CN101531660B - Industrialization production process of entecavir-monohydrate - Google Patents
Industrialization production process of entecavir-monohydrate Download PDFInfo
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- 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 12
- 238000004519 manufacturing process Methods 0.000 title abstract description 15
- 229950010614 entecavir monohydrate Drugs 0.000 title abstract 2
- 238000006243 chemical reaction Methods 0.000 claims abstract description 34
- 238000002360 preparation method Methods 0.000 claims abstract description 28
- 238000000034 method Methods 0.000 claims abstract description 27
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims abstract description 10
- 230000008569 process Effects 0.000 claims abstract description 8
- 239000007818 Grignard reagent Substances 0.000 claims abstract description 5
- 150000004795 grignard reagents Chemical class 0.000 claims abstract description 5
- GNEPOXWQWFSSOU-UHFFFAOYSA-N dichloro-methyl-phenylsilane Chemical compound C[Si](Cl)(Cl)C1=CC=CC=C1 GNEPOXWQWFSSOU-UHFFFAOYSA-N 0.000 claims abstract description 4
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 28
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 21
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 18
- 229910052757 nitrogen Inorganic materials 0.000 claims description 14
- 238000001035 drying Methods 0.000 claims description 12
- 239000007788 liquid Substances 0.000 claims description 10
- 238000005406 washing Methods 0.000 claims description 10
- 229960000980 entecavir Drugs 0.000 claims description 9
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 8
- 239000005046 Chlorosilane Substances 0.000 claims description 7
- KOPOQZFJUQMUML-UHFFFAOYSA-N chlorosilane Chemical compound Cl[SiH3] KOPOQZFJUQMUML-UHFFFAOYSA-N 0.000 claims description 7
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical group CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 6
- NUUNDIOOYFEMQN-UHFFFAOYSA-N cyclopenta-1,3-diene;sodium Chemical compound [Na].C1C=CC=C1 NUUNDIOOYFEMQN-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 3
- DOBRDRYODQBAMW-UHFFFAOYSA-N copper(i) cyanide Chemical compound [Cu+].N#[C-] DOBRDRYODQBAMW-UHFFFAOYSA-N 0.000 claims description 3
- PQVSTLUFSYVLTO-UHFFFAOYSA-N ethyl n-ethoxycarbonylcarbamate Chemical compound CCOC(=O)NC(=O)OCC PQVSTLUFSYVLTO-UHFFFAOYSA-N 0.000 claims description 3
- GLXDVVHUTZTUQK-UHFFFAOYSA-M lithium hydroxide monohydrate Substances [Li+].O.[OH-] GLXDVVHUTZTUQK-UHFFFAOYSA-M 0.000 claims description 3
- 229940040692 lithium hydroxide monohydrate Drugs 0.000 claims description 3
- 239000011777 magnesium Substances 0.000 claims description 3
- 229910052749 magnesium Inorganic materials 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 229910021591 Copper(I) chloride Inorganic materials 0.000 claims description 2
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- MHABMANUFPZXEB-UHFFFAOYSA-N O-demethyl-aloesaponarin I Natural products O=C1C2=CC=CC(O)=C2C(=O)C2=C1C=C(O)C(C(O)=O)=C2C MHABMANUFPZXEB-UHFFFAOYSA-N 0.000 claims description 2
- 239000007810 chemical reaction solvent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- OXBLHERUFWYNTN-UHFFFAOYSA-M copper(I) chloride Chemical compound [Cu]Cl OXBLHERUFWYNTN-UHFFFAOYSA-M 0.000 claims description 2
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 238000001556 precipitation Methods 0.000 claims description 2
- 238000001953 recrystallisation Methods 0.000 claims description 2
- IWCVDCOJSPWGRW-UHFFFAOYSA-M magnesium;benzene;chloride Chemical compound [Mg+2].[Cl-].C1=CC=[C-]C=C1 IWCVDCOJSPWGRW-UHFFFAOYSA-M 0.000 claims 1
- 239000003054 catalyst Substances 0.000 abstract description 3
- 230000009471 action Effects 0.000 abstract description 2
- 230000001012 protector Effects 0.000 abstract 3
- 238000002444 silanisation Methods 0.000 abstract 3
- OJZNZOXALZKPEA-UHFFFAOYSA-N chloro-methyl-diphenylsilane Chemical compound C=1C=CC=CC=1[Si](Cl)(C)C1=CC=CC=C1 OJZNZOXALZKPEA-UHFFFAOYSA-N 0.000 abstract 2
- 230000002194 synthesizing effect Effects 0.000 abstract 1
- 238000003756 stirring Methods 0.000 description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000047 product Substances 0.000 description 13
- 238000010792 warming Methods 0.000 description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- 239000012044 organic layer Substances 0.000 description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 8
- 238000009413 insulation Methods 0.000 description 8
- 238000005516 engineering process Methods 0.000 description 7
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical class [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 5
- 239000008367 deionised water Substances 0.000 description 5
- 229910021641 deionized water Inorganic materials 0.000 description 5
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 238000009833 condensation Methods 0.000 description 4
- 230000005494 condensation Effects 0.000 description 4
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 3
- KRWMERLEINMZFT-UHFFFAOYSA-N O6-benzylguanine Chemical compound C=12NC=NC2=NC(N)=NC=1OCC1=CC=CC=C1 KRWMERLEINMZFT-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- -1 methylols Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 2
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 2
- 101100136092 Drosophila melanogaster peng gene Proteins 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 241000700721 Hepatitis B virus Species 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- 238000002425 crystallisation Methods 0.000 description 2
- 230000008025 crystallization Effects 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000006735 epoxidation reaction Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 208000002672 hepatitis B Diseases 0.000 description 2
- 230000001681 protective effect Effects 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 235000010265 sodium sulphite Nutrition 0.000 description 2
- CMBMUYICTPOEOA-UHFFFAOYSA-N (2-chloro-1-methoxyethyl)benzene Chemical compound COC(CCl)C1=CC=CC=C1 CMBMUYICTPOEOA-UHFFFAOYSA-N 0.000 description 1
- FGRBYDKOBBBPOI-UHFFFAOYSA-N 10,10-dioxo-2-[4-(N-phenylanilino)phenyl]thioxanthen-9-one Chemical compound O=C1c2ccccc2S(=O)(=O)c2ccc(cc12)-c1ccc(cc1)N(c1ccccc1)c1ccccc1 FGRBYDKOBBBPOI-UHFFFAOYSA-N 0.000 description 1
- DYOOCKYPJSMCFX-UHFFFAOYSA-N 2-phenylmethoxy-7h-purine Chemical compound N=1C=C2NC=NC2=NC=1OCC1=CC=CC=C1 DYOOCKYPJSMCFX-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- JEQPOGOWCGWUKL-UHFFFAOYSA-O C=CC(C=C)[SH+]c1ccccc1 Chemical compound C=CC(C=C)[SH+]c1ccccc1 JEQPOGOWCGWUKL-UHFFFAOYSA-O 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 239000004593 Epoxy Substances 0.000 description 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 1
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 1
- 102000003929 Transaminases Human genes 0.000 description 1
- 108090000340 Transaminases Proteins 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- LVZGQWKTUCVPBQ-UHFFFAOYSA-N acetic acid;trifluoroborane Chemical compound CC(O)=O.FB(F)F LVZGQWKTUCVPBQ-UHFFFAOYSA-N 0.000 description 1
- 230000006978 adaptation Effects 0.000 description 1
- 125000002947 alkylene group Chemical group 0.000 description 1
- 235000019270 ammonium chloride Nutrition 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 150000007942 carboxylates Chemical class 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 125000001309 chloro group Chemical group Cl* 0.000 description 1
- KWYZNESIGBQHJK-UHFFFAOYSA-N chloro-dimethyl-phenylsilane Chemical compound C[Si](C)(Cl)C1=CC=CC=C1 KWYZNESIGBQHJK-UHFFFAOYSA-N 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- VSSAZBXXNIABDN-UHFFFAOYSA-N cyclohexylmethanol Chemical compound OCC1CCCCC1 VSSAZBXXNIABDN-UHFFFAOYSA-N 0.000 description 1
- 238000006298 dechlorination reaction Methods 0.000 description 1
- NKLCNNUWBJBICK-UHFFFAOYSA-N dess–martin periodinane Chemical compound C1=CC=C2I(OC(=O)C)(OC(C)=O)(OC(C)=O)OC(=O)C2=C1 NKLCNNUWBJBICK-UHFFFAOYSA-N 0.000 description 1
- LSXWFXONGKSEMY-UHFFFAOYSA-N di-tert-butyl peroxide Chemical compound CC(C)(C)OOC(C)(C)C LSXWFXONGKSEMY-UHFFFAOYSA-N 0.000 description 1
- FBCCMZVIWNDFMO-UHFFFAOYSA-N dichloroacetyl chloride Chemical compound ClC(Cl)C(Cl)=O FBCCMZVIWNDFMO-UHFFFAOYSA-N 0.000 description 1
- XEBCWEDRGPSHQH-YUMQZZPRSA-N dipropan-2-yl (2s,3s)-2,3-dihydroxybutanedioate Chemical compound CC(C)OC(=O)[C@@H](O)[C@H](O)C(=O)OC(C)C XEBCWEDRGPSHQH-YUMQZZPRSA-N 0.000 description 1
- 150000002118 epoxides Chemical class 0.000 description 1
- 239000002223 garnet Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000000977 initiatory effect Effects 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- 239000010410 layer Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 238000005822 methylenation reaction Methods 0.000 description 1
- 239000002808 molecular sieve Substances 0.000 description 1
- CCTHTLJWXPUNGT-UHFFFAOYSA-L nysted reagent Chemical compound C1CCOC1.Br[Zn]C[Zn]C[Zn]Br CCTHTLJWXPUNGT-UHFFFAOYSA-L 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 238000007254 oxidation reaction Methods 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 1
- 235000015320 potassium carbonate Nutrition 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 238000007670 refining Methods 0.000 description 1
- 238000005057 refrigeration Methods 0.000 description 1
- 230000000630 rising effect Effects 0.000 description 1
- 238000007789 sealing Methods 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 238000010025 steaming Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- VXUYXOFXAQZZMF-UHFFFAOYSA-N titanium(IV) isopropoxide Chemical compound CC(C)O[Ti](OC(C)C)(OC(C)C)OC(C)C VXUYXOFXAQZZMF-UHFFFAOYSA-N 0.000 description 1
- FAQYAMRNWDIXMY-UHFFFAOYSA-N trichloroborane Chemical compound ClB(Cl)Cl FAQYAMRNWDIXMY-UHFFFAOYSA-N 0.000 description 1
- 238000001291 vacuum drying Methods 0.000 description 1
- 230000029812 viral genome replication Effects 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
Abstract
The invention provides an industrialization production process of entecavir-monohydrate. The special features of the process different from the other process are that: methyldiphenylchlorosilane is used as the silanization protector and special catalyst, thus the reaction temperature is -40 DEG C and the object product is smoothly produced (the reaction temperature is -78 DEG C in the prior process). Thus the production process is more suitable for industry production and because the silanization protector is cheaper and easily obtained, the production cost is greatly reduced. The invention comprises the preparation of methyldiphenylchlorosilane as the silanization protector which is obtained by directly synthesizing the methylphenyldichlorosilane and Grignard reagent of chlorobenzene under the action of special catalyst.
Description
Technical field:
The invention belongs to the organic synthesis pharmaceutical field, particularly a kind of synthesis technique of Entecavir hydrate.
Technical background:
Entecavir hydrate is an anti-hepatic-B virus medicine; Research and develop by U.S. Bristol Myers Squibb company; Went on the market in the U.S. first in 2005; The clinical virus replication that is used to treat adult patients is active, and serum transaminase (ALT or AST) continues to raise or liver histological shows the chronic viral hepatitis B of reactivity pathology.These article are 2 '-deoxy-guanine carbocyclic analogs, can suppress the startup in the viral dna replication process and prolong step through suppressing the hepatitis B virus DNA polysaccharase.
Its molecular formula: C
12H
15N
5O
3H
2Its chemical name of O is: 2 one amino 1 [(1S, 3R, 4S) 4 monohydroxies, one 3 one methylols, one 2 one methylene radical cyclopentyl] one 1,9 one dihydros, one 6H, one purine, one 6 one ketone monohydrates. English name:
2-Amino-1,9-dihydro-9-[(1S, 3R, 4S)-4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one monohydrate another name: Entecavir hydrate
Structural formula is seen figure:
U.S. Pat 5206244, US20040192912, US20050272932 disclose the clinical application and the preparation method of this compound, and international monopoly WO9809964 and WO2004052310 also disclose the preparation method of this compound.
Synthetic this compound is a starting raw material with cyclopentadiene sodium generally, and a route is to carry out the silylanization protection with the phenyl dimethylchlorosilane at-78 ℃ earlier, carries out acidylate again; Dechlorination, hydrolysis splits; Epoxidation gets epoxide, carries out condensation with 2-amino-6-benzyloxy purine again; Carry out alkylene then, after the alkaline hydrogen peroxide oxidation, refining product.
Its synthetic route is following:
The route that international monopoly WO9809964 announces is with cyclopentadiene sodium and chloromethyl benzyl methyl ether; (+)-a-firpene is a starting raw material, directly obtains chiral intermediate, again through epoxidation; With 6-benzyloxy-2-aminopurine condensation; With the Dess-Martin reagent react, carry out methylenation with Nysted reagent again, under the boron trichloride effect, slough the basic product that gets of protection at last.The direct synthesis of chiral midbody of the advantage of this method splits, and yield is high, and its shortcoming is that almost per step product was all wanted post and separated, and is difficult to suitability for industrialized production.
In addition; CN101050216A also discloses a kind of compound method of hepatitis B resisting medicated Entecavir, and the first step of this method also is to be protective material with methyldiphenyl base chlorosilane, but needs under-78 ℃, obtain silylanization protection thing; The 4th step was that esterifying reagent has synthesized carboxylate with the hexahydrobenzyl alcohol; Its 6th step is to get benzyloxy purine condenses with epoxy material and 2-amino-6-benzyloxy purine condensation, and this method intention is new, but method is easy inadequately;
CN101182322A has announced a kind of preparation method of hepatitis B virus resisting medicine Entecavir, and this method is to be the basis with WO9809964, has prepared a kind of oxabicyclo [3; 1; 0] verivate of hexane makes product prepn more economical because of having adopted a kind of new protection base, and quality product is better.
In addition, CN1964972A, CN101235034A have also announced the preparation method of Entecavir, mostly be to be the basis with above-mentioned two patent routes, and former technology has been done some improvement.
Summary of the invention:
The present invention is in order to overcome existing Entecavir---and the product in production technique that exists in the hydrate industrialized producing technology all wants process to separate; Do not fit into suitability for industrialized production; Method simply waits the technical problem that exists inadequately; It is simple that the present invention discloses a kind of production technique, do not need all to want the isolating industrialized producing technology of process at each production technique product.
The present invention realizes through following technical scheme:
1, a kind of Entecavir---the industrialized producing technology of hydrate is characterized in that the synthetic route that the present invention adopted is:
Ph is a phenyl in above-mentioned synthesis technique, Ph
2CH
3SiCl is that oneself is synthetic, and CA is R, R-(-)-chloramphenicol Base, and structural formula is:
Wherein the preparation method of ent-1A is: under special catalyst action, under nitrogen protection, obtain-40 ℃ of reactions with methyldiphenyl base chlorosilane and cyclopentadiene sodium, reaction solvent is THF, MTBE or normal hexane, and used catalyzer is: DMSO, DMF, DMAC; Reaction formula is following:
Ph wherein
2CH
3The preparation method of SiCl is: chlorobenzene and magnesium chips are processed Grignard reagent earlier; This Grignard reagent again with dichloromethyl phenylsilane reaction with same mole in THF or MTBE; The catalyzer that uses obtains product as CuCl or CuCN, the mixing liquid that obtains through rectifying, and reaction formula is following:
Wherein the preparation method of ent-4 is: ent-3 is dissolved with anhydrous methanol, drip the vitriol oil, reflux, add ethyl acetate extraction, and washing, drying, evaporate to dryness obtains, and reaction formula is following:
Wherein, the preparation method of ent-6 is: with ent-5,2-amino-6-chloropurine, DMF Lithium Hydroxide Monohydrate drop in the reaction flask; Nitrogen protection refluxed 24 hours adds ETHYLE ACETATE after the cooling, washing, drying; Precipitation, the normal hexane recrystallization gets product, and reaction formula is following:
Technique effect of the present invention is:
1, owing to use the methyldiphenyl base chlorosilane of own preparation to make the silylanization protective material, cheap and easy to get because of its raw material, thereby the synthetic cost of object is reduced greatly, the adaptation suitability for industrialized production;
2, invented the simple and production cost lower preparation method of production technique of a cover methyldiphenyl base chlorosilane, this method is direct synthetic intermediate not only, and yield is high, and per step product does not need process to separate, so is adapted to suitability for industrialized production.
3, because of using special catalyzer, make ent-1A more be prone to preparation, make temperature of reaction bring up to-40 ℃ by-78 ℃ of former technology, make reaction conditions more adapt to a large amount of preparations of industry, thereby reduced production cost;
4, ent-4 uses anhydrous methanol to make esterifying agent, and not only product is prone to purifying, and cost is also cheap;
5, with ent-5 and the direct condensation of 2-amino-6-chloropurine, can obtain the chloro condenses, simplify technology.
This quality product situation is:
Outward appearance: white and off-white powder
Content: 99.51% (HPLC)
Fusing point: 235 ℃-236 ℃
Specific optical rotation :+34 ° (c=0.3water)
Embodiment:
Below in conjunction with embodiment technical scheme of the present invention is done further explanation:
The preparation of embodiment 1, methyldiphenyl base chlorosilane:
In the 500ml four-hole bottle, add and use sodium exsiccant THF 50ml in advance, magnesium chips 16.7g (0.687mol), chlorobenzene 5ml adds initiation of iodine; Temperature rise to 70 ℃ continues to drip the 200ml THF solution of 65ml chlorobenzene, keeps little boiling, and finishes; Back flow reaction 6 hours, reaction is finished, and sealing is preserved subsequent use.
In another 1000ml four-hole bottle, add THF 400ml, cuprous cyanide 3g, dichloromethyl phenylsilane 133g (0.695mol) is warming up to 50 ℃; Under this temperature, drip above-mentioned Grignard solution, finish insulation reaction 3 hours; Add normal hexane 200ml, stirred 30 minutes, filter; Concentrating under reduced pressure filtrating is collected the about 112g of 128-133 ℃/670pa cut, yield about 70%.
The preparation of embodiment 2, ent-1A:
In the 500ml four-hole bottle, add and use sodium exsiccant THF 100ml in advance, 20.5g (0.088mol) methyldiphenyl base chlorosilane, logical nitrogen; Be cooled to-40 ℃; 44ml (0.088mol) cyclopentadiene sodium solution (2M inTHF) is fully dissolved with 60mlTHF, and add catalyzer 1ml, stir.
Nitrogen protection drips the cyclopentadiene sodium solution down, adds in about two hours, is incubated 2 hours; Stop refrigeration, let reaction solution be warming up to 0 ℃ gradually, carefully add water 80ml; Stirred 30 minutes, layering, organic layer is with 50ml * 2 water washings 2 times; Anhydrous sodium sulfate drying 2 hours filters, and is evaporated to dried the about 22.5g of garnet oily matter ent-1A under 50 ℃
The preparation of embodiment 3, ent-1B:
In 500ml exsiccant four-hole bottle, add ent-1A 22.5g (0.0857mol), normal hexane 200ml is cooled to-10 ℃ under the nitrogen protection, drip dichloroacetyl chloride 25.3g (0.171mol); Finish, stirred 30 minutes, drip triethylamine 17.3g (0.171mol), added in 90 minutes; Reaction solution slowly rises to room temperature, stirring at room 12 hours, and reaction is finished, and adds water 50ml; Stirred 30 minutes, layering, organic layer is washed once with saturated sodium carbonate solution 50ml, 50ml * 2 washing secondaries; Anhydrous sodium sulfate drying 2 hours filters, be concentrated under 50 ℃ dried, the about 32g of scarlet oily matter ent-1B
The preparation of embodiment 4, ent-2:
Under nitrogen protection, in 500ml exsiccant four-hole bottle, add ent-1B 32g (0.0857mol), trimethyl carbinol 50g, deionized water 150ml; Open stirring, drip triethylamine 48g, stirred temperature rising reflux 4 hours 30 minutes; Be cooled to 10 ℃, add salt of wormwood 48g in batches, stirred 30 minutes, add Peng Qinghuana 2.6g; Stirring reaction 2 hours adds hydrochloric acid and transfers reaction solution PH=2-3, adds ETHYLE ACETATE 160ml, stirs 2 hours; Layering, organic layer are filtered with anhydrous sodium sulfate drying 2 hours, are evaporated to dried the about 25.6g of brown oil ent-2.
The preparation of embodiment 5, ent-3:
Under nitrogen protection, in 250ml exsiccant there-necked flask, add ent-224g (0.071mol), absolute ethanol 240ml, R; R-(-)-chloramphenicol Base 12.7g (0.06mol) stirs, and is warming up to 60 ℃, insulated and stirred 5 hours; Be cooled to 20-25 ℃, add crystal seed 1g, stirred crystallization 5 hours is filtered; Filter cake is washed twice, 50 ℃ with a small amount of absolute ethanol and was dried by the fire 10 hours down, gets the about 16.2g of white crystalline powder ent-3.
The preparation of embodiment 6, ent-4:
Under nitrogen protection, in 250ml exsiccant there-necked flask, add ent-316g (0.029mol), add methyl alcohol 50g, be cooled to-5 ℃; Under this temperature, drip vitriol oil 6g, stirred 30 minutes, be warming up to room temperature, stirring reaction is 24 hours under the room temperature; 50 ℃ of steaming methyl alcohol that reduce pressure down add ETHYLE ACETATE 40ml, and deionized water 60ml stirred 30 minutes; Layering, organic layer is washed once with saturated sodium carbonate solution 20ml, and deionized water 20ml washed once, with anhydrous sodium sulfate drying 2 hours; Filter, be evaporated to dried, the about 9.9g of brown oily liquids ent-4.
The preparation of embodiment 7, ent-5:
Under nitrogen protection, in 250ml exsiccant there-necked flask, drop into 4A molecular sieve 6g, methylene dichloride 40ml is cooled to-30 ℃, adds D-(-)-tartrate diisopropyl ester 0.7g, stirs 30 minutes; Add isopropyl titanate 0.7g, stirred 30 minutes, slowly drip the solution of 9g (0.0255mol) ent-4, finish, be incubated 30 minutes, drip the 11ml tertbutyl peroxide at the 25ml methylene dichloride; Finish, insulation reaction 2 hours, insulation is finished, and drips the solution of 10g sodium sulfite anhy 96 in the 24ml deionized water, finishes, and stirs 30 minutes; Filter, layering, organic layer washes twice with saturated sodium carbonate solution, washes twice with deionized water again, anhydrous sodium sulfate drying; Filter, be evaporated to dried, the about 9.1g of yellow liquid (0.0245mol), in its input 250ml four-hole bottle, add the 40ml Virahol under the nitrogen protection; Stirring and dissolving is cooled to 0 ℃, adds Peng Qinghuana 2.5g, finishes, and stirs 24 hours; Drip ammonium chloride solution 50ml, stirred one hour, add ETHYLE ACETATE 40ml, stirred layering 30 minutes; Organic layer is washed once with saturated sodium carbonate solution, washing once, anhydrous sodium sulfate drying 2 hours filters, and is evaporated to dried the about 8.1g of glassy yellow liquid ent-5.
The preparation of embodiment 8, ent-6:
With 17.7g (0.052mol) ent-5.11.4g (0.0668mol) 2-amino-6-chloropurine, drop in the 250ml reaction flask, add DMF 80ml, Lithium Hydroxide Monohydrate 2g stirs and is warming up to 80 ℃; 80-85 ℃ of following insulation reaction 24 hours is cooled to room temperature, adds 90ml ETHYLE ACETATE, 30ml water; Stirred 30 minutes, layering, organic layer is washed once with citric acid solution, with washing 2 times; Anhydrous sodium sulfate drying 2 hours filters, and concentrating under reduced pressure filtrating gets the about 15g of yellow liquid ent-6 to doing.
The preparation of embodiment 9, ent-7:
Under nitrogen protection, in 250ml exsiccant there-necked flask, drop into ent-611.4g (0.0223mol), methylene dichloride 60ml, tosic acid pyridinium salt 0.24g; Be cooled to 0-5 ℃ under fully stirring, slowly drip acetate diethoxy methyl esters 18ml, finish, be warming up to 25 ℃; Stirring reaction 90 minutes adds saturated sodium carbonate solution 80ml, stirs one hour, and feed liquid is changed in the 500ml there-necked flask; Add ETHYLE ACETATE 150ml, stirred 30 minutes, layering, organic layer is with water washing 2 times; Anhydrous sodium sulfate drying 1 hour filters, be evaporated to dried, the about 12g of yellow oil.
Yellow liquid is dropped in the 250ml there-necked flask, add aceticanhydride 40ml, be warming up to 120 ℃, insulation reaction is 24 hours under this temperature; Be cooled to 60 ℃, add methyl alcohol 100ml, 65 ℃ of refluxed one hour; Add the 23ml concentrated hydrochloric acid, continue reaction 5 hours, be cooled to 25 ℃; Layering, organic layer is evaporated to dried, gets the about 9.2g of brown oily liquids.
Brown liquid is dropped in the 250ml there-necked flask, be warming up to 60 ℃, transfer PH=12-13, be warming up to 70 ℃ with NaOH; Insulation reaction 5 hours is cooled to room temperature, transfers PH=6-7 with hydrochloric acid, stirred crystallization 5 hours; Filter, use cold water washing, oven dry gets the about 5.8g of white crystalline powder solid ent-7.
10, the preparation of Entecavir hydrate:
5.8g ent-7 is dropped in the 250ml four-hole bottle, and ice acetic acid 10ml adds acetate boron trifluoride 7ml under the nitrogen protection, stirs, and is warming up to 95-98 ℃; Insulation reaction 5 hours is cooled to room temperature, adds methyl alcohol 40ml, transfers reaction solution PH=9.5-10 with 10N KOH solution, slowly drips 30% hydrogen peroxide 5.8g; Finish, be warming up to 70 ℃, insulation reaction 12 hours is cooled to 5 ℃, adds sodium sulfite anhy 96 10ml; Stirred one hour, 50 ℃ are evaporated to driedly, and gains are cooled to 0-5 ℃, slowly add concentrated hydrochloric acid 8ml, are warming up to room temperature; Add 80ml ETHYLE ACETATE, water layer is transferred reaction solution PH=10-11 with 10N KOH solution, fully stirs 2 hours, transfers PH=6.5-7.0 with concentrated hydrochloric acid again; 0-5 ℃ was stirred 12 hours down, filtered, and filter cake washs with cold purified water, gets white wet article.
The article that will wet drop in the 250ml there-necked flask, add the 80ml purified water, are warming up to 90-95 ℃, add gac 1g, stirred 30 minutes, and filtered while hot, filtrating stirring is cooled to room temperature, stirs 5 hours, filters, and 55 ℃ of vacuum-dryings got the about 1.8g of finished product in 20 hours.
Claims (5)
1. the industrialized preparing process of an Entecavir hydrate is characterized in that having adopted following synthetic route:
Ph is a phenyl in said synthesis route, Ph
2CH
3SiCl is that oneself is synthetic, and PhMgCl and PhCH
3SiCl
2Be in THF or MTBE, to react;
CA is R, R-(-)-chloramphenicol Base, and structural formula is:
In the step of preparation ent-1A, catalyzer is DMSO, DMF, DMAC.
2. method according to claim 1 is characterized in that the preparation method of ent-1A is: under nitrogen protection, obtain-40 ℃ of reactions with methyldiphenyl base chlorosilane and cyclopentadiene sodium, reaction solvent is THF, MTBE or normal hexane.
3. according to claim 1 or claim 2 method is characterized in that Ph
2CH
3The preparation method of SiCl is: chlorobenzene and magnesium chips are processed Grignard reagent earlier, this Grignard reagent again with dichloromethyl phenylsilane reaction with same mole in THF or MTBE, the catalyzer that uses obtains product as CuCl or CuCN, the mixing liquid that obtains through rectifying.
4. the method for claim 1 is characterized in that the preparation method of ent-4 is: ent-3 dissolved with anhydrous methanol, drips the vitriol oil, reflux, add ethyl acetate extraction, and washing, drying, evaporate to dryness obtains.
5. the method for claim 1 is characterized in that the preparation method of ent-6 is: with ent-5, and 2-amino-6-chloropurine, DMF; Lithium Hydroxide Monohydrate drops in the reaction flask, and nitrogen protection refluxed 24 hours adds ETHYLE ACETATE after the cooling, washing; Drying, precipitation, the normal hexane recrystallization gets product.
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| CN102898453A (en) * | 2011-12-20 | 2013-01-30 | 长沙理工大学 | Synthesis method of diphenylmethylchlorosilane |
| CN104230933A (en) * | 2014-09-11 | 2014-12-24 | 赵明亮 | Process for synthesizing entecavir |
| CN105001258A (en) * | 2015-08-12 | 2015-10-28 | 黄石市利福达医药化工有限公司 | Preparation method for diphenylphosphinic acid |
| CN113004281A (en) * | 2019-12-21 | 2021-06-22 | 南通诺泰生物医药技术有限公司 | Preparation method of entecavir intermediate |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| WO1998009964A1 (en) * | 1996-09-03 | 1998-03-12 | Bristol-Myers Squibb Company | IMPROVED PROCESS FOR PREPARING THE ANTIVIRAL AGENT [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENECYCLOPENTYL]-6H-PURIN-6-ONE |
| US20040192912A1 (en) * | 2002-12-11 | 2004-09-30 | Pendri Yadagiri R. | Process for preparing the antiviral agent [1S-(1alpha,3 alpha,4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one |
| CN101050216A (en) * | 2006-04-05 | 2007-10-10 | 杭州容立医药科技有限公司 | Method for synthesizing medication Entecavir of anti hepatitis B |
-
2009
- 2009-04-14 CN CN2009101165320A patent/CN101531660B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5206244A (en) * | 1990-10-18 | 1993-04-27 | E. R. Squibb & Sons, Inc. | Hydroxymethyl (methylenecyclopentyl) purines and pyrimidines |
| WO1998009964A1 (en) * | 1996-09-03 | 1998-03-12 | Bristol-Myers Squibb Company | IMPROVED PROCESS FOR PREPARING THE ANTIVIRAL AGENT [1S-(1α, 3α, 4β)]-2-AMINO-1,9-DIHYDRO-9-[4-HYDROXY-3-(HYDROXYMETHYL)-2-METHYLENECYCLOPENTYL]-6H-PURIN-6-ONE |
| US20040192912A1 (en) * | 2002-12-11 | 2004-09-30 | Pendri Yadagiri R. | Process for preparing the antiviral agent [1S-(1alpha,3 alpha,4beta)]-2-amino-1,9-dihydro-9-[4-hydroxy-3-(hydroxymethyl)-2-methylenecyclopentyl]-6H-purin-6-one |
| CN101050216A (en) * | 2006-04-05 | 2007-10-10 | 杭州容立医药科技有限公司 | Method for synthesizing medication Entecavir of anti hepatitis B |
Non-Patent Citations (1)
| Title |
|---|
| G.S.Bisacchi,et al.,.BMS-200475,a novel carbocyclic 2’-deoxyguanosine analog with potent and selective anti-hepatitis B virus activity in vitro.《Bioorganic &Medicinal Chemistry Letters》.1997,第7卷(第2期),127-132. * |
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