOLEDO, Swiss) for use by differential scanning calorimetry (DSC) It was performed. Results of X-ray diffraction analysis results in Figure 1, the differential scanning calorimetry are shown in Fig.

Results of X-ray diffraction analysis, the crystalline complex according to an embodiment of the present invention exhibited a characteristic peak at 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4 and 2θ of 43.9 ° .

Experimental Example 3. HPLC analysis

To a crystalline complex obtained in Example 1 under the conditions of Table 1 and Table 2 it was carried out to HPLC (high performance liquid chromatography) analysis.

TABLE 1

column	Ascentis Express RP-Amide 4.6mm × 150mm (diameter × height), 2.7㎛ (Aldrich)
The mobile phase	A: Formic acid 1mL/1000mL in H 2 OB: Formic acid 1mL/1000mL in Acetonitrile (ACN)
Test Solution	Acetonitrile Test specimen 5mg / 10mL in 50% (ACN)
Column temperature	25 ℃
Wavelength detector	UV, 220nm
Dose	3 ㎕
Flow rate	0.7 mL / min
Operating hours	40 min

Table 2

Gradient systems
Time (min)	Mobile phase A (%)	Mobile phase B (%)
0	75	25
0-25	35	65
25-26	30	70
26-29	30	70
29-35	75	25
35-40	75	25

As described above, the results of the HPLC analysis, the crystalline complex of Example 1, it was confirmed that the purity of 99% or more. In addition, the crystalline complex of Example 1, it was confirmed that the water content measured by Karl-Fischer method of 2.9%.

Claims

To a crystalline complex comprising a dapa THE glyph having the structure of formula 3: [Formula 3]

According to claim 1, wherein said crystalline complex is in the X- ray diffraction pattern of 9.7, 11.1, 13.7, 17.3, 18.7, 20.0, 20.4, 21.4, 27.5, 33.9, 36.2, 40.4, and the characteristic peaks at 2θ of 43.9 ± 0.2 ° containing crystalline complexes.

According to claim 1, wherein said crystalline complex is the measured moisture content in accordance with the Karl-Fischer method which is characterized in that 2 to 5%, the crystalline complex.

1) preparing a mannitol solution by mixing mannitol (mannitol) and the solvent 2) a mixture of binary (dapagliflozin) and alcohol in dapa glyph for preparing an alcohol solution; 3) wherein the mannitol solution and the alcohol mixing the solution and heated to 50 ~ 100 ℃; And 4) the production method to cool the heated solution to 0 ~ 15 ℃ comprising the step of obtaining a polycrystalline composite having a structure of formula (3), a crystalline complex: [Formula 3]

[Claim 5]

According to claim 4, wherein the solvent is the production of water, the crystalline complex.

According to claim 4, wherein the alcohol is a C ₁ ~ C _4, a method of producing a crystalline complex comprising at least one kind of alcohol.

According to claim 6, wherein the alcohol is ethanol, the method of the crystalline complex prepared.

According to claim 4, wherein the mixing ratio by the spirit and mannitol dapa glyph is 1: 0.5 to 2 mole ratio, the method of producing a crystalline complex.

FIGURES

Figure 1 illustrates a X- ray diffraction spectrum of the crystalline complex in accordance with an embodiment of the present invention.

2 is a result of the differential scanning calorimetry of the crystalline complexes (DSC) in accordance with an embodiment of the present invention.

3 is of the crystalline complex in accordance with an embodiment of the present invention ¹ shows the H-NMR measurement results.

[Figure 1]

[Figure 2]

[Figure 3]

CEO, YOUNG KIL CHANG
/////////WO 2016018024, DAPAGLIFLOZIN, HANMI FINE CHEMICAL CO., LTD, New patent

WO 2016015596, Omarigliptin, Sunshine Lake Pharma Co Ltd, New patent

(WO2016015596) PROCESS FOR PREPARING 2, 3-DISUBSTITUTED-5-OXOPYRAN COMPOUND

SUNSHINE LAKE PHARMA CO., LTD. [CN/CN]; Northern Industrial Area, Songshan Lake Dongguan, Guangdong 523000 (CN)

SUN, Guodong; (CN).
LIU, Yongjun; (CN).
WEI, Mingjie; (CN).
LAI, Cailang; (CN).
LI, Dasheng; (CN).
ZHANG, Shouhua; (CN).
WANG, Zhongqing; (CN)

A 2, 3-disubstituted 5-oxopyran compound of formula (04) :

in which Ar is phenyl optionally substituted with R₄, R₄ is F, Cl, C1-C6 alkyl unsubstituted or substituted with fluorine, or C1-C6 alkoxy unsubstituted or substituted with fluorine； each of R₁ and R₂ is independently hydrogen, or an amino-protecting group； is useful in the synthesis of Omarigliptin or other compounds, is an important intermediate.

US Patent No. 7902376 and PCT Publication WO2007097931 disclose methods to prepare compounds of formula (04) , but both of the methods disclosed are complex to operate and need a special catalyst. So it is necess ary to explore an easy process.

Example 1:

tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5- (iodomethylene) tetrahydrofuran-3-yl) carbamate

To a mixture of methanol (42 mL) and tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn -2-yl) carbamate (7.0 g) cooled to-5℃ was added a solution of KOH (3.2 g) in methanol (28 mL) dropwise. After dropwise addition, the resulting mixture was stirred for 30 minutes, then iodine (5.7 g) was added to the mixture. The reaction mixture was stirred at 0 ℃ for 10 minutes, followed by 25 ℃ for 6 hours, and then quenched with water (140 mL) . Then the mixture was stirred at 25 ℃ for 2 hours. The precipitate was collected by filtration and washed sequentially with methanol/water (40 mL, v: v＝1: 1) . The resulting solid was dried at 45 ℃ in vacuo to give the title compound as awhite solid (8.8 g, purity: 95.0％)

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z : 460.2, [M+Na] +；

1H NMR (600 MHz, CDCl₃) δ (ppm) : 7.09-6.90 (m, 3H) , 5.46 (s, 1H) , 4.92 (d, 1H) , 4.86 (d, 1H) , 4.36 (s, 1H) , 2.95 (ddd, 1H) , 2.62 (dd, 1H) , 1.43 (s, 9H) .

Example 2:

tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran- 3-yl) carbamate

To a mixture of methanol (150 mL) and sodium methoxide (13.0 g) cooled to -10 ℃ was added a solution of tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn-2-yl) carbamate (31.1 g) in methanol (200 mL) dropwise. After dropwise addition, N-bromosuccinimide (21.5 g) was added to the resulting mixture. The mixture was stirred at 0 ℃ for 10 minutes, followed by 25 ℃ for 6 hours, and then quenched with water (350 mL) and stirred for 30 minutes. The mixture was concentrated in vacuo until the precipitate appeared. After stirring at 25 ℃ for 30 minutes, the precipitate was collected by filtration and washed sequentially with methanol (80 mL) and water (80 mL) . The resulting solid was dried at 45 ℃ in vacuo to give the title compound as a white solid (35.4 g, purity: 92.8％) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.0, [M+Na] ⁺；

¹H NMR (600 MHz, CDCl₃) δ (ppm) : 7.11 -6.87 (m, 3H) , 5.53-5.30 (m, 1H) , 5.13-5.06 (m, 1H) , 4.33 (s, 1H) , 2.95-2.86 (m, 1H) , 2.62-2.56 (m, 1H) , 1.43 (s, 9H) .

Example 3:

tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran-3-yl) carbamate

To a mixture of water (42 mL) , methanol (100 mL) and KOH (15.0 g) cooled to -10 ℃ was added a solution of tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxypent-4-yn-2-yl) carbamate (41.6 g) in methanol (550 mL) dropwise. After dropwise addition, dibromohydantoin (23.1 g) was added to the resulting mixture. The reaction mixture was stirred at 0 ℃ for 30 minutes, followed with a temperature from 20 ℃ to 25 ℃ for 8 hours, and then quenched with water (650 mL) and stirred for 1.5 hours. The precipitate was collected by filtration and washed sequentially with methanol/water (400 mL, v: v＝1: 1) . The resulting solid was dried at 50 ℃ in vacuo to give the title compound as a white solid (46.5 g) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 414.0, [M+Na] ⁺.

Example 4:

tert-butyl ( (1R, 2S) -1- (2, 5-difluorophenyl) -1-hydroxy-5-iodo-4-oxopentan-2-yl) carbamate

A solution of sodium hydrogen sulfate monohydrate (2.2 g) and tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5- (iodomethylene) tetrahydrofuran-3-yl) carbamate (7.2 g) in THF/water (35 mL/7 mL) was stirred at a temperature from 28 ℃ to 33 ℃ for 12 hours. Then the organic phase of the reaction mixture was separated and concentrated in vacuo at 40 ℃ to remove THF. Isopropyl acetate (35 mL) and water (28 mL) was added to the residue and the resulting mixture was stirred for 10 minutes. The seperated organic phase was concentrated in vacuo to give the title compound as brown oil (8.6 g) , which could be used for the next step without purification.

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 477.8, [M+Na] ⁺, 381.8, [M-BuO] ⁺ .

Example 5:

tert-butyl ( (1R, 2S) -5-bromo-1- (2, 5-difluorophenyl) -1-hydroxy-4-oxopentan-2-yl) carbamate

A solution of sodium hydrogen sulfate monohydrate (6.9 g) and tert-butyl ( (2R, 3S) -5- (bromomethylene) -2- (2, 5-difluorophenyl) tetrahydrofuran-3-yl) carbamate (39.0 g) in THF/water (200 mL/40 mL) was stirred at 60 ℃ for 10 hours to complete the reaction. Then the organic phase of the reaction mixture was separated and concentrated in vacuo to remove THF. The residue was diluted with isopropyl acetate (200 mL) and water (120 mL) , and stirred to dissolve. The organic phase was seperated and concentrated in vacuo to give the title compound as brown oil (43.5 g) , which was used for the next step without purification.

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 336.1, [M-BuO] ⁺.

Example 6:

tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl) carbamate

To the brown oil (8.6 g) obtained from Example 4 were added THF (40 mL) and K₂CO₃ (2.6 g) . The reaction was stirred at 30 ℃ for 16 hours. Then the mixture was concentrated in vacuo to remove THF and the resulting residue was diluted with a mixture of ethyl acetate (40 mL) and water (20 mL) . The separated organic phase was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (2.5 mL) , heated to 40 ℃ and stirred to dissolve. Then the mixture was cooled to 20 ℃ and n-heptane (7.5 mL) was added. After sitrring for 4 hours at 20 ℃, the precipitate was collected by filtration to give the title compound as a white solid (4.0 g) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0, [M+Na] ⁺, 368.0, [M+K] ⁺；

¹H NMR (600 MHz, CDCl₃) δ (ppm) : 7.24 (m, 1H) , 7.04 (m, 2H) , 4.85 (s, 1H) , 4.68 (s, 1H) , 4.31 (dd, 1H) , 4.16-4.11 (m, 1H) , 4.11-4.04 (m, 1H) , 3.10-3.02 (m, 1H) , 2.75 (s, 1H) , 1.64 (s, 1H) , 1.37-1.25 (s, 9H) .

Example 7:

tert-butyl ( (2R, 3S) -2- (2, 5-difluorophenyl) -5-oxotetrahydro-2H-pyran-3-yl) carbamate

To the brown oil (43.5 g) obtained from Example 5 were added THF (500 mL) and K₂CO₃ (15.2 g) . The reaction was stirred at 35 ℃ for 16 hours. Then the organic phase was separated and concentrated in vacuo at 40 ℃ to remove THF and the resulting residue was diluted with a mixture of ethyl acetate (500 mL) and water (100 mL) . Then the separated organic phase was concentrated in vacuo and the resulting residue was diluted with ethyl acetate (13 mL) , heated to 40 ℃ and stirred to dissolve. Then the mixture was cooled to 20 ℃ and n-heptane (39 mL) was added. After sitrring for 4 hours at 20 ℃, the precipitate was collected by filtration to give the title compound as a white solid (23.9 g) .

The compound was characterized by the following spectroscopic data: LC-MS (ESI, pos. ion) m/z: 350.0.

//////////WO 2016015596, Omarigliptin,  Sunshine Lake Pharma Co Ltd, NEW PATENT

WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

(WO2016016766) A PROCESS FOR THE PREPARATION OF ISAVUCONAZONIUM OR ITS SALT THEREOF

WOCKHARDT LIMITED [IN/IN]; D-4, MIDC Area, Chikalthana, Aurangabad 431006 (IN)

KHUNT, Rupesh Chhaganbhai; (IN).
RAFEEQ, Mohammad; (IN).
MERWADE, Arvind Yekanathsa; (IN).
DEO, Keshav; (IN)

The present invention relates to a process for the preparation of stable Isavuconazonium or its salt thereof. In particular of the present invention relates to process for the preparing of isavuconazonium sulfate, Isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide has purity more than 90%. The process is directed to preparation of solid amorphous form of isavuconazonium sulfate, isavuconazonium iodide hydrochloride and Boc-protected isavuconazonium iodide. The present invention process of Isavuconazonium or its salt thereof is industrially feasible, simple and cost effective to manufacture of isavuconazonium sulfate with the higher purity and better yield.

Habil Khorakiwala, chairman of Indian generic drugmaker Wockhardt

Isavuconazonium sulfate is chemically known l-[[N-methyl-N-3-[(methylamino) acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl)thiazol-2-yl]butyl]-lH-[l,2,4]-triazo-4-ium Sulfate and is structurally represented by formula (I):

Formula I

Isavuconazonium sulfate (BAL8557) is indicated for the treatment of antifungal infection. Isavuconazonium sulfate is a prodrug of Isavuconazole (BAL4815), which is chemically known 4-{2-[(lR,2R)-(2,5-Difluorophenyl)-2-hydroxy-l-methyl-3-(lH-l ,2,4-triazol-l-yl)propyl]-l ,3-thiazol-4-yl}benzonitrile compound of Formula II

Formula II

US Ppatent No. 6,812,238 (referred to herein as '238); 7,189,858 (referred to herein as '858); 7,459,561 (referred to herein as '561) describe Isavuconazonium and its process for the preparation thereof.

The US Pat. '238 patent describes the process of preparation of Isavuconazonium chloride hydrochloride.

The US Pat. '238 described the process for the Isavuconazonium chloride hydrochloride, involves the condensation of Isavuconazole and [N-methyl-N-3((tert-butoxycarbonyl methylamino) acetoxymethyl) pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester. The prior art reported process require almost 15-16 hours, whereas the present invention process requires only 8-10 hours. Inter alia prior art reported process requires too many step to prepare isavuconazonium sulfate, whereas the present invention process requires fewer steps.

Moreover, the US Pat. '238 describes the process for the preparation Isavuconazonium hydrochloride, which may be used as the key intermediate for the synthesis of isavuconazonium sulfate, compound of formula I. There are several drawbacks in the said process, which includes the use of anionic resin to prepare Isavuconazonium chloride hydrochloride, consequently it requires multiple time lyophilization, which makes the said prior art process industrially, not feasible.

The inventors of the present invention surprisingly found that Isavuconazonium or a pharmaceutically acceptable salt thereof in yield and purity could be prepared by using substantially pure intermediates in suitable solvent.

Thus, an object of the present invention is to provide simple, cost effective and industrially feasible processes for manufacture of isavuconazonium sulfate. Inventors of the present invention surprisingly found that isavuconazonium sulfate prepared from isavuconazonium iodide hydrochloride, provides enhanced yield as well as purity.

The process of the present invention is depicted in the following scheme:

Formula I

Formula-IA

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Synthesis of l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino) acetoxymethyl]pyridin-2-yl]carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3 - [4-(4-cyanophenyl)thiazol-2-yl]butyl] - 1 H-[ 1 ,2,4] -triazo-4-ium iodide

Isavuconazole (20 g) and [N-methyl-N-3((tert-butoxycarbonylmethylamino)acetoxy methyl)pyridine-2-yl]carbamic acid 1 -chloro-ethyl ester (24.7 g) were dissolved in acetonitrile (200ml). The reaction mixture was stirred to add potassium iodide (9.9 g). The reaction mixture was stirred at 47-50°C for 10-13 hour. The reaction mixture was cooled to room temperature. The reaction mass was filtered through celite bed and washed acetonitrile. Residue was concentrated under reduced pressure to give the crude solid product (47.7 g). The crude product was purified by column chromatography to get its pure iodide form (36.5 g).

Yield: 84.5 %

HPLC Purity: 87%

Mass: m/z 817.4 (M- 1)⁺

Example-2: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride

l-[[N-methyl-N-3-[(t-butoxycarbonylmethylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide (36.5 g) was dissolved in ethyl acetate (600 ml). The reaction mixture was cooled to -5 to 0 °C. The ethyl acetate hydrochloride (150 ml) solution was added to reaction mixture. The reaction mixture was stirred for 4-5 hours at room temperature. The reaction mixture was filtered and obtained solid residue washed with ethyl acetate. The solid dried under vacuum at room temperature for 20-24 hrs to give 32.0 gm solid.

Yield: 93 %

HPLC Purity: 86%

Mass: m/z 717.3 (M-HC1- 1)

Example-3: Preparation of Strong anion exchange resin (Sulfate).

Indion GS-300 was treated with aqueous sulfate anion solution and then washed with DM water. It is directly used for sulfate salt.

Example-4: Synthesis of l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium Sulfate

Dissolved 10.0 g l-[[N-methyl-N-3-[(methylamino)acetoxymethyl]pyridin-2-yl] carbamoyloxy]ethyl-l-[(2R,3R)-2-(2,5-difluorophenyl)-2-hydroxy-3-[4-(4-cyanophenyl) thiazol-2-yl]butyl]-lH-[l ,2,4]-triazo-4-ium iodide hydrochloride in 200 ml deminerahzed water and 30 ml methanol. The solution was cooled to about 0 to 5°C. The strong anion exchange resin (sulfate) was added to the cooled solution. The reaction mixture was stirred to about 60-80 minutes. The reaction was filtered and washed with 50ml of demineralized water and methylene chloride. The aqueous layer was lyophilized to obtain

(8.0 g) white solid.

Yield: 93 %

HPLC Purity: > 90%

Mass: m/z 717.4 (M- HS0₄) ⁺

////////WOCKHARDT, WO 2016016766, ISAVUCONAZONIUM SULPHATE, NEW PATENT

LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

(WO2016016865) A PROCESS FOR THE PREPARATION OF NUCLEOSIDE PHOSPHORAMIDATE

LUPIN LIMITED [IN/IN]; 159 CST Road, Kalina, Santacruz (East), State of Maharashtra, Mumbai 400 098 (IN)

ROY, Bhairab, Nath; (IN).
SINGH, Girij, Pal; (IN).
SHRIVASTAVA, Dhananjai; (IN).
MEHARE, Kishor, Gulabrao; (IN).
MALIK, Vineet; (IN).
DEOKAR, Sharad, Chandrabhan; (IN).
DANGE, Abhijeet, Avinash; (IN)

The present invention pertains to process for preparing nucleoside phosphoramidates and their intermediates. Phosphoramidates are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. One of the recently approved phosphoramidate by USFDA is Sofosbuvir [1190307-88-0]. Sofosbuvir is a component of the first all-oral, interferon-free regimen approved for treating chronic hepatitis C. The present invention provides novel intermediate, its process for preparation and use for the preparation of Sofosbuvir. The present invention also gives one pot process for preparation of Sofosbuvir.

Hepatitis C virus (HCV) infection is a major health problem that leads to chronic liver disease, such as cirrhosis and hepatocellular carcinoma, in a substantial number of infected individuals. There are limited treatment options for individuals infected with hepatitis C virus. The current approved therapeutic option is the use of immunotherapy with recombinant interferon- [alpha] alone or in combination with the nucleoside analog ribavirin.

US 7964580 ('580) is directed towards novel nucleoside phosphoramidate prodrug for the treatment of hepatitis C virus infection.

US'580 patent claims Sofosbuvir and rocess for preparation of Sofosbuvir of Formula 1.

Formula 1

Process for preparation of Sofosbuvir as per US '580 patent involve reaction of compound of Formula 4" with a nucleoside 5'

Compound 4" nucleoside 5'

Wherein X' is a leaving group, such as CI, Br, I, tosylate, mesylate, trifluoroacetate, trifluroslfonate, pentafluorophenoxide, p-nitro-phenoxide.

Objects of the invention

The object of the present invention is to provide a novel intermediate of Formula 2

Formula 2

wherein X' is a leaving group selected from 1-hydroxybenzotriazole, 5-(Difluoromethoxy)-lH-benzimidazole-2-thiol, 2-Mercapto-5-methoxybenzimidazole, cyanuric acid, 2-oxazolidinone, 2-Hydroxy Pyridine. The above leaving group can be optionally substituted with n-alkyl, branched alkyl, substituted alkyl; cycloalkyl; halogen; nitro; or aryl, which includes, but not limited to, phenyl or naphthyl, where phenyl or naphthyl are further optionally substituted with at least one of Ci-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl, Ci-C₆ alkoxy, F, CI, Br, I, nitro, cyano, Ci-C₆ haloalkyl, -N(R^r)2, Ci-C₆ acylamino, -NHS0₂Ci-C₆ alkyl, -S0₂N(R^r)₂, COR^1", and -S0₂Ci-C₆ alkyl; (R^r is independently hydrogen or alkyl, which includes, but is not limited to, Ci-C₂o alkyl, Ci-Cio alkyl, or Ci-C₆ alkyl, R¹" is -OR¹ or -N(R^r)₂).

Another object of the present invention is to provide a process to prepare the intermediate of Formula 2.

Another object of the present invention is use of the intermediate of Formula 2 in the preparation of Sofosbuvir of Formula 1.

Formula 1

Example 1:

Process for the preparation of S-oxazolidinone derivative of Formula 2

Step-1 Preparation of phosphorochloridate solution:

Dichloromethane (DCM 400ml) was charged in round bottom flask flushed with nitrogen. Phenyl phosphodichloridate (18.30ml) was added in one portion in the flask. The flask was cooled to -60°-70°C with a dry ice-acetone bath. Solution of L-alanine isopropyl ester hydrochloride (20.6gm)) in DCM (50ml) was added to the reaction flask. To this was added a solution of triethylamine (11.20ml) in MDC (100 ml) was added over a course of 60 minutes, while maintaining internal temperature below -70 °C throughout the addition. After completion of reaction, temperature of reaction mass was raised to room temperature.

100ml THF was charged in another round bottom flask flushed with nitrogen followed by the addition of S-4-phenyloxazolidnone (lOgm). Triethyl-amine (11.2ml) & LiCl (2.85gm) were added to the above flask. The reaction mass was stirred for 15-30 min at room temperature and was cooled to 0-5 °C. Phosphorochloridate solution from step-1 was added drop- wise to the reaction flask in 15-45 min maintaining reaction temperature at 0-5 °C. The reaction mass was stirred for 30-60min at 0°-5°C. The reaction progress was monitored on thin layer chromatography. After completion of the reaction, the reaction temperature was raised to room temperature. Agitation was resumed for an additional 30min. The reaction mass was filtered and concentrated under reduced pressure. To this was added diisopropyl ether (400ml) and aqueous saturated ammonium chloride solution and reaction mass was stirred for 10-15 minutes. Organic layer was separated and was washed with water (100ml) & dried over sodium sulfate and concentrated under vacuum. Cyclohexane (50ml) was charged to the obtained oily mass and reaction mass was stirred till solid precipitated out. Solid was filtered and washed with cyclohexane and dried under vacuum (8.80gm MP 56.5°-56.6°C). The obtained product was characterized by mass, NMR & IR. 1H NMR (DMSO-d₆) δ 1.142 -1.18

(m, 9H), 3.85-3.92 (m, 1H), 4.72-4.89(m, 2H), 5.31-5.32(d, 1H), 6.25-6.3 (m, 1H), 6.95-7.31 (m, 10H); MS, m/e 433 (M+l) ⁺

Example 2: Process for the preparation of 2-hydroxy pyridine derivatives of formula 2:

Anhydrous dichloromethane (DCM) 700ml was charged in round bottom flask flushed with nitrogen. The flask was cooled to -60° to -70°C in a dry ice acetone bath. Phenyl phosphodichloridate (76.04 gm) was added in one portion in the flask at -65°C. Solution of L-alanine isopropyl ester hydrochloride (60.56 gm) in DCM (50 ml) was added to the reaction mass. Solution of triethylamine (72.44gm) in DCM (50ml) was added to the reaction mass over a course of 60 minutes, while maintaining internal temperature below -70°C throughout the addition. The resulting white slurry was agitated for additional 60 minutes. Then the temperature of reaction mass was raised to room temperature. Reaction mass was stirred for 60 min & TLC was checked. Reaction mass was filtered and rinsed with anhydrous dichloromethane (2 XI 00 mL). The filtrate was concentrate under vacuum to 20 V and reaction mass was filtered, washed with DCM (15ml). The filtrate was transferred to RBF. The reaction mass was cooled to 0°-10°C. A solution of 2-hydroxy-3-nitro-5- (trifluoromethyl) pyridine (15.gm) in DCM (100ml) & triethyl amine (21.89gm) was added to the reaction mass. Temperature of reaction mass was raised to 20-30°C. Reaction mass was stirred overnight. Reaction was monitored using TLC. After completion, the reaction mass was filtered and washed with DCM (30ml). Filtrate was washed with water (150 ml x 2). Organic layer was concentrated under vacuum and degased. Diisopropyl ether (200ml) was charged to reaction mass and reaction mass was stirred for 15 minutes , filtered and washed with methyl ter-butyl ether (MTBE 30ml). Filtrate was concentrated under vacuum and dried. (8.68gm, MP-125.5°-131.5°C). Obtained compound was characterized by Mass, NMR & IR. 1H NMR (DMSO-d₆) δ 1.07 -1.27 (m, 9H), 4.04-4. l l(m, 1H), 4.73-4.79(m, 1H), 6.76-7.43 (m, 5H), 9.00-9.02 (d, 2H); MS, m/e 478 (M+l) ⁺; FTIR, 1203, 1409, 1580, 1732, 3217.

Other 2-hydroxy pyridine derivatives of Formula 2 were prepared by following the process disclosed in example 2-

2-Hydroxy-5-fluoropyridine derivative of Formula 2;-1H NMR (DMSO-d₆) δ 1.09 -1.23 (m, 9H), 3.02-3.06 (m, lH), 3.85-4.01 (m,lH), 4.79-4.87(m, 1H), 6.4-6.52 (m,lH), 7.10-7.89 (m,6H); MS, m/e 383 (M+l) ⁺,

2-Hydroxy-5-nitropyridine derivative of Formula 2:- 1H NMR (DMSO-d₆) δ 1.06 -1.22 (m, 9H),4.0-4.02 (m,lH), 4.7-4.8(m,lH), 6.5-6.6 (m,lH),7.12-7.42 (m,6H),8.66-8.68 (d, lH),9.07-9.13(d,lH); MS, m/e 410 (M+l) ⁺

2-Hydroxy-3, 5-dinitropyridine derivative of Formula 2:- 1H NMR (DMSO-d₆) δ 1.11 -1.24 (m, 9H), 3.04-3.09(m,lH), 4.8-4.86(m,lH), 7.09-7.39 (m,5H),8.97-9.06 (d,2H)

Example 3: Process for the preparation of Sofosbuvir by coupling of isopropyl(((3-nitro-5-(trifluromethyl)pyridin-2-yl)oxy)phenoxy)phosphoryl-L-alaninate with 1-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione :

To a solution of l-((2R,3R,4R,5R)-3-fluoro-4-hydroxy-5-(hydroxymethyl)-3-methyltetrahydrofuran-2-yl)pyrimidine-2,4(lH,3H)-dione (0.2gm) in THF (4 ml), tert- butylmagnesium chloride (0.80ml, 1.7 M solution in THF) was added dropwise at room temperature and reaction mass was stirred for 30 minutes. A solution of pyridine derivative from example 2 (0.36gm) in THF (4ml) was added dropwise to the reaction mass at room temperature. Completion of reaction was monitored using TLC. After completion of reaction, reaction mass was quenched by using saturated ammonium chloride solution (10ml). Reaction mass was extracted with ethyl acetate (50ml). Organic layer was separated, dried over magnesium sulfate and concentrated under vacuum. The resulting residue was purified by column chromatography on silica gel & obtained solid product was characterized. MS, m/e 530.2 (M+l) ⁺.

/////////LUPIN, SOFOSBUVIR, NEW PATENT, WO 2016016865

Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED

WO2016016774, CRYSTALLINE FORMS OF CANAGLIFLOZIN

SUN PHARMACEUTICAL INDUSTRIES LIMITED [IN/IN]; Sun House, Plot No. 201 B/1 Western Express Highway Goregaon (E) Mumbai, Maharashtra 400 063 (IN)

SANTRA, Ramkinkar; (IN).
NAGDA, Devendra, Prakash; (IN).
THAIMATTAM, Ram; (IN).
ARYAN, Satish, Kumar; (IN).
SINGH, Tarun, Kumar; (IN).
PRASAD, Mohan; (IN).
GANGULY, Somenath; (IN).
WADHWA, Deepika; (IN)

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus. A crystalline Form R1of canagliflozin emihydrate. The crystalline Form R1 of canagliflozin hemihydrate of claim 1, characterized by an X-ray powder diffraction peaks having d-spacing values at about 3.1, 3.7, 4.6, and 8.9 A

The present invention relates to crystalline forms of canagliflozin, processes for their preparation, and their use for the treatment of type 2 diabetes mellitus.

Canagliflozin hemihydrate, chemically designated as (l<S)-l,5-anhydro-l-[3-[[5-(4-fluorophenyl)-2-thienyl]methyl]-4-methylphenyl]-D-glucitol hemihydrate, is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus. Its chemical structure is represented by Formula I.

Formula I

U.S. Patent Nos. 7,943,582 and 8,513,202 disclose crystalline forms of canagliflozin hemihydrate.

PCT Publication No. WO 2009/035969 discloses a crystalline form of

canagliflozin, designated as I-S.

PCT Publication No. WO 2013/064909 discloses crystalline complexes of canagliflozin with L-proline, D-proline, and L-phenylalanine, and the processes for their preparation.

PCT Publication No. WO 2014/180872 discloses crystalline non-stoichiometric hydrates of canagliflozin (HxA and HxB), and the process for their preparation.

PCT Publication No. WO 2015/071761 discloses crystalline Forms B, C, and D of canagliflozin.

Chinese Publication Nos. CN 103980262, CN 103936726, CN 103936725, CN 103980261, CN 103641822, CN 104230907, CN 104447722, CN 104447721, and CN 104130246 disclose different crystalline polymorphs of canagliflozin.

In the pharmaceutical industry, there is a constant need to identify critical physicochemical parameters of a drug substance such as novel salts, polymorphic forms, and co-crystals, that affect the drug's performance, solubility, and stability, and which may play a key role in determining the drug's market acceptance and success.

The discovery of new forms of a drug substance may improve desirable processing properties of the drug, such as ease of handling, storage stability, and ease of purification. Accordingly, the present invention provides novel crystalline forms of canagliflozin having enhanced stability over known crystalline forms of canagliflozin.

EXAMPLES

Example 1 : Preparation of a crystalline Form Rl of canagliflozin hemihydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours to obtain a solid. The solid was further dried under vacuum at 60°C for 6 hours.

Yield: 4.71 g

Example 2: Preparation of a crystalline Form R2 of canagliflozin monohydrate

Amorphous canagliflozin (5 g) was suspended in an aqueous solution of sodium formate (80 mL of a solution prepared by dissolving 137.7 g of sodium formate in 180 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water (100 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 1.5 hours. De-ionized water (50 mL) was added to the reaction mixture, and then the reaction mixture was stirred for 30 minutes. The reaction mixture was filtered, then washed with de-ionized water (300 mL), and then dried under vacuum for 12 hours at room temperature.

Yield: 4.71 g

Example 3 : Preparation of a crystalline Form R2 of canagliflozin monohydrate

Canagliflozin hemihydrate (0.15 g; Form Rl obtained as per Example 1) was suspended in de-ionized water (3 mL). The suspension was stirred at room temperature for 24 hours. The reaction mixture was filtered, then dried at room temperature under vacuum for 5 hours.

Yield: 0.143 g

Example 4: Preparation of a crystalline Form R3 of canagliflozin hydrate

Amorphous canagliflozin (100 g) was suspended in an aqueous solution of sodium formate (1224 g of sodium formate in 1600 mL of de-ionized water). The suspension was stirred at room temperature for 20 hours to obtain a reaction mixture. De-ionized water

(2000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for one hour. De-ionized water (1000 mL) was added to the reaction mixture, and then the reaction mixture was stirred for another one hour. The reaction mixture was filtered, then washed with de-ionized water (6000 mL), and then dried under vacuum for 30 minutes to obtain a solid. The solid was then dried under vacuum at 30°C to 35°C until a water content of 8% to 16% was attained.

Yield: 100 g

 

From top left: Abhay Gandhi (CEO-India Business-Sun Pharma), Kal Sundaram (CEO-TARO). Middle row (L-R): Israel Makov (chairman, Sun Pharma), Dilip Shanghvi (Founder and MD, Sun Pharma) Uday Baldota (CFO, Sun Pharma). Bottom: Kirti Ganorkar (Senior VP, Business development, Sun Pharma)

./////////////Canagliflozin , New patent, WO 2016016774, SUN PHARMACEUTICAL INDUSTRIES LIMITED