WO1997024357A1

WO1997024357A1 - Process for synthesis and purification of a compound useful in the preparation of acyclovir

Info

Publication number: WO1997024357A1
Application number: PCT/US1996/020216
Authority: WO
Inventors: Henry J. Buehler; Douglas C. Caskey
Original assignee: Mallinckrodt Chemical, Inc.
Priority date: 1995-12-28
Filing date: 1996-12-17
Publication date: 1997-07-10

Abstract

Intermediate chemical compounds useful in the preparation of acyclovir and a method of synthesizing and purifying the intermediate chemical compounds. Diacetyl-guanine is alkylated and the resulting product washed with an alcohol to produce a relatively pure, crystalline diacetyl-acyclovir (DA-ACV). The diacetyl-acyclovir (DA-ACV) is hydrolyzed in the presence of potassium hydroxide to a novel potassium salt of acyclovir, acyclovir potassium enolate. The acyclovir potassium salt is converted into essentially pure acyclovir. The step of hydrolyzing diacetyl-acyclovir and forming the potassium salt occurs simultaneously. The potassium salt of acyclovir is converted to acyclovir by dissolving in water in the presence of an acid to generate an essentially pure acyclovir. The resulting acyclovir normally needs no further purification and meets the specification of U.S.P. XXIII. Thus, the invention is directed to the synthesis of intermediate purified diacetyl-acyclovir, the conversion of the diacetyl-acyclovir to an acyclovir-potassium salt, and the conversion of the acyclovir-potassium salt to acyclovir.

Description

PROCESS FOR SYNTHESIS AND PURIFICATION OF A

COMPOUND USEFUL IN THE PREPARATION OF ACYCLOVIR

Background ofthe nvention

This invention relates generally to the preparation of a purified pharmaceutical

agent and, more particularly, to a method of preparing a purified form of diacetyl-

acyclovir and a method of converting diacetyl-acyclovir to the highly purified potassium

salt of acyclovir which, in turn, can be converted to essentially pure acyclovir.

Pharmaceutically acceptable derivatives of purines, particularly guanine, have

antiviral activity against various classes of viruses both in vitro and in vivo. Acyclovir is

one such well-established antiviral disclosed in United States Patent No. 4,199,574 owned

by Burroughs Wellcome Co. Chemically, acyclovir is 9-(2-hydroxyethoxymethyl)guanine

and has the following structure:

It should be noted that this structure exists as a keto-enol tautomer and can also be shown

with the following structure:

It will be appreciated that a major objective in the synthesis of acyclovir is to

obtain a highly purified, pharmaceutically acceptable acyclovir. The major issue in purifying acyclovir is the removal of guanine. There are other impurities present, but

guanine is particularly difficult to remove because of its structural similarity to acyclovir.

United States Patent No. 4,199,574, as stated above, describes the synthesis of

acyclovir. In general, the methods described therein require a starting product of 6-

chloropurine or 2,6-dichloropurine and include purification of intermediates by column

chromatography. However, these methods require the use of expensive purine starting

products and costly purification technology and equipment.

The same patent also describes a guanine-based route of synthesis in which

silylation chemistry is employed. Purification using this route requires a methanol

recrystallization of an intermediate alkylated species, 9-(2-benzoyloxyethoxymethyl)-

guanine and the methanol recrystallization of the final product. Yields were

approximately 14% to 32% for the intermediate. However, low yields, impracticably low

concentrations, and huge excesses of silylating agent, such as hexamethyldisilazane, make

this approach unattractive for producing useful quantities of purified acyclovir. Burroughs Wellcome U.S. Patent No. 4,146,715 discloses an intermediate

compound, diacetyl-acyclovir (DA-ACV) and describes the synthesis of acyclovir starting

from diacetylguanine (DAG), the alkylation of DAG, aminolysis of the acetyl groups with

methylamine, and the purification of the product by crystallization from methanol. The

yields reported are low, 22% to 52% and the concentrations impracticably dilute.

More specifically, in Examples 44 and 45 of United States Patent 4,146,715

procedures employing this synthetic scheme are described. Both examples employ lengthy tedious processing sequences in which diacetyl-acyclovir (DA-ACV) is

synthesized by alkylating diacetyl-guanine (DAG) with, 2-oxa-l,4-butanediol-diacetate

(OBD) as the alkylating agent and p-toluenesulfonic acid as the catalyst. The resulting

DA-ACV product is not isolated. In Example 44, after the alkylation is complete, the toluene solvent is decanted. The residue is triturated several times with benzene.

Methanol then is added to the residue and subsequently evaporated under pressure. In

Example 45, after alkylation is complete, the reaction mixture is cooled and the product

triturated with chloroform and methanol. The solvents then are removed by flash

evaporation. Ethanol is added and flash evaporated. The DA-ACV products is

aminolyzed using aqueous methylamine to form acyclovir. After aminolysis, excess water

and methylamine are stripped. Ethanol is added and then stripped. The resulting residue

is extracted by boiling in a relatively large volume of methanol. For Example 44, the

methanolic solution of product is evaporated to remove the methanol solvent and the

resulting residue is triturated with cold ethanol and then recrystallized from methanol. For

Example 45, the methanolic solution is cooled to crystallize the product, which is collected

by filtration.

The processing schemes of Examples 44 and 45 are impracticably labor intensive,

tedious and include steps wherein the product concentrations are impracticably dilute. For example, the combined methanol extracts in Example 44 employ a product concentration

of approximately 0.017 lbs/gallon. On a plant scale, such a low concentration would result in enormous solvent recovery and recycle requirements.

Further, these examples employ solvents (benzene in Example 44 and chloroform

in Example 45) which usually are avoided today because they are extremely toxic. Both

solvents are known to be carcinogenic and mutagenic. Moreover, the overall yields of

acyclovir based upon DAG of 21.7% and 51.7% as provided by Examples 44 and 45

respectively are not particularly good.

In the prior art procedures for synthesizing DA-ACV, one problem consistently

encountered is the formation of a product in the form of a "semi-solid having the

consistency of a paste" as described in Example 45. A product in this physical form

cannot be separated from the mother liquor by conventional solid-liquid separation

techniques, such as filter presses, centrifuges, Nutsche filters, etc. The '715 patent skirts

this problem by not isolating the DA-ACV intermediate. Instead, the patented process

employs a lengthy series of triturations. After the trituration, the DA-ACV is aminolyzed

to form the acyclovir (ACV) product.

The triturating operations detract from the invention for the following reasons.

First, they require too many unit operations; second, such operations would result in a

significant number of personnel being exposed to toxic chemicals; third, there would be

significant environmental emissions; and, fourth, the product undoubtedly would be of a

lower quality since there is no discrete separation of mother liquor from the product.

United States Patent No. 4,544,634 also discloses a method of producing acyclovir

wherein the compound 6-deoxyacyclovir is enzymatically converted to acyclovir by

xanthine-oxidase/dehydrogenase or aldehyde oxidase in vivo and, theoretically, in vitro as

a method of producing acyclovir. Such conversion, in vitro, using enzymes or enzyme- producing microorganisms is not easily applied to conventional commercial chemical

operations designed to synthesize chemical compounds through conventional chemical

reactions. Moreover, the '634 patent does not address in vitro yields or levels of purity of

the resulting active product (Example 2). U.S. Patent No. 4,609,662 also discloses a method of producing related antiviral

purines by enzymatic action. U.S. Patent 4,649,140 is directed to the compound 6-

deoxyacyclovir which is enzymatically converted to acyclovir in the method of the '634

patent.

Other United States patents of interest include U.S. Patent No. 4,701,526 which

provides a process of preparing acyclovir and the intermediates used in the process and

U.S. Patent No. 5,223,619 which discloses a process for preparing 9-substituted guanine

derivatives, including acyclovir, by cyclizing a 1 -substituted 5-(thiocarbamoyl)amino-lH-

imidazole-4-carboxamide.

A Russian patent, U.S.S.R. No. 1705296, dated June, 1992 (referenced in

Chemical Abstracts 1 17(9): 90052e) provides a method of making improved quality

acyclovir by using sulfolane as the solvent for the DAG alkylation reaction. However, the

Russian patent indicates the disclosed method produced, at best (Example 5), an end

product containing 1% guanine, which is unacceptably high. The United States

Pharmacopoeia (U.S.P XXIII standard is less than 0.7% guanine.

It is desirable, therefore, to develop a method of synthesizing an acceptable yield of

essentially pure acyclovir from relatively inexpensive starting products without

introducing additional or expensive purification steps to the process. This can be

accomplished by synthesizing an intermediate product, preferably a highly purified

diacetyl-acyclovir and then preparing a highly purified salt of acyclovir, that is essentially

free of guanine and that can be converted into a highly purified acyclovir. Summarv of the Invention

It is, therefore, among the principal objects of the present invention to provide

intermediate chemical compounds that are useful in the preparation of acyclovir as well as

a method of synthesizing and purifying the compounds.

Another object of the present invention is to provide a method of synthesizing and

purifying a chemical intermediate that can be converted to an essentially pure acyclovir and eliminate guanine contaminants.

It is still another object of the present invention to provide a method of synthesizing a highly purified intermediate that will yield a relatively high concentration

of an acceptably pure acyclovir salt.

Another object of the invention is to provide a simple and effective method of

synthesizing diacetyl-acyclovir.

Still another object of the invention is to provide such a method of preparing

diacetyl-acyclovir that yields a relatively pure, crystalline form of diacetyl-acyclovir.

It is yet another object of the present invention to provide a method of synthesizing

and purifying a novel salt of acyclovir that is easily converted into essentially pure

acyclovir.

A still further object of the present invention is to provide a method of synthesizing

and purifying the novel salt of acyclovir wherein the step of converting an intermediate

chemical compound to the acyclovir salt is simultaneous with the step of hydrolyzing the

intermediate compound to acyclovir.

Another object of the invention is to provide a highly purified acyclovir salt and

method of making the same which is simple and elegant in operation, does not require sophisticated purification equipment, is economical to practice and well-suited for its

intended purposes.

In accordance with the present invention, intermediate chemical compounds useful

in the preparation of acyclovir and methods of synthesizing and purifying those

intermediate chemical compound are provided in which a relatively pure form of diacetyl-

acyclovir is prepared by the alkylation of diacetyl guanine. The diacetyl-acyclovir (DA-

ACV) is converted into a novel potassium salt of acyclovir, acyclovir potassium enolate,

which is easily converted into essentially pure acyclovir. The method comprises

hydrolyzing diacetyl-acyclovir to acyclovir and simultaneously forming the novel

potassium salt in one step. The potassium salt formed in this step is of a very high purity.

After isolation, the potassium salt of acyclovir can be conveniently converted, by one

skilled in the art to an essentially pure acyclovir by dissolving in water, adding an

equivalent amount of an acid and carbon treating to generate an essentially pure acyclovir.

The resulting acyclovir normally needs no further purification and meets the specification

of U.S.P. XXIII.

The invention includes the conversion of diacetyl-guanine (DAG) to a highly

purified form of diacetyl-acyclovir (DA-ACV):

ALKYLATION REACTION:

d i acet y I guan i ne 2-oxa-1 ,4-butanediol (DAG) d i acetate (M.W.235) (M.W.176)

d i acety I -acyc I ov i r acet i c anhyd r i de

the conversion ofthe diacetyl-acyclovir to a novel acyclovir-potassium salt:

and. the conversion ofthe novel acyclovir-potassium salt to acyclovir: 0^" K^T o

H. " N

N - N ~ N

, - \ , .. , H.O~A. c -► _u I I - J i l ' \ ' KOAc

H

0 o

\ I

° - H °^{^} H

Detailed Description:

The process of the present invention includes: 1) alkylation of the DAG with an

alkylating agent, 2-oxa-l ,4-butanediol-diacetate (OBD) to produce a highly purified

diacetyl-acyclovir (DA-ACV); 2) hydrolysis of the DA-ACV to acyclovir with the

simultaneous formation of a novel potassium salt of acyclovir (ACV-K); and, 3) the

purification ofthe ACV-K to form purified acyclovir (ACV).

It will be appreciated that OBD is readily available and prepared in a number of

ways. For example, the preparation of OBD is described in Liu et al, Zhongguo Yiyao

Gongye Zazhi (1992), 129 abstracted in Chemical Abstracts 1 17:211980; Senkus et al,

Journal Amer. Chem. Society. Vol. 68; 734 (1946); Roskowsky et al, Journal of

Medicinal Chemistry. 24(10), 1177-81 (1981); and Mizuno et al, Japan Kokai Tokkvo

Koho 63107981 A2 880512 Showa, abstracted in Chemical Abstracts 109:92668, the

English language publications and abstracts being hereby incoφorated by reference.

The diacetyl-guanine (DAG) is commercially available and can be produced by the

methods disclosed in Robins, M.J., Canadian Journal of Chemistry. (1987), 65,1436;

Matsumo, H. et al. Chem. Pharm. Bulletin, fl 988). 36(3), 2253-7; and Chen, X. et al,

Zhongguo Yaoke Daxue Xuebao, (1992), 23(1), 43-44, abstracted in Chemical Abstracts. 1 17:151269e, the English language publications and abstracts being hereby incoφorated

by reference.

The following Examples illustrate the present invention without, however,

limiting the same.

EXAMPLE 1

Alkylation of diacetvl guanine to form diacetyl-acvclovir

The alkylating agent, 2-oxa-l ,4-butanediol diacetate (OBD) is used to alkylate

diacetyl-guanine (DAG) to form diacetyl-acyclovir (DA-ACV).

Charge the following, in the order written, to a one (1) liter round bottom flask

equipped with a motor-driven stirrer, a reflux condenser and a nitrogen inlet: 276.0 g

distilled OBD (98.4% basis) and 3.4 g methanesulfonic acid, 99%. Stir for approximately

30 minutes, then charge 182 g diacetyl-guanine (DAG), followed by 1084 ml toluene (940

g). Once the charging is complete, heat the reaction mixture to the reflux temperature of

113° C. Hold the temperature at approximately 113° to 115° C for a total of 18.5 hours,

maintaining vigorous agitation throughout that time. Once the hold period at reflux is

complete, cool the reaction mixture to 5° C. Collect the diacetyl-acyclovir (DA-ACV)

product by filtration or centrifugation. Wash the product with 179 ml cold toluene. The

product wet weight is approximately 293 g. The wet cake is slurried in 289.1 g (1.588 g

ethanol per g DAG) of 5°C 3 A ethanol for approximately 15 to 30 minutes. The procedure

produces a granular DA-ACV. The solids then are recovered and dried for assay and yield

calculations. The expected weight is 203.3 g. The inventors have determined that the washing of the DA-ACV is a critical step.

As illustrated above, DA-ACV is prepared by alkylating diacetyl-guanine (DAG) with

OBD, generating a mole of acetic anhydride:

ALKYLATION REACTION:

d i acet y 1 guan i ne 2-oxa-1 ,4-butanediol

(DAG) d i acetate

(M.W.235) + (M.W.176)

O

CH,

diacetyl -acyclo i r acet ic anhydride

There exists the possibility that there can be some residual acetic anhydride and/or

OBD in the isolated DA-ACV product. This can occur because an excess of OBD is used

in the above alkylation reaction and since OBD is not very volatile and, therefore, difficult

to dry from the DA-ACV. Also, there is some unreacted DAG, which is a major guanine-

forming impurity and acetate-forming species, present in the final product. If the DA-

ACV product is not scrupulously dried or vigorously washed free of acetic anhydride, they will be carried forward into the hydrolysis and potassium salt formation procedure

immediately described below. In the hydrolysis step, all of the acetate-forming species

will liberate two (2) moles of potassium acetate on reaction with potassium hydroxide.

The inventors have determined that when there is an elevated level of acetate- forming

species in the hydrolysis procedure, there can be significant yield loss caused by the solubilization ofthe resulting ACV-K salt.

Data listed below in Tables 1 and 2 demonstrate the effectiveness of washing the

intermediate DA-ACV with ethanol to remove the DAG (which is analyzed as monoacetyl

guanine (MAG)) and other guanine-forming precursors. This dramatically improves the purity and results in the production of acyclovir final product that consistently passes the

USP XXIII specification for guanine.

Table 1.0 Effect of Ethanol Wash On DA-ACV Purity

Toluene Washed (wgt %) Ethanol Washed(wgt %)

MAG 5.0 1.0

Guanine precursor #1 ' 0.6 0.6

DA-ACV 88.13 92.1

DA-isoACV¹ 0.9 0.8

Table 2.0: Effects of Ethanol Wash On DA-ACV Purity

Toluene Washed (wgt %) Ethanol Washed (wgt %)

MAG 0.33 0.89

Guanine precursor #1 ' 0.74 0.92

Guanine precursor #2' 0.05 0.8

DA-ACV 103 93.2

DA-isoACV¹ 0.15 0.8

' Area percent relative to DA-ACV

Although drying can remove some of the acetate-forming species, the inventors

have determined that washing the DA-ACV with certain solvents is a more efficient and

expedient method of removing the acetate forming species. Moreover, the alcohol washing removes the unreacted DAG (both an acetate forming species and a guanine

precursor) and the other two guanine-forming precursors that drying cannot remove.

As the data in the above tables shows, the selective washing of the wet DA-ACV

results in a DA-ACV of greater purity that the toluene-washed DA-ACV. Various

solvents were tried including methanol, ethanol, 3 A ethanol, blends of ethanol and

methanol, anhydrous ethanol and isopropanol. Although all of the solvents resulted in

DA-ACV having greater purity than the toluene-washed DA-ACV, the 3 A ethanol

provided the best balance of purification, yield, economics and marked decrease in cycle

time.

EXAMPLE 2

Preferred hydrolysis of DA-ACV to ACV with the formation of ACV-potassium salt

In this procedure, DA-ACV is hydrolyzed with methanolic potassium hydroxide

with an extra mole of potassium hydroxide to form the potassium enolate salt of acyclovir,

represented by formula I.

Charge to a one liter round bottom 3-neck flask equipped with a motor driven

stirrer, reflux condenser and nitrogen inlet 630 ml anhydrous methanol (498 g) and 229 g

DA-ACV (97.9% weight, dry basis). With good stirring, add over a 50 minute period 48.1

g potassium hydroxide (KOH), 85% pellets. It will be appreciated by those skilled in the

art that the invention also includes a reverse addition process wherein the KOH is charged

to the methanol in the flask and the DA-ACV is added. Use slight external cooling, as

needed, to keep the temperature at 18° to 22°C. The slurry becomes very viscous during

this time. Over approximately 45 minutes, heat the reaction mixture to 67°C. After

approximately 25 minutes of stirring at 67°C, reduce the heating on the mantle and begin

the addition of another 48.1 g charge of KOH, 85% pellets. This KOH addition requires

approximately 25 minutes. Stir about 15 minutes, then add another 48.1 g KOH, 85% pellets over approximately 30 minutes. It will be appreciated that the entire charge of

potassium hydroxide pellets can be done at one time by adding all of the pellets over 1 to

30 minutes or more and then stirring for 60 to 120 minutes or more.

Hold the reaction mixture at the reflux temperature of approximately 68° to 69°C

for 3 hours. Turn off the heat and allow the reaction mixture to slowly cool to 20° to 25°C.

Stir at 20° to 25°C for 4 to 6 hours. Apply an ice water bath to cool to 5°C or lower.

Collect the product by filtration. Wash the product with approximately 115 ml cold

methanol. Expected wet weight is approximately 210 g.

It has been determined that the temperature at which the potassium hydroxide is

added to the DA-ACV (or at which DA-ACV is added to KOH) is critically important.

The inventors have determined that the addition must be done at 18° to 22°C if a good

separation of guanine is to be accomplished. EXAMPLE 3

Alternative hydrolysis of DA-ACV to ACV with the formation of ACV-potassium salt

In this procedure, DA-ACV is hydrolyzed in the presence of potassium hydroxide

o form the potassium salt of acyclovir (ACV-K), represented by formula I.

Charge to a two (2) liter round bottom flask equipped with a motor driven stirrer,

reflux condenser, and nitrogen inlet 1000 ml ethanol, absolute (785 g) and 240 g dry DA-

ACV. Begin slow addition of a total of 148 g potassium hydroxide (KOH), 85% pellets.

This addition results in an exothermic reaction. It will be appreciated that the scope ofthe

invention also includes a reverse addition procedure wherein the potassium hydroxide

(KOH) first is added to the 1000 ml of ethanol and the dry DA-ACV is slowly added to the

reaction solution.

The reaction passes through a very viscous stage before becoming an almost

completely transparent, chocolate colored solution. The temperature should ultimately be

at the reflux of 80°C for two hours. When it is confirmed that the reaction is complete,

cool the reaction mixture to <5°C. Collect the product by filtration. Wash the product

ACV-K product, acyclovir potassium enolate, with approximately 200 ml cold 3A ethanol. The expected wet weight of the ACV-K salt is about 219 g. On a dry basis the expected

weight is about 163 g. It is not necessary to dry the wet acyclovir potassium salt. It can be

taken directly to a purification process.

It should be noted that this procedure hydrolyzes the DA-ACV to ACV and forms

the ACV-K salt in one procedure.

EXAMPLE 4 Purification of acyclovir-potassium salt

In this procedure, ACV-K salt is neutralized with acetic acid, treated with carbon

and crystallized from water to form a purified acyclovir product. Charge to a two liter

round bottom flask equipped with a motor-driven stirrer, reflux condenser, and nitrogen inlet 1305 ml deionized water and 163 g ACV-K salt (dry basis). With good stirring,

slowly add approximately 36 g glacial acetic acid (34 ml). This step causes the reaction

mixture to get very viscous, but stirrable. Heat to 98° to 100°C to dissolve the resulting

acyclovir (ACV). At approximately 90°C, take a sample and check the pH. The pH

should be approximately 6.0 to 6.5. If the pH is higher, add glacial acetic acid to bring the

pH into the range of 6.0 to 6.5. Once the pH has been adjusted, add from 4g to lOg

activated charcoal to the reaction mixture. Stir no longer than approximately 15 minutes

to 1 1/2 hours at 98° to 100°C. Filter the hot solution at 98° to 100°C through a steam

jacketed filter to remove the carbon. After the hot filtration, slowly cool to 20° to 25°C

over a 4 to 6 hour period. The liquors should then be cooled to approximately 5°C and

subsequently stirred for 2 to 3 hours to complete the crystallization. Collect the acyclovir

product by filtration. Wash on the filter with about 210 ml cold deionized water. The

expected wet weight ofthe purified AVC product is approximately 220 g. Dry the product

at 70° to 75°C under vacuum. Expected dry weight of purified ACV product is approximately 112 g. The purified ACV product meets the specifications of U.S.P.

XXIII.

It will be appreciated by those skilled in the art that changes or modifications can

be made in the foregoing description and examples without departing from the scope of

the appended claims. Therefore description and examples are intended to be illustrative

only and should not be construed in a limiting sense.

The text of the priority document, United States serial number 60/009,352 (filed

1995 December 28), is incoφorated herein by reference.

Claims

We claim:

1. A compound of the formula:

2. A compound of the formula:

3. A method of preparing a compound of the formula:

comprising the steps of:

hydrolyzing diacetyl-acyclovir to acyclovir in the presence of potassium

hydroxide; and

simultaneously forming a potassium salt of acyclovir.

4. The method of claim 3 wherein the step of hydrolyzing the diacetyl-acyclovir to

acyclovir in the presence of potassium hydroxide further comprises the step of maintaining the reaction temperature at approximately 18° to 22°C.

5. The method of claim 4 wherein the diacetyl-acyclovir is washed with an alcohol prior

to hydrolysis to remove impurities.

6. A method of preparing a compound ofthe formula:

comprising the steps of: adding an alcohol to a vessel;

adding diacetyl-acyclovir to the vessel;

adding potassium hydroxide to the vessel to form a reaction mixture;

keeping the reaction mixture at approximately 18° to 22°C;

heating the reaction mixture;

adding additional potassium hydroxide to the reaction mixture;

stirring the reaction mixture;

adding additional potassium hydroxide to the reaction mixture;

refluxing the reaction mixture;

cooling the reaction mixture;

collecting product by filtration; and

washing the product.

7. The method of claim 6 wherein the step of adding an alcohol to a vessel further

comprises adding an alcohol selected from the group containing ethanol, methanol and a

mixture of ethanol and methanol.

8. The method of claim 7 wherein said alcohol comprises anhydrous methanol.

9. The method of claim 6 wherein the step of adding the potassium hydroxide to the

vessel precedes the step of adding the diacetyl-acyclovir to the vessel.

10. The method of claim 6 wherein the step of adding additional potassium hydroxide to

the reaction mixture is combined with the step of adding potassium hydroxide to the vessel so that all the potassium hydroxide is added in one step.

1 1. A method of preparing substantially purified acyclovir comprising the steps of:

hydrolyzing diacetyl-acyclovir in the presence of potassium hydroxide and

simultaneously forming an acyclovir potassium salt;

maintaining the hydrolysis reaction at approximately 18° to 22°C; and

converting the acyclovir potassium salt to substantially purified acyclovir in the presence of an acid.

12. A method of preparing substantially purified acyclovir comprising the steps of:

alkylating diacetyl-guanine to form diacetyl-acyclovir;

hydrolyzing the diacetyl-acyclovir in the presence of potassium hydroxide to form

an acyclovir potassium salt; and crystallizing the substantially purified acyclovir from water in the presence of an acid.

13. The method of claim 12 further comprising the step of washing the diacetyl-acyclovir

to remove impurities.

14. The method of claim 13 wherein the step of washing the diacetyl-acyclovir to remove

impurities further includes washing the diacetyl-acyclovir with an alcohol.

15. The method of claim 14 wherein the alcohol is selected from the group containing

methanol, blends of methanol and ethanol, and absolute ethanol.

16. The method of claim 14 wherein the alcohol is 3A ethanol.

17. A method of preparing substantially pure acyclovir by:

alkylating diacetyl-guanine with an alkylating agent to form diacetyl-acyclovir;

washing the diacetyl-acyclovir;

hydrolyzing the diacetyl-acyclovir in the presence of potassium hydroxide to

simultaneously form acyclovir potassium salt;

neutralizing the acyclovir potassium salt with an acid to form substantially purified

acyclovir; and

recovering the substantially purified acyclovir.

18. The method of claim 17 wherein the alkylating agent employed in the step of

alkylating diacetyl-guanine to form diacetyl-acyclovir is 2-oxa-l ,4-butanediol diacetate.

19. The method of claim 18 where the step of washing the diacetyl-acyclovir further

comprises washing the diacetyl-acyclovir with an alcohol.

20. The method of claim 19 wherein the alcohol is selected from a group containing

methanol, a blend of methanol and ethanol, and absolute ethanol.

21. The method of claim 19 wherein the alcohol is 3 A ethanol.

22. A method of preparing diacetyl-acyclovir comprising the steps of;

alkylating diacetyl-guanine with 2-oxa-l,4-butanediol diacetate to form diacetyl-

acyclovir; and

washing the diacetyl-acyclovir to remove impurities.

23. The method of claim 22 wherein the step of washing the diacetyl-acyclovir to remove

impurities further includes washing the diacetyl-acyclovir with an alcohol.

24. The method of claim 22 wherein the alcohol is 3 A ethanol.

25. A method of preparing a crystalline diacetyl-acyclovir comprising the steps of:

adding 2-oxa-l ,4 butanediol diacetate to a vessel;

adding methanesulfonic acid to the vessel;

adding diacetyl-guanine to the vessel;

adding toluene to the vessel to form a reaction mixture; heating the reaction mixture;

collecting diacetyl-acyclovir; and

washing the diacetyl-acyclovir.

26. The method of claim 25 wherein the step of washing the diacetyl-acyclovir further comprises washing with an alcohol.

27. The method of claim 26 wherein the alcohol is selected from a group containing methanol, a blend of methanol and ethanol, and absolute ethanol.

28. The method of claim 26 wherein the alcohol is 3A ethanol.