WO2016147205A1

WO2016147205A1 - Novel substituted 3-spirophosphoryl pyrazole-2-oxindoles as anti-infectives and process for the synthesis thereof

Info

Publication number: WO2016147205A1
Application number: PCT/IN2016/050085
Authority: WO
Inventors: Gurunath Mallappa Suryavanshi; Anil Maruti SHELKE
Original assignee: Council of Scientific and Industrial Research CSIR
Current assignee: Council of Scientific and Industrial Research CSIR
Priority date: 2015-03-13
Filing date: 2016-03-11
Publication date: 2016-09-22
Anticipated expiration: 2017-09-13

Abstract

The present invention relates to novel substituted 3-spirophosphoryl, pyrazole-2-oxindoles of Formula (I) and its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and pplymorphs. The present invention further relates to one pot, one step process for the synthesis of spirophosphoiyl pyrazole oxindoles of Formula (I) with yield in the range of 70-85%.

Description

NOVEL SUBSTITUTED 3-SPIROPHOSPHORYL PYRAZOLE-2-OXI NDOLES AS ANTI-INFECTIVES AND

PROCESS FOR THE SYNTHESIS THEREOF

5

The following specification particularly describes the invention and the manner in 10 which it is to be performed.

FIELD OF THE INVENTION:

The present invention relates to novel substituted 3-spirophosphoryl pyrazole-2- oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof.

15 The present invention further relates to one pot, one step process for the synthesis of spirophosphoryl pyrazole oxindoles of Formula (I) with yield ranging from 70-85%.

BACKGROUND AND PRIOR ART:

Naturally occurring spirocylic 2-oxindoles have drawn tremendous interests in 0 synthetic and medicinal chemistry due to their various biological activities. Spirocyclic hydrocarbons and heterocycles are attractive synthetic targets owing to their broad applications in the area of medicinal organic chemistry. Organo phosphorous pyrazoles shows diverse and potent biological activities and pyrazole containing molecules like Viagra, Celebrex and Acomplia are sought after drugs in the world market. The 5 compounds are also known to possess anti HIV, anti cancer and anti tubercular activities.

Owing to this, it is attractive to provide novel substituted spirophosphoryl pyrazole oxindoles. The new molecules may find use in several therapeutic areas and will prove 0 to viable and advantageous alternatives to existing range of medicaments available.

Article titled "Three-component reaction using the Bestmann-Ohira Reagent: A regioselective synthesis of Phosphonyl Pyrazole Rings" by Kishor Mohanan et al. published in Angewandte Chemie, 2010, 49(18), pp 3196-3199 reports a new one -pot multicomponent reaction involving the use of an aldehyde, a cyanoacid derivative, and the Bestmann-Ohira reagent (BOR) has been developed for the synthesis of substituted phosphonyl pyrazoles. This process was also combined with a copper- catalyzed azide-alkyne 1,3-dipolar cycloaddition to generate five new bonds and two heterocyclic rings in a one-pot fashion.

Article titled "Design and synthesis of pyrazole-oxindole conjugates targeting tubulin polymerization as new anticancer agents" by Ahmed Kamal et al. published in European Journal of Medicinal Chemistry, 2015, Volume 92, Pages 501-513 reports a series of twenty one compounds with pyrazole and oxindole conjugates were synthesized by Knoevenagel condensation and investigated for their antiproliferative activity on different human cancer cell lines.

Article titled "Organocatalytic asymmetric assembly reactions: Synthesis of spirooxindoles via organocascade strategies" by Daojuan Cheng et al. published in ACS Catalysis, 2014, 4, pp 743-762 reports enantioselective synthesis of spirooxindoles via organocascade strategies and is organized on the basis of three primary starting materials and then further subdivided according to the types of organocatalyst. These methods are of importance for the synthesis of complex natural products and the design of new pharmaceutical compounds.

Article titled "Domino reaction involving the Bestmann-Ohira reagent and α,β- unsaturated aldehydes: efficient synthesis of functionalized pyrazoles" by Shakir Ahamad et al. published in Organic and Biomolecular Chemistry, 2015,13, 1492- 1499, first published online 25 Nov 2014 reports a mild, efficient and rapid domino reaction involving the Bestmann-Ohira reagent (BOR) and α,β-unsaturated aldehydes has been developed for the synthesis of densely functionalized vinylpyrazoles. This reaction demonstrates the dual reactivity of BOR as a homologation reagent as well as a cycloaddition partner, thus constituting a domino reaction in an operationally simple procedure. The application of this efficient synthesis of pyrazoles has been demonstrated for the synthesis of phosphonyl analogues of pyrrolopyrazole alkaloids.

Article titled "Phosphonylpyrazoles from Bestmann-Ohira reagent and nitroalkenes: synthesis and dynamic NMR studies" by Rajendran Muruganantham et al. published in Journal of Organic Chemistry, 2010, 75 (7), pp 2197-2205 reports application of diethyl 1 -diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent) as a cycloaddition partner with nitroalkenes has been extensively investigated. Base-mediated reaction of the Bestmann-Ohira reagent with various nitroalkenes such as β-substituted, α,β- disubstituted, and nitroethylene that are part of a carbocyclic or heterocyclic ring provided functionalized phosphonylpyrazoles through a one -pot regioselective reaction at room temperature in high yield.

Article titled "Regioselective synthesis of 3-Carbo-5-phosphonylpyrazoles through a one -pot Claisen-Schmidt/l,3-Dipolar Cycloaddition/Oxidation sequence" by Anthony R. Martin et al. published in European Journal of Organic Chemistry, 2011,17, pages 3184-3190 reports a one-pot reaction involving an aldehyde, a methyl ketone, and the Bestmann-Ohira reagent has been developed for the synthesis of variously substituted 3-carbo-5-phosphonylpyrazoles. Synthetic methodology features a domino Claisen- Schmidt/1, 3-dipolar cycloaddition/oxidation sequence, which leads to the target compounds in excellent yields.

Article titled "Base-mediated reaction of the Bestmann-Ohira reagent with Nitroalkenes for the regioselective synthesis of phosphonylpyrazoles" by R. Muruganantham et al. published in Organic Letter, 2007, 9 (6), pp 1125-1128 reports 1,3-Dipolar cycloaddition of the anion of diethyl 1-diazomethylphosphonate, generated in situ from diethyl 1 -diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent), with conjugated nitroalkenes provides regioisomerically pure phosphonylpyrazoles in moderate to good yield. These pyrazoles are formed in one pot via spontaneous elimination of the nitro group. However, nitropyrazoles could be synthesized by the same strategy using a-bromonitroalkenes. The methodology works for the synthesis of phosphonylpyrazoles fused to other carbo- and heterocycles as well.

Article titled "A novel one-pot method for the preparation of pyrazoles by 1,3 -Dipolar cycloadditions of diazo compounds generated in situ" by Varinder K. Aggarwal et al. published in Journal of Organic Chemistry, 2003, 68 (13), pp 5381-5383 reports a convenient one -pot procedure for the preparation of pyrazoles by 1,3-dipolar cycloaddition of diazo compounds generated in situ has been developed. Diazo compounds derived from aldehydes were reacted with terminal alkynes to furnish regioselectively 3,5-disubstituted pyrazoles. Furthermore, the reaction of N- vinylimidazole and diazo compounds derived from aldehydes gave exclusively 3- substituted pyrazoles in a one -pot process.

Article titled "Highly selective synthesis of pyrazole and spiropyrazoline phosphonates via base-assisted reaction of the Bestmann-Ohira Reagent with enones" by Deepti Verma et al. published in Journal of Organic Chemistry, 2011, 76 (11), pp 4764—4770 reports novel carbonylated pyrazole phosphonates have been synthesized as single regioisomers by treating conjugated enones, dienones, tropone, and quinone with the Bestmann-Ohira reagent under KOH/EtOH conditions at room temperature. Through an "interrupted" version of the above reaction, carbonylated spiropyrazoline phosphonates have been synthesized from arylidenecycloalkanones under similar conditions (K^COs/EtOH) with absolute regio- and diastereoselectivity. The key structures were confirmed by detailed spectroscopic analysis and X-ray crystallography. Prior art disclosed processes suffer from several drawbacks such as long reaction sequences, using corrosive reagents, and poor yields and so on. Therefore, there is need to overcome the above drawbacks. The inventors propose a novel substituted spirophosphoryl pyrazole oxindoles and a simple process for the synthesis of the same.

OBJECTIVE OF INVENTION:

The main objective of the present invention is to provide a novel substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof. The another objective of the present invention is to provide a pharmaceutical composition comprising compound of Formula (I) and at least one pharmaceutically acceptable carrier for activity against bacteria, fungi, virus and such like.

Still another objective of the present invention is to provide one pot, one step process for the synthesis of substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof.

Yet another objective of the present invention is to provide one pot, one step and simple process for the synthesis of substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof by using mild reaction conditions and short reaction time with high yield.

SUMMARY OF THE INVENTION:

Accordingly, the present invention provides a novel substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof.

3-Spirophosphonyl

pyrazole-2-oxindoles

Formula I

Wherein

Ri= H, F, Br, CI, N0₂, OCF₃

R₂= benzyl, i-butyl carbonyl, methyl, acetyl, tert-butyloxy carbonyl and para methoxybenzyl ether

R₃= COOEt, COOMe, COPh, COAr, CN and

P = Et, Me

The present invention further relates to a pharmaceutical composition comprising compound of Formula I and at least one pharmaceutically acceptable carrier for activity against bacteria, fungi, virus and such like.

The present invention further relates to one pot, one step process for the synthesis of substituted spirophosphoryl pyrazole oxindoles of Formula (I) including the steps of adding a base to a stirred solution of Bestmann- Ohira Reagent in a solvent at temperature ranging from 20-30°C in air and stirring the resulting mixture for 2-4 mins followed by adding oxindolylidene acetate to the mixture and stirring the resultant solution for 5-6 min to afford substituted 3-spirophosphonyl pyrazole-2- oxindoles of Formula (I).

The above process is shown below in Scheme 1 :

Oxindolylidene Ohira Bestmann

acetate Reagent 70-85%

1 2 3a-h

Scheme 1: Synthesis of spirophosphoryl pyrazole oxindoles

In an embodiment, said base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, triethyl amine, potassium carbonate, potassium tert. butoxide, diazabicycloundecene and such like.

In another embodiment, said solvent is selected from methanol, ethanol, acetonitrile, dimethyl sulfoxide, or tetrahydrofuran.

DETAILED DESCRIPTION OF THE INVENTION:

The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated. In view of above, the present invention provides a novel substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof.

3-Spirophosphonyl

pyrazole-2-oxindoles

Formula I

Wherein

Ri= H, F, Br, CI, N0₂, OCF₃

R₃= COOEt, COOMe, COPh, COAr, CN and

R₄= Et, Me

In a preferred embodiment, the compounds of Formula (I) are selected from compounds 3a-3n.

d 70% 3e 72% 3f 79%

g 80% ^3h 83%

31, 83% 3m, 79%

The preferred compounds are listed below in Table 1.

Table 1

3g Ethyl 5-bromo-5'-(diethoxyphosphoryl)-2-oxospiro[indoline- 3,3'-pyrazole]-4'-carboxylate

3h Ethyl 5'-(dimethoxyphosphoryl)-2-oxo-2',4'- dihydrospiro[indoline-3,3'-pyrazole]-4'-carboxylate

3i Ethyl 5 '-(diethoxyphosphoryl)-5-methoxy-2- oxospiro[indoline-3,3'-pyrazole]-4'-carboxylate

3j Ethyl 5'-(diethoxyphosphoryl)-2-oxo-5-

(trifluoromethoxy)spiro[indoline-3,3'-pyrazole]-4'- carboxylat

3k Ethyl 5 '-(diethoxyphosphoryl)-5-nitro-2- oxospiro[indoline3,3'-pyrazole]-4'-carboxylate

31 Methyl 5'-(dimethoxyphosphoryl)-2-oxospiro[indoline- 3,3'pyrazole]-4'-carboxylat

3m Ethyl 4-chloro-5 '-(diethoxyphosphoryl)-2- oxospiro[indoline3,3'-pyrazole]-4'-carboxylate

3n Ethyl 6-bromo-5 '-(diethoxyphosphoryl)-2- oxospiro[indoline3,3'-pyrazole]-4'-carboxylat

The compound of Formula I may further find use in the therapeutic classes of cancer and cell proliferation.

In another preferred embodiment, the compound of Formula I is active against Mycobacteria like E.coli, Pseudomonas flurescence, Staphylococcus aureus, Bacillus subtillus.

In still another preferred embodiment, the compound of Formula I is active against HIV.

In yet another preferred embodiment, the present invention further relates to a pharmaceutical composition comprising compound of Formula I and at least one pharmaceutically acceptable carrier for activity against bacteria, fungi, virus and such like. In still yet another preferred embodiment, the present invention further relates to one pot, one step process for the synthesis of substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof including the steps of (a) adding a base to a stirred solution of Bestmann- Ohira Reagent in a solvent at temperature ranging from 20-30°C in air and stirring the resulting mixture for 2-4 mins; (b) adding oxindolylidene acetate to the mixture and stirring the resultant solution for 5-6 min to afford substituted 3-spirophosphonyl pyrazole-2-oxindoles of Formula (I). In still yet another preferred embodiment, the present invention further relates to one pot, one step process for the synthesis of substituted spirophosphoryl pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof comprising adding a base (2.0 equiv.) to a stirred solution of Bestmann- Ohira Reagent (2.0 equiv.) in a solvent at temperature ranging from 20-30°C in air and stirring the resulting mixture for 2-4 mins; adding oxindolylidene acetate (1.0 equiv.) to the mixture and stirring the resultant solution for 5-6 min to afford substituted 3-spirophosphonyl pyrazole-2- oxindoles of Formula (I). After completion of reaction (monitored by TLC), evaporating the solvent and purifying the crude residue by column chromatography (silica gel, ethyl acetate) to afford pure substituted 3-Spirophosphonyl pyrazole-2- oxindoles of Formula (I).

The above process is shown below in Scheme 1 :

Oxindolylidene Ohira Bestmann

acetate Reagent 70-85%

1 2 3a-h

Scheme 1 : Synthesis of spirophosphoryl pyrazole oxindoles

In still yet another preferred embodiment, said base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, triethyl amine, potassium carbonate, potassium tert. butoxide, diazabicycloundecene and such like. In still yet another preferred embodiment, said solvent is selected from methanol, ethanol, acetonitrile, dimethyl sulfoxide, tetrahydrofuran and such like.

In still yet another preferred embodiment, yield of said process is ranging from 70% to

85%.

The pharmaceutically acceptable salt includes both acid and base addition salts. The acid addition salts are formed with both inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, nitric acid and the like; the organic acids are selected from but not limited to acetic acid, benzenesulfonic acid, benzoic acid, cinnamic acid, citric acid, formic acid, fumaric acid, and the like. The base addition salts are derived from inorganic bases which include, but are not limited to, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like; from organic bases such as salts of ammonia, primary, secondary, and tertiary amines, cyclic amines etc.

The pharmaceutical compositions of the invention can be prepared by combining a compound of the invention with an appropriate pharmaceutically acceptable carrier, diluent or excipient, and may be Formulated into preparations in solid, semi-solid, liquid or gaseous forms, such as tablets, capsules, powders, granules, ointments, solutions, injections, gels and microspheres,

In another embodiment, the present invention relates to administering 'an effective amount' of the 'composition of invention ' to the subject suffering from said disease. Accordingly, compound of Formula I and pharmaceutical compositions containing them may be administered using any amount, any form of pharmaceutical composition via any route of administration effective for treating the disease. Typical routes of administering such pharmaceutical compositions include, without limitation, oral, topical, transdermal, inhalation, parenteral, sublingual, buccal, rectal, vaginal, and intranasal.

Pharmaceutical compositions of the invention are Formulated so as to allow the active ingredients contained therein to be bioavailable upon administration of the composition to a patient. Compositions that will be administered to a subject or patient may take the form of one or more dosage units. The dosage forms can also be prepared as sustained, controlled, modified and immediate dosage forms.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples:

Example 1: General procedure for the 1,3 dipolar reaction of Bestmann- Ohira Reagent with oxindolylidene acetates:

KOH was used as a base which (2.0 equiv.) was added to a stirred solution of Bestmann- Ohira Reagent (2 equiv.) in methanol at temperature ranging from 20-30°C in air. The resulting mixture was stirred for 2 min. Then Oxindolylidene acetate (1.0 equiv.) was added. Then again mixture was stirred for 5-6 min. After completion of reaction (monitored by TLC) methanol was evaporated. The crude residue was purified by column chromatography (silica gel, ethyl acetate) to afford pure substituted 3-Spirophosphonyl pyrazole-2-oxindoles of Formula (I).

Example 2: Synthesis of Ethyl 5'-(diethoxyphosphoryl)-2-oxospiro [indoline-3,3'- pyrazole]-4'-carboxylate (3a):

Yield: 84%; White solid; mp: 120-122 °C; 1H NMR (500 MHz, CDC1₃) δ: 1.36-1.39 (m, 6H), 1.46 (t, = 7.6 Hz, 3H), 4.28- 4.34 (m, 4H), 4.45 (q, = 7.6 Hz, 1H), 7.19- 7.21 (m, 1H), 7.46 (m, 2H), 8.76-8.77 (m, 1H), 11.4 (br s, 1H); ¹³C NMR (125 MHz, CDCI₃) δ: 14.6, 16.9 (d, J_C-p = 6.4 Hz), 17.0 (d, J_C-p = 6.4 Hz), 62.6, 64.3 (d, J_C-p = 5.9 Hz), 64.4 (d, _c-p = 5.9 Hz), 112.3, 117.1, 124.5, 127.2, 132.5, 135.5, 145.1, 150.4, 163.3; ³¹P NMR (202.4 MHz, CDC1₃) δ: 6.59; HRMS (ESI) calcd for C^oNsOeNaP [M+Na]⁺ 416.0982; found 416.0979.

Example 3: Synthesis of Ethyl l-benzyl-5'-(diethoxyphosph< oxospiro[indoline-3,3 '-pyrazole] -4' -carboxylate (3b) :

Yield: 82%; White solid; mp: 168-170 °C; 1H NMR (200 MHz, CDC1₃) δ: 1.41-1.51 (m, 9H), 4.29-4.37 (m, 4H), 4.48 (q, / = 7.5 Hz, 2H), 5.59 (s, 2H), 7.28-7.36 (m, 2H), 7.48-7.53 (m, IH), 9.01- 9.03 (m, IH); ¹³C NMR (50 MHz, CDC1₃) δ: 13.3, 15.6 (d, c-p = 6.6 Hz), 15.8 (d, J_C-p = 6.6 Hz)„ 47.5, 61.5, 63.0 (d, J_C-p = 6.0 Hz), 63.1(d, J_C-p = 6.0 Hz), 112.1, 114.9, 123.5, 125.9, 127.1 (d, J_C-p = 12.5 Hz), 127.3 (d, J_C-p = 12.5 Hz), 128.4, 131.5, 134.1, 135.0, 144.5, 162.2; ³¹P NMR (202.4 MHz, CDC1₃) δ: 6.12; HRMS (ESI) calcd for C₂₄H₂6N₃0₆NaP [M+Na]⁺ 506.1451 ; found 506.1451.

Example 4: Synthesis of Ethyl -5'-(diethoxyphosphoryl)-5-fluoro-2- oxospiro[indoline-3,3 '-pyrazole] -4-carbox late (3c) :

Yield: 78%; White solid; mp: 210-212 °C; 1H NMR (200 MHz, CDC1₃) δ: 1.40-1.53 (m, 9H), 3.84 (s, 3H), 3.92- 4.40 (m, 6H), 7.59-7.67 (m, IH), 8.94- 8.98 (m, IH); ¹³C NMR (50 MHz, CDC1₃) δ: 13.8, 16.1(d, J_C-p = 6.4 Hz), 16.3 (d, J_C-p = 6.4 Hz), 31.4, 61.8, 63.3 (d, _C-p = 6.1 Hz), 63.4 (d, _C-p = 6.1 Hz), 112.3, 113.7, 114.4, 123.8, 127.3, 132.0, 136.1, 140.3, 144.4, 150.1, 162.6; ³¹P NMR (202.4 MHz, CDC1₃) δ: 6.17; HRMS (ESI) calcd for Ci₈H₂2N₃0₆NaP [M+Na]⁺ 430.1138; found 430.1137.

Example 5: Synthesis of l-(tert-Butyl)4 '-ethyl 5'-(diethoxyphosphoryl)-2-oxospiro [indoline-3,3'-pyrazole]-l,4'-dicarboxylate (3d):

Yield: 80%; white solid; mp: 155-157 °C; 1H NMR (200 MHz, CDC1₃) δ: 1.17 (t, J = 7.6 Hz, 3H), 1.32-1.41 (m, 6H), 1.46 (s, 9H), 4.18^.35 (m, 6H), 7.05-7.09 (m, 1H), 7.30-7.40 (m, 1H), 7.55-7.67 (m, 1H), 7.99-8.01 (m, 1H); 13C NMR (50 MHz, CDC1₃) δ: 13.8, 16.32 (d, JC-P = 6.6 Hz), 16.39 (d, JC-P = 6.6 Hz), 28.3, 61.0, 63.7 (d, JC-P = 6.0 Hz), 63.8 (d, JC-P = 6.0 Hz), 80.4, 122.8, 128.3, 130.0, 130.9, 136.7, 153.2, 162.3; 3 IP NMR (202.4 MHz, CDC1₃) δ: 5.03; HRMS (ESI) calcd for C₂₂H₂₈N₃0₈NaP [M + Na]⁺ 516.1512; found 516.1515.

Example 6: Synthesis of Methyl 5'-(diethoxyphosphoryl)-2-oxospiro [indoline- 3,3'pyrazole]-4'-carboxylate (3e):

Yield: 77%; yellow orange powder; mp: 178-180 °C; 1H NMR (400 MHz, CDC1₃) δ: 1.34-1.42 (m, 6H), 4.0 (s, 3H), 4.28-4.35 (m, 4H), 7.36-7.43 (m, 2H), 7.50-7.56 (m, 1H), 8.78-8.85 (m, 1H), 11.0 (s, 1H); 13C NMR (100 MHz, CDC1₃) δ: 16.3 (d, JC-P = 6.9 Hz), 16.4 (d, JC-P = 6.9 Hz), 52.5, 63.82 (d, JC-P = 6.4 Hz), 63.87 (d, JC-P = 6.4 Hz), 117.7, 116.3, 124.2, 126.8, 132.1, 134.6, 144.5, 163.0; 31P NMR (202.4 MHz, CDC1₃) δ: 6.26; HRMS (ESI) calcd for Ci₆Hi₈N₃0₆NaP [M + Na]⁺ 402.0825; found 402.0846. Example 7: Synthesis of Ethyl 5-bromo-5'-(diethoxyphosph< oxospiro[indoline3,3'-pyrazole]-4'-carboxylate (3f) :

Yield: 81%; white solid; mp: 175-177 °C; IH NMR (400 MHz, CDC1₃) δ: 1.35-1.50 (m, 9H), 4.29-4.33 (m, 4H), 4.46-4.50 (q, J = 7.2 Hz, 2H), 7.39-7.55 (m, 2H), 9.00-

9.03 (m, IH), 11.6 (br s, IH); 13C NMR (100 MHz, CDC1₃) δ: 14.0, 16.34 (d, JC-P =

5.4 Hz), 16.39 (d, JC-P = 5.4 Hz), 62.1, 63.80 (d, JC-P = 6.1 Hz), 63.85 (d, JC-P = 6.1 Hz), 113.1, 116.6, 118.2, 129.2, 131.9, 134.1 (d, JC-P = 16.4 Hz), 134.8 (d, JC-P = 16.4 Hz), 140.8, 143.9, 148.7, 162.2; 3 IP NMR (202.4 MHz, CDC1₃) δ: 6.52; HRMS (ESI) calcd for Cn^oNsOeBrP [M + H]⁺ 472.0268; found 472.0265.

Example 8: Synthesis of Ethyl 5-chloro-5'-(diethoxyphosph< oxospiro [indoline3,3 '-pyrazole] -4 '-carbox late (3g) :

Yield: 80%; white solid; mp: 190-192 °C; IH NMR (400 MHz, CDC1₃) δ: 1.35-1.50 (m, 9H), 4.27^1.33 (m, 4H), 4.45^1.50 (q, J = 7.2 Hz, 2H), 7.37-7.47 (m, 2H), 8.86 (d, J = 2.0 Hz, IH), 11.6 (br s, IH); 13C NMR (100 MHz, CDC1₃) δ: 14.0, 16.32 (d, JC-P = 6.4 Hz), 16.38 (d, JC-P = 6.4 Hz), 62.0, 63.83 (d, JC-P = 5.7 Hz), 63.89 (d, JC-P = 5.7 Hz), 112.7, 118.0, 126.2, 129.2, 132.0 (d, JC-P = 22.6 Hz), 133.7 (d, JC-P = 22.6 Hz), 140.9, 143.7, 146.5, 148.8, 162.2; 3 IP NMR (202.4 MHz, CDC1₃) δ: 6.45; HRMS (ESI) calcd for Ci₇H₂oN₃0₆ClP [M + H]⁺ 428.0775; found 428.0773.

Example 9: Synthesis of Ethyl 5'-(diethoxyphosphoryl)-5-fluoro-2- oxospiro [indoline3,3 '-pyrazole] -4 '-carboxylate (3h) :

Yield: 76%; white solid; mp: 194-196 °C; IH NMR (400 MHz, CDC1₃) δ: 1.35-1.49 (m, 9H), 4.29-4.33 (m, 4H), 4.44-4.50 (q, J = 7.0 Hz, 2H), 7.19-7.23 (m, IH), 7.49- 7.52 (m, IH), 8.60-8.63 (m, IH), 11.6 (br s, IH); 13C NMR (100 MHz, CDC1₃) δ: 14.0, 16.30 (d, JC-P = 6.1 Hz), 16.37 (d, JC-P = 6.1 Hz), 62.0, 63.7 (d, JC-P = 6.5 Hz), 63.8 (d, JC-P = 6.5 Hz), 112.6, 118.3, 120.0, 131.6, 141.4, 143.9, 146.2, 148.8, 157.2, 159.6, 162.3; 3 IP NMR (202.4 MHz, CDC1₃) δ: 5.50; HRMS (ESI) calcd for Ci₇H₂oN₃0₆FP [M + H]⁺ 412.1068; found 412.1065. Example 10: Synthesis of Ethyl 5'-(diethoxyphosphoryl)-5-methoxy-2- oxospiro[indoline-3,3 '-pyrazole -4 '-carboxylate (3i) :

Yield: 85%; white solid; mp: 212-214 °C; IH NMR (500 MHz, CDC1₃) δ: 1.37-1.49 (m, 9H), 3.84 (s, 3H), 4.29-1.48 (m, 6H), 7.03 (d, J = 8.0 Hz, IH), 7.35 (d, J = 8.0 Hz, IH), 8.48 (s, 1H),11.1 (br s, IH); 13C NMR (125 MHz, CDC1₃) δ: 14.0, 14.3, 16.4, 55.6, 61.9, 63.7 (d, JC-P = 6.4 Hz), 63.8 (d, JC-P = 6.4 Hz), 108.7, 112.4, 114.0, 114.2, 117.6, 121.1, 128.7, 142.3, 144.3, 156.0, 162.6; 3 IP NMR (202.4 MHz, CDC1₃) δ: 6.52; HRMS (ESI) calcd for Ci₈H₂₂N₃0₇PNa [M + Na]⁺ 446.1088; found 446.1106.

Example 11: Synthesis of Ethyl 5'-(diethoxyphosphoryl)-2-oxo-5- (trifluoromethoxy)spiro[indoline-3,3'-pyrazole]-4'-carboxylate (3j) :

Yield: 82%; white solid; mp: 164-166 °C; IH NMR (200 MHz, CDC1₃) δ: 1.37-1.49 (m, 9H), 3.84 (s, 3H), 4.29-1.48 (m, 6H), 7.03 (d, J = 8.0 Hz, IH), 7.35 (d, J = 8.0 Hz, IH), 8.48 (s, 1H),11.1 (br s, IH); 13C NMR (100 MHz, CDC1₃) δ: 14.0, 16.4 (d, JC-P = 6.6 Hz), 16.5 (d, JC-P = 6.6 Hz), 62.1 (d, JC-P = 5.8 Hz), 62.2 (d, JC-P = 5.8 Hz), 64.3, 112.6, 117.8, 118.4, 118.9, 119.3 (d, JC-P = 25.4 Hz), 119.5 (d, JC-P = 25.4 Hz), 121.8, 125.3, 144.9, 153.3, 162.0; 31P NMR (202.4 MHz, CDC1₃) δ: 6.54; HRMS (ESI) calcd for Ci₈H₁₉N₃0₇F₃PNa [M + Na]⁺ 500.0805; found 500.0824.

Example 12: Synthesis of Ethyl 5'-(diethoxyphosphoryl)-5-nitro-2- oxospiro[indoline3,3 '-pyrazole] -4 '-carbox late (3k) :

Yield: 79%; brown solid; mp: 185-187 °C; IH NMR (200 MHz, CDC1₃) δ: 1.32-1.44 (m, 9H), 3.87 (q, J = 7.2 Hz, 2H), 4.13 (m, 4H), 7.68 (s, IH), 8.02 (d, J = 2.0 Hz, IH), 8.16 (dd, J = 2.0, 7.2 Hz, IH), 9.91 (br s, IH); 13C NMR (100 MHz, CDC1₃) δ: 13.7, 16.3 (d, JC-P = 6.5 Hz), 16.4 (d, JC-P = 6.5 Hz), 61.9, 63.4 (d, JC-P = 5.7 Hz), 63.6 (d, JC-P = 5.7 Hz), 111.0, 121.1, 137.1, 139.5, 143.2, 148.1, 165.9, 177.6; 31P NMR (202.4 MHz, CDC1₃) δ: 6.27; HRMS (ESI) calcd for Ci₇Hi₉N40₈PNa [M + Na]⁺ 461.0838; found 461.0842.

Example 13: Synthesis of Methyl 5'-(dimethoxyphosphoryl)-2-oxospiro[indoline- 3,3 'pyrazole] -4 '-carboxylate (31) :

Yield: 83%; white solid; mp: 202-204 °C; IH NMR (200 MHz, CDC1₃) δ: 3.93 (s, 3H), 3.99 (s, 3H), 4.04 (s, 3H), 7.30-7.37 (m, IH), 7.41-7.60 (m, 2H), 8.85 (d, J = 7.2 Hz, IH), 11.1 (br s, IH); 13C NMR (125 MHz, CDC1₃) δ: 52.5, 54.13 (d, JC-P = 5.0 Hz), 54.17 (d, JC-P = 5.0 Hz), 111.8, 114.2, 116.3, 124.2, 127.0, 132.1, 134.8, 142.4, 144.5, 146.5, 162.8; 3 IP NMR (202.4 MHz, CDC1₃) δ: 6.01; HRMS (ESI) calcd for Ci₄H₁₄N₃0₆PNa [M + Na]⁺ 374.0512; found 374.0893.

Example 14: Synthesis of Ethyl 4-chloro-5'-(diethoxyphosph< oxospiro [indoline3,3 '-pyrazole] -4 '-carbox late (3m) :

Yield: 79%; white solid; mp: 180-182 °C; IH NMR (200 MHz, CDC1₃) δ: 1.34-1.52 (m, 9H), 4.24-4.55 (m, 6H), 7.39-7.63 (m, 3H), 11.4 (br s, IH); 13C NMR (50 MHz, CDC13) δ: 13.9, 16.2 (d, JC-P = 6.2 Hz), 16.3 (d, JC-P = 6.2 Hz), 62.0, 63.7 (d, JC-P = 5.2 Hz), 63.8 (d, JC-P = 5.2 Hz), 112.5, 112.6, 112.8, 114.4 (d, JC-P = 28.2 Hz), 114.6 (d, JC-P = 28.2 Hz), 118.2, 119.7, 120.0, 131.6, 141.3, 143.8, 146.5, 148.7, 157.1, 159.5, 162.2; 3 IP NMR (202.4 MHz, CDC1₃) δ: 5.50; HRMS (ESI) calcd for Ci₇H₂oN₃0₆ClP [M + H]⁺ 428.0775; found 428.0774.

Example 15: Synthesis of Ethyl 6-bromo-5'-(diethoxyphosph< oxospiro[indoline3,3 '-pyrazole] -4 '-carbox late (3n) :

Yield: 84%; white solid; mp: 168-170 °C; 1H NMR (200 MHz, CDC1₃) δ: 1.36-1.54 (m, 9H), 4.25-4.57 (m, 6H), 7.41-7.74 (m, 2H), 8.99 (d, J = 8.0 Hz, 1H), 10.5 (br s, 1H); 13C NMR (50 MHz, CDC1₃) δ: 13.6, 15.9 (d, JC-P = 6.3 Hz), 16.0 (d, JC-P = 6.3 Hz), 61.7, 63.4 (d, JC-P = 5.3 Hz), 63.5 (d, JC-P = 5.3 Hz), 112.2, 112.3, 112.5, 114.1 (d, JC-P = 22.5 Hz), 114.3 (d, JC-P = 22.5 Hz), 117.9, 119.5, 119.7, 131.3, 141.0, 143.6, 146.2, 148.4, 156.8, 159.3, 161.9; 31P NMR (202.4 MHz, CDC1₃) δ: 6.26; HRMS (ESI) calcd for Ci₇H₂₀N₃O₆BrP [M + H]⁺ 472.0268; found 472.0266.

Example 16: Optimisation of reaction conditions for the 1,3-dipolar cycloaddition reactions:

Scheme 2: Synthesis of Ethyl 5'-(diethoxyphosphoryl)-2-oxospiro[indoline-3,3'- pyrazole]-4'-carboxylate

Methyleneindolinone la was treated with Bestmann-Ohira reagent 2a in the presence of 2.0 equiv. K₂CO₃ in anhydrous MeOH at room temperature in open air, the desired 3,3'-spiro-phosphonylpyrazole-oxindole 3a was obtained in 40% yield at 25 °C after 12 h (Table 1, entry 1). The reaction was highly regioselective, with the carbon end of the dipole adding to the β-position of the methyleneindolinone la which was further confirmed by detailed spectroscopic analysis and X-ray crystallography. Table 2: Optimization of the reaction conditions for the 1,3-dipolar cycloaddition reactions of methyleneindolinone (la) with Bestmann- Ohira reagent (2a)

Entry Base Solvent Temp (°C) Time Yield (%)

1 K₂C0₃ MeOH 25 12 h 40

2 - MeOH 25 24 h No reaction

3 - MeOH reflux 4 days No reaction

4 NEt₃ MeOH 25 24 h complex

5 DBU MeOH 25 24 h traces

6 NaOMe MeOH 25 18 h 55

7 KOH MeOH 25 10 min 80

8 KOH EtOH 25 10 min 75

9 KOH CH₃CN 25 24 h No reaction

10 KOH DMSO 25 24 h No reaction

11 KOH THF 25 24 h 30

12 NaOEt EtOH 25 24 h 65

Example 17: A general experimental procedure for sequential multicom nentreaction of isatin 4, phosphonium ylide 5 and BOR reagent:

Scheme 3: Sequential multicomponent reaction of isatin, phosphonium ylide and Bestmann-Ohira reagent (BOR)

A general experimental procedure for sequential multicomponent reaction of isatin 6, phosphonium ylide 5, and BOR reagent 2a To a solution of the corresponding substituted isatin 4 (5 mmol, 1 equiv.) in methanol (30 mL) was added phosphonium ylide 5 (5 mmol, 1.1 equiv.) and the mixture was stirred at room temperature for 12 h. Then a solution of Bestmann-Ohira reagent 2a in 2 ml of MeOH was added to the reaction mixture. After the completion of reaction, as indicated by TLC, the solvent was evaporated and the crude reaction mixture was extracted using ethyl acetate. The organic layer was dried over Na₂S0₄ and evaporated under reduced pressure. The residue was purified using column chromatography (100-200 mesh silica gel) using pet. ether-ethyl acetate as the eluent.

Example 18: Activity testing of substituted 3-spirophosphoryl pyrazole-2- oxindoles:

3e 83.0 59. 45. 84. 62. 48. 85. 64. 51.1 83. 61. 47.

7 2 0 3 7 4 5 3 7 9

Advantages of invention:

1. Mild reaction conditions

2. Atom economical

3. Short reaction time

4. High yielding

5. Broad substrate scope

Claims

WE CLAIM:

1. A novel substituted 3-spirophosphoryl pyrazole-2-oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters, ethers, isomers, stereoisomers, positional isomers and polymorphs thereof,

3-Spirophosphonyl

pyrazole-2-oxindoles

Formula (I) wherein,

Ri= H, F, Br, CI, N0_2, OCF₃

R₃= COOEt, COOMe, COPh, COAr, CN and

R₄= Et, Me

2. The compound as claimed in claim 1, wherein said compound is selected from a) Ethyl 5'-(diethoxyphosphoryl)-2-oxospiro[indoline-3,3'-pyrazole]-4'- carboxylate

b) Ethyl 5'-(diethoxyphosphoryl)-5-fluoro-2-oxospiro[indoline-3,3'- pyrazole] -4-carboxylate

c) Ethyl 5'-(dimethoxyphosphoryl)-2-oxospiro[indoline-3,3'-pyrazole]-4'- carboxylate

d) Ethyl l-benzyl-5'-(diethoxyphosphoryl)-2-oxospiro[indoline-3,3'- pyrazole]-4'-carboxylate e) Ethyl 5-chloro-5'-(diethoxyphosphoryl)-2-oxospiro[indoline-3,3'- pyrazole]-4'-carboxylate

f) Ethyl 5'-(diethoxyphosphoryl)-5-nitro-2-oxospiro[indoline-3,3'- pyrazole]-4'-carboxylate

g) Ethyl 5-bromo-5'-(diethoxyphosphoryl)-2-oxospiro[indoline-3,3'- pyrazole]-4'-carboxylate

h) Ethyl 5'-(dimethoxyphosphoryl)-2-oxo-2',4'-dihydrospiro[indoline-3,3'- pyrazole]-4'-carboxylate

i) Ethyl 5'-(diethoxyphosphoryl)-5-methoxy-2-oxospiro[indoline-3,3'- pyrazole]-4'-carboxylate

j) Ethyl 5'-(diethoxyphosphoryl)-2-oxo-5-

(trifluoromethoxy)spiro[indoline-3,3'-pyrazole]-4'-carboxylat k) Ethyl 5'-(diethoxyphosphoryl)-5-nitro-2-oxospiro[indoline3,3'- pyrazole]-4'-carboxylate

1) Methyl 5'-(dimethoxyphosphoryl)-2-oxospiro[indoline-3,3'pyrazole]-4'- carboxylat

m) Ethyl 4-chloro-5'-(diethoxyphosphoryl)-2-oxospiro[indoline3,3'- pyrazole]-4'-carboxylate

n) Ethyl 6-bromo-5'-(diethoxyphosphoryl)-2-oxospiro[indoline3,3'- pyrazole]-4'-carboxylat

3. The compound as claimed in claim 1 and 2, wherein said compound is active against Mycobacteria selected from E.coli, Pseudomonas flurescence, Staphylococcus aureus, or Bacillus subtillus.

4. A pharmaceutical composition comprising compound of Formula (I) as claimed in claim 1 or at least one pharmaceutically acceptable carrier.

5. One pot, one step process for the synthesis of substituted spirophosphoryl

pyrazole oxindoles of Formula (I) or its pharmaceutically acceptable salts, esters,

ethers, isomers, stereoisomers, positional isomers and polymorphs thereof as claimed in claim 1 comprising:

adding a base to a stirred solution of Bestmann- Ohira Reagent in a solvent at temperature ranging from 20-30°C in air and stirring the resulting mixture for 2-4 mins;

adding oxindolylidene acetate to the

mixture and stirring the resultant solution for 5-6 min to afford substituted

3- spirophosphonyl pyrazole-2-oxindoles of Formula (I).

6. The process as claimed in claim 4, said base is selected from sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, triethyl amine, potassium carbonate, potassium tert. butoxide, or diazabicycloundecene.

7. The process as claimed in claim 4, said solvent is selected from methanol, ethanol, acetonitrile, dimethyl sulfoxide, or tetrahydro furan.

8. The process as claimed in claim 4, the yield of said process is ranging from 70% to 85%.