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

WO 2016014324, New Patent, Omarigliptin, MERCK SHARP & DOHME CORP

Omarigliptin , MK-3102

WO2016014324, PROCESS FOR PREPARING CHIRAL DIPEPTIDYL PEPTIDASE-IV INHIBITORS

MERCK SHARP & DOHME CORP. [US/US]; 126 East Lincoln Avenue Rahway, New Jersey 07065-0907 (US).

CHUNG, John, Y. L.; (US).
PENG, Feng; (US).
CHEN, Yonggang; (US).
KASSIM, Amude Mahmoud; (US).
CHEN, Cheng-yi; (US).
MAUST, Mathew; (US).
MCLAUGHLIN, Mark; (US).
ZACUTO, Michael, J.; (US).
CHEN, Qinghao; (US).
TAN, Lushi; (US).
SONG, Zhiguo Jake; (US).
CAO, Yang; (US).
XU, Feng; (US)

A process for preparing a compound of structural Formula Ia: comprising Boc deprotection with TFA of, reductive amination of:.

The present invention is directed to a novel process for the preparation of omarigliptin, (2R,35^,,5R)-2-(2,5-difluorophenyl)-5-[2-(methylsulfonyl)-2,6-dihydropyrrolo[3,4-c]pyrazol-5(4H)-yl]tetrahydro-2H-pyran-3 -amine, a dipeptidyl peptidase-IV (DPP-4) inhibitor, for the treatment of Type 2 diabetes, and related intermediates.

BACKGROUND OF THE INVENTION

Syntheses of omarigliptin have previously been described in PCT international patent applications numbers WO 2010/056708 and WO2013/003250. The process described in WO 2010/056708 does not result in a favorable yield of the compound of structural Formula la, as it results in a racemic mixture. WO2013/003250 describes the following scheme to make the compound of structural Formula la, an intermediate for synthesizing omarigliptin:

In WO2013/003250, synthesis of the compound of structural Formula la involves using benzenesulfonic acid (BSA) to remove the Boc protecting group of the compound of structural Formula 1, by first forming a BSA salt of the compound of structural Formula la. The BSA salt is then isolated and undergoes reductive amination with Boc -ketone of the compound of structural Formula 7, to produce the compound of structural Formula la, as a 19: 1 diastereomeric mixture. The BSA mediated Boc deprotection requires up to 72 h to reach full conversion.

An alternative process which eliminates the need to isolate the BSA salt of the compound of Formula la and reduces the overall reaction time of the process is desired. The inventors have now discovered a process for making the compound of structural Formula la which eliminates the step of isolating a salt of the compound of structural Formula la and reduces the overall reaction time. The present process also produces an end-of reaction homogeneous solution via reductive amination, which facilitates crystallization of the compound of structural Formula la. The described process also improves the diastereoselectivity, overall yield, cost and cycle time over the process described in WO2013/003250.

WO2013/003250 also describes the Boc deprotection of the compound of Formula la to produce omarigliptin (Formula I) shown below. As described in WO2013/003250, the Boc deprotection of the compound of Formula la involves aging the substrate in aqueous sulfuric acid in DMAc at 30 °C for 15-20 h, then working up with ammonium hydroxide. This work up produces large amounts of poorly soluble ammonium sulfate which co-crystallizes with the desired product. As a result, isolation of the desired product requires a long cycle time for filtration, washing and drying.

Formula I (omarigliptin)

Because the processes described herein use trifluoroacetic acid with or without a co-solvent for the transformation of the compound of Formula la to omarigliptin, which offers good solubility for the compound of Formula la, omarigliptin is achieved with fast reaction kinetics and good purity profiles.

the compound of structural Formula 1 is prepared by the following processes:

reagents

and,

or alternatively

10 R = Ms

X=OAc

SCHEME 3: Synthesis of the Boc Ketone

16 17 18 19

IPA, H₂Q ,

¹⁾⁹⁵⁶

Step 1 : As

A round bottom flask was charged with ligand L (0.829 g), Cu(II) propionate

monohydrate (0.402 g) (or Cu(II) acetate (0.31 g) or CuCl or CuCl₂) and EtOH (350 ml) and agitated at room temperature for lh. 2,4-Difluorobenzaldehyde (100.0 g) was added followed by DABCO (2.368 g) (or 2,4-dimethylpiperizine) and the mixture was cooled to -5 - -15 °C. Cold (0°C) nitromethane (190 ml or 215 g) was added slowly to the cold solution and the solution was aged at -5 to -15 °C for 20-24 h and at 0 °C for 2-4h. 5 wt% EDTA^»2Na (500 ml) followed by

water (200 mL) and MTBE (1.0 L) was added to the cold solution, and the temperature was raised to 20°C. The layers were separated and the organic layer was washed with additional 5 wt% EDTA^»2Na (500 ml), followed by water (50 mL) and brine (250 mL). The organic layer, containing Compound 17, was concentrated to remove nitromethane, then the solvent was switched to THF.

Step 2: Michael-Lactolization - Nitro lactol

To Compound 17 in 2 volumes of THF (258 mL) from Step 1 under 2 and cooling at 0 °C, 1 equivalent of Hunig's base was added. 1.15 equivalents of acrolein was added over 1 h via syringe pump at 0-5 °C. The reaction was stirred at -10-0 °C overnight. The resulting mixture was used directly in the next step.

Alternatively, the mixture was concentrated at 0-5 °C to remove excess acrolein, then the residue was flushed with acetonitrile until Hunig's base and water are mostly removed. The residue was taken up in 8 volumes of acetonitrile and used directly in the next step.

Alternatively, at the end of the reaction the mixture was worked up by diluting with MTBE and washing with aqueous citric acid solution, and aqueous NaHCC solution, and the solvent was switched to acetonitrile. Alternatively, the end reaction mixture was taken forward directly to the next step.

Step 3: Dehydration - Nitro dihydropyrans

1.1 Equivalents of TEA was added to the acetonitrile solution of lactol 18 from Step 2 followed by 1.2 equivalents of mesyl chloride and 1.2 equivalents of S-collidine under < +10 °C . The reaction was aged at 10°C for 0.5-1 h. Alternatively, the end of the reaction mixture from Step 2 was cooled to between -20 °C to 0 °C. Two equivalents of S-collidine and 1.4 equivalents of mesyl chloride were then added. The mixture was heated to 36 °C and aged overnight. The mixture was cooled to room temperature. 15 volumes of MTBE was added and the solution was

washed with 3 volumes 10 wt% citric acid and 6 volumes water, 10 volumes water, then 3 volumes of 5% aHC03 solution and 6 volumes water. The organic was concentrated with 20 volumes of MTBE using 10 volumes MTBE. The organic solution was stirred with 20-30 wt% AQUAGUARD for 2 hours at room temperature. The mixture was filtered and washed with 2 volumes of MTBE.

Step 4: Dynamic Kinetic Resolution (DKR) crystallization - rraws-nitro-dihydropyran (19t)

The organic MTBE solution of Step 3 was solvent switched to 2 volumes of IPA and the final volume was -300 mL. 10 Mol% of TEA (or DAB CO or morpholine or DMAP) was added. Then water (1 15 mL) was slowly added over 3 hours. The slurry was filtered, washed with 80/20 IP A/water (2x100 mL) and vacuum dried under N₂.

Step 5: Hydroboration/oxidation - Trans-nitro-pyranol

To a vessel charged with /raws-nitro-dihydropyran (10 g), MTBE (100 mL) was added under nitrogen. The mixture was stirred at room temperature to give a clear orange solution. The solution was cooled to +2 °C and borane dimethyl sulfide complex (9.55 ml) was added. The clear solution was aged for 2-5h until >99% conversion by HPLC analysis. The reaction was slowly quenched with water (7.25 ml) keeping at < +9 °C. After the solution was aged at 5°C for 5 min, water (78 mL) was added at < +13 °C. Solid sodium percarbonate (13.26 g, 84 mmol) was added. The suspension was stirred at 5 °C for 15h. The mixture was transferred to a separatory funnel with the aid of 60 mL MTBE and 20 mL water. The mixture was allowed to warm to room temperature. The aqueous phase was back-extracted with 40 mL MTBE. The combined organic phase was washed once with 30 mL half saturated sodium chloride solution, once with 15 mL brine and 15 mL 0.2N HC1, and once with 30 mL half-saturated sodium chloride solution. The organic layer was dried over a2S04. The organic was filtered, washed with 10 mL MTBE and concentrated to an oil. The oil was diluted to 200 mL for a 0.191M solution.

Step 6: Nitro Reduction/Boc protection - Pyranol

A 3 -neck jacketed round bottom flask equipped with overhead stirrier was charged with 0.191M (5R,6S)-5-nitro-pyran-3-ol (119 ml) (Compound 20) in ethanol and ethanol (32 ml). The solution was cooled to 1 1-12 °C. Cold 6N HC1 (19.55 ml, 1 17 mmol) was added at <

+17°C. Zinc dust (12.93 g) was added in five portions (5x2.59g) at < +26 °C. The mixture was stirred at 12 °C for 22 h. 1M K₂C0₃ (76 mL) was added in one portion. MTBE (59 mL) was added then EDTA 2K 2H₂0 (22.55 g) was added over 10 min at < +14 °C. To the solution 45 wt% KOH (4.86 mL) solution was added. The solution was cooled to 5 °C, and 1.1 equivalents of B0C2O (5.46 g) was added. The solution was rinsed with MTBE (10 mL) and stirred at 5 °C for 2h, then at 12 °C for 16h, and then at 24 °C for lOh until >99.5% conversion. The solution was transferred to a separatory funnel with the aid of MTBE (30 mL) and water (5 mL). The organic layer was filtered and washed with MTBE (20 mL). The organic filtrate was concentrated. MTBE (60 mL), water (30 mL) and saturated sodium chloride solution (15 mL) were added. The mixture was warmed in a 30 °C bath to dissolve solid, and then concentrated. The concentrate was flushed with toluene in a 60 °C bath, then concentrated. Toluene (8.4 mL) was added and the mixture was heated to 80 °C. Heptane (70.8 mL) was added over lh at 80 °C, then cooled slowly to room temperature. The mixture was filtered and washed with 1 :2 toluene/heptane (23.55 mL), filterated and vacuum dried under nitrogen until a constant weight.

The purity could be further upgraded by the following procedure: a round bottom flask was charged with the product of Step 6 (7.069 g) from above. EtOH (21 mL) was added and the mixture was heated to 45 °C. Water (31.5 mL) was slowly added over 1 h at 45 °C. The mixture was aged for lh. Water (31.5 mL) was added in one portion, then cooled slowly to room temperature and aged overnight. The slurry was filtered and washed with 1 :3.5 EtOH/water (23.56 mL). Crystals were vacuum dried under nitrogen until a constant weight.

Alternatively, Compound 20 was reduced with 100 psi hydrogen in 20 volume wet THF in the presence of 10-30 wt% Raney nickel at 50 °C. Then the reaction mixture was basified with 2 equivalent of K2CO₃ and a slight execess B0C2O to afford crude Compound 21 after aqueous work up.

Compound 7 was obtained from 21via oxidation as described in WO2013/003250.

S

Boc-mesyl-pyrazole solid 1 was added to 2.5 volumes of TFA at 0-2 °C, over 2-3 minutes under nitrogen, followed by 0.5 volume of TFA rinse. Conversion to TFA salt was complete within 0.5-lh at 1-2 °C. DMAc (14 vol) followed by triethylamine (5 equivalents or 2.3 volumes) were slowly added to the TFA reaction mixture at 0 °C maintaining < +20 °C. Boc-ketone 7 (0.89 equivalent) was then added at -15 °C followed by solid NaBH(OAc)₃ (1.4 equivalents) which was added in three portions over lh. The reaction solution was aged at -15 °C overnight. The solution was then warmed to 22 °C, and after aging for 2-5 h. Diastereomeric ratio was > 96.5:3.5.

The solution was seeded with Boc amine 1 wt% at 22 °C and stirred at 22-40 °C for 2-4 h. 0.36 volume 28% ammonium hydroxide was added over 2-4 h, then, 3.64 volumes 28% ammonium hydroxide was added over 4-10h at 22-60 °C. After cooling to 22 °C, the batch was filtered, washed with 5: 1 DMAc/water, then water. The wet cake was vacuum dried under nitrogen at ambient affording the product. Diastereoselectivity was > 30: 1.

Boc Deprotection of Formula la

A reactor was charged with 2.5 X (by volume) of trifluoroacetic acid. The batch was cooled to 5-10 °C. The reactor was then charged with 0.4 X (by volume) water. The batch was cooled to 0-5 °C. The reactor was then charged with 1 equivalent (1 kg) of the compound of Formula la over 0.5-lh while maintaining the temperature between 0 -5°C. The reactor was then charged with 0.5 X (by volume) trifluoroacetic acid to reactor while maintaining the temperature between 0-5°C. The batch was then heated between 15-20°C and aged for 2-2.5 h. The batch was then cooled to between 5-10°C. A crystallizer was charged with water 5.0 X (by volume) and 0.1 X (by volume) of ammonia water and adjusted to between 3-13°C. To generate a seed bed, Compound I seed (lwt% vs la) was added and the temperature as adjusted to between 3-13°C. A solution of ammonia water 3.8 X (by volume) and of the compound of Formula la was added simultaneously to the seed bed over 2.5 - 3.5 hours while maintaining temperature at 3-13°C and pH -9-10. The batch was aged for at least 30 minutes and then filtered. The resulting crystals were washed with 3. OX (by volume) water at 3 - 13°C twice and vacuum dried at < 50°C to afford the compound of formula I.

//////WO 2016014324, New Patent, Omarigliptin, MERCK SHARP & DOHME CORP, MK-3102