CN109970662A - A method of it prepares and dislikes La Geli intermediate - Google Patents
A method of it prepares and dislikes La Geli intermediate Download PDFInfo
- Publication number
- CN109970662A CN109970662A CN201711444122.XA CN201711444122A CN109970662A CN 109970662 A CN109970662 A CN 109970662A CN 201711444122 A CN201711444122 A CN 201711444122A CN 109970662 A CN109970662 A CN 109970662A
- Authority
- CN
- China
- Prior art keywords
- formula
- methylpyrimidine
- organic layer
- product
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
- C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
- C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
- C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
- C07D239/52—Two oxygen atoms
- C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Plural Heterocyclic Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The present invention relates to the preparation method that a kind of formula dislikes La Geli intermediate (IV), the method is prepared by following route, and synthetic route is short, this method safety simple to operation, yield is good, while environmental pollution is small, there are good economic benefits, is suitable for industrial production
Description
Technical field
The present invention relates to a kind of methods for preparing and disliking La Geli intermediate, belong to field of medicine and chemical technology.
Technical background
Endometriosis is the common disease of gynaecology, frequently-occurring disease, is a kind of common benign wellability of women at fertile age
Disease belongs to one of Gynecological stubborn diseases.Middle-aged women illness rate is about 15%；Its age of onset is mostly between 30-49 years old.Fertility
The disease incidence of phase women, accounts for about 70%-the 80% of Sterility patient, seriously affects physical and mental health, work and the fertility of women.
Disliking La Geli (elagolix) is opened by AbbVie and Neurocrine Biosciences Inc (NBIX) cooperation
A kind of non-peptide gonadotropin-releasing hormone receptor of Orally active (GnRH) antagonist of hair, for treating mullerianosis
Disease.The drug submits application for quotation to U.S. FDA at present.
Formula IV compound dislikes La Geli key intermediate as preparation, and existing literature report is few.
The synthetic route one of CN200480019502 report is as follows:
The route uses toxic and explosive ketene dimer, and production safety risk is higher, is not suitable for industrialized production.
The synthetic route two of WO 2009062087A1 report is as follows:
The synthetic route yield only has 63%, we repeat the route yield and there was only 57%, and the process yield is relatively low, causes
Material largely wastes, and cost is caused to increase, and post-processes and need to be stirred overnight, and activity time is long, is not suitable for industrialized production.
And it finds in formula IV with the presence of a large amount of formula IV-imp impurity, the impurity purification difficult.
It can be seen that the preparation method for developing a kind of new evil La Geli intermediate is of great significance.
Summary of the invention
The present invention relates to a kind of preparation methods for disliking La Geli intermediate (formula IV).
A kind of preparation method of formula IV compound, is summarized as follows:
By making Formulas I and II compound, ammonolysis is prepared under base catalysis in organic solvent.
Wherein X represents Cl, Br, I or OH in halogen in Formulas I.
In the preparation method of formula IV compound, it is characterised in that the organic solvent is selected from n,N-Dimethylformamide
(DMF), one or more of dimethyl sulfoxide (DMSO), methylene chloride；Reaction is anti-further preferably in dimethyl sulfoxide
It answers.
It is characterized in that the alkali is selected from potassium carbonate, sodium carbonate, saleratus, sodium bicarbonate, potassium hydroxide, hydroxide
One or more of sodium, sodium hydrogen, morpholine, piperidines, diethylamine, piperazine, triethylamine；The further preferred potassium carbonate of alkali.
It is characterized in that reacting at -40 DEG C~80 DEG C, preferable reaction temperature is -10 DEG C~40 DEG C.
Experiment route: compound of formula I and Formula II compound obtain formula IV compound under the conditions of base catalysis in organic solvent.
The utility model has the advantages that the present invention, which compared with prior art, avoids multistep reaction, prepares key intermediate formula IV, to avoid
Total recovery caused by multistep synthesizes reduces problem, and the maximum innovation of the present invention makes to receive in one-step synthesis to key intermediate
Rate is obviously improved, and improves raw material availability, comparison original grinds compound and preparation patent is with the obvious advantage, and yield is obviously improved；This
Reaction condition is mild, has post-processing simple, high income is easy to the advantages that industrializing.
Specific embodiment
The present invention is further illustrated below by the mode of embodiment, but does not therefore limit the present invention to the reality
It applies among a range.
Embodiment 1:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
2- fluoro- 6- (trifluoromethyl) bromobenzyl (10g) is slowly added dropwise into added with 2,4- dihydroxy -6- methylpyrimidine
(7.3g), dimethyl sulfoxide (100ml), potassium carbonate (16.1g) 250ml flask in stir -10 DEG C~0 DEG C reaction 4h.To anti-
It answers and ethyl acetate and water stratification is added in system, retain upper organic layer, salt water washing organic layer, concentration of organic layers obtains
Product is beaten with methyl tertiary butyl ether(MTBE), product 10.11g obtained by drying, formula IV product assay 99.2%, IV-imp content
0.31%, yield 86%.1H NMR (400MHz, CDCl3) δ 2.15 (s, 3H), 5.37 (s, 2H), 5.60 (s, 2H), 7.23~
7.56(m,3H),9.02(s,1H).MS(ESI)m/z 303.0([M+H]+)。
Embodiment 2:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
2- fluoro- 6- (trifluoromethyl) bromobenzyl (100g) is slowly added dropwise into added with 2,4- dihydroxy -6- methylpyrimidine
(73g), dimethyl sulfoxide (1000ml), potassium carbonate (161g) 2L flask in stir -5 DEG C~5 DEG C reaction 4h.To reaction system
Middle addition ethyl acetate and water stratification retain upper organic layer, salt water washing organic layer, concentration of organic layers, obtained product use
Methyl tertiary butyl ether(MTBE) mashing, product 100.0g obtained by drying, formula IV product assay 99.1%, IV-imp content 0.25%, yield
85%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 3:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
By 2- fluoro- 6- (trifluoromethyl) bromobenzyl (40g), 2,4- dihydroxy -6- methylpyrimidine (29g), dimethyl sulfoxide
0 DEG C~10 DEG C reaction 4h are stirred in the 1L flask of (400ml), potassium carbonate (64.4g).Into reaction system be added ethyl acetate and
Water stratification, reservation upper organic layer, salt water washing organic layer, concentration of organic layers, obtained product are beaten with methyl tertiary butyl ether(MTBE),
Drying is to get product 40.38g, formula IV product assay 99.0%, IV-imp content 0.34%, yield 86%.MS (ESI) m/z
303.0([M+H]+)。
Embodiment 4:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
2- fluoro- 6- (trifluoromethyl) bromobenzyl (100g) is slowly added dropwise into added with 2,4- dihydroxy -6- methylpyrimidine
(73g), N,N-dimethylformamide (1000ml), potassium carbonate (161g) 2L flask in stir -5 DEG C~5 DEG C reaction 4h.To anti-
It answers and ethyl acetate and water stratification is added in system, retain upper organic layer, salt water washing organic layer, concentration of organic layers obtains
Product is beaten with methyl tertiary butyl ether(MTBE), product 96.20g obtained by drying, formula IV product assay 98.9%, IV-imp content
0.29%, yield 82%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 5:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
2- fluoro- 6- (trifluoromethyl) bromobenzyl (50g) is slowly added dropwise into added with 2,4- dihydroxy -6- methylpyrimidine
(36.5g), methylene chloride (600ml), potassium carbonate (80g) 2L flask in stir -5 DEG C~5 DEG C reaction 4h.Into reaction system
Second water stratification is added, water layer is extracted with dichloromethane, and merges methylene chloride phase, salt water washing organic layer, and concentration of organic layers obtains
Product be beaten with methyl tertiary butyl ether(MTBE), product 47.0g obtained by drying, formula IV product assay 98.5%, IV-imp content
0.46%, yield 80.0%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 6:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
2- fluoro- 6- (trifluoromethyl) bromobenzyl (100g) is slowly added dropwise into added with 2,4- dihydroxy -6- methylpyrimidine
(73g), dimethyl sulfoxide (1000ml), sodium carbonate (123.7g) 2L flask in stir -5 DEG C~5 DEG C reaction 4h.To reactant
Ethyl acetate and water stratification are added in system, retains upper organic layer, salt water washing organic layer, concentration of organic layers, obtained product
It is beaten, product 94.04g obtained by drying, formula IV product assay 98.7%, IV-imp content 0.38%, is received with methyl tertiary butyl ether(MTBE)
Rate 80%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 7:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
2- fluoro- 6- (trifluoromethyl) bromobenzyl (25g) is added added with 2,4- dihydroxy -6- methylpyrimidine (18.3g), diformazan
Base sulfoxide (250ml), saleratus (29.2g) 500mL flask in stir 10 DEG C~20 DEG C reaction 4h.Add into reaction system
Enter ethyl acetate and water stratification, retains upper organic layer, salt water washing organic layer, concentration of organic layers, obtained product methyl
Tertbutyl ether mashing, product 23.60g obtained by drying, formula IV product assay 98.6%, IV-imp content 0.57%, yield
80.0%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 8:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
By 2- fluoro- 6- (trifluoromethyl) bromobenzyl (40g), 2,4- dihydroxy -6- methylpyrimidine (29g), dimethyl sulfoxide
0 DEG C~10 DEG C reaction 6h are stirred in the 1L flask of (400ml), triethylamine (47.2g).Into reaction system be added ethyl acetate and
Water stratification, reservation upper organic layer, salt water washing organic layer, concentration of organic layers, obtained product are beaten with methyl tertiary butyl ether(MTBE),
Drying is to get product 40.0g, formula IV product assay 98.0%, IV-imp content 0.77%, yield 80.0%.MS (ESI) m/z
303.0([M+H]+)。
Embodiment 9:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
By 2- fluoro- 6- (trifluoromethyl) bromobenzyl (30g), 2,4- dihydroxy -6- methylpyrimidine (21.7g), dimethyl sulfoxide
0 DEG C~10 DEG C reaction 6h are stirred in the 500mL flask of (250ml), diethylamine (8.5g).Ethyl acetate is added into reaction system
And water stratification, reservation upper organic layer, salt water washing organic layer, concentration of organic layers, obtained product are beaten with methyl tertiary butyl ether(MTBE)
Slurry is dried to get product 28.46g, formula IV product assay 97.6%, IV-imp content 0.85%, yield 81.0%.MS (ESI)
m/z303.0([M+H]+)。
Embodiment 10:
The synthesis of -1 (6H)-t-butyl formate of tert-butyl 4- methyl -2,6- dioxo -2,3- dihydro-pyrimidin
2,4- dihydroxy -6- methylpyrimidine (1.0g), pyridine (5ml) are added in 25mL flask and are stirred, cooling 0 DEG C~10
It DEG C is slowly added dropwise BOC acid anhydrides (1.9g), drop finishes, and insulation reaction 6h filters reaction system, filtrate concentration, concentration fluid column chromatography
(PE/EA=6:1) obtain product 0.85g, yield 85%.1H NMR (400MHz, CDCl3) δ 1.38 (s, 9H), 2.26 (d,
3H),5.42(m,1H),6.0(br,1H).MS(ESI)m/z 127.2([M-100(Boc)H+]。
Embodiment 11:
The synthesis of -1 (6H)-t-butyl formate of (9H- fluorenes -9- base) methyl 4- methyl -2,6- dioxo -2,3- dihydro-pyrimidin
2,4- dihydroxy -6- methylpyrimidine (1.0g), pyridine (6ml) are added in 25mL flask and are stirred, cooling 0 DEG C~10
Chloro-carbonic acid -9- fluorenyl methyl ester (2.05g) DEG C is slowly added dropwise, drop finishes, and insulation reaction 4h filters reaction system, filtrate concentration, dense
Contracting fluid column chromatography (PE/EA=3:1) obtains product 2.29g, yield 83%.1H NMR (400MHz, CDCl3) δ 2.26 (s, 3H),
4.46 (t, 1H), 4.70 (d, 2H), 5.42 (s, 1H), 6.0 (br, 1H), 7.20~7.40 (m, 4H), 7.55 (dd, 2H), 7.87
(dd,2H).MS(ESI)m/z 349.3([M+H]+)。
Embodiment 12:
The synthesis of -1 (6H)-formic acid 1- chloroethene ester of 4- methyl -2,6- dioxo -2,3- dihydro-pyrimidin
2,4- dihydroxy -6- methylpyrimidine (1.0g), pyridine (5ml) are added in 25mL flask and are stirred, cooling 0 DEG C~10
1- chloroethylchloroformate ester (1.1g) DEG C is slowly added dropwise, drop finishes, and insulation reaction 4h filters reaction system, filtrate concentration, concentration
Fluid column chromatography (PE/EA=6:1) obtains product 1.58g, yield 86%.1H NMR (400MHz, CDCl3) δ 1.93 (d, 3H),
2.26(s,3H),5.42(s,1H),6.0(br,1H),6.12(q,1H).MS(ESI)m/z 233.6([M+H]+)。
Embodiment 13:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
By 2- fluoro- 6- (trifluoromethyl) bromobenzyl (2.0g), tert-butyl 4- methyl -2,6- dioxo -2,3- dihydro-pyrimidin -1
(6H)-t-butyl formate (1.81g), dimethyl sulfoxide (40ml), potassium carbonate (2.34g) 100mL flask in stir 0 DEG C~10
DEG C reaction 4h.Ethyl acetate and water stratification are added into reaction system, retains upper organic layer, salt water washing organic layer, concentration
Methylene chloride 30ml is added into concentrate for organic layer, and trifluoroacetic acid 2.0g is added and is warming up to 30 DEG C~40 DEG C reaction 4h, system
Saturated sodium bicarbonate solution is added to be quenched, is layered, water layer is extracted with 20ml methylene chloride, merges organic layer, and salt water washing is organic
Layer, concentrate are beaten with methyl tertiary butyl ether(MTBE), are dried to get product 2.23g, formula IV product assay 97.6%, IV-imp content
1.0%, yield 95.0%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 14:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
By 2- fluoro- 6- (trifluoromethyl) bromobenzyl (1.0g), (9H- fluorenes -9- base) methyl 4- methyl -2,6- dioxo -2,3-
Dihydro-pyrimidin -1 (6H)-t-butyl formate (1.36g), dimethyl sulfoxide (20ml), potassium carbonate (2.34g) 100mL flask in
Stir 0 DEG C~10 DEG C reaction 4h.Ethyl acetate and water stratification are added into reaction system, retains upper organic layer, salt water washing
Methylene chloride (30ml) is added into concentrate in organic layer, concentration of organic layers, and diethylamine (3.0g) is added and is warming up to 30 DEG C~40
DEG C reaction 3h, system be added saturated ammonium chloride solution be quenched, be layered, water layer with 20ml methylene chloride extract, merge organic layer, salt
Water washing organic layer, concentrate are beaten with methyl tertiary butyl ether(MTBE), are dried to get product 1.07g, formula IV product assay 97.8%,
IV-imp content 0.93%, yield 91.0%.MS (ESI) m/z 303.0 ([M+H]+).
Embodiment 15:
1- [2- fluoro- 6- (trifluoromethyl) benzyl] -6- methylpyrimidine -2,4 (1H, 3H)-diketone (formula IV) synthesis
By 2- fluoro- 6- (trifluoromethyl) bromobenzyl (3g), -1 (6H)-formic acid of 4- methyl -2,6- dioxo -2,3- dihydro-pyrimidin
1- chloroethene ester (2.71g), dimethyl sulfoxide (60ml), potassium carbonate (3.5g) 500mL flask in stirring 0 DEG C~10 DEG C reaction
4h.Addition ethyl acetate and water stratification into reaction system, reservation upper organic layer, salt water washing organic layer, concentration of organic layers,
Methanolic HCl solution (30ml) is added into concentrate, is warming up to 30 DEG C~40 DEG C reaction 4h, dichloromethane is added in system concentration
Alkane is added saturated sodium bicarbonate aqueous solution and is quenched, is layered, and water layer is extracted with 20ml methylene chloride, merges organic layer, salt water washing
Organic layer, concentrate are beaten with methyl tertiary butyl ether(MTBE), are dried to get product 3.24g, formula IV product assay 97.3%, IV-imp
Content 1.13%, yield 92.0%.MS (ESI) m/z 303.0 ([M+H]+).
Claims (5)
1. a kind of method of preparation formula IV compound, by making Formulas I and II compound ammonolysis system under base catalysis in organic solvent
It is standby to obtain
Wherein X represents Cl, Br, I or OH in halogen in Formulas I,
R represents H, tertbutyloxycarbonyl, tablet held before the breast by officials methoxycarbonyl group, 1- chloroethene carbamate base in Formula II.
2. the method according to claim 1, wherein the organic solvent be selected from n,N-Dimethylformamide,
One or more of dimethyl sulfoxide, methylene chloride；Preferably reacted in dimethyl sulfoxide.
3. the method according to claim 1, wherein the alkali be selected from potassium carbonate, sodium carbonate, saleratus,
One or more of sodium bicarbonate, potassium hydroxide, sodium hydroxide, sodium hydrogen, morpholine, piperidines, diethylamine, piperazine, triethylamine；It is excellent
It is selected as potassium carbonate.
4. preferably being reacted the method according to claim 1, wherein the reaction temperature is -40 DEG C~80 DEG C
Temperature is -10 DEG C~40 DEG C.
5. Formula II compound:
Wherein: R represents H, Boc, Fmoc, ACE (1- chloroethene carbamate base),
The Formula II compound is preferred are as follows: 2,4- dihydroxy -6- methylpyrimidine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711444122.XA CN109970662B (en) | 2017-12-27 | 2017-12-27 | Method for preparing oxaagoli intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711444122.XA CN109970662B (en) | 2017-12-27 | 2017-12-27 | Method for preparing oxaagoli intermediate |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109970662A true CN109970662A (en) | 2019-07-05 |
| CN109970662B CN109970662B (en) | 2023-06-30 |
Family
ID=67072039
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711444122.XA Active CN109970662B (en) | 2017-12-27 | 2017-12-27 | Method for preparing oxaagoli intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109970662B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220242831A1 (en) * | 2019-05-24 | 2022-08-04 | Dr. Reddy's Laboratories Limited | Improved process for the preparation of elagolix and its intermediates |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006070292A2 (en) * | 2004-10-12 | 2006-07-06 | Queen's University At Kingston | Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents |
| US20110098472A1 (en) * | 2007-11-07 | 2011-04-28 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CA2927641A1 (en) * | 2013-10-30 | 2015-05-07 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Pyrazolopyrimidone or pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof |
-
2017
- 2017-12-27 CN CN201711444122.XA patent/CN109970662B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2006070292A2 (en) * | 2004-10-12 | 2006-07-06 | Queen's University At Kingston | Pyrimidine compounds as anti-ictogenic and/or anti-epileptogenic agents |
| US20110098472A1 (en) * | 2007-11-07 | 2011-04-28 | Neurocrine Biosciences, Inc. | Processes for the preparation of uracil derivatives |
| CA2927641A1 (en) * | 2013-10-30 | 2015-05-07 | Shanghai Hengrui Pharmaceutical Co., Ltd. | Pyrazolopyrimidone or pyrrolotriazone derivatives, method of preparing same, and pharmaceutical applications thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20220242831A1 (en) * | 2019-05-24 | 2022-08-04 | Dr. Reddy's Laboratories Limited | Improved process for the preparation of elagolix and its intermediates |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109970662B (en) | 2023-06-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN112321602A (en) | Preparation method of Ruogeli drug intermediate | |
| CN105399736B (en) | It is a kind of according to the new preparation method of piperazine azoles | |
| CN107141261A (en) | Quinazoline compounds and preparation method thereof and the application in tyrosine kinase inhibitor is prepared | |
| CN108586465A (en) | A kind of Ba Rui replaces the preparation method of Buddhist nun | |
| CN103012382B (en) | A kind of preparation method of olmesartan medoxomil | |
| CN105085484B (en) | A kind of preparation method of Vonoprazan fumarate | |
| CN104447620B (en) | 1-[3-[3-(4-chlorphenyl) propoxyl group] propyl group] preparation method of-piperidine hydrochlorate | |
| CN102351778A (en) | Preparation method of arbidol hydrochloride | |
| CN106045983A (en) | Preparing method of Afatinib | |
| CN103601645B (en) | The preparation method of 1-(phenethyl amino) propane-2-alcohol compound or its salt | |
| US9593101B2 (en) | Avanafil preparation method | |
| CN105198821A (en) | Preparation method of Rociletinib | |
| CN106749259A (en) | A kind of synthetic method of cyclopenta pyrimido azoles | |
| CN109970662A (en) | A method of it prepares and dislikes La Geli intermediate | |
| CN103304478B (en) | Alkaloidal intermediate of one class synthesis renieramycins type and preparation method thereof | |
| CN109053525A (en) | The preparation method of one kind (R) -2- (2- substitution -5- fluorobenzene) pyrrolidines | |
| CN103664959B (en) | Preparation method of five-membered bicyclic guanidine compounds | |
| CN109748902A (en) | A kind of hydrochloric acid peace sieve replaces the preparation method of Buddhist nun | |
| CN103980134B (en) | A kind of preparation method of succsinic acid S-metoprolol | |
| CN105461617A (en) | Preparation method for 4-[4-(trifluoromethoxy)phenoxyl]piperidine | |
| CN106349229B (en) | The preparation method and midbody compound of Lei Dipawei intermediates | |
| CN102964259A (en) | Preparation method of related substance E of metoprolol | |
| CN110218189A (en) | A kind of simple and convenient process for preparing of Abbe Seeley intermediate and Abbe Seeley | |
| CN111116493B (en) | Method for preparing Apabetalone, intermediate and preparation method of intermediate | |
| CN106946724A (en) | The synthetic method of the benzyl malonic acid mono ethyl ester of 2 acetylamino of monoamine base inhibitor class intermediate 2 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |