Claims:1. A process for synthesis of (3-chloropyridin-2-yl)-hydrazine with good yield and purity comprising:
a) reacting 2,3-dichloropyridine in ethoxyethanol as a solvent with 50% hydrazine hydrate at reflux temperature;
b) cooling the reaction mass to room temperature to affect the precipitation of (3-chloropyridin-2-yl)-hydrazine crystals; and
c) isolating the crystals of (3-chloropyridin-2-yl)-hydrazine.

2. The process according to claim 1, wherein, the ethoxyethanol can be reused or recycled for next batch.

3. A process for synthesis of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid comprising:
a) preparing (3-chloropyridin-2-yl)-hydrazine according to the process of claim 1;
b) condensing (3-chloropyridin-2-yl)-hydrazine with diethyl maleate in presence of sodium ethoxide under reflux followed by adjusting the pH to 5-6 by adding acetic acid to obtain ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate;
c) brominating the ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate using POBr3 followed by adjusting the pH to 8 with saturated solution of Na2CO3 to obtain Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate;
d) oxidizing the ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate with potassium persulphate to obtain Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate;
e) hydrolysing the Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate to obtain 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid; and
f) recrystallizing the 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid from isopropanol.
, Description:Technical field:
This invention relates to cost effective synthesis of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid, a key intermediate used as a building block for Novel Active Pharmaceutical Ingredients and selective activator of ryanodine receptor such as Chlorantraniliprole. More particularly, the invention relates to efficient synthesis of (3-chloropyridin-2-yl)-hydrazine and its further conversion into 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid.

Background and prior art
Various synthetic routes have been reported for the synthesis of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid. WO2003/015519 discloses preparation of 3-bromo-l-(3-chloro-2-pyridinyl)-lH-pyrazole-5-carboxylic acid which comprises reaction of 2-(3-bromo-lH-pyrazol-l-yl)-3-chloropyridine in dry tetrahydrofuran at -76 °C with a solution of lithium diisopropylamide in tetrahydrofuran, followed by bubbling carbon dioxide and quenching with water. The product is separated through layer separation.

WO2006/062978 reports various methods for the preparation of pyrazolecarboxylic acids. According to WO’978, pyrazolecarboxylic acids can be prepared by condensing Pyrazoles of Formula (13) with aryl iodides (14) using methods such as those reported by A. Klapars, J. C. Antilla, X. Huang and S. L. Buchwald, J. Am. Chem. Soc. 2001, 123, 7727-7729, or with aryl boronic acids (14) using methods such as those reported by P. Y. S. Lam, C. G. Clark, S. Saubern, J. Adams, M. P. Winters, D. M. T. Chan and A. Combs, Tetrahedron Lett. 1998, 39, 2941-2944. The resulting adducts of Formula (15) is oxidized with oxidizing agents such as potassium permanganate to afford the pyrazolecarboxylic acids of Formula (2b). The reaction method is shown below in scheme 1.
Scheme 1

Further, an article titled “Synthesis, Structure and Insecticidal Activities of Some Novel Amides Containing N-Pyridylpyrazole Moieties” reports an alternate route for the preparation of pyrazole carboxylic acid. According to this article, 2,3-dichloropyridine (1) is reacted with hydrazine hydrate at reflux using ethanol as solvent to afford (3-chloropyridin-2-yl)-hydrazine(2). Condensation of diethyl maleate with hydrazine (2) in the presence of sodium ethoxide afforded the pyrazolidinone (3), which is treated with phosphorus oxybromide in acetonitrile to afford pyrazoline (4). Pyrazoline (4) is oxidized with potassium persulfate to obtain (5) and further hydrolysed to obtain 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6) using known methods. The reaction method is shown below in scheme 2.
Scheme 2

Reagents and conditions: (i) N2H4, EtOH; (ii) Diethyl maleate, NaOC2H5/C2H5OH; (iii) POBr3, CH3CN; (iv) K2S2O8, H2SO4, CH3CN; (v) NaOH, MeOH.

The method reported as above for the synthesis of (2) uses ethanol as solvent which affords (3-chloropyridin-2-yl)-hydrazine (2) in moderate yield with reaction time more than 36hrs with product purity less than 90%. The low yield and purity of the product of step 1 translates into much lower yield and purity of the final desired product, 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6). Therefore, the applicant has envisaged a need in the art to provide an improved cost effective and environmental friendlyprocess for the production of (3-chloropyridin-2-yl)-hydrazine (2) in good yields and better purity,thereby enhancing the purity and overall yield of the final desired product, 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid and optimization of rest of the reaction sequences for commercial production of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6) in good yields and high purity.

Thus the objective of the present invention is to provide an improved and efficient process for the preparation of (3-chloropyridin-2-yl)-hydrazine (2), a key intermediate in the production of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6).

Summary of the invention:
In line with the above objective, the present invention provides an improved process for preparation of (3-chloropyridin-2-yl)-hydrazine (2), with good yields and purity.

In an attempt to improve the quality and yield of the (3-chloropyridin-2-yl)-hydrazine(2), the present inventors have screened various solvents viz. MeOH, iPrOH, n-BuOH, tet-BuOH, Toluene, 2-ethoxyethanol etc. by changing various parameters including time and temperatures that guarantees optimum results, viz., the desired product, (3-chloropyridin-2-yl)-hydrazine (2) with more than 94% yield and with more than 99% purity by NMR, HPLC and LCMS.

Accordingly, in an aspect, the present invention provides a process for preparation of (3-chloropyridin-2-yl)-hydrazine (2), which process comprises; reacting 2,3-dichloropyridine with hydrazine hydrate at reflux in presence of 2-ethoxy ethanol as solvent to afford (3-chloropyridin-2-yl)-hydrazine (2).

The advantage involved in selection of the 2-ethoxyethanol as a suitable solvent reduces reaction period from 36 hrs to 5 hrs. The selection of 2-ethoxy ethanol as a solvent had direct impact on production costs as it substantially reduces the reaction time; product crystallized in reaction solvent at ambient temperature, zero effluent generation and solvent as such can be recycled for the repeated batches. The additional advantage of the present invention is that it avoids the use of large volumes of ethanol as it is expensive compared to 2-ethoxy ethanol. Moreover, use of 2-ethoxy ethanol increases the yields of the (3-chloropyridin-2-yl)-hydrazine (2) by 20 % when compared to the use of ethanol and other solvents such as butanol that needs longer reaction time and further cooling is required to precipitate the product.

In yet another aspect, the present invention provides process for preparation of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid which comprises:
a) preparing (3-chloropyridin-2-yl)-hydrazine by reacting 2,3-dichloropyridine with hydrazine hydrate at reflux in presence of 2-ethoxy ethanol;
b) condensing (3-chloropyridin-2-yl)-hydrazine with diethyl maleate in presence of sodium ethoxide under reflux followed by adjusting the pH to 5-6 by adding acetic acid to obtain ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate;
c) brominating the ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate using POBr3 followed by adjusting the pH to 8 with saturated solution of Na2CO3 to obtain Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate;
d) oxidizing the ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate with potassium persulphate to obtain Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate;
e) hydrolysing the Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate to obtain 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid; and
f) recrystallizing the 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid from isopropanol.

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.

Accordingly, in an embodiment, the present invention provides a process for preparation of (3-chloropyridin-2-yl)-hydrazine (2), which process comprises; reacting 2,3-dichloropyridine with hydrazine hydrate ( commercial 50%) in presence of 2-ethoxy ethanol as solvent under reflux for 5 to 6 hrs, followed by cooling to room temperature directly to afford (3-chloropyridin-2-yl)-hydrazine (2), as a precipitate with purity of 99.83% by HPLC analysis. (3-chloropyridin-2-yl)-hydrazine (2) thus precipitated can be separated from the reaction mixture by simple filtration yield 95%. A second crop can also be obtained from the filtrate by further maintaining the filtrate at room temperature for couple of hrs. Thus, the 3(3-chloropyridin-2-yl)-hydrazine (2) can be obtained in quantitative yields and the solvent, 2-ethoxyethanol can be reused directly for the next batch without subjecting to distillation. The beauty of the invention lies in the use of the solvent, 2-ethoxyethanol that facilitates the direct precipitation of the product from the reaction mass upon cooling to room temperature and further permits multiple reuse of the solvent for subsequent batches without subjecting to recycle by distillation. Thus the process of the present invention can be taken up for large scale production of (3-chloropyridin-2-yl)-hydrazine (2), as the process surprisingly, results in consistent yields and purity.

In another embodiment, condensation of (3-chloropyridin-2-yl)-hydrazine (2) with diethylmaleate is designed to improve the yield and purity of the Ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate. Because, the processes reported in the prior art such as Bandala et al., 2009; Stefan, Bercean, Paul, & Gruia, 2011 and He, Liu, Tan, Xia, & Zhu, 2009 are associated with certain disadvantage such as longer reaction periods and multiple crystallization steps.
According to the inventor’s preliminary analysis, the lower yield of cyclization productmay be attributed to formation of the maleaimidic compound due to competitive parallel cyclization reaction.

In order to address this issue, several methods have been attempted by employing various maleic acid derivatives to achieve constant yields.

In accordance with the same, the condensation reaction of diethyl maleate with (3-chloropyridin-2-yl)-hydrazine (2) is conducted in the presence of commercial sodium ethoxide under reflux for about 10 mins. The pH of reaction mass is adjusted between 5 to 6 with acetic acid and further poured on ice water to get solid, which is collected and washed with aqueous ethanol to afford the desired product, Ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate (3) in more than 58 % yield with 99.69 % purity.
Thus the present inventors are able to successfully modify the reaction conditions to avoid the use of large volume of solvent and its distillation, instead the process proceeds with pH adjustment between 5 to 6, followed by pouring the mass on ice cold water to directly precipitate the solid product with good yield and purity. This modification further avoids the column purification or lengthy crystallization at 0 °C, as the solid product can be directly obtained from the pH adjustment that could be collected by simple filtration from the aqueous phase. The simple modification in the work up substantially reduces the operational costs on large scale and further avoided large volume of expensive solvents and large scale purification by column chromatography.

In the next step, the preparation of Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (4) has been successfully carried out with the literature procedure using POBr3 as brominating agent. However, careful monitoring of the reaction results in reduction of the reflux time from 5 hrs to 1.5 hrs and further avoided extraction in work up process. According to the invention, after completion of the reaction, the pH of the reaction mass is brought to 8 by adding saturated Na2CO3 to directly precipitate beige color solid in 97.7 % yield, which can be separated by simple filtration and dried to afford intermediate that can be directly used in the next step. The pH adjustment avoids the extraction work up processas it directly yields the product in solid form. Thus, the present process reduces the solvent usage, easy separation of the product with good yield and purity thereby facilitating the easy operation and scaling up of the reaction. Also, due to the avoidance of column chromatographic purification, the improved process of the present invention makes considerable impact on production cost by reducing number of operations and reduced solvent usage.

In the next stage, Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (5) is obtained by oxidizing the Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate in acetonitrile in presence of potassium persulfate and sulphuric acid as per prior art method.
The hydrolysis of the Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (5) in the final synthesis of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6) is achieved in more than 47 % overall yield with final purity of 99.69 % as against 12-30 % overall yield with less than 90% purity as reported in literature. Accordingly, the hydrolysis of Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (5) is carried out in presence of aqueous methanol for about 1 hr. After the completion of the reaction, the mixture is poured in ice water and neutralized using concentrated hydrochloric acid and brought to pH 2. The solid thus obtained is collected by filtration, washed with water and dried to give pyrazolecarboxylic acid (6), which is recrystallized from isopropanol to afford the product with purity >99.5%. The process of the present invention is shown in scheme 3.

Scheme 3:

Thus, the present invention is successful in rendering significant contributions to each of the above steps thereby increasing the overall yield of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid by over 20% with reference to the teachings of the prior arts.
Thus the present invention is able to successfully demonstrate a novel and cost-effective process for the manufacture of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid in very good yields with high purity thereby advantageously having a direct impact on production cost and scalability.

Moreover, the reduction in the reaction time significantly impacts on production cost and saves overall energy and subsequently minimizes the overhead costs.

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
Synthesis of (3-chloropyridin-2-yl)-hydrazine (2)

To a suspension of 2,3-dichloropyridine (1000 g, 6.76 mol) in ethoxyethanol (4000 mL), was added 50% hydrazine hydrate (2800 mL, 2.88 mol). The resulting mixture was refluxed for 5 h, and then cooled to room temperature. The product was precipitated out of solution as white crystals, which were collected by filtration, dried. (921.00 g, 95%), mp(lit) 163-164 ?C; mp (observed) 166 ?C. 1H NMR (DMSO-d6, 400 MHz) d 8.04 (d, 1H, J = 3.4 Hz, pyridyl-H), 7.55 (d, 1H, J = 7.07 Hz, pyridyl-H), 6.60 (d, 1H, J= 4.75 Hz, pyridyl-H), 4.22 (br s, 2H, NH2). MASS (ESI)(M+1): 143.7.HPLC Purity 99.82. RT: 5.293 min.
A second crop was observed from the filtrate and recovered from the filtrate to get the quantitative yield of product. The recovered solvent was as such used in repeated batches with no loss in yields.

Synthesis of Ethyl 2-(3-Chloro-2-pyridinyl)-5-oxopyrazolidine-3-carboxylate (3)

Sodium ethoxide (16.66 g, 0.245 moles, commercial) was taken in ethanol (1000 mL) in a 5 L three-necked round-bottomed flask. The mixture was heated to reflux; to this mixture was added 3-Chloro-2-hydrazinopyridine (100 g, 0. 696 mol). The mixture was kept at this temperature for 10 min, and then diethyl maleate (180 g, 1.046 mol) was added drop-wise through an additional funnel. The resulting orange-red solution was held at reflux for 10 min and cooled to 65°C; the pH of the reaction mass was adjusted to 5-6 by adding acetic acid and poured on ice water to get the solid precipitate. The solid was collected by filtration, washed with aqueous ethanol to give pyrazolidinone (108.8 g, 58%), mp (Lit) 132–134 °C; Observed mp136°C.1H-NMR (CDCL3, 400 MHz): d8.3(br s, 1H, NH).8.20(dd, J = 1.46, 3.3 Hz, 1H, pyridyl-H), 7.67 (dd, J = 1.46, 6.34 Hz, 1H, pyridyl-H), 7.02(dd, J = 3.3, 6.34 Hz, 1H, pyridyl-H),5.27(dd, J = 2.00, 7.80 Hz, 1H, CH2), 4.26 (m, 2H, CH2CH3), 3.08 (q, J = 7.19, 9.75 Hz, 1H, CH), 2.73 (dd, J = 2.00, 14.87 Hz, 1H, CH2), 1.28(t, J = 7.01 Hz, 3H, CH2CH3). MASS (ESI) (M+1) = 269.8; HPLC Purity 99.82 % (RT= 9.72 min).

Synthesis of Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-4,5-dihydro-1H-pyrazole-5-carboxylate (4)

Phosphorus oxybromide (107 g, 0.37 mole) was added to a solution of carboxylate (100 g, 0.37 mol) in acetonitrile (1100 mL) at ambient temperature and the reaction mixture was refluxed for 1.5 h, then most of the solvent was removed by distillation. The pH of the reaction mass was adjusted to 8, by adding saturated Na2CO3 to obtain precipitate, which was filtered and dried to afford intermediate 4. Yield 120.6 g, 97.7 %, mp (Lit)59–60; mp (observed) 52 °C.1H-NMR (DMSO-d6, 400 MHz) d: 8.10 (dd, J = 1.4, 3.3 Hz, 1H, pyridyl-H, 7.83 (dd, J = 1.5,6.35 Hz, 1H, pyridyl-H),), 6.98 (dd, J = 3.04, 4.75, Hz, 1H, pyridyl-H), 5.17 (dd, J = 3.2, 8.65 Hz, 1H, CH),4.09 (q, J = 7.07 Hz, 2H, CH2CH3),3.58 (dd, J = 5.6, 11.95 Hz, 1H, CH),3.24–3.31 (dd, J = 8.4, 17.6 Hz, 1H, CH),1.12 (t, J = 7.19 Hz, 3H, CH2CH3). MASS (ESI) (m+1) = 331.7

Synthesis of Ethyl 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylate (5)

To a solution of bromoester (100 g, 0.3 mol) in acetonitrile (1450 mL) was added sulfuric acid (98%, 58.87 g, 0.599 mol). After being stirred for several minutes, the reaction mixture was treated with K2S2O8 (121 g, 0.446 mol) and refluxed for 4 h. After that, the reaction was cooled to 60 °C, the mixture was filtered; the filtered cake was washed with acetonitrile. The filtrate was concentrated and then poured slowly on ice water under stirring. The solid was collected by filtration, washed with acetonitrile and water and then dried to give carboxylate 5. Yield 92.43 g, 93 %, mp (lit) 117–118 °C; mp (observed) 120 °C. 1H-NMR (CDCl3, 400 MHz) d: 8.51(dd, J = 1.5, 3.1 Hz, 1H, pyridyl-H),7.91 (dd, J = 1.58, 6.46 Hz, 1H, pyridyl-H),7.44 (dd, J = 3.41,4.63 Hz,1H, pyridyl-H),7.03 (s, 1H,pyrazolyl-H),4.22 (q, J = 7.19 Hz, 2H, CH2CH3),1.21 (t, J = 7.19 Hz, 3H, CH2CH3).MASS (ESI) (m+1) = 329.6.

Synthesis of 3-Bromo-1-(3-chloro-2-pyridinyl)-1H-pyrazole-5-carboxylic acid (6)

Bromocarboxylate(100 g, 0.302 mol) was taken in methanol (760 mL), added 10 % NaOH in water (150 mL) and stirred at room temperature for 1hr, monitored by TLC for the completion of reaction. The reaction was completed in one hour, and then the methanol was removed by distillation. The concentrated mixture was poured into ice water. The aqueous solution was acidified using concentrated hydrochloric acid to pH 2. The solid was collected by filtration, washed with water dried to give pyrazolecarboxylic acid (6). Yield, 86 g 94%, mp (Lit) 197–200 °C.; mp (observed) 195°C. Recrystallization from iPrOH afforded the pure product having mp 198 °C. 1H-NMR (DMSO-d6, 400 MHz) d: 13.88 (s, 0.5H, carboxylic H), 8.54(dd, J = 1.46, 3.17 Hz,1H, pyridyl-H), 8.22 (dd, J = 1.46, 6.58 Hz,1H, pyridyl-H), 7.66 (dd, J =3.41, 4.75 Hz, 1H, pyridyl-H), 7.23(S, 1H, pyrazolo-H). MASS (ESI) (m+1) = 303.6 HPLC purity: 99.69 % RT 11.47 min