Description:FIELD OF INVENTION
The current invention relates to a method of making 5-bromo-7-aza-indole compound. The invention describes a green and non-hazardous way of making 5-bromo-7-aza-indole compound with significant cost and resource saving.
BACKGROUND
Azaindoles have been recognized as structures that display significant biological activities in the field of biological process modulation, medicinal chemistry and drug discovery programs.
5-bromo-7-azaindoles are intermediates for synthesis of various medicinal molecules. 5-bromo-7-azaindoles have been used together with 3-chloro-7-azaindole and 3-iodo-7-azaindole, for the preparation of the platinum(II) dichloride and oxalate (ox) complexes of the general formula cis-[PtCl2(nHaza)2], and [Pt(ox)(nHaza)2], respectively (Štarha et al., 2012); nHaza stands for the above-mentioned 7-azaindole halogeno-derivatives. The prepared Pt(II)-dichlorido complexes were found to be highly cytotoxic against the osteosarcoma (HOS), breast carcinoma (MCF7) and prostate carcinoma (LNCaP) human cancer cell lines.
Few references for making 5-bromo-7-azaindoles have been reported. These rely heavily upon palladium other heavy metal catalysts rendering the process environmentally hazardous, costly in terms of raw material and reagent cost. These also have scalability issues. The heavy metals used are difficult to remove during the subsequent steps.
Over the past decade, continuous flow chemistry is one of the primary strategies used by the pharmaceutical industry to improve the efficiency of chemical synthesis. Benefits from conducting chemical reactions in flow include improved safety at a range of temperatures and pressures, smaller reactor volumes, more efficient scale-up, and waste reduction through telescoping multi-step processes. Thus, the pharmaceutical and fine chemical industries have identified continuous processing as the most important area of research for improving sustainability.
The present invention discloses a method of making 5-bromo-7-azaindole compounds that has low cost and is a less hazardous process. The present invention discloses a method of making 5-bromo-7-azaindole compounds with lesser reaction time and high scalability by use of a continuous flow reactor. The disclosed route of synthesis presents a solution with lesser carbon foot prints, and is less resource and cost intensive.
It is therefore an object of the present invention to provide a process for manufacturing the azaindole compounds which uses few reaction steps and less hazardous reagents. The present process is a green process as there is no chemical wastage produced during overall process and also no heavy metals are used. Thus the present invention is useful particularly useful in large scale manufacturing of these compounds.
BRIEF DESCRIPTION OF DRAWINGS:
FIG: 1 shows the schematic for synthesis of compound of formula IV
FIG: 2 shows Continuous flow reactor for amine to nitro conversion, conversion of compound of formula II to compound of formula III

SUMMARY
The current invention encompasses a method of making the compound of formula V, 5-bromo-7-aza-indole.
One aspect of the invention is method of making a compound of formula V, the method comprising the steps of
a. reacting a compound of formula I with a mixture of acetic acid and water to obtain a reaction mixture
b. Cooling the reaction mixture in step a) to a temperature of 0-7°C followed by addition of bromine;
c. Adjusting the pH of the reaction mixture between 7.5-10 to obtain compound of formula II followed by extracting compound of formula II;
d. Preparing a solution of sulphuric acid and hydrogen peroxide
e. Preparing a solution of sulphuric acid and compound of formula extracted in step c).
f. Reacting the solution in step d) and e) to obtain a reaction mix comprising compound of formula III followed by extracting compound of formula III
g. Mixing the compound of formula III with DMF , DMF-DMA , raising the temperature to above 95°C to obtain a compound of formula IV
h. Mixing ethyl acetate with the compound of formula IV followed by iron addition and acetic acid to obtain compound of formula V
i. Extracting compound of formula V.

In one aspect, the compound of formula V has a purity of 99%. In one aspect the compound of formula V has yield of 60%. In one aspect, the reaction mix in step f) is maintained at a temperature below 20°C. In one aspect the solution of sulphuric acid and hydrogen peroxide is maintained at a temperature of 5-15°C in step d). In one aspect the solution of sulphuric acid and compound of formula II is maintained at a temperature of 5-15°C in step e). In one aspect the pH is adjusted in step c) by adding 50% NaOH. In one aspect the compound of formula II is added once the temperature of sulphuric acid reaches 5-15°C in step e). In one aspect the compounds of formula II, III and IV are extracted in a dry form from the reaction mixture. In one aspect the amount of compound of formula I is not more than 2% before quenching the reaction in step c). In one aspect the moisture content for extracted compounds of formula II, III and IV is less than 2%.

In one aspect, the reaction in steps d, e and f is conducted in a continuous flow reactor. In one embodiment, the temperature of the reaction mix in step f. is maintained at a temperature of 25°C - 30°C. In one embodiment, the continuous flow reactor is comprised of a glass coil reactor. In one embodiment, the glass coil reactor is equipped with a condenser to control temperature. In one embodiment, the glass coil reactor is equipped with a continuous flow pump to maintain reactant and solvent flow
In one aspect the reaction is quenched by adding cooled water in steps in c, d, g, and h.
In one aspect, extracting the compound of formula V comprises the steps of;
i) Filtering the reaction mixture and washing with ethyl acetate
ii) Separating the layers by addition of sodium chloride solution to obtain an ethyl acetate layer and a water based layer.
iii) Repeating the step of filtering the ethyl acetate layer and washing with ethyl acetate.
DETAILED DESCRIPTION
The current invention encompasses a method of making a compound of Formula V that is green, less hazardous and cost effective.
There exist prior references for making 5-bromo-7-azaindoles and these rely heavily upon palladium and other heavy metal catalysts rendering the process environmentally hazardous, costly in terms of raw material and reagent cost. These also have scalability issues. The heavy metals used are difficult to remove during the subsequent steps.
The present invention discloses a method of making 5-bromo-7-azaindole compounds that has low cost and is a less hazardous process. The disclosed route of synthesis presents a solution with lesser carbon footprints and is less resource and cost intensive.
The prior art lacks an efficient, green approach to synthesize 5-bromo-7-azaindoles.
The current invention discloses a preparation method of making 5-bromo-7-azaindoles in cost effective manner without use of hazardous chemicals and heavy metal catalysts.

DEFINITIONS:
As used herein the term "5-Bromo-7-azaindole" refers to compounds 5-bromo-1H-pyrrolo [2, 3-b] pyridine, CAS: 183208-35-7.

As used herein the term” bromine” refers to Br2 (molecular formula) , CAS No. 7726-95-6 , or dibromine a dark reddish-brown fuming liquid with a pungent odor.
As used herein, the term “extracted” with reference to compounds of the present invention to the form physically separated from the reaction mixture, where it is formed. Extraction of the compound of the invention can be carried out by any of the techniques known in literature, and including, without limitation, filtration, and crystallization.
As used herein, the term "mixture" refers to a homogenous or a heterogenous solution, aqueous or non-aqueous of one or more components or reactants or catalysts.
As used herein, "dissolving/dissolution in water" implies dissolving in water, wherein the water may have additives like salt, minerals present. The resulting mixture may be a homogenous or heterogenous solution.
As used herein, “iron powder” refers to iron with chemical formula Fe, CAS Number 7439-89-6.
As used herein, the term “purification” refers to removing impurities from the isolated compounds from the reaction mixture. Purification of the compound of the invention can be carried out by techniques including distillation, re-crystallization, sublimation, differential extraction, and chromatography.
As used herein, the term “sub zero temperature” refers to temperatures that are below 0° centigrade or, below 0° Fahrenheit.
As used herein, the term "w/v" (weight/ volume) refers to amount of solute in grams in 100ml of solvent including water or other organic solvents like isopropyl alcohol.
As used herein, the term "yield" refers to purified/dried amount of compound of formula I.

EMBODIMENTS:
One embodiment of the current invention is a method to prepare a compound of formula V. The compound of formula V is 5-bromo-7-azaindoles.
In one embodiment, the method of making a compound of formula V, comprises the steps of;
a) reacting a compound of formula I with a mixture of acetic acid and water to obtain a reaction mixture
b) Cooling the reaction mixture in step a) to a temperature of 0-7°C followed by addition of bromine;
c) Adjusting the pH of the reaction mixture between 7.5-10 to obtain compound of formula II followed by extracting compound of formula II;
d) Preparing a solution of sulphuric acid and hydrogen peroxide
e) Preparing a solution of sulphuric acid and compound of formula II extracted in step c).
f) Reacting the solution in step d) and e) to obtain a reaction mix comprising compound of formula III followed by extracting compound of formula III
g) Mixing the compound of formula III with DMF , DMF-DMA , raising the temperature to above 95°C to obtain a compound of formula IV
h) Mixing ethyl acetate with the compound of formula IV followed by iron addition and acetic acid to obtain compound of formula V
i) Extracting compound of formula V.

In one embodiment the ratio of acetic acid to water in step a) is 1:1. In one embodiment the ratio of acetic acid to water in step a) is 1:1.5.
In one embodiment the bromine added in step b) is in liquid form. In one embodiment the reaction mixture in step b) was stirred at 0-5 °C for 2-4 hrs after bromine addition. In one embodiment the reaction mixture in step b) was stirred at 2-5 °C for 2-4 hrs after bromine addition.

In one embodiment the compound of formula II is extracted in dry form in step c).
In one embodiment after adjusting the pH of the reaction mixture in step c), the amount of compound of formula I is analyzed. In one embodiment the amount of compound of formula I is analyzed by TLC or HPLC. In one embodiment the reaction mixture is maintained for at least 35 minutes if the amount of compound of formula II is more than 2% as determined by TLC or HPLC. In one embodiment the amount of compound I is not more than 2% before quenching the reaction in step c). In one embodiment, the amount of compound I is not more than 1.5% before quenching the reaction in step c).
In one embodiment the reaction is quenched in step c) by adding water at a temperature range of 0-10°C. In one embodiment the reaction is quenched in step c) by adding water at temperature range of 0-5 °C.
In embodiment the reaction mix in step f) is maintained at a temperature below 20°C. In embodiment the reaction mix in step f) is maintained at a temperature below 15°C. In embodiment the reaction mix in step f) is maintained at a temperature below 10°C. In embodiment the reaction mix in step f) is maintained at a temperature below 5°C.

In one embodiment the solution of sulphuric acid and hydrogen peroxide is maintained at a temperature of 5-15°C in step d). In one embodiment the solution of sulphuric acid and hydrogen peroxide is maintained at a temperature of 5-10°C in step d). In one embodiment the solution of sulphuric acid and hydrogen peroxide is maintained at a temperature of 7-10°C in step d). In one embodiment the hydrogen peroxide used is 50% Hydrogen peroxide.

In one embodiment, the solution of sulphuric acid and compound of formula II is maintained at a temperature of 5-15°C in step e). In one embodiment, the solution of sulphuric acid and compound of formula II is maintained at a temperature of 5-10°C in step e). In one embodiment, the solution of sulphuric acid and compound of formula II is maintained at a temperature of 7-10°C in step e).

In one embodiment the pH of the reaction mixture is adjusted between 7.5-10 to obtain compound of formula II in step c) by adding 50% NaOH. In one embodiment the pH of the reaction mixture is adjusted between 8-10 to obtain compound of formula II in step c) by adding 50% NaOH. In one embodiment the pH of the reaction mixture is adjusted between 9-10 to obtain compound of formula II in step c) by adding 50% NaOH.
Even though reaction for the oxidation of compound of formula II (2-amino-5-bromo-3-methylpyridine) to formula III (5-bromo-3-methyl-2-nitropyridine), the reaction is very hazardous and explosive in nature in batch process. The reaction time also takes 36-48 hrs for each batch process. There is a continuous chilling required for 48 hrs which consumes lot of power energy.
In one embodiment the ratio of ethyl acetate to compound of formula IV is 1:7 in step h). In one embodiment of the invention, iron is added in form of iron powder in step h). In one embodiment, the iron powder of 200 mesh size is added to mixture of ethyl acetate and compound of formula IV.

In one embodiment the compound of formula II is added once the temperature of sulphuric acid in step e) reaches 5-15°C. In one embodiment the temperature of sulphuric acid in step e) is reduced by 10°C-15°C. In one embodiment the temperature of sulphuric acid in step e) is cooled from 20-25°C to 5-15°C.
In one embodiment, reacting solution in step d. and step e. in step f. comprises the step of adding solution in step e. to step d. at a temperature of 5-15°C.

In one embodiment the reaction in steps d, e and f is conducted in a continuous flow reactor. In one embodiment, the temperature of the reaction mix in step f. is maintained at a temperature of 25°C - 30°C. In one embodiment, the temperature of the reaction mix in step f. is maintained at a temperature of 25°C - 28°C. In one embodiment, the temperature of the reaction mix in step f. is maintained at a temperature of 25°C - 27°C. In one embodiment, the temperature of the reaction mix in step f. is maintained at a temperature of 25°C. In one embodiment, the continuous flow reactor is comprised of a glass coil reactor. In one embodiment, the glass coil reactor is equipped with a condenser to control temperature. In one embodiment, the glass coil reactor is equipped with a continuous flow pump to maintain reactant and solvent flow.
In one embodiment the ratio of ethyl acetate to compound of formula IV in step h) is 7:1.
In one embodiment the compounds of formula II, III and IV are extracted in a dry form from the reaction mixture. In one embodiment the drying is done by means selected from air drying, vacuum drying, convective drying, use of drying agents, or a combination thereof. In one embodiment extracted compounds are dried by air drying. In one embodiment the extracted compounds are Formula II (2-Amino-5-bromo-3-methylpyridine), Formula III (5-bromo-3-methyl-2-nitropyridine), Formula IV (E-2-5-Bromo-2-nitropyridin-3-yl)-N,N-dimethylethenamine), Compound of formula V (5-Bromo-7-azaindole).

In one embodiment the moisture content for extracted compounds of formula II, III and IV is less than 2%. Moisture content is measured by Karl fisher moisture analyzer or any other suitable analyzer.
In one embodiment the reaction is quenched by addition of water at a temperature range of 0-5 °C in steps c, d, g, and h. In one embodiment the reaction is quenched by addition of water at a temperature range of 2 °C in steps c, d, g, and h. In one embodiment the reaction is quenched by addition of water at a temperature range of 3 °C in steps c, d, g, and h. In one embodiment the reaction is quenched by addition of water at a temperature range of 4 °C in steps c, d, g, and h.

In one embodiment the method of extracting the compound of formula V in step i) comprises the steps of;
i) Filtering the reaction mixture and washing with ethyl acetate
ii) Separating the layers by addition of sodium chloride solution to obtain an ethyl acetate layer and a water based layer.
iii) Repeating the step of filtering the ethyl acetate layer and washing with ethyl acetate.

In one embodiment the sodium chloride solution has a ratio of 1:9 sodium chloride to water in step ii).

Due to the use of iron powder in step h) higher amount of impurity is formed so the compound for formula V is not easily and completely extracted by one filtration, so 2-3 iterations were required to take out all material form the iron powder thereby increasing the yield.

In one embodiment of the invention, wherein the compound of formula V has a purity of 99%. In one embodiment of the invention, compound of formula V obtained in step e) has a purity of 99%. In one embodiment of the invention, compound of formula V obtained in step e) has a purity of 99%. In one embodiment of the invention, compound of formula V obtained in step e) has a purity of 95%. In one embodiment of the invention, compound of formula V obtained in step e) has a purity of 97%.

In one embodiment, the purity measured by using HPLC instrument.
In one embodiment of the invention, the compound of formula V has yield of 60%. In one embodiment of the invention, the compound of formula V obtained in step e) has yield of 60% of raw material. In one embodiment of the invention, the compound of formula V obtained in step e) has yield of 50%. In one embodiment the raw material constitutes compound of formula I
One embodiment of the invention is the compound of formula V obtained by the method encompassed in the invention.

EXAMPLES
Example 1: Conversion of Compound of Formula I (2-amino-3-methylpyridine) to Formula II (2-Amino-5-bromo-3-methylpyridine)
Water , 2 volumes w.r.t to starting material , was added into the reactor at 20-25 °C followed by acetic acid to form a reaction mixture. The reactor temperature was maintained at 20-25 °C. Reaction mixture cooled to 0-15 °C. Compound of formula I (2-Amino-3-methylpyridine) was added to the reactor at 0-15 °C. Slowly bromine was added to the reactor at 0-5 °C. The resulting reaction mixture was stirred at 0-5 °C for 3-4 hrs. TLC (Thin layer Chromatography) was conducted.
TLC used to check the content of compound 1 using 20:80 ethyl acetate: n-Hexane mobile phase or HPLC analysis used to check the content of compound of formula I. As the amount of compound I was less than 2% the reaction was proceeded to the next stage.
In case the compound of formula I is more than 2%, the reaction mixture was maintained for 1 more hour.
More Water was added to the reaction mixture at 0-5 °C followed by pH adjustment of the RM to 8-9 using 50% sodium hydroxide (NaOH) solution at 0-15 °C.
The additional water served to remove the sodium bromide salts formed during the adjustment of pH using 50% NaOH solution.
50% NaOH soln. prepared by adding water: NaOH in a ratio of 1:1. This was stirred at room temperature for 1 hr The solids were filtered and washed with water to obtain compound of formula II (2-Amino-3-bromo-5-methylpyridine). The compound of formula II was dried at 45-50 °C for 8-10 hrs. It was checked for moisture content and separated.
Example 2 : Conversion of Compound of formula II (2-amino-5-bromo-3-methylpyridine) to Formula III (5-bromo-3-methyl-2-nitropyridine)
Solution 1 was prepared by adding H2SO4 into the reactor at 20-25 °C followed by cooling to 5-10 °C. 50% H2O2 was added slowly into reactor at 5 -15 °C (Note: Exothermic reaction observed, scrubber and blower were kept on).
Solution II was prepared by adding H2SO4 into the reactor at 20-25 °C. followed by cooling to 5-15 °C. Compound of formula II was added into reactor at 5-15 °C (Note: Exothermic observed).
Solution Sol. no. II was added to the solution no. I at 5-15 °C. (Note: Exothermic reaction was observed, scrubber and blower were on to maintain the temperature of RM to <20 °C).
TLC was conducted to check the amount of compound II. As the amount of compound of formula II was less than 2%, the reaction was quenched by adding reaction mixture into ice cold water at a temperature of 0-5 °C.
The reaction mixture was stirred for 1-2 hrs. The solid material was Filtered washed with water. The filtered and washed solid was loaded onto a material tray dryer. Drying was done via an air dryer. Moisture content was checked for dry form of compound of formula III. It was less than 1% as measured by Karl Fisher moisture analyzer.
Example 3: Conversion of Compound of formula II (2-amino-5-bromo-3-methylpyridine) to Formula III (5-bromo-3-methyl-2-nitropyridine) In a Continuous Flow Reactor
Conversion of compound of formula II (2-amino-5-bromo-3-methylpyridine) to formula III (5-bromo-3-methyl-2-nitropyridine) was done by reaction in continuous flow reactor. For this reaction a glass coil reactor equipped with the condenser to control the temperature and continuous flow pumps for the reactant and solvent flow was used. The reaction was carried out at room temperature, where as in batch process the temperature was 10 °C with continuous chilling supply. The reaction has the potential to yield an output of 1gm/hour.
Example 4: Conversion of Compound of formula III (5-bromo-3-methyl-2-nitropyridine) To compound of Formula IV (E-2-5-Bromo-2-nitropyridin-3-yl)-N,N-dimethylethenamine)
DMF was added to into a reactor at 20-25 °C followed by addition of compound of formula III at 20-25 °C to the reactor to form a reaction mixture. DMF-DMA was added into the reactor at 20-25 °C. The temperature was raised to 105-110 °C followed by stirring for 1-2 hrs.
TLC used to check the content of compound of formula III using 20:80 ethyl acetate: n-Hexane mobile phase or HPLC analysis was used to check the amount of compound of formula III. It was less than 2.0%.
The reaction was quenched by using cold water at a temperature of 0-10 °C
The solid material in dark red color was filtered and washed with water. The material was dried at 45-50 °C and checked for moisture content.
Example 5: Conversion of Compound of formula IV (E-2-5-Bromo-2-nitropyridin-3-yl)-N,N-dimethylethenamine ) to Compound of formula V (5-Bromo-7-azaindole)
Ethyl acetate was added into the reactor at 20-25°C followed by addition of compound of formula IV to the reactor at 20-25°C. The resulting reaction mixture was stirred for 30-40 min. Water, 1 volume of water wrt to compound of formula IV, was added further followed by slow addition of iron powder to the reactor. Acetic acid was slowly added to the reactor.
The temperature of reaction mass increased to 65-70 °C was maintained for 1-2 hrs.
TLC was conducted to check the amount of Compound of formula IV. The amount of compound of formula IV was less than 2%.
The reaction mixture was run over hiflow bed Nutch filter and washed with ethyl acetate to obtain a filtrate.
The filtrate was added to the reactor, water was added. The resulting reaction mixture was, stirred and allowed to settle followed by separation of both the layers, the water based layer and the organic ethyl acetate layer. The water layer was taken into the reactor and add ethyl acetate, stir, settle and separate both the layers.
Both the organic layer were I added into the reactor, followed by 10% sodium chloride solution . The reaction mix was stirred, settled and separated both the layers. charcoal was added to the reactor and stirred for 30-40 min at 40-45 °C. The solid material was filtered over hiflow bed, and washed with ethyl acetate at a temperature range of 40-45 °C. The organic layer was added into the reactor. The solvent was distilled under vacuum below 55°C. Co-distillation was done with the crude material with acetone and degassed. The reactor was cooled to room temperature. Acetone was added to the crude and stirred for 1 hr. The solid material was filtered again and washed with acetone. The material was dried at 40-45 °C to obtain compound of formula V.
, Claims:1. A method of making a compound of formula V, the method comprising the steps of
a. reacting a compound of formula I with a mixture of acetic acid and water to obtain a reaction mixture
b. Cooling the reaction mixture in step a. to a temperature of 0-7°C followed by addition of bromine;
c. Adjusting the pH of the reaction mixture between 7.5-10 to obtain compound of formula II followed by extracting compound of formula II;
d. Preparing a solution of sulphuric acid and hydrogen peroxide
e. Preparing a solution of sulphuric acid and compound of formula II extracted in step c.
f. Reacting the solution in step d. and e. to obtain a reaction mix comprising compound of formula III followed by extracting compound of formula III
g. Mixing the compound of formula III with DMF , DMF-DMA , raising the temperature to above 95°C to obtain a compound of formula IV
h. Mixing ethyl acetate with the compound of formula IV followed by iron addition and acetic acid to obtain compound of formula V
i. Extracting compound of formula V.

2. The method as climed in claim 1 wherein the compound of formula V has a purity of 99%.
3. The method as claimed in claim 1 wherein the compound of formula V has yield of 60%.
4. The method as claimed in claim 1, wherein the reaction mix in step f. is maintained at a temperature of 25°C - 30°C.
5. The method as claimed in claim 1 wherein the reaction in steps d, e and f is conducted in a continuous flow reactor.
6. The method as claimed in claim 1 wherein the pH is adjusted in step c. by adding 50% NaOH.
7. The method as claimed in claim 1 wherein the compound of formula II is added once the temperature of sulphuric acid reaches 5-15°C in step e.
8. The method as claimed in claim 1 wherein the compounds of formula II, III and IV are extracted in a dry form from the reaction mixture.
9. The method as claimed in claim 1 wherein the amount of compound I not more than 2% before quenching the reaction in step c.
10. The method as claimed in claim 9 wherein the moisture content for extracted compounds of formula II, III and IV is less than 2%.
11. The method as claimed in claim 1 wherein the reaction is quenched by adding cooled water in steps in c, d, g, and h.
12. The method as claimed in claim 1 wherein extracting the compound of formula V in step i. comprises the steps of;
i) Filtering the reaction mixture and washing with ethyl acetate
ii) Separating the layers by addition of sodium chloride solution to obtain an ethyl acetate layer and a water based layer.
iii) repeating the step of filtering the ethyl acetate layer and washing with ethyl acetate.