WO2013144295A1 - Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts - Google Patents

Synthesis of 2-(3,4-difluorophenyl)cyclopropanamine derivatives and salts Download PDF

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WO2013144295A1
WO2013144295A1 PCT/EP2013/056703 EP2013056703W WO2013144295A1 WO 2013144295 A1 WO2013144295 A1 WO 2013144295A1 EP 2013056703 W EP2013056703 W EP 2013056703W WO 2013144295 A1 WO2013144295 A1 WO 2013144295A1
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formula
compound
difluorophenyl
converting
configuration
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English (en)
French (fr)
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Borut ZUPANCIC
Parven Kumar Luthra
Rashid Khan
Raji Nair
Tonmoy Das
Sanket Gudekar
Aziz SYED
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Sandoz Ag
Lek Pharmaceuticals D.D.
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Priority claimed from EP12162507.3A external-priority patent/EP2644590A1/en
Application filed by Sandoz Ag, Lek Pharmaceuticals D.D. filed Critical Sandoz Ag
Priority to CN201380027677.8A priority Critical patent/CN104603098B/zh
Publication of WO2013144295A1 publication Critical patent/WO2013144295A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C247/00—Compounds containing azido groups
    • C07C247/20—Compounds containing azido groups with azido groups acylated by carboxylic acids
    • C07C247/22—Compounds containing azido groups with azido groups acylated by carboxylic acids with the acylating carboxyl groups bound to hydrogen atoms, to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/24—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids
    • C07C243/36—Hydrazines having nitrogen atoms of hydrazine groups acylated by carboxylic acids with acylating carboxyl groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C253/00—Preparation of carboxylic acid nitriles
    • C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/06—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C259/00—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups
    • C07C259/04—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids
    • C07C259/08—Compounds containing carboxyl groups, an oxygen atom of a carboxyl group being replaced by a nitrogen atom, this nitrogen atom being further bound to an oxygen atom and not being part of nitro or nitroso groups without replacement of the other oxygen atom of the carboxyl group, e.g. hydroxamic acids having carbon atoms of hydroxamic groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C263/00—Preparation of derivatives of isocyanic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C269/02—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups from isocyanates with formation of carbamate groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/06—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/58—Preparation of carboxylic acid halides
    • C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring

Definitions

  • the present invention relates to the field of organic synthesis, in particular to the synthesis of specific intermediates suitable for the synthesis of triazolopyrimidine compounds.
  • An important triazolopyrimidine compound is ticagrelor (TCG; Brilinta ® ; 3-[7-[[(1 ?,2Sj-2-(3,4- difluorophenyl)cyclopropyl]amino]-5-(propylthio)-3/-/-'/.2.3-triazolo[4.5-d]pyrimidin-3-yl]-5-(2- hydroxyethoxy)-(1 S.2S,3R,5S)-1 ,2-cyclopentanediol) having the following structural formula
  • Ticagrelor shows pharmaceutical activity by functioning as a P2Y12 receptor antagonist and thus is indicated for the treatment or prevention of thrombotic events, for example stroke, heart attack, acute coronary syndrome or myocardial infection with ST elevation, other coronary artery diseases and arterial thrombosis as well as other disorders related to platelet aggregation (WO 00/34283).
  • CPA is prepared as shown in Scheme 4.
  • First step involves reacting 1.2-difluorobenzene with chloroacetyl chloride in the presence of aluminium trichloride to produce 2-chloro-1 -(3.4-difluorophenyl)ethanone.
  • the keto group of the latter is then reduced by the use of chiral oxazaborolidine catalyst and borane dimethylsulfide complex to yield 2-chloro-1-(3.4-difluorophenyl)ethanol, which is then reacted with triethylphosphoacetate in the presence of sodium hydride in toluene to produce (1 R,2R)- 2-(3,4- difluorophenyl)cyclopropyl carboxylate.
  • the ester compound is first converted to amide by methyl formate in the presence of ammonia, said amide is then reacted with sodium hydroxide and sodium hypochlorite to produce CPA.
  • keto group of the latter intermediate is in the subsequent step stereochemically reduced to hydroxyl group by the use of chiral oxazaborolidine together with borane dimethyl sulfide or borane- A/.A/-diethyl aniline complex in the presence of tetrahydrofurane.
  • Scheme 5 Synthesis of CPA as described in WO 1 1/132083.
  • the disadvantage of the process described in WO 1 1/132083 is the use of expensive chiral oxazaborolidine and palladium catalyst, sodium iodide, toxic borane dimethylsulfide complex, heavy metals and hazardous diethyl azodicarboxylate.
  • WO 12/001531 describes another alternative synthetic path for preparation of CPA (Scheme 6).
  • the starting reagent 3.4-difluorobenzaldehide is reacted with a mixture of methyltriphenylphosphonium bromide, 1.8-diazabicyclo[5.4.0]undec-7-ene (DBU) and toluene to yield 3.4-difluorostyrene.
  • DBU 1.8-diazabicyclo[5.4.0]undec-7-ene
  • the obtained carboxylic acid is with aqueous hydroxylamine solution further converted to (1 R,2R)-2-(3,4-difluorophenyl)-1-cyclopropanecarboxamide, which is mixed with pyridine and acetic anhydride to yield (1 2f?)-A/-(acetyloxy)-2-(3,4-difluorophenyl)-1 -cyclopropane carboxamide.
  • DBU diazabicyclo[5.4.0]undec-7-ene
  • the object of the present invention was to provide an industrially applicable and economical process for obtaining (1 R,2S)-2-(3,4-difluorophenyl)cyclopropylamine (CPA), an important intermediate in preparation of ticagrelor (TCG).
  • the present invention provides a process for the preparation of a compound of formula IX or a salt thereof
  • the process defined above allows for preparation or synthesis of (1 R,2S)-2-(3,4- difluorophenyl)cyclopropylamine with an industrially applicable and economical process while using environmentally friendly and non-explosive reagents. Preferred embodiments will be described below. Furthermore, the present invention provides for isolation of crystalline (1 R,2S)-2-(3,4- difiuorophenyl)cyclopropylamine hydrochloride (CPA.HCI) without previous isolation of CPA base.
  • CPA.HCI crystalline (1 R,2S)-2-(3,4- difiuorophenyl)cyclopropylamine hydrochloride
  • the present invention further provides novel compounds that are useful as an intermediate the preparation of ticagrelor (TCG).
  • Fig. 1 shows an X-Ray diffraction pattern of crystalline (1 2S)-2-(3,4-difluorophenyl)- cyclopropylamine hydrochloride (CPA.HCI) prepared according to example 18.
  • the azide compound of formula VI is converted to a compound of formula IX directly or through a compound of formula Vlll as shown in Scheme 7.
  • chirai center * is in its (R) or (S) configuration
  • the compound of formula VI can be converted to a compound of formula Vlll through isocyanate VII
  • the hydrazide V is prepared from frar?s-2-(3,4-difluorophenyl)- cyclopropanecarboxyiic acid IV directly or optionally via ester compound 1Mb.
  • ?rans-2-(3,4-difluorophenyl)- cyclopropanecarboxylic acid IV is prepared as shown in Scheme 8.
  • the process is based on cyciopropanation of alkene II, which can be prepared from 3,4- difluorobenzaldehyde I through aldol condensation or Wittig reaction.
  • the cyciopropanation is carried out with a suitable reagent, for example with trimethylsulfoxonium iodide.
  • the substituent Q in compounds of formula II and III can be any group that can be converted to either carboxylic group and allows cyciopropanation of II.
  • Q is selected from the group selected of Ci-C 6 -alkyl carboxylic ester, carboxylic ester with a chiral alcohol such as L- menthol, N-substituted or unsubstituted carboxamide, cyano, hydroxymethyl, formyl, aldehyde, trihalomethyl, imide such as phthalimide etc.
  • Cyclopropane III is then hydrolysed under acidic or basic conditions or oxidized to give frans-2-(3,4-difluorophenyl)cyclopropanecarboxylic acid IV.
  • the process of Scheme 8 selectively leads to irans-substituted racemic cyclopropanes.
  • the enantiomers can be separated from the obtained racemic mixture in any step of preparation of compound IX, using principles in the art such as chromatographic separation, or crystallisation technics after preparation of diastereoisomers by introduction of a chiral moiety or by preparation diastereoisomeric salts with chiral counterion.
  • Q is COO(L-menthyl)
  • the racemic compound III can be separated to enantiomers by crystallisation as described in WO 01 /092200.
  • trans-2-(3A- difluorophenyl)-cyclopropanecarboxylic acid IV begins with reacting 1 ,2-difluorobenzaldehyde and acetonitrile in the presence of a base, preferably KOH or BuLi, to give (E)-3-(3,4- difluorophenyl)acrylonitrile Ila as a white solid.
  • Ila is then transformed to Ilia by cyclopropanation using trimethylsulfoxonium iodide and NaH or NaOH in DMSO.
  • Enantiomerically enriched Ilia can be formed from Ila using methods for asymmetric cyclopropanation as described in the literature.
  • Ilia is hydrolyzed using basic or acidic conditions, preferably base, most preferably LiOH, to give frans-2-(3,4-difluorophenyl)- cyclopropanecarboxylic acid IV.
  • basic or acidic conditions preferably base, most preferably LiOH
  • methyl frans-2-(3.4-difluorophenyl)cyclopropanecarboxylate Illb is prepared from 1 ,2-difluorobenzaldehyde (Scheme 10).
  • Mb is prepared according to the procedure described in WO 01/92200 and WO 01/92263. This is followed by esterification, for which any acid in MeOH can be used, preferably H 2 S0 4 , to give lie as white solid, which is subsequently cyclopropanated using trimethylsulfoxonium iodide and NaH or NaOH in DMSO.
  • the enantiomerically enriched Illb can be formed from lie using methods for asymmetric cyclopropanation as described in the literature.
  • the carboxylic acid IV is transformed to irans-2-(3.4-difluorophenyl)- cyclopropanecarbonyl azide VI (Scheme 1 1 ).
  • IV can be converted directly to hydrazide V or through ester lllb, which can be prepared by cyclopropanation of lie as described above, or by esterification of IV using any acid in MeOH, preferably H 2 S0 4 .
  • Hydrazide V can be prepared as a white solid compound directly from the carboxylic acid IV by heating it with SOCI 2 in any aprotic solvent, preferably toluene, followed by reaction with hydrazine.
  • hydrazide V is prepared by stirring ester lllb and hydrazine in any solvent, preferably solvent from Ci-C 6 alcohols, most preferably methanol, in a temperature range from 0 to 150 C, preferably the temperature is 70 C.
  • Hydrazide V can be then reacted with nitrite, preferably NaN0 2 in acidic media, preferably in AcOH, to form frans-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI.
  • the preferred enantiomer can be obtained from the racemic mixture in any step of preparation of compound IX using principles well known in the art.
  • the carboxylic acid of formula IV is provided in enantiomerically pure form (1 /?,2f?)-2-(3.4-difluorophenyl)cyclopropanecarboxylic acid (IV).
  • Use of enantiomerically pure carboxylic acid IV gives (1 ,2R)-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide (compound VI') according to Scheme 12.
  • the enantiomerically pure (1 2f?)-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI' or racemic frans-2-(3,4-difluorophenyl)cyclopropanecarbonyl azide VI can then be directly transformed to (1 2S)-2-(3,4-difluorophenyl)cyclopropanamine (CPA) or trans-2-(3A- difluorophenyl)cyclopropanamine IX, respectively, by a one-pot reaction as described in WO 01 /92200 and WO 01 /92263.
  • the carbamate protected amine VIII can also be prepared directly from VI or through isocyanate VII (Scheme 13), which can be prepared by simple heating of compound VI in any aprotic solvent, preferably toluene, at a temperature falling into the range of 25 to 150 C, preferably the temperature is 80 C. VII is then transformed to Villa by reaction with iBuOH at 25 to 150 C, preferably at the temperature of reflux, or by reacting KOfBu in any aprotic solvent at a temperature falling in the range of -50 to 100 C, preferably at 0 C.
  • any aprotic solvent preferably toluene
  • VII is then transformed to Villa by reaction with iBuOH at 25 to 150 C, preferably at the temperature of reflux, or by reacting KOfBu in any aprotic solvent at a temperature falling in the range of -50 to 100 C, preferably at 0 C.
  • Scheme 14 Synthesis of (1 2S)-2-(3.4-difluorophenyl)cyclopropanamine (CPA) and its Boc protected analog Villa' from (1 2f?)-2-(3.4-difluorophenyl)cyclopropanecarbonyl azide VI' representing the embodiment of the invention.
  • the intermediate Villa or Villa' is hydrolysed by hydrochloric acid in the mixture of methanol and water.
  • This mixture is preferred due to unexpected lower solubility of hydrochloride salt in water.
  • Said hydrochloride salt is provided in crystalline form and smoothly precipitates from the mixture, giving the product in high yield.
  • Such approach is advantageous over the prior art process described in CN102249929, in which hydrolysis occurs in ethyl acetate/water mixture and the product is finally isolated following the neutralization, as a base from the organic phase.
  • the crystalline hydrochloride salt of CPA can be prepared also in the absence of water by introducing gaseous hydrogen chloride, optionally dissolved in an organic solvent, preferably diethyl ether, to a solution comprising CPA base in an organic solvent such as aromatic hydrocarbons or ethers.
  • the compound of formula V is prepared by reaction of cyclopropanation from a compound of formula B as shown in Scheme 15. Suitable reagents for this reaction are for example trimethyl sulfoxonium iodide, trimethyl sulfoxonium bromide, trimethyl sulfonium iodide and trimethyl sulfonium bromide.
  • Preferred reagent is trimethyl sulfoxonium iodide.
  • Scheme 15 Synthetic steps showing the embodiment of the present invention.
  • the compound of formula B is further converted to the hydrazide compound of formula V.
  • This step can be performed directly by reacting the compound of formula V with hydrazine hydrate.
  • the compound of formula B can be hydrolyzed into 2-(3.4- difluorophenyl)cyclopropanecarboxylic acid (IV), which is then converted into its ester (Illb).
  • Said ester which is for example ester with a linear or branched alkyl, preferably Ci to C 6 alkyl ester, is then reacted with hydrazine hydrate giving the compound of formula V.
  • the compound of formula IX can be further converted to a stereochemicaily pure (1 R,2S)-2-(3,4-difluorophenyl)cyclopropanamine in a form of a salt, for example by chiral resolution of the racemic amine IX with an optically active acid.
  • a preferred optically active acid is R-mandelic acid.
  • Scheme 16 represents a preferred embodiment of the present invention.
  • (£)-3-(3,4- Difluorophenyl) acrylic acid (lib) is converted into its acid chloride by reaction with thionyl chloride or oxalyl chloride in DM F.
  • the obtained acid chloride (lid) is reacted with N.O-dimethyl hydroxylamine hydrochloride in the presence of pyridine to obtain (£)-3-(3.4-difluorophenyl)-A/- methoxy-AZ-methylacrylamide (A).
  • This compound is then cyclopropanated with trimethyl sulfoxonium iodide in sodium hydride and DMSO to give 2-(3.4-difluorophenyl)-A/-methoxy-/V- methylcyclopropanecarboxamide (B).
  • sodium hydroxide can be used instead of sodium hydride to perform this step.
  • the intermediate B can be converted into 2-(3,4- difluorophenyl)cyclopropanecarbohydrazide (V) by either
  • trans- 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide useful in the synthesis of ticagrelor (TCG):
  • the intermediate is enantiomerically pure (1 ?,2 ?)-2-(3,4- difluorophenyl)cyclopropanecarbohydrazide (V)
  • Still further aspect of the present invention resides in the provision of crystalline trans-2-(3,4- difluorophenyl)cyclopropanamine hydrochloride (IX.HCI), wherein the chiral center * is in its (R) or (S) configuration.
  • the compound Mb was prepared through procedure described in (WO 2001/92200 and WO 2001/92263).
  • the compound IV was prepared through procedure described in WO 2001/92200 and WO 2001/92263.
  • CPA was prepared as above or through procedure described in WO 2001/92200 and WO 2001/92263.
  • Reaction mixture was then cooled to 20°C and it was slowly added to a stirred mixture of 37% HCI (aq., 30 mL) and water (10 mL) at 60 C. When all of the solution was added, the reaction mixture was stirred at 60 C for additional 15 min, then it was cooled to 20 C, and organic layer was separated. Water layer was then washed with MeTHF/toluene mixture (2:1 , 3 x 30 mL) and neutralized with Na 2 C0 3 .
  • the semisolid obtained was dissolved in about 100 ml acetone and used as such in next step.
  • the resultant biphasic mixture was stirred for about 15 minutes and then the layers were allowed to settle for about 10 minutes.
  • the lower organic layer was separated and washed 500 ml with saturated bicarbonate solution followed by 250 ml water.
  • the solvent was distilled under reduced pressure below 40 C to obtain 1 14.5 g of product.
  • reaction mixture was stirred at 25 C to 30 C for 3 h and diluted with about 2.5 L water and extracted with toluene.
  • the toluene solution was washed with brine followed by water and distilled under vacuum to obtain 106 g of the cyclopropanated product in the form of oil. This oil was used as such for the next step.
  • Example 23 Preparation of 2-(3,4-difluorophenyl)cyclopropanamine (IX) 20 g (94.3 mmoles) 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide was added to 50 ml of water and the slurry was cooled to 0-5 ' C. 100 ml (6N) Hydrochloric acid was added slowly and stirred to dissolve the solid. To the resultant clear solution sodium nitrite solution (6.5 g dissolved in 100 ml) was added slowly at 0-5 C over a period of 30 min followed by 200 ml of toluene. The reaction mixture was stirred for 15 min, stirring stopped to separate layers.
  • IX 2-(3,4-difluorophenyl)cyclopropanamine
  • Toluene layer containing azide intermediate collected and was added slowly over one hour to 50 ml of toluene at 1 10 °C.
  • the reaction mixture was refluxed for 1 h at 1 10 C and the hot toluene solution was transferred to 200 ml (6N) hydrochloric acid at 100 C under stirring and the reflux continued for another 2 hr.
  • the reaction mixture was cooled to 25 °C and the layers were allowed to separate.
  • Aqueous layer collected and the pH was adjusted to 10.
  • 200 ml of methylene dichloride was added and stirred for 15 min.
  • the dichloromethane layer separated and concentrated under vacuum below 40 C to get 10 g of 2-(3.4-difluorophenyl)- cyclopropanamine as an oil.
  • reaction mixture was refluxed at 65 C for 3 h.
  • the reaction mixture was distilled at 60-65 C to remove solvent completely. A concentrated reaction mass was obtained.
  • To the residue was added 200 ml water followed by 200 ml dichloromethane and stirred to dissolve the solid.
  • the organic layer was separated and washed with 200 ml water. The organic layer was then concentrated under vacuum at 35-40 C to give 20 g of 2-(3,4-difluorophenyl)cyclopropanecarbohydrazide (87% of theory).
  • the organic layer containing azide intermediate was then added slowly to 50 ml of hot toluene at 1 10 C over a period of 1 h.
  • the reaction mass was refluxed for 1 h at 1 10 C and then transferred to 200 ml (6N) hydrochloric acid at 1 10 under stirring. The reflux was continued for 2 hrs.
  • After completion of reaction the reaction mixture was cooled to 25 °C and the layers were separated.
  • sodium hydroxide solution was added to adjust to pH 10.
  • XRD powder X-ray diffraction
  • the powder X-ray diffraction patterns were obtained by methods known in the art using Philips X'Pert PRO diffractometer with X'Celerator detector using CuKa radiation (tube operating at 45 kV and 40 mA) in the Bragg-Brentano (reflection) geometry. Data were recorded from 2 to 40 °2 ⁇ in steps of 0.033 °2 ⁇ and the measurement time of 50 seconds per step. Variable divergence and anti scatter slits were used to maintain 12 mm of sample length irradiated.
  • MS spectra were recorded with LC-MS system composed of Waters Alliance HPLC and Micromass Quattro micro mass spectrometer equipped with electrospray ionisation source.

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