WO 2016145990, Ledipasvir, New patent, SHANGHAI FOREFRONT PHARMACEUTICAL CO., LTD

WO 2016145990, Ledipasvir, New patent, SHANGHAI FOREFRONT PHARMACEUTICAL CO., LTD

(WO2016145990) METHOD OF PREPARATION FOR LEDIPASVIR AND DERIVATIVE THEREOF, AND INTERMEDIATE COMPOUND FOR PREPARATION OF LEDIPASVIR

SHANGHAI FOREFRONT PHARMCEUTICAL CO., LTD [CN/CN]; Room 1306, No.781 Cailun Road China (Shanghai) Pilot Free Trade Zone, Pudong New Area Shanghai 201203 (CN)

HUANG, Chengjun; (CN).
FU, Gang; (CN).
FU, Shaojun; (CN).
WEI, Zhewen; (CN).
LI, Wei; (CN).
ZHANG, Xixuan; (CN)

chinese machine translation please bear...........

Leidipawei (Ledipasvir, LDV, the structure as shown in Formula 1-LDV) was developed by Gilead hepatitis C drugs, FDA has granted LDV / SOF (Sofosbuvir) fixed dose combination drug therapy breakthrough finds that this combination therapy is expected in the short 8-week period to cure patients with genotype 1HCV, but without injections of interferon or ribavirin (ribavirin).

US20100310512 Leidipawei reported synthetic route is as follows:

2 side chain compound 1-LDV are Moc-Val, but in the compound 21 in the first to introduce Cbz-, then introduced into the left Moc-Val 13-Br in the compound by hydrolysis and condensation, and the right side chains prior to 17 -Br Boc-introduced, and then condensed by the introduction of the right hydrolyzed Moc-Val, i.e., it is not required to introducing a protecting group, then 2 times by hydrolysis, condensation of 2 times the target product. Cumbersome reaction steps, and the product raw material is expensive, tedious synthetic methods to make the product more expensive raw material costs, requires the use of more efficient ways to reduce material costs.

US2013324740 reported Leidipawei the following preparation method:

Law methodology US20100310512 efficiency in high, but still prepared Boc protected compound 24, compound 27, as well as through hydrolysis to remove the protecting group Boc, the yield is still not high, but also increase the waste emissions.

Thus, there remains the need to find simpler, more efficient Leidipawei preparation.

 

 

Route 1

Law Compound 11 first introduced in Moc-val group, Boc protection is not required, can significantly improve the synthesis efficiency and reduce waste emissions.

Route 2

Law Compound 11, Compound 3-Moc were first introduced Moc-Val, got rid of all the protection, deprotection, significantly reduced synthetic steps to improve the synthesis efficiency, production cycle reduced significantly, waste emissions significantly lower raw material costs significantly reduction, with significant industrial significance.

Route 3

Law of the compound 4-Br-Moc-Boc, the compound 5-Moc-Boc protecting group is introduced, it can reduce the effects of electron-rich N atoms of catalyst, dramatically reducing the amount of catalyst and promote the reaction, an increase of raw materials utilization. Since the catalyst and raw materials expensive, so this route can significantly reduce raw material costs. Meanwhile, the product line also reduces the defluorination impurities content.

Synthesis of Compound 1-LDV: Example 32

In three bottle was charged with compound 1'-LDV-Bz-Bz (5.25g, 4.5mmol), potassium phosphate aqueous solution (1M / L, 50mL) and tert-amyl alcohol (50 mL), warmed to 90 deg.] C, stirred for 5 hours, cooled to room temperature, ethyl acetate (100 mL). The organic phase was dried over anhydrous sodium sulfate, and concentrated to give the product (4G, yield 100%).

/////WO 2016145990, Ledipasvir, New patent, SHANGHAI FOREFRONT PHARMACEUTICAL CO., LTD

WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED

WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED

LINK>>> (WO2016147197) A NOVEL PROCESS FOR PREPARING (2S,3R,4R,5S,6R)-2-[4-CHLORO-3-(4-ETHOXYBENZYL)PHENY 1] -6-(HY DROXY METHYL)TETRAHYDRO-2H-PY RAN-3,4,5-TRIOL AND ITS AMORPHOUS FORM

HARMAN FINOCHEM LIMITED [IN/IN]; 107, Vinay Bhavya Complex 159-A, C.S.T. Road Kalina, Mumbai 400098 Maharashtra (IN)

KADAM, Vijay Trimbak; (IN).
SAIKRISHNA; (IN).
CHOUDHARE, Tukaram Sarjerao; (IN).
MINHAS, Harpreet Singh; (IN).
MINHAS, Gurpreet Singh; (IN)

CHAIRMAN

HARPREET SINGH MINHAS

Owner, HARMAN FINOCHEM LIMITED

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is sodium dependent glucose transporter (SGLT) which is currently under investigation for the treatment of type-2 diabetes. (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is marketed under the tradename Farxiga or Forxiga.

(2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is also known as D-glucitol, l,5-anhydro-l-C-[4-chloro-3-[(4ethoxyphenyl)methyl]phenyl]-, (I S). (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3, 4,5 -triol is a white to off-white powder with a molecular formula of C2iH25C106 and a molecular weight of 408.87

Formula-I

US 6,515,117 B2 discloses (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol and its pharmaceutically acceptable salts. US 6,515,117 B2 also describes process for preparation of (2S,3R,4R,5S,6R)-2-[4- chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol which comprises reaction of 5-bromo-2-chloro-4'-ethoxydiphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl- -D-glucolactone in presence of THF/Toluene, methansulfonic acid to yield o-methylglucoside product which further reacts with Et3SiH, BF3Et20 in presence of MDC and acetonitrile to yield yellow solidified foam which is dissolved in MDC, pyridine and followed by acetylation with acetic anhydride, DMAP to yield tetra acetylated- β-C-glucoside as a white solid which is further deprotected with LiOH H20 in presence of THF/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The drawback of said prior art is having multiple process steps which makes the process very lengthy and tedious. Moreover the process discloses use of hazardous chemicals like pyridine which is not applicable to industry.

Process for preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenylJ-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol is disclosed in US 7,375,213 B2 and J.Med.Chem.2008, 51, 1145-1149. The preparation process is depicted in Scheme-I.

Scheme-1

Prior art US'213 describes reaction of 2-chloro-5-bromo-4'-ethoxy-diphenylmethane with 2,3,4,6-tetra-O-trimethylsilyl-D-gluconolactone, n-BuLi in presence of THF and Heptane. After basification with TEA, the oily residue of methyl- l-C-(2-chloro-4'- ethoxy-diphenylmethan-3-yl)-a-D-glucopyranose obtained as solid compound after workup. This compound reacts with acetic anhydride in presence of THF, DIPEA and DMAP to get oily residue of methyl-2,3,4,6 tetra-0-acetyl-l-C-(2-chloro-4'-ethoxydiphenylmethan-3-yl)-a-D-glucopyranose which further undergoes reduction reaction in presence of acetonitirle, t riethylsilane, boron trifluoride etherate to yield 2,3,4,6-tetra-0-acetyl-l-C-(2-chloro-4'-ethoxydi henylmethan-3-yl)-β-D-glucopyranose which is further deprotected by reacting with LiOH monohydrate in presence of THF/MeOH/H20 to get (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

The said prior art describes multiple, time consuming process steps which involves getting the intermediate products as oily residue at various stages of the process, which is difficult to purify and handle for further process step. More over the workup involves multiple evaporation of product which may result in decomposition. Another drawback of the process is that the process describes n-BuLi reaction with two pot reaction. It is very difficult to transfer the material from one reactor to second reactor at -78 °C at industrial level with highly moisture sensitive reaction mass. This makes process uneconomical, cumbersome and commercially not viable. Further when practically the said method followed, a-Isomer of the final product is formed in the range of 6-8% along ith Des-bromo impurity formed in the range of 7-9 %, which increases after addition of n-butyllithium and kept the mass for overnight reaction. Moreover lactone ring cleavage is also observed in the range of 3-4% after addition of Methanesulphonic Acid/Methanol and maintained overnight for reaction completion, the removal of which is difficult from the final product.

WO 2008002824 A 1 discloses crystalline forms of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol comprising (S)-propylene glycol (PG), (R)-PG, EtOH, ethylene glycol (EG), 1 :2 L-proline, 1 : 1 L-proline, 1 : 1 L-proline hemihydrate, 1 : 1 L-phenylalanine and its preparation process.

In the light of the above drawbacks, it is necessitated to provide economical, robust, safe and commercially viable process for preparing (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

Accordingly, it is an objective of the present invention to provide a commercially viable process for the preparation of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxyb.enzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol, prepared via riovel intermediates which gives higher yield and purity and facilitates easy recovery of the final compound. The purification process does not involve any costly technique/equipment, however, carried out with solvents which are industrially feasible. More over the present invention discloses the n-BuLi insitu reaction that makes the present invention cost-effective over the teachings of prior art.

Scheme-II

Formula-Ill Formula-IV

Formula-V where R1= allyl, prop-2-ynyl,isopropyl

Scheme-Ill

where R = allyl, prop-2-ynyl

Scheme-IV

Scheme-V

Examples:

Example-1: Preparation of 3,4,5-Tris-trimethylsiIanyloxy-6-trimethylsiIanyloxymethyl-tetrahydro-pyran-2-one

To 750 cc of dry THF added 1.12 mole 3,4,5-Trihydroxy-6-hydroxymethyl-tetrahydro-pyran-2-one at ambient temperature and stirred for 20 min. To the reaction mass added 9.0 mole N-Methyl morpholine and stirred for another 30.0 min at ambient temperature. Reaction mass was cooled to -5 °C to 0 °C and stirred for 30.0 min. Added 18.0 mole Trimethyl sillyl chloride at the temp -5 °C to 0 °C and stirred for 30.0 min. Temperature was raised to 25 °C to 30 °C and maintained for 18-20hrs. After reaction complies by GC, the reaction mass was cooled to -5 deg to 0 deg. Added Sat.Sodium bicarbonate solution to obtain the pH 7-8 and stirred for 1 hr at 0 °C. Added 500 cc toluene and stirred for lhr. Reaction mass was settled down for 30.0 min and layers were separated. To the Aqueous layer added 250 cc of toluene and stirred for 30.0 min. Layers separated and both the organic layers mixed and back washed with sat.brine solution. Organic layer was distilled under reduced pressure at a temperature of about 40 - 48 deg. Unload the oily mass . Purity: 92-96 %

Example-2: Preparation of 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-triol

To the mixture of 10 cc THF and 10 cc Toluene added 0.138 mole 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether at ambient temperature and stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, reaction mass was quenched with Methane sulphonic acid and Allyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred overnight. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline and stirred for 30.0 min. Layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer was combined and washed with 30cc water and 50 cc sat. brine solution. Organic layer was distilled under reduced pressure to recover toluene. Solid compound was dissolved in 50cc of toluene and quenched in n-Hexane to obtain 83 % the compound as crystalline solid.

HPLC purity: 88 - 91 %

I R data:

Anomeric C-0 stretching: 1242 cm"1

Allylic C- O stretching: 1 177 cm"1

Allylic C- H stretching: 3010 - 3120 cm"1

Aromatic C- CI stretching: 820 cm"1

Lactones O - H stretching: 3240 - 3380 cm"1

Lactones C - 0 stretching: 1045 - 1092 cm"1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm"1

Alkane C - H stretching: 2877,2866, 2956, 2958, 2962 cm"1

Aromatic C - H stretching: 3050 - 3090 cm"1

Dip-Mass

(M+Na) 487.19 m/z

(M+K) 503.17 m/z

Example 3: Preparation of 2-prop-2ynyl-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture of 10 cc THF and 10 cc Toluene added 0.138 mole 4-(5-bromo-2-chlorobenzyl)phenyl ethyl ether at ambient temperature and stirred for 15 min. Cooled to -70 to -80°C in dry ice /acetone bath and stirred for 15 min. Added a solution of 0.014 mole n-Butyl lithium (1.9M in hexanes) at -70 to -80°C. and stirred for lhr. Added solution of 3, 4, 5-Tris-trimethylsilanyloxy-6-trimethylsilanyloxymethyl-tetrahydro-pyran-2-one in 5 cc of Toluene at -70 to -80°C and stirred for 2 to 3hrs. After the compliance of the reaction, the reaction mass was quenched with Methane sulphonic acid and propargyl alcohol mixture at -70 to -80°C. Temperature was raised to ambient temperature and stirred overnight. Reaction mass was quenched with 30 cc sat.sodiumbicarbonate solution to bring the pH neutral to alkaline. Reaction mass stirred for 30.0 min. Layers separated and aqueous layer was extracted with 10 cc of Toluene. Organic layer were combined and washed with 30cc water and 50 cc sat. brine solution. Organic layer was distilled under reduced pressure to recover toluene. Solid compound dissolved in 50cc of toluene and quenched in n-Hexane to obtain 75 - 80 % the compound as crystalline solid.

HPLC purity: 88 - 93 %

IR data:

Anomeric C-0 stretching: 1242 cm"1

Propargyl ~c CH stretching: 2125 cm"1

Propargyl C- H stretching : 3010 - 3120 cm"1

Aromatic C- CI stretching: 820 cm"1

Lactones O - H stretching: 3240 - 3380 cm"1

Lactones C - 0 stretching: 1045 - 1092 cm"1

Aromatic C=C stretching: 1510 , 1548 , 1603 , 1703 cm"1

Alkane C - H stretching: 2877, 2866,2956,2958,2962 cm"1

Aromatic C - H stretching: 3050 - 3090 cm"1

Dip-Mass

(M+Na) 485.25 m/z

(M+K) 501.25 m/z

Example-4: Preparation of 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyI-tetrahydro-pyran-3,4,5-trioI

To the mixture of 20 cc (1 : 1 MDC + ACN) added 0.1 1 mole 2-Allyloxy-2-[4-chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon atmosphere, and stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°C and stirred the reaction mass for 30.0 min at -50 to -55°C. Slowly added Borontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C . and stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled down the reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and wash with 500 cc water. Washed the organic layer with 500 cc of sat. Brine solution. Distilled out the MDC under reduced pressure below 40°C. to get 85 %the light yellow solid.

HPLC purity: 92-95 %

Example 5: Preparation of 2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol

To the mixture of 20 cc (1 :1 MDC + ACN) added 0.11 mole 2-prop-2-ynyl-2-[4-Chloro-3-(4-ethoxy-benzyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol under argon

atmosphere. Stirred the reaction mass for 30.0 min. Cooled the reaction mass to -40 to -55°C in a dry ice/acetone bath under argon atmosphere. Charged 3 mole Triethylsilane at -40 to -55°C and stirred the reaction mass for 30.0 min at -50 to -55°C. Slowly added Borontrifloride in diethyl ether solution at -40 to -55°C and stirred the reaction mass for 2 hrs. Quenched the reaction mass with 50 cc sat. sodium bicarbonate solution at -40 to -55°C and Stirred the reaction mass for 30.0 min. Slowly raised the temperature to 25 to 30°C. Settled down the reaction mass and separated the layers, extracted the aqueous layer with 100 cc of MDC. Combined the organic layer and washed with 500 cc water. Washed the organic layer with 500 cc of sat. Brine solution. Distilled out the MDC under reduced pressure below 40°C. to get 85%the light yellow solid.

HPLC purity: 90%

Example 6: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the solid obtained from example 4 charged 500cc of n-heptane and stirred for ½hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs.; cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the, cake with 100 cc n-heptane. Dried at 40-45°C under vacuum to get 85% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

HPLC purity: 91-93%

Example 7: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the solid obtained from example 5 charged 500cc of n-heptane and stirred for ½ hrs at ambient temperature. Heated the reaction mass to 55-60°C and stirred it for 2-3 hrs., cooled to room temperature and maintained for 4-5 hrs. Filtered the solid and washed the cake with 100 cc n-heptane. Dried at 40-45 °C under vacuum to get 85-88% amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6- (hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol.

HPLC purity: 89-91%

Example 8: Preparation of L-proline - (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyI]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol co crystal

To the 10 cc of Ethyl acetate charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 - 65°C and stirred for 1 hr. Slowly added L-proline at 60 -65°C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 -65°C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55°C under reduced pressure to get 92% titled compound.

HPLC purity: 99%

Example 9: Preparation of L-proline - (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triolco crystal

To the 10 cc of acetone charged 1.0 mole (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol under argon atmosphere at ambient temperature and stirred for 30.0 min to get clear solution. Slowly heated the reaction mass to 60 - 65°C and stirred for 1 hr. Slowly added" proline at 60 -65°C and maintained for 1 hr. Slowly added 15 cc n-Heptane to the reaction mass at 60 -65°C and stirred the mass for 2.5 hrs. Cooled the mass to ambient temperature for 3-4 hrs and maintained for 5 hrs. Filtered the mass under argon atmosphere. Washed the cake with 10 cc n-Heptane. Dried the cake at 50-55°C under reduced pressure to get 93-95% titled compound.

HPLC purity: 98-99%

Example 10: Preparation of amorphous form of (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol

To the 15 cc ethyl acetate added (2S,3R,4R,5S,6R)-2-[4-chloro-3-(4-ethoxybenzyl)phenyl]-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol at ambient temperature and stirred for 30.0 min. Slowly added 5- 8 cc sat. sodium bicarbonate solution at ambient temperature and stirred for 1.5 hr to get the clear solution. Settled down and separated layers. Extracted the aqueous layer with 25 cc ethyl acetate.

Combined the organic layers and washed the ethyl acetate layer with 50 cc sat. Sodium chloride solution. Distilled out ethyl acetate under reduced pressure at 40 - 45°C to get ■fluffy solid. Charged 50 cc n-Heptane and stirred for 5 hrs to get 70-78% the title compound as Amorphous soild.

HPLC purity: 99.8-99.95 %

Example 11: Preparation of 2-chloro -4'- ethoxydiphenylmethane (impurity)

To the 20 cc THF and 20 cc Toluene added 0.25 mole 2-ehloro-5-bromo-4'- ethoxydiphenylmethane under argon atmosphere. Cooled the reaction mass to - 78° C. Slowly added n-Butyl lithium (1.9 M in hexane) at - 78° C and stirred for 30 min. Slowly added 20 % Ammonium chloride solution to the reaction mass. Brought the reaction mass to ambient temperature and stirred for 30 min. Settled and separated layers. Extracted the aqueous layer with 50 cc toluene. Washed the combined organic layer with 500 cc brine solution. Distilled out the toluene and charged heptanes, stirred for 2 - 3 hrs at ambient temperature. Filtered the product and dried the product at 45 - 50°C under reduced pressure to get 93 % titled compound.

Mass: (m+1) 247 m/z found 247.1 1

HPLC purity: 96.33 %

SHENDRA AURANGABAD, MAHARASHTRA, INDIA

Bhupinder Singh Manhas

////////WO 2016147197, DAPAGLIFLOZIN, NEW PATENT, HARMAN FINOCHEM LIMITED

WO 2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

WO-2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

SMILAX LABORATORIES LIMITED [IN/IN]; Plot No. 12/A, Phase - III, I.D.A. Jeedimetla, Hyderabad 500 055 (IN).

The present invention relates to an improved process for the preparation of substantially pure compound of 2-Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of Formula I, with a reduced content of desethyl impurity less than 0.1% and an efficient, commercially viable process for the preparation of pure intermediates of Azilsartan.

KOTAGIRI, Vijaya Kumar; (IN).
YENUMULA, Raghavendra Rao; (IN).
BANDARI, Mohan; (IN).
SURYADEVARA, Murali Krishna; (IN)

(WO2016147120) AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE AZILSARTAN

Azilsartan (I) is an angiotensin receptor II antagonist used in the treatment of hypertension. Angiotensin II causes vasoconstriction via an angiotensin II receptor on the cell membrane and elevates blood pressure.

Azilsartan medoxomil i.e. (5-methyl-2-oxo-l,3-dioxol-4-yl)methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid is developed by Takeda pharmaceuticals and is marketed under the trade name Edarbi. It was approved by USFDA on 25 Feb, 2011 and EMEA on 7 Dec 2011 for the treatment of high blood pressure in adults.

Azilsartan medoxomil and its salts thereof are imbibed with properties such as strong and long lasting angiotensin II antagonistic activity and hypotensive action which has an insulin sensitizing activity useful for the treatment of metabolic diseases such as diabetes and the like., and a useful agent for the prophylaxis or treatment of circulatory diseases such as hypertension, cardiac diseases, nephritis and stroke. Azilsartan medoxomil is the prodrug of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan).

Methods of preparing benzimidazole derivative useful as an angiotensin II receptor antagonist such as Azilsartan Medoxomil and salts thereof are disclosed by Takeda in US 5,243,054 (herein after referred as US '054 patent). The US'054 patent describes several synthetic routes for preparing Azilsartan. According to one of the synthetic process, the compound of formula II is reacted with hydroxylamine hydrochloride in a conventional organic solvent and sodium methoxide in methanol to give the amidoxime compound of formula III which on further reaction with ethyl chloroformate in presence of triethylamine base in refluxing xylene undergoes cyclization to provide a compound of formula IV. Azilsartan was prepared by hydrolysis of compound of formula IV in presence of lithium hydroxide by adjusting the pH with HC1. The process is as depicted below in Scheme A:

However, the amidoxime compound of formula III obtained by the above process contains about 50% of amide imputiy along with desired product, owing to the strong reaction conditions which impairs the quality and loss of yield. The pH adjustment with HC1 in the hydrolysis step of compound IV results in the formation of an undesired desethyl impurity of formula V due to acid sensitive nature of the ether linkage in the benzimidazole moiety of Azilsartan.

Formula V

According to another method disclosed in US'054 for the preparation of Azilsartan comprises by reacting ethoxycarboimidoyl biphenyl benzimidazole derivative of compound with ethyl chloroformate to give N-methoxycarbonyl ethoxycarboimidoyl biphenyl benzimidazole derivative, which is further converted to compound of formula IV and then to Azilsartan of formula I by hydrolysis.

According to one another embodiment method for the preparation of Azilsartan disclosed in US '054, cyanobiphenyl aminobenzoate derivative compound reacts with hydroxylamine hydrochloride in presence of triethylamine subsequently followed by addition of ethyl chlorocarbonate results in the formation of compound of formula IV which is further hydrolyzed to obtain Azilsartan of formula I.

J. Med. Chem. Vol. 39, No. 26, 5230-5237 (1996) describes the use of triethylamine as base during the conversion of compound of formula II to amidoxime compound of formula III and use of 2-ethylhexylchloroformate instead of ethylchloroformate as cyclizing agent.

Processes for the preparation of Azilsartan medoxomil and its potassium salt are described in US 7,157,584 which comprises reacting Azilsartan with 4-hydroxymethyl-5-methyl-l,3-dioxol-2-one in presence of dimethylacetamide, p-toluoyl sulfonylchloride, 4-dimethylaminopyridine and potassium carbonate.

PCT publication WO 2012/107814 discloses process for the preparation of Azilsartan or its esters or salts by reacting amidoxime compound of formula III with carbonyl source such as carbodiimides, dialkyl carbonate and phosgene equivalents in presence of a suitable base to obtain compound of formula IV which is further converted to Azilsartan and its pharmaceutically acceptable salts. The process for the preparation of Azilsartan is as depicted in Scheme B:

Scheme - B

This publication also discloses that use of a carbonyl source reduces the formation of the content of desethyl impurity during cyclization.

Polymorphs of Azilsartan and its salts are disclosed in WO 2013/044816 and WO 2013/186792.

All the above prior art methods for the preparation of Azilsartan have inherent disadvantages such as the usage of unsafe reagents, high boiling solvents, extreme reaction conditions invariably resulting in the formation of low pure intermediates as well as Azilsartan having a considerably higher content of desethyl impurity. Accordingly, there remains a need for the industrial preparation of substantially pure Azilsartan which is free of impurities with high yield.

Examples

Example-1: Preparation of Methyl-2-ethoxy-l-[[2'- ((hydroxycarbamimidoyl)biphenyl)-4-yl]methyl]-lH-benzimidazole-7-carboxylate (Formula-Ill):

To a stirred solution of DMSO (1500.0 mL), Hydroxylamine hydrochloride ( 126.7g 1.83mol) and Dipotassium hydrogen phosphate (634.9g 3.65mol) was added Methyl l-[[2'-cyanobiphenyl-4-yl]methyl]-2-ethoxybenzimidazole-7-carboxylate (lOO.Og 0.243mol) at 25-30°C. The reaction mass temperature was raised to 80-85°C and maintained for 30-40 hours. Reaction completion was monitored by TLC. Upon completion of reaction, reaction mass was cooled to 10- 15°C, and was poured into water (3000.0 mL), stirred for 45min at 20-25°C. and was filtered. The filtered wet solid was washed with water and dried at 65°C to get crude Methyl-2-ethoxy-l-[[(2'-(hydroxycarbarmrmdoyl)biphenyl-4-yl]methyl]-lH-benzimidazole-7-carboxylate. The wet material was slurried in Acetone (optional) at reflux and filtered at room temperature to obtain pure compound.

Yield: 79.92 g, 74.0%; HPLC Purity: 97.78%; Desethyl impurity: 0.318%; Amide impurity: 1.42%.

Example-2: Preparation of Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (Formula-IV) :

To the pre cooled solution of Methylene dichloride (375.0 mL) and Methyl-2-ethoxy-1 -[[2' -((hydroxycarbamimidoyl)biphenyl)-4-yl] methyl]- lH-benzimidazole-7-carboxylate (75.0g, 0.168mol) was added ethyl chloroformate ( 18.3g 0.168mol)

followed by addition of triethylamine (18.75g 0.185mol). The reaction mass was maintained at 0-5 °C for about 1 hour. Upon completion of the reaction, reaction mass was poured into water (200.0 mL), organic layer was separated and washed with 5% NaHC03 solution (150.0 mL) and then with water (150.0 mL). The organic layer was dried over sodium sulfate and distilled to obtain the crude material (optionally be isolated using cyclohexane solvent). To this obtained crude material, ethyl acetate (750.0mL) and potassium carbonate (112.5g 0.814mol) were added and heated to reflux for 6 to 8 hours. The contents were cooled, filtered and wet solid was slurried in water. Wet material so obtained was slurried in ethyl acetate at reflux and filtered at room temperature and dried at 60-65°C to give Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate.

Yield: 64.27 g, 81.0 %; HPLC Purity: 99.80%; Desethyl impurity: 0.085%.

Example-3: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (395.8 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (25. Og) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (125.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 5.0 using dilute acetic acid at 0-5 °C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.

Yield: 20.0 g, 82.47%; HPLC Purity : 99.80%; Desethyl impurity: 0.10%.

Example-4: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (633.33 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (40.0g) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (200.0mL). pH of the separated aqueous product layer was adjusted to 4.0 to 4.5 using acetic acid at 10-15°C. The obtained solid material was filtered and washed with water (lOO.OmL). This material was dried to obtain the title product.

Yield: 32.35 g, 83.37%; HPLC Purity: 99.45%; Desethyl impurity: 0.12%.

Example-5: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (791.66 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (50.0g) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (250.0mL). pH of the separated aqueous product layer was adjusted to 3.0 to 4.0 using citric acid at 10-15°C. The obtained solid material was filtered and washed with water (125.0mL). This material was dried to obtain the title product.

Yield: 37.0 g, 76.28%; HPLC Purity: 99.69%; Desethyl impurity: 0.083%.

Example-6: Preparation of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

A mixture of 0.4N NaOH solution (395.83 mL) and Methyl 2-ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylate (25. Og) were stirred at 50-55°C for period of 60min. The reaction mass was cooled to room temperature and the product layer was washed with ethyl acetate (lOO.OmL). pH of the separated aqueous product layer was adjusted to 3.0 to 4.0

using hydrochloric acid at 10-15°C. The obtained solid material was filtered and washed with water (72.5 mL). This material was dried to obtain the title product. Yield: 20.22 g, 83.37%; HPLC Purity: 99.45%; Desethyl impurity: 0.217%.

Example-7: Purification of 2-Ethoxy-l-[[2'-(2,5-dihydro-5-oxo-l,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan)

Charged 2-Ethoxy- 1 - [[2' -(2,5-dihydro-5-oxo- 1 ,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (lOO.Og), methanol (600.0ml) and methylene dichloride (600.0ml) and were stirred for 10 min at 25-30°C to get a clear solution. Above solution was treated with Activated carbon (lO.Og) and stirred for 10.0 min at 25-30°C. Reaction mixture was passed through a hyflow bed and washed with a mixture of (1: 1) ratio of 200.0ml methanol and methylene dichloride. The solvent mixture was distilled out at below 50°C till the solid formation was observed. Reaction mixture is stirred for 30.0min at 30°C, then the solid was filtered and washed with 200.0ml of methylene dichloride. To the obtained solid, methanol (450.0 ml) was charged at 25-30°C, heated to 45°C, stirred for 30 min at 45°C and then cooled to 30°C. After cooling, the solid was filtered and washed with methanol (90.0ml) which was further dried at 50-55°C for 12 hours.

Yield: 80.0 g, 80.0%; HPLC Purity: 99.96%; Desethyl impurity : 0.012%.

Smilax Managing Director, S. Murali Krishna received the award from Hon’ble Chief Minister of Andhra Pradesh Shri. N. Kiran Kumar Reddy.

//////////WO 2016147120, AZILSARTAN, NEW PATENT, SMILAX Laboratories Ltd

WO 2016113415, Sandoz, Riociguat, New Patent

WO 2016113415, Sandoz, Riociguat, New Patent

STEFINOVIC, Marijan; (AT).
RICHTER, Frank; (AT).
GRIESSER, Ulrich; (AT).
LANGES, Christoph; (AT)

SANDOZ AG [CH/CH]; Lichtstrasse 35 4056 Basel (CH)

WO 2016113415

Novel method for purifying riociguat, useful for treating chronic thromboembolic pulmonary hypertension, pulmonary arterial hypertension, systemic sclerosis and Raynaud's phenomenon. Also claims novel crystalline solvates of riociguat (eg ethyl acetate or butan-2-one solvate), useful as intermediates in the purification of riociguat. Bayer and licensee Merck have developed and launched riociguat.

The present filing appears to be the first filing from Sandoz on riociguat; however see WO2015095515, assigned to Novartis, parent company of Sandoz, claiming an ophthalmic composition comprising a soluble guanylate cyclase activator (eg riociguat).

Riociguat (BAY 63-2521 ), having the chemical name N-[4,6-Diamino-2-[1-(2-fluorobenzyl)-1 H-pyrazolo[3,4-b]pyridin-3-yl]pyrimidin-5-yl]-N-methylcarbamic acid methyl ester, or sometimes also called or also sometimes called Methyl-(4,6-diamino-2-(1-(2-fluorobenzyl)-1 H-pyrazolo[3, 4-b]pyridin-3-yl)-5-pyrimidinyl)(methyl)carbamate is a stimulator of the soluble guanylate cyclase.

Riociguat has been approved for the treatment of inoperable, or persistent, recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after surgery in adult patients and for the treatment of pulmonary arterial hypertension and is in development for the treatment of systemic sclerosis and Raynaud's phenomenon.

(I)

The preparation of the compound of formula (I) and its purification are known. According to the experimental procedure of Example 8 of WO 03/095451 (comparable description in Chem. Med. Chem 2009, 4, 853-865), iodomethane is used as an alkylating agent in a late step and the purification of the crude riociguat either comprised preparatory HPLC steps or several steps of extracting, precipitating, suspending, washing, redissolving and reprecipitating riociguat, resulting in a long and tedious workup procedure with moderate yield.

In WO 201 1/064171 a potential genotoxic azo compound of formula III is used as a key intermediate, which under catalytic hydrogenation forms a compound of formula VIII.

The compound of formula VIII is further reacted with a methyl chloroformate or with a dimethyl carbonate derivative to form a compound of formula VI. The compound of formula VI is then methylated to form crude riociguat of formula (I).

Crude riociguat of formula (I) is then purified by a process comprising the intermediate isolation of a riociguat DMSO solvate of formula (II).

For the pharmaceutical use of riociguat, the solvent DMSO has to be removed. To that end, the compound of formula (II) is boiled in pharmaceutically acceptable solvents such as ketones, esters, ethers or alcohols. However, the riociguat obtained in this manner contains detectable amounts of DMSO.

These processes for the preparation of riociguat and their laborious purification protocols have a number of disadvantages which are unfavorable for industrial realization on a large scale.

On the one hand, the purification process according to WO 03/095451 require the repeated isolation of solid intermediates or preparatory HPLC, which ultimately results in a reduced yield of pure riociguat of formula (I) of pharmaceutical grade. Yet, traces of compound of formula (III) remain.

It is therefore one of the objects of the present invention to provide a process for the preparation of pure riociguat - compound of the formula (I) - which yields riociguat free from any genotoxic impurity and/or mutagenic impurity.

On the other hand, the process for the preparation of riociguat described in WO 201 1/064171 has a different serious drawback. It comprises the use of a DMSO solvate.

DMSO is an active pharmaceutical ingredient by itself. It is used as an active pharmaceutical ingredient in the treatment of interstitial cystitis. DMSO removal is difficult to achieve by the published processes. It is thus a further object of the invention to provide riociguat essentially free from DMSO and suitable for pharmaceutical use.

WO 2014/128109 discloses forms of riociguat, such as polymorphs and solvates, and describes a ¼ ethyl acetate solvate of riociguat in example 6. The X-ray powder

diffractogram in Tab.3 and figure 4 comprises reflexes at °2Theta positions of 9.1 and 25.6.

Thus, there is a need in the art for a process, which allows the preparation of pure riociguat free from any genotoxic impurity and/or mutagenic impurity which at the same time does not comprise residual DMSO.

Surprisingly, we have now identified a process for the purification of crude riociguat which yields riociguat which is essentially free from genotoxic impurities and DMSO. In particular, this novel process differs from the processes known to date in that the isolation of intermediates prior to the formation of riociguat is not required. This process allows to overcome the disadvantages of the processes known to date and to obtain riociguat in high yield and high purity and pharmaceutical acceptable quality essentially free of genotoxic impurities.

Examples

Preparative example

Preparation of crude riociguat

Riociguat was prepared as disclosed in example 7 of WO 201 1/064171 and had a chemical purity of 91.7% by the area of the riociguat peak in the HPLC-UV elution profile.

Comparative Example 1

Preparation of DMSO solvate

An amount of 4.505 g (0.0107 moles) of crude riociguat was dissolved in 8 ml DMSO at 100 °C. The obtained brownish, turbid solution was then cooled to 75 °C within 16 minutes. After that 55 ml of ethylacetate were added and the mixture was cooled to 25 °C (30 minutes). After 22 h the obtained precipiate was filtered off, washed with 14 ml EtOAc and dried for 4 hours at 50 °C at reduced pressure (50 mbar). The precipitate was analysed with XRPD, confirming that riociguat DMSO was obtained. The product was also analyzed by HPLC-UV-MS. Purity was calculated based on UV detection at 254nm. The so obtained riociguat DMSO solvate was 91 .92% pure.

Comparative Example 2

Preparation of riociguat form I from riociguat DMSO solvate

The entire product prepared in comparative example 1 (4.283 g = 0.009 moles) was reflux heated in 77 ml of ethylacetate at 78 °C for 1 h and then cooled to 25 °C. The white solid was filtered off with suction, washed with a total of 18 ml of ethyl acetate and dried at 50 °C under reduced pressure (50 mbar) for 5 hours. The dried product was then analyzed by XRPD, confirming identity of riociguat form I unequivocally.

Yield (dry): 3.224 g (0.0076 moles) = 75% for comparative example 2 and 72% overall (C.ex. 1 and 2). Total organic volatile impurity is higher than 1000 ppm and total DMSO content is higher than 100 ppm.

Example 1 ; Preparation of Riociguat ethylacetate solvate

Crude Riociguat (500 mg; Form I; 91 .7% percentage area purity) was dissolved in 2 ml DMF and heated to 100 °C to obtain a slightly turbid solution. After filtration through a 0.44 micron filter, 20 ml EtOAc were added to the hot solution (water bath 70°C) and allowed to stand. The temperature was slowly decreased to ambient temperature. Crystallization started after

10min. The yellowish, fine powder was filtered off and dried at ambient conditions. The PXRD indicated the formation of a new ethylacetate solvate. Yield 71 %, 97.8% purity.

Example 2; Preparation of the Methyl ethyl ketone (butan-2-one) solvate of Riociguat.

Crude Riociguat (500 mg; Form I; 91 .7% percentage area purity) was dissolved in 2 ml DMF at 100 °C to obtain a clear solution. After filtration through a 0.44 micron filter, 20 ml MEK were added. The hot solution (water bath 70 °C) was allowed stand. The temperature was then slowly decreased to ambient temperature. After 30 minutes yellowish, square-shaped crystals appeared, which were analyzed. Analysis confirmed that they were a new crystalline MEK-solvate. Yield 43%, 97.2% purity.

Example 3 ; Conversion of Solvated forms to Form I

Both the solvates from examples 1 and 2 can be converted to riociguat Form I by heating the material to 150°C under vacuum for an appropriate amount of time.

Example 4; Direct preparation of riociguat form I from crude riociguat using DMF-Acetone Crude Riociguat (200 mg; Form I; 91 .7% percentage area purity) was dissolved in 1.0 ml DMF at 100 °C to obtain a clear solution. After filtration through a 0.44 micron filter, 5 ml acetone was added. The hot solution (water bath 70 °C) was allowed to stand. Crystallisation occurred while the temperature was slowly decreased to ambient temperature. After 24 hours the precipitate was filtered off and dried at ambient conditions to obtain form I. Yield 78% ; 97.6% purity

///////////WO 2016113415, Sandoz, Riociguat, New Patent