CN115819422A - Novel preparation process and analysis method of entecavir intermediate - Google Patents
Novel preparation process and analysis method of entecavir intermediate Download PDFInfo
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- CN115819422A CN115819422A CN202211592998.XA CN202211592998A CN115819422A CN 115819422 A CN115819422 A CN 115819422A CN 202211592998 A CN202211592998 A CN 202211592998A CN 115819422 A CN115819422 A CN 115819422A
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- 229960000980 entecavir Drugs 0.000 title claims abstract description 19
- YXPVEXCTPGULBZ-WQYNNSOESA-N entecavir hydrate Chemical compound O.C1=NC=2C(=O)NC(N)=NC=2N1[C@H]1C[C@H](O)[C@@H](CO)C1=C YXPVEXCTPGULBZ-WQYNNSOESA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 7
- 238000004458 analytical method Methods 0.000 title claims description 12
- 238000006243 chemical reaction Methods 0.000 claims abstract description 76
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 28
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 24
- 238000010791 quenching Methods 0.000 claims abstract description 24
- 238000003756 stirring Methods 0.000 claims abstract description 23
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 22
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 21
- 239000012074 organic phase Substances 0.000 claims abstract description 20
- CIHOLLKRGTVIJN-UHFFFAOYSA-N tert‐butyl hydroperoxide Chemical compound CC(C)(C)OO CIHOLLKRGTVIJN-UHFFFAOYSA-N 0.000 claims abstract description 20
- 238000000034 method Methods 0.000 claims abstract description 18
- 230000000171 quenching effect Effects 0.000 claims abstract description 16
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 claims abstract description 13
- 229910052796 boron Inorganic materials 0.000 claims abstract description 13
- GLYOPNLBKCBTMI-UHFFFAOYSA-N [2-chloro-2-(1-chloro-2-phenylethoxy)ethyl]benzene Chemical compound C=1C=CC=CC=1CC(Cl)OC(Cl)CC1=CC=CC=C1 GLYOPNLBKCBTMI-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003054 catalyst Substances 0.000 claims abstract description 10
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000003960 organic solvent Substances 0.000 claims abstract description 9
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims abstract description 9
- 239000012312 sodium hydride Substances 0.000 claims abstract description 9
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229960005524 O6-benzylguanine Drugs 0.000 claims abstract description 8
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims abstract description 8
- 230000001590 oxidative effect Effects 0.000 claims abstract description 7
- 239000000543 intermediate Substances 0.000 claims description 46
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 31
- 239000007788 liquid Substances 0.000 claims description 30
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 claims description 27
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 14
- 238000000605 extraction Methods 0.000 claims description 13
- 235000010265 sodium sulphite Nutrition 0.000 claims description 13
- 239000002904 solvent Substances 0.000 claims description 13
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical class [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 11
- 230000006837 decompression Effects 0.000 claims description 11
- 239000012071 phase Substances 0.000 claims description 10
- 238000001514 detection method Methods 0.000 claims description 9
- 239000007791 liquid phase Substances 0.000 claims description 9
- 238000004519 manufacturing process Methods 0.000 claims description 9
- 238000005406 washing Methods 0.000 claims description 9
- 239000007864 aqueous solution Substances 0.000 claims description 8
- FSJSYDFBTIVUFD-SUKNRPLKSA-N (z)-4-hydroxypent-3-en-2-one;oxovanadium Chemical group [V]=O.C\C(O)=C\C(C)=O.C\C(O)=C\C(C)=O FSJSYDFBTIVUFD-SUKNRPLKSA-N 0.000 claims description 7
- 230000007062 hydrolysis Effects 0.000 claims description 7
- 238000006460 hydrolysis reaction Methods 0.000 claims description 7
- 229910000103 lithium hydride Inorganic materials 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 7
- 238000010828 elution Methods 0.000 claims description 5
- 239000012156 elution solvent Substances 0.000 claims description 4
- 238000010438 heat treatment Methods 0.000 claims description 4
- JQUZTGJSSQCTPV-UHFFFAOYSA-N sodium;cyclopenta-1,3-diene Chemical compound [Na+].C1C=CC=[C-]1 JQUZTGJSSQCTPV-UHFFFAOYSA-N 0.000 claims description 4
- 239000000203 mixture Substances 0.000 claims description 3
- WHXSMMKQMYFTQS-UHFFFAOYSA-N Lithium Chemical group [Li] WHXSMMKQMYFTQS-UHFFFAOYSA-N 0.000 claims 1
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 5
- 238000009776 industrial production Methods 0.000 abstract description 3
- 239000002910 solid waste Substances 0.000 abstract description 3
- 150000001875 compounds Chemical class 0.000 abstract description 2
- NUUNDIOOYFEMQN-UHFFFAOYSA-N cyclopenta-1,3-diene;sodium Chemical compound [Na].C1C=CC=C1 NUUNDIOOYFEMQN-UHFFFAOYSA-N 0.000 abstract description 2
- 230000003301 hydrolyzing effect Effects 0.000 abstract 1
- 239000000047 product Substances 0.000 description 26
- 238000000926 separation method Methods 0.000 description 16
- 238000004809 thin layer chromatography Methods 0.000 description 15
- 239000000243 solution Substances 0.000 description 10
- SIAPCJWMELPYOE-UHFFFAOYSA-N lithium hydride Chemical group [LiH] SIAPCJWMELPYOE-UHFFFAOYSA-N 0.000 description 6
- 229920006395 saturated elastomer Polymers 0.000 description 6
- 238000004064 recycling Methods 0.000 description 5
- OHUVHDUNQKJDKW-UHFFFAOYSA-N sodium;cyclopenta-1,3-diene Chemical compound [Na+].C=1C=C[CH-]C=1 OHUVHDUNQKJDKW-UHFFFAOYSA-N 0.000 description 5
- 239000012043 crude product Substances 0.000 description 4
- 230000003647 oxidation Effects 0.000 description 4
- 238000007254 oxidation reaction Methods 0.000 description 4
- 238000004807 desolvation Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- SYPCZZWUNIHLBU-COROXYKFSA-N (1s,2s,3s,5s)-5-(2-amino-6-phenylmethoxypurin-9-yl)-3-phenylmethoxy-2-(phenylmethoxymethyl)cyclopentan-1-ol Chemical compound C=12N=CN([C@@H]3[C@H]([C@H](COCC=4C=CC=CC=4)[C@@H](OCC=4C=CC=CC=4)C3)O)C2=NC(N)=NC=1OCC1=CC=CC=C1 SYPCZZWUNIHLBU-COROXYKFSA-N 0.000 description 2
- UCSBYEUUBDCVKP-UHFFFAOYSA-N 4,6,6-trimethylbicyclo[3.1.1]hept-3-en-5-ol Chemical compound CC1=CCC2C(C)(C)C1(O)C2 UCSBYEUUBDCVKP-UHFFFAOYSA-N 0.000 description 2
- 239000006227 byproduct Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- ZSWFCLXCOIISFI-UHFFFAOYSA-N cyclopentadiene Chemical compound C1C=CC=C1 ZSWFCLXCOIISFI-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000000199 molecular distillation Methods 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 1
- 238000011065 in-situ storage Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
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Abstract
The invention belongs to the technical field of compounds, and discloses a novel preparation process method of an entecavir intermediate, which comprises the steps of reacting sodium cyclopentadiene with benzyl chloromethyl ether, dropwise adding boron trifluoride-THF complex, oxidizing and hydrolyzing, quenching, and desolventizing to obtain an intermediate S01; oxidizing the intermediate S01 with tert-butyl hydroperoxide under the action of a catalyst, quenching, and eluting with water to obtain an intermediate S02; reacting the intermediate S02 with sodium hydride, then dropwise adding benzyl bromide for reaction, adding ethanol after the reaction is completed to quench the reaction, performing reduced pressure desolventizing, extracting and separating with ethyl acetate/water, and desolventizing an organic phase to obtain an intermediate S03; and (3) stirring S03 and O-6-benzylguanine in an organic solvent under the action of a catalyst to completely react, removing DMF (dimethyl formamide) under reduced pressure, purifying residues by silica gel chromatography, and recrystallizing to obtain a finished product. A brand new process is adopted to replace a chiral boron reagent, so that hidden dangers are eliminated; meanwhile, a brand new purification method is adopted, so that a large amount of solid waste is avoided, the time cost is saved, the working hours are reduced, and the industrial production is facilitated.
Description
Technical Field
The invention relates to a novel preparation process method and an analysis method of an entecavir intermediate, belonging to the technical field of compounds.
Background
Entecavir intermediate, chemical name: (1S, 2S,3S, 5S) -5- (2-amino-6-benzyloxy-9H-purin-9-yl) -3-benzyloxy-2-benzyloxymethylcyclopentanol CAS number: 142217-77-4. Is used for producing the antiviral drug entecavir.
The process route in the prior art is as follows:
there are problems in that: the starting material adopts a chiral boron reagent, which is expensive, and the boron reagent is easy to release heat and spontaneously combust when meeting air; the process for preparing sodium cyclopentadiene by cyclopentadiene and sodium hydride in situ releases a large amount of hydrogen, the reaction is easy to wash materials, and potential safety hazards exist; the silica gel column chromatography is adopted for purification, a large amount of waste silica gel is generated, and the method has slow process and long working procedure time; the purification process needs to remove isomers, needs multiple times of crystallization and has low yield.
Therefore, the synthetic method in the prior art has a plurality of problems, and a brand-new process is adopted to replace a chiral boron reagent, so that hidden dangers are eliminated; meanwhile, a brand new purification method is adopted, so that a large amount of solid waste is avoided, the time cost is saved, the working hours are reduced, and the industrial production is facilitated.
Disclosure of Invention
The invention aims to provide a novel preparation process method and an analysis method of an entecavir intermediate, and in order to achieve the aim, the invention is realized by adopting the following technical scheme:
the invention discloses a novel preparation process method of an entecavir intermediate, which comprises the following steps:
the specific method comprises the following steps:
(1) Stirring sodium cyclopentadienide and benzyl chloromethyl ether at low temperature until the reaction is complete, then dropwise adding boron trifluoride-THF complex, heating for reaction, adding 30% hydrogen peroxide and saturated sodium hydroxide aqueous solution, adding sodium sulfite for quenching after oxidizing hydrolysis is finished, washing, extracting, separating liquid, and removing solvent by organic phase under reduced pressure to obtain an intermediate S01;
(2) Oxidizing the intermediate S01 by tert-butyl hydroperoxide under a catalyst, adding a sodium sulfite aqueous solution to quench after the reaction is completed, washing the extraction liquid, and desolventizing to obtain an intermediate S02;
(3) Reacting the intermediate S02 with sodium hydride in an organic solvent, then dropwise adding benzyl bromide for reaction, adding ethanol for quenching reaction after the reaction is completed, extracting and separating liquid by ethyl acetate/water after decompression and desolventizing, and obtaining an intermediate S03 after organic phase desolventizing;
(4) And (3) stirring S03 and O-6-benzylguanine in an organic solvent under the action of a catalyst to completely react, removing DMF (dimethyl formamide) under reduced pressure, purifying residues by silica gel chromatography, and recrystallizing to obtain a finished product.
Further, in step 1, the molar ratio of the sodium cyclopentadienide to the benzyl chloromethyl ether is: 1: (0.8-2.5).
Further, in step 2, the molar ratio of the intermediate S01 to the tert-butyl hydroperoxide is: 1: (2.4-3.8).
Further, in step 2, the catalyst is vanadyl acetylacetonate.
Further, in step 3, the reaction temperature is reduced to 5 ℃ or below.
Further, in step 3, the organic solvent is tetrahydrofuran.
Further, in step 4, the organic solvent is DMF.
Further, in step 4, the catalyst is lithium hydride.
Further, in step 4, the elution solvent is dichloromethane and methanol.
Further, in step 4, the recrystallization is ethanol recrystallization.
Simultaneously, the method for detecting the content of the entecavir intermediate is also disclosed, and specifically comprises the following steps:
the high performance liquid phase analysis method is adopted and comprises the following steps:
a chromatographic column: innoval ODS-3 (250 mm. Times.4.6 mm,5 μm);
mobile phase A: water;
mobile phase B: acetonitrile;
flow rate: 1.0ml/min; detection wavelength: 254nm; column temperature: 35 deg.C
Sample concentration: 0.8mg/ml; sample introduction amount: 10 mu l of the mixture;
solvent: 80% acetonitrile in water;
elution gradient:
| Time | mobile phase A% | Mobile phase B% |
| 0 | 97 | 3 |
| 10 | 97 | 3 |
| 30 | 10 | 90 |
| 35 | 10 | 90 |
| 40 | 97 | 3 |
| 60 | 97 | 3 |
Compared with the prior art, the invention has the following beneficial effects: the novel process is adopted to replace a chiral boron reagent, so that hidden dangers are eliminated; meanwhile, a brand new purification method is adopted, so that a large amount of solid waste is avoided, the time cost is saved, the working hours are reduced, and the industrial production is facilitated.
Drawings
FIG. 1 is a liquid chromatogram of intermediate S02 of example 1 of the present invention;
FIG. 2, liquid chromatogram of the product of example 1 of the present invention;
FIG. 3 is a liquid chromatogram of intermediate S02 of example 2 of the present invention;
FIG. 4, liquid chromatogram of the product of example 2 of the present invention;
FIG. 5 is a liquid chromatogram of intermediate S02 of example 3 of the present invention;
FIG. 6 is a liquid chromatogram of the product of example 3 of the present invention.
Detailed Description
The invention is further described below. The following examples are only for illustrating the technical solutions of the present invention more clearly, and the protection scope of the present invention is not limited thereby.
Example 1
22g of cyclopentadienyl sodium is added into a reaction bottle, stirring is started, 47g of benzyl chloromethyl ether is added into the reaction bottle at low temperature and stirred until the reaction is completed, then the prepared boron trifluoride-THF complex is dropwise added into the reaction bottle, 25ml of 30% hydrogen peroxide and 10ml of saturated sodium hydroxide aqueous solution are added after the temperature rise reaction, 25g of sodium sulfite is added for quenching after the oxidation hydrolysis is completed, and after water washing extraction liquid separation, organic phase decompression is carried out to obtain 33.26g of intermediate S01 altogether, and the yield is 65.2%.
34g of crude product of S01, 4.4g of vanadyl acetylacetonate and 175ml of DCM are added into a reaction bottle, 18g of tert-butyl hydroperoxide are added in batches, TLC is used for detecting the reaction completion, 100ml of saturated aqueous sodium sulfite solution is added for quenching, standing and liquid separation are carried out, an organic phase is washed by 100ml of water for extraction, liquid separation is carried out, desolventization is carried out, 30.7g of intermediate S02 is obtained totally, and the yield is 83.7%. The purity of the product is 99.08%, and is shown in a liquid phase analysis spectrogram 1 shown in the attached figure.
30.0g of S02 and 300ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to below 5 ℃, 6.55g of sodium hydride is added, 30g of benzyl bromide is added after stirring for 10min, ethanol is added after TLC detection reaction is completed to quench the reaction, ethyl acetate/water (250 ml/250 ml) is used for extraction and liquid separation after decompression and desolventization, 30.69g of intermediate S03 is obtained after organic phase desolventization, and the yield is 72.6%.
Adding 31g of S03, 26.55g of O-6-benzylguanine, 425mg of lithium hydride and 250ml of DMF into a reaction bottle, stirring for reaction, detecting by TLC (thin layer chromatography), removing the DMF under reduced pressure, purifying residues by silica gel chromatography, taking dichloromethane and methanol as eluting solvents, collecting a product part, recycling the solvents by desolventizing under reduced pressure, recycling the solvents for direct use, and recrystallizing the distilled product by using 100ml of ethanol to obtain 46.06g of a finished product, wherein the yield is 83.6%. The purity of the product is 99.94%, see liquid phase analysis spectrogram 2 shown in the attached figure.
Example 2
22.0g of cyclopentadienyl sodium is added into a reaction bottle, stirring is started, 41g of benzyl chloromethyl ether is added into the reaction bottle at low temperature, stirring is carried out till the reaction is complete, then the prepared boron trifluoride-THF complex is dropwise added into the reaction bottle, 30ml of 30% hydrogen peroxide and 15ml of saturated sodium hydroxide aqueous solution are added after the temperature rise reaction, 20g of sodium sulfite is added for quenching after the oxidation hydrolysis is finished, and after washing, extraction and liquid separation are carried out, organic phase decompression is carried out, and 31.02g of the intermediate S01 is obtained.
34g of crude product of S01, 4.1g of vanadyl acetylacetonate and 200ml of DCM are added into a reaction bottle, 15g of tert-butyl hydroperoxide are added in batches, TLC is used for detecting the reaction completion, 100ml of saturated aqueous sodium sulfite solution is added for quenching, standing and liquid separation are carried out, an organic phase is washed by 100ml of water for extraction, liquid separation is carried out, and desolventization is carried out to obtain 25.8g of intermediate S02. The product purity is 99.08%, see liquid phase analysis spectrogram 3 shown in figure.
30.0g of S02 and 300ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to below 5 ℃, 6.14g of sodium hydride is added, 25g of benzyl bromide is added dropwise after stirring for 10min, ethanol is added to quench the reaction after the TLC detection reaction is completed, the reaction is carried out, ethyl acetate/water (250 ml/250 ml) is used for extraction and liquid separation after decompression and desolventization, and 25.82g of the intermediate S03 is obtained after organic phase desolventization.
Adding 31g of S03, 21.59g of O-6-benzyl guanine, 450mg of lithium hydride and 250ml of DMF into a reaction bottle, stirring for reaction, detecting by TLC (thin layer chromatography), removing DMF under reduced pressure, purifying residues by silica gel chromatography, using dichloromethane and methanol as eluting solvents, collecting product parts, recycling the solvents by decompression and desolvation, and recrystallizing the distilled products by 100ml of ethanol to obtain 42.15g of finished products. The purity of the product is 99.94%, and is shown in a liquid phase analysis spectrogram 4 shown in the attached figure.
Example 3
22.0g of cyclopentadienyl sodium is added into a reaction bottle, stirring is started, 47g of benzyl chloromethyl ether is added into the reaction bottle at low temperature and stirred until the reaction is completed, then prepared boron trifluoride-THF complex is dropwise added into the reaction bottle, 25ml of 30% hydrogen peroxide and 10ml of saturated sodium hydroxide aqueous solution are added after the temperature rise reaction, 25g of sodium sulfite is added for quenching after the oxidation hydrolysis is completed, and after washing, extraction and liquid separation, organic phase decompression is carried out to obtain 33.26g of intermediate S01 altogether, and the yield is 65.2%.
34g of crude S01 product, 4.4g of vanadyl acetylacetonate and 175ml of DCM are added into a reaction bottle, 18g of tert-butyl hydroperoxide are added in batches, TLC is used for detecting the reaction is completed, 100ml of saturated aqueous sodium sulfite solution is added for quenching, standing and liquid separation are carried out, an organic phase is washed by 100ml of water for extraction liquid separation and then desolventization is carried out, 30.7g of intermediate S02 is obtained, and the yield is 83.7%. The purity of the product is 99.08%, see liquid phase analysis spectrogram 5 shown in the attached figure.
30.0g of S02 and 300ml of tetrahydrofuran are added into a reaction bottle, the temperature is reduced to below 5 ℃, 6.55g of sodium hydride is added, 30g of benzyl bromide is added after stirring for 10min, ethanol is added after TLC detection reaction is completed to quench the reaction, ethyl acetate/water (250 ml/250 ml) is used for extraction and liquid separation after decompression and desolventization, 30.69g of intermediate S03 is obtained after organic phase desolventization, and the yield is 72.6%.
Adding 31g of S03, 26.55g of O-6-benzylguanine, 425mg of lithium hydride and 250ml of DMF into a reaction bottle, stirring for reaction, detecting by TLC (thin layer chromatography), removing the DMF under reduced pressure, purifying residues by silica gel chromatography, taking dichloromethane and methanol as eluting solvents, collecting a product part, recycling the solvents by desolventizing under reduced pressure, recycling the solvents for direct use, and recrystallizing the distilled product by using 100ml of ethanol to obtain 46.06g of a finished product, wherein the yield is 83.6%. The product purity is 99.94%, see liquid phase analysis spectrogram 6 shown in figure.
Example 4
The liquid phase detection method in examples 1 to 3 was:
a chromatographic column: innoval ODS-3 (250 mm. Times.4.6 mm,5 μm);
mobile phase A: water;
mobile phase B: acetonitrile;
flow rate: 1.0ml/min; detection wavelength: 254nm; column temperature: 35 deg.C
Sample concentration: 0.8mg/ml; sample introduction amount: 10 mu l of the mixture;
solvent: 80% acetonitrile in water;
elution gradient:
| Time | mobile phase A% | Mobile |
| 0 | 97 | 3 |
| 10 | 97 | 3 |
| 30 | 10 | 90 |
| 35 | 10 | 90 |
| 40 | 97 | 3 |
| 60 | 97 | 3 |
Example 5
1) Adding 4.40 Kg of cyclopentadienyl sodium into a reaction kettle, starting stirring, adding 9.40 Kg of benzyl chloromethyl ether at low temperature, stirring till the reaction is complete, dropwise adding the prepared boron trifluoride-THF complex, heating for reaction, adding 5L of 30% hydrogen peroxide and 2L of saturated aqueous sodium hydroxide solution, quenching by adding 5Kg of sodium sulfite after the oxidation and hydrolysis are finished, washing, extracting, separating liquid, decompressing and dissolving by organic phase, and removing by-product pinenol by molecular distillation of the desolvated substance to obtain 6.17 Kg of intermediate S01 with the yield of 60.4%.
2) 6.80 Kg of S01 crude product, 0.88 Kg of vanadyl acetylacetonate and 35L of DCM are added into a reaction kettle, 3.6 Kg of tert-butyl hydroperoxide are added in batches, TLC is used for detecting the reaction is completed, 20L of saturated sodium sulfite aqueous solution is added for quenching, standing and liquid separation are carried out, an organic phase is washed by 20L of water for extraction, liquid separation is carried out, desolventization is carried out, 5.74 Kg of intermediate S02 is obtained, and the yield is 78.2%.
3) Adding 3.0 Kg of S02 and 30L of tetrahydrofuran into a reaction kettle, cooling to below 5 ℃, adding 0.65Kg of sodium hydride, stirring for 10min, then dropwise adding 2.8 Kg of benzyl bromide, adding ethanol to quench the reaction after TLC detection, extracting and separating the solution by using ethyl acetate/water (25L/25L) after decompression and desolvation, and obtaining 2.78 Kg of intermediate S03 in total after organic phase desolvation, wherein the yield is 65.8%.
4) 3.1 Kg of S03,2.6 Kg of O-6-benzylguanine, 42 g of lithium hydride and 25L of DMF are added into a reaction kettle for stirring reaction, TLC detects that the reaction is complete, the DMF is removed under reduced pressure, the residue is purified by silica gel chromatography, dichloromethane and methanol are used as elution solvents, the product part is collected, the elution solution is recovered by reduced pressure desolventization and is directly used, the distillation product is recrystallized by 10L of ethanol to obtain 4.31 Kg of finished product, and the yield is 78.2%.
Example 6
1) Adding 4.40 Kg of cyclopentadienyl sodium into a reaction kettle, starting stirring, adding 10.80 Kg of benzyl chloromethyl ether at low temperature, stirring till the reaction is complete, dropwise adding the prepared boron trifluoride-THF complex, heating for reaction, adding 5L of 30% hydrogen peroxide and 2L of saturated aqueous sodium hydroxide solution, quenching by adding 5Kg of sodium sulfite after oxidizing hydrolysis, washing, extracting, separating liquid, decompressing and dissolving the organic phase, and removing a byproduct pinenol by molecular distillation of a desolventized substance to obtain 6.19Kg of intermediate S01.
2) 6.19Kg of crude product of S01, 0.94Kg of vanadyl acetylacetonate and 35L of DCM are added into a reaction kettle, 3.8Kg of tert-butyl hydroperoxide are added in batches, TLC is used for detecting the reaction is completed, 20L of saturated aqueous sodium sulfite solution is added for quenching, standing and liquid separation are carried out, the organic phase is washed by 20L of water for extraction, liquid separation is carried out, and desolventization is carried out to obtain 5.47Kg of intermediate S02.
3) Adding 5.47Kg of S02 and 30L of tetrahydrofuran into a reaction kettle, cooling to below 5 ℃, adding 0.71Kg of sodium hydride, stirring for 10min, dropwise adding 3.0 Kg of benzyl bromide, adding ethanol to quench the reaction after the TLC detection reaction is completed, performing decompression and desolventization, extracting and separating by using ethyl acetate/water (25L/25L), and obtaining 4.98 Kg of intermediate S03 in total after the organic phase is desolventized.
4) 4.98 Kg of S03,4.6 Kg of O-6-benzylguanine, 45g of lithium hydride and 25L of DMF are added into a reaction kettle for stirring reaction, TLC detects that the reaction is complete, the DMF is removed under reduced pressure, the residue is purified by silica gel chromatography, dichloromethane and methanol are used as elution solvents, the product part is collected, the elution solution is recovered by reduced pressure desolventization and is directly used, and the distilled product is recrystallized by 10L of ethanol to obtain 5.02Kg of finished product.
The above is only a preferred embodiment of the present invention, and it should be noted that, for those skilled in the art, it is possible to make several improvements and modifications without departing from the technical principle of the present invention, and these improvements and modifications should also be considered as the protection scope of the present invention.
Claims (10)
1. A novel preparation process method of an entecavir intermediate is characterized by comprising the following steps:
(1) Stirring sodium cyclopentadienide and benzyl chloromethyl ether at low temperature until the reaction is complete, then dropwise adding boron trifluoride-THF complex, heating for reaction, adding 30% hydrogen peroxide and saturated sodium hydroxide aqueous solution, adding sodium sulfite for quenching after oxidizing hydrolysis is finished, washing, extracting, separating liquid, and removing solvent by organic phase under reduced pressure to obtain an intermediate S01;
(2) Oxidizing the intermediate S01 by tert-butyl hydroperoxide under a catalyst, adding a sodium sulfite aqueous solution to quench after the reaction is completed, washing the extraction liquid, and desolventizing to obtain an intermediate S02;
(3) Reacting the intermediate S02 with sodium hydride in an organic solvent, then dropwise adding benzyl bromide for reaction, adding ethanol for quenching reaction after the reaction is completed, extracting and separating liquid by ethyl acetate/water after decompression and desolventizing, and obtaining an intermediate S03 after organic phase desolventizing;
(4) And (3) stirring S03 and O-6-benzylguanine in an organic solvent under the action of a catalyst to completely react, removing DMF (dimethyl formamide) under reduced pressure, purifying residues by silica gel chromatography, and recrystallizing to obtain a finished product.
2. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: in step 1, the molar ratio of sodium cyclopentadienide to benzyl chloromethyl ether is: 1: (0.8-2.5).
3. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: the molar ratio of the intermediate S01 to the tert-butyl hydroperoxide is as follows: 1: (2.4-3.8).
4. The novel process for preparing entecavir intermediates of claim 1, wherein: the catalyst is vanadyl acetylacetonate.
5. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: the reaction temperature is reduced to 5 ℃ or below.
6. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: the organic solvent is tetrahydrofuran.
7. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: the organic solvent is DMF.
8. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: the catalyst is lithium hydride.
9. The novel process for preparing entecavir intermediate as claimed in claim 1, wherein: the elution solvents were dichloromethane and methanol.
10. A method for detecting the content of an entecavir intermediate specifically comprises the following steps:
conditions for high performance liquid phase analysis
A chromatographic column: innoval ODS-3 (250 mm. Times.4.6 mm,5 μm);
mobile phase A: water;
and (3) mobile phase B: acetonitrile;
flow rate: 1.0ml/min; detection wavelength: 254nm; column temperature: 35 deg.C
Sample concentration: 0.8mg/ml; sample introduction amount: 10 mu l of the mixture;
solvent: 80% acetonitrile in water;
elution gradient:
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