Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

PERAMPANEL

Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

(US20160039759) PROCESS FOR THE PREPARATION OF PERAMPANEL

CADILA HEALTHCARE LIMITED

Sanjay Jagdish DESAI
Jayprakash Ajitsingh Parihar
Kuldeep Natwarlal Jain
Sachin Ashokrao Patil

Perampanel, a non-competitive AMPA receptor antagonist, is the active ingredient of FYCOMPA® tablets (U.S) which is approved as an adjunctive therapy for the treatment of partial on-set seizures with or without secondarily generalized seizures in patients with aged 12 years and older. Chemically, Perampanel is 5′-(2-cyanophenyl)-1′-phenyl-2,3′-bipyridinyl-6′(1′H)-one, with an empirical formula C23H15N30 and molecular weight 349.384 g/mol which is represented by Formula (I).
 

U.S. Pat. No. 6,949,571 B2 discloses perampanel and its various processes for preparation thereof.

U.S. Pat. No. 7,759,367 B2 discloses the pharmaceutical composition of perampanel and an immunoregulatory agent and their uses.

U.S. Pat. No. 8,304,548 B2 discloses the reaction of 5′-bromo-1′-phenyl-[2,3′-bipyridin]-6′(1′H)-one with 2-(1,3,2-dioxaborinan-yl)benzonitrile in the presence of palladium compound, a copper compound, a phosphorus compound and a base to form perampanel of Formula (I). Also discloses the crystalline hydrate, anhydrous crystal Form I, anhydrous crystal Form III, & anhydrous crystal Form V of perampanel of Formula (I).

U.S. Pat. No. 7,803,818 B2 discloses an amorphous form of perampanel. U.S. Pat. No. 7,718,807 B2 discloses salts of perampanel. International (PCT) publication No. WO 2013/102897 A1 discloses anhydrous crystalline Form III, V & VII of perampanel.

U.S. PG-Pub. No. 2013/109862 A1 discloses the method for preparing 2-alkoxy-5-(pyridin-2-yl)pyridine, which is an intermediate for preparing perampanel key starting material 5-(2′-pyridyl)-2-pyridone.

U.S. Pat. No. 7,524,967 B2 discloses the preparation of 5-(2′-pyridyl)-2-pyridone, an intermediate in the preparation perampanel.

 International (PCT) publication No. WO 2014/023576 A1 discloses the preparation of cyanophenyl boronic acid, an intermediate in the preparation perampanel.

The prior-art processes suffer with problems of poor yield and requirement of chromatographic purification or series of crystallizations which further reduces the overall yield of the final product, which is overcome by the process of the present invention.

Pankaj Patel, chairman, Zydus Cadila

EXAMPLES

The present invention is further illustrated by the following examples which is provided merely to be exemplary of the invention and do not limit the scope of the invention. Certain modification and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.

Example-A: Preparation of 5-(2-pyridyl)-1,2-dihydropyridin-2-one In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 188.80 g 5-bromo-2-methoxypyridine in 190 mL tetrahydrofuran and 12.92 g pyridine-2-yl boronic acid were added and refluxed. The reaction mixture was cooled to 25-30° C. and aqueous solution of hydrochloric acid was added and stirred for 1 hour. The reaction mixture was neutralized with aqueous sodium hydroxide and extracted with tetrahydrofuran.

 The organic layer was washed with saline water, dried over anhydrous magnesium sulfate, and then evaporated to obtain the titled compound.

Example-1

Preparation of 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 201.5 g 5-(2-pyridyl)-1,2-dihydropyridin-2-one, 208.3 g N-bromosuccinimide and 1300 mL N,N-dimethylforamide were stirred at 25-30° C. for 2-3 hours. After completion of the reaction, the reaction mixture was poured into water and stirred for 30 min. The precipitate was filtered, washed with N,N-dimethylforamide and dried at 50° C. to obtain 230 g title compound.

Example-2

Preparation of 3-bromo-5-2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

 In a 500 mL round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a solution of 18.75 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one in 300 mL methylene dichloride, 18.36 g 1-phenyl boronic acid, 3.47 g palladium triphenylphosphine and 10 mL triethyl amine were added and the reaction mixture was stirred for 1 hour at 25-35° C. The reaction mixture was filtered and the filtrate was evaporated to dryness. The residue was crystallised from ethyl acetate to obtain the title compound.

Example-3

Preparation of Perampanel

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, a suspension of 188 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one, 161.2 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile, 3.0 g tetrakis(triphenylphosphine)-palladium(0), 10 mL triethylamine (10 mL) in 300 mL methylene dichloride were stirred at 25-30° C. for 12 hours. To the reaction mixture was added 5 mL conc. aqueous ammonia, 10 mL water and 40 mL ethyl acetate. The separated organic layer was washed with water and saturated saline solution and dried over magnesium sulfate. The solvent was removed under vacuum. Ethyl acetate was added to the residue and heated obtain clear solution. n-hexane was added to this solution and cooled to 25-30° C. The obtained solid was filtered and washed with ethyl acetate and dried to obtain perampanel.

Example-4

Preparation of 3-Bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one

 In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 5-(2-pyridyl)-1,2-dihydropyridin-2-one, 108.5 g N-bromosuccinimide and 500 mL N,N-dimethylforamide were stirred at 30-35° C. for 3 hours. 100 mL water was added to the reaction mixture at 5-15° C. and stirred at 30-35° C. for 1 hour. The solid obtained was filtered, washed with water and dried to obtain 129 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one.

Example-5

Preparation of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 2 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1,2-dihydropyridin-2-one, 72.8 g phenylboronic acid and 500 mL N,N-dimethylformamide were added at 30-35° C. and stirred. 11.9 g copper acetate and 15.7 g pyridine were added and air was purged into the reaction mixture and stirred for 16 hours at 30-35° C. After the completion of the reaction, the reaction mixture was poured into 1200 mL aqueous ammonia at 10-15° C. and stirred for 2 hours at 30-35° C. The obtained solid was filtered, washed with water and dried to obtain 120 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one.

Example-6

Purification of 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one

In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one and 500 mL isopropyl alcohol were stirred at 60-65° C. for 30 min. The reaction mixture was cooled to 20-25° C. and stirred for 30 min. The reaction mixture was filtered, washed with isopropanol and dried to obtain 96 g pure 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one.

Example-7

Preparation of Perampanel

 In a 1 L round bottom flask, equipped with a mechanical stirrer, thermometer and an addition funnel, 100 g 3-bromo-5-(2-pyridyl)-1-phenyl-1,2-dihydropyridine-2-one and 125 g 2-(1,3,2-dioxaborinan-2-yl)benzonitrile and 1500 mL N,N-dimethylformamide were added under inert atmosphere. 44 g potassium carbonate and 4.2 g palladium tetrakis were added and stirred at 115-125° C. for 3 hours. The solvent was removed under vacuum. Ethyl acetate was added to the residue and the organic layer was distilled off to obtain perampanel (78 g).

////////Zydus Cadila, New Patent,US 20160039759, PERAMPANEL

Palbociclib, Sun Pharmaceutical Industries Ltd, New patent, WO 2016016769

Palbociclib

WO2016016769,  A PROCESS FOR THE PREPARATION OF PALBOCICLIB

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

TYAGI, Vipin; (IN).
MOHAMMAD, Kallimulla; (IN).
RAI, Bishwa Prakash; (IN).
PRASAD, Mohan; (IN)

The present invention relates to a process for the preparation of palbociclib utilizing a silyl-protected crotonic acid derivative to produce a silyl-protected 5-(1-methyl-3 carboxy-prop-1-en-1-yl)-2-chloro-piperazine followed by intramolecular cyclization of the compound the piperazine intermediate to produce 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one which is then converted to palbociclib.

Sun Pharma managing director Dilip Shanghvi.

Palbociclib chemically is 6-acetyl-8-cyclopentyl-5-methyl-2-[[5-(l-piperazinyl)-2-pyridinyl]amino]pyrido 2,3-d]pyrimidin-7(8H)-one, represented by the Formula I.

Formula I

U.S. Patent No. 6,936,612 discloses palbociclib and a process for the preparation of its hydrochloride salt.

U.S. Patent No. 7,781,583 discloses a process for the preparation of palbociclib, wherein 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-d]pyrimidin-7-one of Formula II

Formula II

prepared by reacting 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine of Formula III

Formula III

with crotonic acid.

U.S. Patent No. 7,863,278 discloses polymorphs of various salts of palbociclib and processes for their preparation.

A first aspect of the present invention provides a process for the preparation of a compound of Formula IV,

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl

comprising reacting a crotonic acid derivative of Formula V

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl

with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV.

A second aspect of the present invention provides a process for the preparation of palbociclib of Formula I,

Formula I

a) reacting a crotonic acid derivative of Formula V,

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) converting the compound of Formula IV to palbociclib of Formula I.

A third aspect of the present invention provides a process for the preparation of a compound of Formula II

Formula II

a) reacting a crotonic acid derivative of Formula V,

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV,

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl; and b) intramolecular cyclization of the compound of Formula IV to give a

compound of Formula II.

A fourth aspect of the present invention provides a process for the preparation of palbociclib of Formula I

Formula I

comprising:

a) reacting a crotonic acid derivative of Formula V,

Formula V

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl with a compound of Formula III

Formula III

in the presence of a palladium catalyst, a base, and optionally a ligand to give a compound of Formula IV

Formula IV

wherein R is trimethylsilyl, dimethylsilyl, or fert-butyldimethylsilyl;

intramolecular cyclization of the compound of Formula IV to give a compound of Formula II; and

Formula II

converting the compound of Formula II to palbociclib of Formula I.

EXAMPLES

Preparation of 2-chloro-8 -cyclopentyl-5 -methyl-8H-pyrido Γ2.3 - lpyrimidin-7-one (Formula II)

Step a: Preparation of trimethylsilyl (2£)-but-2-enoate (Formula V, when R is trimethylsilyl)

Crotonic acid (18.68 g) was taken in dichloromethane (80 mL) at room

temperature to obtain a solution. Hexamethyldisilazane (HMDS) (21 g) followed by imidazole (0.4 g) was added to the solution at room temperature under stirring. The reaction mixture was refluxed for 2 hours. Dichloromethane was recovered completely under vacuum at 45°C. Dichloromethane (200 mL) was again added to the reaction mixture, and then recovered completely under vacuum at 45°C. The colorless liquid obtained was taken as such for next step.

Step b: Preparation of 2-chloro-8-cyclopentyl-5-methyl-8H-pyrido[2,3-i/|pyrimidin-7-one (Formula II)

Method A

Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (52 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (20 g, Formula III) in tetrahydrofuran (100 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Trans-dichlorobis(acetonitrile) palladium (II) (0.970 g) followed by the addition of tri-o-tolylphosphine (0.770 g) was added to the reaction mixture under a nitrogen atmosphere.

The reaction system was again degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75°C to 80°C overnight. The progress of the reaction was monitored by thin layer chromatography (TLC) (60% ethyl acetate/toluene). Trans-dichlorobis(acetonitrile) palladium (II) (0.725 g) was again added followed by the addition of tri-o-tolylphosphine (0.725 g) to the reaction mixture at 75°C to 80°C. The reaction mixture was heated at 75°C to 80°C for 4 hours. After completion of the reaction, acetic anhydride (17 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (100 mL) and IN hydrochloric acid (100 mL) were added and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (40 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (2 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo^® bed and then washed with dichloromethane (40 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (80 mL) was added to the residue and the solvent was evaporated under reduced pressure until 40 mL of isopropyl alcohol remained. Isopropyl alcohol (40 mL) was again added to the mixture, and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered, thenwashed with isopropyl alcohol (20 mL), and then dried under vacuum at 45°C to obtain the title compound.

Yield: 0.535% w/w

Chromatographic purity: 99.51%

Method B

Trimethylsilyl (2£)-but-2-enoate (obtained from step a) and diisopropylethylamine (26.5 mL) were added to a solution of 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine (Formula III, 10 g) in tetrahydrofuran (50 mL) at room temperature under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. Trans-dichlorobis(acetonitrile) palladium (II) (1.39 g) followed by the addition of tri-o- tolylphosphine (1.1 g) was added to the reaction mixture under a nitrogen atmosphere. The reaction system was degassed under vacuum and then flushed with nitrogen; this evacuation procedure was repeated three times. The reaction mixture was heated at 75 °C to 80°C overnight. After completion of the reaction, acetic anhydride (20 mL) was added, and then the mixture was stirred at 75°C to 80°C for 3 hours. The reaction mixture was cooled to room temperature. Dichloromethane (50 mL) and IN hydrochloric acid (50 mL) were added, and then the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was re-extracted with dichloromethane (20 mL) and separated. The combined organic layers were washed with a 5% sodium bicarbonate solution (200 mL) at room temperature. The organic layer was separated and activated carbon (1 g) was added to the mixture. The mixture was stirred for 20 minutes at room temperature. The mixture was filtered through a Hyflo^® bed and then washed with dichloromethane (20 mL). The organic layer was evaporated under vacuum to obtain a residue. Isopropyl alcohol (40 mL) was added to the residue and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. Isopropyl alcohol (20 mL) was again added to the mixture and then the solvent was evaporated under reduced pressure until 20 mL of isopropyl alcohol remained. The mixture was stirred for 3 hours at room temperature. The product was filtered and washed with isopropyl alcohol (10 mL), and then dried under vacuum at 45°C to obtain the title compound.

Yield: 0.46% w/w

Chromatographic purity: 98.1%

/////Palbociclib, Sun Pharmaceutical Industries Ltd, New patent, WO 2016016769

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