WO2011064798A1 - Process for the preparation of a pyrazole derivative - Google Patents
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- WO2011064798A1 WO2011064798A1 PCT/IN2010/000769 IN2010000769W WO2011064798A1 WO 2011064798 A1 WO2011064798 A1 WO 2011064798A1 IN 2010000769 W IN2010000769 W IN 2010000769W WO 2011064798 A1 WO2011064798 A1 WO 2011064798A1
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- 238000000034 method Methods 0.000 title claims abstract description 30
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 150000003217 pyrazoles Chemical class 0.000 title description 5
- 150000001875 compounds Chemical class 0.000 claims abstract description 16
- JVVRJMXHNUAPHW-UHFFFAOYSA-N 1h-pyrazol-5-amine Chemical class NC=1C=CNN=1 JVVRJMXHNUAPHW-UHFFFAOYSA-N 0.000 claims abstract description 13
- NWZSZGALRFJKBT-KNIFDHDWSA-N (2s)-2,6-diaminohexanoic acid;(2s)-2-hydroxybutanedioic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O.NCCCC[C@H](N)C(O)=O NWZSZGALRFJKBT-KNIFDHDWSA-N 0.000 claims abstract description 10
- IKDUDTNKRLTJSI-UHFFFAOYSA-N hydrazine monohydrate Substances O.NN IKDUDTNKRLTJSI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 9
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract description 5
- 238000006243 chemical reaction Methods 0.000 claims description 25
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- MLIREBYILWEBDM-UHFFFAOYSA-N cyanoacetic acid Chemical compound OC(=O)CC#N MLIREBYILWEBDM-UHFFFAOYSA-N 0.000 claims description 12
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- GKASDNZWUGIAMG-UHFFFAOYSA-N triethyl orthoformate Chemical compound CCOC(OCC)OCC GKASDNZWUGIAMG-UHFFFAOYSA-N 0.000 claims description 6
- 125000000217 alkyl group Chemical group 0.000 claims description 5
- 125000004494 ethyl ester group Chemical group 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- RCUIWQWWDLZNMS-UHFFFAOYSA-N benzyl 2-cyanoacetate Chemical compound N#CCC(=O)OCC1=CC=CC=C1 RCUIWQWWDLZNMS-UHFFFAOYSA-N 0.000 claims 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 abstract 1
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- YPXGHKWOJXQLQU-UHFFFAOYSA-N ethyl 5-amino-1h-pyrazole-4-carboxylate Chemical compound CCOC(=O)C=1C=NNC=1N YPXGHKWOJXQLQU-UHFFFAOYSA-N 0.000 description 7
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000010992 reflux Methods 0.000 description 6
- 239000000047 product Substances 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 4
- ZIUSEGSNTOUIPT-UHFFFAOYSA-N ethyl 2-cyanoacetate Chemical compound CCOC(=O)CC#N ZIUSEGSNTOUIPT-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- -1 benzyl ester Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 125000005907 alkyl ester group Chemical group 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 238000005804 alkylation reaction Methods 0.000 description 2
- 150000001411 amidrazones Chemical class 0.000 description 2
- JEUHJKUDMBBWLQ-UHFFFAOYSA-N ethyl 2-cyano-3-morpholin-4-ylprop-2-enoate Chemical compound CCOC(=O)C(C#N)=CN1CCOCC1 JEUHJKUDMBBWLQ-UHFFFAOYSA-N 0.000 description 2
- JHEHBQQUKRWMGB-UHFFFAOYSA-N ethyl 3-amino-1-benzylpyrazole-4-carboxylate Chemical compound N1=C(N)C(C(=O)OCC)=CN1CC1=CC=CC=C1 JHEHBQQUKRWMGB-UHFFFAOYSA-N 0.000 description 2
- 239000012265 solid product Substances 0.000 description 2
- 238000005292 vacuum distillation Methods 0.000 description 2
- 0 *C(c1c[n](*)nc1N)=O Chemical compound *C(c1c[n](*)nc1N)=O 0.000 description 1
- 201000005569 Gout Diseases 0.000 description 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 201000001431 Hyperuricemia Diseases 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical class C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000008051 alkyl sulfates Chemical class 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- OFCNXPDARWKPPY-UHFFFAOYSA-N allopurinol Chemical compound OC1=NC=NC2=C1C=NN2 OFCNXPDARWKPPY-UHFFFAOYSA-N 0.000 description 1
- 229960003459 allopurinol Drugs 0.000 description 1
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 description 1
- 229940073608 benzyl chloride Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- KTMGNAIGXYODKQ-VOTSOKGWSA-N ethyl (e)-2-cyano-3-ethoxyprop-2-enoate Chemical compound CCO\C=C(/C#N)C(=O)OCC KTMGNAIGXYODKQ-VOTSOKGWSA-N 0.000 description 1
- KTMGNAIGXYODKQ-UHFFFAOYSA-N ethyl 2-cyano-3-ethoxyprop-2-enoate Chemical compound CCOC=C(C#N)C(=O)OCC KTMGNAIGXYODKQ-UHFFFAOYSA-N 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 230000002062 proliferating effect Effects 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000007363 ring formation reaction Methods 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 229910000104 sodium hydride Inorganic materials 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000000990 untiurolithic effect Effects 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
- C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D231/38—Nitrogen atoms
Definitions
- the present invention provides a process for preparation of 3 - amino pyrazole derivatives represented by Formula - 1,
- the compound 3 - amino pyrazole derivative of Formula - I is a useful active intermediate for the preparation of pharmaceutical compounds used for treatment of hyperuricemia and chronic gout, antiurolithic viz. Allopurinol, an inhibitor of smooth muscle cell growth particularly vascular re-narrowing after percutaneous transluminal coronary angioplasty, membrane proliferative nephris, arterioscleotic diseases, hypertension, or diabetes mellitus.
- the starting ethoxy-methylene-cayanoacetic acid ethyl ester was prepared according to the process described in the Journal, J. Amer. Chem. Soc, 74(19), 4889 - 4891 (1952), wherein the reaction of ethyl orthoformate with ethyl cyanoacetate is carried out at reflux to afford oily product which is distilled under vacuum to isolate pure intermediate compound..
- the intermediate compound requires high vacuum distillation to isolate pure compound
- the present invention provides an improved process for the preparation of 3 - amino pyrazole derivatives in which the intermediate formed is solid and does not require high vacuum distillation of the intermediate and the reaction with hydrazine hydrate is carried out in water at lower temperature which makes the process rigid and operator friendly, therefore industrially useful.
- the object of the present invention is to provide a rigid and robust synthetic process for the preparation of 3 - amino pyrazole derivatives of Formula - I.
- Another object of the present invention is to provide a process for the preparation of 3 - amino pyrazole derivatives of Formula - I, using economical and environment friendly solvent.
- Another objective of the present invention is to prepare 3 - amino pyrazole derivatives of Formula - 1 having high purity.
- the present invention provides a process for the preparation of 3 - amino pyrazole derivative of Formula - 1 ;
- R ⁇ H, d - C 4 alkyl group or benzyl group or phenyl group;
- R 2 Q alkyl group or benzyl group;
- the present invention describes the process of preparation of pyrazole derivative of Formula - 1
- the ester of cyano acetic acid is reacted with morpholine in presence of triethylorthoformate and diluent to yield the intermediate compound of Formula - III.
- the ester of cyanoacetic acid for the reaction is selected from alkyl ester having Q - C 6 carbon atoms or benzyl ester.
- the preferred ester for the reaction is alkyl ester.
- the most preferred ester is ethyl cyanoacetate.
- the reaction is carried out in presence of diluent selected from d - C 4 linear or branched alcohol; wherein the preferred diluent used is isopropyl alcohol.
- the reaction is carried out at temperature of 60 - 90°C, wherein the preferred temperature of the reaction is 70 - 90°C and the most preferred temperature of the reaction is 85 - 90°C.
- the reaction is maintained at reflux for 3 - 5 hours for the completion, cooled to 25 - 30°C and further to 0 - 10°C. Stirred and filtered the solid to recover the intermediate compound of Formula - III.
- the reaction sequence is as given below in scheme - IV;
- the intermediate compound of Formula - III is reacted with Hydrazine hydrate in presence of polar solvent at temperature of 15 - 60°C to isolate the pyrazole derivative of Formula - II.
- the preferred temperature of reaction is 15 - 30°C for 1 hour, 25 - 30°C for 3 hours and 40 - 45°C for 2 hours. The gradual raising of temperature help to get the completion of the reaction without formation of unwanted impurities.
- the reaction is further cooled to 25 - 30°C and subsequently to 0 - 5°C and filtered to isolate the pyrazole derivative of Formula - II.
- the reaction sequence is as iven below in scheme - V
- the alkylating agent used is selected from alkyl halide, alkyl sulfate, and benzyl halide.
- the suitable base used for the alkylation reaction is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride.
- the suitable solvent for alkylation is selected from water, Q - C 4 alcohol and dimethylformamide.
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Disclosed here is a process for the preparation of 3 - amino pyrazole derivative of Formula (I) where R1 = H, C1 - C4 alkyl group or benzyl group or phenyl group; R2 = C1 - C6 alkyl group or benzyl group; comprising a step of reacting the compound of Formula (Ill) with hydrazine hydrate.
Description
PROCESS FOR THE PREPARATION OF A PYRAZOLE DERIVATIVE
FIELD OF INVENTION:
The present invention provides a process for preparation of 3 - amino pyrazole derivatives represented by Formula - 1,
Formula - 1
Where Ri = H, Cj - C4 alkyl group or benzyl group or phenyl group; R = Ct - C6 alkyl group or benzyl group.
BACKGROUND AND PRIOR ART:
The compound 3 - amino pyrazole derivative of Formula - I is a useful active intermediate for the preparation of pharmaceutical compounds used for treatment of hyperuricemia and chronic gout, antiurolithic viz. Allopurinol, an inhibitor of smooth muscle cell growth particularly vascular re-narrowing after percutaneous transluminal coronary angioplasty, membrane proliferative nephris, arterioscleotic diseases, hypertension, or diabetes mellitus.
The prior art discloses various methods for the preparation of the base moiety of pyrazole derivative of Formula - II
Formula - II
Where Ri =H & R2 is as described above.
The preparation of ethyl 3-amino-l H-pyrazole-4-carboxylate is disclosed in US Patent No US 2,868,803 wherein the process involves cyclization of ethoxy-methylene-cyanoacetic acid ethyl ester with hydrazine hydrate in presence of alcohol at reflux condition for 6 hours to afford ethyl 3-amino-lH-pyrazole-4-carboxylate as represented in scheme - 1.
Scheme - I
The starting ethoxy-methylene-cayanoacetic acid ethyl ester was prepared according to the process described in the Journal, J. Amer. Chem. Soc, 74(19), 4889 - 4891 (1952), wherein the reaction of ethyl orthoformate with ethyl cyanoacetate is carried out at reflux to afford oily product which is distilled under vacuum to isolate pure intermediate compound..
Another method for preparation of ethyl 3-amino-lH-pyrazole-4-carboxylate is reported in the Journal, Bulletin of the Chemical Society of Japan, 50(4), 957 - 960 (1977). The process disclosed involves reaction of amidrazone derivatives and ethyl 2-cyano-3- ethoxyacrylate in ethanol to give intermediate N-(2-cyano-2-ethoxycarbonylvinyl) amidrazone derivative, which is cyclised by refluxing in toluene to give ethyl 3-amino- lH-pyrazole-4-carboxylate. The method is as reported in scheme - II.
Scheme - II
The US patent US 4,468,353 disclosed a process for preparation of intermediate alkoxymethylene compounds used for preparing 3-amino-lH-pyrazole-4-carboxylic acid ethyl ester. Wherein the ethoxy-methylene-cayanoacetic acid ethyl ester is prepared by reacting ethyl cyanoacetate with orthoformic acid triethyl ester in the presence of acetic anhydride at 130°C to 150°C. The method is as reported in scheme - 111.
Scheme - III
The drawbacks of the prior art are:
1. the intermediate compound requires high vacuum distillation to isolate pure compound;
2. requires the use of acetic anhydride for the reaction which is to be removed under vacuum to isolate pure intermediate;
3. requires high temperature of 130°C for the preparation of the intermediate;
4. requires the use of solvent for reaction with hydrazine hydrate and during the cyclisation of the intermediate.
Therefore there remains a need for an improved process which ameliorates the problems of the prior art processes and is industrially rugged and useful.
The present invention provides an improved process for the preparation of 3 - amino pyrazole derivatives in which the intermediate formed is solid and does not require high vacuum distillation of the intermediate and the reaction with hydrazine hydrate is carried out in water at lower temperature which makes the process rigid and operator friendly, therefore industrially useful.
OBJECT OF THE INVENTION:
The object of the present invention is to provide a rigid and robust synthetic process for the preparation of 3 - amino pyrazole derivatives of Formula - I.
Another object of the present invention is to provide a process for the preparation of 3 - amino pyrazole derivatives of Formula - I, using economical and environment friendly solvent.
Another objective of the present invention is to prepare 3 - amino pyrazole derivatives of Formula - 1 having high purity.
SUMMARY OF THE INVENTION:
In accordance with the above objectives, the present invention provides a process for the preparation of 3 - amino pyrazole derivative of Formula - 1 ;
Formula - 1
Where R\ = H, d - C4 alkyl group or benzyl group or phenyl group; R2 = Q alkyl group or benzyl group;
comprising of reacting the compound of Formula - III, with hydrazine hydrate.
Formula - III
Where R is as defined above.
1. The process for the preparation of 3 - amino pyrazole derivative comprising the steps of ;
i. reacting ester of cyano acetic acid with morpholine in presence of triethylorthoformate and diluent to give the intermediate compound of Formula - in;
Formula - III ii. reacting the compound of Formula - III with hydrazine hydrate in presence of water to yield 3 - amino pyrazole derivative of Formula - 1.
DESCRIPTION OF THE INVENTION:
The present invention describes the process of preparation of pyrazole derivative of Formula - 1
Formula - 1
Where Ri = H, C2 - C6 alkyl benzyl group or phenyl group; R2 = Ci - C6 alkyl group or benzyl group.
In one of the embodiment of the present invention, the ester of cyano acetic acid is reacted with morpholine in presence of triethylorthoformate and diluent to yield the intermediate compound of Formula - III. The ester of cyanoacetic acid for the reaction is selected from alkyl ester having Q - C6 carbon atoms or benzyl ester. The preferred ester for the reaction is alkyl ester. The most preferred ester is ethyl cyanoacetate. The reaction is carried out in presence of diluent selected from d - C4 linear or branched alcohol; wherein the preferred diluent used is isopropyl alcohol. The reaction is carried out at temperature of 60 - 90°C, wherein the preferred temperature of the reaction is 70 - 90°C and the most preferred temperature of the reaction is 85 - 90°C. The reaction is maintained at reflux for 3 - 5 hours for the completion, cooled to 25 - 30°C and further to
0 - 10°C. Stirred and filtered the solid to recover the intermediate compound of Formula - III. The reaction sequence is as given below in scheme - IV;
Formula - III
Scheme - IV
In another embodiment of the present invention the intermediate compound of Formula - III is reacted with Hydrazine hydrate in presence of polar solvent at temperature of 15 - 60°C to isolate the pyrazole derivative of Formula - II. The preferred temperature of reaction is 15 - 30°C for 1 hour, 25 - 30°C for 3 hours and 40 - 45°C for 2 hours. The gradual raising of temperature help to get the completion of the reaction without formation of unwanted impurities. The reaction is further cooled to 25 - 30°C and subsequently to 0 - 5°C and filtered to isolate the pyrazole derivative of Formula - II. The reaction sequence is as iven below in scheme - V
Formula - III Formula - II
Scheme - V
In another embodiment compound of Formula - II (R2 = - C2H5) is reacted with an alkylating agent in presence of a base and suitable solvent to afford N - substituted pyrazole derivative of Formula - IV;
Formula - IV
The alkylating agent used is selected from alkyl halide, alkyl sulfate, and benzyl halide. The suitable base used for the alkylation reaction is sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, or sodium hydride. The suitable solvent for alkylation is selected from water, Q - C4 alcohol and dimethylformamide.
Further details of the process of the present invention will be apparent from the examples presented below. The examples presented are purely illustrative and are not limited to the particular embodiments illustrated herein but include the permutations, which are obvious as set forth in the description.
EXAMPLES:
Example 1 : Preparation of Ethyl 2 - cyano - 3 - morpholinoacrylate:
Charged in a flask ethyl cyanoacetate (220gm, 1 .95moles), triethyl orthoformate (3 14gm, 2.12 moles), morpholine (306.5gm, 3.52moles) and isopropyl alcohol (35 ml). Stirred and raised the temperature to reflux and maintained for 3 hours. The solid product crystallized out during the reaction was cooled to 25 - 30°C and further chilled to 0 - 5°C and stirred for 1 hour The crystalline solid was filtered and washed with chilled isopropyl alcohol. Dried the product till constant weight.
Dry wt = 325gm. (79.48 %)
Example 2: Preparation of ethyl 3 - amino - 1H- pyrazole - 4 - carboxylate:
Charged ethyl 2 - cyano - 3- morpholinoacrylate (250gm, 1.19 moles) to water ( 600mL) maintaining temperature at 15 - 20°C. Charged under stirring hydrazine hydrate (80 % technical, 74gm, 1.18 moles) to the reaction solution. The mixture was stirred at 15 - 20°C one hour, at 25 - 30°C for 3 hours and 40 - 45°C for 2 hours. After completion of
the reaction, the reaction mass was cooled to 25 - 30°C and further chilled to 0 - 5°C. Filtered the solid product and washed with chilled water to isolate ethyl 3 - amino - 1H - pyrazole - 4 - carboxylate. Dried the product till constant weight at 50 - 55°C.
Dry wt = 170gm. (92.14 %)
Example 3: Preparation of ethyl 3 - amino - 1 - benzyl - 1H - pyrazole - 4 - carboxylate:
Charged in the flask containing ( dimethylformamide (500 ml), sodium methoxide (91.8gm, 1.7 moles), ethyl 3 - amino- 1H- pyrazole - 4 - carboxylate (250gm, 1 .61 moles), benzyl chloride (208.72 ml, 1.65 moles) and stirred. Raised the temperature of the reaction mixture to reflux and maintained 3 hours. After completion of the reaction, concentrated the reaction mass completely under reduced pressure. To the residual mass charged water and stirred. The product was extracted in dichloromethane (3 X 200 ml) separated the organic layer and distilled the solvent. The residual mass was taken in acetone to isolate the required product ethyl 3 - amino - 1 - benzyl - 1H - pyrazole - 4 - carboxylate. The compound was filtered and dried at 50 - 55°C till constant weight. Dry wt = 316gm (80 %).
Claims
1. A process for the preparation of 3 - amino pyrazole derivative of Formula - 1
Formula - 1
Where R\ = H, C\ - C4 alkyl group or benzyl group or phenyl group; R2 = Ci - C alkyl group or benzyl group;
comprising a step of reacting the compound of Formula - III, with hydrazine hydrate.
Formula - III
2. The process for the preparation of 3 - amino pyrazole derivative as claimed in claim 1 comprising of ;
i. reacting ester of cyano acetic acid with morpholine in presence of triethylorthoformate and diluent to give the intermediate compound of Formula -
III;
Formula - III ii. reacting the compound of Formula - III with hydrazine hydrate in presence of water to yield 3 - amino pyrazole derivative of Formula - 1.
3. The process as claimed in claim 2 (i), wherein the ester of cyano acetic acid is selected from
Methyl, ethyl, propyl, isopropyl or benzyl ester of cyanoacetic acid.
4. The process as claimed in claim 3; wherein the preferred ester of cyano acetic acid is ethyl ester.
5. The process as claimed in claim 2 (i), wherein the diluent used is selected from CI - C4 linear or branched chain alcohol.
6. The process as claimed in claim 5; wherein the preferred diluent selected is isopropyl alcohol.
7. The process as claimed in claim 2(i); wherein the reaction is carried out at temperature of 60 - 90°C.
8. The process as claimed in claim 7; wherein the preferred temperature of the reaction is 85 - 90°C.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2755MU2009 | 2009-11-27 | ||
| IN2755/MUM/2009 | 2009-11-27 |
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| Publication Number | Publication Date |
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| WO2011064798A1 true WO2011064798A1 (en) | 2011-06-03 |
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2868803A (en) | 1956-02-10 | 1959-01-13 | Ciba Pharm Prod Inc | New pyrazoles and method of preparing same |
| US4468353A (en) | 1976-08-10 | 1984-08-28 | Dynamit Nobel Ag | Method of preparing alkoxymethylene compounds |
| EP0810217A1 (en) * | 1996-05-29 | 1997-12-03 | Japan Energy Corporation | Pyrazole derivatives and their pharmaceutical use as smooth muscle cell growth inhibitors |
| WO2008134035A1 (en) * | 2007-04-27 | 2008-11-06 | Panacos Pharmaceuticals, Inc. | Alpha-unsubstituted arylmethyl piperazine pyrazolo[1,5-a] pyrimidine amide derivatives |
-
2010
- 2010-11-26 WO PCT/IN2010/000769 patent/WO2011064798A1/en active Application Filing
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|---|---|---|---|---|
| US2868803A (en) | 1956-02-10 | 1959-01-13 | Ciba Pharm Prod Inc | New pyrazoles and method of preparing same |
| US4468353A (en) | 1976-08-10 | 1984-08-28 | Dynamit Nobel Ag | Method of preparing alkoxymethylene compounds |
| EP0810217A1 (en) * | 1996-05-29 | 1997-12-03 | Japan Energy Corporation | Pyrazole derivatives and their pharmaceutical use as smooth muscle cell growth inhibitors |
| WO2008134035A1 (en) * | 2007-04-27 | 2008-11-06 | Panacos Pharmaceuticals, Inc. | Alpha-unsubstituted arylmethyl piperazine pyrazolo[1,5-a] pyrimidine amide derivatives |
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| Title |
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| JOURNAL, BULLETIN OF THE CHEMICAL SOCIETY OF JAPAN, vol. 50, no. 4, 1977, pages 957 - 960 |
| JOURNAL, J. AMER. CHEM. SOC., vol. 74, no. 19, 1952, pages 4889 - 4891 |
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