CN105503924A - Method for synthesizing N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester - Google Patents
Method for synthesizing N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester Download PDFInfo
- Publication number
- CN105503924A CN105503924A CN201610014646.4A CN201610014646A CN105503924A CN 105503924 A CN105503924 A CN 105503924A CN 201610014646 A CN201610014646 A CN 201610014646A CN 105503924 A CN105503924 A CN 105503924A
- Authority
- CN
- China
- Prior art keywords
- tetrahydropyridine
- boric acid
- replaces
- synthesis
- acid ester
- 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
Abstract
The invention discloses a method for synthesizing N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester. According to the method, N-substitute-1, 2, 3, 6-tetrahydropyridine-5-carboxylic acid (ester) serves as the raw material, conducts addition with halogen and then is subjected to alkaline condition elimination to form alkenyl halide and then subjected to coupling with al boron ester under the condition of metal palladium catalyzation, and the N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester is obtained. According to the method, the obtained midbody alkenyl halide does not contain isomer, separation is easy to conduct, purity of an obtained product is high, and the method provides a simple way for synthesis of compounds of the type.
Description
Technical field
The present invention relates to a kind of method that synthesis N-replaces-1,2,3,6-tetrahydropyridine-5-boric acid esters, belong to pharmaceutical intermediate synthesis field.
Background technology
N-replaces-1,2,3,6-tetrahydropyridine-5-boric acid esters as important structural unit, synthesizes various active medicine after being widely used in Suzuki coupling.In existing data, majority is all directly directly used as raw material by this compounds, only has minority document and patent reports synthetic method.
Existing synthetic method mainly comprises: the piperidone replaced from N-, under HMDSLi or LDA and the two trifluoro-methylsulfonyl aniline condition of ultralow temperature of N, N-, carbonyl is transformed into thiazolinyl triflate, obtains product subsequently after Suzuki coupling.
The maximum shortcoming of aforesaid method is: it is very poor that raw material becomes thiazolinyl triflate selectivity through alkali, usually the isomer proportion obtained is nearly 2:1-3:1, this intermediate is separated and needs column chromatography, and separation yield is usually at 24-50%, also inseparable mixture is usually obtained after the direct coupling of intermediate, even and if the method for column chromatography also cannot effectively be separated, these constrain the amplification synthesis of this compounds all further, and application is restricted.
Summary of the invention
In order to overcome above-mentioned defect, the present invention replaces-1 with N-, 2,3,6-tetrahydropyridine-5-carboxylic acid (ester) is raw material, with halogen addition, then alkaline condition is eliminated and is formed thiazolinyl halogen, obtains N-replace-1,2 under catalyzing by metal palladium with connection boron ester after carrying out coupling subsequently, 3,6-tetrahydropyridine-5-boric acid ester.
A kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters, it is characterized in that comprising the following steps:
The first step, in organic solvent, N-replaces-1,2,3,6-tetrahydropyridine-5-carboxylic acid (ester) and halogen generation addition reaction, then add alkali, be warming up to 40-120 DEG C of reaction, alkaline hydrolysis, elimination and decarboxylic reaction occur simultaneously and generates N-replacement-1,2,3,6-tetrahydropyridine-5-halogen, yield 52-77%;
Second step, N-replace-1,2,3,6-tetrahydropyridine-5-halogen, Glacial acetic acid potassium, connection boric acid ester and palladium catalyst add in organic solvent, intensification 80-120 DEG C of reaction, and reaction terminates, diatomite filtration, after filtrate evaporate to dryness, after adding activated carbon decolorizing, obtain N-after mixed solvent recrystallization and replace-1,2,3,6-tetrahydropyridine-5-boric acid ester, yield 55-79%.
Further, in technique scheme, in the first step, organic solvent is selected from methylene dichloride, 1,2-ethylene dichloride, toluene or tetrahydrofuran (THF).
Further, in technique scheme, in the first step, halogen is selected from chlorine, bromine or iodine.
Further, in technique scheme, in the first step, starting raw material is carboxylic acid, and alkali is selected from pyridine, 4-picoline, DBU, DBN, N-methyl piperidine or tetramethyl guanidine; Starting raw material is carboxylicesters, and alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.
Further, in technique scheme, in the first step, it is 1:0.95-1.05:2-6 that N-replaces-1,2,3,6-tetrahydropyridine-5-carboxylic acids (ester), halogen and alkali equivalent ratio.
Further, in technique scheme, in second step, organic solvent is selected from dioxane, DMSO, DMF, tetrahydrofuran (THF), glycol dimethyl ether or toluene.
Further, in technique scheme, in second step, palladium catalyst is selected from the two Diphenyl phosphino ferrocene palladium chloride of tetrakis triphenylphosphine palladium, two (tri-butyl phosphine) palladium or 1,1'-.
Further, in technique scheme, in second step, connection boric acid ester is selected from connection pinacol borate or connection boric acid DOPCP.
Further, in technique scheme, in second step, it is 1:1.5-3:1-1.1:0.01-0.05 that N-replaces-1,2,3,6-tetrahydropyridine-5-halogen, Glacial acetic acid potassium, connection boric acid ester and palladium catalyst equivalence ratio.
Further, in technique scheme, in second step, mixed solvent is selected from ethanol or Virahol mixes according to different ratios with normal heptane.
the beneficial effect of the invention
The present invention adopts the starting raw material that market can buy (or from 1,2,3, after 6-tetrahydropyridine-5-carboxylic acid hydrochloride is free, obtain after reacting from different bromo-derivatives) through bromine addition, then the method for alkali elimination, optionally by the position of Double bond location at needs, eliminate isomer, intermediate product thiazolinyl bromine directly can carry out the coupling of palladium chtalyst, after coupling terminates, product is through simple process, just can obtain sterling, avoid column chromatography, synthesis technique is applicable to amplification quantity and produces very much.
Specific embodiments
embodiment 1
N-methyl isophthalic acid, the synthesis of 2,3,6-tetrahydropyridine-5-pinacol borate:
In 250mL reaction flask, add N-methyl isophthalic acid, 2,3,6-tetrahydropyridine-5-carboxylic acid, ethyl ester 16.9g (0.1mol) and 110mL methylene dichloride, under room temperature, be added dropwise to bromine 16.0g (0.1mol).After adding, first stirring at room temperature reacts 30 minutes, after TLC detection reaction, add 20mL tetramethylene sulfone to dissolve, be warming up to 50-60 DEG C, start to drip 2MKOH (0.3mol), have bubble to emerge in dropping process, the effusion speed according to bubble controls rate of addition, after dropwising, when bubble is no longer overflowed, be warming up to 80-90 DEG C of reaction 2-3 hour, rectification under vacuum obtains 11.6g colourless liquid N-methyl isophthalic acid, 2,3,6-tetrahydropyridine-5-bromine, yield 66%.
Under nitrogen protection, in three mouthfuls of reaction flasks, add 90mL dioxane, N-methyl isophthalic acid, 2,3,6-tetrahydropyridine-5-bromine (11.6g), PdCl
2dppf0.97g (1.32mmol), Glacial acetic acid potassium 12.9g (0.13mol) and connection pinacol borate 16.7g (66mmol), finish and be slowly warming up to 80 DEG C of stirring reactions and spend the night, GC detection reaction completely (product/raw material is greater than 80:1), diatomite filtration after cooling, filtrate is distilled to dry, add ethyl acetate and gac, back flow reaction 1 hour, decolorization filtering, filtrate is distilled to dry, after adding ethanol and normal heptane, be cooled to-10 DEG C of stirring reactions, filtration obtains 9.9g white solid product N-methyl isophthalic acid, 2, 3, 6-tetrahydropyridine-5-pinacol borate, yield 71%.
embodiment 2
The synthesis of N-ethyl-1,2,3,6-tetrahydropyridine-5-pinacol borate:
In 250mL reaction flask, add N-ethyl-1,2,3,6-tetrahydropyridine-5-carboxylic acid 15.5g (0.1mol) and 110mL tetrahydrofuran (THF), under room temperature, be added dropwise to bromine 16.6g (0.1mol).After adding, first stirring at room temperature reacts 30 minutes, TLC(triketohydrindene hydrate develop the color) can't detect raw material after, add 20mL tetramethylene sulfone to dissolve, be warming up to 50-60 DEG C, start to drip 30.4gDBU (0.2mol), have bubble to emerge in dropping process, the effusion speed according to bubble controls rate of addition, after dropwising, when bubble is no longer overflowed, be warming up to 80-90 DEG C of reaction 2-3 hour, rectification under vacuum obtains 14.1g colourless liquid N-ethyl-1,2,3,6-tetrahydropyridine-5-bromine, yield 74%.
Under nitrogen protection, in three mouthfuls of reaction flasks, add 90mL dioxane, N-ethyl-1,2,3,6-tetrahydropyridine-5-bromine (14.1g), PdCl
2dppf0.54g (0.74mmol), Glacial acetic acid potassium 14.5g (0.15mol) and connection pinacol borate 18.8g (74mmol), finish and be slowly warming up to 100 DEG C of stirring reactions and spend the night, GC detection reaction completely (product/raw material is greater than 60:1), diatomite filtration after cooling, filtrate is distilled to dry, add ethyl acetate and gac, back flow reaction 1 hour, decolorization filtering, filtrate is distilled to dry, after adding ethanol and normal heptane, be cooled to-10 DEG C of stirring reactions, filtration obtains 11.2g white solid product N-ethyl-1, 2, 3, 6-tetrahydropyridine-5-pinacol borate, yield 64%.
embodiment 3
The synthesis of N-benzyl-1,2,3,6-tetrahydropyridine-5-pinacol borate:
In 250mL reaction flask, add N-benzyl-1,2,3,6-tetrahydropyridine-5-carboxylic acid 15.5g (0.1mol) and 110mL methylene dichloride, under room temperature, add iodine 25.4g (0.1mol).After adding, first stirring at room temperature reacts 30 minutes, TLC(triketohydrindene hydrate develops the color) detect after raw material no longer changes, add 40mL tetramethylene sulfone to dissolve, be warming up to 50-60 DEG C, start to drip 37.2gDBN (0.3mol), have bubble to emerge in dropping process, the effusion speed according to bubble controls rate of addition, after dropwising, when bubble is no longer overflowed, be warming up to 90-100 DEG C of reaction 2-3 hour, rectification under vacuum obtains 15.8g light yellow liquid N-benzyl-1,2,3,6-tetrahydropyridine-5-iodine, yield 53%.
Under nitrogen protection, in three mouthfuls of reaction flasks, add 90mLDMSO, N-benzyl-1,2,3,6-tetrahydropyridine-5-iodine (15.8g), PdCl
2dppf0.39g (0.53mmol), Glacial acetic acid potassium 14.5g (0.15mol) and connection pinacol borate 13.4g (53mmol), finish and be slowly warming up to 80 DEG C of stirring reactions and spend the night, GC detection reaction completely (product/raw material is greater than 100:1), diatomite filtration after cooling, filtrate is distilled to dry, add ethyl acetate and gac, back flow reaction 1 hour, decolorization filtering, filtrate is distilled to dry, after adding ethanol and normal heptane, be cooled to-10 DEG C of stirring reactions, filtration obtains 12.4g off-white color solid phase prod N-benzyl-1, 2, 3, 6-tetrahydropyridine-5-pinacol borate, yield 78%.
embodiment 4
The synthesis of N-Boc-1,2,3,6-tetrahydropyridine-5-pinacol borate:
In 250mL reaction flask, add 22.7gN-Boc-1,2,3,6-tetrahydropyridine-5-carboxylic acid (0.1mol) and 120mL toluene, under room temperature, be added dropwise to bromine 16.6g (0.1mol).After adding, first stirring at room temperature reacts 30 minutes, after TLC detection reaction, add 20mL tetramethylene sulfone to dissolve, be warming up to 50-60 DEG C, start to drip pyridine 31.2g (0.4mol), have bubble to emerge in dropping process, the effusion speed according to bubble controls rate of addition, after dropwising, when bubble is no longer overflowed, be warming up to 80-90 DEG C of reaction 2-3 hour, rectification under vacuum obtains 18.1g colourless liquid N-Boc-1,2,3,6-tetrahydropyridine-5-bromine, yield 69%.
Under nitrogen protection, in three mouthfuls of reaction flasks, add 90mL dioxane, N-Boc-1,2,3,6-tetrahydropyridine-5-bromine (18.1g), PdCl
2dppf1.01g (1.38mmol), Glacial acetic acid potassium 16.9g (0.17mol) and connection pinacol borate 17.5g (69mmol), finish and be slowly warming up to 80 DEG C of stirring reactions and spend the night, GC detection reaction completely (product/raw material is greater than 50:1), diatomite filtration after cooling, filtrate is distilled to dry, add ethyl acetate and gac, back flow reaction 1 hour, decolorization filtering, filtrate is distilled to dry, after adding ethanol and normal heptane, be cooled to-10 DEG C of stirring reactions, filtration obtains 15.6g white solid product N-Boc-1, 2, 3, 6-tetrahydropyridine-5-pinacol borate, yield 73%.
embodiment 5
The synthesis of N-Cbz-1,2,3,6-tetrahydropyridine-5-boric acid DOPCP:
In 250mL reaction flask, add 22.7gN-Cbz-1,2,3,6-tetrahydropyridine-5-carboxylic acid (0.1mol) and 120mL1,2-ethylene dichloride, lower of room temperature passes into chlorine to no longer inhaling.After, first stirring at room temperature reacts 30 minutes, TLC(triketohydrindene hydrate develop the color) detect raw material disappear after, add 20mL tetramethylene sulfone to dissolve, be warming up to 50-60 DEG C, start to drip N-methyl piperidine 29.7g (0.3mol), have bubble to emerge in dropping process, the effusion speed according to bubble controls rate of addition, after dropwising, when bubble is no longer overflowed, be warming up to 80-90 DEG C of reaction 2-3 hour, rectification under vacuum obtains 18.1g colourless liquid N-Cbz-1,2,3,6-tetrahydropyridine-5-chlorine, yield 72%.
Under nitrogen protection, in three mouthfuls of reaction flasks, add 90mL dioxane, N-Cbz-1,2,3,6-tetrahydropyridine-5-chlorine (18.1g), Pd (
t-Bu
3p)
21.1g (2.16mmol), Glacial acetic acid potassium 17.6g (0.18mol) and connection boric acid DOPCP 17.4g (77mmol), finish and be slowly warming up to 110 DEG C of stirring reactions and spend the night, GC detection reaction completely (product/raw material is greater than 40:1), diatomite filtration after cooling, filtrate is distilled to dry, add ethyl acetate and gac, back flow reaction 1 hour, decolorization filtering, filtrate is distilled to dry, after adding ethanol and normal heptane, be cooled to-10 DEG C of stirring reactions, filtration obtains 13.0g white solid product N-Cbz-1, 2, 3, 6-tetrahydropyridine-5-boric acid DOPCP, yield 55%.
Claims (10)
1. the method for synthesis N-replacement-1,2,3,6-tetrahydropyridine-5-boric acid esters, is characterized in that comprising the following steps:
The first step: in organic solvent, N-replaces-1,2,3,6-tetrahydropyridine-5-carboxylic acid (ester) and halogen generation addition reaction, then add alkali, be warming up to 40-120 DEG C of reaction, alkaline hydrolysis, elimination and decarboxylic reaction occur simultaneously and generates N-replacement-1,2,3,6-tetrahydropyridine-5-halogen, yield 52-77%;
Second step: N-replaces-1,2,3,6-tetrahydropyridine-5-halogen, Glacial acetic acid potassium, connection boric acid ester and palladium catalyst add in organic solvent, intensification 80-120 DEG C of reaction, and reaction terminates, diatomite filtration, after filtrate evaporate to dryness, after adding activated carbon decolorizing, obtain N-after mixed solvent recrystallization and replace-1,2,3,6-tetrahydropyridine-5-boric acid ester, yield 55-79%.
2. a kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters according to claim 1, and it is characterized in that: in the first step, organic solvent is selected from methylene dichloride, 1,2-ethylene dichloride, toluene or tetrahydrofuran (THF).
3. a kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters according to claim 1, and it is characterized in that: in the first step, halogen is selected from chlorine, bromine or iodine.
4. a kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters according to claim 1, and it is characterized in that: in the first step, starting raw material is carboxylic acid, and alkali is selected from pyridine, 4-picoline, DBU, DBN, N-methyl piperidine or tetramethyl guanidine; Starting raw material is carboxylicesters, and alkali is selected from sodium hydroxide, potassium hydroxide, sodium carbonate or salt of wormwood.
5. a kind of synthesis N-replaces-1,2,3 according to claim 1, the method of 6-tetrahydropyridine-5-boric acid ester, is characterized in that: in the first step, and N-replaces-1,2,3,6-tetrahydropyridine-5-carboxylic acid (ester), halogen and alkali equivalent ratio are 1:0.95-1.05:2-6.
6. a kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters according to claim 1, and it is characterized in that: in second step, organic solvent is selected from dioxane, DMSO, DMF, tetrahydrofuran (THF), glycol dimethyl ether or toluene.
7. a kind of synthesis N-replaces-1 according to claim 1,2,3, the method of 6-tetrahydropyridine-5-boric acid ester, it is characterized in that: in second step, palladium catalyst is selected from the two Diphenyl phosphino ferrocene palladium chloride of tetrakis triphenylphosphine palladium, two (tri-butyl phosphine) palladium or 1,1'-.
8. a kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters according to claim 1, it is characterized in that: in second step, and connection boric acid ester is selected from connection pinacol borate or connection boric acid DOPCP.
9. a kind of synthesis N-replaces-1 according to claim 1,2,3, the method of 6-tetrahydropyridine-5-boric acid ester, it is characterized in that: in second step, N-replaces-1,2,3,6-tetrahydropyridine-5-halogen, Glacial acetic acid potassium, connection boric acid ester and palladium catalyst equivalence ratio are 1:1.5-3:1-1.1:0.01-0.05.
10. a kind of synthesis N-replaces the method for-1,2,3,6-tetrahydropyridine-5-boric acid esters according to claim 1, and it is characterized in that: in second step, mixed solvent is selected from ethanol or Virahol mixes according to different ratios with normal heptane.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610014646.4A CN105503924B (en) | 2016-01-11 | 2016-01-11 | A kind of synthesis N replaces the method for the borate of 1,2,3,6 tetrahydropyridine 5 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201610014646.4A CN105503924B (en) | 2016-01-11 | 2016-01-11 | A kind of synthesis N replaces the method for the borate of 1,2,3,6 tetrahydropyridine 5 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105503924A true CN105503924A (en) | 2016-04-20 |
CN105503924B CN105503924B (en) | 2017-05-31 |
Family
ID=55712282
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201610014646.4A Active CN105503924B (en) | 2016-01-11 | 2016-01-11 | A kind of synthesis N replaces the method for the borate of 1,2,3,6 tetrahydropyridine 5 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN105503924B (en) |
Cited By (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN109762007A (en) * | 2019-02-27 | 2019-05-17 | 大连联化化学有限公司 | A kind of process synthesizing N- substitution -1,2,5,6- tetrahydropyridine -4- borate |
CN110922421A (en) * | 2019-12-17 | 2020-03-27 | 蚌埠中实化学技术有限公司 | Synthesis method of N-methyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester |
CN111484407A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Preparation method of 1-halogenated-2-methyl-4-substituted carbonyloxy-2-butene |
-
2016
- 2016-01-11 CN CN201610014646.4A patent/CN105503924B/en active Active
Non-Patent Citations (2)
Title |
---|
DAVID W J. ET AL: ""Synthesis of the Putative Structure of Tridachiahydropyrone"", 《ORG. LETT》 * |
ZHAN F X. ET AL: ""Formation of Enehydrazine Intermediates through Coupling of Phenylhydrazines with Vinyl Halides: Entry into the Fischer Indole Synthesis"", 《ANGEW. CHEM. INT. ED》 * |
Cited By (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN111484407A (en) * | 2019-01-25 | 2020-08-04 | 新发药业有限公司 | Preparation method of 1-halogenated-2-methyl-4-substituted carbonyloxy-2-butene |
CN111484407B (en) * | 2019-01-25 | 2023-04-07 | 新发药业有限公司 | Preparation method of 1-halogenated-2-methyl-4-substituted carbonyloxy-2-butene |
CN109762007A (en) * | 2019-02-27 | 2019-05-17 | 大连联化化学有限公司 | A kind of process synthesizing N- substitution -1,2,5,6- tetrahydropyridine -4- borate |
CN110922421A (en) * | 2019-12-17 | 2020-03-27 | 蚌埠中实化学技术有限公司 | Synthesis method of N-methyl-1, 2,5, 6-tetrahydropyridine-4-boronic acid pinacol ester |
CN110922421B (en) * | 2019-12-17 | 2023-05-05 | 安徽英特美科技有限公司 | Synthesis method of N-methyl-1, 2,5, 6-tetrahydropyridine-4-boric acid pinacol ester |
Also Published As
Publication number | Publication date |
---|---|
CN105503924B (en) | 2017-05-31 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP3712130B1 (en) | Method for synthesis of roxadustat and intermediate compounds thereof | |
KR101609898B1 (en) | A process for preparing r-beta-amino phenylbutyric acid derivatives | |
CN105503924A (en) | Method for synthesizing N-substitute-1, 2, 3, 6-tetrahydropyridine-5-boric acid ester | |
CN103420893B (en) | Prepare the method for Silodosin intermediate | |
CN103570696B (en) | A kind of preparation method of Axitinib intermediate and preparing the application in Axitinib | |
CN102093194A (en) | New method for synthesizing 3-cyclopropyl methoxy-4-(difluoromethoxy) benzoic acid | |
CN102639486A (en) | Process for manufacture of N-acylbphenyl alanine | |
CN104650142B (en) | A kind of preparation method of fosaprepitant dimeglumine | |
US9796678B2 (en) | Method for manufacturing optically active compound | |
CA2971093A1 (en) | Process of making cenicriviroc and related analogs | |
CN102964269A (en) | Novel preparation method of iopromide | |
CN104151359A (en) | Quinazoline compound as well as preparation method and application thereof in preparing tyrosine kinase inhibitor | |
CN101628886B (en) | Synthesis method for 2- methoxyl-4-amino-5-ethylsulfonylbenzoic acid | |
CN103896940B (en) | A kind of synthetic method of Eliquis | |
CN112939814B (en) | Preparation method of deuterated dacarbazine intermediate | |
CN103086948A (en) | Preparation method of (S,S,S)-2-azabicyclo[3,3,0]octane-3-carboxylic acid | |
CN104557678A (en) | Method for preparing aranidipine | |
CN102471267A (en) | Process for production of optically active nipecotamide | |
WO2021238965A1 (en) | Method for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenylpropionate and salt thereof | |
CN103842345A (en) | Method for producing 1-substituted-3- fluoroalkylpyrazole-4-carboxylic acid ester | |
WO2021242807A1 (en) | Methods for preparing methyl (s)-2-amino-3-(4-(2,3-dimethylpyridin-4-yl)phenyl)propionate and hydrochloric acid salts thereof | |
JP2008105956A (en) | Method for producing alpha-trifluoromethylacrylic ester | |
CN102807567B (en) | Synthesis method of (7R)-pyridino [1,2-alpha]-7-amino-6,7,8,9-tetrahydro-10-indol propyl acetate | |
CN105085278A (en) | Method for preparing 2-methyl-1-substituted phenyl-2-propyl amine compound | |
CN111100110A (en) | Process for preparing 7-piperazinylbenzothiophenes or salts thereof |
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 |