WO2016078542A1 - 一种盐酸洛氟普啶的制备方法 - Google Patents
一种盐酸洛氟普啶的制备方法 Download PDFInfo
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- WO2016078542A1 WO2016078542A1 PCT/CN2015/094462 CN2015094462W WO2016078542A1 WO 2016078542 A1 WO2016078542 A1 WO 2016078542A1 CN 2015094462 W CN2015094462 W CN 2015094462W WO 2016078542 A1 WO2016078542 A1 WO 2016078542A1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms directly attached in position 2
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/472—Non-condensed isoquinolines, e.g. papaverine
- A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines having two or more nitrogen atoms in the same ring, e.g. oxadiazines
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
- C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
- C07D239/20—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D239/22—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms directly attached to ring carbon atoms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
Definitions
- the invention relates to the field of medicine, in particular to a preparation method of lofluprene hydrochloride.
- 2,4-dihydroxy-5,6-dimethylpyrimidine (2) is reacted with phosphorus oxychloride to form 2,4-dichloro-5,6-dimethylpyrimidine (3), and then Alkylation of 1-methyl-1,2,3,4-tetrahydroisoquinoline to give 2-chloro-4-(1-methyl 1,2,3,4-tetrahydroisoquinoline-2 -yl)-5,6-dimethylpyrimidine (4), and finally alkylation with 4-fluoroaniline, salt formation with hydrochloric acid to give lofluprene hydrochloride, due to the method in 3 and 1-methyl There is a problem of positional selectivity during the reaction of -1,2,3,4-tetrahydroisoquinoline, the yield is low, and the application is limited.
- the quality of the intermediate was affected by the large amount of phosphate encapsulated in the product.
- the literature is to use ethylene glycol and n-butanol as solvent, react in the presence of triethylamine at 130 ° C for about 30 hours, add acetone after the reaction, then add water, stir for 2 hours.
- the solid is filtered, the solid is dissolved in dichloromethane, pickled, washed with alkali, dried, and the methylene chloride layer is concentrated. The residue is dissolved in ethanol, and then hydrogen chloride or hydrochloric acid is added to form a salt. Long time, complicated post-processing and other issues.
- the present invention provides a preparation method of lofluprene hydrochloride which is easy to industrialize and has high yield.
- the invention is characterized in that in the preparation of 4-hydroxy-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (6), only 4-fluorophenylhydrazine carbonate and 2-methyl are required. Ethyl acetoacetate is heated and dehydrated in a solvent until the starting material is completely reacted.
- the invention is characterized in that 4-hydroxy-2-(4-fluoroaniline)- in the preparation process of 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7)
- the reaction of 5,6-dimethylpyrimidine (6) with phosphorus oxychloride in a solvent until the starting material is completely obtained is obtained.
- the invention is characterized in that 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) and 1-methyl-1,2 are prepared during the preparation of loflupredil hydrochloride. , 3,4-tetrahydroisoquinoline is heated in a solvent with or without a base to the reaction of the starting material completely.
- the preparation method of lofluprene hydrochloride of the invention comprises the following steps:
- loflupredil hydrochloride 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) and 1-methyl-1,2,3,4-tetra Hydrogen isoquinoline or its hydrochloride is heated in a solvent until the starting material is completely reacted, ethanol and hydrochloric acid are added, and filtration is carried out to obtain lofluprene hydrochloride.
- the above-mentioned steps (1) to (3) are also carried out under a gas atmosphere of argon or nitrogen, preferably nitrogen.
- the step (1) of the present invention preferably comprises a base reaction, in particular, wherein the molar ratio of 4-fluorophenylhydrazine carbonate, ethyl 2-methylacetoacetate and alkali is 1:1 to 2:0-2, preferably 1:1.2-1.6: 0.5-1.
- the alkali reaction may be further carried out, specifically, wherein the molar ratio of the 4-fluorophenylhydrazine carbonate to the ethyl 2-methylacetoacetate is 1:1-2, preferably 1:1.2. -1.6.
- the alkali or strong base salt in the above step (1) includes, but is not limited to, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium methoxide and sodium ethoxide. Or more than one, preferably sodium hydroxide and potassium hydroxide.
- the 4-fluorophenylhydrazine carbonate described in the above step (1) is 4-fluorophenylhydrazine carbonate (FC 6 H 4 NHC(NH 2 )NH ⁇ H 2 CO 3 ) (1:1) or 4- Fluoroquinone carbonate (1:0.5) (FC 6 H 4 NHC(NH 2 )NH ⁇ 1/ 2 H 2 CO 3 ), preferably 4-fluorophenylhydrazine carbonate is 4-fluorophenylhydrazine carbonate (1:0.5) (FC 6 H 4 NHC(NH 2 )NH ⁇ 1/ 2 H 2 CO 3 ) is 4-fluorophenylhydrazine carbonate (5).
- the solvent described in the above step (1) is selected from any one or more of toluene, xylene, benzene, chlorobenzene and cyclohexane, preferably toluene.
- the weight feed ratio is 1:2-20, preferably 1:4-8.
- the weight charge ratio is a weight ratio of 4-fluorophenylhydrazine carbonate to solvent.
- the molar charge ratio of 4-hydroxy-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (6) and phosphorus oxychloride described in the above step (2) is 1:0.5-2, preferably 1: 0.6-1.0.
- the solvent in the above step (2) reaction includes, but is not limited to, one or more of toluene, xylene, benzene, chlorobenzene, cyclohexane, n-hexane and DMF (dimethylformamide), preferably toluene or two.
- the weight feed ratio is 1:2-20, preferably 1:3-8.
- the weight charge ratio refers to the weight ratio of 4-hydroxy-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (6) to a solvent.
- the base described in the above step (2) includes, but is not limited to, one or more of sodium hydroxide, potassium hydroxide and barium hydroxide, preferably sodium hydroxide, and the pH is adjusted with a base, and is 1-10, preferably 2 -7.
- step (2) of the present invention when the solvent in the heating reaction is a polar solvent such as DMF, after the reaction is completed, a non-polar solvent such as toluene is added, then water is added, and the pH is adjusted to 1-10 with a base. , preferably 2-7.
- a polar solvent such as DMF
- step (3) of the present invention the preparation of lofluprene hydrochloride is classified into the following two cases.
- Method 1 The 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) and 1-methyl-1,2,3,4-tetrahydroisoquinoline or The hydrochloride is heated in a solvent, and after completion of the reaction, ethanol and hydrochloric acid are added to obtain lofluprene hydrochloride, wherein 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) and 1
- the molar ratio of methyl-1,2,3,4-tetrahydroisoquinoline is 1:1 to 2, preferably 1:1.1 to 1.5.
- Method 2 the 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) and 1-methyl-1,2,3,4-tetrahydroisoquinoline Or the hydrochloride or the base is heated in a solvent, and after the reaction is completed, water and dichloromethane are added to the reaction solution, stirred, and the aqueous layer is separated, the aqueous layer is extracted with dichloromethane, and the combined dichloromethane layer is diluted.
- the 1-methyl-1,2,3,4-tetrahydroisoquinoline or the hydrochloride thereof described in the above step (3) may be the optical isomer (R)-(+)-1-A thereof.
- the solvent described in the above step (3) includes, but not limited to, ethylene glycol, glycerin, 1,2 propanediol, 1,3 propanediol, DMF (dimethylformamide), DMSO (dimethyl sulfoxide), One or more of dimethylacetamide, N-methylpyrrolidone, ethylene glycol monomethyl ether and dioxane, and the solvent is preferably ethylene glycol, glycerol and DMF.
- the weight feed ratio is 1:0.1-10, preferably 1:0.5-3.
- the weight charge ratio refers to the weight ratio of 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) to a solvent.
- the reaction temperature is 100 to 180 ° C, preferably 120 to 140 ° C.
- the base described in the above step (3) includes, but is not limited to, one or more of triethylamine, diisopropylethylamine, pyridine, 4-dimethylaminopyridine, and N-methylmorpholine, preferably two. Isopropylethylamine.
- the ethanol concentration described in the above step (3) is from 10% to 100%, preferably from 50% to 80%.
- step (1) 4-hydroxy-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (6), it is not required to be catalyzed by an organic base such as sodium alkoxide or pyridine, and it is not required to slowly add 2- Ethyl methyl acetoacetate, it is not necessary to distill off the low boiling point solvent during the reaction.
- organic base such as sodium alkoxide or pyridine
- 2- Ethyl methyl acetoacetate it is not necessary to distill off the low boiling point solvent during the reaction.
- Do not use higher-priced DMF as solvent do not use water-miscible and difficult to recycle solvent (DMF, methanol and ethanol), and the solvent used can be recycled after simple treatment.
- step (2) 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) is prepared by using only a small amount of phosphorus oxychloride, and the solvent used can be recovered and applied.
- a small amount of a single solvent may be used, and no catalyst may be added.
- step (1) 4-hydroxy-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (6), it is only necessary to separate the water produced by the reaction, and it is not necessary to filter out the generated salt while hot. There is also no need to adjust the pH.
- the reaction is completed, only the product needs to be filtered; in step (2) 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) preparation, the material is added to the reactor at room temperature, It is necessary to add phosphorus oxychloride at a high temperature of 85 ° C.
- the reaction time is remarkably shortened, so that the overall reaction time is further shortened.
- step (2) 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7), since the product is dissolved in an organic solvent, the phosphate dissolved after the phosphorus oxychloride reaction In water, it is separated to avoid a large amount of phosphate encapsulated in the product; in step (1) 4-hydroxy-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (6) preparation, steps ( 2) 4-chloro-2-(4-fluoroaniline)-5,6-dimethylpyrimidine (7) preparation, step (3) preparation of loflupredil hydrochloride product purity of up to 99% or more, the final product The trait is a white powder.
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Abstract
Description
Claims (13)
- 一种盐酸洛氟普啶的制备方法,其特征在于,包括如下步骤:(1)4-羟基-2-(4-氟苯胺)-5,6-二甲基嘧啶的制备:将4-氟苯胍碳酸盐和2-甲基乙酰乙酸乙酯加入到反应器中,加入溶剂,加入碱或强碱盐或不加碱加热回流脱水至原料反应完全,降温,加入水搅拌,过滤,水洗,即得;(2)4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶的制备:将4-羟基-2-(4-氟苯胺)-5,6-二甲基嘧啶(6)与三氯氧磷在溶剂中加热回流至原料反应完全,冷却,加入水,直接分液或用碱调节pH后再分液,水层用溶剂提取,合并有机层,有机层用水洗至中性,浓缩有机层,即得;(3)盐酸洛氟普啶的制备:4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶(7)和1-甲基-1,2,3,4-四氢异喹啉或其盐酸盐在溶剂中加热至原料反应完全,冷却,加入乙醇和盐酸,过滤,即得盐酸洛氟普啶;或向4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶(7)和1-甲基-1,2,3,4-四氢异喹啉中加入碱,在溶剂中加热至原料反应完全,加入水和二氯甲烷,分出水层,水层用二氯甲烷提取,合并的二氯甲烷层用稀盐酸和水洗涤,浓缩二氯甲烷层,残留物溶于乙醇中,加入盐酸调pH=1,搅拌析晶,即得盐酸洛氟普啶。
- 如权利要求1所述的制备方法,其特征在于:步骤(1)所述加碱或强碱盐是氢氧化钠、氢氧化钾、氢氧化钡、氢氧化锂、碳酸钠、碳酸钾、碳酸锂、甲醇钠和乙醇钠的一种或一种以上,其中4-氟苯胍碳酸盐:2-甲基乙酰乙酸乙酯:碱摩尔投料比=1:1-2:0-2;或所述不加碱,其中4-氟苯胍碳酸盐与2-甲基乙酰乙酸乙酯摩尔投料比为=1:1-2。
- 如权利要求1或2所述的制备方法,其特征在于:步骤(1)中所述的4-氟苯胍碳酸盐是F-C6H4NHC(NH2)NH·H2CO3或F-C6H4NHC(NH2)NH·1/2H2CO3。
- 如权利要求1所述的制备方法,其特征在于:步骤(1)所述溶剂选自甲苯、二甲苯、苯、氯苯和环己烷中的一种或一种以上,重量投料比为1:2-20。
- 如权利要求1所述的制备方法,其特征在于:步骤(2)所述4-羟基-2-(4-氟苯胺)-5,6-二甲基嘧啶(6):三氯氧磷的摩尔投料比=1:0.5-2。
- 如权利要求1所述的制备方法,其特征在于:所述步骤(2)中的溶剂选自甲苯、二甲苯、苯、氯苯、环己烷、正己烷和DMF一种或一种以上,重量投料比为1:2-20。
- 如权利要求1所述的制备方法,其特征在于:步骤(2)中所述的碱调节pH值,其中碱是 氢氧化钠、氢氧化钾、氢氧化钡中一种或一种以上,pH值为1-10。
- 如权利要求1所述的制备方法,其特征在于,所述的步骤(3)中4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶(7)和1-甲基-1,2,3,4-四氢异喹啉或其盐酸盐在溶剂中加热反应,反应完成后加入乙醇和盐酸即得盐酸洛氟普啶,其中4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶(7):1-甲基-1,2,3,4-四氢异喹啉或其盐酸盐摩尔投料比=1:1-2;或向4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶(7)和1-甲基-1,2,3,4-四氢异喹啉中加入碱,在溶剂中加热反应,反应完成后,稍冷,向反应液中加入水和二氯甲烷,搅拌,分出水层,水层用二氯甲烷提取,合并的二氯甲烷层用稀盐酸和水洗涤,浓缩二氯甲烷层,残留物溶于乙醇中,加入盐酸调pH=1,搅拌析晶,即得盐酸洛氟普啶,其中4-氯-2-(4-氟苯胺)-5,6-二甲基嘧啶(7):1-甲基-1,2,3,4-四氢异喹啉或其盐酸盐:碱的摩尔投料比=1:1-2:0-5。
- 如权利要求1或8所述的制备方法,其特征在于,步骤(3)中所述的碱是三乙胺、二异丙基乙胺、吡啶、4-二甲氨基吡啶、N-甲基吗啉中一种或一种以上。
- 如权利要求8所述的制备方法,其特征在于:所述的乙醇浓度10%-100%。
- 如权利要求8所述的制备方法,其特征在于:所述的1-甲基-1,2,3,4-四氢异喹啉或其盐酸盐还可以是(R)-(+)-1-甲基-1,2,3,4-四氢异喹啉或(S)-(-)-1-甲基-1,2,3,4-四氢异喹啉或它们的盐酸盐。
- 如权利要求8所述的制备方法,其特征在于:步骤(3)中所述的溶剂可以在乙二醇、丙三醇、1,2丙二醇、1,3丙二醇、DMF(二甲基甲酰胺)、DMSO(二甲基亚砜)、二甲基乙酰胺、N-甲基吡咯烷酮、乙二醇单甲醚和二氧六环中一种或一种以上,重量投料比为1:0.1-10,所述反应温度是100-180℃。
- 如权利要求1所述的制备方法,其特征在于,所述的步骤(1)-(3)中的所述的反应也可在气体保护下进行。
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RU2017113099A RU2702625C2 (ru) | 2014-11-19 | 2015-11-12 | Способ получения гидрохлорида ревапразана |
US15/519,886 US9981917B2 (en) | 2014-11-19 | 2015-11-12 | Preparation method for revaprazan hydrochloride |
JP2017524015A JP6592085B2 (ja) | 2014-11-19 | 2015-11-12 | レバプラザン塩酸塩の調製方法 |
KR1020177012550A KR20170084075A (ko) | 2014-11-19 | 2015-11-12 | 레바프라잔 염산염의 제조 방법 |
CA2966810A CA2966810C (en) | 2014-11-19 | 2015-11-12 | Preparation method for revaprazan hydrochloride |
ZA2017/02350A ZA201702350B (en) | 2014-11-19 | 2017-04-03 | Preparation method for revaprazan hydrochloride |
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CN107759562B (zh) * | 2016-08-21 | 2020-10-23 | 常州四药制药有限公司 | 一种盐酸洛氟普啶的制备方法 |
WO2019082869A1 (ja) * | 2017-10-24 | 2019-05-02 | アドバンスト・ソフトマテリアルズ株式会社 | 低包接率ポリロタキサンの製造方法 |
CN112062669A (zh) * | 2019-06-11 | 2020-12-11 | 上海复星星泰医药科技有限公司 | 芳烃类化合物的制备方法 |
CN112661753B (zh) * | 2020-12-29 | 2022-06-03 | 山东铂源药业股份有限公司 | 一种帕布昔利布中间体的制备方法 |
CN114029092B (zh) * | 2021-12-29 | 2024-03-05 | 苏利制药科技江阴有限公司 | 一种金属催化剂的合成方法 |
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CN1217722A (zh) * | 1996-05-04 | 1999-05-26 | 株式会社柳韩洋行 | 制备嘧啶衍生物的方法 |
WO2014060908A1 (en) * | 2012-10-17 | 2014-04-24 | Lupin Limited | Improved process for preparation of revaprazan hydrochloride |
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US5750531A (en) | 1994-08-13 | 1998-05-12 | Yuhan Corporation | Pyrimidine derivatives and processes for the preparation thereof |
IN188411B (zh) * | 1997-03-27 | 2002-09-21 | Yuhan Corp |
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CN1217722A (zh) * | 1996-05-04 | 1999-05-26 | 株式会社柳韩洋行 | 制备嘧啶衍生物的方法 |
WO1998018784A1 (en) * | 1996-10-29 | 1998-05-07 | Yuhan Corporation | Process for preparation of pyrimidine derivatives |
WO2014060908A1 (en) * | 2012-10-17 | 2014-04-24 | Lupin Limited | Improved process for preparation of revaprazan hydrochloride |
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CA2966810C (en) | 2022-06-28 |
RU2702625C2 (ru) | 2019-10-09 |
RU2017113099A (ru) | 2018-10-18 |
KR20170084075A (ko) | 2017-07-19 |
CA2966810A1 (en) | 2016-05-26 |
RU2017113099A3 (zh) | 2019-04-15 |
CN105669642A (zh) | 2016-06-15 |
CN105669642B (zh) | 2020-06-09 |
ZA201702350B (en) | 2018-05-30 |
US20170267646A1 (en) | 2017-09-21 |
JP6592085B2 (ja) | 2019-10-16 |
JP2017534637A (ja) | 2017-11-24 |
US9981917B2 (en) | 2018-05-29 |
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