CN117486904A - Synthesis and refining method of ganciclovir impurity - Google Patents
Synthesis and refining method of ganciclovir impurity Download PDFInfo
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- CN117486904A CN117486904A CN202311404151.9A CN202311404151A CN117486904A CN 117486904 A CN117486904 A CN 117486904A CN 202311404151 A CN202311404151 A CN 202311404151A CN 117486904 A CN117486904 A CN 117486904A
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- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 229960002963 ganciclovir Drugs 0.000 title claims abstract description 61
- 239000012535 impurity Substances 0.000 title claims abstract description 59
- 238000000034 method Methods 0.000 title claims abstract description 41
- 238000007670 refining Methods 0.000 title claims abstract description 31
- 238000003786 synthesis reaction Methods 0.000 title claims description 14
- 230000015572 biosynthetic process Effects 0.000 title claims description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 66
- 150000001875 compounds Chemical class 0.000 claims abstract description 49
- 230000002194 synthesizing effect Effects 0.000 claims abstract description 20
- 229930040373 Paraformaldehyde Natural products 0.000 claims abstract description 11
- GILZZWCROUGLIS-UHFFFAOYSA-N n-(9-acetyl-6-oxo-3h-purin-2-yl)acetamide Chemical compound N1C(NC(=O)C)=NC(=O)C2=C1N(C(C)=O)C=N2 GILZZWCROUGLIS-UHFFFAOYSA-N 0.000 claims abstract description 11
- 229920002866 paraformaldehyde Polymers 0.000 claims abstract description 11
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 10
- 239000002994 raw material Substances 0.000 claims abstract description 10
- 239000002841 Lewis acid Substances 0.000 claims abstract description 9
- 150000008064 anhydrides Chemical class 0.000 claims abstract description 9
- 150000007517 lewis acids Chemical class 0.000 claims abstract description 9
- BRLQWZUYTZBJKN-UHFFFAOYSA-N Epichlorohydrin Chemical compound ClCC1CO1 BRLQWZUYTZBJKN-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 48
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 18
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 16
- 230000035484 reaction time Effects 0.000 claims description 16
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- 239000012043 crude product Substances 0.000 claims description 12
- 239000012065 filter cake Substances 0.000 claims description 11
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- 238000002425 crystallisation Methods 0.000 claims description 8
- 230000008025 crystallization Effects 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 8
- 150000007524 organic acids Chemical class 0.000 claims description 7
- 238000000967 suction filtration Methods 0.000 claims description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000007788 liquid Substances 0.000 claims description 6
- 239000012074 organic phase Substances 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 6
- 239000000047 product Substances 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- DAMJCWMGELCIMI-UHFFFAOYSA-N benzyl n-(2-oxopyrrolidin-3-yl)carbamate Chemical compound C=1C=CC=CC=1COC(=O)NC1CCNC1=O DAMJCWMGELCIMI-UHFFFAOYSA-N 0.000 claims description 5
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 239000011259 mixed solution Substances 0.000 claims description 4
- QAEDZJGFFMLHHQ-UHFFFAOYSA-N trifluoroacetic anhydride Chemical compound FC(F)(F)C(=O)OC(=O)C(F)(F)F QAEDZJGFFMLHHQ-UHFFFAOYSA-N 0.000 claims description 4
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- WYYQVWLEPYFFLP-UHFFFAOYSA-K chromium(3+);triacetate Chemical compound [Cr+3].CC([O-])=O.CC([O-])=O.CC([O-])=O WYYQVWLEPYFFLP-UHFFFAOYSA-K 0.000 claims description 3
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 3
- LRWZZZWJMFNZIK-UHFFFAOYSA-N 2-chloro-3-methyloxirane Chemical compound CC1OC1Cl LRWZZZWJMFNZIK-UHFFFAOYSA-N 0.000 claims description 2
- ZQPVMSLLKQTRMG-UHFFFAOYSA-N 4-acetamidobenzenesulfonic acid Chemical compound CC(=O)NC1=CC=C(S(O)(=O)=O)C=C1 ZQPVMSLLKQTRMG-UHFFFAOYSA-N 0.000 claims description 2
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 2
- 150000008065 acid anhydrides Chemical class 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- 239000012141 concentrate Substances 0.000 claims description 2
- OPQARKPSCNTWTJ-UHFFFAOYSA-L copper(ii) acetate Chemical compound [Cu+2].CC([O-])=O.CC([O-])=O OPQARKPSCNTWTJ-UHFFFAOYSA-L 0.000 claims description 2
- 239000000178 monomer Substances 0.000 claims description 2
- 229910017604 nitric acid Inorganic materials 0.000 claims description 2
- WYVAMUWZEOHJOQ-UHFFFAOYSA-N propionic anhydride Chemical compound CCC(=O)OC(=O)CC WYVAMUWZEOHJOQ-UHFFFAOYSA-N 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims 1
- 239000000126 substance Substances 0.000 abstract description 2
- 238000001816 cooling Methods 0.000 description 9
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 8
- 238000003756 stirring Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- 238000001914 filtration Methods 0.000 description 6
- 239000007789 gas Substances 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 6
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 5
- -1 1, 3-dihydroxyl-2-propoxymethyl Chemical group 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 125000000738 acetamido group Chemical group [H]C([H])([H])C(=O)N([H])[*] 0.000 description 3
- 238000001819 mass spectrum Methods 0.000 description 3
- 235000011056 potassium acetate Nutrition 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000011534 incubation Methods 0.000 description 2
- 229910017053 inorganic salt Inorganic materials 0.000 description 2
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 2
- 239000007791 liquid phase Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 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 description 2
- 238000004321 preservation Methods 0.000 description 2
- 238000000425 proton nuclear magnetic resonance spectrum Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- YDYOYUPJKSJCMF-UHFFFAOYSA-N 1-(2-hydroxyethoxymethyl)pyrimidine-2,4-dione Chemical class OCCOCN1C=CC(=O)NC1=O YDYOYUPJKSJCMF-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- 239000005711 Benzoic acid Substances 0.000 description 1
- YYMFRRGZXXIFMH-UHFFFAOYSA-N CC(OC(COCCl)CCl)=O Chemical compound CC(OC(COCCl)CCl)=O YYMFRRGZXXIFMH-UHFFFAOYSA-N 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 206010011831 Cytomegalovirus infection Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061598 Immunodeficiency Diseases 0.000 description 1
- 208000029462 Immunodeficiency disease Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 1
- 238000006640 acetylation reaction Methods 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000010233 benzoic acid Nutrition 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229960004397 cyclophosphamide Drugs 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000007813 immunodeficiency Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a method for synthesizing and refining ganciclovir impurities. The method for synthesizing and refining ganciclovir impurity takes epichlorohydrin as raw material, and reacts under the catalysis of Lewis acid to obtain compound M 1 The method comprises the steps of carrying out a first treatment on the surface of the Then compound M 1 Reacting with paraformaldehyde under the catalysis of inorganic acid, slowly dripping anhydride to continue reaction to obtain a compound M 2 The method comprises the steps of carrying out a first treatment on the surface of the Finally M is arranged 2 And performing condensation reaction with N2, 9-diacetylguanine to finally obtain ganciclovir impurities. Compared with the traditional method, the method has the advantages of easily available raw materials, easily controllable reaction, simple post-treatment, high yield and the like.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemical synthesis, and in particular relates to a method for synthesizing and refining ganciclovir impurities.
Background
Ganciclovir (ganciclovir), an organic compound of the formula C 9 H 13 N 5 O 4 The chemical name is 9- (1, 3-dihydroxyl-2-propoxymethyl) guanine, which is mainly used as antiviral agent for preventing and treating cytomegalovirus infection of patients with immunodeficiency, such as AIDS patients, tumor patients receiving chemotherapy, and organ transplantation patients using immunosuppressant.
At present, few reports about the synthesis of ganciclovir impurities are few, and only few similar reports exist, and although products can be synthesized through reaction, the raw materials are expensive, or the post-treatment is complex.
Document The Syntheses of Purine and Pyrimidine Secoribo-nucleic acids: acyclo-uridine Derivative of Cyclophosphamide [ J ]. Helvetica Chimica Acta,1990,73 (4): 912-915.Zakerinia,M,H.Davary,and G.H.Hakimelahi. The synthetic route for similar compounds is reported as follows:
the method takes epichlorohydrin as an initial raw material, under the action of stoichiometric potassium acetate, the epichlorohydrin reacts with benzoic acid in DMF as a solvent, then reacts with paraformaldehyde and dry HCl gas, and finally carries out condensation reaction with diacetyl guanine, thereby synthesizing ganciclovir impurities. According to the method, a large amount of organic solvent DMF and a large amount of inorganic salt are required to be used in the reaction, meanwhile, dry HCl gas is also used, the danger coefficient is large, and the purity and yield of the obtained ganciclovir impurity are required to be improved.
Chinese patent CN112661757a reports the synthetic route for similar compounds as follows:
the route takes 1, 3-dichloro-2-acetoxy methoxy propane as a starting material, and carries out acetylation reaction with sodium acetate in DMF solvent in the presence of a phase transfer catalyst, and then carries out condensation reaction with diacetyl guanine, so as to prepare ganciclovir impurities. The method requires a large amount of DMF (dimethyl formamide) which is an organic solvent and a large amount of inorganic salt for reaction, the raw materials used are high in price, and the purity and yield of the obtained ganciclovir impurity are required to be improved.
Disclosure of Invention
The invention aims to solve the technical problems that: overcomes the defects in the prior art, provides a method for synthesizing and refining ganciclovir impurities, and can improve the purity and yield of ganciclovir impurities.
The technical scheme adopted for solving the technical problems is as follows:
the method for synthesizing and refining ganciclovir impurities specifically comprises the following steps:
step a, synthesizing Compound M 1
Using epichlorohydrin as raw material, under the catalysis of Lewis acid (Lewis acid), making reaction time t 1 Reacting to obtain a reaction system I, and performing first post-treatment on the reaction system I to obtain a compound M 1 The chemical reaction formula is as follows:
step b, synthesis of Compound M 2
The compound M prepared in the step a is reacted with 1 Reacts with paraformaldehyde under the catalysis of inorganic acid for a reaction time t 2 After the reaction, a reaction system II is prepared, the reaction system II is cooled, acid anhydride is slowly dripped at low temperature, and then the reaction time t is passed at room temperature 3 After the reaction, a reaction system III is prepared, and then the reaction system III is subjected to second post-treatment to obtain a compound M 2 The chemical reaction formula is as follows:
step c, condensation reaction
The compound M prepared in the step b 2 Adding into organic solvent, and under the catalysis of organic acid, performing condensation reaction with N2, 9-diacetylguanine for reaction time t 4 Reacting to obtain a reaction system IV, and then performing third post-treatment on the reaction system IV to obtain a ganciclovir impurity crude product; and then refining the ganciclovir impurity crude product by using a refining liquid to obtain a finished product ganciclovir impurity, wherein the chemical reaction formula is as follows:
further, the molar ratio of the epichlorohydrin to the Lewis acid in the step a is 1:0.02-1:0.05, preferably 1:0.02-1:0.03; the reaction temperature is 80-100 ℃, preferably 80-85 ℃; reaction time t 1 2 to 8 hours, preferably 3 to 5 hours; the Lewis acid in the step a is one or more selected from antimony trichloride, chromium acetate and copper acetate.
Further, compound M in step b 1 The molar ratio of the monomer to the paraformaldehyde is 1:1-1:5, preferably 1:2-1:3; the reaction temperature after adding paraformaldehyde is 80-100 ℃, preferably 90-95 ℃; reaction time t 2 4 to 16 hours, preferably 5 to 8 hours;
the temperature of the reaction system in the step b is reduced to 0-25 ℃, and the temperature is preferably 10-15 ℃; slowly dripping anhydride with the dripping speed of 0.1L/min; compound M in step b 1 The molar ratio of the catalyst to the anhydride is 1:1.5-1:5, preferably 1:2-1:3; reaction time t 3 5 to 10 hours, preferably 6 to 8 hours. The invention adopts a dripping mode to avoid the instant heat release risk caused by adding a large amount of anhydride at one time; meanwhile, the impurity generation can be avoided, and the purity of the finished product is improved.
Further, in the step b, the inorganic acid is selected from one or more of concentrated sulfuric acid, concentrated phosphoric acid and concentrated nitric acid, and the anhydride is selected from one or more of acetic anhydride, propionic anhydride and trifluoroacetic anhydride.
Further, provided thatCompound M in step c 2 The molar ratio of the N2, 9-diacetylguanine to the N2, 9-diacetylguanine is 1:2-1:4, preferably 1:2.2-1:2.5; the molar ratio of N2, 9-diacetylguanine to organic acid is 1:0.02-1:0.05, preferably 1:0.02-1:0.025; the reaction temperature in step c is from 90 to 120℃and preferably from 95 to 100℃and the reaction time t 4 4 to 16 hours, preferably 8 to 10 hours.
Further, in the step c, the organic acid is selected from one or more of p-toluenesulfonic acid (p-TAS), p-acetamidobenzenesulfonic acid and trifluoroacetic acid, the organic solvent is selected from one or more of N, N' -Dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and toluene, and the refined solution is selected from one or more of methanol, ethanol and isopropanol.
Further, the first post-treatment in the step a is specifically that the obtained reaction system I is cooled to room temperature, a mixed solution composed of ethyl acetate and water is added, the volume ratio of the ethyl acetate to the water in the mixed solution is 1:1, and then the mixture is subjected to liquid separation, organic phase drying and concentration to obtain a compound M 1 。
Further, the second post-treatment in the step b is specifically that antimony trichloride is added into the obtained reaction system III, suction filtration is carried out, residues are added into water, extraction is carried out by ethyl acetate, the extraction is repeated for three times, the organic phase is dried, and the compound M is obtained by concentration 2 。
Further, the third post-treatment in the step c is specifically to concentrate the obtained reaction system IV, add petroleum ether into the residue to cool, perform crystallization overnight, perform suction filtration, wash the obtained filter cake with petroleum ether, and dry to obtain a ganciclovir impurity crude product. In the second post-treatment, the crystallization temperature is 10-20 ℃.
Further, in the refining process in the step c, the ganciclovir impurity crude product and the refined solution are mixed for refining to obtain a refining system, the refining system is sequentially subjected to crystallization and suction filtration to obtain a filter cake, and the filter cake is sequentially washed and dried to obtain the finished ganciclovir impurity. The refining temperature is 75-85 ℃, the refining time is 1h, the crystallization temperature is 0-5 ℃, and the filter cake washing solvent is ethanol.
Step a and step b are preferably performed by GC and step c is preferably performed by TLC.
Compound M 1 And compound M 2 The pure ganciclovir is colorless liquid, crude ganciclovir impurity is off-white solid, and finished ganciclovir impurity is white solid.
The beneficial effects of the invention are as follows: the invention has reasonable design and has the following advantages:
epoxy chloropropane is used as a raw material, and reacts under the catalysis of Lewis acid to obtain a compound M 1 The method comprises the steps of carrying out a first treatment on the surface of the Then compound M 1 Reacting with paraformaldehyde under the catalysis of inorganic acid, slowly dripping anhydride to continue reaction to obtain a compound M 2 The method comprises the steps of carrying out a first treatment on the surface of the Finally, compound M 2 Condensation reaction is carried out with N2, 9-diacetylguanine, and ganciclovir impurity is finally obtained;
the process route is short and easy to operate, the purity of the obtained ganciclovir impurity reaches more than 99.1%, silica gel column chromatography is not needed, and batch synthesis can be realized; compared with the existing synthesis method, the method has the advantages of short process route, simple operation, easily available raw materials, high product yield and the like.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings that are needed in the description of the embodiments or the prior art will be briefly described, and it is obvious that the drawings in the description below are some embodiments of the present invention, and other drawings can be obtained according to the drawings without inventive effort for a person skilled in the art.
FIG. 1 shows ganciclovir impurity in the present invention 1 H-NMR spectrum.
FIG. 2 is an LC-MS spectrum of ganciclovir impurity in the present invention.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the present application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. In the present invention, all raw material components are commercially available products well known to those skilled in the art unless specified otherwise.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of example embodiments in accordance with the present application. As used herein, the singular forms also include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that when the terms "comprises" and/or "comprising" are used in this specification, they specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
The technical solutions of the present invention will be clearly and completely described in connection with the embodiments, and it is apparent that the described embodiments are some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1
Compound M 1 Is synthesized by (a)
200g of epichlorohydrin and 9.91g of antimony trichloride were charged into a 500mL reaction flask, and the mixture was stirred and heated to 83℃to carry out a reaction for 3 hours. After incubation, cooling to 20 ℃, adding 200mL of ethyl acetate and 200mL of water, stirring for 5-10 minutes, separating phases, extracting the aqueous phase once with ethyl acetate, combining ethyl acetate, washing once with saturated saline, and drying with anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to remove ethyl acetate to obtain compound M 1 406.85g, the gas phase purity was 95.3%.
Synthesis of Compound M in this example 1 The chemical reaction formula of (2) is as follows:
example 2
Compound M 1 Is synthesized by (a)
200g of epichlorohydrin and a 500ml reaction flask were charged with8.63g of chromium acetate, stirring and heating to 83 ℃, and preserving heat for reaction for 4 hours. After incubation, cooling to 20 ℃, adding 200mL of ethyl acetate and 200mL of water, stirring for 5-10 minutes, separating phases, extracting the aqueous phase once with ethyl acetate, combining ethyl acetate, washing once with saturated saline, and drying with anhydrous sodium sulfate. Filtering, concentrating under reduced pressure to remove ethyl acetate to obtain compound M 1 406.85g, the gas phase purity was 95.2%.
Synthesis of Compound M in this example 1 The chemical reaction formula of (2) is as follows:
example 3
Compound M 2 Is synthesized by (a)
Into a 1000mL reaction flask, compound M was introduced 1 400g, 30g of paraformaldehyde and 2mL of concentrated sulfuric acid, and the temperature is raised to 93 ℃ for reaction for 6 hours. 502.7g of acetic anhydride is slowly added dropwise at the temperature of 15 ℃, the adding speed is preferably 0.1L/min, the temperature is raised to room temperature for preserving heat for reaction for 7 hours after the adding, and stirring is carried out overnight. Adding 10.5g potassium acetate, stirring for 15 min, vacuum filtering, adding the residue into water, extracting with ethyl acetate, repeating the extraction for three times, drying the organic phase, and concentrating to obtain compound M 2 655.1g, the gas phase purity was 95.8%.
Synthesis of Compound M in this example 2 The chemical reaction formula of (2) is as follows:
example 4
Compound M 2 Is synthesized by (a)
Into a 1000mL reaction flask, compound M was introduced 1 400g, 30g of paraformaldehyde and 2mL of concentrated phosphoric acid, and the temperature is raised to 93 ℃ for reaction for 6 hours. Cooling to 15 ℃, slowly dripping 503.1g of acetic anhydride with the preferable dripping speed of 0.1L/min, heating to room temperature for preserving heat for reaction for 7 hours after dripping, and stirring overnight. 10.5g of potassium acetate is added, stirred for 15 minutes and pumpedFiltering, adding the residue into water, extracting with ethyl acetate, repeating the extraction for three times, drying the organic phase, and concentrating to obtain compound M 2 631.5g, the gas phase purity was 95.4%.
Synthesis of Compound M in this example 2 The chemical reaction formula of (2) is as follows:
example 5
Synthesis of ganciclovir impurity
Into a 2000mL reaction flask, 880g of N2, 9-diacetylguanine and compound M were introduced 2 650g, 1000mL of DMF and 6.5g of p-toluenesulfonic acid, and the temperature is raised to 97 ℃ and the reaction is carried out for 9 hours. After heat preservation, concentrating, adding 800mL of petroleum ether into the residue, cooling to 15 ℃, crystallizing overnight, filtering, washing the obtained filter cake with petroleum ether, and drying to obtain 1021.1g of ganciclovir impurity crude product. Mixing ganciclovir impurity crude product with ethanol, heating to 80 ℃ and stirring for 1h, cooling to room temperature, cooling the obtained refined system to 5 ℃, standing overnight for crystallization, suction filtering, washing the obtained filter cake with ethanol, and drying to obtain 980.5g ganciclovir impurity with HPLC purity of 99.2%.
The chemical reaction formula for synthesizing ganciclovir impurities in this example is as follows:
example 6
Synthesis of ganciclovir impurity
Into a 2000mL reaction flask, 855.4g of N2,9 diacetylguanine and Compound M were introduced 2 630.0g, 1000mL of toluene and 6.3g of p-toluenesulfonic acid, and the temperature was raised to 97 ℃ and the reaction was carried out for 9 hours. After heat preservation, concentrating, adding 800mL of petroleum ether into the residue, cooling to 15 ℃, crystallizing overnight, filtering, washing the obtained filter cake with petroleum ether, and drying to obtain 1011.2g of ganciclovir impurity crude product. Mixing ganciclovir impurity crude product with ethanol, heating to 80deg.CStirring for 1h, cooling to room temperature, cooling the refined system to 5 ℃, standing overnight for crystallization, carrying out suction filtration, washing the obtained filter cake with ethanol, and drying to obtain 960.6g of ganciclovir impurity with the HPLC purity of 99.1%.
The chemical reaction formula for synthesizing ganciclovir impurities in this example is as follows:
as shown in FIG. 1, the figure is a ganciclovir impurity 1 H-NMR spectra, in which 10 groups of peaks are visible, of which δ=2.49 is the peak of the solvent DMSO, δ=3.34 is the water peak, the number of hydrogens is half of the original one, δ=12.06 is a group of single peaks of one amino hydrogen of guanine 3, δ= 11.79 is a group of single peaks of one amino hydrogen of acetamido 2 of guanine, δ=8.15 is a group of single peaks of 1 one aryl hydrogen of guanine 8, δ=5.58 is a group of single peaks of 2 hydrogens of 10 of methylene, δ=4.08 is a group of quadruple peaks of 1 hydrogen of 12 of tertiary carbon, δ=3.74 is a group of multiple peaks of 2 hydrogens of 11 of methylene, δ=3.64 is a group of multiple peaks of 2 hydrogens of 2 of 13 of acetamido, and δ=5.58 is a group of single peaks of 3 hydrogens of acetyl of 3 of methyl of 11 of the acetamido of methyl of 12 of the amino group; therefore, the nuclear magnetic data is 1 H NMR(400MHz,DMSO-d 6 ) δ12.06 (s, 1H), 11.79 (s, 1H), 8.15 (s, 1H), 5.58 (s, 2H), 4.08 (q, j=5.1 hz, 1H), 3.74 (dd, j=11.8 hz, j=4.4 hz, 2H), 3.64 (dd, j=11.8 hz, j=5.7 hz, 2H), 2.17 (s, 3H). Figure 1 can demonstrate that ganciclovir impurity is produced.
As shown in FIG. 2, which shows the LC-MS spectrum of ganciclovir impurity, there can be seen two spectra, upper in the liquid phase and lower in the mass spectrum, where Time=2.17 is the peak of ganciclovir impurity in the liquid phase, detected in the mass spectrum [ M+C 4 H 5 ] + = 665.2 corresponds to reality; thus the mass spectrum data of ganciclovir impurity is HRMS (ESI) M/z: [ M+C ] 4 H 5 ] + calcd for,C 26 H 31 C l2 N 10 O 7 665.2,found 665.2, further demonstrated that the synthesized compound was ganciclovir impurity.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.
Claims (10)
1. A method for synthesizing and refining ganciclovir impurities is characterized in that: the method specifically comprises the following steps:
step a, synthesizing Compound M 1
Epoxy chloropropane is used as raw material, and the reaction time t is passed under the catalysis of Lewis acid 1 Reacting to obtain a reaction system I, and performing first post-treatment on the reaction system I to obtain a compound M 1 The chemical reaction formula is as follows:
step b, synthesis of Compound M 2
The compound M prepared in the step a is reacted with 1 Reacts with paraformaldehyde under the catalysis of inorganic acid for a reaction time t 2 After the reaction, a reaction system II is prepared, the reaction system II is cooled, acid anhydride is slowly dripped at low temperature, and then the reaction time t is passed at room temperature 3 After the reaction, a reaction system III is prepared, and then the reaction system III is subjected to second post-treatment to obtain a compound M 2 The chemical reaction formula is as follows:
step c, condensation reaction
The compound M prepared in the step b 2 Adding into organic solvent, and under the catalysis of organic acid, performing condensation reaction with N2, 9-diacetylguanine for reaction time t 4 Reacting to obtain a reaction system IV, and then performing third post-treatment on the reaction system IV to obtain a ganciclovir impurity crude product; and then refining the ganciclovir impurity crude product by using a refining liquid to obtain a finished product ganciclovir impurity, wherein the chemical reaction formula is as follows:
2. the method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: in the step a, the mol ratio of the epichlorohydrin to the Lewis acid is 1:0.02-1:0.05, the reaction temperature is 80-100 ℃, and the reaction time t is the following 1 2-8 h; the Lewis acid in the step a is one or more selected from antimony trichloride, chromium acetate and copper acetate.
3. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: compound M in said step b 1 The molar ratio of the polymer to the paraformaldehyde monomer is 1:1-1:5; the reaction temperature after adding paraformaldehyde is 80-100 ℃ and the reaction time t 2 4-16 h;
b, slowly dropwise adding anhydride after the temperature of the reaction system in the step is reduced to 0-25 ℃; compound M in step b 1 The molar ratio of the catalyst to the anhydride is 1:1.5-1:5, and the reaction time t is as follows 3 For 5-10 h.
4. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: in the step b, the inorganic acid is selected from one or more of concentrated sulfuric acid, concentrated phosphoric acid and concentrated nitric acid, and the anhydride is selected from one or more of acetic anhydride, propionic anhydride and trifluoroacetic anhydride.
5. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: compound M in said step c 2 The molar ratio of the N2, 9-diacetylguanine to the organic acid is 1:2-1:4, and the molar ratio of the N2, 9-diacetylguanine to the organic acid is 1:0.02-1:0.05; in the step c, the reaction temperature is 90-120 ℃ and the reaction time t 4 4-16 h.
6. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: in the step c, the organic acid is selected from one or more of p-toluenesulfonic acid, p-acetamidobenzenesulfonic acid and trifluoroacetic acid, the organic solvent is selected from one or more of N, N' -dimethylformamide, dimethyl sulfoxide and toluene, and the refined solution is selected from one or more of methanol, ethanol and isopropanol.
7. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: the first post-treatment in the step a is specifically to cool the obtained reaction system I to room temperature, add a mixed solution composed of ethyl acetate and water, wherein the volume ratio of the ethyl acetate to the water in the mixed solution is 1:1, and then carry out liquid separation, organic phase drying and concentration to obtain a compound M 1 。
8. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: the second post treatment in the step b is specifically that antimony trichloride is added into the obtained reaction system III, suction filtration is carried out, residues are added into water, extraction is carried out by ethyl acetate, the extraction is repeated for three times, the organic phase is dried, and the compound M is obtained by concentration 2 。
9. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: and c, the third post-treatment is specifically to concentrate the obtained reaction system IV, add petroleum ether into the residue to cool, perform crystallization overnight, perform suction filtration, wash the obtained filter cake with petroleum ether, and dry to obtain ganciclovir impurity crude products.
10. The method for synthesizing and refining ganciclovir impurities according to claim 1, wherein the method is characterized in that: and c, the refining process is specifically that the ganciclovir impurity crude product and the refining liquid are mixed and refined to obtain a refining system, the refining system is sequentially subjected to crystallization and suction filtration to obtain a filter cake, and the filter cake is sequentially washed and dried to obtain the finished ganciclovir impurity.
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