Showing posts with label New patent. Show all posts
Showing posts with label New patent. Show all posts

Wednesday, 29 March 2017

QUILSECONAZOLE, VT 1129, New Patent, WO, 2017049080, Viamet


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VT 1129 BENZENE SULFONATE
CAS 1809323-18-9

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VT 1129

1340593-70-5 CAS
MF C22 H14 F7 N5 O2, MW 513.37
2-Pyridineethanol, α-(2,4-difluorophenyl)-β,β-difluoro-α-(1H-tetrazol-1-ylmethyl)-5-[4-(trifluoromethoxy)phenyl]-, (αR)-
R ISOMER
ROTATION +
QUILSECONAZOLE, VT-1129
Viamet, in collaboration with Therapeutics for Rare and Neglected diseases, is investigating quilseconazole benzenesulfonate (VT-1129), a small-molecule lanosterol demethylase (CYP51) inhibitor, developed using the company's Metallophile technology, for treating fungal infections, including Cryptococcus neoformans meningitis.
WO-2017049080
  

////////////QUILSECONAZOLE, VT-1129, New Patent, WO, 2017049080, Viamet

Tuesday, 7 February 2017

New Patent, (S)-pregabalin, WO 2017019791, Teva

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Synthesis of (S)-pregabalin, Teva
TEVA PHARMACEUTICALS INTERNATIONAL GMBH [CH/CH]; Schusselstrasse 12 8645 Jona (CH) (For All Designated States Except US).
JANAGANI, Satyanarayana [US/US]; (US) (US only)
Improved process for preparing (S)-pregabalin, useful for treating pain, seizures, convulsions and anxiety. Also claims novel intermediates of (S)-pregabalin and their preparation method.
Pregabalin, a GABA alpha-2-delta subunit agonist, had been developed and launched by Pfizer.
Teva received a FDA approval for its generic pregabalin capsules (25, 50, 75, 100, 150, 200, 225 and 300 mg).
S)-Pregabalin, (S)-(+)-3-(aminomethyl)-5-methylhexanoic acid, a compound having the chemical structure,
str1
is also known as pregabalin, γ-amino butyric acid or (S)-3-isobutyl GABA. (S)-Pregabalin, marketed under the name LYRICA®, has been found to activate GAD (L-glutamic acid decarboxylase). (S)-Pregabalin has a dose dependent protective effect on seizure, and is a CNS-active compound. (S)-Pregabalin is useful in anticonvulsant therapy, due to its activation of GAD, promoting the production of GABA, one of the brain's major inhibitory neurotransmitters, which is released at 30 percent of the brains synapses. (S)-Pregabalin has analgesic, anticonvulsant, and anxiolytic activity.
Several processes for the synthesis of (S)-Pregabalin are known. For example, U.S. Patent No. 5,599,973 ("'973 patent") discloses the preparation of (S)-Pregabalin using a stoichiometric amount of (4R,5S)-(+) 4-methyl-5-phenyl-2-oxazolidinone as a chiral auxiliary that may be recycled. See, e.g., '973 patent, col. 14, 1. 29 to col. 18, 1. 23 (example 1). In general, however, the route disclosed in the '973 patent is of limited use on an industrial scale, principally due to the low temperature required for the reaction (e.g., -78°C), the use of pyrophoric reagent (e.g., butyl lithium), and a low overall yield (e.g. , 59%, 65%).
U.S. Publication No. 2003/0212290 ("'290 publication") discloses the synthesis of (S)-Pregabalin by an asymmetric hydrogenation of a cyano-substituted olefin of formula 7, to produce a cyano precursor of (S)-3-(aminomethyl)-5-methyl hexanoic acid of formula 8, which i btain (S)-Pregabalin, as described in the following scheme.
[(R,R)-MeD PHOS]Rh(COD)+BF4-
However, the disclosed method requires the use of carbon monoxide under high pressure, raising serious problems in adapting this process for production scale.
Another process is disclosed by G.M. Sammis, et al, J. Am. Chem. Soc , 125(15): 4442-43 (2003), in which an aluminum salen catalyst is used in the conjugate addition of hydrogen cyanide to a, β-unsaturated imides.
str1
Pregabalin
This process is also not practical for large scale production due to the use of highly poisonous reagents. In addition, the last reduction step requires high hydrogen pressure, which only adds to the difficulties required for adapting this process for use on an industrial scale.
International Publication WO 2006/110783 reports several processes for preparing (S)-Pregabalin via the following intermediate and its analogues.
R^OC "COOR2
wherein Ri and R2 are independently H, a straight or branched Ci-10 alkyl, C6-10 aryl, or C3-6 allyl.
U.S. Publication Nos. 2007/0191636 and 2007/0197827 also disclose processes for preparing (S)-Pregabalin.
Thus, there is a need in the art for additional process for the preparation of (S)-Pregabalin that provide (S)-Pregabalin in high quality and high yield, and that can be adapted to large (industrial) scale production.
EXAMPLES
Example 1: Preparation of (3S)-5-methyl-3-(2-oxo-2{[(lS)-l-phenylethyllamino} ethyl) hexanoic acid (III, wherein Ar = phenyl and R = methyl) with recycling of compound (Ilia)
A. 3-isobutylglutaric acid (700g) and acetic anhydride (420g) were heated to 130-140°C and maintained for about 3 hrs. At the end of the reaction, the reaction mixture was cooled to 70-80°C and acetic acid and acetic anhydride were distilled off under vacuum. Toluene (700 mL) was added to the reaction mixture and further evaporated=for 1.5-2 hrs at 90-95°C. Another 700mL of toluene were added and the resulting 4-isobutylglutaric anhydride (IBG anhydride) solution was cooled to 25-30°C.
B. A different reactor was charged with toluene (4L), S-phenylethylamine (1.05 mol equivalent) and 4-dimethylaminopyridine (DMAP) (4.5g) and the mixture was cooled to
-25 to -15°C. The IBG anhydride solution was added and stirred at -25 to -15°C for 2-3 hrs. The mixture was heated to 25-30°C, 180 mL of aq. HC1 (30%) and water (180 mL) were added and the mixture was heated to 70-75°C. The phases were separated and the organic phase was cooled to 15-30°C and stirred for 2-2.5 hrs. The mixture was filtered and washed twice with toluene (2 vol.).
C. The toluene mother liquor, contained 226 g of the compound of formula Ilia (Ar = phenyl and R = methyl) (ee 76.7 %). The toluene was distilled off to 3 vol and 136 g acetylchloride were added. The mixture was heated to 78-82°C and stirred for 5-6 hrs. At the end of the reaction time, 1130 mL water was added at 50-60°C and the phases were separated. 47.39 g NaOH in 474 mL of water were added to the organic phase and the reaction mixture was heated to 78-82°C and stirred for 8-10 hrs. Then, the reaction mixture was cooled to 25-30°C and the pH was adjusted to 1-3 with 30% HC1. Toluene (8 vol.) was added to the mixture and the phases were separated at 80°C. The organic phase was cooled to 25-30°C and filtered. The filtrate was washed with toluene (2 vol.) and re-crystallized from toluene. Yield 44.94%, purity 97.5%, ee 99.88%.
Example 2: Preparation of (3S)-5-methyl-3-(2-oxo-2{[(lS)-l-phenylethyllamino} ethyl) hexanoic acid
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with toluene (400 ml), (S)-(-)-phenylethylamine (142.35 g,1.1764 mole), and 4-dimethylaminopyridine (0.7176 g, 0.0059 mole). The mixture was cooled to a temperature of -10°C to -15°C, followed by addition of a solution of 3- isobutyl glutaric anhydride (100 g, 0.59 mole) [e.g. obtained in accordance with the process disclosed Drugs of the Future, 24 (8), 862-870 (1999) or according to Example 1 step (A) above] in toluene (100 ml), over a period of 45-60 minutes, and stirring for additional 1.5-2 hours, at a temperature of -10°C to -15°C. The mixture was then extracted with 10% aqueous solution of NaOH (500 ml), and the aqueous phase was washed with toluene (1x250 ml). The pH of the aqueous phase was adjusted to 2-2.5 by adding a solution of hydrochloric acid (1-12N). The aqueous phase was further extracted with toluene (lx 800 ml) at a temperature of 70-80°C. The toluene layer was washed with 10% sodium chloride solution {700ml) at a temperature of 70-80°C followed by crystallization to get 125 g (73.0% yield) of a white solid of (3S)-5-methyl-3-(2-oxo-2-{[(l S)-l-phenylethyl]amino}ethyl) hexanoic acid with an optical purity of 99.75 %, as measured by chiral HPLC.
The toluene mother liquor obtained from the crystallization, which contains a mixture of diastereomers [i.e. compound (Ilia) and (III) wherein Ar = phenyl and R = methyl) is then further processed in accordance with Example 1, step C, in order to convert the compound of formula (Ilia) to (III).
Example 3; Preparation of (3S)-5-methyl-3-(2-oxo-2{[(l S)-l-phenylethyllamino} ethyl) hexanoic acid
Desired major
To a cooled (0 °C) solution of 4-Isobutylglutaric anhydride (0.1 moles) in toluene is added (lS)-l-phenylethanamine (0.1 moles) slowly during 30 minutes and the mixture is warmed to 70 °C, washed with dilute HC1 followed by brine and cooled to ambient temperature during several hours. The precipitate is filtered, washed with toluene and vacuum dried until constant weight to yield (3S)-5-methyl-3-[2-oxo-2-[[(lS)-l-phenylethyl] amino] ethyl]hexanoic acid. Diastereomeric purity by HPLC = 99.5%.
The toluene mother liquor obtained from the precipitation, which contains a mixture of diastereomers [i.e. compound (Ilia) and (III) wherein Ar = phenyl and R = methyl) is then further processed in accordance with Example 1, step C, in order to convert the compound of formula (Ilia) to (III).
Example 4: Preparation of {(S)-4-methyl-2-[((S)-l-phenylethylcarbamoyl)-methyllpentvUcarbamic acid methyl ester
A three-necked flask equipped with an addition funnel, thermometer pocket, drying tube and a mechanical stirrer, was charged with acetone (25 ml), (3S)-5-methyl-3-(2-oxo-2{[(l S)-l-phenylethyl]amino} ethyl) hexanoic acid (5 g, 0.0172 mole), and with
triethylamine (2.17g, 0.0215 mole), and cooled to -10° to -20°C followed by addition of solution of ethyl chloroformate (2.05 g, 0.0189 mole in 5 ml acetone). The mixture was stirred for 1 hour at a temperature of -10° to -20°C, followed by addition of solution of sodium azide (2.8g, 0.0429 mole in water). The resulted slurry was maintained for 1 hour at -10° to -20°C, quenched over ice water followed by extracting the mass with sufficient amount of toluene. The toluene layer was slowly added over a refluxing mixture of toluene and methyl alcohol, followed by stirring for 2 to 4 hours. The stripping off the solvent results in 4.95 g (89.7% yield) of {(S)-4-methyl-2-[((S)-l-phenylethylcarbamoyl)-methyl]pentylcarbamic acid methyl ester (120) with a purity of 97.4% area, as measured by HPLC.
Example 5: Preparation of (S)-Pregabalin
A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120°C for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Β¾Ν was added in an amount sufficient to provide a pH of 4. The (S)-Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.
Example 6: Preparation of (S)-Pregabalin
A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain
pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). B¾N (3.8 g) was added. The mixture was cooled to 2°C for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.
Example 7: Conversion of the Compound of Formula 4 to (S)-Pregabalin: Example 14 of International Publication No. WO 2007/035890
A 0.2 1 reactor was loaded with 70% sulfuric acid (200 g) containing compound 26 (10 g, 0.031 mole), and was heated to 115-120°C for 5-10 hours, and then cooled to room temperature, i.e., about 20° to about 25°C. An aqueous 40% sodium hydroxide solution was added in an amount sufficient to provide a pH of 1. The solution was then extracted with 35 ml of iso-butanol, the organic layer was separated, and Bu3N was added in an amount sufficient to provide a pH of 4. The (S) Pregabalin was precipitated, filtered, and washed with 10 ml of iso-butanol. After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 40.4% yield. Purity: 99.95% area by HPLC.
Compound 26 has the following chemical structure:
str2
wherein Ar is a C6-1o aromatic group, and R is a straight or branched C1-4 alkyl, ester or carboxylic acid.
Example 8: Conversion of the Compound of Formula 4 to (S)-Pregabalin: Example 16 of International Publication No. WO 2007/035890
A flask was loaded with 47% HBr (12 ml), water (6 ml), and compound 26 (6 g), and then was heated to reflux for 3 hours. The solution was cooled to room temperature, and water (12 ml) was added. An aqueous 47% sodium hydroxide solution was added to obtain pH of 3. The solution was then extracted twice with isobutanol (15 ml), the combined organic layers were evaporated and fresh isobutanol was added (15 ml). Bu3N (3.8 g) was added. The mixture was cooled to 2°C for 1 hour, then (S)-Pregabalin was filtered, and washed with of iso-butanol (3 ml). After drying at 55°C under vacuum, (S)-Pregabalin was obtained as white crystals in a 90% yield.
/////////////// (S)-pregabalin, WO 2017019791

Monday, 6 February 2017

New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410

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New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410
Preparation method for antitumor drug AP26113
Suzhou MiracPharma Technology Co Ltd
SUZHOU MIRACPHARMA TECHNOLOGY CO., LTD [CN/CN]; Room 1305, Building 1,Lianfeng Commercial Plaza, Industrial District Suzhou, Jiangsu 215000 (CN)
XU, Xuenong; (CN)
Improved process for preparing brigatinib, useful for treating cancer eg non-small cell lung cancer (NSCLC). The present filing represents the first PCT patenting to be seen from Suzhou MiracPharma that focuses on brigatinib;  In February 2017, brigatinib was reported to be in pre-registration phase.
Disclosed is a preparation method for an antitumor drug AP26113 (I). The method comprises the following preparation steps: cyclizing N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine and N,N-dimethylamino acrylate, condensing N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine and 4-(dimethyl phosphitylate)aniline, and chlorinating N-[2-methoxyl-4-[4-(dimethyl amino)piperid-1-yl]aniline]guanidine by means of a chlorinating agent, sequentially, so as to prepare AP26113 (I). The preparation method adopts easily-obtained raw materials, causes few side reactions, and is economical, environmentally-friendly, and suitable for industrial production.
front page image
AP26113 is an experimental drug developed by Ariad Pharmaceuticals to target small molecule tyrosine kinase inhibitors for the treatment of anaplastic lymphoma kinase-positive (ALK) metastases resistant to crizotinib Non-small cell lung cancer (NSCLC) patients. The drug was approved by the US Food and Drug Administration in August 2014 for breakthrough drug treatment. The current clinical data show that AP26113 on ALK-positive non-small cell lung cancer patients, including patients with brain metastases, have a sustained anti-tumor activity. And the inhibitory activity against ALK is about 10 times that of zolotriptan, which can inhibit all 9 kinds of identified mutations of kotatinib resistant ALK.
 
The chemical name of AP26113 is 5-chloro-N- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- Phosphono) phenyl] -2,4-pyrimidinediamine (I) having the structural formula:
 
 
Methods for the preparation of AP26113 have been reported. AP26113 and its starting materials A and B are prepared by PCT Patent WO2009143389 of Ariad and U.S. Patent No. 20130225527, US20130225528 and US20140066406 of Ariad. The target compound AP26113 is prepared by substituting 2,4,5-trichloropyrimidine with the pyrimidine ring of starting materials A and B in turn.
 
 
Although the synthetic procedure is simple, the nucleophilic activity of the three chlorine atoms on 2,4,5-trichloropyrimidine is limited. When the same or similar aniline group is faced, its position Selectivity will inevitably produce interference, resulting in unnecessary side effects, thus affecting the quality of the product. At the same time, the reaction process for the use of precious metal palladium reagent also increased the cost of production is not conducive to the realization of its industrialization.
 
Therefore, how to use modern synthesis technology, the use of readily available raw materials, design and development of simple and quick, economical and environmentally friendly and easy to industrialization of the new synthesis route, especially customer service location on the pyrimidine ring side effects of selectivity, for the drug Economic and technological development is of great significance
 
The synthesis step comprises the following steps: N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) and N, N-dimethylaminoacrylates Amino-4 (1H) -pyrimidinone (III) in the presence of a base such as N, N-dimethylformamide, N, N-dimethylformamide, (III) was reacted with 4- (dimethyl (dimethylamino) -1-piperidinyl) -2-methoxyphenyl] (A) is condensed under the action of a condensing agent and a base accelerator to obtain N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxybenzene (IV); the N2- [4- [4- (dimethylamino) -l- (4-fluorophenyl) (IV) with a chlorinating agent in the presence of a base such as sodium hydride, sodium hydride, sodium hydride, potassium hydride, AP26113 (I).
 
Example 1:
 
A solution of 2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline (24.9 g, 0.1 mol) and 250 mL of methanol was added to the reaction flask and the temperature was lowered to 0C (15 mL, 0.15 mol) and a 50% solution of cyanamide (10 mL, 0.15 mol) were added successively. The reaction was stirred for 12 to 14 hours and the reaction was complete by TLC. After cooling to 0-5 ° C, 250 mL of methyl tert-butyl ether was added to the reaction mixture. A solid precipitated and was filtered, washed successively with water and cold acetonitrile, and dried to give N- [2-methoxy- 16.3 g, yield 56.0%, FAB-MS m / z: 292 [M + H] + . [4- (Dimethylamino) piperidin-1-yl] aniline] guanidine (II)
 
Example 2:
 
A solution of N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) (2.9 g, 10 mmol), N, Methyl methacrylate (1.8 g, 13.7 mmol) and toluene (50 mL). The mixture was heated to reflux and stirred for 24-26 hours. The reaction was complete by TLC. After cooling to room temperature, a solid precipitated. The filter cake was washed with cold methanol and dried in vacuo to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] 1H) -pyrimidinone (III), yield 77.3%, FAB-MS m / z: 344 [M + H] + .
 
Example 3:
 
A solution of N- [2-methoxy-4- [4- (dimethylamino) piperidin-1-yl] aniline] guanidine (II) (2.9 g, 10 mmol), N, (2.0 g, 14.0 mmol) and N, N-dimethylformamide (30 mL) was added and the temperature was raised to 115-125 ° C. The reaction was stirred for 22-24 hours and the reaction was complete by TLC. The mixture was concentrated under reduced pressure, and 50 mL of ethanol was added to the resulting residue. The mixture was cooled to room temperature while stirring to precipitate a solid. The filter cake was washed with cold ethanol and dried in vacuo to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] 1H) -pyrimidinone (III) in 79.6% yield, FAB-MS m / z: 344 [M + H] + .
 
Example 4:
 
A mixture of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] amino-4 (1H) -pyrimidinone III) (3.43 g, 10 mmol), benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafluorophosphate (6.63 g, 15 mmol) and acetonitrile 100 mL. Diazabicyclo [5.4.0] -undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise at room temperature for 12 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was evaporated under reduced pressure, 100 mL of ethyl acetate was dissolved, and the mixture was washed with 20 mL of 2M sodium hydroxide and 20 mL of water. The organic layer was dried over anhydrous sodium sulfate, and 50 mL of tetrahydrofuran-dissolved 4- (dimethylphosphoranylidene) A) (2.2 g, 13 mmol) and sodium hydride (0.31 g, 13 mmol) was added and the temperature was raised to 50-55 ° C. The reaction was stirred for 6-8 hours and monitored by TLC. The reaction was quenched with saturated brine, the organic phase was separated, dried and the solvent was distilled off under reduced pressure. The crude product was recrystallized from ethanol to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidine Yl] -2-methoxyphenyl] -N4- [2- (dimethylphosphono) phenyl] -2,4-pyrimidinediamine (IV) in a yield of 83.2%. FAB-MS m / z: 495 [M + H] + .
 
Example 5:
 
A mixture of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] amino-4 (1H) -pyrimidinone (Dimethylamino) phosphonium hexafluorophosphate (BOP) (6.63 g, 15 mmol), 4- (dimethylsulfamoyl) phosphonium hexafluorophosphate Phosphoryl) aniline (A) (2.2 g, 13 mmol) and N, N-dimethylformamide. Diazabicyclo [5.4.0] undec-7-ene (DBU) (2.28 g, 15 mmol) was added dropwise and reacted at room temperature for 12 hours. The temperature was raised to 60 ° C and the reaction was continued for 12 hours. The solvent was distilled off under reduced pressure, 100 mL of ethyl acetate was added to dissolve, and the mixture was washed with 2 M sodium hydroxide 20 mL. The organic phase was separated, dried and concentrated under reduced pressure. The residue was recrystallized from ethanol to give an off-white solid of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- Phenylidene] -2,4-pyrimidinediamine (IV) was obtained in a yield of 48.6%. FAB-MS m / z: 495 [M + H] + .
 
Example 6:
 
A solution of N2- [4- [4- (dimethylamino) -1-piperidinyl] -2-methoxyphenyl] -N4- [2- (dimethylphosphono) Phenyl] -2,4-pyrimidinediamine (IV) (4.9 g, 10 mmol) and 100 mL of acetonitrile were added and stirred at room temperature. N-Chlorosuccinimide (1.6 g, 12 mmol) was added in three portions, The reaction was allowed to proceed at room temperature for 4-6 hours, and the reaction was terminated by TLC. The reaction solution was poured into 50 mL of water to quench the reaction. Dichloromethane, and the combined organic layers were washed successively with saturated sodium bicarbonate solution, saturated brine and water. Dried over anhydrous sodium sulfate and concentrated. The resulting crude oil was recrystallized from ethyl acetate / n-hexane to give 3.5 g of a white solid AP26113 (I) in 66.3% yield, FAB-MS m / z: 529 [M + the H] + , 1 the H NMR (CDCl 3 ) 1.67 (m, 2H), 1.81 (S, 3H), 1.85 (S, 3H), 1.93 (m, 2H), 1.96 (m, 2H), 2.10 (m, 2H), 3.86 (s, 3H), 6.50 (m, 1H), 6.57 (m, 1H), 7.12 (m, 1H) ), 7.31 (m, 1H), 7.50 (m, 1H), 8.13 (m, 2H), 8.64 (m, 1H).
 
////////////New Patent, Suzhou MiracPharma Technology Co Ltd, Brigatinib, WO 2017016410

Tuesday, 3 January 2017

WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc


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WO 2016200930, New patent, Citarinostat, Acetylon Pharmaceuticals Inc
citarinostat
Acetylon Pharmaceuticals Inc
(WO2016200930) METHODS OF MAKING PROTEIN DEACETYLASE INHIBITORS
(I)
Compound (I) is disclosed in U.S. Patent No. 8,148,526 as an HDAC inhibitor.
Example 2 of U.S. Patent Application Publication No. 2015/0099744 discloses a synthesis of compound (I). As detailed herein in Example 3, this synthesis procedure resulted in the formation of significant amounts of de-chlorination and chlorine-migration side products. These impurities have solubilities that are similar to the solubilities of the desired
intermediates. Removal of the impurities is very challenging, requiring lengthy work-ups, involving numerous washes, triturations and crystallizations. Triturations, in particular, are known to be inefficient and unscalable processes. When compound (I) was prepared according to Example 2, the necessary purification steps resulted in a significant loss of desired intermdiates, led to a modest overall yield, and rendered further industrial scale up of the synthesis route unpractical. There remains a need for new methods for the synthesis of compound (I), and related compounds, that minimize the formation of impurities, and that are amenable to industrial scale-up.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 depicts a generic synthesis of compound (I) according to the improved method described herein.
Figure 2 depicts a specific synthesis of compound (I) according to the improved method described herein.
Figure 6 depicts 1HNMR data for compound (I).
str1 str2 str3
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Acetylon president and CEO Walter Ogier
Example 1: Comparative Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl) pyrimidine-5-carboxamide
Reaction Scheme
Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), compound 1 (7.5 g, 40 mmol), and K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to r.t. and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml χ 3). The organic layers were separated and dried over Na2S04, evaporated to dryness and purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).
Synthesis of Intermediate 3: A mixture of compound 2 (6.2 g, 25 mmol), iodobenzene (6.12 g, 30 mmol), Cul (955 mg, 5.0 mmol), Cs2C03 (16.3 g, 50 mmol) in TEOS (200 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 14 hrs.
After cooling to r.t., the residue was diluted with EtOAc (200 ml). 95% EtOH (200 ml) and H4F-H20 on silica gel [50g, pre-prepared by the addition of H4F (lOOg) in water (1500 ml) to silica gel (500g, 100-200 mesh)] was added, and the resulting mixture was kept at r.t. for 2 hrs. The solidified materials were filtered and washed with EtOAc. The filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 10/1) to give a yellow solid (3 g, 38%).
Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 χ 200 ml), and the organic layers were separated, washed with water (2 χ 100 ml), brine (2 χ 100 ml), and dried over Na2S04. Removal of the solvent gave a brown solid (2.5 g, 92 %).
Synthesis of Intermediate 6: A mixture of compound 4 (2.5 g, 8.58 mmol), compound 5 (2.52 g, 12.87 mmol), HATU (3.91 g, 10.30 mmol), and DIPEA (4.43 g, 34.32 mmol) was stirred at r.t. overnight. After the reaction mixture was filtered, the filtrate was evaporated to dryness and the residue was purified by silica gel chromatography (petroleum ethers/EtOAc = 2/1) to give a brown solid (2 g, 54 %).
Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A mixture of the compound 6 (2.0 g, 4.6 mmol), sodium hydroxide (2N, 20 mL) in MeOH (50 ml) and DCM (25 ml) was stirred at 0 °C for 10 min. Hydroxylamine (50%) (10 ml) was cooled to 0 °C and added to the mixture. The resulting mixture was stirred at r.t. for 20 min. After removal of the solvent, the mixture was neutralized with 1M HCl to give a white precipitate. The crude product was filtered and purified by pre-HPLC to give a white solid (950 mg, 48%).
Example 2: Comparative Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7- (hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide - Compound (I)
Reaction Scheme
Step (1)
Synthesis of Intermediate 2: A mixture of aniline (3.7 g, 40 mmol), ethyl 2-chloropyrimidine-5-carboxylate 1 (7.5 g, 40 mmol), K2C03 (11 g, 80 mmol) in DMF (100 ml) was degassed and stirred at 120 °C under N2 overnight. The reaction mixture was cooled to rt and diluted with EtOAc (200 ml), then washed with saturated brine (200 ml x 3). The organic layer was separated and dried over Na2S04, evaporated to dryness and purified by silica gel
chromatography (petroleum ethers/EtOAc = 10/1) to give the desired product as a white solid (6.2 g, 64 %).
Step (2)
Synthesis of Intermediate 3: A mixture of compound 2 (69.2 g, 1 equiv.), l-chloro-2-iodobenzene (135.7 g, 2 equiv.), Li2C03 (42.04 g, 2 equiv.), K2C03 (39.32 g, 1 equiv.), Cu (1 equiv. 45 μπι) in DMSO (690 ml) was degassed and purged with nitrogen. The resulting mixture was stirred at 140 °C for 36 hours. Work-up of the reaction gave compound 3 at 93 % yield.
Step (3)
Synthesis of Intermediate 4: 2N NaOH (200 ml) was added to a solution of the compound 3 (3.0 g, 9.4 mmol) in EtOH (200 ml). The mixture was stirred at 60 °C for 30min. After evaporation of the solvent, the solution was neutralized with 2N HCl to give a white precipitate. The suspension was extracted with EtOAc (2 x 200 ml), and the organic layer was separated, washed with water (2 x 100 ml), brine (2 x 100 ml), and dried over Na2S04. Removal of solvent gave a brown solid (2.5 g, 92 %).
Step (4)
Synthesis of Intermediate 5: A procedure analogous to the Synthesis of Intermediate 6 in Example 1 was used.
Step (5)
Synthesis of 2-((2-chlorophenyl)(phenyl)amino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide: A procedure analogous to the Synthesis of 2-(diphenylamino)-N-(7-(hydroxyamino)-7-oxoheptyl)pyrimidine-5-carboxamide in Example 1 was used.
Exam le 3: Process development for Steps 2-3 of Example 2
Table 2. Reactants and reagents
(13.8, leq)
(22.2g, 2eq) Cu
5 24.3g (l.Oeq) 47.7g (2.0eq) 240mL 140 °C
K2C03 (1.0 ε¾45μπι)
(19.65, leq)
(42.04g, 2eq) Cu
6 69.2g (l.Oeq) 135.7g (2.0eq) 690mL 140 °C
K2C03 (1.0 ε¾45μπι)
(39.32g, leq)
Table 3. Results
Table 4. Purification of Compound 4 by extraction and slurry
MTBE/Heptane (lOvol/lOvol) 2.83% 2.67% 92.57%
MEK/Heptane (3vol/6vol) 4.42% 3.16% 90.00%
93.48%
EtoAc 3.87% 1.43%
iProAc 3.91% 2.81% 90.91%
Example 4: Improved synthesis of Compound (I)
Reaction Scheme
4 5 (I)
Step (1)
Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (ACY-5, 7.0 Kgs), ethanol (60 Kgs), 2-Chloroaniline (9.5 Kgs, 2 eq) and acetic acid (3.7 Kgs, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis (method TM-113.1016). When analysis indicated reaction completion (< 1% ACY-5), the mixture was cooled to 70 ± 5 °C and N,N-Diisopropylethylamine (DIPEA) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 6 Kgs) and heptane (24 Kgs). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 8.4 Kgs compound 11 (81% yield and 99.9% purity (method TM-113.1016)). See 1HNMR data in Figure 3.
Step (2)
Synthesis of Compound 3: Copper powder (0.68 Kgs, 1 eq, <75 micron), potassium carbonate (4.3 Kgs, 3.0 eq), and dimethyl sulfoxide (DMSO, 12.3 Kgs) were added to a reactor (vessel A). The resulting solution was heated to 120 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (2.9 Kgs) and iodobenzene (4.3 Kgs, 2 eq) in DMSO (5.6 Kgs) was
heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 120 ± 5°C for 8-24 hours, until HPLC analysis (method TM-113.942) determined that < 1% compound 11 was remaining.
Step (3)
Synthesis of Compound 4: The mixture of Step (2) was cooled to 90-100 °C and purified water (59 Kgs) was added. The reaction mixture was stirred at 90-100 °C for 2-8 hours until HPLC (method TM-113.942-see step 2) showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with methyl t-butyl ether twice (2 x 12.8 Kgs). The aqueous layer was cooled to 0-5 °C, then acidified with 6N hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 2.2 kg (65% yield) compound 4 in 90.3% AUC purity (method TM-113.942-see step 2). No dechlorinated product or Cl-migration product (i.e., de-Cl-4 or m-Cl-4) was observed. See 1HNMR data in Figure 4.
Step (4)
Synthesis of Compound 5: Dichloromethane (40.3 Kgs), DMF (33g, 0.04 eq) and compound 4 (2.3 Kg) were charged to a reaction flask. The solution was filtered through a 0.2 μπι filter and was returned to the flask. Oxalyl chloride (0.9 Kgs, 1 eq) was added via addition funnel over 30-120 minutes at < 30 °C. The batch was then stirred at < 30°C until reaction completion (compound 4 <3 %) was confirmed by HPLC (method TM-113.946). Next, the dichloromethane solution was concentrated and residual oxalyl chloride was removed under reduced pressure at < 40 °C. When HPLC analysis (method TM-113.946) indicated that < 0.10%) oxalyl chloride was remaining, the concentrate was dissolved in fresh
dichloromethane (24 Kgs) and transferred back to the reaction vessel (Vessel A).
A second vessel (Vessel B) was charged with Methyl 7-aminoheptanoate
hydrochloride (Compound Al, 1.5 Kgs, 1.09 eq), DIPEA (2.5 Kgs, 2.7 eq), 4
(Dimethylamino)pyridine (DMAP, 42g, 0.05 eq), and DCM (47.6 Kgs). The mixture was cooled to 0-10 °C and the acid chloride solution in Vessel A was transferred to Vessel B while maintaining the temperature at 5 °C to 10 °C. The reaction is stirred at 5-10 °C for 3 to 24 hours at which point HPLC analysis indicated reaction completion (method TM-113.946, compound 4 <5%). The mixture was then extracted with a 1M HC1 solution (20 Kgs), purified water (20 Kgs), 7% sodium bicarbonate (20 Kgs), purified water (20 Kgs), and 25% sodium chloride solution (20 Kgs). The dichloromethane was then vacuumdistilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% DCM was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (6.4 Kgs). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 2.2 Kgs (77% yield) was isolated in 95.9% AUC purity (method TM-113.953) and 99.9 wt %. See 1HNMR data in Figure 5.
Step (5)
Synthesis of Compound (I): Hydroxylamine hydrochloride (3.3 Kgs, 10 eq) and methanol (9.6 Kgs) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (11.2 Kgs, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 2.1 Kgs). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C. Compound 5 (2.2 Kgs) was added. The reaction was stirred until the reaction was complete (method TM-113.964, compound 5 < 2%). The mixture was filtered and water (28 Kgs) and ethyl acetate (8.9 Kgs) were added to the filtrate. The pH was adjusted to 8 - 9 using 6N HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (25.7 Kgs), then dried under reduced pressure to constant weight. The crude solid compound (I) was determined to be Form IV/ Pattern D.
The crude solid (1.87 Kgs) was suspended in isopropyl alcohol (IP A, 27.1 Kg). The slurry was heated to 75±5 °C to dissolve the solids. The solution was seeded with crystals of Compund (I) (Form I/Pattern A), and was allowed to cool to ambient temperature. The resulting precipitate was stirred for 1-2 hours before filtering. The filter cake was rinsed with IPA (2 x 9.5 Kgs), then dried at 45-55°C to constant weight under reduced pressure to result in 1.86 kg crystalline white solid Compound (I) (Form I/Pattern A) in 85% yield and 99.5% purity. See 1HNMR data in Figure 6.
Example 5: Alternative synthesis of Compound (I)
Reaction Scheme
(I)
Step (1)
Synthesis of Compound 11: Ethyl 2-chloropyrimidine-5-carboxylate (ACY-5, 250g), ethanol (2179 g), 2-Chloroaniline (339.3 g, 2 eq) and acetic acid (132.1 g, 1.6 eq) were charged to a reactor under inert atmosphere. The mixture was heated to reflux. After at least 5 hours the reaction was sampled for HPLC analysis. When analysis indicated reaction completion (< 1% ACY-5), the mixture was cooled to 70 ± 5 °C and Ν,Ν-Diisopropylethylamine (DIPEA, 553.6 g, 3.2 eq) was added. The reaction was then cooled to 20 ± 5°C and the mixture was stirred for an additional 2-6 hours. The resulting precipitate is filtered and washed with ethanol (2 x 401 g) and heptane (2 x 428 g). The cake is dried under reduced pressure at 50 ± 5 °C to a constant weight to produce 307. lg compound 11 (82.5% yield and 99.7% purity.
Step (2)
Synthesis of Compound 3: Cuprous iodide (17.5g, 8 eq), potassium carbonate (373.8 g, 3 eq), L-Prolin (11.4 g, 0.11 eq.) and dimethyl sulfoxide (DMSO, and 1180 g ) were added to a reactor (vessel A). The resulting solution was heated to 90 ± 5°C. In a separate reactor (vessel B), a solution of compound 11 (250g) and iodobenzene (1469.5 g, 8 eq) in DMSO (402.5 g) was heated at 40 ± 5°C. The mixture was then transferred to vessel A over 2-3 hours. The reaction mixture was heated at 90 ± 5°C for 8-24 hours, until HPLC analysis determined that < 1%) compound 11 was remaining.
Step (3)
Synthesis of Compound 4: The mixture of Step (2) was cooled to 40-50 °C and water (500g) and potassium hydroxide solution 10% (700.0 g, 2.8 eq) were added. The reaction mixture was stirred at 40-50 °C for 2-8 hours until HPLC showed that <1% compound 3 was remaining. The reactor was cooled to 25 °C. The reaction mixture was filtered through Celite, then a 0.2 micron filter, and the filtrate was collected. The filtrate was extracted with toluene (3 x 150g). The aqueous layer was cooled to 0-5 °C, then acidified with hydrochloric acid (HC1) to pH 2-3 while keeping the temperature < 25°C. The reaction was then cooled to 5-15 °C. The precipitate was filtered and washed with cold water. The cake was dried at 45-55 °C under reduced pressure to constant weight to obtain 291 g (81% yield) compound 4 in 98% AUC purity. No dechlorinated product or Cl-migration product (i.e., de-Cl-4 or m-Cl-4) was observed.
Step (4)
Synthesis of Compound 5 :
Compound 4 (250.0 g), A-l (159.2 g, 1.06 eq) and Methy-THF (5113 g) were charged to the reactor. DIPEA (283.7 g, 2.85 eq), hydroxybenzotriazole (HOBt, 12.5 g, 0.11 eq) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC.HC1, 216.3 g, 1.47 eq) were added. The reaction solution was stirred at ambient temperature for 6-24 hours, at which point HPLC analysis indicated reaction completion (compound 4 <3%). The mixture was then extracted with a 1M HC1 solution (2270 g), purified water (2270 g), 7% sodium bicarbonate (2270 g), purified water (2270 g), and 25% sodium chloride solution (2270 g). The Methyl-THF was then vacuumdi stilled at < 40 °C and chased repeatedly with isopropyl alcohol. When analysis indicated that <1 mol% methyl-THF was remaining, the mixture was gradually cooled to 0-5 °C and was stirred at 0-5 °C for an at least 2 hours. The resulting precipitate was collected by filtration and washed with cold isopropyl alcohol (700g). The cake was sucked dry on the filter for 4-24 hours, then was further dried at 45-55 °C under reduced pressure to constant weight. 294g (82% yield) was isolated in 99.6% AUC purity and 99.4 wt %.
Step (5)
Synthesis of Compound (I): Hydroxylamine hydrochloride (330g, 10 eq) and methanol (960g) were charged to a reactor. The resulting solution was cooled to 0-5 °C and 25% sodium methoxide (1120 g, 11 eq) was charged slowly, maintaining the temperature at 0-10 °C. Once
the addition was complete, the reaction was mixed at 20 °C for 1-3 hours and filtered, and the filter cake was washed with methanol (2 x 210 g). The filtrate (hydroxylamine free base) was returned to the reactor and cooled to 0±5°C. Compound 5 (220 g) was added. The reaction was stirred until the reaction was complete (compound 5 < 2%). The mixture was filtered and water (280 g) and ethyl acetate (890 g) were added to the filtrate. The pH was adjusted to 8 -9 using HC1 then stirred for up to 3 hours before filtering. The filter cake was washed with cold water (2570 g), then dried under reduced pressure to constant weight to yield 980 g crude solid in 83% yield. The crude solid compound (I) was determined to be Form IV/ Pattern D.
The crude solid (980 g) was suspended in 1-propanol (400 g) and purified water (220 g). The suspension was heated to 40°C. The batch was then cooled to 38°C over 30 minutes. The solution was seeded with crystals of Compund (I) (Form I/Pattern A, 2-5 wt %). The batch was kept at 37-38°C for 2-4 hours, then was gradually cooled to 20±2°C. Water (950 g) was charged over 3 -5 hours. The batch was cooled to 12°C and was stirred for 2 hrs at this temperature. The batch was filtered and washed with cold 1-propanol/water, then dried at 50±5°C to constant weight to yield 910 g purified compound (I) in 93% yield and 99.8% AUC purity.
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