CN1045963C - 嘌呤的制备 - Google Patents
嘌呤的制备 Download PDFInfo
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- CN1045963C CN1045963C CN95193489A CN95193489A CN1045963C CN 1045963 C CN1045963 C CN 1045963C CN 95193489 A CN95193489 A CN 95193489A CN 95193489 A CN95193489 A CN 95193489A CN 1045963 C CN1045963 C CN 1045963C
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- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 150000003212 purines Chemical class 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 10
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 8
- 239000001257 hydrogen Substances 0.000 claims abstract description 8
- 238000006114 decarboxylation reaction Methods 0.000 claims abstract description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims abstract 9
- 150000002431 hydrogen Chemical group 0.000 claims abstract 5
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims abstract 5
- 125000002252 acyl group Chemical group 0.000 claims abstract 4
- 125000002467 phosphate group Chemical class [H]OP(=O)(O[H])O[*] 0.000 claims abstract 4
- 229910052736 halogen Inorganic materials 0.000 claims abstract 3
- 125000004185 ester group Chemical group 0.000 claims abstract 2
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 10
- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 claims description 4
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 4
- 229910052801 chlorine Inorganic materials 0.000 claims 4
- 239000000460 chlorine Chemical group 0.000 claims 4
- 150000002367 halogens Chemical class 0.000 claims 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical class [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims 1
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical group O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 claims 1
- 125000005466 alkylenyl group Chemical group 0.000 claims 1
- -1 azido- Chemical class 0.000 claims 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims 1
- 125000001309 chloro group Chemical group Cl* 0.000 abstract description 3
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 abstract 2
- 125000003277 amino group Chemical group 0.000 abstract 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 abstract 1
- 125000006700 (C1-C6) alkylthio group Chemical group 0.000 abstract 1
- 125000004390 alkyl sulfonyl group Chemical group 0.000 abstract 1
- 125000000852 azido group Chemical group *N=[N+]=[N-] 0.000 abstract 1
- 125000005843 halogen group Chemical group 0.000 abstract 1
- 125000004356 hydroxy functional group Chemical group O* 0.000 abstract 1
- CBOIHMRHGLHBPB-UHFFFAOYSA-N hydroxymethyl Chemical compound O[CH2] CBOIHMRHGLHBPB-UHFFFAOYSA-N 0.000 abstract 1
- QWPPOHNGKGFGJK-UHFFFAOYSA-N hypochlorous acid Chemical group ClO QWPPOHNGKGFGJK-UHFFFAOYSA-N 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 21
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 13
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 12
- 239000000047 product Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 10
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 238000005406 washing Methods 0.000 description 8
- 239000011541 reaction mixture Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- RYYIULNRIVUMTQ-UHFFFAOYSA-N 6-chloroguanine Chemical compound NC1=NC(Cl)=C2N=CNC2=N1 RYYIULNRIVUMTQ-UHFFFAOYSA-N 0.000 description 6
- JNTOCHDNEULJHD-UHFFFAOYSA-N Penciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(CCC(CO)CO)C=N2 JNTOCHDNEULJHD-UHFFFAOYSA-N 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 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 description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 6
- 229960004396 famciclovir Drugs 0.000 description 5
- 229960001179 penciclovir Drugs 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-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
- 229910052799 carbon Inorganic materials 0.000 description 3
- 238000001816 cooling Methods 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 235000019253 formic acid Nutrition 0.000 description 3
- 239000006210 lotion Substances 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 238000004440 column chromatography Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 239000012065 filter cake Substances 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 description 2
- 239000000543 intermediate Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000002002 slurry Substances 0.000 description 2
- ISTBVJOFZNQWJF-UHFFFAOYSA-N 2-(hydroxyamino)-3,7-dihydropurin-6-one Chemical compound O=C1NC(NO)=NC2=C1NC=N2 ISTBVJOFZNQWJF-UHFFFAOYSA-N 0.000 description 1
- MWBWWFOAEOYUST-UHFFFAOYSA-N 2-aminopurine Chemical compound NC1=NC=C2N=CNC2=N1 MWBWWFOAEOYUST-UHFFFAOYSA-N 0.000 description 1
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical class CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical class Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 1
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- 238000013019 agitation Methods 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- FFBHFFJDDLITSX-UHFFFAOYSA-N benzyl N-[2-hydroxy-4-(3-oxomorpholin-4-yl)phenyl]carbamate Chemical compound OC1=C(NC(=O)OCC2=CC=CC=C2)C=CC(=C1)N1CCOCC1=O FFBHFFJDDLITSX-UHFFFAOYSA-N 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011167 hydrochloric acid Nutrition 0.000 description 1
- 230000003301 hydrolyzing effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000000199 molecular distillation Methods 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002777 nucleoside Substances 0.000 description 1
- 150000003833 nucleoside derivatives Chemical class 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
- 238000001556 precipitation Methods 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 150000003254 radicals Chemical class 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Chemical Treatment Of Metals (AREA)
- Preparation Of Compounds By Using Micro-Organisms (AREA)
Abstract
一种制备通式(A)的化合物的方法，式中，X是氢、羟基、氯、C1-6烷氧基或苯基C1-6烷氧基；Ra和Rb是氢、或酰基或其磷酸酯衍生物，该方法包括：(i)通式(Ⅰ)的化合物的制备，式中R1是C1-6烷基或苯基C1-6烷基(其中苯基被任选取代);R2是氢、羟基、氯、C1-6烷氧基、苯基C1-6烷氧基或氨基；R3是卤素、C1-6烷基硫代、C1-6烷基磺酰基、叠氮基、氨基或被护氨基、该制备反应包括将通式(Ⅱ)(式中，R2和R3如通式(Ⅰ)所定义)的化合物与通式(Ⅴ)(式中，L是离去基团，R1如通式(Ⅰ)所定义)的化合物反应，得到通式(Ⅵ)的化合物，然后通过脱羧反应将通式(Ⅵ)的中间体化合物转化为通式(Ⅰ)的化合物，并且在必要时或根据需要，将变量R1、R2和R3互换为其它值的R1、R2和R3；(ii)通过将变量R3(当R3不是氨基时)转化为氨基，将酯基CO2R1还原为CH2OH，并任选形成酰基或其磷酸酯衍生物而将所得到的通式(Ⅰ)的化合物转化为通式(A)的化合物，并在必要时或根据需要，将通式(Ⅰ)的化合物中的变量R2转化为通式(A)的化合物中的变量X；其特征在于通式(Ⅰ)中R2是氯。
Description
本发明涉及一种制备药物化合物的方法。
具有如下通式的化合物2-氨基-6-氯嘌呤(ACP)：
是制备核苷类似物抗病毒剂的有用的中间体，如喷西洛维(penciclovir，原先叫做BRL 39123)和泛西洛维(famciclovir，原先叫做BRL 42810)，分别描述在EP-A-141927(实施例1)和EP-A-182024(实施例2)中。该中间体在9位被合适的支链前体取代，接着将6-氯基团转换为羟基(鸟嘌呤)或氢(2-氨基嘌呤)。
一种从ACP制备的方法概述在EP-A-302644和美国专利号5175288中，现已发现一种比具体描述在该出版物中的方法优越的改进方法。其重要区别在于在原先的方法里嘌呤分子6-位的氯基在该方法的初期被消除(参见反应流程1)。在本发明的方法中通过在整个流程中将6-氯取代基保留在分子中，只是在最后一步将其消除，获得了产率的显著提高和加工好处(参见反应流程2)。通过使工艺流程更为有效，并且除去了柱色谱步骤(该柱色谱步骤会使不利的路径作为生产方法)，总产率从10.6％增加到41％。
相应地，本发明提供一种从ACP制备喷西洛维(penciclovir)/泛西洛维(famciclovir)的方法，该方法包括如EP-302644所述的从ACP制备的方法，其特征在于在脱羧和水解步骤后将6-氯取代基消除。
因为在偶合步骤没有采用含水的稀释物沉淀产品，从而具有大的容量优势，二甲基甲酰胺(DMF)更容易回收，因为它不必从大量的水中分离。
本发明的方法有更大的总容积效率。
用下面的实施例说明本发明。实施例1(步骤1产物)
2-氨基-6-氯-9-(2-甲酯基丁酸甲酯-4-基)嘌呤的制备
将2-氨基-6-氯嘌呤(9.18g,53.1毫摩尔)、3-溴-1,1,1-丙三羧酸三乙酯(20.33g,57.3毫摩尔)、碳酸钾(11.1g,80.3毫摩尔)和DMF(190ml)的混合物在60-63℃下一起搅拌22小时。在此之后将反应混合物用塞里床热过滤，并将滤饼用DMF(30ml)洗涤。将滤液和洗涤液合并，在高真空蒸馏下除去溶剂，得到粗红棕色油。将该红棕色油溶解在甲醇(140ml)中，冷却到20℃，然后在搅拌下加入甲醇钠(1.2g)的甲醇溶液(40ml)。约20分钟后形成沉淀物，并继续搅拌约1小时。然后将反应混合物冷却到15℃，并在此温度下保持30分钟。将产品滤出，用甲醇(10ml)洗涤，并在40℃、真空下干燥16小时。产率：12.0g，纯度为95％。
实施例2
(步骤2产物)
9-(4-乙酰氧基-3-乙酰氧基甲基丁-1-基)-2-氨基-6-氯嘌呤的制备
将2-氨基-6-氯-9-(2-甲酯基丁酸甲酯-4-基)嘌呤(32.7g,0.1摩尔)、硼氢化钠(11.5g,0.3摩尔)和二氯甲烷(125ml)在20℃下搅拌。在冷却下将反应温度保持在20-22℃的同时，在约2.0小时内滴加入甲醇(75ml)。让反应混合物再搅拌1.5小时。加入水(100ml)，接着在将反应温度保持在20～22℃下滴加浓盐酸(20～22ml)，使pH值在6.7～7.0之间。在真空下除去二氯甲烷和甲醇，直至得到150ml的反应液量。将反应混合物冷却到5℃，并在此温度下搅拌30分钟。将生成的沉淀物滤出，并将产物滤饼用冷水(20ml)洗涤。将所得到的湿固体物(40～50g)与二氯甲烷(250ml)溶液中的三乙胺(15ml)和4-二甲氨基吡啶(1.0g)一起搅拌。在20～30分钟内将乙酐(75ml,0.79摩尔)以这种速率滴加入以控制回流。将反应混合物在回流下再加热1.5小时。将反应混合物冷却到20℃，并用20％(重量比)的氢氧化钠中和至pH6.4～6.5。将二氯甲烷层分离，并将水相用二氯甲烷(100ml)萃取。将合并的二氯甲烷相蒸发至干燥。将粗的湿固体物从75ml甲醇∶水(3∶1)中重结晶，在过滤前将沉淀物冷却到-5℃约1小时。将产品用0℃的冷甲醇∶水(3∶1)洗涤，并在40℃真空炉中干燥16小时。产率：23g，纯度为97％～98％。
实施例3
(步骤3产品)
a)9-(4-乙酰氧基-3-乙酰氧基丁-1-基)-2-氨基嘌呤(泛西洛维)的制备
将9-(4-乙酰氧基-3-乙酰氧基丁-1-基)-2-氨基-6-氯嘌呤(15.4g,43毫摩尔)、5％钯/碳(6.16g)、三乙胺(6.6ml,47毫摩尔)和乙酸乙酯(77ml)在高压釜内、50℃和氢气中、1巴压力下搅拌3～5小时。在反应完成后，将混合物从高压釜中取出，用乙酸乙酯(30ml)洗涤高压釜，使洗液保持在50℃下。将主反应混合物滤过塞里床，接着将洗液最后将乙酸乙酯(30ml)滤过塞里床。将水(40ml)加入到合并的乙酸乙酯滤液和洗液中。将乙酸乙酯蒸发至干燥，得到粗的白色固体。将该固体从正丁醇(62ml)中重结晶，在过滤前将冷却的溶液在0～5℃搅拌3小时。将产品滤出，并用母液洗涤。将该固体再悬浮在正庚烷(50ml)中，搅拌30分钟并过滤。将产品在40℃、真空下干燥16小时。产率：11～11.3g
b)9-(4-羟基-3-羟甲基丁-1-基)鸟嘌呤(喷西洛维)的制备。
将9-(4-乙酰氧基-3-乙酰氧基甲基-丁-1-基)-2-氨基-6-氯嘌呤(10g,28.1毫摩尔)、甲酸(96％,6.3ml)和水(55ml)的混合物搅拌并加热至回流约4小时。冷却后，将该溶液与氢氧化钠溶液(12.5M,27ml)混合而被碱化，将所得到的溶液搅拌1.5小时。加入甲酸而将溶液中和。将生成的浆料加热至回流(约105℃)，然后冷却至40～45℃，并搅拌约3小时。将粗产品分离并用水(20ml)洗涤。将分离的产物溶解在氢氧化钠溶液(3M,80ml)中。加入碳(约1.5g)，并将该浆料搅拌约1小时，然后过滤除去碳并用水(20ml)洗涤。加入甲酸将溶液中和，并加热到约100℃而将生成的沉淀物再溶解，然后再冷却。将沉淀的产物搅拌约3小时，然后分离，并在干燥前用水(2×20ml)洗涤。产率：5.3～5.5g。
(流程2)
Claims (7)
1、一种制备具有下列通式(A)的化合物的方法其中：X是氢、羟基、氯、C1～6烷氧基或苯基C1～6烷氧基；Ra和Rb是氢，或酰基或其磷酸酯衍生物，该方法包括：(ⅰ)通式(Ⅰ)的化合物的制备：其中，R1是C1～6烷基或苯基C1～6烷基，其中苯基任选地被取代；R2是氢、羟基、氯、C1～6烷氧基、苯基C1～6烷氧基或氨基；R3是卤素、C1～6烷基硫代、C1～6烷基磺酰基、叠氮基、氨基或被保护的氨基，该制备包括将通式(Ⅱ)的化合物与通式(Ⅴ)的化合物的反应：
通式(Ⅱ)中，R2和R3如通式(Ⅰ)所定义；通式(Ⅴ)中，L是离去基团，R1如通式(Ⅰ)所定义；得到通式(Ⅵ)的化合物：然后，通过脱羧反应将通式(Ⅵ)的中间体化合物转化为通式(Ⅰ)的化合物，并且在必要时或根据需要，将变量R1、R2和R3转化为其它值的R1、R2和R3；(ⅱ)通过在R3不是氨基时，将变量R3转化为氨基，将酯基CO2R1还原为CH2OH，并任选地形成酰基或磷酸酯衍生物而将所得到的通式(Ⅰ)的化合物转化为通式(A)的化合物，在必要时或根据需要将通式Ⅰ的化合物中的变量R2转化为通式(A)的化合物中的变量X；其特征在于在通式(Ⅰ)中R2是氯。
2、一种制备如权利要求1所定义的通式(Ⅰ)的化合物的方法，该方法包括将其中R2和R3如权利要求1所定义的通式(Ⅱ)化合物与其中R1是C1～4烷基且L是卤素的通式(Ⅴ)化合物反应，接着将生成的通式(Ⅵ)的化合物脱羧，并且在必要时或根据需要，将所生成的通式(Ⅰ)的化合物中的R1、R2和R3互换为如权利要求1中所定义的通式(Ⅰ)中的R1、R2和R3的其它值。
3、一种式中R2是氯的通式(Ⅰ)的化合物或其盐：
式中，R1、R2和R3如权利要求1所定义。
4、一种根据权利要求3的化合物或其盐，其中，R1是甲基或乙基，R2是氨基。
5、2-氨基-6-氯-9-(2-甲酯基丁酸甲酯-4-基)嘌呤。
6、一种根据权利要求1制备9-(4-乙酰氧基-3-乙酰氧基甲基丁-1-基)-2-氨基嘌呤的方法。
7、一种根据权利要求1制备9-(4-羟基-3-羟甲基丁-1-基)鸟嘌呤的方法。
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| GB9407698A GB9407698D0 (en) | 1994-04-19 | 1994-04-19 | Pharmaceuticals |
| GB9407698.1 | 1994-04-19 |
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| CN1045963C true CN1045963C (zh) | 1999-10-27 |
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| GB (1) | GB9407698D0 (zh) |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| GB9615253D0 (en) * | 1996-07-20 | 1996-09-04 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9615276D0 (en) * | 1996-07-20 | 1996-09-04 | Smithkline Beecham Plc | Pharmaceuticals |
| GB9807116D0 (en) * | 1998-04-02 | 1998-06-03 | Smithkline Beecham Plc | Novel process |
| GB9807114D0 (en) * | 1998-04-02 | 1998-06-03 | Smithkline Beecham Plc | Novel process |
| CA2496684A1 (en) * | 2002-08-26 | 2004-03-04 | Teva Pharmaceutical Industries Ltd | Crystalline solid famciclovir forms i, ii, iii and preparation thereof |
| CA2522573A1 (en) * | 2003-04-30 | 2004-11-18 | Teva Pharmaceutical Industries Ltd. | Process for the preparation of famciclovir |
| WO2005026167A1 (en) * | 2003-09-04 | 2005-03-24 | Teva Pharmaceutical Industries Ltd. | Process for preparing famciclovir |
| US7458839B2 (en) * | 2006-02-21 | 2008-12-02 | Fci Americas Technology, Inc. | Electrical connectors having power contacts with alignment and/or restraining features |
| US20050215787A1 (en) * | 2004-03-26 | 2005-09-29 | Joshi Ramesh A | An improved process for the preparation of purines |
| US7473780B2 (en) | 2004-05-18 | 2009-01-06 | Teva Pharmeceutical Industries Ltd. | Drying process for preparing crystalline solid famciclovir |
| GB2426247A (en) * | 2005-05-20 | 2006-11-22 | Arrow Int Ltd | Methods of preparing purine derivatives such as famciclovir |
| CN102070636B (zh) * | 2011-01-17 | 2012-05-23 | 浙江大学 | 喷昔洛韦的制备方法 |
| CN104086552B (zh) * | 2014-07-31 | 2016-01-13 | 济南兆康医药科技有限公司 | 一种喷昔洛韦的精制方法 |
| CN104496991A (zh) * | 2014-11-04 | 2015-04-08 | 常州康丽制药有限公司 | 高品质2-氨基-6-氯-9-(4-羟基-3–羟甲基丁基)嘌呤的制备方法 |
| CN104744472A (zh) * | 2015-03-12 | 2015-07-01 | 常州康丽制药有限公司 | 高品质2-氨基-6-氯-9-(4-羟基-3-羟甲基丁基)嘌呤的制备方法 |
| CN108314685B (zh) * | 2018-03-16 | 2020-08-25 | 上药康丽（常州）药业有限公司 | 一种2-氨基-6-氯-9-(4-乙酰氧基-3-乙酰氧甲基丁基)嘌呤的制备方法 |
| CN110713490A (zh) * | 2018-07-12 | 2020-01-21 | 浙江医药股份有限公司新昌制药厂 | 一种喷昔洛韦的制备方法 |
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| EP0302644A2 (en) * | 1987-08-01 | 1989-02-08 | Beecham Group Plc | Purine compounds and their preparation |
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| EP0141927B1 (en) * | 1983-08-18 | 1991-10-30 | Beecham Group Plc | Antiviral guanine derivatives |
| DE3582399D1 (de) * | 1984-09-20 | 1991-05-08 | Beecham Group Plc | Purin-derivate und ihre pharmazeutische verwendung. |
| GB8817607D0 (en) * | 1988-07-23 | 1988-09-01 | Beecham Group Plc | Novel process |
| GB8822236D0 (en) * | 1988-09-21 | 1988-10-26 | Beecham Group Plc | Chemical process |
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| EP0302644A2 (en) * | 1987-08-01 | 1989-02-08 | Beecham Group Plc | Purine compounds and their preparation |
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