CA1096863A - Improved process for preparing 9-substituted derivatives of guanine and adenine - Google Patents
Improved process for preparing 9-substituted derivatives of guanine and adenineInfo
- Publication number
- CA1096863A CA1096863A CA285,592A CA285592A CA1096863A CA 1096863 A CA1096863 A CA 1096863A CA 285592 A CA285592 A CA 285592A CA 1096863 A CA1096863 A CA 1096863A
- Authority
- CA
- Canada
- Prior art keywords
- hydroxy
- adenine
- formula
- guanine
- amino
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
Abstract
Callada Hungary ABSTRACT
A process for preparing the 9-(2-hydroxyethoxymethyl) derivatives of guanine and 2-amino-adenine comprising hydrolysing in the presence of a base a compound of formula (II) (II) wherein R1 is hydroxy or , and X1 and X2 are the same or different and each represent an alkyl or phenyl group, and R2 is hydrogen or
A process for preparing the 9-(2-hydroxyethoxymethyl) derivatives of guanine and 2-amino-adenine comprising hydrolysing in the presence of a base a compound of formula (II) (II) wherein R1 is hydroxy or , and X1 and X2 are the same or different and each represent an alkyl or phenyl group, and R2 is hydrogen or
Description
This invention relates to a method of synthesising substituted purine compounds in particular 9-(2-hydrGxy-ethoxymethyl) derivatives of the purines 2-amino-adenine and guanine.
9-(2-Hydroxyethoxymethyl)derivatives of purines have antiviral activity against various classes of D~A and RNA viruses both 1n vitro and ln vivo experiments. In parti-cular these compounds are active as antiviral ~gents against adenovirus, such as adenovirus 5 and rhinovirus. They are especially active as an antiviral agent against vaccinia and herpes viruses, including simplex, zoster and varicella, in mammals, which viruses cause such diseases as herpetic keratitis in rabbits and herpetic encephalitis in mice.
Examples of 9-(2-hydroxyethoxymethyl)derivatives of purines showing particularly good antiviral activity are 9-(2-hydroxyethoxymethyl)guanine and 2-amino-9~(2-hydroxy-ethoxymethyl) adenine.
A number of methods of synthesis are known for 9-(2-hydroxyethoxymethyl) derivatives of purine, for example they may be prepared by the removal of a protective group from the 2 position on the side chain. Alternatively they can be formed by the conversion of the 2 and/or 6 substituent on the purine ring into a different substituent (see Canadian Patent 1,062,257, Howard J~ Schaeffer, issued September 11, 1979).
~q6~63 It has no;~ been found that certain 9-(2-hydroxy-ethoxymethyl) derivatives of purines can be prepared by a new and advantageous synthetic route Thus, according to the present invention there is provided a process for pre-paring compounds of formula (I):
R
~ N
N
CH2~o cH2~cH2~OH
whPrein R is amlno or hydroxy, comprising hydrolysing in the presence of a base a compound of formula (II) X -C-~R ~ o (II) ~ 2 wherein Rl is hydroxy or _NR2.C.Xl, and Xl and x2 are the O
same or different and each represents an alkyl or phenyl group, and R2 is hydrogen or -CXl provided that when is hydroxy, R is hydrogen~ When Xl and x2 are alkyl groups they preferably have 1 to 4 carbon atoms, most preferably they are the same and each represent a methyl ; ~ group.
~: :
, ' ' : , ,- ,' :.
-1(~46863 The base used in the hydrolysis m~y be anaqueous or alcoholic primary or secondary aliphatic amine, an alko~ide in alcohol, or an aqueous or alcoholic hydroxide, for example, sodium alkoxide or hydroxide, the preferred base being an aqueous primary aliphatic amine for example aqueous methylamine. Depending on the base used, the hydrolysis can be carried out at a temperature from room temperature up to that of a steam bath. In general the lower the reaction temperature, the longer the reaction time but the fewer the side reactions.
An intermediate of formula (II), in which Rl i9 -~R2CXl, and R is -IXl, may be completely hydrolysed in O. O
~- one step using for example a~ueous methylamine. Alter-natively, and more preferably, the intermediate of formula (II) is deacylated in 2-steps: in the first step a single C-Xl group is removed from the 2 and 6-positions on the purine ring~by mild hydrolysis at room temperature using for ~example butylamine in a lower alcohol. The second step~of the hydrolysis,~;to remove the remaining -C-X
O
20~ ~groups,~is carried out uslng a stronger base such as aqyeous methy1amlre.
.
~96863 The intermediates of formula (II) are novel, and therefore according to a second aspect of the invention there is provided intermediate compounds of formula (II) as defined above. These compounds ran be prepared by reacting guanine, or 2-amino ~denine in which the 2 and 9, or 2, 6 and 9 positions respectively are acylated, with a diester or, 2-oxa-1,4-butanediol in the presence of a catalytic amount of a strong acid such as sulphuric acid, sulphonic acids, SUC~ as E~toluene-sulphonic, methanesulphonic or trifluoromethanesulphonic acid, sulphamic acid or polyphosphoric acid.-The acylated purine may in turn be preparedby reacting the appropriate purine with an acid anhydride - ~ such as acetic anhydride, or other acylating agent for examplè an acid halide.
To p~epare the diester of 2-oxa-1,4-butane-diol, dioxolane is reacted with an acid anhydride in the presence of a catalytic amount of a strong acid such as one of those acids Iisted above.
20 ~ ~ The invention will now ~e illustrated with ~ reference to the following examples.
t~
~:
~'~...................... ' :
~; ' '. ' ', . . .
''''' ' , ' ' ' ~C~96863 - 9-(2-Hydroxyethoxymethyl)quanine To a mixture of acetic anhydride (102 g), acetic acid (15 g), and ~-toluenesulfonic acid (5.0 g) cooled to 10C, dioxolane (70 g) was added with stirring and cooling at such a rate that the pot temperature never exceeded 40c. The mixture was then cooled to room temperature and toluene (300 ml) and diacetylguanine (50 g) added. The reaction mixture was then heated at reflux with stirring for 16 hours. It was then cooled to room temperature, chloroform (50 ml3 was added and the solid product removed by filtration. The filter cake was thoroughly washed with chloroform and dried.
The dried filter cake was added to 40/0 aqueous methyl-amine (350 ml) and the mixture was heated at reflux with stirring for 40 minutes, cooled and filtered. The filtrate was evaporated under reduced pressure to a thick slurry. The slurry was cooled and filtered, and the filter cake was washed with ethanol and dried to give 9-(2-hydroxyethoxymethyl)guanine (27 g, greater than 9G% pure), m.pt. 255-257C. yield = 56%.
9-(2-Hydroxyethoxymethyl)~uanine A mixture of diacetylguanine (50 g), 2-oxa-1,4-butanediol diacetate (59.8 g), and ~-toluene sulfonic acid (1.2 g) in toluene (350 ml) was heated with stirring at reflux for 16 hours. The mixture was cooled to room temperature, filtered and the filter cake thoroughly washed with toluene. The filter cake was dried and added to 4~/O aqueous methylamine (350 ml~. The mixture was heated at reflux with stirring or 40 minutes, cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to give a thick slurry. Ethanol (200 ml) was added to the slurry which was then cooled, filtered, washed with ethanol and dried .~
to give 9-(2-hydroxyethoxymethyl)guanine (36 g, greater than~9~/O pure), yield = 75%.
9-(2-Hydroxyethoxymethyl)derivatives of purines have antiviral activity against various classes of D~A and RNA viruses both 1n vitro and ln vivo experiments. In parti-cular these compounds are active as antiviral ~gents against adenovirus, such as adenovirus 5 and rhinovirus. They are especially active as an antiviral agent against vaccinia and herpes viruses, including simplex, zoster and varicella, in mammals, which viruses cause such diseases as herpetic keratitis in rabbits and herpetic encephalitis in mice.
Examples of 9-(2-hydroxyethoxymethyl)derivatives of purines showing particularly good antiviral activity are 9-(2-hydroxyethoxymethyl)guanine and 2-amino-9~(2-hydroxy-ethoxymethyl) adenine.
A number of methods of synthesis are known for 9-(2-hydroxyethoxymethyl) derivatives of purine, for example they may be prepared by the removal of a protective group from the 2 position on the side chain. Alternatively they can be formed by the conversion of the 2 and/or 6 substituent on the purine ring into a different substituent (see Canadian Patent 1,062,257, Howard J~ Schaeffer, issued September 11, 1979).
~q6~63 It has no;~ been found that certain 9-(2-hydroxy-ethoxymethyl) derivatives of purines can be prepared by a new and advantageous synthetic route Thus, according to the present invention there is provided a process for pre-paring compounds of formula (I):
R
~ N
N
CH2~o cH2~cH2~OH
whPrein R is amlno or hydroxy, comprising hydrolysing in the presence of a base a compound of formula (II) X -C-~R ~ o (II) ~ 2 wherein Rl is hydroxy or _NR2.C.Xl, and Xl and x2 are the O
same or different and each represents an alkyl or phenyl group, and R2 is hydrogen or -CXl provided that when is hydroxy, R is hydrogen~ When Xl and x2 are alkyl groups they preferably have 1 to 4 carbon atoms, most preferably they are the same and each represent a methyl ; ~ group.
~: :
, ' ' : , ,- ,' :.
-1(~46863 The base used in the hydrolysis m~y be anaqueous or alcoholic primary or secondary aliphatic amine, an alko~ide in alcohol, or an aqueous or alcoholic hydroxide, for example, sodium alkoxide or hydroxide, the preferred base being an aqueous primary aliphatic amine for example aqueous methylamine. Depending on the base used, the hydrolysis can be carried out at a temperature from room temperature up to that of a steam bath. In general the lower the reaction temperature, the longer the reaction time but the fewer the side reactions.
An intermediate of formula (II), in which Rl i9 -~R2CXl, and R is -IXl, may be completely hydrolysed in O. O
~- one step using for example a~ueous methylamine. Alter-natively, and more preferably, the intermediate of formula (II) is deacylated in 2-steps: in the first step a single C-Xl group is removed from the 2 and 6-positions on the purine ring~by mild hydrolysis at room temperature using for ~example butylamine in a lower alcohol. The second step~of the hydrolysis,~;to remove the remaining -C-X
O
20~ ~groups,~is carried out uslng a stronger base such as aqyeous methy1amlre.
.
~96863 The intermediates of formula (II) are novel, and therefore according to a second aspect of the invention there is provided intermediate compounds of formula (II) as defined above. These compounds ran be prepared by reacting guanine, or 2-amino ~denine in which the 2 and 9, or 2, 6 and 9 positions respectively are acylated, with a diester or, 2-oxa-1,4-butanediol in the presence of a catalytic amount of a strong acid such as sulphuric acid, sulphonic acids, SUC~ as E~toluene-sulphonic, methanesulphonic or trifluoromethanesulphonic acid, sulphamic acid or polyphosphoric acid.-The acylated purine may in turn be preparedby reacting the appropriate purine with an acid anhydride - ~ such as acetic anhydride, or other acylating agent for examplè an acid halide.
To p~epare the diester of 2-oxa-1,4-butane-diol, dioxolane is reacted with an acid anhydride in the presence of a catalytic amount of a strong acid such as one of those acids Iisted above.
20 ~ ~ The invention will now ~e illustrated with ~ reference to the following examples.
t~
~:
~'~...................... ' :
~; ' '. ' ', . . .
''''' ' , ' ' ' ~C~96863 - 9-(2-Hydroxyethoxymethyl)quanine To a mixture of acetic anhydride (102 g), acetic acid (15 g), and ~-toluenesulfonic acid (5.0 g) cooled to 10C, dioxolane (70 g) was added with stirring and cooling at such a rate that the pot temperature never exceeded 40c. The mixture was then cooled to room temperature and toluene (300 ml) and diacetylguanine (50 g) added. The reaction mixture was then heated at reflux with stirring for 16 hours. It was then cooled to room temperature, chloroform (50 ml3 was added and the solid product removed by filtration. The filter cake was thoroughly washed with chloroform and dried.
The dried filter cake was added to 40/0 aqueous methyl-amine (350 ml) and the mixture was heated at reflux with stirring for 40 minutes, cooled and filtered. The filtrate was evaporated under reduced pressure to a thick slurry. The slurry was cooled and filtered, and the filter cake was washed with ethanol and dried to give 9-(2-hydroxyethoxymethyl)guanine (27 g, greater than 9G% pure), m.pt. 255-257C. yield = 56%.
9-(2-Hydroxyethoxymethyl)~uanine A mixture of diacetylguanine (50 g), 2-oxa-1,4-butanediol diacetate (59.8 g), and ~-toluene sulfonic acid (1.2 g) in toluene (350 ml) was heated with stirring at reflux for 16 hours. The mixture was cooled to room temperature, filtered and the filter cake thoroughly washed with toluene. The filter cake was dried and added to 4~/O aqueous methylamine (350 ml~. The mixture was heated at reflux with stirring or 40 minutes, cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure to give a thick slurry. Ethanol (200 ml) was added to the slurry which was then cooled, filtered, washed with ethanol and dried .~
to give 9-(2-hydroxyethoxymethyl)guanine (36 g, greater than~9~/O pure), yield = 75%.
2-Acetam}do-9-(2-acetylo ~ethoxyme~thyl)hypoxanthine A mixture of diacetylguanine (1.0 g), 2-oxa-1,4-~ butanediol diacetate (0.82 g) and E~toluenesulfonic acid (23 mg)~in mlneral o11 (4 g) was~heated at llSC with 9tirring~at reduced pressure overnight. The mineral oil ;was~decanted off. ~The residue was triturated with chloro-form: and~ then extracted with boiling methanol. The methanol~extract was concentrated to~50 ml, chilled, and ~iltered.~The filtrate w~as evaporated to dryness, giving a solid~residue (0.43 g). `The solid was purified by :''' ~ ' ' - ~ ' ' ~ -' :
:
: '- , , '15~C'6863 column chromatography (silica gel, 10 g, in chloroform, eluted with 1:1 chloroform:acetone) followed by recrystallisation from ethanol to give 2-acetamido-9-(2-acetyloxyethoxymethyl)hypoxanthine (0.14 g), m.p.
202.5-204.5C.
2-Amino-9-(2-hydroxyethoxymethyl)adenine (a) 2-Formamido adenine (89.0 g) was placed in a 5-liter flask equipped with an air-stirrer and reflux condenser (CaC12 drying tube), to which acetic anhydride (4 1) were added. The mixture was brought to reflux and held for 60 hour~. At the end of this time, the :
excess anhydride was removed by distillation at atmospheric pressure until approximately 3.5 1. of distillate had been obtained. The distillation was continued under reduced pressure to remove most of the remaining anhydride. The dark brown pot residue became a viscous gummy mass upon coollng to room temperature and was then d1ssolved in~dichloromethane, filtered to remove any suspended solids,~and the soLvent removed ln vacuo to give ~211;.0 g (> 10~/o) of 2,6-bis-(dlacetylamino)-9-acetyl purine.;~The ~assayed yield wss 96.7% based upon the~ nmr ~with the~balance of the material being acetic 3nhydride.~
' `~ ' : ' ~ - . . : : -~ : ' .
(b) The ~enta-acetyl p~rine (174 g) was combined with 1,4-diacetoxy-2-oxabutane (126.8 g) in a flask equipped with an air-stirrer and drying tube. This mixture was then placed in an oil bath at 130C and stirred for a few minutes to homogenize the batch. The acid catalyst, para toluenesulphonic acid (2.74 g), was then added in one portion and heating was continued _ vacuo for 4 hours at which time nearly quantitative conversion to products was observed. The reaction mixture was then cooled to room temperature and stored under dry nitrogen. I
(c) The fusion product (208.5 ~) was dissolved in ethanol (5 ml/g) at room temperature and transferred to flask equipped with a dropping funnel, air-stirrer, and thermometer. The n-butylamine (140.4 g) was then added dropwise over a 2 hour period and the exothermic reaction was controlled with the use of a water bath. The maximum temperature which the reaction was allowed to reach being only 30C. The product began to separate from the reaction mixture during the course of the addition.
After completion of the addition, the mixture was stirred at room temperature for 3 hours and then placed in the cold room overnight. The product was removed by filtration to give a pasty mass which was slurried with acetone (1 x 500 ml) and refiltered. This was dried ln vacuo at 65C for 3 hours and then at room temperature overnight to give 154.2 g (91.P/o) of a light brown hard solid.
The product was purified by dissolving it in hot dimethyl-formamide (10 ml/g) at 100-110C to give an opaque brown solution. After cooling overnight at 5C, the product was removed by filtration, washed with acetone (1 x 250 ml) and air dried to give 121.7 g (78.~/o) of 2,~-di-acetamido-9-(2-acetoxyethoxymethyl)purine.
(d) The 2,6-diacetamido-9-(2-acetoxyethoxymethyl)- -purine (121.7 g) was added to a stirred solution of aqueous methylamine (608.5 ml of 4~/O solution) over a 5-minute period. The addition was accompanied by a mild exotherm which raised the temperature of the mixture to 35C and all of the solid material dissolved in a few minutes.
After stirring for 2-1/2 hours the tlc of the mixture indicated completion of the reaction. The mixture was then concentrated ln vacuo on a water ~ath at 45 50C to give a thick mass of brown crystals. This was then slurried with acetone (545 ml, 7 ml/g) for 15 minutes to remove N-methyl acetamide and vacuum filtered. The cake was rinsed with acetone (1 x 200 ml) and air-dried to give 74.7 g (96.0%) of crude, hydrated 2-amino-9-(2-hydroxyethoxymethyl)adenine as light brown crystals.
mese were dried in vacuo at 80C for 18 hours to give 69.3 g. (39.~) of dry pr duct.
:
: '- , , '15~C'6863 column chromatography (silica gel, 10 g, in chloroform, eluted with 1:1 chloroform:acetone) followed by recrystallisation from ethanol to give 2-acetamido-9-(2-acetyloxyethoxymethyl)hypoxanthine (0.14 g), m.p.
202.5-204.5C.
2-Amino-9-(2-hydroxyethoxymethyl)adenine (a) 2-Formamido adenine (89.0 g) was placed in a 5-liter flask equipped with an air-stirrer and reflux condenser (CaC12 drying tube), to which acetic anhydride (4 1) were added. The mixture was brought to reflux and held for 60 hour~. At the end of this time, the :
excess anhydride was removed by distillation at atmospheric pressure until approximately 3.5 1. of distillate had been obtained. The distillation was continued under reduced pressure to remove most of the remaining anhydride. The dark brown pot residue became a viscous gummy mass upon coollng to room temperature and was then d1ssolved in~dichloromethane, filtered to remove any suspended solids,~and the soLvent removed ln vacuo to give ~211;.0 g (> 10~/o) of 2,6-bis-(dlacetylamino)-9-acetyl purine.;~The ~assayed yield wss 96.7% based upon the~ nmr ~with the~balance of the material being acetic 3nhydride.~
' `~ ' : ' ~ - . . : : -~ : ' .
(b) The ~enta-acetyl p~rine (174 g) was combined with 1,4-diacetoxy-2-oxabutane (126.8 g) in a flask equipped with an air-stirrer and drying tube. This mixture was then placed in an oil bath at 130C and stirred for a few minutes to homogenize the batch. The acid catalyst, para toluenesulphonic acid (2.74 g), was then added in one portion and heating was continued _ vacuo for 4 hours at which time nearly quantitative conversion to products was observed. The reaction mixture was then cooled to room temperature and stored under dry nitrogen. I
(c) The fusion product (208.5 ~) was dissolved in ethanol (5 ml/g) at room temperature and transferred to flask equipped with a dropping funnel, air-stirrer, and thermometer. The n-butylamine (140.4 g) was then added dropwise over a 2 hour period and the exothermic reaction was controlled with the use of a water bath. The maximum temperature which the reaction was allowed to reach being only 30C. The product began to separate from the reaction mixture during the course of the addition.
After completion of the addition, the mixture was stirred at room temperature for 3 hours and then placed in the cold room overnight. The product was removed by filtration to give a pasty mass which was slurried with acetone (1 x 500 ml) and refiltered. This was dried ln vacuo at 65C for 3 hours and then at room temperature overnight to give 154.2 g (91.P/o) of a light brown hard solid.
The product was purified by dissolving it in hot dimethyl-formamide (10 ml/g) at 100-110C to give an opaque brown solution. After cooling overnight at 5C, the product was removed by filtration, washed with acetone (1 x 250 ml) and air dried to give 121.7 g (78.~/o) of 2,~-di-acetamido-9-(2-acetoxyethoxymethyl)purine.
(d) The 2,6-diacetamido-9-(2-acetoxyethoxymethyl)- -purine (121.7 g) was added to a stirred solution of aqueous methylamine (608.5 ml of 4~/O solution) over a 5-minute period. The addition was accompanied by a mild exotherm which raised the temperature of the mixture to 35C and all of the solid material dissolved in a few minutes.
After stirring for 2-1/2 hours the tlc of the mixture indicated completion of the reaction. The mixture was then concentrated ln vacuo on a water ~ath at 45 50C to give a thick mass of brown crystals. This was then slurried with acetone (545 ml, 7 ml/g) for 15 minutes to remove N-methyl acetamide and vacuum filtered. The cake was rinsed with acetone (1 x 200 ml) and air-dried to give 74.7 g (96.0%) of crude, hydrated 2-amino-9-(2-hydroxyethoxymethyl)adenine as light brown crystals.
mese were dried in vacuo at 80C for 18 hours to give 69.3 g. (39.~) of dry pr duct.
Claims (8)
1. A process for preparing compounds of formula (I) (I) wherein R is amino or hydroxy, comprising hydrolysing in the presence of a base a compound of formula (II) (II) wherein R1 is hydroxy or , and X1 and X2 are the same or different and each represents an alkyl or phenyl group, and R2 is hydrogen or provided that when R1 is hydroxy, R2 is hydrogen.
2. A process as claimed in claim 1, wherein the alkyl group contains from 1 to 4 carbon atoms.
3. A process as claimed in claim 1, wherein X1 and X2 are both methyl groups.
4. A process as claimed in claim 1, 2 or 3, wherein the base is an aqueous or alcoholic primary or secondary aliphatic amine, an alkoxide in alcohol or aqueous or alcoholic hydroxide.
5. A process as claimed in claim 1, wherein the compound of formula (II) has been prepared by reacting guanine, or 2-amino adenine in which the 2 and 9, or 2, 6 and 9 positions respectively are acylated, with a diester of 2-oxa-1,4-butanediol in the presence of a catalytic amount of a strong acid.
6. A process as claimed in claim 5, wherein the acid catalyst is p-toluenesulphonic acid.
7. A process as claimed in claim 1, 2 or 3, in which R is hydroxy.
8. A process as claimed in claim 1, 2 or 3, in which R is amino.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US71810576A | 1976-08-27 | 1976-08-27 | |
| US718,105 | 1976-08-27 | ||
| US05/773,135 US4146715A (en) | 1975-08-27 | 1977-02-28 | 2-amido-9-(2-acyloxyethoxymethyl)hypoxanthines |
| US773,135 | 1977-02-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1096863A true CA1096863A (en) | 1981-03-03 |
Family
ID=27109837
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA285,592A Expired CA1096863A (en) | 1976-08-27 | 1977-08-26 | Improved process for preparing 9-substituted derivatives of guanine and adenine |
| CA354,538A Expired CA1096864A (en) | 1976-08-27 | 1980-06-20 | Intermediates for the preparation of derivatives of guanine and adenine |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA354,538A Expired CA1096864A (en) | 1976-08-27 | 1980-06-20 | Intermediates for the preparation of derivatives of guanine and adenine |
Country Status (12)
| Country | Link |
|---|---|
| AT (1) | AT357566B (en) |
| CA (2) | CA1096863A (en) |
| CH (1) | CH634843A5 (en) |
| CS (1) | CS196384B2 (en) |
| DD (1) | DD131856A6 (en) |
| DK (1) | DK147857C (en) |
| FI (1) | FI64160C (en) |
| GB (1) | GB1567671A (en) |
| NL (1) | NL7709458A (en) |
| NO (2) | NO147186C (en) |
| SE (2) | SE432764B (en) |
| YU (1) | YU41079B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4880820A (en) * | 1983-06-24 | 1989-11-14 | Merck & Co., Inc. | Guanine derivatives |
| IE842642L (en) * | 1983-10-31 | 1985-04-30 | Harvard College | Purine Derivatives |
| US4918219A (en) * | 1983-10-31 | 1990-04-17 | Warner-Lambert Company | Glycerine derivatives |
| YU45690B (en) * | 1984-12-22 | 1992-07-20 | Krka Tovarna Zdraviln.Sol.O. | PROCEDURE FOR PREPARING 9- (2-HYDROXYETHOXYMETHYL) -GUANINE |
| EP0564006A3 (en) * | 1987-05-04 | 1993-12-15 | Krka Tovarna Zdravil | Process for preparing purine derivatives and novel purine derivatives |
| US5756737A (en) * | 1993-09-10 | 1998-05-26 | Recordati S.A. Chemical And Pharmaceutical Company | Process for the preparation of 9-(2-hydroxy)-ethoxymethyl-guanine |
| DE19536164A1 (en) * | 1995-09-28 | 1997-04-03 | Boehringer Ingelheim Kg | Improved Process for the Production of 9 - [(2-Hydroxyethoxy) methyl] guanine (Acyclovir) |
| IT1276126B1 (en) * | 1995-11-14 | 1997-10-27 | Archimica Spa | PROCEDURE FOR THE PREPARATION OF 9 - ((2-HYDROXYETHOXY) METHYL) GUANINE |
| WO1997024357A1 (en) * | 1995-12-28 | 1997-07-10 | Mallinckrodt Chemical, Inc. | Process for synthesis and purification of a compound useful in the preparation of acyclovir |
-
1977
- 1977-08-24 YU YU2022/77A patent/YU41079B/en unknown
- 1977-08-26 NL NL7709458A patent/NL7709458A/en active Search and Examination
- 1977-08-26 AT AT620177A patent/AT357566B/en not_active IP Right Cessation
- 1977-08-26 NO NO772959A patent/NO147186C/en unknown
- 1977-08-26 CH CH1046677A patent/CH634843A5/en not_active IP Right Cessation
- 1977-08-26 CS CS775615A patent/CS196384B2/en unknown
- 1977-08-26 FI FI772548A patent/FI64160C/en not_active IP Right Cessation
- 1977-08-26 DK DK380377A patent/DK147857C/en not_active IP Right Cessation
- 1977-08-26 GB GB35914/77A patent/GB1567671A/en not_active Expired
- 1977-08-26 CA CA285,592A patent/CA1096863A/en not_active Expired
- 1977-08-26 DD DD7700200760A patent/DD131856A6/en not_active IP Right Cessation
- 1977-08-26 SE SE7709606A patent/SE432764B/en not_active IP Right Cessation
-
1980
- 1980-06-20 CA CA354,538A patent/CA1096864A/en not_active Expired
-
1982
- 1982-07-20 NO NO822502A patent/NO150119C/en unknown
-
1983
- 1983-08-23 SE SE8304549A patent/SE447113B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| GB1567671A (en) | 1980-05-21 |
| SE432764B (en) | 1984-04-16 |
| YU41079B (en) | 1986-12-31 |
| NO147186B (en) | 1982-11-08 |
| DK380377A (en) | 1978-02-28 |
| CS196384B2 (en) | 1980-03-31 |
| NO150119C (en) | 1984-08-22 |
| ATA620177A (en) | 1979-12-15 |
| NO772959L (en) | 1978-02-28 |
| DD131856A6 (en) | 1978-07-26 |
| YU202277A (en) | 1983-02-28 |
| DK147857B (en) | 1984-12-24 |
| CH634843A5 (en) | 1983-02-28 |
| NO822502L (en) | 1978-02-28 |
| FI772548A (en) | 1978-02-28 |
| NL7709458A (en) | 1978-03-01 |
| NO150119B (en) | 1984-05-14 |
| SE8304549L (en) | 1983-08-23 |
| SE7709606L (en) | 1978-02-28 |
| NO147186C (en) | 1983-02-16 |
| SE8304549D0 (en) | 1983-08-23 |
| SE447113B (en) | 1986-10-27 |
| CA1096864A (en) | 1981-03-03 |
| FI64160B (en) | 1983-06-30 |
| FI64160C (en) | 1983-10-10 |
| AT357566B (en) | 1980-07-25 |
| DK147857C (en) | 1985-06-10 |
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