CN109438373A - A kind of synthetic method of N- methylhomopiperazin - Google Patents
A kind of synthetic method of N- methylhomopiperazin Download PDFInfo
- Publication number
- CN109438373A CN109438373A CN201811512661.7A CN201811512661A CN109438373A CN 109438373 A CN109438373 A CN 109438373A CN 201811512661 A CN201811512661 A CN 201811512661A CN 109438373 A CN109438373 A CN 109438373A
- Authority
- CN
- China
- Prior art keywords
- methylhomopiperazin
- synthetic method
- catalyst
- amide
- anhydrous
- 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.)
- Pending
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D243/00—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms
- C07D243/06—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4
- C07D243/08—Heterocyclic compounds containing seven-membered rings having two nitrogen atoms as the only ring hetero atoms having the nitrogen atoms in positions 1 and 4 not condensed with other rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)
Abstract
The invention discloses a kind of synthetic methods of N- methylhomopiperazin, including following synthesis step: (1) using N- methylpiperidone as raw material, Beckmann rearrangement occurs and generates amide with hydroxylamine hydrochloride under the action of suitable temperature and Lewis acid catalyst；(2) amide that will be synthesized in step (1) carries out reduction reaction and obtains N- methylhomopiperazin under suitable reducing agent, catalyst, temperature and solvent condition.The synthetic method of N- methylhomopiperazin of the present invention uses N- methylpiperidone that is inexpensive, being easy to get for raw material, and Beckmann rearrangement occurs and generates amide with hydroxylamine hydrochloride under Lewis acid catalysis, then obtains N- methylhomopiperazin through composite reduction system；Using the purity is high of the obtained target product of this technique, reaction condition is mild, excellent yield, and convenience easy to operate, production cost is low, is suitble to amplification production.
Description
Technical field
The present invention relates to medicine intermediate synthesis technical fields, more particularly to a kind of synthesis side of N- methylhomopiperazin
Method.
Background technique
In chemical research field, many heterocyclic compounds are all very ideal medicine synthesis starting materials, be can be used as
Important raw material synthesizes certain drugs or important material product with bioactivity or special efficacy.
In nitrogen-containing heterocycle compound, the compound containing Isosorbide-5-Nitrae-Diazesuberane ring structure (being commonly called as homopiperazine), is one
The very important nitrogen-containing heterocycle compound of class, this contains the seven membered heterocyclic of two nitrogen-atoms, the electricity of two nitrogen-atoms in female ring
Negativity is higher, can react with many organic compounds, be intermediate important in synthesis field, be widely used in
The production in the fields such as medicine, fuel, pesticide, surfactant, energetic material.
So far, pharmaceuticals type relevant to homopiperazine compound up to more than 20 both at home and abroad, common are salt
The drugs such as sour Fasudil, chloreyclizine, carbamazepine, quinolone and homopiperazine hydrochloride, with the continuous depth of researcher
Enter research, is that the cancer of mankind's many years is perplexed in treatment, cardiovascular and cerebrovascular disease mentions using homopiperazine and its derivative as the drug of precursor
New direction is supplied.
N- methylhomopiperazin compound is second generation bisfentidine Emedastine in homopiperazine series compound
Critical materials have also been applied to the synthesis of numerous antihistamine drugs, cardiovascular drugs, drug for hypertension, it is seen that it is one
Extremely important chemical products.
For N- methylhomopiperazin, the synthetic route reported mainly has the following two kinds:
(1) using mono-protected homopiperazine as raw material, N- methylhomopiperazin, the technique road are synthesized through methylation, Deprotection
Line expensive raw material price is not suitable for being applied to mass production.
(2) N- methylpiperidone is dissolved in the concentrated sulfuric acid, the rearranged generation amide of sodium azide is added, by tetrahydro lithium
Aluminium reducing synthesizes N- methylhomopiperazin；First step reaction will use hypertoxic raw material sodium azide in the production method, and react
Acutely, risk is very high, and operability is low, does not have amplification manufacturing feasibility.
It is an extremely important chemical products in view of N- methylhomopiperazin, application prospect is good, and has good
Market, price are up to per kilogram 20,000 or so, find a kind of novel synthetic method to realize that its industrialized production is very intentionally
Justice, and key issues of to solve raw material supply, production cost and production operation.
Detailed description of the invention
Fig. 1 is the nuclear magnetic spectrum using the N- methylhomopiperazin product of the synthetic method production in the present invention.
Summary of the invention
It is an object of the invention to study, solve the shortcoming in current existing N- methylhomopiperazin production technology, mention
For a kind of easy to operate, cost is relatively low, the method that can be realized the amplification production of N- methylhomopiperazin.
In order to solve the above technical problems, one technical scheme adopted by the invention is that:
A kind of synthetic method of N- methylhomopiperazin is provided, synthetic route is as follows:
Including following synthesis step:
(1) using N- methylpiperidone as raw material, under the action of suitable temperature and Lewis acid catalyst and hydrochloric acid hydroxyl
Amine occurs Beckmann rearrangement and generates amide；
(2) amide that will be synthesized in step (1) carries out under suitable reducing agent, catalyst, temperature and solvent condition
Reduction reaction obtains N- methylhomopiperazin.
In a preferred embodiment of the present invention, in step (1), N- methylpiperidone, hydroxylamine hydrochloride and Lewis acid are urged
The molal weight ratio of agent is 1:1.1~2:0.01~0.1.
In a preferred embodiment of the present invention, in step (1), the temperature range of reaction is at 80~150 DEG C.
In a preferred embodiment of the present invention, the Lewis acid catalyst employed in step (1) is in following substance
One or more: anhydrous zinc chloride, anhydrous aluminum chloride, anhydrous ferric chloride, boron trifluoride ether, copper trifluoromethanesulfcomposite, three
Fluorine methanesulfonic acid iron, trifluoromethanesulfonic acid zinc, silver trifluoromethanesulfonate, tetrafluoro boric acid zinc, cobalt, tetrafluoro boric acid iron, benzene sulfonyl
Chlorine, phosphorus oxychloride.
In a preferred embodiment of the present invention, in step (2), the molal weight ratio of amide, reducing agent and catalyst
For 1:1.5~2:1.5~2.
In a preferred embodiment of the present invention, in step (2), range of reaction temperature is 0~100 DEG C.
In a preferred embodiment of the present invention, the reducing agent used in step (2) is sodium borohydride or hydroboration
Potassium.
In a preferred embodiment of the present invention, the catalyst employed in step (2) is anhydrous zinc chloride, anhydrous chlorine
Change one of aluminium, anhydrous ferric chloride, boron trifluoride ether, iodine, concentrated sulfuric acid.
In a preferred embodiment of the present invention, the solvent employed in step (2) is tetrahydrofuran, methyl tetrahydro furan
It mutters, one of 1,4- dioxane, glycol dimethyl ether, butyl cellosolve, diethylene glycol dimethyl ether or a variety of mixing
Object.
The beneficial effects of the present invention are: the synthetic method of N- methylhomopiperazin of the present invention is using N- methyl that is inexpensive, being easy to get
Piperidones is raw material, and Beckmann rearrangement occurs and generates amide with hydroxylamine hydrochloride under Lewis acid catalysis, then through multiple
It closes reduction system and obtains N- methylhomopiperazin；Using the purity is high of the obtained target product of this technique, reaction condition is mild, yield
Excellent, convenience easy to operate, production cost is low, is suitble to amplification production.
Specific embodiment
The preferred embodiments of the present invention will be described in detail below so that advantages and features of the invention can be easier to by
It will be appreciated by those skilled in the art that so as to make a clearer definition of the protection scope of the present invention.
A kind of synthetic method of N- methylhomopiperazin, synthetic route are as follows:
Including following synthesis step:
(1) using N- methylpiperidone as raw material, under the action of 80~150 DEG C of temperature and Lewis acid catalyst and salt
Sour azanol occurs Beckmann rearrangement and generates amideWherein, N- methylpiperidone, hydroxylamine hydrochloride and
The molal weight ratio of Lewis acid catalyst is 1:1.1~2:0.01~0.1；Reaction temperature is preferably 100~130 DEG C；It uses
Lewis acid catalyst is one or more of following substance: anhydrous zinc chloride, anhydrous aluminum chloride, anhydrous ferric chloride, trifluoro
Change borate ether, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid iron, trifluoromethanesulfonic acid zinc, silver trifluoromethanesulfonate, tetrafluoro boric acid zinc, tetrafluoro
Cobalt borate, tetrafluoro boric acid iron, benzene sulfonyl chloride, phosphorus oxychloride, and preferably use trifluoromethanesulfonic acid zinc, tetrafluoro boric acid zinc, tetrafluoro boron
Sour cobalt.
(2) amide that will be synthesized in step (1) carries out under suitable reducing agent, catalyst, temperature and solvent condition
Reduction reaction obtains N- methylhomopiperazinWherein, the molal weight ratio of amide, reducing agent and catalyst is
1:1.5~2:1.5~2；Range of reaction temperature is 0~100 DEG C, and temperature is preferably≤80 DEG C, and reducing agent is sodium borohydride or boron
Hydrofining；Catalyst is anhydrous zinc chloride, anhydrous aluminum chloride, anhydrous ferric chloride, boron trifluoride ether, iodine, one in the concentrated sulfuric acid
Kind, catalyst preferentially selects anhydrous zinc chloride, anhydrous aluminum chloride, boron trifluoride ether, iodine；Solvent is tetrahydrofuran, methyl four
One of hydrogen furans, 1,4- dioxane, glycol dimethyl ether, butyl cellosolve, diethylene glycol dimethyl ether are a variety of
Mixture, same preferential selection tetrahydrofuran, methyltetrahydrofuran or glycol dimethyl ether.
Embodiment 1:
50 grams of N- methylpiperidones and 150 grams of polyphosphoric acids are added in reaction flask, 65 grams of salt are added portionwise after warm dissolution
Sour azanol is warming up to 120 DEG C and reacts 4 hours；25 DEG C are cooled to, 500 grams of ice water are slowly added into, stirring sufficiently, filters, washing,
The drying of solid infrared lamp.
Solid is suspended in 200 milliliters of tetrahydrofurans, and 18 grams of sodium borohydrides are added, are cooled to 0 DEG C, and 50 grams of iodine are slowly added dropwise
250 milliliters of tetrahydrofuran solutions；It is added dropwise, is heated to reflux 12 hours, cooling reaction system, it is raw to no gas that methanol is added dropwise
At；Concentration removes solvent, and 300 milliliters of 6N hydrochloric acid are added, are heated to reflux 1 hour, cooling, and 32% liquid alkaline adjusts pH~12, dichloro
Methane extraction merges organic phase, and sodium carbonate is dry, and concentration removes solvent, is evaporated under reduced pressure using water punching pump, collects 60-65
DEG C fraction, obtains 15 grams of N- methylhomopiperazins, yield 30%, gas phase purity 99.6%.
Embodiment 2:
Under nitrogen protection, 113 grams of N- methylpiperidones are added in reaction flask and 138 grams of hydroxylamine hydrochlorides add after mixing evenly
Enter 20 grams of cobalt hydrates, reaction 2 hours is sufficiently stirred in 140 DEG C of heat preservation；25 DEG C are cooled to, 800 grams of ice are slowly added into
Water, stirring sufficiently, filter, washing, the drying of solid infrared lamp.
Solid is suspended in 1 liter of glycol dimethyl ether, and 60 grams of sodium borohydrides are added, are cooled to 0 DEG C, are added portionwise 210 grams
Aluminum trichloride (anhydrous)；Charging finishes, and is heated to reflux 5 hours, cooling reaction system, and methanol to no gas is added dropwise and generates；It is added 500
Milliliter 6N hydrochloric acid, is heated to reflux 1 hour, cooling, and 32% liquid alkaline adjusts pH~12, and methylene chloride extraction merges organic phase, carbonic acid
Sodium is dry, and concentration removes solvent, is evaporated under reduced pressure using water punching pump, collects 60-65 DEG C of fraction, obtain 98 grams of high piperazines of N- methyl
Piperazine, yield 86%, gas phase purity 99.5%.
Embodiment 3:
Under nitrogen protection, 50 grams of N- methylpiperidones and 55 grams of hydroxylamine hydrochlorides are added in reaction flask, after mixing evenly, are added
Reaction 2 hours is sufficiently stirred in 10 grams of tetrafluoro boric acid zinc hydrates, 130 DEG C of heat preservation；25 DEG C are cooled to, 200 grams of ice water are slowly added into,
Stirring sufficiently, filters, washing, the drying of solid infrared lamp.
Solid is suspended in 300 milliliters of diethylene glycol dimethyl ethers, and 38 grams of potassium borohydrides are added, is cooled to 0 DEG C, is slowly added dropwise
115 grams of boron trifluoride ether solutions；It is added dropwise, keeps the temperature 80 DEG C and react 12 hours, methanol is added dropwise to no gas in cooling reaction system
Body generates；30 grams of solid sodium hydroxides are added, keeps the temperature 80 DEG C and reacts 1 hour, low boiling point solvent is distilled off, reuse water punching pump
It is evaporated under reduced pressure, collects 60-65 DEG C of fraction, obtain 38 grams of N- methylhomopiperazins, yield 75%, gas phase purity 99.2%.
Embodiment 4:
50 grams of N- methylpiperidones, 55 grams of hydroxylamine hydrochlorides and 5 grams of phosphorus oxychloride are added in reaction flask, stir evenly, heat up
It is reacted 5 hours to 100 DEG C；25 DEG C are cooled to, 200 grams of ice water is slowly added into and extracts reaction of going out, stirring sufficiently, filters, washing, solid
Infrared lamp drying.
Solid is suspended in 200 milliliters of tetrahydrofurans, and 20 grams of sodium borohydrides are added, are cooled to 0 DEG C, and slowly 45 grams of dropwise addition is dense
150 milliliters of tetrahydrofuran solutions of sulfuric acid；It is added dropwise, is heated to reflux 12 hours, cooling reaction system, methanol is added dropwise to no gas
Body generates；Concentration removes solvent, and 100 milliliters of 6N hydrochloric acid are added, are heated to reflux 1 hour, cooling, and 32% liquid alkaline adjusts pH~12,
Methylene chloride extraction merges organic phase, and sodium carbonate is dry, and concentration removes solvent, is evaporated under reduced pressure, is collected using water punching pump
60-65 DEG C of fraction obtains 13 grams of N- methylhomopiperazins, yield 26%, gas phase purity 99.8%.
Embodiment 5:
Under nitrogen protection, 250 grams of N- methylpiperidones are added in reaction flask and 230 grams of hydroxylamine hydrochlorides add after mixing evenly
Enter 40 grams of cobalt hydrates, reaction 4 hours is sufficiently stirred in 130 DEG C of heat preservation；25 DEG C are cooled to, 800 grams of ice are slowly added into
Water, stirring sufficiently, filter, washing, the drying of solid infrared lamp.
Solid is suspended in 2 liters of tetrahydrofurans, and 120 grams of sodium borohydrides are added, are cooled to 0 DEG C, and 450 grams of trifluoros are slowly added dropwise
Change borate ether solution；Charging finishes, and is heated to reflux 5 hours, cooling reaction system, and methanol to no gas is added dropwise and generates；Concentration removes
Solvent is removed, 600 milliliters of 6N hydrochloric acid are added, is heated to reflux 1 hour, cooling, 32% liquid alkaline adjusts pH~12, and methylene chloride extracts,
Merge organic phase, sodium carbonate is dry, and concentration removes solvent, is evaporated under reduced pressure using water punching pump, collects 60-65 DEG C of fraction, obtain
To 225 grams of N- methylhomopiperazins, yield 89%, gas phase purity 99.5%.
The above description is only an embodiment of the present invention, is not intended to limit the scope of the invention, all to utilize this hair
Equivalent structure or equivalent flow shift made by bright description is applied directly or indirectly in other relevant technology necks
Domain is included within the scope of the present invention.
Claims (9)
1. a kind of synthetic method of N- methylhomopiperazin, which is characterized in that its synthetic route is as follows:
Including following synthesis step:
(1) it using N- methylpiperidone as raw material, is sent out under the action of suitable temperature and Lewis acid catalyst with hydroxylamine hydrochloride
Raw Beckmann rearrangement generates amide；
(2) amide synthesized in step (1) is restored under suitable reducing agent, catalyst, temperature and solvent condition
Reaction obtains N- methylhomopiperazin.
2. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that in step (1), N- methyl
The molal weight ratio of piperidones, hydroxylamine hydrochloride and Lewis acid catalyst is 1:1.1~2:0.01~0.1.
3. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that in step (1), reaction
Temperature range is at 80~150 DEG C.
4. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that employed in step (1)
Lewis acid catalyst be one or more of following substance: anhydrous zinc chloride, anhydrous aluminum chloride, anhydrous ferric chloride, three
It is fluorinated borate ether, copper trifluoromethanesulfcomposite, trifluoromethanesulfonic acid iron, trifluoromethanesulfonic acid zinc, silver trifluoromethanesulfonate, tetrafluoro boric acid zinc, four
Fluoboric acid cobalt, tetrafluoro boric acid iron, benzene sulfonyl chloride, phosphorus oxychloride.
5. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that in step (2), amide,
The molal weight of reducing agent and catalyst ratio is 1:1.5~2:1.5~2.
6. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that in step (2), reaction temperature
Spending range is 0~100 DEG C.
7. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that used in step (2)
Reducing agent be sodium borohydride or potassium borohydride.
8. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that employed in step (2)
Catalyst be one of anhydrous zinc chloride, anhydrous aluminum chloride, anhydrous ferric chloride, boron trifluoride ether, iodine, the concentrated sulfuric acid.
9. the synthetic method of N- methylhomopiperazin according to claim 1, which is characterized in that employed in step (2)
Solvent be tetrahydrofuran, methyltetrahydrofuran, 1,4- dioxane, glycol dimethyl ether, butyl cellosolve, diethylene glycol
One of dimethyl ether or a variety of mixtures.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811512661.7A CN109438373A (en) | 2018-12-11 | 2018-12-11 | A kind of synthetic method of N- methylhomopiperazin |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201811512661.7A CN109438373A (en) | 2018-12-11 | 2018-12-11 | A kind of synthetic method of N- methylhomopiperazin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109438373A true CN109438373A (en) | 2019-03-08 |
Family
ID=65557974
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201811512661.7A Pending CN109438373A (en) | 2018-12-11 | 2018-12-11 | A kind of synthetic method of N- methylhomopiperazin |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109438373A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113512007A (en) * | 2021-08-20 | 2021-10-19 | 江苏君若药业有限公司 | Synthesis of flurarana |
| CN114957163A (en) * | 2022-02-12 | 2022-08-30 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62114972A (en) * | 1985-11-14 | 1987-05-26 | Oouchi Shinko Kagaku Kogyo Kk | Production of n-methylhomopiperazine |
| US20050227989A1 (en) * | 2004-04-13 | 2005-10-13 | Icagen, Inc. | Polycyclic thiazoles as potassium ion channel modulators |
| CN102120732A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of homopiperazine and derivative thereof |
| CN103121976A (en) * | 2012-12-07 | 2013-05-29 | 苏州百灵威超精细材料有限公司 | Preparation method of N-monosubstituted homopiperazines |
| CN107382883A (en) * | 2017-07-18 | 2017-11-24 | 苏州百灵威超精细材料有限公司 | The process of N methylhomopiperazins is prepared using 2 halo ethylamine compounds |
-
2018
- 2018-12-11 CN CN201811512661.7A patent/CN109438373A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS62114972A (en) * | 1985-11-14 | 1987-05-26 | Oouchi Shinko Kagaku Kogyo Kk | Production of n-methylhomopiperazine |
| US20050227989A1 (en) * | 2004-04-13 | 2005-10-13 | Icagen, Inc. | Polycyclic thiazoles as potassium ion channel modulators |
| CN102120732A (en) * | 2010-01-07 | 2011-07-13 | 成都欣捷高新技术开发有限公司 | Preparation method of homopiperazine and derivative thereof |
| CN103121976A (en) * | 2012-12-07 | 2013-05-29 | 苏州百灵威超精细材料有限公司 | Preparation method of N-monosubstituted homopiperazines |
| CN107382883A (en) * | 2017-07-18 | 2017-11-24 | 苏州百灵威超精细材料有限公司 | The process of N methylhomopiperazins is prepared using 2 halo ethylamine compounds |
Non-Patent Citations (1)
| Title |
|---|
| ALAN E. MOORMANN等: ""Selective Heterocyclic Amidine Inhibitors of Human Inducible Nitric Oxide Synthase"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113512007A (en) * | 2021-08-20 | 2021-10-19 | 江苏君若药业有限公司 | Synthesis of flurarana |
| CN114957163A (en) * | 2022-02-12 | 2022-08-30 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
| CN114957163B (en) * | 2022-02-12 | 2024-05-10 | 合肥亿帆生物制药有限公司 | Preparation method of N-methyl homopiperazine |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109438373A (en) | A kind of synthetic method of N- methylhomopiperazin | |
| CN108129513A (en) | A kind of method for synthesizing Bouguer and replacing Buddhist nun's intermediate | |
| CN112028809A (en) | Preparation method of 3-amino-4-phenylseleno maleimide compound | |
| CN105541714A (en) | Preparation methods of papaverine and papaverine hydrochloride | |
| CN107118215B (en) | A kind of preparation method for treating breast cancer medicines Rui Boxini intermediate | |
| CN103896788A (en) | Preparation method of S-1-(4-ethyoxylbenzyl)-3-azapentane-1,5-diaminetrihydrochloride | |
| CN110218189B (en) | Abelide intermediate and simple preparation method of Abelide | |
| CN106749117A (en) | A kind of preparation method of 3 amino methyl tetrahydrofuran | |
| CN113957461B (en) | Electrochemical synthesis method of 1,1' -binaphthyl compound | |
| CN102432594B (en) | Method for preparing 1-(3-hydroxymethylpyridine-2-yl)-2-phenyl-4-methyl piperazine serving as medicinal intermediate | |
| CN104744336B (en) | A kind of Silodosin intermediate and preparation method thereof, and the method for preparing with the intermediate silodosin | |
| WO2022252789A1 (en) | Method for preparing jak inhibitor key intermediate | |
| CN108558758A (en) | A kind of synthetic method of 4- fluorine isoquinolin -5- amine | |
| CN103497138A (en) | Method of preparing cis-octahydroisoindole by zinc chloride and potassium borohydride | |
| WO2018187717A1 (en) | Continuous flow synthesis of ibuprofen | |
| CN104447355A (en) | Novel method for preparing bromhexine hydrochloride | |
| CN114702402A (en) | Synthetic method of fluorophenyl amino acid hydrochloride | |
| Tantrakarn et al. | Synthesis of redox-active biscalix [4] quinones and their electrochemical properties | |
| CN103694170B (en) | The fluoro-1-methyl isophthalic acid of 6,7-bis-, the synthetic method of 2,3,4-four hydrogen isoquinoline hydrochloric acid salt | |
| CN101659630B (en) | Method for preparing 2, 4, 5-trifluoro-phenylacetonitrile | |
| CN110343056A (en) | A kind of preparation method of N- tertbutyloxycarbonyl-N- methyl-2-amino -4,4- dimethyl valeric acid | |
| CN111302930B (en) | Preparation method of p-phenylbutoxy benzoic acid | |
| CN104402737A (en) | New method for preparing bromhexine hydrochloride | |
| CN105801553B (en) | A kind of preparation method of Benzochromene derivatives | |
| CN103073498A (en) | Novel preparation method for (R)-Alpha-amino-e-caprolactam |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190308 |