CN108314685B - Preparation method of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine - Google Patents
Preparation method of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine Download PDFInfo
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- CN108314685B CN108314685B CN201810218224.8A CN201810218224A CN108314685B CN 108314685 B CN108314685 B CN 108314685B CN 201810218224 A CN201810218224 A CN 201810218224A CN 108314685 B CN108314685 B CN 108314685B
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- purine
- diacetoxy
- propanol
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- KXPSHSVVYGZKAV-UHFFFAOYSA-N [2-(acetyloxymethyl)-4-(2-amino-6-chloropurin-9-yl)butyl] acetate Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1Cl KXPSHSVVYGZKAV-UHFFFAOYSA-N 0.000 title claims abstract description 29
- 238000002360 preparation method Methods 0.000 title claims abstract description 11
- MAVWMUZGVUQHCC-UHFFFAOYSA-N (3-acetyloxy-2-bromopropyl) acetate Chemical compound C(C)(=O)OCC(COC(C)=O)Br MAVWMUZGVUQHCC-UHFFFAOYSA-N 0.000 claims abstract description 15
- 229940051269 1,3-dichloro-2-propanol Drugs 0.000 claims abstract description 11
- DEWLEGDTCGBNGU-UHFFFAOYSA-N 1,3-dichloropropan-2-ol Chemical compound ClCC(O)CCl DEWLEGDTCGBNGU-UHFFFAOYSA-N 0.000 claims abstract description 11
- ZTCCWFRLVUFEBT-UHFFFAOYSA-N 9-(2-bromoethyl)-6-chloropurin-2-amine Chemical compound NC1=NC(Cl)=C2N=CN(CCBr)C2=N1 ZTCCWFRLVUFEBT-UHFFFAOYSA-N 0.000 claims abstract description 9
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims abstract description 8
- VNDYJBBGRKZCSX-UHFFFAOYSA-L Zinc bromide Inorganic materials Br[Zn]Br VNDYJBBGRKZCSX-UHFFFAOYSA-L 0.000 claims abstract description 8
- 229940102001 zinc bromide Drugs 0.000 claims abstract description 8
- MPPODKLDCLFLKT-UHFFFAOYSA-N (3-acetyloxy-2-hydroxypropyl) acetate Chemical compound CC(=O)OCC(O)COC(C)=O MPPODKLDCLFLKT-UHFFFAOYSA-N 0.000 claims abstract description 6
- 238000004128 high performance liquid chromatography Methods 0.000 claims abstract description 4
- 238000000034 method Methods 0.000 claims description 20
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N Propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 claims description 12
- 239000001294 propane Substances 0.000 claims description 9
- 239000003795 chemical substances by application Substances 0.000 claims description 8
- 150000003839 salts Chemical class 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- IJOOHPMOJXWVHK-UHFFFAOYSA-N chlorotrimethylsilane Chemical compound C[Si](C)(C)Cl IJOOHPMOJXWVHK-UHFFFAOYSA-N 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical compound [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 claims description 6
- AMXOYNBUYSYVKV-UHFFFAOYSA-M lithium bromide Chemical compound [Li+].[Br-] AMXOYNBUYSYVKV-UHFFFAOYSA-M 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- 230000003213 activating effect Effects 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 4
- 239000003153 chemical reaction reagent Substances 0.000 claims description 4
- 239000003999 initiator Substances 0.000 claims description 4
- KWGKDLIKAYFUFQ-UHFFFAOYSA-M lithium chloride Chemical compound [Li+].[Cl-] KWGKDLIKAYFUFQ-UHFFFAOYSA-M 0.000 claims description 4
- 235000019270 ammonium chloride Nutrition 0.000 claims description 3
- YJVFFLUZDVXJQI-UHFFFAOYSA-L palladium(ii) acetate Chemical compound [Pd+2].CC([O-])=O.CC([O-])=O YJVFFLUZDVXJQI-UHFFFAOYSA-L 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 claims description 3
- NRTLTGGGUQIRRT-UHFFFAOYSA-N triethylazanium;bromide Chemical group [Br-].CC[NH+](CC)CC NRTLTGGGUQIRRT-UHFFFAOYSA-N 0.000 claims description 3
- 239000005051 trimethylchlorosilane Substances 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical group [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 2
- 230000009471 action Effects 0.000 claims description 2
- BFNBIHQBYMNNAN-UHFFFAOYSA-N ammonium sulfate Chemical group N.N.OS(O)(=O)=O BFNBIHQBYMNNAN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052921 ammonium sulfate Inorganic materials 0.000 claims description 2
- 235000011130 ammonium sulphate Nutrition 0.000 claims description 2
- 238000006555 catalytic reaction Methods 0.000 claims description 2
- 238000005859 coupling reaction Methods 0.000 claims description 2
- 239000003446 ligand Substances 0.000 claims description 2
- BBFCIBZLAVOLCF-UHFFFAOYSA-N pyridin-1-ium;bromide Chemical compound Br.C1=CC=NC=C1 BBFCIBZLAVOLCF-UHFFFAOYSA-N 0.000 claims description 2
- 239000001632 sodium acetate Substances 0.000 claims description 2
- 235000017281 sodium acetate Nutrition 0.000 claims description 2
- GGXKWVWZWMLJEH-UHFFFAOYSA-N famcyclovir Chemical compound N1=C(N)N=C2N(CCC(COC(=O)C)COC(C)=O)C=NC2=C1 GGXKWVWZWMLJEH-UHFFFAOYSA-N 0.000 abstract description 10
- 229960004396 famciclovir Drugs 0.000 abstract description 9
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 abstract description 6
- 229960001179 penciclovir Drugs 0.000 abstract description 6
- 238000006411 Negishi coupling reaction Methods 0.000 abstract description 2
- 238000005893 bromination reaction Methods 0.000 abstract description 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 18
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 12
- 238000006243 chemical reaction Methods 0.000 description 11
- -1 2, 2-diethoxycarbonyl ethyl Chemical group 0.000 description 9
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 5
- 238000005886 esterification reaction Methods 0.000 description 5
- 238000006722 reduction reaction Methods 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 238000006482 condensation reaction Methods 0.000 description 4
- 230000032050 esterification Effects 0.000 description 4
- 238000010438 heat treatment Methods 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 229910000033 sodium borohydride Inorganic materials 0.000 description 4
- 239000012279 sodium borohydride Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000006114 decarboxylation reaction Methods 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- LTMRRSWNXVJMBA-UHFFFAOYSA-L 2,2-diethylpropanedioate Chemical compound CCC(CC)(C([O-])=O)C([O-])=O LTMRRSWNXVJMBA-UHFFFAOYSA-L 0.000 description 2
- FSJCDRZLIWVLEH-UHFFFAOYSA-N 2-[2-(2-amino-6-chloropurin-9-yl)ethyl]propane-1,3-diol Chemical compound NC1=NC(Cl)=C2N=CN(CCC(CO)CO)C2=N1 FSJCDRZLIWVLEH-UHFFFAOYSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- 208000001688 Herpes Genitalis Diseases 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 239000003443 antiviral agent Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 201000004946 genital herpes Diseases 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 239000011701 zinc Substances 0.000 description 2
- 229910052725 zinc Inorganic materials 0.000 description 2
- PAAZPARNPHGIKF-UHFFFAOYSA-N 1,2-dibromoethane Chemical compound BrCCBr PAAZPARNPHGIKF-UHFFFAOYSA-N 0.000 description 1
- LDLCZOVUSADOIV-UHFFFAOYSA-N 2-bromoethanol Chemical compound OCCBr LDLCZOVUSADOIV-UHFFFAOYSA-N 0.000 description 1
- 241000701022 Cytomegalovirus Species 0.000 description 1
- 230000004543 DNA replication Effects 0.000 description 1
- 241000700721 Hepatitis B virus Species 0.000 description 1
- 208000004898 Herpes Labialis Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 241000701044 Human gammaherpesvirus 4 Species 0.000 description 1
- 206010067152 Oral herpes Diseases 0.000 description 1
- 206010036376 Postherpetic Neuralgia Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 241000700605 Viruses Species 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000031709 bromination Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000012141 concentrate Substances 0.000 description 1
- 238000009833 condensation Methods 0.000 description 1
- 230000005494 condensation Effects 0.000 description 1
- 230000000911 decarboxylating effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 238000005984 hydrogenation reaction Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 230000009385 viral infection Effects 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/40—Heterocyclic compounds containing purine ring systems with halogen atoms or perhalogeno-alkyl radicals directly attached in position 2 or 6
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Catalysts (AREA)
Abstract
The invention relates to a preparation process of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine, which comprises the following steps: 1, 3-dichloro-2-propanol reacts with acetate to obtain 1, 3-diacetoxy-2-propanol, obtaining 1, 3-diacetyloxy-2-bromopropane through bromination reaction, then reacting with zinc powder to prepare 1, 3-diacetyloxy-2-zinc bromide propyl, then carrying out Negishi Coupling reaction with 2-amino-6-chloro-9-bromoethyl purine to obtain 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methyl butyl) purine, wherein the HPLC purity of the obtained 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methyl butyl) purine is more than 99.5 percent, and the 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methyl butyl) purine can be used for producing famciclovir and penciclovir.
Description
Technical Field
The invention belongs to the technical field of chemical synthesis, and relates to a preparation method of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine.
Background
Penciclovir and famciclovir are antiviral drugs developed by SmithKline Beecham in UK in 20 actual 90 s, play antiviral roles mainly by inhibiting virus DNA replication, and are suitable for treating severe herpes zoster patients and virus infections such as primary genital herpes. Famciclovir is the first oral drug approved for herpes labialis and genital herpes in the united states and is also the only antiviral drug for reducing postherpetic neuralgia, and further research shows that famciclovir has a broad-spectrum antiviral effect and has activity on herpes viruses, hepatitis b viruses, cytomegaloviruses, epstein barr viruses and the like. Penciclovir is the active metabolite of famciclovir in human body, and famciclovir has better oral bioavailability.
In the currently widely adopted preparation methods of famciclovir and penciclovir, 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methyl butyl) purine is prepared as a key intermediate, and the preparation of famciclovir from 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methyl butyl) purine requires a further hydrogenation reaction and a further two-step reaction, so that the quality and cost of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxyl methyl butyl) purine have a great influence on the quality and cost of famciclovir and penciclovir.
There are three methods for preparing 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine that are widely used at present:
in the first method, 2-amino-6-chloropurine and 3-bromopropane-1, 1, 1-triethyl tricarboxylate are subjected to condensation reaction to obtain 2-amino-6-chloro-9- (2, 2-diethoxycarbonyl ethyl butyrate-4-yl) purine; then decarboxylating with sodium alkoxide to obtain 2-amino-6-chloro-9- (2-ethoxycarbonylbutyrate-4-yl) purine; then reducing with sodium borohydride to obtain 2-amino-6-chloro-9- (4-hydroxy-3-hydroxymethyl butyl) purine; then reacting with acetic anhydride to obtain 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine.
The reaction route is as follows:
the method has the advantages that the isomer of 2-amino-6-chloro-7- (2, 2-diethoxycarbonyl ethyl butyrate-4-yl) purine generated in the preparation of 2-amino-6-chloro-9- (2, 2-diethoxycarbonyl ethyl butyrate-4-yl) purine is very few, and the method is widely adopted in the industry at present. However, the disadvantage of this route is that the key material 2-amino-6-chloropurine is reacted in the first step and then undergoes decarboxylation, reduction and esterification, and the utilization rate of 2-amino-6-chloropurine is not high, resulting in high overall cost of the final product.
In the second method, 2-amino-6-chloropurine reacts with bromoethanol or 1, 2-dibromoethane to obtain 2-amino-6-chloro-9-bromoethyl purine, then the 2-amino-6-chloro-9- (2-ethoxycarbonylethyl butyrate-4-yl) purine is obtained by condensation with diethyl malonate, and the 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethylbutyl) purine is obtained by reduction with sodium borohydride and esterification with acetic anhydride.
The reaction route is as follows:
compared with the first method, the decarboxylation reaction step is omitted, but the condensation reaction of the 2-amino-6-chloro-9-bromoethyl purine and diethyl malonate is difficult to carry out, and the yield is not high.
In the method, tri-2-amino-6-chloropurine and 3-bromopropane-1, 1-diethyl dicarboxylate are subjected to condensation reaction, N-7 isomer 2-amino-6-chloro-7- (2-ethoxycarbonylethyl butyrate-4-yl) purine is separated through recrystallization to obtain 2-amino-6-chloro-9- (2-ethoxycarbonylethyl butyrate-4-yl) purine, and the 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethylbutyl) purine is obtained through sodium borohydride reduction and acetic anhydride esterification.
The reaction route is as follows:
compared with the first method, the decarboxylation reaction step is omitted, but in the condensation reaction process, a great amount of N-7 isomer 2-amino-6-chloro-7- (2-ethoxycarbonylethyl butyrate-4-yl) purine is generated and needs to be separated through recrystallization, and the total yield is not high.
The common characteristics of the preparation methods are that 2-amino-6-chloro-9- (2-ethoxycarbonyl ethyl butyrate-4-yl) purine is prepared, and then is subjected to sodium borohydride reduction and acetic anhydride esterification to obtain 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethyl butyl) purine.
Disclosure of Invention
The technical problem to be solved by the invention is as follows: in view of the above problems, the present invention provides a method for producing 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine.
The technical scheme adopted by the invention for solving the technical problems is as follows: reacting 1, 3-dichloro-2-propanol with acetate to obtain 1, 3-diacetoxy-2-propanol, obtaining 1, 3-diacetoxy-2-bromopropane through bromination, then reacting with zinc powder to prepare 1, 3-diacetoxy-2-zinc bromide-based propane, and then carrying out Negishi Coupling reaction with 2-amino-6-chloro-9-bromoethyl purine to obtain 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine, wherein the reaction route is shown as the following figure:
the method specifically comprises the following steps:
(1) reacting 1, 3-dichloro-2-propanol with acetate in the presence of a strong acid weak base salt to obtain 1, 3-diacetoxy-2-propanol;
(2) reacting 1, 3-diacetoxy-2-propanol with a bromization reagent to obtain 1, 3-diacetoxy-2-bromopropane;
(3) reacting 1, 3-diacetoxy-2-bromopropane with zinc powder under the action of anhydrous lithium bromide or anhydrous lithium chloride serving as an activating agent and trimethylchlorosilane serving as an initiator to obtain 1, 3-diacetoxy-2-bromozinc propane; the amount of the activating agent is 5-15% of the mass of the 1, 3-diacetoxy-2-bromopropane, the amount of the initiator is 1-5% of the mass of the 1, 3-diacetoxy-2-bromopropane, and the amount of the zinc powder is 25-35% of the mass of the 1, 3-diacetoxy-2-bromopropane.
(4) Carrying out coupling reaction on 1, 3-diacetyloxy-2-zinc bromide propane and 2-amino-6-chloro-9-bromoethyl purine under the catalysis of a palladium acetate catalyst taking S-Phos (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) as a ligand to obtain 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine; the molar ratio of the 1, 3-diacetyloxy-2-zinc bromide propane to the 2-amino-6-chloro-9-bromoethylpurine is 1.1-2: 1.
further, in the step (1), the strong acid and weak base salt is ammonium sulfate or ammonium chloride, and the molar ratio of the strong acid and weak base salt to the 1, 3-dichloro-2-propanol is 0.8-1.2: 1. the strong acid weak base salt is added into the reaction system to change the pH value of the reaction system so as to reduce the occurrence of side reactions.
Further, in the step (1), the acetate is sodium acetate or potassium acetate, and the molar ratio of the acetate to the 1, 3-dichloro-2-propanol is 2.5-3.5: 1.
further, in the step (2), the brominating agent is triethylamine hydrobromide or pyridine hydrobromide, and the molar ratio of the brominating agent to 1, 3-dichloro-2-propanol is 1.3-1.8: 1.
further, in the step (4), the HPLC purity of 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine is 99.5% or more.
The invention has the beneficial effects that: the preparation method of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine is the most different from the method reported in the literature in that the step of using 2-amino-6-chloropurine is relatively late, so that the raw material cost can be effectively reduced; the preparation of 2-amino-6-chloro-9- (4-hydroxy-3-hydroxymethyl butyl) purine as an intermediate is not needed, the reduction reaction and esterification reaction processes are avoided, the process safety is better, the amount of high-concentration salt-containing wastewater is greatly reduced, and the method is more suitable for large-scale industrial production. The famciclovir and penciclovir are produced by using the 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine prepared by the method, and the product quality meets the requirements of European and American pharmacopoeia standards.
Detailed Description
The invention will now be further illustrated by reference to specific examples, which are intended to be illustrative of the invention and are not intended to be a further limitation of the invention.
Examples
(1) 129g of 1, 3-dichloro-2-propanol, 1000ml of DMF, 300g of potassium acetate and 53.5g of ammonium chloride are put into a 2000ml reaction bottle, and stirred and reacted for 10 hours at the temperature of 100-110 ℃. After heat preservation, cooling to room temperature, filtering out solids in the system, decompressing and concentrating filtrate to remove DMF, adding 1000ml ethyl acetate to dissolve concentrated solution, washing for 2 times by using water, drying by using anhydrous sodium sulfate, adding 270g of triethylamine hydrobromide, heating to 70-80 ℃, stirring, preserving heat, reacting for 5-6 hours, cooling to room temperature, filtering out solids in the system, washing for 2 times by using saturated sodium chloride solution, decompressing and concentrating to remove ethyl acetate, and then rectifying to obtain 110g of 1, 3-diacetoxy-2-bromopropane with the GC content of 90.4%.
(2) Adding THF 100ml, anhydrous lithium bromide 9g and zinc powder 33g into a reaction bottle, performing nitrogen replacement for 3 times, adding 1, 3-diacetoxy-2-bromopropane 100g, finally adding TMSCl (trimethylchlorosilane) 2.3g, heating to 50 ℃, reacting for 1-3 h at 50-55 ℃, heating to 60-65 ℃, reacting for 15-24 h at the temperature, detecting by GC, and finishing the reaction when the GC peak area is 1, 3-diacetoxy-2-bromopropane/1, 3-diacetoxy-2-zinc bromide propane < 5%, thus obtaining a zinc reagent (1, 3-diacetoxy-2-zinc bromide propane) for later use.
(3) Adding THF (5 ml) into a reaction bottle, replacing 3 times with nitrogen, adding palladium acetate 0.15g and S-Phos (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) 1.1g at room temperature, and stirring for 20-30 minutes under the protection of nitrogen to obtain a catalyst for later use.
(4) Adding 375ml of tetrahydrofuran and 75g of 2-amino-6-chloro-9-bromoethyl purine into a reaction bottle, adding a newly prepared catalyst under the protection of nitrogen, heating to 50-60 ℃, slowly dropwise adding a newly prepared zinc reagent, reacting for 10 hours at 50-60 ℃ after dropwise adding, cooling to 15-20 ℃, dropwise adding 10ml of ethanol, and stirring for 2 hours. Concentrating under reduced pressure to dryness, adding 500ml of dichloromethane, 300ml of water and 50ml of glacial acetic acid, stirring for 20-30 minutes, demixing, washing an organic layer with a sodium bicarbonate solution for 2 times, then washing with water for 2 times, concentrating to dryness, recrystallizing a concentrate with ethanol, and drying under reduced pressure to obtain about 80g of 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine with the HPLC purity of more than 99.5%.
In light of the foregoing description of the preferred embodiment of the present invention, many modifications and variations will be apparent to those skilled in the art without departing from the spirit and scope of the invention. The technical scope of the present invention is not limited to the content of the specification, and must be determined according to the scope of the claims.
Claims (5)
1. A preparation method of 2-amino-6-chloro-9- (4-acetoxyl-3-acetoxymethyl butyl) purine is characterized by comprising the following steps: the method comprises the following steps:
(1) reacting 1, 3-dichloro-2-propanol with acetate in the presence of a strong acid weak base salt to obtain 1, 3-diacetoxy-2-propanol;
(2) reacting 1, 3-diacetoxy-2-propanol with a bromization reagent to obtain 1, 3-diacetoxy-2-bromopropane;
(3) reacting 1, 3-diacetoxy-2-bromopropane with zinc powder under the action of anhydrous lithium bromide or anhydrous lithium chloride serving as an activating agent and trimethylchlorosilane serving as an initiator to obtain 1, 3-diacetoxy-2-bromozinc propane; the amount of the activating agent is 5-15% of the mass of the 1, 3-diacetoxy-2-bromopropane, the amount of the initiator is 1-5% of the mass of the 1, 3-diacetoxy-2-bromopropane, and the amount of the zinc powder is 25-35% of the mass of the 1, 3-diacetoxy-2-bromopropane;
(4) carrying out coupling reaction on 1, 3-diacetyloxy-2-zinc bromide propane and 2-amino-6-chloro-9-bromoethyl purine under the catalysis of a palladium acetate catalyst taking S-Phos (2-dicyclohexylphosphine-2 ',6' -dimethoxybiphenyl) as a ligand to obtain 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine; the molar ratio of the 1, 3-diacetyloxy-2-zinc bromide propane to the 2-amino-6-chloro-9-bromoethylpurine is 1.1-2: 1.
2. the process according to claim 1, wherein the 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine is prepared by: in the step (1), the strong acid and weak base salt is ammonium sulfate or ammonium chloride, and the molar ratio of the strong acid and weak base salt to the 1, 3-dichloro-2-propanol is 0.8-1.2: 1.
3. the process according to claim 1, wherein the 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine is prepared by: in the step (1), the acetate is sodium acetate or potassium acetate, and the molar ratio of the acetate to the 1, 3-dichloro-2-propanol is 2.5-3.5: 1.
4. the process according to claim 1, wherein the 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine is prepared by: in the step (2), the brominating agent is triethylamine hydrobromide or pyridine hydrobromide, and the molar ratio of the brominating agent to 1, 3-dichloro-2-propanol is 1.3-1.8: 1.
5. the process according to claim 1, wherein the 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine is prepared by: in the step (4), the HPLC purity of the 2-amino-6-chloro-9- (4-acetoxy-3-acetoxymethylbutyl) purine is more than 99.5 percent.
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Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0141927B1 (en) * | 1983-08-18 | 1991-10-30 | Beecham Group Plc | Antiviral guanine derivatives |
| CN1150427A (en) * | 1994-04-19 | 1997-05-21 | 史密斯克莱·比奇曼公司 | Preparation of purines |
| EP1288215B1 (en) * | 2001-08-30 | 2004-12-15 | Ajinomoto Co., Inc. | Production method of famciclovir and production and crystallization method of intermediate therefor |
| CN100455583C (en) * | 2003-06-13 | 2009-01-28 | 京东制药株式会社 | 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9- 4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same |
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0141927B1 (en) * | 1983-08-18 | 1991-10-30 | Beecham Group Plc | Antiviral guanine derivatives |
| CN1150427A (en) * | 1994-04-19 | 1997-05-21 | 史密斯克莱·比奇曼公司 | Preparation of purines |
| EP1288215B1 (en) * | 2001-08-30 | 2004-12-15 | Ajinomoto Co., Inc. | Production method of famciclovir and production and crystallization method of intermediate therefor |
| CN100455583C (en) * | 2003-06-13 | 2009-01-28 | 京东制药株式会社 | 2-amino-9-(2-substituted ethyl)purines and preparing methods for 9- 4-acetoxy-3-(acetoxymethyl)but-1-yl]- 2- aminopurine using the same |
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