CN110105263A - A kind of synthetic method of amikacin intermediate - Google Patents
A kind of synthetic method of amikacin intermediate Download PDFInfo
- Publication number
- CN110105263A CN110105263A CN201910396090.3A CN201910396090A CN110105263A CN 110105263 A CN110105263 A CN 110105263A CN 201910396090 A CN201910396090 A CN 201910396090A CN 110105263 A CN110105263 A CN 110105263A
- Authority
- CN
- China
- Prior art keywords
- synthetic method
- amikacin
- hydroxyl
- phthaloyl
- reaction
- 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.)
- Withdrawn
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
- C07D209/44—Iso-indoles; Hydrogenated iso-indoles
- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of synthetic method of amikacin intermediate.Acid binding agent and catalyst is added using o-phthaloyl chloride and 2-hydroxy-4-amino-butyrate as starting material in the present invention, and passes through heating, washing, the techniques such as recrystallization, finally obtain target product amikacin intermediate 2- hydroxyl -4- phthaloyl imino butyric acid, synthetic method raw material of the invention is easy to get, it is few to participate in reaction reagent, step is simple, easy to operate, and reaction condition is mild, product yield is high, is suitble to industrialization large-scale production.
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to a kind of synthetic method of amikacin intermediate.
Background technique
Amikacin is commonly called as amikacin, mainly in conjunction with bacterial ribosome 30S subunit, inhibits bacterioprotein
The synthesis of matter.2- hydroxyl -4- phthaloyl imino butyric acid is as kanamycins pharmaceutical intermediate, synthetic method superiority and inferiority pair
In improving pharmaceutical synthesis product quality, reducing by-products content has Important Economic meaning.2- hydroxyl -4- O-phthalic imide
Base butyric acid is also known as γ-phthaloyl imino-alpha-hydroxybutyric acid or phthaloyl imino hydroxybutyric acid.
The Chinese invention patent of number of patent application CN201410338034.1, which discloses, describes 2- hydroxyl -4- phthalyl
The synthetic method of imino group butyric acid, synthesis step are as follows: using Pidolidone as raw material, through diazotising, hydrolysis, ammonolysis, Hoffman
Five steps such as degradation react to obtain target product.The method reaction step is more, and the reaction reagent of participation is more, and yield is low, and diazonium
It is unstable to change this step, is easy explosion, brings difficult and safety factor to industrialized production.Number of patent application is
The Chinese patent of CN201610813959.6 describes the synthetic method of 2- hydroxyl -4- phthaloyl imino butyric acid, closes
At step are as follows: using phthalic anhydride and L- γ-azanol base-alpha-hydroxybutyric acid as raw material, reacted in cyclohexane solution
The transparent fusant of brown is obtained, using being added in Klorvess Liquid, pH is adjusted after molecular sieve decoloration, washs, dehydration obtains 2- hydroxyl
Base -4- phthaloyl imino butyric acid.Raw material L- γ-azanol base-alpha-hydroxybutyric acid in the synthetic method is difficult to obtain, and adds
The big difficulty of synthesis 2- hydroxyl -4- phthaloyl imino butyric acid, and reaction step is cumbersome, obtained product purity
Low, yield is also low, affects the use scope of product, increase production 2- hydroxyl -4- phthaloyl imino butyric acid at
This.
Summary of the invention
The technical problems to be solved by the invention: being not easy to obtain for prior synthesizing method raw material, and reaction step is cumbersome, obtains
The problems such as low to product yield, provides a kind of method for synthesizing amikacin intermediate.
In order to solve the above-mentioned technical problem, the technical solution adopted by the present invention is that:
The reaction equation that the present invention synthesizes is as follows:
The synthesis of reaction equation 1:2- hydroxyl -4- phthaloyl imino butyric acid
A kind of synthetic method of amikacin intermediate of the present invention, specific synthetic method are as follows:
(1) 2~2.2:1 in molar ratio, weighs o-phthaloyl chloride and 2-hydroxy-4-amino-butyrate, by 2- hydroxyl-respectively
4-Aminobutanoicacid be fitted into blender, thermometer, drying tube reaction flask in, be warming up to 40~60 DEG C, be added acid binding agent and
Catalyst, then to o-phthaloyl chloride is added portionwise in reaction flask；
(2) after o-phthaloyl chloride is all added, 90~100 DEG C is warming up to, continues to be stirred to react 30~50min, to
2-hydroxy-4-amino-butyrate after reaction, filters while hot, and filtrate increases temperature to 128-130 DEG C, and decompression steams extra original
Expect that o-phthaloyl chloride, recovery obtain 2- hydroxyl -4- phthaloyl imino butyric acid crude product, be with mass fraction
50% ethanol water recrystallization, obtains 2- hydroxyl -4- phthaloyl imino butyric acid.
Acid binding agent described in step (1) is any one in sodium methoxide, potassium tert-butoxide or sodium ethoxide.
Acid binding agent described in step (1) and 2-hydroxy-4-amino-butyrate molar ratio are 3~4:1；
Catalyst described in step (1) is 4-dimethylaminopyridine, and additional amount is 2-hydroxy-4-amino-butyrate quality
0.01~0.03%；
The number that o-phthaloyl chloride described in step (1) is added portionwise be 2~4 times, each interval time be 5~
8min。
Decompression steams extra raw material o-phthaloyl chloride in step (2), to collect fraction when 1.1-1.2KPa.
It is on sale on reagent and raw materials market used in synthesis step of the present invention.
The method have the benefit that:
(1) it is raw material and reaction dissolvent that o-phthaloyl chloride, which is added, in the present invention, and the excess of o-phthaloyl chloride is protected
2-hydroxy-4-amino-butyrate energy fully reacting has been demonstrate,proved, the output of reaction is increased, has been also avoided using other solvent bring costs
The problems such as increase and environmental pollution.The fully reacting of 2-hydroxy-4-amino-butyrate energy also facilitates post-processing purification process；
(2) present invention joined acid binding agent during reaction, can neutralize the hydrogen chloride that reaction takes off in time, have
Conducive to reaction forward progress, and as dehydrating agent, influence of the water to reaction process is eliminated, carries out reaction more fully；
(3) synthetic method raw material of the invention is easy to get, and participation reaction reagent is few, and step is simple, easy to operate, reaction condition
Mildly, post-processing approach is simple, and 2- hydroxyl -4- phthaloyl imino butyric acid yield obtained is up to 96% or more, purity
Up to 97% or more, new approaches are brought for the large-scale production of 2- hydroxyl -4- phthaloyl imino butyric acid.
Specific embodiment
A kind of comparative example: number of patent application CN201610813959.6: methoxy kanamycins pharmaceutical intermediate γ-neighbour's benzene
Phthalimido group-alpha-hydroxybutyric acid synthetic method.
In the reaction vessel for being equipped with distilling apparatus, phthalic anhydride 0.16mol, L- γ-azanol base-α-hydroxyl is added
Base butyric acid 0.12mol, cyclohexane solution 90ml control mixing speed 130rpm, increase solution temperature to 90 DEG C, after 40min, rise
For high solution temperature to 110 DEG C, 1.7kPa is evaporated under reduced pressure 5h, obtains the transparent fusant of brown, and after cooling, solidification obtains brown solid, adds
Entering 400ml mass fraction is to increase 70 DEG C of solution temperature, molecular sieve decoloration, mass fraction, which is added, is in 15% Klorvess Liquid
35% oxalic acid solution is 3 until pH value of solution, and solid is precipitated, and is filtered, potassium nitrate solution washing, phosphorus pentoxide dehydration, in second eyeball
Middle recrystallization obtains γ-phthaloyl imino-alpha-hydroxybutyric acid 25.10g, yield 84%.
Example 1
2mol o-phthaloyl chloride and 1mol2- hydroxyl -4-Aminobutanoicacid are weighed respectively.2-hydroxy-4-amino-butyrate is filled
Enter to have in the reaction flask of blender, thermometer, drying tube, be warming up to 40 DEG C, 3mol sodium ethoxide and 2- are added into reaction flask
Hydroxyl -4-Aminobutanoicacid quality 0.01%4- dimethylamino naphthyridine then divides 2 addition o-phthaloyl chlorides, every minor tick
Time is 5min；90 DEG C are warming up to after o-phthaloyl chloride is all added, continues to be stirred to react 30min, to 2- hydroxyl -4- ammonia
Base butyric acid after reaction, filters while hot, and filtrate increases temperature to 128-130 DEG C, and it is extra that decompression (1.1-1.2KPa) steams
Raw material o-phthaloyl chloride, recovery obtain 2- hydroxyl -4- phthaloyl imino butyric acid crude product, are with mass fraction
50% ethanol water recrystallization, obtains 2- hydroxyl -4- phthaloyl imino butyric acid, yield 93.1%, HPLC purity
97.3%.
Example 2
2.1mol o-phthaloyl chloride and 1mol2- hydroxyl -4-Aminobutanoicacid are weighed respectively.By 2-hydroxy-4-amino-butyrate
It is fitted into the reaction flask for having blender, thermometer, drying tube, is put into oil bath pan, is warming up to 50 DEG C, is added into reaction flask
The 0.03%4- dimethylamino naphthyridine of 3.5 potassium tert-butoxides and 2-hydroxy-4-amino-butyrate quality is then added three times adjacent benzene two
Formyl chloride, each interval time are 6min；95 DEG C are warming up to after o-phthaloyl chloride is all added, continues to be stirred to react
40min after reaction to 2-hydroxy-4-amino-butyrate is filtered while hot, and filtrate increases temperature to 128-130 DEG C, is depressurized
(1.1-1.2KPa) steams extra raw material o-phthaloyl chloride, and recovery obtains 2- hydroxyl -4- phthaloyl imino
Butyric acid crude product is 50% ethanol water recrystallization with mass fraction, obtains 2- hydroxyl -4- phthaloyl imino butyric acid,
Yield 94.9%, HPLC purity 97.2%.
Example 3
2.2mol o-phthaloyl chloride and 1mol2- hydroxyl -4-Aminobutanoicacid are weighed respectively.By 2-hydroxy-4-amino-butyrate
It is fitted into the reaction flask for having blender, thermometer, drying tube, is put into oil bath pan, is warming up to 60 DEG C, is added into reaction flask
The 0.02%4- dimethylamino naphthyridine of 4mol sodium methoxide and 2-hydroxy-4-amino-butyrate quality then divides 4 addition O-phthalics
Acyl chlorides, each interval time are 8min；100 DEG C are warming up to after o-phthaloyl chloride is all added, continues to be stirred to react
50min after reaction to 2-hydroxy-4-amino-butyrate is filtered while hot, and filtrate increases temperature to 128-130 DEG C, is depressurized
(1.1-1.2KPa) steams extra raw material o-phthaloyl chloride, and recovery obtains 2- hydroxyl -4- phthaloyl imino
Butyric acid crude product is 50% ethanol water recrystallization with mass fraction, obtains 2- hydroxyl -4- phthaloyl imino butyric acid,
Yield 96.3%, HPLC purity 98.1%.
By after example 1~3 and comparative example comparison:
(1) yield of synthetic method of the invention, obtained 2- hydroxyl -4- phthaloyl imino butyric acid obviously mentions
Height, 93% or more, purity is all 97% or more；
(2) for the raw material that the present invention uses for o-phthaloyl chloride and 2-hydroxy-4-amino-butyrate, which all can be from market
Upper acquisition solves the problems, such as that raw material obtains difficult in comparative example.O-phthaloyl chloride is raw material and reaction dissolvent, neighbour
The excess of phthalyl chloride ensure that 2-hydroxy-4-amino-butyrate energy fully reacting, increase the output of reaction, also avoid
The problems such as using other solvent bring increased costs and environmental pollution.2-hydroxy-4-amino-butyrate energy fully reacting also facilitates
Last handling process.
(3) present invention joined acid binding agent during reaction, and the purpose of the acid binding agent is anti-in order to neutralize in time
The hydrogen chloride that should be taken off, is conducive to reaction forward reaction, and the acid binding agent that uses of the present invention be it is slightly excessive, another
Purpose is to absorb water, to eliminate influence of the water to reaction process, carries out reaction more sufficiently, of the present invention to tie up acid
Agent is any one in sodium methoxide, potassium tert-butoxide or sodium ethoxide, can finally be removed it by simply filtering, Ke Yiti
The purity of high target product；
(4) reaction raw materials known in comparative example need to be reacted under cyclohexane solvent, and finally also need grass
Acid for adjusting pH is to 3, which is unfavorable for protecting environment, and the reaction in the present invention does not need in the solvent except reaction raw materials
It carries out, excessive o-phthaloyl chloride, and o-phthaloyl chloride reactivity with higher and 2- hydroxyl-is added in reaction
4-Aminobutanoicacid is sufficiently reacted under no solvent, increases output, and extra o-phthaloyl chloride passes through vacuum distillation
It steams, applies repeatedly, saved cost, protect environment, avoid dirty using other solvent bring increased costs and environment
Dye.
Claims (6)
1. a kind of synthetic method of amikacin intermediate, it is characterised in that the synthetic method are as follows:
(1) 2~2.2:1 in molar ratio, weighs o-phthaloyl chloride and 2-hydroxy-4-amino-butyrate, by 2- hydroxyl -4- ammonia respectively
Base butyric acid is fitted into the reaction flask for having blender, thermometer, drying tube, is warming up to 40~60 DEG C, and acid binding agent and catalysis is added
Agent, then to o-phthaloyl chloride is added portionwise in reaction flask；
(2) after o-phthaloyl chloride is all added, 90~100 DEG C is warming up to, continues to be stirred to react 30~50min, to 2- hydroxyl
Base -4-Aminobutanoicacid after reaction, filters while hot, and filtrate increases temperature to 128-130 DEG C, and it is adjacent that decompression steams extra raw material
Phthalyl chloride, recovery obtain 2- hydroxyl -4- phthaloyl imino butyric acid crude product, are 50% second with mass fraction
Alcohol solution recrystallization, obtains 2- hydroxyl -4- phthaloyl imino butyric acid.
2. a kind of synthetic method of amikacin intermediate according to claim 1, it is characterised in that: institute in step (1)
The acid binding agent stated is any one in sodium methoxide, potassium tert-butoxide or sodium ethoxide.
3. a kind of synthetic method of amikacin intermediate according to claim 1 or 4, it is characterised in that: in step (1)
Acid binding agent and 2-hydroxy-4-amino-butyrate molar ratio are 3~4:1.
4. a kind of synthetic method of amikacin intermediate according to claim 1, it is characterised in that: institute in step (1)
The catalyst stated is 4-dimethylaminopyridine, and additional amount is that 2-hydroxy-4-amino-butyrate is added the 0.01~0.03% of quality.
5. a kind of synthetic method of amikacin intermediate according to claim 1, it is characterised in that: adjacent in step (1)
The number that phthalyl chloride is added portionwise is 2~4 times, and each interval time is 5~8min.
6. a kind of synthetic method of amikacin intermediate according to claim 1, it is characterised in that: step subtracts in (2)
Pressure steams extra raw material o-phthaloyl chloride, to collect fraction when 1.1-1.2KPa.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910396090.3A CN110105263A (en) | 2019-05-13 | 2019-05-13 | A kind of synthetic method of amikacin intermediate |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201910396090.3A CN110105263A (en) | 2019-05-13 | 2019-05-13 | A kind of synthetic method of amikacin intermediate |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN110105263A true CN110105263A (en) | 2019-08-09 |
Family
ID=67489757
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201910396090.3A Withdrawn CN110105263A (en) | 2019-05-13 | 2019-05-13 | A kind of synthetic method of amikacin intermediate |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN110105263A (en) |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1658875A (en) * | 2002-04-18 | 2005-08-24 | 先灵公司 | 1-(4-piperidinyl) benzimidazolones as histamine H3 antagonists |
| CN1803795A (en) * | 2000-10-17 | 2006-07-19 | 先灵公司 | Substituted piperidine compounds for use as h3 histamine receptor antagonists |
| WO2012175991A1 (en) * | 2011-06-24 | 2012-12-27 | Pharminox Limited | Fused pentacyclic anti - proliferative compounds |
| CN104098502A (en) * | 2014-07-16 | 2014-10-15 | 成都丽凯手性技术有限公司 | Synthetic method of PHBA |
| CN105503696A (en) * | 2015-12-24 | 2016-04-20 | 成都卡迪夫科技有限公司 | Synthesis method of gamma-phthalimido-alpha-hydroxybutyrate serving as methoxy kanamycin drug intermediate |
-
2019
- 2019-05-13 CN CN201910396090.3A patent/CN110105263A/en not_active Withdrawn
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1803795A (en) * | 2000-10-17 | 2006-07-19 | 先灵公司 | Substituted piperidine compounds for use as h3 histamine receptor antagonists |
| CN1658875A (en) * | 2002-04-18 | 2005-08-24 | 先灵公司 | 1-(4-piperidinyl) benzimidazolones as histamine H3 antagonists |
| WO2012175991A1 (en) * | 2011-06-24 | 2012-12-27 | Pharminox Limited | Fused pentacyclic anti - proliferative compounds |
| CN104098502A (en) * | 2014-07-16 | 2014-10-15 | 成都丽凯手性技术有限公司 | Synthetic method of PHBA |
| CN105503696A (en) * | 2015-12-24 | 2016-04-20 | 成都卡迪夫科技有限公司 | Synthesis method of gamma-phthalimido-alpha-hydroxybutyrate serving as methoxy kanamycin drug intermediate |
Non-Patent Citations (1)
| Title |
|---|
| KAZUMASA TAKAHASHI等: "New syntheses of 1-amino- and 1-(2-aminoethyl)-2,6-dicyanopiperidines and diazabicyclo compounds by a Strecker reaction using glutaraldehyde and diamines, and their stereochemistry", 《HETEROCYCLES》 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103319414A (en) | Improved telmisartan preparation process | |
| CN109456277A (en) | A kind of preparation method of Mirabegron | |
| CN102617542A (en) | Method for preparing and purifying olmesartan intermediate | |
| CN101823968B (en) | Method for preparing 1,8-diaminonaphthalene by reducing 1,8-dinitronaphthalene with hydrazine hydrate | |
| CN106278929B (en) | A kind of preparation method of Ioversol | |
| CN101701026B (en) | Catalytic cracking method for guanosine | |
| CN110105263A (en) | A kind of synthetic method of amikacin intermediate | |
| CN106748630A (en) | A kind of synthetic method of antalgesic intermediate Bromomethylcyclobutane | |
| CN113929648A (en) | Preparation method of cyclobutane-1, 2-dicarboxylic anhydride and intermediate thereof | |
| CN107935975A (en) | One kettle way prepares the method that lactone founds in benzoyl section | |
| CN111116430B (en) | Preparation method of sodium taurate | |
| CN110577472A (en) | Preparation method of (1R,3S) -3-amino-1-cyclopentanol hydrochloride | |
| CN110938075B (en) | Ganciclovir preparation method | |
| CN102964225A (en) | Preparation method of 2, 3-dichloroanisole | |
| CN104513170B (en) | A kind of trans production technology to cyclohexane-carboxylic acid | |
| CN104230880B (en) | The simple and convenient process for preparing of 2-((4R, 6R)-6-aminoethyl-2,2-dimethyl-1,3-dioxane-4-yl) acetic acid esters | |
| CN104276979B (en) | The preparation method of agomelatine intermediate body | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN106831536B (en) | Preparation method of gliclazide synthesis process | |
| CN106542958A (en) | A kind of preparation method of adjacent Iodoaniline | |
| CN109836374A (en) | A kind of vitamin B6Environment-friendly preparation method | |
| CN101735132B (en) | Synthesis method of N-methyl-2-hydroxyethyl hydroxyethyl | |
| CN112457235B (en) | Preparation method of 7-methylindole | |
| CN108503642A (en) | A kind of preparation method of high-purity single acetyl Ganciclovir | |
| CN110452172B (en) | Synthesis method of benzocaprolactam |
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 | ||
| WW01 | Invention patent application withdrawn after publication |
Application publication date: 20190809 |
|
| WW01 | Invention patent application withdrawn after publication |