Title of Invention


Abstract A process for the preparation of 2,4-lutidine, 2, 5-lutidine and 2,3,5-collidine which comprises reacting y-picoline, p-picoline and 3,5-lutidine respectively with methanol in a pressure reactor at 30-65 kg/cm2 vapour pressure in the presence of Raney nickel as catalyst and if desired, recycling the catalyst.
Full Text Process for preparing 2,4-lutidine, 2,5-lutidine and 2,3,5-colIidine
The present invention relates to a process for making lutidines and collidines,
which are used as intermediates in the manufacture of commercially useful final products and as precursors of many other substituted pyridine derivatives used in chemical and pharmaceutical industries.
Objective of the present invention is to provide a process which is more
economical and industrially feasible. For synthesizing lutidines and collidines various processes have been proposed like high temperature vapour phase catalytic synthesis or high-pressure pyridine base alkylation with alcohols in presence of catalysts. However economy of the process depends on the cheaper availability of the raw materials and process efficiencies.
Therefore, the objective of the present invention is to provide a process for preparing 2,4-lutidine, 2,5-lutidine and 2,3,5-collidine by reacting y-picoline, p-picoline and 3,5-lutidine respectively with methanol in presence of a catalyst under pressure at elevated temperature. The catalyst plays a major role in such reaction. Therefore main objective of this invention is to provide a process which becomes more economical by recycling of the used catalyst and utilising the cheaper raw materials of lower purity. PRIOR ART
Various processes heretofore have been proposed for the synthesis of lutidines
and collidines but most of them are not satisfactory from industrial point of view. British patent,No. 924527 utilises Acetone, Crotonaldehyde and ammonia to produce 2,4-
lutidine over Silica-Alumina modified catalyst at 400° C. US Patent No. 5,780,635 discloses synthesis of 2,4 lutidine and 2,5-lutidine using acrolein, crotonaldehyde, ammonia and formaldehyde / acetone and ammonia respectively over zeolite catalyst at 350-550° C temp. Similarly ^uropian Patent no. 0885884Adiscloses high temperature, vapour phase fluidised bed catalytic synthesis of 2,3,5-collidine over silica alumina catalyst using methacrolein and methyl ethyl ketone as reactants. All the above cited processes are not very attractive due to very low selectivities as a result of lot of side product formation, moreover it is difficult to get desired high purity product suitable for
pharmaceutical industries due to presence of interfering impurities. Therefore, as a consequence the scope of application of above patents for industrial manufacturing purpose is limited.
Japanese Patent No. 61-271274^ssigned to M/s Koei Chemicals reveals a process for manufacturing methyl pyridine bases like a-picoline, 2,6-lutidine, 2,5-lutidine, 2,4-lutidines, collidines and many other derivatives (except 2,3,5-collidine) by using high pressure catalytic methylation of pyridine nucleus. This patent discloses the manufacturing of the above by utilising pyridine base having no substitution group at 2nd and/or 6th position These bases are reacted with Raney cobalt catalyst, 2-60 % by weight against the raw material in a temperature range of 190-240° C at 10-70 kg/cm2 vapour pressure. Though the yield and selectivities mentioned in the examples are industrially feasible but the quantity of catalyst recommended for the reaction is very high and the time cycle particularly for 2,5-lutidine is high approx. 24 hrs. These factors make the process less attractive as economy depends on the minimal use of the catalyst along with the lower time cycle.
(tJSPatent No. 4,658,^52>assigned to the same company discloses the synthesis of 2,3,5-collidine from 3,5-lutidine utilising the similar high-pressure catalytic methylation as mentioned in the(JPJSk). 61-27Jj7JiP This patent gives liberty to use either Raney Nickel or Raney Cobalt for 3,5-lutidine alkylation but emphasises to use Raney Cobalt. It further recommends use of aliphatic alcohol having 1-4 carbon atoms at 230-270° C and 10-60 kg/cm2 pressure. Raney Cobalt catalyst is costlier than Raney Nickel and the quantity used in the examples of patent are considerably higher. Since major cost of production is contributed by the catalyst quantity, therefore its judicious utilisation is very important on which both of the above patents are silent. OBJECTS OF THE INVENTION
The present inventors earnestly researched for a industrially advantageous process where cost of production of 2,4-lutidine, 2-5, lutidine and 2,3,5-collidines are relatively lower without compromising the quality.
Another object of the invention is to utilise a cheaper and an easily available Raney Nickel Catalyst for 2,4-lutidine, 2,5-lutidine and 2,3,5-collidine.
Yet another object of the invention is to recycle the used catalyst in the subsequent batches to cut down the cost of the catalyst required.
It is a further object of the invention to provide an efficient process of catalyst recycling by taking out a small quantity of the used catalyst and replacing with an equal amount of fresh catalyst.
Yet one more object of this invention is to provide a process where the cost of manufacturing is lowered by using starting materials of lower purity, which could be cheaply obtained as compared to highly priced extremely pure raw materials. DETAILED DESCRIPTION OF THE INVENTION
Present invention utilises y-picoline or 4-methyl pyridine as starting material for 2,4-lutidine, p-picoline or 3-methyl pyridine for producing 2,5-lutidine and 3,5-lutidine or 3,5-dimethyl pyridine for 2,3,5-collidine.
As far as purity of the starting material is concerned, inventors have used raw materials with purity ranging from 90-99.5% for y-picoline and (3-picolin for 2,4-lutidine and 2,5-lutidine synthesis and 89-99.5% of 3,5-lutidine for 2,3,5-collidine synthesis. There is no remarkable variation in the catalyst activity observed when the starting materials of the above purity are used.
The starting materials are made to react with methanol at 200-260° C in presence of Raney nickel catalyst where mainly the 2nd position of pyridine nucleus is subjected to methylation.
Economical use of the catalyst for the alkylation in the present invention is emphasised. Commercially available Raney Nickel has been used for the methylation in the range of 4 to 40 weight % of the raw material used. First catalyst charge is made by using Raney Nickel and then after used catalyst is recycled in the subsequent batches by replacing 10-40% of used catalyst with equivalent amount of fresh Raney Nickel. Inventors have restricted the number of recycles up to 3 to 5 only, however more recycling are possible by utilising the technique mentioned in the invention.
As to the alkylating agents though many alcohols can be used for the purpose, Ref : USP 4,658,032 but the inventors have restricted to methanol which is easily and most cheaply available commercially.
The reaction pressure in this invention is between 30-60 kg/cm2, which could be easily operated at commercial scale. Reaction pressure rises due to generation of cracked gases during the reaction, which needs periodic venting to maintain the appropriate pressure inside the reactor. Vent gases contain a part of the raw material and product that has formed. This is further condensed, collected and recirculated back into the reaction vessel or can be mixed with the next batch reaction. Flu gases can also be utilised as a source of energy.
Starting material is charged in the autoclave and stirring is commenced. Raney Nickel slurry in the starting material is prepared and added to autoclave. Initial pressure of 2-5 kg/cm2 is maintained inside the autoclave with nitrogen and heating is started. Appropriate temp, is maintained and the methanol feeding is started maintaining the desired pressure inside the autoclave. Pressure release valve is set to maintain the required pressure, which does so by allowing the degraded gases to escape out the reaction system. Outlet or the vent is connected to a reflux condenser, which arrests the condensables including the escaped starting material and the reaction product.
There is no good advantage of using solvent. Therefore, the inventors have avoided use of any solvent. After the reaction is completed, the autoclave is cooled to room temperature and the liquid contents are taken out leaving beside the catalyst. Reaction product is subjected to simple distillation over a 2 m. long 1 inch diameter glass distillation column packed with structured packing.
Next batch is charged in the autoclave utilizing the same used catalyst but a small amount of fresh catalyst is charged as mentioned earlier and an equal amount used catalyst is taken out. Though it is not necessary to take out the used catalyst. However to maintain the operating volume of the autoclave the removal is recommended. Throughout the operation it is necessary to keep the catalyst in an inert atmosphere.
The amount of the fresh catalyst recommended for addition in the used catalyst is sufficient for reactivating the catalyst activity.
The more economical use and recycling of the catalyst in the process, as well as the cheaper starting material has made this invention industrially very advantageous.
The present invention is further described with the help of the following examples, which are given by the way of illustrations and therefore should not be construed to limit the scope of invention.
Synthesis of 2,4-Lutidine
1.0 kg y-picoline with purity 99.0%and 45.0 gm Raney Nickel were filled into a 2.0 liter capacity autoclave equipped with vent condenser which was cooled by circulating water. Autoclave was purged with nitrogen and stirring started at 600-650rpm. Inside temperature was raised to 260-262° C in presence of initial 5-6 kg/cm2 nitrogen pressure During this heating the vapour pressure increased to 30-40 kg/cm2 . Methanol feeding was stared at 55-65 gm/hr. Pressure release valve was set at 56 kg/cm2 to maintain the internal pressure at 55-58 kg/cm2. Reaction was over within 7-9 hrs. Autoclave was cooled to ambient temperature and the liquid portion was removed after the setting of the catalyst.
The reaction was subjected to fractional distillation over a 2 m length, 1 inch diameter glass column, packed with structure packing. Pure 2,4-lutidine with 93.1% yield was isolated with GC purity of 99.6%. EXAMPLE 2
Example 1 was repeated except that the purity of y-picoline used for methylation was 92.5%. From the reaction mass 2,4 lutidine with GC purity of 99.0% and yield 92.1% was obtained. EXAMPLE 3
Example 2 was repeated using 80% of the catalyst used in example 2 and 20% replaced with fresh Raney Nickel. After the reaction was over, 2,4-lutidine in a yield of 90.7%and purity 99.1% was obtained from the reaction mass. EXAMPLE 4
Example 3 was repeated using 80% catalyst of example 3 and 20% fresh Raney Nickel. 2,4-lutidine with a yield of 90% and purity 99.07% was obtained.
Example 4 was repeated with the used catalyst of example 4 but substituting with 20% fresh Raney Nickel. This gave 90.1% 2,4-lutidine with GC purity 99.0%.
Synthesis of 2,5-Lutidine EXAMPLE 6
P-picoline 744 g of 99.5% purity and Raney Nickel 55g were added in a 2.0 liter pressure autoclave equipped with a high pressure dosing pump. Autoclave was purged
fwith nitrogen and a pressure of about 5-7 kg/cm was maintained. Stirring was started at 600-650 rpm and temp, of the inside mass was increased to 230-235° C. At this stage the methanol dosing was started at the rate of 80-85 gm/hr maintaining inside pressure between 35-38 kg/cm2'
Producer gases were scrubbed and recycled back. Within 7-9 hrs the reaction was complete. It was additionally maintained for 1-2 hrs and was cooled then after to room temperature and reaction product was taken out for fractional distillation over a 2 m long glass column packed with structured packing. A final distilled product with GC purity 98.9% and yield 86% was obtained. EXAMPLE 7
Example 6 was repeated but P-picoline used was of 93.1% GC purity. From the reaction mass after purification 85.2% 2,5-lutidine with purity 98.4% was obtained. EXAMPLE 8
Example 6 was repeated but 80% used Raney Nickel of example 6 and 20% fresh catalyst were charged for the reaction. 2,5-lutidine was isolated with 84.8% yield and 98.42% purity. EXAMPLE 9
Example 6 was repeated using 70% catalyst used in example 8 and 30% fresh Raney Nickel. This gave an yield of 2,5-lutidine 84.0% based on p-picoline charged with GC purity 98.3%.
Synthesis of 2,3,5-CoIIidine EXAMPLE 10
1 kg 3,5-lutidine of 99.4% and Raney Nickel 89.0 g were charged in an autoclave and stirring started at 650-675 rpm. Autoclave was purged with nitrogen and an initial pressure of 3-6 kg/cm2 was maintained. Inside heating was increased to 260° where upon the internal pressure increased to 28.30 kg/cm2. Methanol was pumped in the autoclave at rate of 110-115 g/hr. Pressure was maintained at 56-58 kg/cm2 throughout the reaction. Condensable vent gases were condensed and recycled back in the reactor.
After the completion of the reaction autoclave was cooled to 30-35° C and liquid contents were taken out and subjected to fractional distillation. The same coloumn for the fractionation was used as mentioned in earlier examples. Thus 972 g of 2,3,5-collidine was obtained having GC purity 99.5%. EXAMPLE 11
Example 10 was repeated but 3,5-lutidine used for the reaction had GC purity 88%. With this reactant 2,3,5-collidine was obtained in 83.8% yield with 99.1% GC purity. EXAMPLE 12
Example 11 was repeated except that 75% used catalyst of example 11 and 25% fresh Raney Nickel was taken for the reaction. Recycling of the catalyst with above blend gave an yield of 2,3,5-collidine 82.8% with GC purity of the product 99.15%.

We claim:
1. A process for the preparation of 2,4-lutidine, 2, 5-lutidine and 2,3,5-collidine which
comprises reacting y-picoline, p-picoline and 3,5-lutidine respectively with methanol
in a pressure reactor at 30-65 kg/cm2 vapour pressure in the presence of Raney nickel
as catalyst and if desired, recycling the catalyst.
2. A process as claimed in claim 1 wherein the catalyst is recycled using 10-40% fresh
catalyst removing equal quantity of used catalyst.
3. A process for the preparation of 2,4-lutidine, 2, 5-lutidine and 2,3,5-collidine
substantially as hereinbefore described with reference to the foregoing examples.







817-del-2002-description (complete).pdf




Patent Number 222262
Indian Patent Application Number 817/DEL/2002
PG Journal Number 37/2008
Publication Date 12-Sep-2008
Grant Date 04-Aug-2008
Date of Filing 05-Aug-2002
# Inventor's Name Inventor's Address
PCT International Classification Number C07D 213/08
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA