EP1565469A1 - Process for the synthesis of ganciclovir - Google Patents
Process for the synthesis of ganciclovirInfo
- Publication number
- EP1565469A1 EP1565469A1 EP02785726A EP02785726A EP1565469A1 EP 1565469 A1 EP1565469 A1 EP 1565469A1 EP 02785726 A EP02785726 A EP 02785726A EP 02785726 A EP02785726 A EP 02785726A EP 1565469 A1 EP1565469 A1 EP 1565469A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- solvent
- formula
- isomer
- mixtures
- methanol
- 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.)
- Withdrawn
Links
- 238000000034 method Methods 0.000 title claims abstract description 35
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 title claims abstract description 12
- 229960002963 ganciclovir Drugs 0.000 title claims abstract description 11
- 230000015572 biosynthetic process Effects 0.000 title abstract description 6
- 238000003786 synthesis reaction Methods 0.000 title abstract description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 54
- 239000002904 solvent Substances 0.000 claims description 33
- 239000000203 mixture Substances 0.000 claims description 25
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 24
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 21
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 18
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 9
- 238000000926 separation method Methods 0.000 claims description 9
- 230000001476 alcoholic effect Effects 0.000 claims description 8
- 238000005804 alkylation reaction Methods 0.000 claims description 8
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 7
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 6
- ZXEKIIBDNHEJCQ-UHFFFAOYSA-N isobutanol Chemical compound CC(C)CO ZXEKIIBDNHEJCQ-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims description 6
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 claims description 5
- DUOPMEBLLUYTNT-UHFFFAOYSA-N [3-acetyloxy-2-(acetyloxymethoxy)propyl] acetate Chemical compound CC(=O)OCOC(COC(C)=O)COC(C)=O DUOPMEBLLUYTNT-UHFFFAOYSA-N 0.000 claims description 5
- QNXFUWFRTWSSOK-UHFFFAOYSA-N n-acetyl-n-(6-oxo-3,7-dihydropurin-2-yl)acetamide Chemical compound O=C1NC(N(C(C)=O)C(=O)C)=NC2=C1NC=N2 QNXFUWFRTWSSOK-UHFFFAOYSA-N 0.000 claims description 5
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 3
- 150000004945 aromatic hydrocarbons Chemical class 0.000 claims description 3
- 150000008280 chlorinated hydrocarbons Chemical class 0.000 claims description 3
- 239000008096 xylene Substances 0.000 claims description 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 150000003138 primary alcohols Chemical class 0.000 claims description 2
- 150000003333 secondary alcohols Chemical class 0.000 claims description 2
- 150000003509 tertiary alcohols Chemical class 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims 3
- DALDUXIBIKGWTK-UHFFFAOYSA-N benzene;toluene Chemical compound C1=CC=CC=C1.CC1=CC=CC=C1 DALDUXIBIKGWTK-UHFFFAOYSA-N 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 230000000840 anti-viral effect Effects 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- 238000006243 chemical reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 9
- 239000006188 syrup Substances 0.000 description 8
- 235000020357 syrup Nutrition 0.000 description 8
- BCRWSSRKKWYTIB-UHFFFAOYSA-N [2-[(2-acetamido-6-oxo-3h-purin-7-yl)methoxy]-3-acetyloxypropyl] acetate Chemical compound O=C1NC(NC(=O)C)=NC2=C1N(COC(COC(C)=O)COC(C)=O)C=N2 BCRWSSRKKWYTIB-UHFFFAOYSA-N 0.000 description 6
- 230000029936 alkylation Effects 0.000 description 6
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 6
- 239000000243 solution Substances 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 238000003756 stirring Methods 0.000 description 3
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 2
- 229960004150 aciclovir Drugs 0.000 description 2
- 239000003377 acid catalyst Substances 0.000 description 2
- 229940100198 alkylating agent Drugs 0.000 description 2
- 239000002168 alkylating agent Substances 0.000 description 2
- 238000013375 chromatographic separation Methods 0.000 description 2
- 239000002777 nucleoside Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 238000004064 recycling Methods 0.000 description 2
- XFEQOLXBMLXKDE-UHFFFAOYSA-N 2-(acetyloxymethoxy)ethyl acetate Chemical compound CC(=O)OCCOCOC(C)=O XFEQOLXBMLXKDE-UHFFFAOYSA-N 0.000 description 1
- WJSVJNDMOQTICG-UHFFFAOYSA-N 2-amino-1-[(2-methyl-4-methylidene-5-oxooxolan-2-yl)methyl]-7h-purin-6-one Chemical compound NC1=NC=2N=CNC=2C(=O)N1CC1(C)CC(=C)C(=O)O1 WJSVJNDMOQTICG-UHFFFAOYSA-N 0.000 description 1
- 150000005019 2-aminopurines Chemical class 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- QSJXEFYPDANLFS-UHFFFAOYSA-N Diacetyl Chemical group CC(=O)C(C)=O QSJXEFYPDANLFS-UHFFFAOYSA-N 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- ZLFNQSRIHJUJHR-UHFFFAOYSA-N [3-phenylmethoxy-2-(phenylmethoxymethoxy)propyl] acetate Chemical compound C=1C=CC=CC=1COCOC(COC(=O)C)COCC1=CC=CC=C1 ZLFNQSRIHJUJHR-UHFFFAOYSA-N 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 125000003835 nucleoside group Chemical group 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
Definitions
- the present invention relates to an industrial useful process for the synthesis of antiviral compound, ganciclovir.
- Ganciclovir is chemically, 9-(1 ,3-dihydroxy-2-propoxymethyl) guanine and has the structural formula I
- N-9 substituted guanine compounds involve the direct alkylation of appropriately substituted 2- aminopurines e.g. guanine derivatives.
- the major drawback in this process is that it always results in a mixture of N-9 and N-7 alkylation products. Since alkylation of guanine derivatives like diacetyl / monoacetyl guanine is a thermodynamically controlled reaction, N-7 isomer is always formed. However, the N-9 isomer being thermodynamically more stable is produced as the major product. The unwanted N-7 isomer is difficult to separate from the desired N-9 isomer and is generally purified by costly and tedious processes requiring chromatographic separation and are highly undesirable on a commercial scale.
- U.S. Patent No. 5,821 ,367 describes a regiospecific process which comprises reacting protected guanine derivative with an alkylating agent selected from 2-oxa-1 ,4-butanediol diacetate, 1-4-diacetoxy- 3-acetoxymethyl-2-oxa-butane, and 1 ,4-dibenzyloxy-3-acetoxymethyl-2- oxabutane in the absence of solvent or any acid catalyst to obtain the penultimate intermediates which are then converted to acylic nucleosides (acyclovir and ganciclovir).
- U.S. Patent No. 6,043,364 teaches a process for the conversion of N-7 isomer to N-9 isomer by heating a suspension of the N-7 isomer in an alkylating agent.
- the crystallization procedure of the present invention is very simple and produces the N-9 isomer having more than 95% purity which can directly be used for the preparation of ganciclovir.
- the present process is cost effective and obviates the need for chromatographic separation.
- the N-7 isomer so separated is recycled in the next batch of alkylation. It has been observed that the recycling of the N-7 isomer during alkylation enhances the formation of N-9 isomer and decreases the formation of N-7 isomer in the subsequent batches. This recycling of the side product improves the overall yield of the N-9 isomer and consequently the desired product i.e. ganciclovir.
- the present invention provides a process which does not require discarding the unwanted N-7 isomer or an additional step of conversion of the N-
- the present invention provides a process for the separation of N-7 and N-9 isomers of structural formulae II and III, respectively,
- FORMULA III which comprises dissolving a mixture comprising the N-7 and N-9 isomers in an organic solvent, or a mixture of organic solvents, and isolating the N-7 and N-9 isomers from a solution thereof.
- N-7 and N-9 isomers are structural formulae II and III.
- solubilities one of them being consistently more soluble than the other.
- the levels of solubility vary according to the solvent, and so a solvent system will desirably be chosen which allows a practical recovery of the two isomers that is present prior to the separation.
- the solvent system from which the isomers may be separated will desirably be selected from alcoholic solvents, which include lower alkanols, water-immiscible solvents, or a mixture thereof.
- the N-7 isomer of structural formula II will preferably be separated from the solvent system which has at least one lower alkanol.
- the lower alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms, for example, methanol, ethanol, n- propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, tertiary butanol, or mixtures thereof. Most preferred being methanol, ethanol, or isopropyl alcohol.
- the N-9 isomer of structural formula III will preferably be separated from a solvent system which in addition to alcoholic solvents may contain water- immiscible solvents which include aromatic hydrocarbons such as benzene, toluene, or xylene, and chlorinated hydrocarbons such as chloroform, dichloromethane, or 1 ,2-dichloroethane.
- alcoholic solvents may contain water- immiscible solvents which include aromatic hydrocarbons such as benzene, toluene, or xylene, and chlorinated hydrocarbons such as chloroform, dichloromethane, or 1 ,2-dichloroethane.
- the concentration of the filtrate containing the N-9 isomer is adjusted by evaporation of the solvent or by dilution.
- the separation may comprise the last stage or stages of a reaction in which the mixture of N-7 and N-9 isomers is formed.
- the reaction in which ganciclovir of the structural formula I, is formed will preferably be an alkylation reaction carried out in the manner described in US Patent No. 4,355,032 which is incorporated herein by reference.
- the solution containing the mixture of N-7 and N-9 isomers may be heated for dissolution, or it may be cooled to separate out the product or the slurry may further be cooled prior to filtration.
- N-7 isomer of structural formula II so separated is used in the next batch of alkylation. Accordingly, a mixture of diacetyl guanine of Formula IV
- N-7 N 2 -acetyl-7(1 ,3-diacetoxy-2- propoxymethyl) guanine
- the N-7 isomer N 2 -acetyl-7(1 ,3-diacetoxy-2- propoxymethyl) guanine
- the solvent is removed under vacuum to yield a dark oil from which N-7 and N-9 isomers are separated in accordance with the process of the present invention and N-7 isomer is again recycled.
- the N-9 isomer so obtained after separation is hydrolyzed to yield ganciclovir by the methods known in the literature (J.E. Martin et. al., J. Med. Chem., 1983, 26, 759-61).
- a mixture of diacetyl guanine (25g, 0.106mole), 2-acetoxymethoxy-1 ,3- diacetoxy propane (40. Og, 0.161 mole), p-toluene sulfonic acid monohydrate (0.5g) in N,N-dimethylformamide (75ml) is heated at 95°C to 100°C under continuous stirring for 42 hours. After completion of the reaction, the solvents are removed under vacuum yielding a dark brown syrup.
- the syrup is dissolved by heating in methanol (400ml). The solution is cooled to 0°C, stirred for 1 hour at 0 to 5°C. The crystalline product is filtered and washed with methanol (50ml) to yield N 2 -acetyl-7-(1 ,3-diacetoxy-2- propoxymethyl) guanine (54.1g). Solvent is removed completely from the filtrate and methanol (100ml) and toluene (800ml) were added to the residue and the mixture is heated to 60°C and then cooled to 5°C and stirred for 30 minutes.
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to an industrial useful process for the synthesis of antiviral compound, ganciclovir.
Description
PROCESS FOR THE SYNTHESIS OF GANCIC OVIR
FIELD OF THE INVENTION
The present invention relates to an industrial useful process for the synthesis of antiviral compound, ganciclovir.
BACKGROUND OF THE INVENTION
Ganciclovir is chemically, 9-(1 ,3-dihydroxy-2-propoxymethyl) guanine and has the structural formula I
FORMULA I
It is one of the most important acyclic nucleosides having significant antiviral properties, especially effective against members of the herpes family and a few other DNA viruses.
The simplest synthetic approach to the N-9 substituted guanine compounds involves the direct alkylation of appropriately substituted 2- aminopurines e.g. guanine derivatives. However, the major drawback in this process is that it always results in a mixture of N-9 and N-7 alkylation products. Since alkylation of guanine derivatives like diacetyl / monoacetyl guanine is a thermodynamically controlled reaction, N-7 isomer is always formed. However, the N-9 isomer being thermodynamically more stable is produced as the major product. The unwanted N-7 isomer is difficult to separate from the desired N-9
isomer and is generally purified by costly and tedious processes requiring chromatographic separation and are highly undesirable on a commercial scale.
Some of the prior art processes for the manufacture of aciclovir / ganciclovir are disclosed in BE 833006; U.S. Patent Nos. 4,199,574 and
4,355,032; Chem Pharm Bull, 36 (3) 1153-1157 and JP 63-107982 and 59- 80685, and EP 532878. One such U.S. Patent No. 5,821 ,367 describes a regiospecific process which comprises reacting protected guanine derivative with an alkylating agent selected from 2-oxa-1 ,4-butanediol diacetate, 1-4-diacetoxy- 3-acetoxymethyl-2-oxa-butane, and 1 ,4-dibenzyloxy-3-acetoxymethyl-2- oxabutane in the absence of solvent or any acid catalyst to obtain the penultimate intermediates which are then converted to acylic nucleosides (acyclovir and ganciclovir). U.S. Patent No. 6,043,364 teaches a process for the conversion of N-7 isomer to N-9 isomer by heating a suspension of the N-7 isomer in an alkylating agent.
However, the separation of N-9 isomer from the form N-7 isomer in said patent has been achieved by column chromatography only. Therefore, the process does not offer any additional benefits from commercial point of view.
Accordingly, none of the processes heretofore described are completely satisfactory.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a simplified, commercially feasible process which gives the desired product in good yield, utilizing easily available commercial raw materials. The crystallization procedure of the present invention is very simple and produces the N-9 isomer having more than 95% purity which can directly be used for the preparation of ganciclovir. The present process is cost effective and obviates the need for chromatographic separation.
According to another aspect of the present invention, the N-7 isomer so separated is recycled in the next batch of alkylation. It has been observed that the recycling of the N-7 isomer during alkylation enhances the formation of N-9 isomer and decreases the formation of N-7 isomer in the subsequent batches. This recycling of the side product improves the overall yield of the N-9 isomer and consequently the desired product i.e. ganciclovir.
Thus, the present invention provides a process which does not require discarding the unwanted N-7 isomer or an additional step of conversion of the N-
7 iisomer to N-9 isomer thereby providing an in-situ conversion to the desired N-9 isomer
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides a process for the separation of N-7 and N-9 isomers of structural formulae II and III, respectively,
FORMULA II
FORMULA III
which comprises dissolving a mixture comprising the N-7 and N-9 isomers in an organic solvent, or a mixture of organic solvents, and isolating the N-7 and N-9 isomers from a solution thereof.
The choice of solvent has been found to be important for the separation of
N-7 and N-9 isomers. We have found that the two isomers of structural formulae II and III have different solubilities, one of them being consistently more soluble than the other. The levels of solubility vary according to the solvent, and so a solvent system will desirably be chosen which allows a practical recovery of the two isomers that is present prior to the separation.
The solvent system from which the isomers may be separated will desirably be selected from alcoholic solvents, which include lower alkanols, water-immiscible solvents, or a mixture thereof. The N-7 isomer of structural formula II will preferably be separated from the solvent system which has at least one lower alkanol. The lower alkanols include primary, secondary and tertiary alcohols having from one to six carbon atoms, for example, methanol, ethanol, n- propyl alcohol, isopropyl alcohol, isobutanol, n-butanol, tertiary butanol, or mixtures thereof. Most preferred being methanol, ethanol, or isopropyl alcohol.
The N-9 isomer of structural formula III will preferably be separated from a solvent system which in addition to alcoholic solvents may contain water- immiscible solvents which include aromatic hydrocarbons such as benzene, toluene, or xylene, and chlorinated hydrocarbons such as chloroform, dichloromethane, or 1 ,2-dichloroethane.
In accordance with the present invention, after the N-7 isomer is separated, the concentration of the filtrate containing the N-9 isomer is adjusted by evaporation of the solvent or by dilution.
The separation may comprise the last stage or stages of a reaction in which the mixture of N-7 and N-9 isomers is formed. The reaction in which ganciclovir of the structural formula I, is formed will preferably be an alkylation
reaction carried out in the manner described in US Patent No. 4,355,032 which is incorporated herein by reference.
Methods known in the art may be used with the process of this invention to enhance any aspect of this invention. For example, the solution containing the mixture of N-7 and N-9 isomers may be heated for dissolution, or it may be cooled to separate out the product or the slurry may further be cooled prior to filtration.
The N-7 isomer of structural formula II so separated is used in the next batch of alkylation. Accordingly, a mixture of diacetyl guanine of Formula IV
FORMULA IV
and 2-acetoxymethoxy-1 ,3-diacetoxypropane of Formula V
FORMULA V
is reacted in the presence of an acid catalyst and N2-acetyl-7(1 ,3-diacetoxy-2- propoxymethyl) guanine (the N-7 isomer), in an organic solvent. After the reaction is completed, the solvent is removed under vacuum to yield a dark oil from which N-7 and N-9 isomers are separated in accordance with the process of the present invention and N-7 isomer is again recycled.
The N-9 isomer so obtained after separation is hydrolyzed to yield ganciclovir by the methods known in the literature (J.E. Martin et. al., J. Med. Chem., 1983, 26, 759-61).
The present invention is illustrated by the following examples, which are not intended to limit the effective scope of this invention in any way.
EXAMPLE - 1
A mixture of diacetyl guanine (25g, 0.106mole), 2-acetoxymethoxy-1 ,3- diacetoxy propane (40. Og, 0.161 mole), p-toluene sulfonic acid monohydrate (0.5g) in N,N-dimethylformamide (75ml) is heated at 95°C to 100°C under continuous stirring for 42 hours. After completion of the reaction, the solvents are removed under vacuum yielding a dark brown syrup.
The syrup is dissolved by heating in methanol (60ml). The resulting solution is stirred at room temperature, cooled to 0°C, stirred for 30 min. at 0- 5°C. The crystallized material is filtered and washed with methanol (2 x 40ml) to yield N2-acetyl-7-(1 ,3-diacetoxy-2-propoxymethyl) guanine (7.67g).
The solvent from the filtrate is removed completely by distillation under reduced pressure to give an oily syrup. The oily syrup is dissolved in isopropyl alcohol and filtered through celite. The solvent is distilled off completely under vacuum. The residue is heated with a mixture of methanol (20ml) and toluene (150ml) at 60°C, stirred at room temperature and then at 0-5°C for 30 minutes. The product is filtered and washed with a mixture of methanol and toluene (1 :4) to yield N2-acetyl-9-(1 ,3-diacetoxy-2-propoxymethyl) guanine (11.0g).
EXAMPLE - 2
A mixture of diacetyl guanine (100g, 0.425mole), 2-acetoxymethoxy-1 ,3- diacetoxy propane (150 ml, 0.605 mole), p-toluene sulfonic acid monohydrate (2.0g), N2 - acetyl-7-(1 ,3-diacetoxy-2-propoxymethyl) guanine (70g) in N,N- dimethylformamide (400ml) is heated at 90°C to 100°C under continuous stirring for 63 hours. After completion of the reaction, the solvents are removed under vacuum from the reaction mixture, yielding a dark brown syrup.
The syrup is dissolved by heating in methanol (400ml). The solution is cooled to 0°C, stirred for 1 hour at 0 to 5°C. The crystalline product is filtered and washed with methanol (2 x 100ml) to yield N2-acetyl-7-(1 ,3-diacetoxy-2- propoxymethyl) guanine (69.0g).
Solvent is removed completely from the filtrate and methanol (100ml) and toluene (800ml) are added to the residue and the mixture is heated to 60°C and then cooled to 5°C and stirred for 30 minutes. The crystalline product is filtered, washed with a mixture of methanol and toluene (1 :4), dried at 60-65°C to afford N2-acetyl-9-(1 ,3-diacetoxy-2-propoxymethyl) guanine (107.0g).
EXAMPLE - 3
A mixture of diacetyl guanine (100g, 0.425mole), 2-acetoxymethoxy-1 ,3- diacetoxy propane (180g, 0.725 mole), p-toluene sulfonic acid monohydrate (5.0g), N2-acetyl-7-(1 ,3-diacetoxy-2-propoxymethyl) guanine (78g) in N,N- dimethylformamide (350ml) is heated at 95°C to 100°C under continuous stirring for 40 hours. After completion of the reaction, the solvents are removed under vacuum from the reaction mixture, yielding a dark brown syrup.
The syrup is dissolved by heating in methanol (400ml). The solution is cooled to 0°C, stirred for 1 hour at 0 to 5°C. The crystalline product is filtered and washed with methanol (50ml) to yield N2-acetyl-7-(1 ,3-diacetoxy-2- propoxymethyl) guanine (54.1g).
Solvent is removed completely from the filtrate and methanol (100ml) and toluene (800ml) were added to the residue and the mixture is heated to 60°C and then cooled to 5°C and stirred for 30 minutes. The crystalline product is filtered, washed with a mixture of methanol and toluene (1 :4), dried at 60-65°C to afford N2-acetyl-9-(1 ,3-diacetoxy-2-propoxymethyl) guanine (114. Og).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Claims
1. A process for the separation of N-7 and N-9 isomers of structural formulae II and III, respectively
FORMULA II
FORMULA III
which comprises dissolving a mixture comprising the N-7 and N-9 isomers in an organic solvent, or a mixture of organic solvents, and isolating the N- 7 and N-9 isomers a solution thereof.
2. The process of claim 1 wherein the organic solvent comprises alcoholic solvents and water immiscible solvents.
3. The process of claim 2 wherein the alcoholic solvents include primary, secondary and tertiary alcohols having from one to six carbon atoms.
4. The process of claim 3 wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof.
5. The process of claim 4 wherein the solvent is preferably methanol, ethanol or isopropyl alcohol.
6. The process of claim 2 wherein the water immiscible solvent includes aromatic or chlorinated hydrocarbons.
7. The process of claim 6 wherein the aromatic hydrocarbon is selected from the group consisting of toluene, benzene, xylene and mixtures thereof.
8. The process of claim 7 wherein the chlorinated hydrocarbon is selected from the group consisting of dichloromethane, chloroform, 1 ,2- dichloroethane, and mixtures thereof.
9. The process of claim 1 wherein the solvent for separation of N-7 isomer comprises at least one alcoholic solvent.
10. The process of claim 9 wherein the alcoholic solvent is selected from the group consisting of methanol, ethanol, isopropyl alcohol, and mixtures thereof.
11. The process of claim 1 wherein the solvent for separation of N-9 isomer comprises alcoholic solvents, water immiscible solvents, and mixtures thereof.
12. The process of claim 11 wherein the solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n- butanol, isobutanol, tertiary butanol, toluene benzene, xylene, dichloromethane, chloroform, 1 ,2-dichloroethane, and mixtures thereof.
3. The process of claim 1 further comprises the alkylation reaction of diacetylguanine of structural formula IV
FORMULA IV
with 2-acetoxymethoxy -1 ,3-diacetoxy propane of structural formula V
FORMULA V
in the presence of N -acetyl-7-(1 ,3-diacetoxy-2-propoxymethyl) guanine.
4. A process for the hydrolysis of N-9 isomer of structural formula
FORMULA III
prepared by the process of claim 1 to give ganciclovir of Formula I.
FORMULA I
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IB2002/004897 WO2004048380A1 (en) | 2002-11-22 | 2002-11-22 | Process for the synthesis of ganciclovir |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP1565469A1 true EP1565469A1 (en) | 2005-08-24 |
Family
ID=34362299
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP02785726A Withdrawn EP1565469A1 (en) | 2002-11-22 | 2002-11-22 | Process for the synthesis of ganciclovir |
Country Status (2)
| Country | Link |
|---|---|
| EP (1) | EP1565469A1 (en) |
| AU (1) | AU2002351016A1 (en) |
-
2002
- 2002-11-22 AU AU2002351016A patent/AU2002351016A1/en not_active Abandoned
- 2002-11-22 EP EP02785726A patent/EP1565469A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO2004048380A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| AU2002351016A1 (en) | 2004-06-18 |
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