CN106083711B - A kind of synthetic method of Rui Gefeini - Google Patents
A kind of synthetic method of Rui Gefeini Download PDFInfo
- Publication number
- CN106083711B CN106083711B CN201610370098.9A CN201610370098A CN106083711B CN 106083711 B CN106083711 B CN 106083711B CN 201610370098 A CN201610370098 A CN 201610370098A CN 106083711 B CN106083711 B CN 106083711B
- Authority
- CN
- China
- Prior art keywords
- phenyl
- chloro
- trifluoromethyl
- added
- water
- 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.)
- Active
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D213/81—Amides; Imides
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pyridine Compounds (AREA)
Abstract
The present invention relates to using 4 chlorine, 3 (trifluoromethyl) aniline as starting material, amidation process first occurs with phenyl chloroformate, intermediate is obtained, amidation process occurs with 4 amino, 3 fluorophenol, obtains intermediate, alkylated reaction occurs with 4 chlorine N methyl of starting material, 2 pyridine carboxamides, acetone water recrystallizes, and obtains target product Rui Gefeini, this preparation method is simple and easy to do, high income, it is high-quality, it is convenient for industrialized production.
Description
Technical field：
The present invention relates to medicinal chemistry arts, and in particular to a kind of synthetic method of Rui Gefeini.
Background technology
Entitled 4- [4- ({ [4- chloro- 3- (trifluoromethyl) phenyl] the amino first of Rui Gefeini (regorafenib, 1) chemistry
Acyl } amino) -3- fluorophenoxies]-N- picoline -2- formamides are that the novel of Bayer Bitterfeld GmbH medicines and health protection company research and development swashs more
Enzyme inhibitor kind anti-cancer drugs can inhibit and promote KIT (CD117), the PDGFR of cancer cell and tumor vascular growth (platelet-derived
Growth factor receptors), the kinases such as VEGFR (vascular endothelial growth factor receptor).The medicine is first for treating metastatic knot
The oral small molecule multi-kinase inhibitor of the intestines carcinoma of the rectum.
The documents such as WO2005/009961A describe a kind of synthetic method of Rui Gefeini, and synthetic route is as follows：
The deficiency of this route is to use the isocyanic acid (chloro- 3- (fluoroforms of 4- with certain toxicity and extremely unstable
Base) phenyl) ester as starting material, furthermore, when being alkylated reaction, amino is not protected, will produce certain
Impurity.
Technical solution
The present invention is directed to above-mentioned document shortcoming, is redesigned to its synthetic route, with the chloro- 3- (trifluoros of 4-
Methyl) aniline (2) be starting material, (2) first with phenyl chloroformate occur amidation process, obtain intermediate (3), (3) and 4-
Amidation process occurs for amino -3- fluorophenols (4), obtains intermediate (5), (5) and starting material 4- chloro-n-methyl -2- pyridines
Alkylated reaction occurs for carboxylic acid amides (6), and acetone water recrystallization obtains target product Rui Gefeini (1), this preparation method is easy easily
Row, high income, it is high-quality, it is convenient for industrialized production, synthetic route as follows：
The selection of the feed postition of the alkali type of experimental example 1, three-step reaction
The selection of the alkali type of three-step reaction, respectively potassium tert-butoxide, cesium carbonate, sodium hydrogen, sodium methoxide, are compared,
The results are shown in Table 1.
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (fluoro- 4- hydroxyls of 3- are sequentially added into dimethyl sulfoxide (DMSO) (1500ml)
Base phenyl) urea (5) (150.0g), 4- chloro-n-methyl -2- pyridine carboxamides (6) (110.0g) and a certain amount of alkali, it is warming up to 40
~45 DEG C, insulated and stirred 15h, after reaction, 1500ml water is added into reaction solution, stirs 1h, filtering, filter cake acetone water
Recrystallization, obtains Rui Gefeini.
The selection of the alkali type of 1 three-step reaction of table
| Alkali type | Base amount | Reaction condition | Conversion ratio | Yield |
| Potassium tert-butoxide | 2.5eq | 40~45 DEG C | 97% | 56% |
| Cesium carbonate | 2.5eq | 40~45 DEG C | 95% | 82% |
| Sodium hydrogen | 2.5eq | 40~45 DEG C | 81% | 63% |
| Sodium methoxide | 2.5eq | 40~45 DEG C | 67% | 47% |
As can be seen from Table 1, when potassium tert-butoxide makees alkali, reaction conversion ratio highest, but product purity is poor, and product needs column
Chromatographic purifying, yield are also relatively low；When cesium carbonate makees alkali, reaction conversion ratio is higher, and product yield is higher；When sodium hydrogen makees alkali, instead
Answer conversion ratio relatively low, product purity is poor, and column chromatography is needed to purify, and yield is also relatively low；When sodium methoxide makees alkali, reaction conversion ratio
Minimum, yield is also minimum.
The investigation of experimental example 2, third step cesium carbonate usage amount
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (fluoro- 4- hydroxyls of 3- are sequentially added into dimethyl sulfoxide (DMSO) (1500ml)
Base phenyl) urea (5) (150.0g), 4- chloro-n-methyl -2- pyridine carboxamides (6) (110.0g) and a certain amount of cesium carbonate, heating
To 40~45 DEG C, insulated and stirred 15h, after reaction, 1500ml water is added into reaction solution, stirs 1h, filtering, filter cake is with third
Ketone water recrystallizes, and obtains 174.5g title compounds.(yield 81.0%).
The reaction condition that 2 cesium carbonate of table makees alkali compares
As can be seen from Table 2,1.5eq cesium carbonates, 2.0eq cesium carbonates, 2.5eq cesium carbonates, 3.0eq cesium carbonates is respectively adopted
When making alkali, conversion ratio is incremented by successively, but yield highest when making alkali with 2.5eq cesium carbonates.
The present invention is prepared that Rui Gefeini (1) purity is high, impurity is few, and stability is strong, is the good raw material of preparation, incite somebody to action this
Drug is made in the dosage form of the crystallization of invention, and crystallization is mixed with auxiliary material additive appropriate, preparation is made.
The present invention preferred formulation be：It is tablet, powder, granule, capsule, syrup, oral containing tablet, inhalant etc.
Preparation；The external preparations such as suppository, ointment, Eye ointments, transdermal agent, eye drops, nasal drop, auristilla, cataplasm, lotion or note
Penetrate agent.
Preferably auxiliary material is：Excipient, adhesive, lubricant, disintegrant, colorant, flavoring rectify olfactory agent, emulsifier, table
Face activating agent, cosolvent, suspension agent, isotonic agent, buffer, preservative, antioxidant, stabilizer, sorbefacient etc..
Preferably excipient is：Lactose, white sugar, glucose, cornstarch, mannitol, D-sorbite, starch, α starch,
Dextrin, avicel cellulose, light silicon anhydride, alumina silicate, calcium silicates, silicic acid magnesium aluminate, calcium monohydrogen phosphate etc..
Preferably adhesive is：Polyvinyl alcohol, methylcellulose, ethyl cellulose, Arabic gum, tragacanth gum, gelatin, worm
Glue, hypromellose, hydroxypropyl cellulose, sodium carboxymethylcellulose, polyvinylpyrrolidone, polyethylene glycol etc..
Preferably lubricant is：Magnesium stearate, calcium stearate, stearyl fumarate sodium, talcum, polyethylene glycol, colloidal state two
Silica etc..
Preferably disintegrant is：Avicel cellulose, agar, gelatin, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, fruit
Glue, low-substituted hydroxypropyl cellulose, carboxymethyl cellulose, calcium carboxymethylcellulose, croscarmellose sodium, carboxymethyl form sediment
Powder, sodium carboxymethyl starch etc..
Preferably colorant is：Di-iron trioxide, Yellow ferric oxide, famille rose, caramel, beta carotene, oxidation
Titanium, talcum, Riboflavin Sodium Phosphate etc..
Preferably corrigent is：Cocoa power, menthol, peppermint oil, borneol, cinnamomi cortex pulveratus etc..
Preferred emulsifier or surfactant are：Octadecyl triethanolamine, lauryl sodium sulfate, dodecyl ammonia
Base propionic acid, lecithin, glyceryl monostearate, sucrose fatty ester, fatty acid glyceride etc..
Preferably cosolvent is：Polyethylene glycol, propylene glycol, benzoic acid benzyl ester, ethyl alcohol, cholesterol, triethanolamine, carbonic acid
Sodium, sodium citrate, Tween 80, niacinamide etc..
Preferably suspension is：Polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, hydroxymethyl cellulose, hydroxyl second
The hydrophilic macromolecules such as base cellulose, hydroxypropyl cellulose.
Preferably isotonic agent is：Glucose, sodium chloride, mannitol, D-sorbite etc..
Preferably buffer is：The buffer solutions such as phosphate, acetate, carbonate, citrate.
Preferably preservative is：Methyl p-hydroxybenzoate, propylparaben, methaform, benzylalcohol, benzyl carbinol,
Dehydroactic acid, sorbic acid etc..
Preferably antioxidant is：Sulphite, ascorbic acid, alpha-tocopherol etc..
Embodiment 1：The synthesis of N- (4- chloro- 3- (trifluoromethyl) phenyl) phenyl carbamate (3)
To addition 4- chloro- 3- (trifluoromethyl) aniline (2) (100g), system control in n,N-Dimethylformamide (1000ml)
Temperature is less than 10 DEG C, sequentially adds pyridine (81.0g) and phenyl chloroformate (121.0g) is added dropwise, be warmed to room temperature, insulated and stirred 3h, instead
After answering, 1500ml water, 2000ml dichloromethane are added into reaction solution, detaches organic phase, organic phase uses 200ml3N successively
Aqueous hydrochloric acid solution, 200ml saturated nacl aqueous solutions, 200ml water washings, anhydrous sodium sulfate drying, decompression steam solvent, normal hexane
Mashing, obtains 151.3g title compounds.(yield 93.7%).
1H-NMR (500MHz, CDCl3)：7.81 (1H, s), 7.60~7.61 (1H, d, J=5.0Hz), 7.24~7.28
(2H, m), 7.20~7.21 (1H, d, J=5.0Hz), 7.01~7.06 (3H, m).
Embodiment 2：The synthesis of 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- hydroxy phenyls of 3-) urea (5)
To addition N- (4- chloro- 3- (trifluoromethyl) phenyl) phenyl carbamate in n,N-Dimethylformamide (1500ml)
(3) (150.0g), system temperature control are less than 15 DEG C, and 4- amino -3- fluorophenols (4) (121.0g) are added, are warmed to room temperature, insulated and stirred
4h.After reaction, 1500ml water, 2000ml dichloromethane are added into reaction solution, detaches organic phase, organic phase is used successively
300ml3N aqueous hydrochloric acid solutions, 300ml saturated nacl aqueous solutions, 300ml water washings, anhydrous sodium sulfate drying, decompression steams molten
Agent, recrystallisation from isopropanol obtain 152.1g title compounds.(yield 91.8%).
LC-MS316.5(M+1)。
1H-NMR (500MHz, DMSO)：9.32 (2H, s), 7.81 (1H, s), 7.59~7.60 (1H, d, J=5.0Hz),
7.49~7.50 (1H, d, J=5.0Hz), 7.21~7.22 (1H, d, J=5.0Hz), 6.51~6.52 (1H, d, J=
5.0Hz), 6.41 (1H, s), 4.87 (1H, s).
Embodiment 3：The synthesis of Rui Gefeini (1)
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (fluoro- 4- hydroxyls of 3- are sequentially added into dimethyl sulfoxide (DMSO) (1500ml)
Base phenyl) urea (5) (150.0g), 4- chloro-n-methyl -2- pyridine carboxamides (6) (110.0g) and cesium carbonate (350.1g), heating
To 40~45 DEG C, insulated and stirred 15h, after reaction, 1500ml water is added into reaction solution, stirs 1h, filtering, filter cake is with third
Ketone water recrystallizes, and obtains 174.5g title compounds.(yield 81.0%).
LC-MS 483.7(M+1-H2O)。
1H-NMR (500MHz, DMSO)：10.46 (1H, s), 9.35 (2H, s), 8.65~8.66 (1H, d, J=5.0Hz),
8.13 (1H, s), 7.83 (1H, s), 7.59~7.60 (1H, d, J=5.0Hz), 7.46~7.49 (2H, m), 7.20~7.21
(1H, d, J=5.0Hz), 6.42~6.46 (2H, m), 2.81 (3H, s).
Embodiment 4：The condition of the HPLC of Rui Gefeini sample purities is：
High performance liquid chromatograph
Chromatographic column：Common C8 columns
Column temperature：35℃
Flow velocity：1.0ml/min
Sample size：10μl
Mobile phase：Using 0.15mol/L trifluoroacetic acid aqueous solutions as mobile phase A, acetonitrile is Mobile phase B, and according to the form below is washed
It is de-.
Detection wavelength：235nm
| Time (minute) | Mobile phase A (%) | Mobile phase B (%) |
| 0 | 65 | 35 |
| 20 | 10 | 90 |
| 25 | 10 | 90 |
| 26 | 65 | 35 |
| 30 | 65 | 35 |
3 product of the embodiment of the present invention, standard items flowing phased soln, take test solution, take 20 μ l injection liquid chromatograies
Instrument records chromatogram, and the peaks Rui Gefeini retention time is 19.7 minutes, and number of theoretical plate is not less than by the calculating of the peaks Rui Gefeini
3000, Rui Gefeini containing compound should be the 99.7%~101.0% of labelled amount.
| The total peak area of impurity/Rui Gefeini peak areas | |
| 4 product of embodiment | 0.017% |
| Commercial standard | 0.098% |
Embodiment 6
Rui Gefeini pieces are formulated by following component, by 1000 dosages：
Preparation method includes the following steps：
1) Rui Gefeini and pharmaceutic adjuvant are pulverized and sieved respectively, it is spare,
2) take raw material and the pharmaceutic adjuvant physical mixed of recipe quantity parts by weight uniform,
3) wet granulation,
4) dry, whole grain,
5) additional auxiliary material is converted, is uniformly mixed, it is tabletted
6) Opadry is dissolved using certain solvent, is coated as coating solution.
Test result
Medicament contg：It is qualified
Disintegration time limited：Meet regulation
Embodiment 7
Rui Gefeini pieces are formulated by following component, by 1000 dosages：
Preparation method includes the following steps：
1) Rui Gefeini and pharmaceutic adjuvant are pulverized and sieved respectively, it is spare,
2) take raw material and the pharmaceutic adjuvant physical mixed of recipe quantity parts by weight uniform,
3) wet granulation,
4) dry, whole grain,
5) additional auxiliary material is converted, is uniformly mixed, it is tabletted
6) Opadry is dissolved using certain solvent, is coated as coating solution.
Test result
Medicament contg：It is qualified
Disintegration time limited：Meet regulation
The embodiments of the present invention have been described in detail above, but content is only the preferred embodiment of the present invention,
It should not be construed as limiting the practical range of the present invention.Any changes and modifications in accordance with the scope of the present application,
It should all still fall within the scope of the patent of the present invention.
Claims (1)
1. a kind of preparation method of Rui Gefeini, it is characterised in that：
It is less than to addition 4- chloro- 3- (trifluoromethyl) aniline (2) 100g, system temperature control in n,N-Dimethylformamide (1000ml)
It 10 DEG C, sequentially adds pyridine 81.0g and phenyl chloroformate 21.0g is added dropwise, be warmed to room temperature, insulated and stirred 3h, after reaction, to
1500ml water, 2000ml dichloromethane are added in reaction solution, detaches organic phase, organic phase use successively 200ml3N aqueous hydrochloric acid solutions,
200ml saturated nacl aqueous solutions, 200ml water washings, anhydrous sodium sulfate drying, decompression steam solvent, and normal hexane mashing obtains
151.3g title compounds N- (4- chloro- 3- (trifluoromethyl) phenyl) phenyl carbamate (3)；
To addition N- (4- chloro- 3- (trifluoromethyl) phenyl) phenyl carbamate (3) in n,N-Dimethylformamide (1500ml)
150.0g, system temperature control are less than 15 DEG C, and 4- amino -3- fluorophenols (4) 121.0g is added, is warmed to room temperature, insulated and stirred 4h, react
After, 1500ml water, 2000ml dichloromethane are added into reaction solution, detaches organic phase, organic phase uses 300ml3N salt successively
Aqueous acid, 300ml saturated nacl aqueous solutions, 300ml water washings, anhydrous sodium sulfate drying, decompression steam solvent, isopropanol weight
Crystallization, obtains 152.1g title compounds 1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (the fluoro- 4- hydroxy phenyls of 3-) urea (5)；
1- (4- chloro- 3- (trifluoromethyl) phenyl) -3- (fluoro- 4- hydroxy benzenes of 3- is sequentially added into dimethyl sulfoxide (DMSO) (1500ml)
Base) urea (5) 150.0g, 4- chloro-n-methyl -2- pyridine carboxamides (6) 110.0g and cesium carbonate 350.1g, it is warming up to 40~45
DEG C, 1500ml water is added into reaction solution after reaction by insulated and stirred 15h, stirs 1h, filtering, and filter cake is tied again with acetone water
Crystalline substance obtains 174.5g title compounds Rui Gefeini (1)；
The condition of the HPLC of Rui Gefeini sample purities is：
High performance liquid chromatograph
Chromatographic column：Common C8 columns
Column temperature：35℃
Flow velocity：1.0ml/min
Sample size：10μl
Mobile phase：Using 0.15mol/L trifluoroacetic acid aqueous solutions as mobile phase A, acetonitrile is Mobile phase B, is eluted,
Detection wavelength：235nm
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610370098.9A CN106083711B (en) | 2016-05-31 | 2016-05-31 | A kind of synthetic method of Rui Gefeini |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201610370098.9A CN106083711B (en) | 2016-05-31 | 2016-05-31 | A kind of synthetic method of Rui Gefeini |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106083711A CN106083711A (en) | 2016-11-09 |
| CN106083711B true CN106083711B (en) | 2018-09-25 |
Family
ID=57230262
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201610370098.9A Active CN106083711B (en) | 2016-05-31 | 2016-05-31 | A kind of synthetic method of Rui Gefeini |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106083711B (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113203A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Deuterium-substituted omega-diphenylurea and derivatives thereof and pharmaceutical compositions comprising the compounds |
| WO2011113368A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Preparation method of fluoro-substituted deuterated diphenylurea |
| US20150175545A1 (en) * | 2012-09-18 | 2015-06-25 | Suzhou Zelgen Biopharmaceutical Co., Ltd | Preparation Method of Fluoro-Substituted Deuterated Diphenylurea |
-
2016
- 2016-05-31 CN CN201610370098.9A patent/CN106083711B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2011113203A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Deuterium-substituted omega-diphenylurea and derivatives thereof and pharmaceutical compositions comprising the compounds |
| WO2011113368A1 (en) * | 2010-03-18 | 2011-09-22 | 苏州泽璟生物制药有限公司 | Preparation method of fluoro-substituted deuterated diphenylurea |
| US20150175545A1 (en) * | 2012-09-18 | 2015-06-25 | Suzhou Zelgen Biopharmaceutical Co., Ltd | Preparation Method of Fluoro-Substituted Deuterated Diphenylurea |
Non-Patent Citations (1)
| Title |
|---|
| 瑞戈非尼的合成;郑德强，等;《中国医药工业杂志》;20160525;第47卷(第5期);528-530 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106083711A (en) | 2016-11-09 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US5276058A (en) | 3,4-dihydroxychalcone derivatives | |
| EP2582689B1 (en) | New polymorphic form of imatinib base and preparation of salts thereof | |
| KR20050040837A (en) | α-Form or β-form crystal of acetanilide derivative | |
| CN103923001B (en) | Rui Gefeini salt and crystal formation, preparation method | |
| EP3263573B1 (en) | Crystal of imidazo-oxazine, pharmaceutical composition containing said crystal, and method for producing said crystal | |
| CN107365275A (en) | The Sai Lexipa of high-purity | |
| CN106458905B (en) | Betrixaban salt and its preparation method and application | |
| CN106083711B (en) | A kind of synthetic method of Rui Gefeini | |
| CN107056695A (en) | It is a kind of to treat the synthetic method that gastric cancer medicament Ah handkerchief replaces Buddhist nun | |
| CN102846609B (en) | Synthesis method for antihypertensive agent isradipine and preparation of isradipine | |
| CN101597272A (en) | The potassium salt compound of Ailamode, its preparation method and medicinal application | |
| CN106083970A (en) | A kind of synthetic method of cholanic acid | |
| EP2610251A1 (en) | Novel polymorphic forms of dabigatran etexilate and process for the preparation thereof | |
| CN104771392A (en) | Histone deacetylase inhibitor and applications thereof | |
| CN110713471B (en) | Synthetic method of trimetazidine hydrochloride | |
| EP3287466A1 (en) | Amorphous piceatannol 3'-o-glucoside and preparation method thereof | |
| CN111377910A (en) | Posaconazole impurity and preparation method and application thereof | |
| CN102718676B (en) | Agomelatine sulfate and preparation method thereof | |
| CN107001284B (en) | A kind of crystal form and preparation method thereof of androgen receptor inhibitor | |
| CN105523957B (en) | The method that one kettle way prepares scheme for lacosamide | |
| CN108530439B (en) | Furan formamide derivative and preparation method and application thereof | |
| CN102267952B (en) | Quinazoline compound and preparation method and application thereof | |
| CN108129537B (en) | Glucocorticoid isomer and its preparation method and use | |
| CN105001197A (en) | Alogliptin derivative I, preparation method and application thereof | |
| CN101209976A (en) | Substituted tartaric acid derivatives and use thereof for preparing beta-secretase inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |