Title of Invention

ORGANOPHOSPHORUS ESTERS OF N-HYDROXY-2-FURAN BENZIMIDAZOLE

Abstract The present invention describes the preparation of new coupling reagents and their applications as coupling activator and coupling reagents for preparation of amides, esters and peptides. The coupling reagents of the present invention are the organophosphorus esters of N-hydroxy-2-furan benzimidazole. Preferred coupling reagents are phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester, phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-l-yl- ester and dipehyl-phosphonic acid 2-furan-yl-benzimidazol-1-yl-ester. Theses reagents are efficiently used for the preparation of carboxylic acid derivatives like amides, esters and peptides. 9 JUN2 008
Full Text THE GAZATTE OF INDIA: EXTRAORIDINARY

PART II-SEC.3 (ii)]

FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
&
Patents Rules, 2003
COMPLETE SPECIFICTION
(See Section 10 and 135 and rule 13)
1. TITLE OF THE INVENTION:
Preparation and applications of new coupling reagents

2. APPLICANT (S)

Dr. Devanand B. Shinde Professor,
Department of Chemical Technology, Dr. Babasaheb Ambedkar Marathwada University, Aurangabad- 431 004






DESCRIPTION FIELD OF INVENTION
This invention describes the synthesis of new coupling reagents, which are the organophosphorus esters of vV-hydroxy-2-furan-benzimidazole and their applications as coupling activator and coupling reagents for preparation of amides, esters and peptides. BACKGROUND OF THE INVENTION
1-Hydroxy benzotriazole (HOBt) (Konig, W.; Gieger, R. Chem. Ber. 1970, 103, 788) and 1-hydroxy-7-aza-benzotriazole (HOAt) (Carpino, L. A. J. Am. Chem. Soc. 1993, 115, 4397; Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc, Chem. Commun. 1994, 201) are commonly used activators in combination with carbodimide reagents like N,N-dicyclohexylcarbodimide (DCC) (Neises and Steglich, Angew. Chem Int. Ed. Engl. 1978, 17, 522; Hassner and Alexanion Tetrahedron Letters, 1978, 4475), N,N'-dicyclohexylcarbodimide (EDC)( Rich, D. H; Singh, J. In the peptide analysis, Synthesis, Biology, Gross, E., Meienhofer, J., Eds.; Acadamic Press: New York, 1979; 1,250), N,N'-dicyclohexylcarbodimide (DIC) and carbonyl diimidazoels (CDI) (Stabb and Mannschreck, Chem. Ber. 1962, 95, 1248; Ohta et al. Synthesis, 1982, 833) for peptide synthesis. From HOBt and HOAt, the uronium / gaunidinium coupling reagents like HBTU and HATU (Synthesis, 1989, 572 - 574 ; and Tetrhedron Letters, 1989, 30 (15), 1927 - 1939) are synthesized and used as peptide coupling reagents. Also, organo¬phosphorus esters of HOBt and HOAt are effectively used as the in peptide synthesis to provide the product with lower racemization (Tetrahedron Letter, 1985, 26, 1341 - 1342). Over the past few years, new organophoshorus coupling reagents were introduced and they were tremendously used for effective coupling, reactions and peptide synthesis with
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lower racemization like Diethoxyphosphinyloxybenzotriazole (DepOBt) (Kim, S.; Chang, A.; Ko, Y. K. Tetrahedron Lett. 1985, 26, 1341), 3-(Diethoxyphophinyloxy)-3,4-dihydro 4-oxo-l,2,3-benzotriazine (DepODht) (Fan, C-X.; Hao, X.-L.; Ye, Y.-H. Synth. Commun. 1996, 26, 1455), 3-(0- (2-oxo-l,3,2-dioxaphosphorinanyl)-3,4-dihydro-4-oxo-1,2,3-benzotriazine (DopODht) (Ueda, M.; Oikawa, H. J. Org. Chem. 1985, 50, 760), 1,2 -Benzisoxazole-yl diphenyl phosphate (Horiki, K: In Peptides: Chemistry, Structures and Biology, Rivier, J. E.; Marshall, G. R.; Eds.; ESCOM: Lieden, The Netherlands, 1990; 907), 3-Phenoxyphosphinyloxy)-3,4 - dihydro-4-oxo-l,3-quinazoline , 1-Diphenoxyphoshinyloxy-2-oxopyridine (Kim, S.; Kim, S. S.; J. Chem. Soc. Chem. Commun. 1986, 719), 1-benzotriazolyloxytris (dimethylamino)- phosphonium hexafluorophosphate (BOP) (Castro, B.; Domoy, J. -R. Tetrahedron Lett. 1973, 3243) and 1 - benzotriazolyloxy-7aza-tris(dimethylamino) - phosphonium hexafluorophosphate (AOP) (Carpino, L. A.; El-Faham, A.; Minor, C. A.; Albericio, F. J. Chem. Soc, Chem. Commun. 1994, 201, Ehrich, A.; Rothemond, S.; Brudel, M.; Beyermann, M.; Carpino, L. A.; Bienert, M. Tetrahedron Lett. 1993, 34, 4781). Recently, we had synthesized the new coupling reagents, organophosphorus esters of iV-hydroxy-2-phenyl benzimidazole and their utility was demonstrated for the amide and peptide coupling reactions (Kokare N. D., Nagawade, R. R., Rane, V. P. and Shinde D. B. 2007, 5, 766 - 772). Although plethora of coupling reagents is available in literature, they exhibit the one or more drawbacks like longer reaction time, lower yields and tedious work-up procedure. The preparation of peptides without loss of configuration is still challenging work. During the peptide coupling via uronium and phosphoniun salts, the N-protected amino carboxylic acid first reacts with the coupling reagent to give an active ester, which then reacts with
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amino component to give the corresponding amide. The latter step is the rate limiting and responsible for loss of configuration. The inherent reactivity of the active ester intermediate is a critical aspect and it depends upon the efficiency of coupling activators. In present invention, novel reagents useful as coupling activator and coupling reagents are described. The novel reagents of the invention include organophosphorus esters of N-hydroxy-2-furan-benzimidazole. The reagents of present invention could be used effectively as coupling activator and coupling reagents for amide, ester, and peptide bond forming reactions. The preferred new reagents are phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-1-yl- ester and dipehyl-phosphonic acid 2-furan-yl-benzimidazol-l-yl-ester. These coupling reagents have advantages of better yields, shorter reaction time and minimum racemization for peptide coupling reactions. The wealth of these reagents is the applicability of amide bond formation of chiral substrate with negligible racemization. Also for achievement of lower racemization, the use of the additives like HOBt or HOAt is not required. The simple and easy work- up procedure is the advantageous aspect of present method, which allows the isolation of desired product with good purity. SUMMARY OF INVENTION Object of invention
The present invention is directed towards the novel reagents that are useful as coupling activators for the synthesis of carboxylic acid derivatives and as coupling reagents in the organic synthesis. The new coupling reagents of the present invention are the organo¬phosphorus esters of N-hydroxy-2-furyl-benzimidazole having the structural formula as formula 1.
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Formula 1
Wherein;
Rl is selected from the groups of aryl, aryloxy and alkoxy.
The present invention is the synthesis of novel coupling reagents of Formula 1 and
efficient method of their utilization for amide, ester and peptide synthesis. In this method,
an amine, a carboxylic acid and the amide-coupling reagent (from formula 1) reacted for
the sufficient time to produce an amide bond between the amine and the carboxylic acid.
The desired product is isolated with the aqueous work-up and purification on the silica
gel column chromatography.
DETAILED DESCRIPTION OF THE INVETION
The present invention relates to the novel reagents of formula 1 and the method of their
utilization as coupling activator and coupling reagents for amides, esters and peptide
bond forming reactions. The novel reagents of the present invention are the organo-
phosphorus esters of N-hydroxy-2-fural-benzimidazole having structural formula as
formula 1.

Formula 1
Wherein;

Rl is selected from the groups of alkyloxy, aryloxy and aryl;
Alkyloxy group from Rl refers to OR2 wherein R2 is selected independently from C1-C6 alkyl groups like methyl, ethyl, propyl, etc., branched alkyl groups like isopropyl, tert-butyl, iso-butyl etc., and C3 - C6 cycloalkyl groups like cyclopropyl, cyclopentyl, cyclohexyl etc.;
Aryloxy group from Rl refers OR3, wherein R3 is selected independently from phenyl or substituted phenyl; and substituients are independently selected from hydrogen, alkyl, halogens, CN and NC2;
Aryl group from Rl refers to phenyl (Ph) or substituted phenyl; and substituients are independently selected from hydrogen, alkyl, halogens, CN and NO2. EXAMPLES OF NEW COUPLING REAGENTS REPRESENTED BY GENERAL STRUCTURAL FORMULA (FORMULA 1) Phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid dimethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid diisopropyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid diisobuyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid dicyclohexyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid di-p-tolyl ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid di-(4-chloro-phenyl) ester 2-furan-2-yl-benzimidazol-l-yl- ester; Phosphoric acid di-(4-cyano-phenyl) ester 2-furan-2-yl-benzimidazol-l-yl- ester; Dipehyl-phosphonic acid 2-furan-yl-benzimidazol-l-yl-ester; Di-p-tolyl-phosphonic acid 2-furan-yl-benzimidazol-l-yl-ester;
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Dicyclohexyl-phosphonic acid 2-furan-yl-benzimidazol-1 -yl-ester; Di-(4-chloro-phenyl)-phosphonic acid 2-furan-yl-benzimidazol-1 -yl-ester; Di-(4-cyano-phenyl)-phosphonic acid 2-furan-yl-benzimidazol-1 -yl-ester.
Coupling regents were prepared using N-hydroxy-furan-benzimidazole (4) and (R1)2P(0)C1. Out of this, N-hydroxy-furan-benzimidazole (4) was prepared according to the scheme 1. Furyl amine was coupled with 2-fluoro-nitrobenzene to get N-(methyl-furan)-o-nitro aniline. It was treated with benzyl bromide and sodium hydride base to afford the N-benyloxy-2-furan-benzimidazole. Using 10 % Pd/C, benzyl group was deprotected to get N-hydroxy-2-furan benzimidazole (4). Scheme 1. Preparation of N-hydroxy-2-furan benzimidazole


bn
12. 3 4
Reagents and conditions: (a) Furyl amine, triethyl amine, acetonitrile, 70 °C, 6 h; (b) NaH, BnBr, 70 °C, 3 h; (c) H2, Pd/C, methanol, 15 min.
The coupling regents were synthesized from the coupling of TV-hydroxy-2-furan
benzimidazole (4) with suitable (R1)2P(0)C1 (dialkyl phosphoryl chloride, dialkyloxy
phosphoryl chloride, or diaryl phosphoryl chloride) in dicloromethane at 0 °C to afford
coupling reagents as shown in Scheme 2.
Scheme 2. Preparation of coupling reagents.


Reagents and conditions: (a) (R1)2P(0)C1, Et3N, CH2C12, 0 °C
6

The most preferred coupling reagents are phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-1-yl-ester (Al), phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-1-yl- ester (A2) and diphenyl-phosphonic acid 2-furan-yl-benzimidazol-1 -yl-ester (A3). These reagents can be isolated as a solid. However, for synthetic purpose, it is advantageous to synthesize reagent in solution phase just prior to use from the reaction of N-hydroxy-2-furan benzimidazole and suitable substituted phosphoric chloride reagent.
Scheme 3. The preparation of amides, peptides, and esters using of coupling reagents of present invention.

The present invention further includes the improved method for the preparation of amide and peptides using the novel reagents as coupling activators. In preferred embodiment, the preparation of amides via activating the carboxylic acid with reagents (Al, or A2, or A3) and nucleophilic attack of amine as illustrated in scheme 3. In present invention, carboxylic acid reacts with the coupling reagents to get the active intermediate 6, which makes the hydroxyl group of carboxylic acid as an easily leaving group. Subsequently, the nucleophilic attack of amine leads to formation of amide and the side product N-hydroxy-2-furan benzimidazole. The side product, iV-hydroxy-2-furan benzimidazole can be easily removed by the acid-base treatment and remaining product was purified on
7

silica gel column chromatography to get the desired product. The isolated side-product, iV-hydroxy-2-furan benzimidazole can be re-used for the preparation reagent.
The term coupling activator as used herein means a reagent will react with carboxylic acid to make the carbonyl group more reactive towards the nucleaoplilic attack. The most preferred coupling activators are phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester (Al), phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-1-yl- ester (A2) and diphenyl-phosphonic acid 2-furan-yl-benzimidazol-l-yl-ester (A3).
The nucleophile as used herein is electron rich compound that reacts with carbonyl carbon of activated intermediate (6). The suitable nucleophiles used in the present invention are selected independently from amines, acid protected amino acids, and alcohols.
The term peptide as used herein refers to a polymer of amino acids chemically bound by amide linkages (CONH). The amino acid is defined as an organic molecule both containing the amino group (NH2) and carboxylic group (COOH). Specifically an amino acid is any compound of general formula RCH(NH2)COOH (a-amino acid) wherein R is selected from groups consisting of H or any suitably protected known amino acid chain. The suitable N-protecting groups may be selected from the many reported N-protecting groups, which are known to those in the art such as (9H-fluoren-9-yl)methyl chloroformate (FMOC), Di-tert-butyl dicarbonate (tert-BOC), bezyl chloroformate (CBZ), benzyl groups, acyl groups or triphenylmethyl groups. The suitable acid protecting groups are selected from the many acid-protecting groups, which are known to those in the art such as various ester-protecting groups.
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The coupling reagents as used herein means a reagent that will couple two compound having the structures R,-COOH and HX-R2 to form the compound having structures R1-C(0)-XR2 wherein R1 and R2 are independently selected from the groups consisting of alkyl, alkenyl, alkynyl and aryl; and X is selected independently from the groups O or NH. The novel reagents of the present invention offer the several advantages over the some of reagents reported in the literature (Bailen, M. A.; Chinchilla, R.; Dodsworth, D. J.; Najera, C. J. Org. Chem. 1999, 64, 8936; Fernando, A.; Miguel A.B.; Rafael C; David J.D.; Carmen N. Tetrahedron. 2001, 57, 9607; Williams, M. W.; Young, G. T. J. Chem. Soc. 1963, 881). Also these reagents preferably phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester (Al), phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-l-yl- ester (A2) and diphenyl-phosphonic acid 2-furan-yl-benzimidazol-1-yl-ester (A3) are advantages to the previously reported our coupling reagents which are organo-phosphorus esters of N-hydroxy-2-phenyl-benzimidazoles (Kokare N. D., Nagawade, R. R., Rane, V. P. and Shinde D. B. 2007, 5, 766 - 772).
(i) The by-product formed in the coupling reaction of acid and suitable nucleophile is N-hydroxy-2-furan benzimidazole, which can be easily separated by acid-base treatment to allow the easy isolation of product. The separated by-product, N-hydroxy-2-furan benzimidazole can be re-used for the preparation of the coupling reagents.
(ii) The active ester formed in coupling reaction using the reagents of the present invention is more facile leaving group than the reagents using organo-phosphorus esters of N-hydroxy-2-phenyl benzimidazole. Since the regents of present invention afford the
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active ester with more facile leaving group, resulting in shorter reaction time and higher yields.
(iii) In peptide coupling reactions, use of reagents of present invention is advantageous as they gives the desired product in shorter reaction time, with higher yields and lower racemization as compared to organo-phosphorus coupling reagents of N-hydroxy-2-phenyl benzimidazole. The advantage obtained for reagent of present invention is may be due to the presence of furan group instead of phenyl. It may be offering the lone pair of oxygen from furan to stabilize the active ester intermediate and prohibiting from the racemization.
Esters and amides (including peptides) were synthesized using the reagents of present invention preferably, phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester (Al), phosphoric acid diphenyl ester 2-furan-2-yl-benzimidazol-l-yl- ester (A2) and dipehyl-phosphonic acid 2-furan-yl-benzimidazol-l-yl-ester (A3). The results obtained are summarized in Table 1.
Entries 1 to 6 from Table - 1 summarize the coupling reagent used, reaction time and percentage yields for synthesis of amides like N-benzyl benzamide and N-benzyl-4-nitro-benzamide. Entries 7 to 12 from Table 1 summarize the coupling reagent used, reaction time, percentage yields and percentage of distreomeric racemization occurred for synthesis of peptides like Cbz-Val-Val-OMe and Bz-Leu-Gly-OEt. Entries 13 to 18 from Table 1 summarize the coupling reagent used, reaction time and percentage yields for preparation of esters like ethyl benzoate and benzyl benzoate. The yields obtained for synthesis of amides, peptides and esters using reagents Al, A2, and A3 are better and in the range of 94% to 99%, 91% to 97%, and 93% to 98% respectively. The method of
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present invention requires shorter reaction time for preparation amides, peptides and esters. The diastreomeric racemization obtained of synthesized peptides using reagents of present invention found to be minimum and it is in the range of 0.3% to 1.2%. Preferably, phosphoric acid diethyl ester 2-furan-2-yl-benzimidazol-l-yl- ester (Al) coupling reagent was found to advantageous in regard with providing the minimum distreomeric racemization for preparation of peptides. Table 1. Synthesis of various amides, peptides, and esters using reagents Al, A2 and A3

Entry Product Reagent Reaction Yield a Racemization
used time (min) (%) DL %b
1 N-benzyl benzamide Al 30 99 -
2 N-benzyl benzamide A2 40 94 -
3 N-benzyl benzamide A3 30 98 -
4 4-nitro N-benzyl benzamide Al 15 95 -
5 4-nitro N-benzyl benzamide A2 20 97 -
6 4-nitro N-benzyl benzamide A3 15 99 -
7 Cbz-Val-Val-OMe Al 90 97 0.3
8 Cbz-Val-Val-OMe A2 90 92 0.6
9 Cbz-Val-Val-OMe A3 80 94 0.4 .
10 Bz-Leu-Gly-OEt Al 90 96 0.4
11 Bz-Leu-Gly-OEt A2 110 93 1.2
12 Bz-Leu-Gly-OEt A3 100 91 0.8
13 Ethyl benzoate Al 55 95 -
14 Ethyl benzoate A2 60 97 -
15 Ethyl benzoate A3 60 93 -
16 Benzyl benzoate Al 70 98 -
17 Benzyl benzoate A2 75 94 -
18 Benzyl benzoate A3 J '65 95 -
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THE GENERAL METHOD FOR THE PREPARATION OF AMIDES
To a mixture of aromatic or aliphatic carboxylic acid in solvent like NN-dimethyl formamide, NN-dimthyl acetamide, acetonitrile, tetrahydofuran, or dioxane preferrebly in acetonitrile; base like triethyl amine, NN-diisopropyl ethyl amine, pyridine, lutidine, or DBU preferably triethyl amine was added. To the cooled reaction mixture, coupling reagent (Al, or A2, or A3) was added and stirred for sufficient time to get the activated intermediate 6. The amine was added to the reaction mixture and it was stirred at room temperature (25 - 30 °C) for the sufficient time to get complete conversion. The reaction was quenched with water, extracted with solvents such as dichloromethane, chloroform or ethyl acetate preferably ethyl acetate for two to three times. To the collectively organic layer, acid - base treatment was given to get the pure product. Some of the products were purified on silica gel column chromatography to get the desired product with good purity. THE GENERAL METHOD FOR THE PREPARATION OF PEPTIDES To a mixture of amine protected amino acid with t-BOC or CBZ or F-MOC in solvent like N,N-dimethyl formamide, N,N-dimthyl acetamide, acetonitrile, tetrahydofuran, or dioxane preferrebly in acetonitrile; base like triethyl amine, N,N-diisopropyl ethyl amine, pyridine, lutidine, or DBU preferably triethyl amine was added. To the cooled reaction mixture, coupling reagent (Al, A2, or A3) was added and stirred for sufficient time to get the activated intermediate. The acid protected amino acid was added to the reaction mixture and it was stirred at room temperature (25 - 30 °C) for the sufficient time to get complete conversion. The reaction was quenched with water, extracted with solvents such as dichloromethane, chloroform or ethyl acetate preferably ethyl acetate for two to three times. To the collectively organic layer, acid-base treatment was given to get the
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pure product. Some of the products were purified on silica gel column chromatography to
get the desired product with good purity.
THE GENERAL METHOD FOR THE PREPARATION OF ESTERS
To a mixture of aromatic or aliphatic carboxylic acid in solvent like N,N-dimethyl formamide, N,N-dimthyl acetamide, acetonitrile, tetrahydofuran, or dioxane preferrebly in acetonitrile; base like triethyl amine, N,N-diisopropyl ethyl amine, pyridine, lutidine, or DBU preferably triethyl amine was added. To the cooled reaction mixture, coupling reagent of present invention was added and stirred for sufficient time to get the activated intermediate. Appropriate alcohol was added to the reaction mixture and it was stirred at room temperature (25 - 30 °C) for the sufficient time to get complete conversion. The reaction was quenched with water, extracted with solvents such as dichloromethane, chloroform or ethyl acetate preferably ethyl acetate for two to three times. To the collectively organic layer, acid - base treatment was given to get the pure product. Some of the products were purified on silica gel column chromatography to get the desired product with good purity.
THE FOLLOWING EXAMPLES ARE PRESENTED TO EXPLAIN AND ILLUSTRATE THE PRESENT INVENTION
Example 1. Preparation of TV-methylfuran-o-niroaniline
To a mixture of 2-fluoro-nitrobenzene (3.52 gm, 25 mmol), triethyl amine (8.6 ml, 62,5 mmol) in acetonitrile (40 ml), furyl amine (2.66 gm, 27.5 mmol) was added. The reaction mixture was stirred at 70 °C for four hours. It was cooled to room temperature and concentrated to dryness. Water (60 ml) was added to residue and solid separated was filtered and dried to get the desired compound as a yellow solid in 5.3 gm quantity (96 %
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yield). 1H NMR (400 MHz, CDC13): δ = 4.5 (d, 2H), 6.25(d, 1H), 6.35(t, 1H), 6.7(t, 1H),
6.95(d, 1H), 7.38(s, 1H), 7.45 (t, 1H), 8.2 (d, 1H), 8.35 (bs, 1H). MS (EI, 70 eV): m/z =
219[M+H]+.
Example 2. Preparation of TV-benzloxy-2-furan-benzimidazole
To a mixture of sodium hydride (2.38 g, 59.5 mmol) in THF (50 ml), N-methylfuran-o-
niroaniline (5.2 gm, 23.8 mmol) was added portion wise at 0 °C and it was stirred for
fifteen minute. Benzylbromide (4.9 g, 28.6 mmol) was added and reaction mixture was
heated to 80 °C for four hours. It was cooled to room temperature and quenched with
water (70 ml). It was extracted with ethyl acetate (30 ml x 2) and collectively organic
layer was dried over sodium sulphate and concentrated to dryness. The residue was
purified on silica gel column chromatography to get the desired product in 5.7 gm
quantity (83 % yield).1'H NMR (400 MHz, CDCI3): 5 =5.25 (s, 2H), 6.6 (dd, 1H) 7.15-
7.3 (m, 8H), 7.4-7.45 (m, 2H), 7.65 (d, 1H). MS (EI, 70 eV): m/z = 291 [M+H]+.
Example 3. Preparation of .N-hydroxy-2-furan-benzimidazole
N-benzyloxy-2-furan benzimidazole (5.5 gm 18 mmol) was dissolved in methanol (55
ml), 550 mg of 10 % Pd/C was added and stirred under H2 atmosphere for 15 minute at
room temperature. The reaction mixture was filtered through high flow and filtrate was
concentrated and purified by column chromatography to get the title compound in 3.5 gm
quantity (92 % yield). Yield - 3.5 gm, (92%). 'H NMR (400 MHz, CDC13): 5 = 5.0 (bs,
1H), 5.9 (dd, 1H), 6.6 (d, 1H), 7.15-7.2 (m, 2H), 7.35-7.4 (m, 2H), 7.6 (d, 1H). MS (EI,
70eV):m/z =201 [M+H]+
Example 4. Preparation of phosphoric acid diethyl ester 2-furylbenzimidazol-l-yl
ester (Al)
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To a mixture of N-hydroxy-2-furyl benzimidazole (1.1 g, 5.5 mmol) and triethyl amine (1.68 ml, 12.1 mmol) in dichloromethane (10 ml), diethyl chlorophoshphate (1.04 gm, 6.0 mmol) was added at 0 °C and the reaction mixture was stirred for 30 minutes. Reaction mixture was concentrated to get the residue. It was stirred with pentane (10 ml) and decanted. The remaining residue was stirred with diethyl ether (10 ml) & decanted for three times. The collectively diethyl ether was concentrated to get the title compound as a white solid in 1.36 gm quantity (74 % yield) !H NMR (400 MHz, CDC13): 5 = 1.4 (t, 6H), 4.2 (q, 4H), 6.4 (dd, 1H), 7.1 (t, 1H), 7.35-7.4 (dd, 2H), 7.6 (d, 1H) 7.7-7.5 (m, 2H); MS (EI, 70 eV): m/z = 337[M+H]+.
Example 5. Preparation of phosphoric acid diphenyl ester 2-furylbenzimidazol-l-yl ester (A2)
The title compound was synthesized using similar procedure as example 4 to provide product in 67 % yield.
'H NMR (400 MHz, CDC13): 5 = 6.45 (dd, 1H), 7.1 (t, 1H), 7.3-7.4 (m, 12H), 7.65 -7.7 (m, 3H); MS (EI, 70 eV): m/z = 433[M+H]+.
Example 6. Preparation of phosphoric acid diphenoxy ester 2-furyIbenzimidazoI-l-yl ester (A3)
The title compound was synthesized using similar procedure as example 4 to provide product in 71 % yield.
'H NMR (400 MHz, CDC13): 6 = 6.4 (dd, 1H), 6.95 (t, 1H), 7.25 -7.4 (m, 12H), 7.6 (dd, 1H), 7.65 -7.7 (m, 2H); MS (EI, 70 eV): m/z =401[M+H]+.
Example 7. Preparation of N-benzyl benzamide
To a mixture of benzoic acid (0.250 gm, 2.04 mmol), triethyl amine (0.57 ml, 4.08
mmol) in acetonitrile (4 ml), coupling reagent Al, or A2, or A3, (2.04 mmol) was added
15

at 0 °C. The reaction mixture was stirred for 15 minutes for active ester formation.
Benzyl amine (0.263 gm, 2.44 mmol) was added to reaction mixture and it was stirred at
room temperature for 30 minutes. Reaction mixture was diluted with saturated NaCl (10
ml) and it was extracted with ethyl acetate (10 ml x 2). The organic layer was washed
with 2N HC1 (15 ml), the saturated NaHC03 (10 ml) and water (2x10 ml). Collectively
organic layer was dried over sodium sulphate and evaporated to get the desired product as
white solid in 0.427 gm quantity (99 % yield).
'H NMR (400 MHz, CDC13): 5 = 6.8 (d, 2H), 6.4(bs, 1H), 7.35-7.6 (m, 8H), 7.8 (d, 2H).
MS (EI, 70 eV): m/z = 212 [M+H]+.
Example 8. Preparation of 4-Nitro N-benzyl benzamide
The title compound was synthesized using similar procedure as example 7 to provide
product in 95 % yield. 1H NMR (400 MHz, CDC13): δ = 4.6 (d, 2H), 6.55 (s, 1H), 7.35
(m, 5H), 7.7 (d, 2H), 8.3 (d, 2H); MS (EI, 70 eV): m/z = 257 [M+H]+.
Example 9. Preparation of Cbz-Val-Val-OMe
To a mixture of Cbz-Val-OH (0.250 gm, 0.99 mmol), triethyl amine (0.34 ml, 2.47
mmol) in acetonitrile (4 ml), coupling reagent Al, or A2, or A3, (2.04 mmol) was added
at 0 °C. The reaction mixture was stirred for 15 minutes for active ester formation. Val-
OMe (0.194 gm, 1.48 mmol) was added to reaction mixture and it was stirred at room
temperature for 90 min. Reaction mixture was diluted with saturated NaCl (10 ml) and it
was extracted with ethyl acetate (10 ml x 2). The organic layer was washed with 2N HC1
(15 ml), the saturated NaHCCb (10 ml) and water (2x10 ml). Collectively organic layer
was dried over sodium sulphate and evaporated to get the desired product as white solid
in 0.353 gm quantity (97 % yield).
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1H NMR (400 MHz, CDCI3): 5 = 0.87-0.98 (m, 12H), 2.04-2.19 (m, 2H), 3.73 (s, 3H), 4-
4.10 (m, 1H), 4.55 (dd, 1H), 5.12 (s, 2H), 5.41 (d, 1H), 6.44 (d, 1H), 7.34 (m, 5H); MS
(El, 70 eV): m/z = 365 [M+H]+.
Example 10. Preparation of Bz-Leu-Gly-OEt
The title compound was synthesized using similar procedure as example 9 to provide
product in 96 % yield.
'H NMR (400 MHz, CDC13): δ = 0.9(d, 6H), 1.25 (t, 3H), 1.58 -1.6 (m, 1H), 1.7 (m, 2H),
4.0 (d, 2H), 4.25 (q, 2H), 5.1 (s, 1H), 5.5'(bs, 1H), 7.25 (m, 5H); MS (EI, 70 eV): m/z =
321 [M+H]+.
Example 11. Preparation of ethyl benzoate
To a mixture of benzoic acid (0.250 gm, 2.04 mmol), triethyl amine (0.57 ml,.4.08 mmol)
in acetonitrile (4 ml), coupling reagent Al, or A2, or A3, (2.04 mmol) was added at 0 °C.
The reaction mixture was stirred for 55 minutes for active ester formation. Ethanol (0.47
gm, 10.2 mmol) was added to reaction mixture and it was stirred at room temperature for
30 minutes. Reaction mixture was diluted with saturated NaCl (10 ml) and it was
extracted with ethyl acetate (10 ml x 2). The organic layer was washed with 2N HC1 (15
ml), the saturated NaHCC3 (10 ml) and water (2x10 ml). Collectively organic layer was
dried over sodium sulphate and evaporated to get the desired product as white solid in
0.291 gm quantity (95 % yield).
1H NMR (400 MHz, CDC13): δ= 1.3 (t, 3H), 4.2 (q, 2H), 7.4 (dd, 2H), 7.5 (d, 1H), 7.8 (d,
2H); MS (EI, 70 eV): m/z = 151[M+H]+,
17

Example 12. Preparation of benzyl benzoate
The title compound was synthesized using similar procedure as example 11 to provide product in 98 % yield. 'H NMR (400 MHz, CDC13): 5 = 5.8 (s, 2H), 7.35-7.5 (m, 8H), 7.9 (d, 2H); MS (EI, 70 eV): m/z = 213[M+H]+.

CLAIMS
1. The compound of organophosphorous ester of jV-hydroxy-2-furan-benzimidazole
having the structural formula as formula 1,

Formula 1
• Wherein;
Rl is selected independently from alkyloxy, aryloxy, or aryl groups;
Alkyloxy group from Rl refers to OR2 wherein R2 is selected independently
from C1-C6 alkyl, branched alkyl, and C3 - C6 cycloalkyl groups;
Aryloxy group from Rl refers OR3, wherein R3 is selected independently from
phenyl or substituted phenyl; and substituients are selected independently from
hydrogen, alkyl, halogens, CN, and NC2;
Aryl group from Rl refers to phenyl or substituted phenyl; and substituients are
selected independently from hydrogen, alkyl, halogens, CN, and NO2
2. The method of synthesizing the compound from formula 1 as claimed in claim 1 comprising the step of reacting the N-hydroxy-2-furan-benzimidazole with (R1)2P(0)C1 in organic solvent at 0 °C wherein Rl is selected independently from alkyloxy, aryloxy, or aryl groups as claimed in claim 1.
3. The method of synthesizing carboxylic acid derivatives from carboxylic acid comprising the steps of reacting carboxylic acid with sufficient quantity of compound from formula 1 as claimed in claim 1 to get the activated intermediate
19

and treatment of activated intermediate with appropriate nucleophile to get the desired carboxylic acid derivative.

20
4. The method of claim 3, wherein said carboxylic acid derivative is an amide and said nucleophile is an amine.
5. The method of claim 3, wherein said carboxylic acid derivative is an ester and said nucleophile is an alcohol.
6. The method of forming peptide linkage between first and second amino acid comprising the steps of reacting a first amino acid having amine protecting group with sufficient quantity of compound from formula 1 as claimed in claim 1 to get the activated intermediate and treatment of activated intermediate with second amino acid having acid protecting group to form peptide linkage.
7. The method of claim 6, wherein said amine protecting group is independently selected from (9H-fluoren-9-yl)methyl chloroformate (FMOC), Di-tert-butyl dicarbonate (tert-BOC), bezyl chloroformate (CBZ), benzyl groups, acyl groups or triphenylmethyl groups
8. The method of claim 6, wherein said acid protecting group independently selected from C1-C6 alkyl, branched alkyl, and C3 - C6 cycloalkyl ester-protecting groups.

Documents:

1218-MUM-2008-ABSTRACT(GRANTED)-(7-6-2011).pdf

1218-mum-2008-abstract.doc

1218-mum-2008-abstract.pdf

1218-MUM-2008-CANCELLED PAGES(19-1-2011).pdf

1218-MUM-2008-CLAIMS(AMENDED)-(19-1-2011).pdf

1218-MUM-2008-CLAIMS(GRANTED)-(7-6-2011).pdf

1218-mum-2008-claims.doc

1218-mum-2008-claims.pdf

1218-MUM-2008-CORRESPONDENCE(IPO)-(9-6-2011).pdf

1218-mum-2008-description(complete).doc

1218-mum-2008-description(complete).pdf

1218-MUM-2008-DESCRIPTION(GRANTED)-(7-6-2011).pdf

1218-MUM-2008-FORM 1(19-1-2011).pdf

1218-MUM-2008-FORM 1(9-6-2008).pdf

1218-mum-2008-form 1.pdf

1218-mum-2008-form 18.pdf

1218-MUM-2008-FORM 2(GRANTED)-(7-6-2011).pdf

1218-MUM-2008-FORM 2(TITLE PAGE)-(9-6-2008).pdf

1218-MUM-2008-FORM 2(TITLE PAGE)-(GRANTED)-(7-6-2011).pdf

1218-mum-2008-form 2(title page).pdf

1218-mum-2008-form 2.doc

1218-mum-2008-form 2.pdf

1218-mum-2008-form 3.pdf

1218-mum-2008-form 5.pdf

1218-MUM-2008-PETITION TO ACCEPT THE PROOF OF RIGHT(19-1-2011).pdf

1218-MUM-2008-REPLY TO EXAMINATION REPORT(19-1-2011).pdf


Patent Number 247978
Indian Patent Application Number 1218/MUM/2008
PG Journal Number 23/2011
Publication Date 10-Jun-2011
Grant Date 07-Jun-2011
Date of Filing 09-Jun-2008
Name of Patentee DR. DEVANAND B. SHINDE
Applicant Address DEPARTMENT OF CHEMICAL TECHNOLOGY, DR. BABASAHEB AMBEDKAR MARATHWADA UNIVERSITY, AURANGABAD,
Inventors:
# Inventor's Name Inventor's Address
1 DR. DEVANAND B. SHINDE DEPARTMENT OF CHEMICAL TECHNOLOGY, DR. BABASAHEB AMBEDKAR MARATHWADA UNIVERSITY, AURANGABAD-431004
2 MR. NAGNNATH D. KOKARE DEPARTMENT OF CHEMICAL TECHNOLOGY, DR. BABASAHEB AMBEDKAR MARATHWADA UNIVERSITY, AURANGABAD-431004
PCT International Classification Number C07F7/00
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA