FORM-2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
[See section 10, rule 13]
An improved process for the preparation of 4,4'-dimethoxytrityl
chloride
APPLICANT:
HERBERT BROWN PHARMACEUTICAL & RESEARCH LABORATORIES
W-256/257/258A, M.I.D.C. Phase II, Shivaji Udyog Nagar, Dombivli (E)-421203, District- Thane, Maharashtra, India.
Indian Company incorporated under the Companies Act 1956
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of 4,4'-dimethoxytrityl chloride.
BACKGROUND OF THE INVENTION
Wide applications of oligonucleotide for therapeutic and diagnostic purposes often require synthesis of oligonucleotide in large quantity. Use of 4,4'-dimethoxytrityl group for protecting 5'-hydroxy group of nucleoside in process for synthesis of oligonucleotide is well known. The 4,4'-dimethoxytrityl chloride having Formula I, is commonly used as reagent to provide 4,4'-dimethoxytrityl protecting group.

Increasing demand for oligonucleoside has indirectly increased the demand for reagent to provide 4,4'-dimethoxytrityl protecting group.
Huaxue Shiji (1989), 11(6). Pg. 361-362, describes a process for the preparation of 4,4'-dimethoxytrityl chloride by Grignard reaction of methylbenzoate with 4-anisylmagnesium bromide followed by chlorination of thus obtained, 4,4'-dimethoxytritanol with acetyl chloride. Formation of unwanted side products due to incomplete conversion of Grignard's reagent makes the process less feasible on

industrial scale.
Indian Journal of Chemistry, Vol. 43, 1995, Pg. 634-635, describes a method for the preparation of 4,4,-dimethoxytrityl chloride. According to the process described, to a mixture of anisole and benzotrichloride, precooled in an ice-bath, was added aluminium chloride in 1.5 hours. After 15 mins of completion of addition, the reaction was allowed to proceed at room temperature for 2 hours. The reaction mixture was then poured into mixture of crushed ice and sulfuric acid and the two layers formed were separated. The aqueous layer was extracted with benzene. The combined organic extracts were washed with conc, sulfuric acid and the benzene was removed using rotavapor to obtain a gummy substance. The gummy substance was steam-distilled and the distillate was first dissolved in benzene and then dried over anhydrous sodium sulphate. The benzene was again removed by rotavapor and acetyl chloride was added to the residue. The mixture was refluxed for 1.5 hours, cooled and dry cyclohexane was added. The mixture was then kept overnight in a freezer to crystallize 4,4'-dimethoxytrityl chloride. The crystals of 4,4,-dimethoxytrityl chloride were separated by filtration and were washed with cold cyclohexane to obtain pure 4,4'-dimethoxytrityl chloride. The major drawbacks of this process can be listed as below
i) use of hazardous solvent like benzene for extraction
ii) use of high volume of antisolvent for precipitation/ separation of product
iii) requirement of overnight freezing for crystallization
iv) multiple unit operations
The above drawbacks make the process environment unsafe, tedious and time consuming.
Indian Patent No. 185801 discloses the synthesis of 4,4'-dimethoxytrityl chloride as


shown in Scheme I.
The synthesis involves preparation of 4,4'-dimethoxytritanol by reaction of benzotrichloride with anisole in presence of aluminum chloride and an organic solvent selected from carbon disulfide or nitrobenzene. The 4,4'-dimethoxytritanol thus formed is isolated by partitioning between water and benzene. The benzene layer is evaporated to get 4,4'-dimethoxytritanol which is subsequently converted to 4,4'-dimethoxytrityl chloride using acetyl chloride as a reagent and benzene as solvent. The 4,4'- dimethoxytrityl chloride obtained by above process needs to be washed by solvent like hexane, pentane or petroleum ether. From an industrial standpoint, however, this process has some distinct disadvantages. Primarily, the process uses multiple solvents in the course of reaction thereby making recovery of the solvent difficult. In addition the hazardous solvents like carbon disulfide and benzene are

used in the reaction.
CN1432553 discloses a process for the preparation of 4,4'-dimethoxytrityl chloride by reacting 1.0 mole of trihalide benzene with 15-20 moles of alkoxybenzene in presence of aluminum chloride at 80°C for 24 hours. Apart from long time required for completion of reaction, the use of excess of alkoxybenzene in this process is undesirable from an environmental and economical point of view. Furthermore, after completion of reaction, the unreacted alkoxybenzene is required to be removed by treatment with toluene in presence of hydrochloric acid thereby making the process laborious.
The drawbacks associated with the prior art are addressed by the present invention wherein a cost effective, operationally simple and environment friendly process for preparation of highly pure 4,4'-dimethoxytrityl chloride is provided. The inventors of the present invention have found that 4,4'-dimethoxytrityl chloride can be prepared by using a single solvent throughout the reaction. The present invention also avoids use of toxic solvents like carbon disulfide and benzene.
OBJECT OF THE INVENTION
i) An object of the present invention is to provide an improved process for
the preparation of 4,4'-dimethoxytrityl chloride.
ii) Another object of the present invention is to provide an improved process for preparation of 4,4'-dimethoxytrityl chloride using single solvent for the reaction.
iii) Yet another object of the present invention to provide a process for the

preparation of 4,4'-dimethoxytrityl chloride wherein the solvents used in the process is recovered and reused.
iv) Yet another object of the present invention is to provide a simple, industrially feasible, environment safe and economical process for preparation of 4,4'-dimethoxytrityl chloride
SUMMARY OF THE INVENTION
According to an aspect of the present invention, there is provided an improved process for the preparation of 4,4'-dimethoxytrityl chloride of Formula I

comprising
a) reacting anisole with benzotrichloride in presence of Lewis acid in a chlorinated solvent at temperature ranging from 0-3 0°C for 6 to 8 hours to obtain a reaction mixture
b) pouring the reaction mixture into ice-water
c) separating an organic layer and drying over sodium sulfate to obtain an anhydrous organic layer
d) adding acetyl chloride to the anhydrous organic layer and heating to 40-65°C
for 4 to 6 hours

e) recovering the chlorinated solvent by distillation and obtaining a concentrated solution
f) adding a C6 to C8 hydrocarbon to the concentrated solution, cooling to 0-5°C and filtering to obtain 4,4'-dimethoxytrityl chloride of Formula I having HPLC purity of more than 95%.
g) purifying the 4,4'-dimethoxytrityl chloride of Formula I obtained in step f) by using a C6 to C8 hydrocarbon to obtain 4,4'-dimethoxytrityl chloride of Formula I having HPLC purity of more than 99%.
DETAILED DESCRIPTION OF THE INVENTION
The 4,4,-dimethoxytrityl chloride is commonly used as reagent in the synthesis of oligonucleotides, to provide 4.4'-dimethoxytrityl protecting group.
According to an embodiment of the present invention, there is provided an improved process for the preparation of 4,4'-dimethoxytrityl chloride of Formula I

comprising
a) reacting anisole with benzotrichloride in presence of Lewis acid in a chlorinated solvent at temperature ranging from 0-30°C for 6 to 8 hours to obtain a reaction mixture
b) pouring the reaction mixture into ice-water

c) separating an organic layer and drying over sodium sulfate to obtain an anhydrous organic layer
d) adding acetyl chloride to the anhydrous organic layer and heating to 40-65°C for 4 to 6 hours
e) recovering the chlorinated solvent by distillation and obtaining a concentrated solution
f) adding a C6 to C8 hydrocarbon to the concentrated solution, cooling to 0-5°C and filtering to obtain 4,4'-dimethoxytrityl chloride of Formula 1 having HPLC purity of more than 95%.
g) purifying the 4,4'-dimethoxytrityl chloride of Formula I obtained in step f) by using a C6 to C8 hydrocarbon to obtain 4,4'-dimethoxytrityl chloride of Formula I having HPLC purity of more than 99%.
The improved process for the preparation of 4,4'-dimethoxytrityl chloride of Formula I can be depicted in Scheme II


According to an embodiment of the present invention, the molar ratio of the anisole used in step a) with respect to benzotnchloride is in range of 2.0 to 2.5
The Lewis acid catalyst like aluminum trichloride, aluminum tribromide, zinc chloride, boron trichloride, boron trifluoride is used
The molar ratio of the Lewis acid used in step a) with respect to benzotrichloride is in the range of 1.0 to 1.5
The chlorinated solvent used in step a) is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, monochlorobenzene, dichlorobenzene and the like, preferably dichloromethane or monochlorobenzene is used.
The amount of the chlorinated solvent used with respect to benzotrichloride is in the range of 4 to 10 volumes, preferably 5 to 7 volumes.
According to another embodiment of the present invention, the molar ratio of acetyl chloride used in step d) with respect to benzotrichloride is in the range of 2 to 3.
According to another embodiment of the present invention, in step e) the chlorinated solvent is recovered completely to obtain a residue and the residue was redissolved in low volume of the chlorinated solvent to obtain a concentrated solution.
According to yet another embodiment of the present invention, in step f) and g) the C6-C8 hydrocarbon like n-hexane, cyclohexane, n-heptane, n-octane is used.
The total amount of the C6-C8 hydrocarbon used, in step f) and g) with respect to

benzotrichloride is in the range of 10 to 18 volumes.
According to an embodiment of the present invention, the purifying step g) comprises of adding a C6-C8 hydrocarbon to the 4,4'-dimethoxytrityl chloride obtained in step f), heating to 45-65°C, cooling to 25-30°C and isolating 4,4'-dimethoxytrityl chloride of Formula I.
The solvents used in the process like monochlorobenzene and heptane are recovered to the extent of 90% with HPLC purity of more than 99%.
The 4, 4'-dimethoxytrityl chloride product obtained by the process of present invention was characterized spectroscopically & found to be identical to that of authentic sample.
The detail of the invention provided in the following example is given by the way of illustration only and should not be construed to limit the scope of the present invention.
EXAMPLES Example 1:
A solution of anisole (585g) in monochlorobenzene (2500ml) was cooled to 15°C to 20°C and aluminum chloride (360g) was added. The mixture was further cooled to 0-5°C and a solution of benzotrichloride (500g) in monochlorobenzene (750ml) was added. The contents were maintained at 0-5°C for 2 hours. The temperature was then raised to 25-30°C and the mixture was stirred for 4 to 6 hours. The mixture was poured into ice-water (5kg). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with monochlorobenzene (1000ml) and the monochlorobenzene extract was combined with the organic layer. The combined

organic layer was dried over sodium sulfate to obtain an anhydrous organic layer. To the anhydrous organic layer was charged acetyl chloride (53 8g) and the contents were heated at 60-65°C for 4 to 6 hours. After completion of the reaction, the monochlorobenzene was distilled out and the solution was concentrated to low volume. To the concentrated solution was added n-heptane (4000ml). The contents were stirred, chilled to 0-5°C and maintained for 2 hours to obtain a solid product. The solid product was filtered and washed with n-heptane. The resulting wet cake having HPLC purity of 95.07% was slurried with n-heptane (4000ml), heated to 60-65°C for 1 hour, cooled to 25-30°C, filtered, washed with n-heptane and dried under vacuum at 30-40°C to afford 685g (79.03%) of 4, 4,-dimethoxytrityl chloride. 'H NMR in CDC13 (δ ppm): 7.24-7.30 (m, 5H, Ar-H), 7.14 (dd, 4H, Ar-H), 6.82 (dd, 4H, Ar-H), 3.80 (s, 6H, 2 x Ar-OMe) GC-MS (EI): 304 (M+-C1) Melting point: 122°C (literature: 119-122°C) Chloride content: 10.50% HPLC purity: 99.40%
Example 2:
A solution of anisole (58.5kg) in monochlorobenzene (2501it) was cooled to 15°C to 20°C and aluminum chloride (36kg) was added. The mixture was further cooled to 0-5°C and a solution of benzotrichloride (50kg) in monochlorobenzene (751it) was added. The contents were maintained at 0-5°C for 2 hours. The temperature was then raised to 25-30°C and the mixture was stirred for 4 to 6 hours. The mixture was poured into ice-water (500kg). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with monochlorobenzene (l00lit) and the monochlorobenzene extract was combined with the organic layer. The combined organic layer was dried over sodium sulfate to obtain an anhydrous organic layer. To the anhydrous organic layer was charged acetyl chloride (53.8kg) and the contents

were heated at 60-65°C for 4 to 6 hours. After completion of the reaction, the monochlorobenzene was distilled out and the solution was concentrated to low volume. To the concentrated solution was added n-heptane (4001it). The contents were stirred, chilled to 0-5°C and maintained for 2 hours to obtain a solid product. The solid product was filtered and washed with n-heptane. The resulting wet cake having HPLC purity of 96.06% was slurried with n-heptane (400lit), heated to 60-65°C for 1 hour, cooled to 25-30°C, filtered, washed with n-heptane and dried under vacuum at 30-40°C to afford 71.5kg (82.49%) of 4, 4'-dimethoxytrityl chloride with 99.37% HPLC purity.
Example 3:
A solution of anisole (58.5g) in monochlorobenzene (250ml) was cooled to 15°C to 20°C and aluminum chloride (36g) was added. The mixture was further cooled to 0-5°C and a solution of benzotrichloride (50g) in monochlorobenzene (75ml) was added. The contents were maintained at 0-5°C for 2 hours. The temperature was then raised to 25-30°C and the mixture was stirred for 4 to 6 hours. The mixture was poured into ice-water (500g). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with monochlorobenzene (2 x 50ml) and the monochlorobenzene extract was combined with the organic layer. The combined organic layer was dried over sodium sulfate to obtain an anhydrous organic layer. To the anhydrous organic layer was charged acetyl chloride (53.8g) and the contents were heated at 60-65°C for 4 to 6 hours. After completion of the reaction, the monochlorobenzene was distilled out completely to obtain a residue. The residue was redissolved in monochlorobenzene (75ml) and n-hexane (300ml) was added to it. The contents were stirred, chilled to 0-5°C and maintained for 2 hours to obtain a solid product. The solid product was filtered and washed with n-hexane. The resulting wet cake having HPLC purity of 96.14% was slurried with n-hexane (300ml), heated to 50-60°C for 1 hour, cooled to 25-30°C, filtered, washed with n-hexane and dried under vacuum at 30-40°C to afford 57.83g (66.72%) of 4, 4'-dimethoxytrityl chloride

with 99.08% HPLC purity .
Example 4:
A solution of anisole (58.5g) in dichloromethane (250ml) was cooled to 15°C to 20°C and aluminum chloride (36g) was added. The mixture was further cooled to 0-5°C and a solution of benzotrichloride (50g) in dichloromethane (75ml) was added. The contents were maintained at 0-5°C for 2 hours. The temperature was then raised to 25-30°C and the mixture was stirred for 4 to 6 hours. The mixture was poured into ice-water (500g). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with dichloromethane (2 x 50ml) and the dichloromethane extract was combined with the organic layer. The combined organic layer was dried over sodium sulfate and the dichloromethane was distilled out under vacuum to obtain approximately 200ml of anhydrous organic layer. To the anhydrous organic layer was charged acetyl chloride (53.8g) and the contents were heated at 40°C for 4 to 6 hours. After completion of the reaction, the dichloromethane was distilled out completely to obtain a residue. The residue was redissolved in dichloromethane (75ml) and n-hexane (300ml) was added to it. The contents were stirred, chilled to 0-5°C and maintained for 2 hours to obtain a solid product. The solid product was filtered and washed with n-hexane. The resulting wet cake having HPLC purity of 98.71% was slurried with n-hexane (300ml), heated to 60-65°C for 1 hour, cooled to 25-30°C, filtered, washed with n-hexane and dried under vacuum at 30-40°C to afford 56.0g (64.61%) of 4, 4'-dimethoxytrityl chloride with 99.70% HPLC purity.
Example 5:
A solution of anisole (58.5g) in dichloromethane (250ml) was cooled to 15°C to 20°C and aluminum chloride (36g) was added. The mixture was further cooled to 0-5°C and a solution of benzotrichloride (50g) in dichloromethane (75ml) was added. The contents were maintained at 0-5°C for 2 hours. The temperature was then raised to

25-30°C and the mixture was stirred for 4 to 6 hours. The mixture was poured into ice-water (500g). The organic layer and the aqueous layer were separated. The aqueous layer was extracted with dichloromethane (2 x 50ml) and the dichloromethane extract was combined with the organic layer. The combined organic layer was dried over sodium sulfate and the dichloromethane was distilled out under vacuum to obtain approximately 200ml of anhydrous organic layer. To the anhydrous organic layer was charged acetyl chloride (53.8g) and the contents were heated at 40°C for 4 to 6 hours. After completion of the reaction, the dichloromethane was distilled out completely to obtain a residue. The residue was redissolved in dichloromethane (75ml) and n-heptane (300ml) was added to it. The contents were stirred, chilled to 0-5°C and maintained for 2 hours to obtain a solid product. The solid product was filtered and washed with n-heptane. The resulting wet cake having HPLC purity of 97.63% was slurried with n-heptane (300ml), heated to 60-65°C for 1 hour, cooled to 25-3 0°C, filtered, washed with n-heptane and dried under vacuum at 30-40°C to afford 59.0g (68.07%) of 4, 4'-dimethoxytrityl chloride with 99.73% HPLC purity.

We Claim
1. An improved process for the preparation of 4,4'-dimethoxytrityl chloride of Formula I

comprising
a) reacting anisole with benzotrichloride in presence of Lewis acid in a chlorinated solvent at temperature ranging from 0-30°C for 6 to 8 hours to obtain a reaction mixture
b) pouring the reaction mixture into ice-water
c) separating an organic layer and drying over sodium sulfate to obtain an anhydrous organic layer
d) adding acetyl chloride to the anhydrous organic layer and heating to 40-65°C
for 4 to 6 hours
e) recovering the chlorinated solvent by distillation and obtaining a concentrated solution
f) adding a C6 to C8 hydrocarbon to the concentrated solution, cooling to 0-5°C and filtering to obtain 4,4'-dimethoxytrityl chloride of Formula I having HPLC purity of more than 95%
g) purifying the 4,4'-dimethoxytrityl chloride of Formula I obtained in step f) by using a C6 to C8 hydrocarbon to obtain 4,4'-dimethoxytrityl chloride of Formula I having HPLC purity of more than 99%.

2. The process as claimed in claim 1, wherein in the molar ratio of the anisole used in with respect to benzotrichloride is in range of 2.0 to 2.5.
3. The process as claimed in claim 1, wherein in the Lewis acid catalyst like aluminum trichloride, aluminum tribromide, zinc chloride, boron trichloride, boron trifluoride is used.
4. The process as claimed in claim 1, wherein in the molar ratio of the Lewis acid used in step a) with respect to benzotrichloride is in the range of 1.0 to 1.5.
5. The process as claimed in claim 1, wherein the chlorinated solvent used in step a) is selected from dichloromethane, dichloroethane, chloroform, carbon tetrachloride, monochlorobenzene, dichlorobenzene and the like, preferably dichloromethane or monochlorobenzene is used.
6. The process as claimed in claim 1, wherein the amount of the chlorinated solvent used with respect to benzotrichloride is in the range of 4 to 10 volumes, preferably 5 to 7 volumes.
7. The process as claimed in claim 1, wherein the molar ratio of acetyl chloride used with respect to benzotrichloride is in the range of 2 to 3.
8. The process as claimed in claim 1, wherein in step f) and g) the C6-C8 hydrocarbon like n-hexane, cyclohexane, n-heptane, n-octane is used.

9. The process as claimed in claim 1, wherein in step f) and g) the total amount of C6-C8 hydrocarbon used with respect to benzotrichloride is in range of 10 to 18 volumes.
10. The process as claimed in claim 1, wherein in the purifying step g) comprises of adding a C6-C8hydrocarbon to the 4,4'-dimethoxytrityl chloride obtained in step f), heating to 45~65°C, cooling to 25-30°C and isolating 4,4'-dimethoxytrityl chloride of Formula 1.