CN107400694A - A kind of preparation method of the amino-cephalo-alkanoic acid of N acetyl bromides 7 - Google Patents
A kind of preparation method of the amino-cephalo-alkanoic acid of N acetyl bromides 7 Download PDFInfo
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- CN107400694A CN107400694A CN201710413519.6A CN201710413519A CN107400694A CN 107400694 A CN107400694 A CN 107400694A CN 201710413519 A CN201710413519 A CN 201710413519A CN 107400694 A CN107400694 A CN 107400694A
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- C12P35/00—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin
- C12P35/04—Preparation of compounds having a 5-thia-1-azabicyclo [4.2.0] octane ring system, e.g. cephalosporin by acylation of the substituent in the 7 position
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- C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
- C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
- C12N9/84—Penicillin amidase (3.5.1.11)
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- C12Y305/01—Hydrolases acting on carbon-nitrogen bonds, other than peptide bonds (3.5) in linear amides (3.5.1)
- C12Y305/01011—Penicillin amidase (3.5.1.11), i.e. penicillin-amidohydrolase
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Abstract
The invention discloses a kind of preparation method of the amino-cephalo-alkanoic acid of N acetyl bromides 7, comprise the following steps:7 amino-cephalo-alkanoic acids are dissolved in weak base aqueous solution, are well mixed with acry radical donor, immobilized penicillin acylated enzyme is added and is reacted, obtain the amino-cephalo-alkanoic acid of N acetyl bromides 7;The 7 amino-cephalo-alkanoic acid concentration is 80mM~350mM.The advantages that the inventive method has that reaction condition is gentle, environment-friendly, technique is simple, and concentration of substrate is high, production efficiency is high.
Description
Technical field
The invention belongs to enzymatic and field of biological pharmacy, and in particular to one kind utilizes immobilization penicillin acylated enzyme catalysis
The method of N- acetyl bromides -7-amino-cephalosporanic acid synthesis.
Background technology
N- acetyl bromides -7-amino-cephalosporanic acid (N- acetyl bromides -7-ACA) are to prepare cefathiamidine and cefapirin sodium etc. half
Synthesize key intermediate (Chinese Journal of Pharmaceuticals, 1978,9 (4) of cynnematin:1;Chinese antibiotic magazine, 2012,37
(6):455).Cefathiamidine is the first independent research in China successfully semi-synthetic cynnematin, has broad spectrum antibiotic activity, to big
Part gram-positive bacteria, part Gram-negative bacteria are respectively provided with stronger killing action, especially to enterococcus killing effect
More than same veriety used in clinic.In recent years, the market of cefathiamidine is in the situation of steady-state growth.Cefapirin sodium is the U.S.
The first generation cephalo-type semisynthetic antibiotics of Bristol research institutes research and development, is introduced technology by Japanese Bristol companies and developed.Head
Spore woods sodium antibacterial activity is similar or slightly excellent with cefoxitin.Hemolytic streptococcus and pneumococcus are highly quick to cefapirin sodium
Sense.
However, N- acetyl bromides -7-amino-cephalosporanic acid is produced in current industrial still uses chemical method:With 7- amino cephalo alkane
Sour (7-ACA) is raw material, and weak base is added in aqueous acetone solution and promotes 7-ACA dissolvings, then adds the height of excess at low temperature
Active bromoacetyl bromide, N- acetyl bromides -7-ACA (Chinese Journal of Pharmaceuticals, 1978,9 (4) are synthesized by chemical acylation:1;China
Antibiotic magazine, 2012,37 (6):455).Therefore, chemical method prepares N- acetyl bromides -7-ACA and not only needs to use high activity
Acry radical donor (bromoacetyl bromide), volatile organic solvent, and low-temp reaction is needed, its severe reaction conditions, process are complicated, ring
Border is seriously polluted, does not meet the requirement of current sustainable society and environmental development.Because raw material bromoacetyl bromide is generally with classics
Hell-Volhard-Zelinsky reacts, with P or PBr3And Br2It is prepared, therefore was preparing under high temperature, even illumination
Inevitably more bromine substituents can be formed in journey in carbonyl α positions.When using bromoacetyl bromide as reactant, being found in commercial Application
Led due to the presence of these impurity in acylate and substitute impurity --- the acetyl bromide -7-ACA of N- bis- containing up to 10% dibromo
(Chinese antibiotic magazine, 2011,36 (4):280), so as to having a strong impact on product quality.In addition, chemical method preparation N- acetyl bromides-
7-ACA yield is generally undesirable, only up to 73% (Chinese Journal of Modern Applied Pharmacy, 2,010 27 (2):126).
The content of the invention
To be prepared in order to solve the above technical problems, it is an object of the invention to provide a kind of green, simple and highly efficient enzyme process
N- acetyl bromides -7-ACA method.
The present invention adopts the following technical scheme that:
A kind of preparation method of N- acetyl bromides -7-amino-cephalosporanic acid, comprises the following steps:7-amino-cephalosporanic acid is molten
Solution is well mixed in weak base aqueous solution with acry radical donor, is added immobilized penicillin acylated enzyme and is reacted, and obtains N- bromines
Acetyl -7-amino-cephalosporanic acid;The 7-amino-cephalosporanic acid concentration is 80mM~350mM.
The 7-amino-cephalosporanic acid concentration is 150mM~200mM.
The weak base is ammoniacal liquor, triethylamine or sodium acid carbonate, saleratus;The weak base aqueous solution be with deionized water or
Phosphate buffer (100mM, pH 7.5) is the weak base aqueous solution of solvent configuration.
The mol ratio of the 7-amino-cephalosporanic acid and weak base is 1:1~1:4.
The mol ratio of the 7-amino-cephalosporanic acid and weak base is 1:1~1:2.
The acry radical donor is methyl bromoacetate, bromoacetate or acetbromamide;The 7-amino-cephalosporanic acid and acyl
The mol ratio of base donor is 1:1.5~1:3.
The mol ratio of the 7-amino-cephalosporanic acid and acry radical donor is 1:2~1:2.5.
The immobilized penicillin acylated enzyme is PA ase PGA-750, the immobilized penicillin acylated enzyme
Dosage is 3U/mL~12U/mL.
The enzyme dosage is 4U/mL~10U/mL, and reaction condition is 10 DEG C~40 DEG C of temperature, reaction time 1h~12h, is shaken
Swing speed 150r/min~300r/min.
The reaction condition is 20 DEG C~30 DEG C of temperature, reaction time 4h~9h.
Compared with prior art, the present invention has the advantage that:
1) efficient biocatalyst is used --- penicillin acylated enzyme catalysis prepares N- acetyl bromides -7-ACA.Enzyme is as one
The natural biocatalyst of kind can be effectively reduced reaction activity, therefore only need using activity medium bromacetate or acetyl bromide
Amine etc. is used as acry radical donor, without using the bromoacetyl bromide of high activity, not only drastically increases the security of reaction, and subtract
Acetyl bromide-the 7-ACA of accessory substance N- bis- formation is lacked, so as to improve product quality.In addition, target product yield is high.
2) enzyme is the large biological molecule of easily biological-degradable, overcomes the disagreeableness shortcoming of chemical catalyst environment.The present invention
Course of reaction is simple and easy to control, mild condition, and using the aqueous solution cheap and easy to get and environment-friendly as reaction medium, without making
Use organic solvent.
3) present invention, after the completion of reaction can be by simply filtering using immobilized penicillin acylated enzyme as catalyst
Immobilised enzymes is reclaimed, the recycling of biocatalyst can be both realized, be easy to isolating and purifying for product again.
4) inventive substrate concentration is high, and reaction speed is fast, and production efficiency is high.
Brief description of the drawings
Fig. 1 is the enzyme reaction liquid chromatogram of embodiment 1.
Embodiment
The present invention is further illustrated by embodiment.
Embodiment 1
10mL phosphate buffers (100mM, pH 7.5), 300mM NaHCO are added in 50mL triangular flasks with cover3With
150mM 7-ACA, vibration mixing, after solution completely clarification, 300mM bromoacetates are added, are eventually adding 40U penicillin acyls
Change enzyme PGA-750 (being purchased from Zhejiang Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.Utilize liquid chromatogram pair
Yield carries out quantitative analysis (Fig. 1,7-ACA and N- acetyl bromide -7-ACA retention times are respectively 2.6 and 4.1 minutes).After 9h, N-
Acetyl bromide -7-ACA yields are 79% up to maximum.
Embodiment 2
10mL phosphate buffers (100mM, pH 7.5), 300mM NaHCO are added in 50mL triangular flasks with cover3With
150mM 7-ACA, vibration mixing, after solution completely clarification, 300mM methyl bromoacetates are added, are eventually adding 40U penicillin acyls
Change enzyme PGA-750 (being purchased from Zhejiang Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 9h, N- acetyl bromides-
7-ACA yields are 80% up to maximum.
Embodiment 3
10mL phosphate buffers (100mM, pH 7.5), 300mM NaHCO are added in 50mL triangular flasks with cover3With
150mM 7-ACA, vibration mixing, after solution completely clarification, 300mM acetbromamides are added, be eventually adding the acylation of 40U penicillin
Enzyme PGA-750 (is purchased from Zhejiang Hydril Company L. P with the wind), is reacted under 20 DEG C and 200r/min.After 9h, N- acetyl bromides -7-
ACA yields are 78% up to maximum.
Embodiment 4
10mL deionized waters, 300mM NaHCO are added in 50mL triangular flasks with cover3And 150mM7-ACA, vibration mixing,
After solution completely clarification, 300mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 6h, N- acetyl bromide -7-ACA yields are up to maximum
79%.
Embodiment 5
10mL deionized waters, 150mM triethylamines and 150mM7-ACA are added in 50mL triangular flasks with cover, vibration mixes,
After solution completely clarification, 300mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 12h, N- acetyl bromide -7-ACA yields are up to maximum
43%.
Embodiment 6
10mL deionized waters, 225mM ammoniacal liquor and 150mM7-ACA are added in 50mL triangular flasks with cover, vibration mixing, is treated
After solution clarification completely, 300mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (it is suitable to be purchased from Zhejiang
Wind Hydril Company L. P), reacted under 20 DEG C and 200r/min.After 9h, N- acetyl bromide -7-ACA yields are up to maximum
53%.
Embodiment 7
10mL deionized waters, 450mM NaHCO are added in 50mL triangular flasks with cover3And 150mM7-ACA, vibration mixing,
After solution completely clarification, 300mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 4h, N- acetyl bromide -7-ACA yields are up to maximum
71%.
Embodiment 8
10mL deionized waters, 600mM NaHCO are added in 50mL triangular flasks with cover3And 150mM7-ACA, vibration mixing,
After solution completely clarification, 300mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 6h, N- acetyl bromide -7-ACA yields are up to maximum
58%.
Embodiment 9
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 400mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 9h, N- acetyl bromide -7-ACA yields are up to maximum
81%.
Embodiment 10
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 400mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 10 DEG C and 200r/min.After 24h, N- acetyl bromide -7-ACA yields are up to maximum
76%.
Embodiment 11
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 400mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 40 DEG C and 200r/min.After 6h, N- acetyl bromide -7-ACA yields are up to maximum
68%.
Embodiment 12
10mL deionized waters, 700mM NaHCO are added in 50mL triangular flasks with cover3And 350mM7-ACA, vibration mixing,
After solution completely clarification, 700mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 9h, N- acetyl bromide -7-ACA yields are up to maximum
53%.
Embodiment 13
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 300mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 6h, N- acetyl bromide -7-ACA yields are up to maximum
70%.
Embodiment 14
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 600mM bromoacetates are added, 40U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 9h, N- acetyl bromide -7-ACA yields are up to maximum
76%.
Embodiment 15
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 400mM bromoacetates are added, 100U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After 4h, N- acetyl bromide -7-ACA yields are up to maximum
78%.
Embodiment 16
10mL deionized waters, 400mM NaHCO are added in 50mL triangular flasks with cover3And 200mM7-ACA, vibration mixing,
After solution completely clarification, 400mM bromoacetates are added, 100U PA ases PGA-750 is eventually adding and (is purchased from Zhejiang
Hydril Company L. P with the wind), reacted under 20 DEG C and 200r/min.After reacting 4h, immobilised enzymes is recovered by filtration, uses deionization
After water washing 3 times, add in fresh reactant and reacted, to realize the recycling of biocatalyst.Immobilised enzymes repeats profit
It is respectively 79%, 76% and 75% with N- acetyl bromide -7-ACA yields during preceding 3 batch.
Claims (10)
1. a kind of preparation method of N- acetyl bromides -7-amino-cephalosporanic acid, it is characterised in that comprise the following steps:By 7- amino
Cephalosporanic acid is dissolved in weak base aqueous solution, is well mixed with acry radical donor, is added immobilized penicillin acylated enzyme and is carried out instead
Should, obtain N- acetyl bromides -7-amino-cephalosporanic acid;The 7-amino-cephalosporanic acid concentration is 80mM~350mM.
2. according to the method for claim 1, it is characterised in that the 7-amino-cephalosporanic acid concentration be 150mM~
200mM。
3. according to the method for claim 2, it is characterised in that the weak base is ammoniacal liquor, triethylamine or sodium acid carbonate, carbonic acid
Hydrogen potassium;The weak base aqueous solution is the weak base aqueous solution configured using deionized water or phosphate buffer as solvent.
4. according to the method for claim 3, it is characterised in that the mol ratio of the 7-amino-cephalosporanic acid and weak base is 1:
1~1:4.
5. according to the method for claim 4, it is characterised in that the mol ratio of the 7-amino-cephalosporanic acid and weak base is 1:
1~1:2.
6. according to the method described in Claims 1 to 5 any one, it is characterised in that the acry radical donor be methyl bromoacetate,
Bromoacetate or acetbromamide;The mol ratio of the 7-amino-cephalosporanic acid and acry radical donor is 1:1.5~1:3.
7. according to the method for claim 6, it is characterised in that the mol ratio of the 7-amino-cephalosporanic acid and acry radical donor
For 1:2~1:2.5.
8. according to the method for claim 7, it is characterised in that the immobilized penicillin acylated enzyme is PA ase
PGA-750, the dosage of the immobilized penicillin acylated enzyme is 3U/mL~12U/mL.
9. according to the method for claim 8, it is characterised in that the enzyme dosage is 4U/mL~10U/mL, and reaction condition is
10 DEG C~40 DEG C of temperature, reaction time 1h~12h, hunting speed 150r/min~300r/min.
10. according to the method for claim 9, it is characterised in that the reaction condition is 20 DEG C~30 DEG C of temperature, during reaction
Between 4h~9h.
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110804635A (en) * | 2019-11-11 | 2020-02-18 | 济南康和医药科技有限公司 | Synthesis method of latamoxef sodium |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3632810A (en) * | 1968-12-11 | 1972-01-04 | Ciba Geigy Corp | Derivatives of 7-amino cephalosporanic acid |
-
2017
- 2017-06-05 CN CN201710413519.6A patent/CN107400694A/en active Pending
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3632810A (en) * | 1968-12-11 | 1972-01-04 | Ciba Geigy Corp | Derivatives of 7-amino cephalosporanic acid |
Non-Patent Citations (1)
Title |
---|
XIAO-LI ZHANG等: "Penicillin acylase-catalyzed synthesis of N-bromoacetyl-7-aminocephalosporanic acid, the key intermediate for the production of cefathiamidine", 《BIORESOURCES AND BIOPROCESSING》 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN110804635A (en) * | 2019-11-11 | 2020-02-18 | 济南康和医药科技有限公司 | Synthesis method of latamoxef sodium |
CN110804635B (en) * | 2019-11-11 | 2021-08-17 | 济南康和医药科技有限公司 | Synthesis method of latamoxef sodium |
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