DESC:FIELD OF THE INVENTION:
The present invention relates to an efficient process for the preparation of a Palbociclib Intermediate. Moreover, the present invention provides a technically simple process for preparing high yields of Palbociclib Intermediate in lesser time.

BACKGROUND OF THE INVENTION:
Palbociclib (PD-0332991) is indicated for the treatment of HR-positive and HER2-negative breast cancer. Palbociclib, sold under the brand name Ibrance® and it was developed by Pfizer. The drug has received FDA breakthrough therapy certification, and was approved for sale in the United State on February 3, 2015.
Palbocicllib (CAS Number: 571190-30-2) is chemically known as 6-acetyl-8-cyclopentyl-5-methyl-2-((5-(piperazin-1-yl)pyridin-2-yl)amino)pyrido[2,3-d] pyrimidin-7(8H)-one. The molecular formula for Palbociclib is C24H29N7O2. The molecular weight is 447.543 g·mol-1 and is structurally represented as below:

Palbociclib is a selective inhibitor of the cyclin-dependent kinases CDK4 and CDK6. It was the first CDK4/6 inhibitor to be approved as a cancer therapy. In the G1 phase of the cell cycle, mammalian cells must pass a checkpoint, known as the restriction point "R", in order to complete the cell cycle and divide. CDK4 and CDK6 complex with cyclin D drive the phosphorylation of the retinoblastoma protein, Rb, which allows the cell to pass R and commit to division. Regulation of one or more proteins involved in this checkpoint is lost in many cancers. However, by inhibiting CDK4/6, palbociclib ensures that the cyclin D-CDK4/6 complex cannot aid in phosphorylating Rb. This prevents the cell from passing R and exiting G1, and in turn from proceeding through the cell cycle. Palbociclib is taken daily orally with food in a cycle of 21 days of active medication followed by 7 days off treatment.
Palbociclib is a first reported in PCT application WO2003/062236. It also reports the synthetic route of Palbociclib Hydrochloride schematically represented as following.

SCHEME-1

The drawback of the above process is the use of very expensive reagents and catalysts such as tributyl(1-ethoxyvinyl)stanene and palladium-tetrakis(triphenylphosphine) (Pd(P(C6H5)3)4) and hence is commercially not viable.

The following two compounds are the key intermediates for the synthesis of Palbociclib.

Intermediate – 1 of palbociclib is chemically known as tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate and the intermediate – 2 of palbociclib is chemically known as tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate.

WO2008/032157 also reports the synthetic route of Palbociclib and their Intermediates. It reports the formation of Intermediate-2 from Intermediate-1 in the presence of [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride (Pd(dppf)2Cl2) and n-butanol under nitrogen pressure.
The corresponding synthetic route of Palbociclib and their Intermediates schematically represented as follows:

SCHEME-2
The drawback associated with the above reaction is that the reaction is highly time consuming, takes 20 hours to complete.

WO2014/128588 discloses formation of Intermediate-2 from Intermediate-1 in the presence of palladium(II) acetate (Pd(OAc)2), bis[(2-diphenylphosphino)phenyl] ether (DPEPhos), N,N-diisopropylethylamine (DIPEA) and n-butanol under nitrogen atmosphere.

The corresponding synthetic route of Palbociclib Intermediate-2 schematically represented as follows:

SCHEME-3
The main disadvantage of the above reaction is that the process is complex and time consuming too.

CN105541832 discloses the formation of Intermediate-2 from Intermediate-1 in the presence of Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), N,N-Diisopropylethylamine (DIPEA) and n-butanol under nitrogen atmosphere.
The corresponding synthetic route of Palbociclib Intermediate-2 schematically represented as follows:

SCHEME-4

The disadvantage associated with the above process is time consuming and reports lesser yields.

Palbociclib Commercial Manufacturing Process Development. Part II: Regioselective Heck Coupling with Polymorph Control for Processability from Organic Process Research & Development (2016), 20(7), 1203-1216 also reports an optimized version of the Heck reaction developed to produce kilogram quantities of the penultimate Intermediate-2 for early clinical supplies.

It describes Intermediate-1 is slurried in n-butanol (6 volume) and treated with n-butyl vinyl ether (3 equivatent), N,N-Diisopropylethylamine (DIPEA) (2.4 equivatent), lithium triflate (LiOTf) (1.0 equivatent), and [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2) (0.04 equivatent) at 95 °C under nitrogen. These conditions can be used to produce Intermedia-2 in 75-82% isolated yield. The corresponding synthetic route of Palbociclib Intermediate-2 schematically represented as follows:

SCHEME-5

However, several key impurities are also formed in the reaction that are difficult to purge. These respective impurities are as shown below:

IMPURITIES

CN105924439 discloses the formation of Intermediate-2 from Intermediate-1 in the presence of Potassium Carbonate (K2CO3), Tris(dibenzylideneacetone) dipalladium (Pd2(dba)3), 1,4-diazabicyclo[2.2.2]octane (DABCO) and dimethylformamide (DMF).

The synthetic route of Palbociclib Intermediate-2 schematically represented as follows:

SCHEME-6

The drawback of the above process is that it is time consuming, takes 10 hours to complete.

WO2019/224194 discloses formation of Intermediate-2 from Intermediate-1 in the presence of mixture of n-butanol and methanol, Palladium(II) acetate (Pd(OAc)2), Bis[(2-diphenylphosphino)phenyl] ether (DPEPhos) and N,N-Diisopropylethyl amine (DIPEA) under nitrogen atmosphere.

The corresponding synthetic route of Palbociclib Intermediate-2 schematically represented as follows:

SCHEME-7

The disadvantage associated with the above process is time consuming, takes 3 hours to complete and the corresponding yields are not disclosed. Further, the mixture of solvents does not affect the duration of reaction.

Therefore, it is proven from the prior-art that most of the processes takes 3 hours or more than 3 hours to complete the reaction. Using different catalysts and ligands does not change the duration of the process. Even in an atmosphere of inert gas nitrogen, the process is not completed quickly. Preparation of Palbociclib Intermediate in the presence of mixture of solvents does not affect the duration of the reaction.

Hence, it is necessitate to find an improved and efficient process for the preparation of Palbociclib Intermediate. The present invention provides an improved and large-scale industrial process for the preparation of Palbociclib Intermediate. The present invention also avoids use of expensive reagents and provides an economical and technically simple process for the preparation of Palbociclib Intermediate. The main advantage of the process for the preparation of Palbociclib Intermediate as per the present invention is that it gives a high yield of the product with high purity along with a low cost in a short time.

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide an industrially advantageous and technically simple process for the preparation of Palbociclib Intermediate.

Yet another object of present invention is to provide an efficient process for the preparation of Palbociclib Intermediate with high yield and purity of product.

Another object of the present invention is to provide a large-scale advantageous process for the preparation of Palbociclib Intermediate to produce low-cost final product.

One more object is that the present invention avoids the use expensive reagents and catalysts and provides an economical process for the preparation of Palbociclib Intermediate.

Yet an another object of present invention is to provide a process for the preparation of Palbociclib Intermediate using solvents which may include but not limited to water, methanol, ethanol, propanol, n-butanol, iso-propanol, 2-butanol and mixture thereof; preferably by using mixture of water, methanol and n-butanol.

Another object of the present invention is to provide a process for the preparation of Palbociclib Intermediate using additives to accelerate the oxidative addition, Additives which may include but are not limited to lithium chloride, copper iodide, lithium bromide, lithium triflate and mixture thereof; preferably by using lithium chloride.

One more object of present invention is to provide a process for the preparation of Palbociclib Intermediate using inorganic bases which may include potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide and mixture thereof; preferably by using potassium carbonate.

Another object of the present invention is to provide a process for the preparation of Palbociclib Intermediate using palladium catalysts which may include but are not limited to [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2), [1,1'-Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)2Cl2), Palladium(II) acetate (Pd(OAc)2), Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), palladium-tetrakis(triphenylphosphine) ([Pd(P(C6H5)3)4]) and mixture thereof; preferably by using [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2).

Yet an another object of the present invention is to provide a process for the preparation of Palbociclib Intermediate using ligands which may include but are not limited to Bis[(2-diphenylphosphino)phenyl] ether (DPEphos), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), Dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphane (Sphos) and ([1,1'-Binaphthalene]-2,2'-diyl)bis(diphenylphosphane) (BINAP) and mixture thereof; preferably by using Bis[(2-diphenylphosphino)phenyl] ether (DPEphos).

One more object of the present invention is to provide a process for the preparation of Palbociclib Intermediate using autoclave to provide an inert atmosphere and pressure, inert gases which may include but are not limited to nitrogen (N2), argon (Ar), and carbon dioxide (CO2) and mixture thereof; preferably by using argon (Ar).

SUMMARY OF THE INVENTION:

One aspect of the present invention relates to a process for the preparation of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate [palbociclib Intermediate-2] comprising the following steps:
a) adding solvent or mixture of solvents in an autoclave reactor under inert condition;
b) adding tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate [palbociclib Intermediate-1], additives, inorganic base, n-butyl vinyl ether, palladium catalyst and ligand to the above reaction mixture;
c) heating the reaction mixture under inert gas pressure for 1 to 5 hours at 80-90°C;
d) cooling the reaction mixture to 25-30°C;
e) stirring the reaction mixture for 15 – 60 minutes at 25-30°C;
f) filtering the reaction mixture under vacuum;
g) washing the reaction mixture with solvent or mixture of solvents;
h) drying at 60-65°C.

Another aspect of the present invention provides a process for the preparation of a Palbociclib Intermediate-2 comprising the following steps.
a) adding n-butanol, methanol and water in autoclave reactor under inert condition;
b) adding Intermediate-1, lithium chloride, potassium carbonate, n-butyl vinyl ether, Tetrabutylammonium iodide (TBAI), [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2) and Bis[(2-diphenylphosphino)phenyl] ether (DPEphos) to the above reaction mixture;
c) heating the reaction mixture under argon (Ar) gas pressure for 3 hours at 80-90°C;
d) cooling the reaction mixture to 25-30°C;
e) stirring the reaction mixture for 60 minutes at 25-30°C;
f) filtering the reaction mixture under vacuum;
g) washing the reaction mixture with n-butanol and methanol;
h) drying at 60-65°C.

In another aspect of the present invention, the process for the preparation of Palbociclib Intermediate-2 depicted as a whole in below Scheme-8.

SCHEME-8

DETAILED DESCRIPTION OF THE INVENTION:
The present invention will now be disclosed by describing certain preferred and optional embodiments, to facilitate various aspects thereof.

The present invention relates to an improved process for the preparation of Palbociclib Intermediate.

The present invention is to provide an industrially advantageous process for the preparation of Palbociclib Intermediate.

The present invention is to provide technically simple process for the preparation of Palbociclib Intermediate.

The present invention is to provide an efficient process for the preparation of Palbociclib Intermediate with yield of product and high purity.

The present invention is to provide large-scale advantageous process for the preparation of Palbociclib Intermediate to produce low-cost final product.

The present invention also avoids use expensive reagents and catalysts and provides an economical process for the preparation of Palbociclib Intermediate.

Yet an another aspect of present invention is to provide process for the preparation of Palbociclib Intermediate using solvents may include water, methanol, ethanol, propanol, n-butanol, iso-propanol, 2-butanol and mixture thereof; Preferably by using mixture of water, methanol and n-butanol.

Another aspect of the present invention also provides process for the preparation of Palbociclib Intermediate using additives to accelerate the oxidative addition, additives may include lithium chloride, copper iodide, lithium bromide, lithium triflate; preferably by using lithium chloride.

Lithium chloride has been found to be a powerful rate accelerant in cases where the halogen group dissociates from palladium (i.e. the open mechanism). The chloride ion is believed to either displace the halogen group on the palladium making the catalyst more active for trans metalation or by coordination to the palladium(0) adduct to accelerate the oxidative addition. Also, lithium chloride salt enhances the polarity of the solvent. As per the present invention the lithium chloride additive is found to suppress formation of the impurities to a certain extent.
One more aspect of present invention is to provide process for the preparation of Palbociclib Intermediate using inorganic bases may include potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide and mixture of; Preferably by using potassium carbonate.

Another aspect of the present invention is to provide process for the preparation of Palbociclib Intermediate using palladium catalysts may include [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), Pd(dppf)Cl2·CH2Cl2, [1,1'-Bis (diphenyl phosphino)ferrocene] palladium(II) dichloride (Pd(dppf)2Cl2), Palladium(II) acetate (Pd(OAc)2), Tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), palladium-tetrakis(triphenylphosphine) ([Pd(P(C6H5)3)4]) and mixture of; Preferably by using [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2).

Yet an another aspect of the present invention is to provide process for the preparation of Palbociclib Intermediate using ligands may include Bis[(2-diphenylphosphino)phenyl] ether (DPEphos), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), Dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphane (Sphos) and ([1,1'-Binaphthalene]-2,2'-diyl)bis(diphenylphosphane) (BINAP); Preferably by using Bis[(2-diphenylphosphino)phenyl] ether (DPEphos).

One more aspect of the present invention is to provide process for the preparation of Palbociclib Intermediate using autoclave to provide an inert atmosphere and pressure, inert gases may include nitrogen (N2), argon (Ar), and carbon dioxide (CO2); Preferably by using argon (Ar).

Argon is a chemically inert gas. It is often used when an inert atmosphere is needed. It is the cheapest alternative when nitrogen is not sufficiently inert. Other noble gases would be equally suitable for most of these applications, but argon is by far the cheapest. Argon is inexpensive, since it occurs naturally in air and is readily obtained as a byproduct of cryogenic air separation in the production of liquid oxygen and liquid nitrogen: the primary constituents of air are used on a large industrial scale. The other noble gases (except helium) are produced this way as well, but argon is the most plentiful by far. The bulk of argon applications arise simply because it is inert and relatively cheap.

The rate of a reaction is a powerful tool. By finding out how fast products are made and what causes reactions to slow down, method was developed to improve production. This information is essential for the large scale manufacture of drugs. As per the present invention, application of argon pressure accelerates the reaction rate and the reaction completes rapidly. Argon is also used in some high-temperature industrial processes where ordinarily non-reactive substances become reactive.

One embodiments the present invention provides a process for the preparation of a Palbociclib Intermediate-2 comprising the following steps.
a) adding n-butanol, methanol and water in autoclave reactor under inert condition;
b) dissolving Intermediate-1, lithium chloride, potassium carbonate, n-butyl vinyl ether, Tetrabutylammonium iodide, [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II) complex with dichloromethane and Bis[(2-diphenylphosphino)phenyl] ether;
c) heating the reaction mixture under 5 kg argon gas pressure for 1 hour at 80-90°C;
d) cooling the reaction mixture to 25-30°C;
e) stirring the reaction mixture for 15 minutes at 25-30°C;
f) filtering the reaction mixture under vacuum;
g) washing the reaction mixture with n-butanol and methanol;
h) drying at 60-65°C.

One more embodiment of the present invention involves formation of Palbociclib Intermediate-2 by charging n-butanol, methanol and water into an autoclave reactor under inert atmosphere. After this, Intermediate-1, lithium chloride, potassium carbonate, n-butyl vinyl ether, tetrabutylammonium iodide, 1,1'-Bis(diphenyl phosphino)ferrocene] dichloropalladium(II), complex with dichloromethane and Bis[(2-diphenylphosphino)phenyl] ether were added to the reaction mixture. The reaction mixture was allowed to stir at 80-90°C for 1 hour under 5kg argon pressure. After completion of the reaction, the reaction mixture was cooled to 25–30 °C and allowed to stir at 25–30 °C for 15 min. After this, reaction mixture was filtered under vacuum and washed the wet cake using mixture of n-butanl and methanol. The reaction mixture was dried well at 60-65°C to get Intermediate-2.

Having described the invention with reference to certain preferred embodiment, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following example describing in detail by the purification of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

The following example is provided for illustrative purpose only and this example is in no way limitative on the present invention.

EXAMPLE:

Preparation of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate [palbociclib intermediate – 2]:

n-Butanol, methanol and water were charged into an autoclave reactor under nitrogen atmosphere. After this, tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate (Intermediate-1), lithium chloride, potassium carbonate, n-butyl vinyl ether, tetrabutylammonium iodide, 1,1'-Bis(diphenyl phosphino)ferrocene] dichloropalladium (II), complex with dichloromethane and Bis[(2-diphenylphosphino)phenyl] ether were added to the reaction mixture. The reaction mixture was allowed to stir at 80-90°C for 1 hour under 5kg argon pressure. After completion of the reaction, the reaction mixture was cooled to 25–30 °C and allowed to stir at 25–30 °C for 15 min. After this, reaction mixture was filtered under vacuum and washed the wet cake using mixture of n-butanol and methanol. The reaction mixture was dried well at 60-65°C to get tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino) pyridin-3-yl)piperazine-1-carboxylate (Intermediate-2) (%Yield: 80%)

The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasized in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.
,CLAIMS:We claim

1. A process for preparation of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido [2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl) piperazine-1-carboxylate [palbociclib Intermediate-2] comprising the following steps:
(a) adding a solvent or mixtures thereof in autoclave reactor under inert condition;
(b) adding tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate [palbociclib Intermediate-1], additives, inorganic base, n-butyl vinyl ether, palladium catalyst and ligand to the above reaction mixture;
(c) heating the reaction mixture under inert gas pressure for 1 to 5 hours at 80-90°C;
(d) cooling the reaction mixture to 25-30°C;
(e) stirring the reaction mixture for 15 – 60 minutes at 25-30°C;
(f) filtering the reaction mixture under vacuum;
(g) washing the reaction mixture with solvent or mixtures thereof;
(h) drying at 60-65°C.

2. The process as claimed in claim 1, wherein the solvent is selected from water, methanol, ethanol, propanol, n-butanol, iso-propanol, 2-butanol or mixture thereof, preferably mixture of water, methanol, n-butanol or mixtures thereof.

3. The process as claimed in claim 1, wherein the additive is selected from lithium chloride, copper iodide, lithium bromide, lithium triflate.

4. The process as claimed in claim 1, wherein the inorganic base is selected from potassium carbonate, potassium hydroxide, sodium carbonate, sodium hydroxide or mixtures thereof.

5. The process as claimed in claim 1, wherein the palladium catalyst is selected from [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), (Pd(dppf)Cl2·CH2Cl2), [1,1'-Bis(diphenylphosphino)ferrocene] palladium(II) dichloride (Pd(dppf)2Cl2), Palladium(II) acetate (Pd(OAc)2), tris(dibenzylideneacetone)dipalladium (Pd2(dba)3), palladium-tetrakis (triphenylphosphine) ([Pd(P(C6H5)3)4]).

6. The process as claimed in claim 1, wherein the ligand is selected from Bis[(2-diphenylphosphino)phenyl] ether (DPEphos), (9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphane) (Xantphos), Dicyclohexyl(2',6'-dimethoxy[1,1'-biphenyl]-2-yl)phosphane (Sphos) and ([1,1'-Binaphthalene]-2,2'-diyl)bis(diphenylphosphane) (BINAP).

7. The process as claimed in claim 1, inert gas used for inert condition of autoclave comprises nitrogen (N2), argon (Ar), or carbon dioxide (CO2).

8. The process as claimed in claim 1, preparation of tert-butyl 4-(6-((6-(1-butoxyvinyl)-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate comprising the following steps:
(a) adding n-butanol, methanol and water in autoclave reactor under inert condition;
(b) adding tert-butyl 4-(6-((6-bromo-8-cyclopentyl-5-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-2-yl)amino)pyridin-3-yl)piperazine-1-carboxylate, lithium chloride, potassium carbonate, n-butyl vinyl ether, Tetrabutylammonium iodide (TBAI), [1,1'-Bis(diphenyl phosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (Pd(dppf)Cl2·CH2Cl2) and Bis[(2-diphenylphosphino)phenyl] ether (DPEphos) to the above reaction mixture;
(c) heating the reaction mixture under argon (Ar) gas pressure for 3 hours at 80-90°C;
(d) cooling the reaction mixture to 25-30°C;
(e) stirring the reaction mixture for 60 minutes at 25-30°C;
(f) filtering the reaction mixture under vacuum;
(g) washing the reaction mixture with n-butanol and methanol;
(h) drying at 60-65°C.