CN113354647A - Ganciclovir sodium synthesis process - Google Patents
Ganciclovir sodium synthesis process Download PDFInfo
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- CN113354647A CN113354647A CN202110741796.6A CN202110741796A CN113354647A CN 113354647 A CN113354647 A CN 113354647A CN 202110741796 A CN202110741796 A CN 202110741796A CN 113354647 A CN113354647 A CN 113354647A
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- ganciclovir
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- JJICLMJFIKGAAU-UHFFFAOYSA-M sodium;2-amino-9-(1,3-dihydroxypropan-2-yloxymethyl)purin-6-olate Chemical compound [Na+].NC1=NC([O-])=C2N=CN(COC(CO)CO)C2=N1 JJICLMJFIKGAAU-UHFFFAOYSA-M 0.000 title claims abstract description 55
- 229960002687 ganciclovir sodium Drugs 0.000 title claims abstract description 54
- 238000000034 method Methods 0.000 title claims abstract description 37
- 230000015572 biosynthetic process Effects 0.000 title abstract description 13
- 238000003786 synthesis reaction Methods 0.000 title abstract description 13
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 105
- 238000002156 mixing Methods 0.000 claims abstract description 61
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000010438 heat treatment Methods 0.000 claims abstract description 37
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 36
- PEZKHGVZZSQDPY-UHFFFAOYSA-N [2-[(2-acetamido-6-oxo-3h-purin-9-yl)methoxy]-3-acetyloxypropyl] acetate Chemical class O=C1NC(NC(=O)C)=NC2=C1N=CN2COC(COC(C)=O)COC(C)=O PEZKHGVZZSQDPY-UHFFFAOYSA-N 0.000 claims abstract description 29
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 28
- 239000003463 adsorbent Substances 0.000 claims abstract description 27
- 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 abstract description 25
- WWECJGLXBSQKRF-UHFFFAOYSA-N n,n-dimethylformamide;methanol Chemical compound OC.CN(C)C=O WWECJGLXBSQKRF-UHFFFAOYSA-N 0.000 claims abstract description 22
- OVYTZAASVAZITK-UHFFFAOYSA-M sodium;ethanol;hydroxide Chemical compound [OH-].[Na+].CCO OVYTZAASVAZITK-UHFFFAOYSA-M 0.000 claims abstract description 21
- WELHAGHWNWCPGP-UHFFFAOYSA-N 4-acetyl-3,4,5-trihydroxy-3-methoxyheptane-2,6-dione Chemical compound COC(O)(C(C)=O)C(O)(C(O)C(C)=O)C(C)=O WELHAGHWNWCPGP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 16
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 67
- 239000000243 solution Substances 0.000 claims description 47
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 46
- 238000005406 washing Methods 0.000 claims description 35
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 30
- 238000001035 drying Methods 0.000 claims description 26
- 239000000126 substance Substances 0.000 claims description 22
- 239000007864 aqueous solution Substances 0.000 claims description 21
- 238000001704 evaporation Methods 0.000 claims description 18
- 238000003756 stirring Methods 0.000 claims description 17
- 229910021536 Zeolite Inorganic materials 0.000 claims description 12
- HNPSIPDUKPIQMN-UHFFFAOYSA-N dioxosilane;oxo(oxoalumanyloxy)alumane Chemical compound O=[Si]=O.O=[Al]O[Al]=O HNPSIPDUKPIQMN-UHFFFAOYSA-N 0.000 claims description 12
- 239000002808 molecular sieve Substances 0.000 claims description 12
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 claims description 12
- 239000010457 zeolite Substances 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 11
- 239000011347 resin Substances 0.000 claims description 11
- 229920005989 resin Polymers 0.000 claims description 11
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 239000002244 precipitate Substances 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 10
- RCBRPVRZSFHFJY-UHFFFAOYSA-N C(C)(=O)C(OC(O)C(O)CO)(C(C)=O)C(C)=O Chemical compound C(C)(=O)C(OC(O)C(O)CO)(C(C)=O)C(C)=O RCBRPVRZSFHFJY-UHFFFAOYSA-N 0.000 claims description 2
- 238000009833 condensation Methods 0.000 abstract description 4
- 230000005494 condensation Effects 0.000 abstract description 4
- 239000002994 raw material Substances 0.000 abstract description 4
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 abstract description 3
- 238000009776 industrial production Methods 0.000 abstract description 2
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 description 18
- 229960002963 ganciclovir Drugs 0.000 description 17
- 235000011121 sodium hydroxide Nutrition 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 10
- 238000002360 preparation method Methods 0.000 description 7
- 238000002347 injection Methods 0.000 description 3
- 239000007924 injection Substances 0.000 description 3
- 239000003443 antiviral agent Substances 0.000 description 2
- 239000006184 cosolvent Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000001514 detection method Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000005518 chemical engineering design Methods 0.000 description 1
- 238000004891 communication Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000967 suction filtration Methods 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine
Abstract
The invention provides a process for synthesizing ganciclovir sodium, which comprises the steps of taking diacetyl guanine as a raw material, mixing and heating the diacetyl guanine with p-toluenesulfonic acid and N, N-dimethylformamide-methanol solution, adding triacetyl methoxyglycerol for condensation, adding methanol and an adsorbent in the condensation process to ensure that the reaction balance moves forward, reducing the generation of isomers of triacetyl ganciclovir, improving the product purity and yield, and finally reacting in sodium hydroxide ethanol water solution to obtain ganciclovir sodium. The ganciclovir sodium produced by the synthesis process is simple to operate, low in cost and easy for industrial production.
Description
Technical Field
The invention relates to the field of medicines, and in particular relates to a synthesis process of ganciclovir sodium.
Background
Ganciclovir (chemical name 9- (1, 3-dihydroxy-2-propoxymethyl) -guanine) is an important member of antiviral drugs in the nucleoside class, and is one of the best drugs for treating CMV infection at present. However, the impurity of ganciclovir prepared at present is generally over 0.4%, and the ganciclovir is used for injection, so that a large risk exists. And ganciclovir has the problems of unstable chemical structure and low solubility, the dilute-alcohol interconversion phenomenon is easy to occur, a certain amount of cosolvent is often added in the preparation of medicinal preparations, particularly aqueous solution preparations, and if the cosolvent is excessively added, the toxic and side effects in clinical use are inevitably increased.
Therefore, how to improve the stability and solubility of ganciclovir and reduce toxic and side effects on the basis of ensuring the drug effect of ganciclovir is very important.
The ganciclovir sodium is obtained by salifying, crystallizing and vacuum drying at low temperature on the basis of ganciclovir, and compared with ganciclovir, the ganciclovir sodium effectively avoids the dilute-alcohol interconversion phenomenon, and also has the advantages of low impurity content, low preparation cost and good water solubility. Therefore, the ganciclovir sodium is a safer and more effective antiviral drug than ganciclovir, and is worthy of further popularization and application. However, few studies on the synthesis process of ganciclovir sodium are reported at present.
Patent CN103570716A entitled ganciclovir sodium anhydrous crystal form and its preparation method discloses a preparation route of ganciclovir sodium, which comprises reacting ganciclovir with sodium hydroxide to form salt, precipitating with ethanol to obtain crystal, adding lower alcohol or ketone into ganciclovir sodium hydrate, heating to crystallize to obtain anhydrous ganciclovir sodium, but the method uses ganciclovir as raw material to prepare ganciclovir sodium.
The 'Ganciclovir synthesis process improvement' written by Liuxin yuan, recorded in 'chemical engineering design communication' at the 5 th stage of 2017, discloses a method for preparing Ganciclovir by using diacetylguanine as an initial raw material and preparing Ganciclovir sodium salt to replace triacetyl Ganciclovir refining and then preparing Ganciclovir, and the method aims to prepare Ganciclovir, and the Ganciclovir sodium exists as an intermediate, and the preparation of Ganciclovir sodium is not deeply researched.
Disclosure of Invention
Aiming at the problems, the invention provides a synthesis process of ganciclovir sodium.
The invention relates to a ganciclovir sodium synthesis process, which comprises the following steps:
s1, mixing diacetylguanine and p-toluenesulfonic acid, adding an N, N-dimethylformamide-methanol solution, heating to 100-120 ℃, adding triacetyl methoxyglycerol and an adsorbent, heating to 165-178 ℃, stirring for reacting for 4-6 hours, concentrating under reduced pressure, evaporating to dryness, washing and evaporating to dryness, and drying to obtain triacetylganciclovir;
s2, mixing the triacetyl ganciclovir obtained in the step S1 with a sodium hydroxide ethanol water solution, heating to 60-65 ℃ for reflux reaction, cooling after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain ganciclovir sodium.
Further, in step S1, the ratio of diacetylguanine, p-toluenesulphonic acid, N-dimethylformamide-methanol solution and triacetylmethoxy-glycerol was 1g: (0.01-0.02) g (5-8) mL: (1-1.2) mL.
Furthermore, the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1 (2-2.5).
Further, the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1 (0.46-0.58).
Further, in step S1, the amount of the adsorbent added is 22-35% by weight of diacetylguanine.
Further, in step S1, the heating is carried out at a rate of 10-15 ℃/min to 165-178 ℃.
Further, the stirring reaction is a stirring reaction at a speed of 40-50 r/min.
Further, the washing and drying of the evaporated substances are that the evaporated substances are washed by water, ethyl acetate and methanol in sequence, and washing liquid of the methanol is taken for drying.
Further, in step S2, the ratio of triacetylganciclovir to the aqueous solution of NaOH is 1g (4-6) mL.
Further, the sodium hydroxide ethanol water solution is obtained by mixing ethanol and water according to the volume ratio of 1 (2-1), adding sodium hydroxide accounting for 65-75% of the weight of the ethanol water solution, and standing for 20-30 min.
Compared with the prior art, the invention has the beneficial effects that:
the method comprises the steps of taking diacetylguanine as a raw material, mixing the diacetylguanine with p-toluenesulfonic acid and N, N-dimethylformamide-methanol solution, heating, adding triacetyl methoxyglycerol for condensation, adding methanol and an adsorbent in the condensation process to enable reaction balance to move forward, reducing the generation of isomers of triacetyl ganciclovir, improving the purity and yield of the product, and finally reacting in sodium hydroxide ethanol water solution to obtain ganciclovir sodium. The ganciclovir sodium produced by the synthesis process is simple to operate, low in cost and easy for industrial production.
According to the invention, by controlling the proportion of diacetylguanine and triacetyl methoxyglycerol and adding the adsorbent consisting of the zeolite molecular sieve and the HPD-600 resin, diacetylguanine and triacetyl methoxyglycerol can fully react, triacetyl ganciclovir is effectively adsorbed, the generation of isomers is reduced, and the product purity and yield are improved.
Compared with the prior art, the synthesis process simplifies the synthesis steps, shortens the reaction time, and obtains the ganciclovir sodium with high purity, wherein the yield can reach 48.7-69.5% by the diacetyl guanine.
Detailed Description
In order to better understand the technical content of the invention, specific examples are provided below to further illustrate the invention.
Example 1
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide-methanol solution, heating to 105 ℃, adding 110mL of triacetyl methoxyglycerol and 25g of adsorbent, heating to 175 ℃ at the speed of 12 ℃/min, stirring at the speed of 45r/min for reaction for 5 hours, concentrating under reduced pressure, evaporating, washing with water, ethyl acetate and methanol in sequence, evaporating the evaporated substances, and drying a washing solution of methanol to obtain 118.2g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.2;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.5;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 70% of the weight of the ethanol aqueous solution, and standing for 25min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 5mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 69.5g of ganciclovir sodium.
Example 2
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1g of p-toluenesulfonic acid, adding 500mL of N, N-dimethylformamide-methanol solution, heating to 100 ℃, adding 100mL of triacetyl methoxyglycerol and 22g of adsorbent, heating to 165 ℃ at the speed of 10 ℃/min, stirring at the speed of 40r/min for reaction for 6 hours, concentrating under reduced pressure, evaporating to dryness, washing the evaporated substances with water, ethyl acetate and methanol in sequence, and drying a washing solution of the methanol to obtain 119.5g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.46;
s2, mixing ethanol and water according to the volume ratio of 1:1, adding sodium hydroxide accounting for 65% of the weight of the ethanol aqueous solution, and standing for 20min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 4mL, heating to 60 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 68.6g of ganciclovir sodium.
Example 3
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 2g of p-toluenesulfonic acid, adding 800mL of N, N-dimethylformamide-methanol solution, heating to 120 ℃, adding 120mL of triacetyl methoxyglycerol and 35g of adsorbent, heating to 178 ℃ at the speed of 15 ℃/min, stirring at the speed of 50r/min for reaction for 4 hours, concentrating under reduced pressure, evaporating to dryness, washing the evaporated substances with water, ethyl acetate and methanol in sequence, and drying a washing solution of the methanol to obtain 117.3g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.5;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.58;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 75% of the weight of the ethanol aqueous solution, and standing for 30min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 6mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 66.3g of ganciclovir sodium.
Example 4
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide-methanol solution, heating to 105 ℃, adding 140mL of triacetyl methoxyglycerol and 25g of adsorbent, heating to 175 ℃ at the speed of 12 ℃/min, stirring at the speed of 45r/min for reaction for 5 hours, concentrating under reduced pressure, evaporating, washing with water, ethyl acetate and methanol in sequence, evaporating the evaporated substances, and drying a washing solution of the methanol to obtain 97.5g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.2;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.5;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 70% of the weight of the ethanol aqueous solution, and standing for 25min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 5mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 54.3g of ganciclovir sodium.
Example 5
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide-methanol solution, heating to 105 ℃, adding 110mL of triacetyl methoxyglycerol and 25g of adsorbent, heating to 175 ℃ at the speed of 12 ℃/min, stirring at the speed of 45r/min for reaction for 5 hours, concentrating under reduced pressure, evaporating, washing with water, ethyl acetate and methanol in sequence, evaporating the evaporated substances, and drying a washing solution of methanol to obtain 115.3g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.2;
the adsorbent is a zeolite molecular sieve;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 70% of the weight of the ethanol aqueous solution, and standing for 25min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 5mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 48.7g of ganciclovir sodium.
Example 6
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide-methanol solution, heating to 105 ℃, adding 110mL of triacetyl methoxyglycerol and 25g of adsorbent, heating to 175 ℃ at the speed of 12 ℃/min, stirring at the speed of 45r/min for reaction for 5 hours, concentrating under reduced pressure, evaporating, washing with water and methanol in sequence, evaporating the evaporated substance, and drying a washing solution of the methanol to obtain 98.3g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.2;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.5;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 70% of the weight of the ethanol aqueous solution, and standing for 25min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 5mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 60.9g of ganciclovir sodium.
Comparative example 1
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide-methanol solution, heating to 105 ℃, adding 110mL of triacetyl methoxyglycerol, heating to 175 ℃ at the speed of 12 ℃/min, stirring and reacting at the speed of 45r/min for 5 hours, decompressing, concentrating, evaporating, washing evaporated substances with water, ethyl acetate and methanol in sequence, and drying a washing solution of the methanol to obtain 85.7g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.2;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.5;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 70% of the weight of the ethanol aqueous solution, and standing for 25min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 5mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 38.5g of ganciclovir sodium.
Comparative example 2
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide, heating to 105 ℃, adding 110mL of triacetyl methoxyglycerol and 25g of adsorbent, heating to 175 ℃ at the speed of 12 ℃/min, stirring at the speed of 45r/min for reaction for 5 hours, concentrating under reduced pressure, evaporating, washing with water, ethyl acetate and methanol in sequence, evaporating the evaporated substances, and drying a washing solution of the methanol to obtain 88.5g of triacetylganciclovir;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.5;
s2, mixing ethanol and water according to a volume ratio of 2:1, adding sodium hydroxide accounting for 70% of the weight of the ethanol aqueous solution, and standing for 25min to obtain a sodium hydroxide ethanol aqueous solution; and (3) mixing the triacetylganciclovir obtained in the step S1 with sodium hydroxide ethanol water solution, wherein the mixing ratio is 1g: and 5mL, heating to 65 ℃ for reflux reaction, cooling to 10-15 ℃ after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain 37.3g of ganciclovir sodium.
Comparative example 3
A process for synthesizing ganciclovir sodium comprises the following steps:
s1, mixing 100g of diacetylguanine and 1.6g of p-toluenesulfonic acid, adding 600mL of N, N-dimethylformamide-methanol solution, 110mL of triacetyl methoxyglycerol and 25g of adsorbent, heating to 175 ℃ at the speed of 12 ℃/min, stirring at the speed of 45r/min for reaction for 5 hours, decompressing, concentrating, evaporating, washing evaporated substances with water, ethyl acetate and methanol in sequence, and drying a washing solution of the methanol to obtain 97.5g of triacetylganciclovir;
the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to the volume ratio of 1: 2.2;
the adsorbent is prepared by mixing a zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1: 0.5;
s2, adding 100ml of 30% sodium hydroxide solution into the triacetyl ganciclovir obtained in the step S1, stirring at room temperature for 30min, separating out a water phase, heating to 75 ℃ for reacting for 2h, after the reaction is finished, dropwise adding 900ml of ethanol, cooling to 0-5 ℃, stirring for 1h, performing suction filtration, and drying to obtain 41.5g ganciclovir sodium.
Test examples
In the examples and comparative examples, wherein the yield is in terms of diacetylguanine, the results are shown in table 1;
the purity detection method comprises the following steps: refer to Ganciclovir for injection in China pharmacopoeia II (2020 edition) under the term of content determination;
the detection method of related substances comprises the following steps: refer to "related substances" in Ganciclovir for injection in China pharmacopoeia second (2020 edition);
TABLE 1
| Purity (%) | Yield (%) | Related substance (%) | |
| Example 1 | 99.6 | 69.5 | 0.14 |
| Example 2 | 99.7 | 68.6 | 0.16 |
| Example 3 | 99.5 | 66.3 | 0.13 |
| Example 4 | 93.6 | 54.3 | 0.81 |
| Example 5 | 91.8 | 48.7 | 0.96 |
| Example 6 | 96.5 | 60.9 | 0.58 |
| Comparative example 1 | 81.3 | 38.5 | 1.46 |
| Comparative example 2 | 85.6 | 37.3 | 1.25 |
| Comparative example 3 | 91.4 | 41.5 | 1.37 |
The experimental data show that the ganciclovir sodium produced by the synthesis process has high purity and yield and few related substances, and can effectively reduce the synthesis cost of the ganciclovir sodium, wherein the ganciclovir sodium synthesized in the embodiment 1 has the best quality.
In the comparative example 1, no adsorbent is added in the reaction process, more isomers of triacetyl ganciclovir exist in the reaction process, and the synthesized ganciclovir sodium has lower purity, low yield and high content of related substances.
Comparative example 2 no methanol was added for reaction, the reaction did not continue to move forward, and the synthesized ganciclovir sodium was of lower purity, low yield, high content of related substances.
In the comparative example 3, the diacetylguanine and the triacetyl methoxyglycerol are mixed and then heated for reaction, and the synthesized ganciclovir sodium has low purity, low yield and high content of related substances.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (10)
1. A process for synthesizing ganciclovir sodium is characterized by comprising the following steps:
s1, mixing diacetylguanine and p-toluenesulfonic acid, adding an N, N-dimethylformamide-methanol solution, heating to 100-120 ℃, adding triacetyl methoxyglycerol and an adsorbent, heating to 165-178 ℃, stirring for reacting for 4-6 hours, concentrating under reduced pressure, evaporating to dryness, washing and evaporating to dryness, and drying to obtain triacetylganciclovir;
s2, mixing the triacetyl ganciclovir obtained in the step S1 with a sodium hydroxide ethanol water solution, heating to 60-65 ℃ for reflux reaction, cooling after the reaction is finished, separating out a precipitate, filtering, washing a filter cake with ethanol, and drying in vacuum to obtain ganciclovir sodium.
2. The process of claim 1, wherein in step S1, the ratio of diacetylguanine, p-toluenesulphonic acid, N-dimethylformamide-methanol solution and triacetylmethoxy-glycerol is 1g: (0.01-0.02) g (5-8) mL: (1-1.2) mL.
3. The process for synthesizing ganciclovir sodium according to claim 1, wherein the N, N-dimethylformamide-methanol solution is obtained by mixing N, N-dimethylformamide and methanol according to a volume ratio of 1 (2-2.5).
4. The process for synthesizing ganciclovir sodium as claimed in claim 1, wherein said adsorbent is obtained by mixing zeolite molecular sieve and HPD-600 resin according to the weight ratio of 1 (0.46-0.58).
5. The process of claim 1 or 4, wherein in step S1, the adsorbent is added in an amount of 22-35% by weight of diacetylguanine.
6. The process of claim 1, wherein in step S1, heating is performed at a rate of 10-15 ℃/min to 165-178 ℃.
7. The process for synthesizing ganciclovir sodium according to claim 1, wherein the stirring reaction is a stirring reaction at a speed of 40-50 r/min.
8. The process of claim 1, wherein the step of washing and drying the evaporated substances comprises washing the evaporated substances with water, ethyl acetate and methanol in sequence, and drying the washing solution of methanol.
9. The process for synthesizing ganciclovir sodium as claimed in claim 1, wherein in step S2, the ratio of triacetyl ganciclovir to aqueous solution of sodium hydroxide in ethanol is 1g (4-6) mL.
10. The process for synthesizing ganciclovir sodium according to claim 1, wherein the aqueous solution of sodium hydroxide and ethanol is obtained by mixing ethanol and water according to the volume ratio of 1 (2-1), adding sodium hydroxide with the weight of 65-75% of that of the aqueous solution of ethanol, and standing for 20-30 min.
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