CN105440090B - A kind of synthetic method of amikacin - Google Patents
A kind of synthetic method of amikacin Download PDFInfo
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- CN105440090B CN105440090B CN201410427822.8A CN201410427822A CN105440090B CN 105440090 B CN105440090 B CN 105440090B CN 201410427822 A CN201410427822 A CN 201410427822A CN 105440090 B CN105440090 B CN 105440090B
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- synthetic method
- amikacin
- kanamycin
- reaction
- hydrazinolysis
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Abstract
The invention discloses a kind of synthetic method of amikacin; using γ N phthalimide-baseds alpha hydroxyl butyrics as direct acylation reaction raw material; 4 N; N lutidines (DMAP) or 1 hydroxy benzo triazole (HOBT) are catalyst; dicyclohexylcarbodiimide is condensing agent; the direct acylation reaction of silicyl kanamycin A is obtained into acylate, then obtains amikacin through acidolysis, hydrazinolysis.This method no longer carries out being manufactured separately the production operation of acylation active ester, simplifies operating procedure and production equipment；Direct acylation reaction does not use the N hydroxyphthalimides for preparing active ester, reduces production cost；By optimizing acylation reaction condition, the selectivity of acylation reaction is improved, ensure that synthesis yield, reduces impurity content, advantage is provided for refined, the purifying of follow-up amikacin.
Description
Technical field
The present invention relates to the synthetic method of amikacin, belong to pharmaceutical technology field.
Background technology
Amikacin is semi-synthetic aminoglycoside antibiotics, and its antimicrobial spectrum is wider, has stronger resist to various bacteria
Bacterium power；Its sulfate has turned into a clinical conventional line anti-infectious agent, and continually developing new formulation and purposes in the world.
Amikacin sulfate be applied to pseudomonas aeruginosa and other pseudomonads, EHEC, Proteus, gram
The sensitive gram negative bacillis such as the primary Pseudomonas of thunder, Enterobacter, Serratia, acinetobacter and staphylococcus (methicillin
Sensitive strain) caused by severe infections, as bacteremia or septicemia, bacterial endocarditis, ALRI, bone joint infection,
Infection of biliary tract, abdominal cavity infection, complexity urinary tract infections, skin soft-tissue infection etc..Because it is passivated to most aminoglycosides
Enzyme is stable, therefore the treatment gram negative bacilli that is particularly suitable for use in is to caused by kanamycins, gentamicin or TOB antibody-resistant bacterium
Severe infections.
Amikacin, also known as amikacin, molecular weight 585.Synthetic route the most frequently used at present is silylation protection
Route, such as document " novel synthesis of amikacin " (author：Jiang is faithful and upright, Wang Yu；Finely and specialty chemicals, 2004,
12 (10), 26-28) record main technique be：(1) it is 11 of raw material through silanization to kanamycins with kanamycin A (KMA)
Individual amino and hydroxyl are protected to obtain methyl-monosilane base kanamycins；(2) with γ-N phlhalimide base-Alpha-hydroxy
Butyric acid (PHBA) and N- hydroxyls-phthalimide (NOP) are that raw material is made in the presence of dicyclohexylcarbodiimide (DCC)
Obtain active ester compound；(3) be acylated (ester exchange reaction) with methyl-monosilane base kanamycins and active ester, then through acidolysis,
Hydrazinolysis reacts to obtain amikacin.Shown in following route：
1st, silanization protection reaction：
2nd, active ester is prepared：
3rd, acylation reaction：
4th, acidolysis reaction：
5th, hydrazinolysis reacts：
The ester that acylation reaction in above-mentioned route is carried out using silylation protection reactant with independently prepared active ester is handed over
Change reaction.Due to using active ester exchange reaction, larger excessive reactant activity ester need to be used to improve reaction yield, and exist
The unit process of one independent preparation active ester, and raw material N- hydroxyls-phthalimide (NOP) has been used, add
The usage amount of reaction dissolvent, the solvent in technique is volatile, and loss is larger, influences environment, increases production cost.
How to seek one kind to enter silylation protection and γ-N phlhalimide base-alpha-hydroxybutyric acid (PHBA)
The direct step acylation reaction of row, synthesis yield is both can guarantee that, and can reduces synthesis step and convenient operation, while does not use system
Material N-hydroxyl-phthalimide (NOP) of standby active ester, the acylation reaction condition of solvent consumption is reduced, be a kind of
Highly beneficial synthesis technique circuit.
The content of the invention
It is an object of the invention to seek a kind of preferably direct acylation reaction condition, the alkyl of kanamycin A is utilized to protect
Reaction product and γ-N phlhalimide base-alpha-hydroxybutyric acid (PHBA) are protected in a reaction vessel, carries out direct acyl
Acylate is reacted to obtain in change, then obtains amikacin through acidolysis, hydrazinolysis.
It was found that reactant is only added in acylation reaction：The alkyl protection reaction product and γ-N- of kanamycins are adjacent
BIDA base-alpha-hydroxybutyric acid (PHBA), reaction need to be heated and reaction yield is extremely low, and accessory substance is more；If
Condensing agent is added in acylation reaction：Dicyclohexylcarbodiimide (DCC), reaction can be carried out at room temperature, but be needed largely excessive
γ-N phlhalimide base-alpha-hydroxybutyric acid (PHBA) and dicyclohexylcarbodiimide (DCC) are added, and yield is still
Not ideal enough, by-product impurities are still more, and the purifying to rear stage amikacin brings difficulty；Tested by substantial amounts of be acylated,
We have found that first adding 4-N in acylation reaction thing, N- lutidines (DMAP) or 1- hydroxy benzo triazoles (HOBT) are made
Catalyst, and reaction temperature is reduced, while condensing agent dicyclohexylcarbodiimide (DCC) is subjected to stream and added, speed is controlled, is carried
The high selectivity of acylation reaction, it is directly acylated to can be achieved one-step method, while ensure that the synthesis yield of amikacin.
The technical scheme is that：A kind of synthetic method of amikacin, comprises the following steps：
(1) hydroxyl and amino of kanamycin A are protected by Silanization reaction, obtains silicyl kanamycins
A；
(2) using silicyl kanamycin A and γ-phthaloyl imino-alpha-hydroxybutyric acid as raw material, 4-N, N- bis-
Picoline (DMAP) or 1- hydroxy benzo triazoles (HOBT) make catalyst, and with N, N- dicyclohexylcarbodiimides are condensation
Agent, direct acylation reaction, obtains acylate；
(3) acylate is reacted to obtain amikacin by acidolysis and hydrazinolysis successively.
The Silanization reaction of above-mentioned steps (1), with HMDS (HMDS) for silylating reagent, specific method
It is：Using acetonitrile as reaction dissolvent, kanamycin A (KMA) and HMDS (HMDS) are added, backflow is warming up to, 75
~80 DEG C of back flow reactions.Reaction finishes, and is cooled to less than 40 DEG C, stands, natural layering, separates and collects lower floor, obtains silylation guarantor
Protect product.
Step (2) is direct acylation reaction, and solvent is preferably acetone, first adds acetone in silylation protects product, opens
Stirring is opened, adds γ-N phlhalimide base-alpha-hydroxybutyric acid (PHBA), adds catalyst 4-N, N- lutidines
(DMAP) after material dissolution is complete, -15~-10 DEG C or 1- hydroxy benzo triazoles (HOBT), are cooled to；With acetone solution N, N-
Dicyclohexylcarbodiimide (DCC), flowed and added in above-mentioned material, control flow 4~6ml/ minutes, control reaction temperature
- 15~-10 DEG C of degree；Stream adds Bi Jixu and reacted 1~1.5 hour.
In step (2), the dosage of catalyst 4-N, N- lutidines (DMAP) or 1- hydroxy benzo triazoles (HOBT)
By throwing kanamycin A weight 2%~3%；Reaction raw materials γ-phthaloyl imino-alpha-hydroxybutyric acid used and institute
The mol ratio for throwing kanamycin A is 1:1.05~1:1.25；That is mould with throwing card for condensing agent N, N- dicyclohexylcarbodiimide
Plain A mol ratio is 1:1.3~1:1.6.
The acidolysis reaction process of step (3) is specifically：Transferred the material into after acylation reaction in acidolysis bottle, unlatching is stirred
Mix, add hydrochloric acidolysis, make material liquid pH 2~3, acidolysis finishes, and stands.After layering, remove layer acid hydrolysis solution by filter, spend from
Sub- water repeatedly washs filter cake, and wash water is incorporated in acid hydrolysis solution.
The hydrazinolysis course of reaction of step (3) is specifically：Acid hydrolysis solution is moved into cucurbit, opens vacuum, vapo(u)rizing temperature control
System removes organic solvent (acetone) at 40~68 DEG C；Distillation finishes, by the PK in cucurbit8Concentrate is moved into hydrazinolysis bottle, is added
Ammoniacal liquor, material liquid pH is set to reach 8.0~8.5；Hydrazine hydrate is added, heating, temperature is at 85~95 DEG C, hydrazinolysis.
Hydrazinolysis terminates, and is cooled to 40~45 DEG C, and it is 3~4 that hydrochloric acid is added into hydrazinolysis bottle and adjusts pH, opens vacuum filter, uses
Deionized water top filter wash slag, obtains amikacin Synthesis liquid；Its material can be directly used for further isolating and purifying, and prepare pure A meter Ka
Star.
The beneficial effects of the present invention are：
(1) γ-N phlhalimide base-alpha-hydroxybutyric acid (PHBA) directly, is subjected to acylation reaction, while no longer
Using substantial amounts of N- hydroxyls-phthalimide (NOP) for preparing active ester, production cost is reduced.
(2), no longer carry out being manufactured separately the cellular manufacture operation of acylation active ester, simplify production operation step, letter
Production equipment is changed.
(3) a small amount of catalyst, is used in acylation reaction, while controls the charging rate of condensing agent, is improved acylated anti-
The selectivity answered, ensure that synthesis yield, reduce impurity content, be provided favorably for refined, the purifying of follow-up amikacin
Condition.
Embodiment
Test raw material and equipment：
Kanamycin A：Pharmaceutical grade potency >=850u/mg
Acetonitrile：Technical grade index of refraction (20 DEG C) 1.3390~1.3480
Acetone：Technical grade content >=98.5%
HMDS (HMDS)：Technical grade content >=95%
γ-N phlhalimide base-alpha-hydroxybutyric acid (PHBA)：Technical grade content >=92%
Hydrazine hydrate：Technical grade content >=80%
Dicyclohexylcarbodiimide (DCC)：Technical grade content >=97%
4-N, N- lutidines (DMAP)：Analysis level content >=99%
1- hydroxy benzo triazoles (HOBT)：Analysis level content >=99%
Rotary evaporator RE5220：Shanghai Yarong Biochemical Instrument Plant
JJ-1 electric mixers：Community of Jin Tan County Rong Hua instrument manufacturings company
Embodiment 1
600mL acetonitriles are put into Silanization reaction bottle, put into 0.1 1,000,000,000 kanamycin A (KMA), close dog-house
After opening stirring 10 minutes, HMDS (HMDS) 400mL is added, backflow is warming up to, in 75~80 DEG C of back flow reactions
7hr.Cooling processing is carried out outside reaction bulb with drinking water, is allowed to be cooled to less than 35 DEG C, stands, natural layering.Separate and collect
Lower floor, obtain silylation protection product.
Protected to silylation and 1000mL acetone is added in product, open stirring, add 60g γ-N phlhalimide
Base-alpha-hydroxybutyric acid (PHBA), 2.5g catalyst 4-N, N- lutidines (DMAP) is added, is cooled to -15~-10 DEG C.
With 300mL acetone solutions 60gN, N- dicyclohexylcarbodiimide, flowed and added in above-mentioned reactant, control
Flow 5mL/ minutes, control temperature of charge -15~-10 DEG C；Stream adds Bi Jixu and reacted 1 hour.
Transferred the material into after acylation reaction in acidolysis bottle, open stirring, add 4.0mol/L hydrochloric acid 400mL acid
Solution, make material liquid pH 3.0, stand 60 minutes.By lower floor's acid hydrolysis solution by collected by suction, washed in three times with 150mL deionized waters
Filter cake (DCU), wash water is incorporated in acid hydrolysis solution.
Acid hydrolysis solution is moved into cucurbit.Open vacuum, vacuum：≤ 0.07Mpa, vapo(u)rizing temperature are controlled 40~68
DEG C, distillation time：Distillation in 2.5 hours finishes；By the PK in cucurbit8Concentrate is moved into hydrazinolysis bottle, adds 7.0mol/L ammonia
Water 200mL, makes material liquid pH reach 8.0；Hydrazine hydrate 180mL is added, heating, temperature is at 85~95 DEG C, hydrazinolysis 3.5 hours, with drink
Cooling processing is carried out outside hydrazinolysis bottle with water, is cooled to 40 DEG C.
4.0mol/L hydrochloric acid 1200mL are added into hydrazinolysis bottle, it is 4.0 to adjust pH.Open vacuum filter.With 500mL deionizations
Water top filter wash slag, obtain amikacin Synthesis liquid 1510mL, amikacin content 5.8% (g/mL), relative to the conjunction of kanamycin A
It is 72.5% into yield.
Embodiment 2
600mL acetonitriles are put into Silanization reaction bottle, put into 0.1 1,000,000,000 kanamycin A (KMA), close dog-house
After opening stirring 10 minutes, HMDS (HMDS) 500mL is added, backflow is warming up to, in 75~80 DEG C of back flow reactions
8hr.Reaction is finished, and 40 DEG C of standings, natural layering are cooled to drinking water.Lower floor is separated and collected, obtains silylation protection product.
Protected to silylation and 1000mL acetone is added in product, open stirring, add 70g γ-N phlhalimide
Base-alpha-hydroxybutyric acid (PHBA), then add 3.0g catalyst 1- hydroxy benzo triazoles (HOBT), after material dissolution is complete, cooling
To -15~-10 DEG C.
With 300mL acetone solutions 70gN, N- dicyclohexylcarbodiimide, flowed and added in above-mentioned reactant, control
Flow 6mL/ minutes, control temperature of charge -15~-10 DEG C；Stream adds Bi Jixu and reacted 1.5 hours.
Acylation reaction, which finishes, to be transferred the material into acidolysis bottle, opens stirring, adds 6.0mol/L hydrochloric acid 300mL acidolysis,
Make material liquid pH 2.0, acidolysis finishes, and stands 50 minutes.By lower floor's acid hydrolysis solution by collected by suction, with 200mL deionizations moisture three
Secondary washing filter cake (DCU), wash water is incorporated in acid hydrolysis solution.
Acid hydrolysis solution is moved into cucurbit.Open vacuum, vacuum：≤ -0.07Mpa, vapo(u)rizing temperature are controlled 40~68
DEG C, distillation time 3.0 hours, except acetone.Distillation finishes, by the PK in cucurbit8Concentrate is moved into hydrazinolysis bottle, is added
10.0mol/L ammoniacal liquor 150mL, material liquid pH 8.5；Hydrazine hydrate 200mL, heating are added, temperature hydrazinolysis 4 hours, is used at 85~95 DEG C
Drinking water carries out cooling processing outside hydrazinolysis bottle, is cooled to 45 DEG C.
6.0mol/L hydrochloric acid 1000mL are added into hydrazinolysis bottle, it is 3.0 to adjust pH.Vacuum filter is opened, with 800mL deionizations
Water top filter wash slag, obtain amikacin Synthesis liquid 1620mL, amikacin content 5.5% (g/mL).Relative to the conjunction of kanamycin A
It is 73.7% into yield.
The method that synthesis amikacin provided by the present invention is described above by embodiment, those skilled in the art
It should be appreciated that in the scope for not departing from essence of the invention, certain change or modification, therefore the present invention can be made to the present invention
Protection domain defined depending on right.
Claims (9)
1. a kind of synthetic method of amikacin, comprises the following steps：
1) hydroxyl and amino of kanamycin A are protected by Silanization reaction, obtains silicyl kanamycin A；
2) using silicyl kanamycin A and γ-phthaloyl imino-alpha-hydroxybutyric acid as raw material, 4-N, N- dimethyl
Pyridine or 1- hydroxy benzo triazoles make catalyst, and N, N- dicyclohexylcarbodiimides are condensing agent, using acetone as solvent, first
Acetone is added in the silicyl kanamycin A obtained by the step 1), then add under agitation γ-N phlhalimide base-
Alpha-hydroxybutyric acid and catalyst 4-N, N- lutidines or 1- hydroxy benzo triazoles, after material dissolution is complete, are cooled to -15
~-10 DEG C；With acetone solution N, N- dicyclohexylcarbodiimides, flowed and added in above-mentioned material, controlling reaction temperature -15
~-10 DEG C, stream adds Bi Jixu and reacted 1~1.5 hour, obtains acylate；
3) acylate is reacted to obtain amikacin by acidolysis and hydrazinolysis successively.
2. synthetic method as claimed in claim 1, it is characterised in that step 1) is tried by silanization of HMDS
Agent.
3. synthetic method as claimed in claim 2, it is characterised in that step 1) is using acetonitrile as reaction dissolvent, and adding card, that is mould
Plain A and HMDS, 75~80 DEG C of back flow reactions being warming up to, reaction, which finishes, is cooled to less than 40 DEG C, stands, layering,
Lower floor is separated and collected, obtains silicyl kanamycin A.
4. synthetic method as claimed in claim 1, it is characterised in that the dosage of catalyst described in step 2) is kanamycins
The 2~3% of A weight.
5. synthetic method as claimed in claim 1, it is characterised in that γ used in step 2)-N phlhalimide base-α-
The mol ratio of hydroxybutyric acid and kanamycin A used in step 1) is 1:1.05~1:1.25.
6. synthetic method as claimed in claim 1, it is characterised in that the cyclohexyl of condensing agent N used in step 2), N- bis- carbonization two
The mol ratio of imines and kanamycin A used in step 1) is 1:1.3~1:1.6.
7. synthetic method as claimed in claim 1, it is characterised in that the acidolysis reaction in step 3) is specifically：By step 2)
Gained acylate adds hydrochloric acidolysis under agitation, makes material liquid pH 2~3, and acidolysis finishes, and stands, removes a layer acid hydrolysis solution and pass through
Filter, and filter cake is repeatedly washed with deionized water, wash water is incorporated in acid hydrolysis solution.
8. synthetic method as claimed in claim 1, it is characterised in that the hydrazinolysis in step 3), which reacts, is specifically：By acid hydrolysis solution
Vacuumize, distillation removes organic solvent, obtains PK8Concentrate；Ammoniacal liquor is added, material liquid pH is reached 8.0~8.5；Hydrazine hydrate is added, is risen
Temperature is to 85~95 DEG C of hydrazinolysis.
9. synthetic method as claimed in claim 1, it is characterised in that 40~45 DEG C are cooled to after step 3) hydrazinolysis, adds salt
It is 3~4 that acid, which adjusts pH, and vacuum filter obtains amikacin Synthesis liquid, further isolates and purifies to obtain amikacin.
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| CN201410427822.8A CN105440090B (en) | 2014-08-27 | 2014-08-27 | A kind of synthetic method of amikacin |
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| CN105440090B true CN105440090B (en) | 2018-03-09 |
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Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866755B (en) * | 2017-03-13 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of amikacin |
| CN108997256A (en) * | 2018-07-20 | 2018-12-14 | 福建康鸿生物科技有限公司 | A kind of preparation method of amikacin and its intermediate activity ester |
| CN111138505B (en) * | 2020-02-17 | 2021-10-08 | 山东安信制药有限公司 | Preparation method of amikacin |
| CN111233952A (en) * | 2020-04-02 | 2020-06-05 | 管炫棣 | Preparation method of acamicin |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPH01275595A (en) * | 1988-04-27 | 1989-11-06 | Sakai Yakuhin Kk | Kanamycin derivative |
| US4902790A (en) * | 1985-10-10 | 1990-02-20 | Pierrel Spa | Novel process for the synthesis of amikacin |
| US5763587A (en) * | 1987-11-27 | 1998-06-09 | Gist Brocades Italy Spa | Process for the synthesis of amikacin |
| WO2011034951A2 (en) * | 2009-09-15 | 2011-03-24 | The Regents Of The University Of California | Assisted enzyme replacement therapy |
| CN102786564A (en) * | 2011-05-19 | 2012-11-21 | 北京化工大学 | New synthetic method of arbekacin and intermediate of dibekacin thereof |
| CN103601768A (en) * | 2013-11-13 | 2014-02-26 | 齐鲁天和惠世制药有限公司 | Preparation method of amikacin |
-
2014
- 2014-08-27 CN CN201410427822.8A patent/CN105440090B/en not_active Expired - Fee Related
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4902790A (en) * | 1985-10-10 | 1990-02-20 | Pierrel Spa | Novel process for the synthesis of amikacin |
| US5763587A (en) * | 1987-11-27 | 1998-06-09 | Gist Brocades Italy Spa | Process for the synthesis of amikacin |
| JPH01275595A (en) * | 1988-04-27 | 1989-11-06 | Sakai Yakuhin Kk | Kanamycin derivative |
| WO2011034951A2 (en) * | 2009-09-15 | 2011-03-24 | The Regents Of The University Of California | Assisted enzyme replacement therapy |
| CN102786564A (en) * | 2011-05-19 | 2012-11-21 | 北京化工大学 | New synthetic method of arbekacin and intermediate of dibekacin thereof |
| CN103601768A (en) * | 2013-11-13 | 2014-02-26 | 齐鲁天和惠世制药有限公司 | Preparation method of amikacin |
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