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Acid Addition Salts Of N [6 (Cis 2,6 Dimethylmorpholin 4 Yl)pyridine 3 Yl] 2 Methyl 4' (Trifluoromethoxy) [1,1' Biphenyl] 3 Carboxamide And Its Process Thereof
Abstract: Abstract The present invention relates to acid addition salts of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4"-(trifluoromethoxy) [I,I"-biphenyl]-3-carboxamide compound of formula-1 and process for its preparation thereof. which is represented by the following structural formula
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Notices, Deadlines & Correspondence
Notices, Deadlines & Correspondence
Patent Information
Application #
Filing Date
22 March 2016
Publication Number
39/2017
Publication Type
INA
Invention Field
CHEMICAL
Status
Email
Parent Application
Applicants
MSN LABORATORIES PRIVATE LIMITED
FACTORY: SY.NO: 317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329.
Inventors
1. SRINIVASAN THIRUMALAI RAJAN
MSN LABORATORIES PRIVATE LIMITED, FACTORY: SY.NO: 317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329.
2. SAJJA ESWARAIAH
MSN LABORATORIES PRIVATE LIMITED, FACTORY: SY.NO: 317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329.
3. GOGULAPATI VENKATA PANAKALA RAO
MSN LABORATORIES PRIVATE LIMITED, FACTORY: SY.NO: 317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329.
4. THIPPIREDDY PURNA CHANDRASEKHAR REDDY
MSN LABORATORIES PRIVATE LIMITED, FACTORY: SY.NO: 317 & 323, RUDRARAM (VIL), PATANCHERU (MDL), MEDAK (DIST) - 502 329.
Specification
Field of the Invention:
The present invention relates to acid addition salts of N-[6-(cis-2,6-dimethyl morpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide compound of formula-1, represented by the following structural formula:
CH3
L jL
Formula-1 c = Oxalate F3C | ] 9H3 O \J CH3
Formula-Id = Maleate ^^^^^^^ks^^-- -^ss/N
Formula-le = Methane sulfonate || [ £j
15 Formula-I
P-XRD Method of Analysis: PXRD analysis of compounds produced by the present invention were carried out using BRUKER D8 ADVANCE/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.03°/min. The process described in the present invention was demonstrated in examples
illustrated below. These examples are provided as illustration only and therefore should not be
construed as limitation of the scope of the invention.
Examples
Example-I:
5 Preparation of crystalline form-A of N-[6-(ciS-2,6-dirnethylmorpholin-4-yI) pyridine-3-ylJ-2-methyl-4'-(trinuoromethoxy)[l,l'-biphenyl]-3-carboxamide:(Formula-l)
A mixture of acetone (10 ml) and N-[6-(cis-2,6-dimethylmorpholin-4-yI)Pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide (1.0 gm) were heated to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to
10 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.8 gm.
The P-XRD pattern of the obtained compound is matching with the P-XRD pattern of figure-3 ofUS8722672B2.
15 Example-2:
Preparation of crystalline form-M of N-[6-(ciS-2,6-dimethylmorPholm-4-yl)pyridine-3-ylI-2-methyl-4'-(trifluoromethoxy)[l,l '-biphenyl]-3-carboxamide hydrobromide salt: (Formula-la)
Aqueous hydro bromic acid (0.70 ml) was added to a mixture of N-[6-(cis-2,6-20 dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30X and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30X and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same 25 temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 1.0 gm.
The P-XRD pattern of the obtained compound is depicted in figure-1. Example-3: Preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)
pyridine-3-ylj-2-methyI-4'-(trifluoromethoxy)[l,l'-biphenyl]-3-carboxamide 30 paratoluene sulfonate salt: (Formula-lb)
P-toluene sulfonic acid (0.38 gm) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same 5 temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.7 gm.
The P-XRD pattern of the obtained compound is depicted in figure-2. 10 ExampIe-4:
Preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yI] -2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide paratoluene sulfonate salt: (Formula-lb)
P-toluene sulfonic acid (0.74 gm) was added to a mixture of N-[6-(cis-2,6-15 dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide (1 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at-the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same 20 temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.7 gm.
The P-XRD pattern of the obtained compound is depicted in figure-3. Example-5:
Preparation of crystalline form-M of N-[6-(eis-2,6-dimethylmorpholin-4-yl)pyridine-3-
25 ylj-2-methyl-4'-(trifluoromethoxy)[l,l'-biphenyl)-3-carboxamide oxalate salt: (Formula-lc)
Oxalic acid (0.27 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-
yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide (1.0 gm) and
acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the
30 reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the
reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the Lille compound. Yield: 0.5 gm; The P-XRD pattern of the obtained compound is depicted in figure-4. 5 ExampIe-6:
Preparation of crystalline form-S of N-[6-(cis-2,6-dimethyImorphoIin-4-yI)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l '-biphenyl]-3-carboxamide oxalate salt: (Formula-lc)
Oxalic acid (0.54 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorphoIin-4-10 yl)pyndine-3-yl]-2-methyl-4'-(trifluoromethoxy)[ljr-biphenyl]-3-carboxam1de(1.0gm)and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30X and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 60 minutes at the same temperature. Filtered the 15 precipitated solid, washed with acetone and dried to get the title compound.
Yield: 0.9 gm; The P-XRD pattern of the obtained compound is depicted in figure-5. Example-7:
Preparation of crystalline form-M of N-[6-(ciS-2,6-dimethylmorpholin-4-yI)pyridine-3-
yl]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamidemaleatesalt: 20 (Formula-Id)
Maleic acid (0.26 gms) was added to a mixture of N-[6-(cis-2J6-dimethyImorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [U'-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the 25 reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the ■ reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.8 gm. The P-XRD pattern of the obtained compound is depicted in figure-6. Examnle-8:
Preparation of crystalline form-S of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy)[l,l '-biphenylJ-3-carboxamide maleate salt: (Formula-Id)
Maleic acid (0.50 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin-4-5 yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [U'-biphenyl]-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours al the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the 10 precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.8 gms.
The P-XRD pattern of the obtained compound is depicted in figure-7. ExampIe-9:
Preparation of crystalline form-M of N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-3-15 yl]-2-methyl-4'-(trinuoroniethoxy)[l,r-bipheny]]-3-carboxamide methane sulfonate salt: (Formula-le)
Methane sulfonic acid (0.21 gms) was added to a mixture of N-[6-(cis-2,6-dimethylmorpholin^-yOpyridine-S-y^^-methyl^'-ftrifluoromethoxy) [1,1'-biphenylj-3-carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same
20 temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 0.9 gm.
25 The P-XRD pattern of the obtained compound is depicted in figure-8.
Example-10: Preparation of crystalline form-S of N-[6-(cis-2,6-dimethyl morpholin-4-yl)
pyridine-3-y]]-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide methane sulfonate salt: (Formula-le)
Methane sulfonic acid (0.41 gm) was added to a mixture of N-[6-(cis-2,6-
30 dimethylmorpho!in-4-yl)pyridine-3-yl]-2-methyl-4'-(trifluoromethoxy) [l,l'-biphenyl]-3-
carboxamide (1.0 gm) and acetone (10 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Heated the reaction mixture to 55-60T and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1 hour at the same 5 temperature. Filtered the precipitated solid, washed with acetone and dried to get the title compound. Yield: 1.0 gm.
The P-XRD pattern of the obtained compound is depicted in figure-9. Example-11:
Preparation of N-[6-(cis-2,6-dimethylmorpholin-4-y])pyridine-3-yl]-2-methyl-4'-10 (trifluoromethoxy)[l,r-biphenyl]-3-carboxamide: (Formula-1)
Dimethoxy ethane (200 ml) was added to S-bromo-N-^-^S^R^-dimethyl morpholine)pyridine-3-yl)-2-methylbenzamide (20 gms) at 25-30°C. (4-(trifluoromethoxy) phenyl)boronic acid (20.38 gms), aqueous sodium carbonate solution (1.0 gms of sodium carbonate in 5.0 ml of water) and tetrakis(triphenylphosphine) palladium(O) (0.13 gms) were
15 added to the reaction mixture at 25-30X. Heated the reaction mixture to 80-85°C and stirred for I hour at the same temperature. Cooled the reaction mixture to 25-30°C. Water and ethyl acetate was added to the reaction mixture at 25-30°C and stirred form 10 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the organic layers and washed with 10% sodium
20 chloride solution. Dried the organic layer with sodium sulphate. Distilled off the solvent completely under reduced pressure and co-distilled with methanol. Water (50 ml) was added to the obtained compound. Adjusted the pH of the reaction mixture to 8-9 using and aqueous sodium carbonate solution at 25-30°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound.
25 Yield: 20 gms; The P-XRD pattern of the obtained compound is depicted in figure-10. Example-12:
Preparation of crystalline form-A of N-[6-(cis-2,6-dimethyI morpholin-4-yl) pyridine-3-ylJ^-methyM'-ftrifluoromethoxy) [1,1 '-biphenyl]-3-carboxamide: (Formula-1)
A mixture of acetonitrile (50 ml) and N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-
3-yl]-2-methyl-4'-(trifluoromethoxy) [M'-biphenylJ^-carboxamide (5.0 gms) were heated to 80-85°C and stirred for 15 minutes at the same temperature. Activated carbon was added to the reaction mixture at 80-85°C. Filtered the reaction mixture through hyflow bed. Cooled the obtained filtrate to 25-30'C and stirred for 2 hours at the same temperature. Cooled the 5 reaction mixture to 0-5°C and stirred for 2 hour at the same temperature. Filtered the precipitated solid, washed with acetonitrile and dried to get the title compound. Yield: 2.5 gms.
The P-XRD pattern of the obtained compound is matching with the P-XRD pattern of figure-3
of US8722672 B2. 10 Example-13:
Preparation of crystalline form-A of N-[6-(cis-2,6-dimethyl morpholin-4-yl) pyridine-3-
ylJ-2-methyl-4'-(trifluoromethoxy)[l,r-biphenyl]-3-carboxamide:(Forniula-l)
A mixture of isopropanol (50 ml) and N-[6-(cis-2,6-dimethylmorpholin-4-yl)pyridine-
3-yl]-2-methyl-4'-(trifluoromethoxy) [l,r-biphenyl]-3-carboxamide (5.0 gms) were heated to 15 80-85X and stirred for 15 minutes at the same temperature. Activated carbon (0.5 gms) was
added to the reaction mixture at 80-85°C. Filtered the reaction mixture through hyflow bed.
Cooled the obtained filtrate to 25-30°C and stirred for 2 hours at the same temperature.
Cooled the reaction mixture to 0-5°C and stirred for 2 hour at the same temperature. Filtered
the precipitated solid, washed with isopropanol and dried to get the title compound. 20 Yield: 2.0 gms.
The P-XRD pattern of the obtained compound is matching with the P-XRD pattern of figure-3 ofUS8722672B2.
Documents
Application Documents
| # | Name | Date |
|---|---|---|
| 1 | 201641009952-Other Patent Document-220316.pdf | 2016-03-23 |
| 1 | Abstract_After Provisional_20-03-2017.pdf | 2017-03-20 |
| 2 | Claims_After Provisional_20-03-2017.pdf | 2017-03-20 |
| 2 | 201641009952-FORM28-220316.pdf | 2016-03-23 |
| 3 | Correspondence By Applicant_Complete_20-03-2017.pdf | 2017-03-20 |
| 3 | 201641009952-Form 2(Title Page)-220316.pdf | 2016-03-23 |
| 4 | Description Complete_After provisional_20-03-2017.pdf | 2017-03-20 |
| 4 | 201641009952-Form 1-220316.pdf | 2016-03-23 |
| 5 | 201641009952 FORM-28.pdf | 2016-08-16 |
| 5 | Drawing_After Provisional_20-03-2017.pdf | 2017-03-20 |
| 6 | Form2 Title Page_Complete_20-03-2017.pdf | 2017-03-20 |
| 6 | Form5 _After Provisional_20-03-2017.pdf | 2017-03-20 |
| 7 | Form2 Title Page_Complete_20-03-2017.pdf | 2017-03-20 |
| 7 | Form5 _After Provisional_20-03-2017.pdf | 2017-03-20 |
| 8 | 201641009952 FORM-28.pdf | 2016-08-16 |
| 8 | Drawing_After Provisional_20-03-2017.pdf | 2017-03-20 |
| 9 | 201641009952-Form 1-220316.pdf | 2016-03-23 |
| 9 | Description Complete_After provisional_20-03-2017.pdf | 2017-03-20 |
| 10 | Correspondence By Applicant_Complete_20-03-2017.pdf | 2017-03-20 |
| 10 | 201641009952-Form 2(Title Page)-220316.pdf | 2016-03-23 |
| 11 | Claims_After Provisional_20-03-2017.pdf | 2017-03-20 |
| 11 | 201641009952-FORM28-220316.pdf | 2016-03-23 |
| 12 | Abstract_After Provisional_20-03-2017.pdf | 2017-03-20 |
| 12 | 201641009952-Other Patent Document-220316.pdf | 2016-03-23 |