CN109836438A - The synthetic method of cefalexin impurity - Google Patents
The synthetic method of cefalexin impurity Download PDFInfo
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- CN109836438A CN109836438A CN201910209245.8A CN201910209245A CN109836438A CN 109836438 A CN109836438 A CN 109836438A CN 201910209245 A CN201910209245 A CN 201910209245A CN 109836438 A CN109836438 A CN 109836438A
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- 239000012535 impurity Substances 0.000 title claims abstract description 46
- ZAIPMKNFIOOWCQ-UEKVPHQBSA-N cephalexin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=CC=C1 ZAIPMKNFIOOWCQ-UEKVPHQBSA-N 0.000 title claims abstract description 44
- 229940106164 cephalexin Drugs 0.000 title claims abstract description 44
- 238000010189 synthetic method Methods 0.000 title claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 30
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 22
- NVIAYEIXYQCDAN-CLZZGJSISA-N 7beta-aminodeacetoxycephalosporanic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](N)[C@@H]12 NVIAYEIXYQCDAN-CLZZGJSISA-N 0.000 claims abstract description 18
- 239000012074 organic phase Substances 0.000 claims abstract description 13
- KYVBNYUBXIEUFW-UHFFFAOYSA-N 1,1,3,3-tetramethylguanidine Chemical compound CN(C)C(=N)N(C)C KYVBNYUBXIEUFW-UHFFFAOYSA-N 0.000 claims abstract description 11
- JVSFQJZRHXAUGT-UHFFFAOYSA-N 2,2-dimethylpropanoyl chloride Chemical compound CC(C)(C)C(Cl)=O JVSFQJZRHXAUGT-UHFFFAOYSA-N 0.000 claims abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 8
- 238000002425 crystallisation Methods 0.000 claims abstract description 5
- 230000008025 crystallization Effects 0.000 claims abstract description 5
- 238000013517 stratification Methods 0.000 claims abstract description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- 230000007062 hydrolysis Effects 0.000 claims description 14
- 238000006460 hydrolysis reaction Methods 0.000 claims description 14
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 8
- -1 2,2- dimethyl -1- oxopropyl Chemical group 0.000 claims description 7
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 5
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims description 4
- 229910000041 hydrogen chloride Inorganic materials 0.000 claims description 4
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 4
- 229910021529 ammonia Inorganic materials 0.000 claims description 3
- YGBFLZPYDUKSPT-MRVPVSSYSA-N cephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C(O)=O)N2C(=O)C[C@H]21 YGBFLZPYDUKSPT-MRVPVSSYSA-N 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000003814 drug Substances 0.000 abstract description 16
- 229940079593 drug Drugs 0.000 abstract description 14
- 238000003786 synthesis reaction Methods 0.000 abstract description 11
- 230000015572 biosynthetic process Effects 0.000 abstract description 10
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 238000003908 quality control method Methods 0.000 abstract description 3
- 239000000047 product Substances 0.000 description 8
- JLNXDMISSHNIAD-GMSGAONNSA-N (6r,7r)-7-(2,2-dimethylpropanoylamino)-3-methyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(C)=C(C(O)=O)N2C(=O)[C@@H](NC(=O)C(C)(C)C)[C@@H]12 JLNXDMISSHNIAD-GMSGAONNSA-N 0.000 description 6
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 238000011160 research Methods 0.000 description 6
- 238000005160 1H NMR spectroscopy Methods 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 230000005311 nuclear magnetism Effects 0.000 description 3
- 125000001820 oxy group Chemical group [*:1]O[*:2] 0.000 description 3
- 238000009938 salting Methods 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001412 amines Chemical class 0.000 description 2
- 230000001413 cellular effect Effects 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- CHJJGSNFBQVOTG-UHFFFAOYSA-N methylguanidine Chemical compound CNC(N)=N CHJJGSNFBQVOTG-UHFFFAOYSA-N 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 241000894006 Bacteria Species 0.000 description 1
- 206010057190 Respiratory tract infections Diseases 0.000 description 1
- 206010062255 Soft tissue infection Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 150000001408 amides Chemical class 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- VILAVOFMIJHSJA-UHFFFAOYSA-N dicarbon monoxide Chemical compound [C]=C=O VILAVOFMIJHSJA-UHFFFAOYSA-N 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000031891 intestinal absorption Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 125000004433 nitrogen atom Chemical group N* 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 230000001954 sterilising effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000041 toxicology testing Toxicity 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
Landscapes
- Cephalosporin Compounds (AREA)
Abstract
The present invention provides a kind of synthetic method of cefalexin impurity, the method comprising the steps of a: 7-aminodesacetoxycephalosporanic acid is reacted to obtain 7-aminodesacetoxycephalosporanic acid salt with tetramethylguanidine；Step b: it is reacted 7-aminodesacetoxycephalosporanic acid salt to obtain (6R with pivaloyl chloride, 7R) -7- [(2,2- dimethyl -1- oxopropyl) amino] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylate；And dilute hydrochloric acid and step b product are sufficiently mixed by step c, reaction are hydrolyzed, after reaction stratification, take lower layer's organic phase and crystallization is evaporated under reduced pressure in taken organic phase, to obtain the cefalexin impurity.Synthetic method of the invention can realize the synthesis of cefalexin impurity, have very big facilitation to the quality control in the relevant drug safety of wider and deeper study cefalexin, reliability, stability and its production process.
Description
Technical field
The present invention relates to technical field of organic synthesis, in particular to a kind of synthetic method of cefalexin impurity.
Background technique
Cefalexin is that the first generation can be used for oral cephalosporin analog antibiotic, is opened by the research of Li Lai company, the U.S. within 1967
Hair, and launched for the first time in 1970.Cefalexin mainly passes through the synthesis for inhibiting cell wall, to make cellular content mistake
Degree growth is expanded to rupture, and cellular content is caused to leak, and kills bacterium.It is with has a broad antifungal spectrum, sterilizing power is strong, acidproof, stomach
The advantages that intestinal absorption is good, is distributed after oral absorption good, and up to peak plasma concentrations, but uptake does not subtract, and can put within one hour
In various tissues.The medicine is mainly used for treating respiratory tract infection, urinary tract infections and skin soft-tissue infection etc..
The quality of drug is to measure the major criterion of drug quality, and the quality of drug is decided by the curative effect of drug itself first
And toxic side effect, i.e. the validity and safety of drug.Therefore it is required that drug in the range for the treatment of, does not generate serious toxicity
Reaction, does not generate or less generation side effect.The content of the effective component of drug is the important symbol of reflection pharmaceutical purity, and medicine
Impurity present in object directly influences the curative effect of drug and may cause the active toxic side effect of non-treatment, it is necessary to be controlled
System.
By the study found that cefalexin can generate a kind of specific impurity (6R, 7R) -7- [(2,2- in process of production
Dimethyl -1- oxopropyl) amino] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid,
No. CAS is 146794-70-9, and the structural formula of the cefalexin impurity is as follows, and there is no its synthetic method of reported in literature so far.
In order to control drug quality, the cefalexin impurity is distinctly claimed during drug registration is declared, but,
At present in the world current method be carry out impurity reference substance to the impurity in drug research and analyse verifying.At the same time, it is
Guarantee Drug safety, it is also desirable to toxicological study be carried out to the cefalexin impurity, specifically included to its toxicity and may
The side effect of generation carries out research assessment.But since the cefalexin impurity is specific impurities, and also rarely have sale should in the market
Impurity, therefore have important value to the quality control of cefalexin drug, security evaluation based on the specific impurities, so grinding
The synthesis for studying carefully the cefalexin impurity just has very important realistic meaning.
Summary of the invention
In view of this, the present invention is directed to propose a kind of synthetic method of cefalexin impurity, to be able to carry out aforementioned cephalo
The synthesis of ammonia benzyl impurity.
In order to achieve the above objectives, the technical scheme of the present invention is realized as follows:
A kind of synthetic method of cefalexin impurity, this method comprise the following steps that
A, 7-aminodesacetoxycephalosporanic acid is reacted to obtain 7- aminodeacetoxy oxygroup cephalo alkane with tetramethylguanidine
Hydrochlorate；
B, 7-aminodesacetoxycephalosporanic acid salt is reacted to obtain (6R, 7R) -7- [(2,2- with pivaloyl chloride
Dimethyl -1- oxopropyl) amino] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid
Salt；
C, dilute hydrochloric acid and step b products therefrom are sufficiently mixed, reaction are hydrolyzed, after reaction stratification, take
Simultaneously crystallization is evaporated under reduced pressure in taken organic phase by lower layer's organic phase, to obtain (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl)
Amino] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid.
Further, step a is to be reacted at 0~10 DEG C, and step b is to be reacted at 0~25 DEG C, step c
To be reacted at 15~40 DEG C.
Further, the molar ratio of the 7-aminodesacetoxycephalosporanic acid in step a and tetramethylguanidine be 1:(1~
1.5)。
Further, the reaction time in step a is 0.5~1 hour.
Further, solvent used in the reaction in step a and b be one of methylene chloride, chloroform and DMF or
Two kinds.
Further, the molar ratio of the 7-aminodesacetoxycephalosporanic acid salt in step b and pivaloyl chloride is 1:
(0.5~1.5).
Further, 2~5 hours reaction time in step b.
Further, the mass concentration of dilute hydrochloric acid is 1%~15% in step c.
Further, dilute hydrochloric acid mass concentration used is 2.5%~10% in step c, and institute in the dilute hydrochloric acid being added
The molar ratio of the hydrogen chloride and step b products therefrom that contain is 1:(1.0~2.0).
Further, the temperature of hydrolysis is 25~35 DEG C in step c, and the time of hydrolysis is 10~60 minutes.
Compared with the existing technology, present invention has the advantage that
Synthetic method of the invention uses 7-aminodesacetoxycephalosporanic acid, tetramethylguanidine and pivaloyl chloride and dilute salt
Acid, and via hydrolysis, standing and crystallization is evaporated under reduced pressure, cefalexin impurity can be made, and it is being mentioned for cefalexin impurity
A kind of effective method is supplied.
Tetramethylguanidine in step a of the present invention plays the role of carboxy protective, can be effectively prevented from carboxyl in subsequent step and join
With react, to reduce the generation of by-product.7-aminodesacetoxycephalosporanic acid salt is with reacting for pivaloyl chloride in step b
The nucleophilic attack of amine reacts, with by the carbonyl carbon of lone pair electrons attack acyl chlorides a pair of of contained by the nitrogen-atoms on amine, thus de-
Fall a molecule hydrogen chloride to obtain amide.And the reaction in step c is then hydrolysis, with remove and carboxyl at salt tetramethyl
Guanidine, and then obtain final composite.
Synthetic method reaction raw materials of the invention are opposite to be easy to get, and reaction process is easy to operate, and consersion unit requires low and anti-
Answer condition relatively mild, synthetic product content is high, higher in the current cefalexin impurity market price and be difficult to the feelings bought
Under condition, relatively convenient reliable acquisition channel is provided for the research of cefalexin impurity, and greatly reduce its cost, for more
Deeply the quality control in extensive research cefalexin relevant administration safety, reliability, stability and production process has
Very big facilitation.
Detailed description of the invention
The attached drawing for constituting a part of the invention is used to provide further understanding of the present invention, schematic reality of the invention
It applies example and its explanation is used to explain the present invention, do not constitute improper limitations of the present invention.In the accompanying drawings:
Fig. 1 is the hydrogen nuclear magnetic spectrogram of cefalexin impurity synthesized by the embodiment of the present invention.
Specific embodiment
It should be noted that in the absence of conflict, the feature in embodiment and embodiment in the present invention can phase
Mutually combination.
The present embodiment is related to the synthetic method of cefalexin impurity, the cefalexin impurity specially (6R, 7R) -7- [(2,
2- dimethyl -1- oxopropyl) amino] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic
Acid, and the synthetic method includes:
Step a, at 0~10 DEG C, by molar ratio be 1:(1~1.5) 7-aminodesacetoxycephalosporanic acid and four
Methylguanidine, which reacts 0.5~1 hour, obtains 7-aminodesacetoxycephalosporanic acid salt.
Step b, at 0~25 DEG C, by molar ratio be 1:(0.5~1.5) 7-aminodesacetoxycephalosporanic acid salt
React with pivaloyl chloride and obtains within 2~5 hours (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl) amino] -3- methyl -
8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylate.
Step c, at 15~40 DEG C, the dilute hydrochloric acid that mass concentration is 1%~15% is sufficiently mixed with step b products therefrom
It closes, 10~60 minutes hydrolysis is carried out at 25~35 DEG C, stratification after hydrolysis takes lower layer's organic phase simultaneously
Crystallization is evaporated under reduced pressure in taken organic phase to get (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl) amino] -3- first is arrived
Base -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid namely the cefalexin impurity.
Wherein, solvent used in the reaction in step a and step b be one of methylene chloride, chloroform and DMF or
Two kinds.And it is contained in the dilute hydrochloric acid that dilute hydrochloric acid mass concentration used is preferably 2.5%~10%, while being added in step c
The molar ratio of some hydrogen chloride and step b products therefrom is also 1:(1.0~2.0).
The synthesis process of the cefalexin impurity of the present embodiment is expressed as follows by structural formula:
And the synthesis of the cefalexin impurity of the present embodiment is then further illustrated with several specific preparating examples below.
Preparating example 1
The steps included are as follows for the synthesis of the cefalexin impurity of this example.
Step a, in the reaction flask of dried and clean, 40ml methylene chloride and 5g 7- aminodeacetoxy oxygroup cephalo is added
Alkanoic acid is cooled to 0 DEG C, and 2.8g tetramethylguanidine is added into reaction flask, and control reaction temperature is not higher than 10 DEG C, reacts 30 minutes,
Obtain 7-aminodesacetoxycephalosporanic acid salting liquid.
Step b, 3g pivaloyl chloride is added into reaction flask in the case where temperature control is no more than 10 DEG C, after charging, controls temperature
At 0 DEG C, react 4 hours.
Step c, the hydrochloric acid 70ml that mass concentration is 5.64% is added into hydrolysis bottle, adjusts the temperature to 30 DEG C, it will
The product of step b after reaction, which pours into hydrolysis bottle, to be sufficiently stirred 30 minutes, is stood 30 minutes, is taken lower layer's organic phase,
Organic phase be evaporated under reduced pressure crystallizing and obtains (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl) amino] -3- methyl -8-
Oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 4.6801g.Measuring its yield is 67.21%, and purity is
98.07%, and its nuclear-magnetism Structural Identification result is as follows:
1H NMR(500MHz,CDCl3) δ: 6.45~6.43 (d, J=8.3Hz, 1H), 5.76~5.73 (dd, J=
8.3Hz, J=4.6Hz, 1H), 5.03~5.02 (d, J=4.6Hz, 1H), 3.59~3.55 (d, J=18.6Hz, 1H), 3.24
~3.28 (d, J=18.6Hz, 1H), 2.21 (s, 2H), 1.25 (s, 9H).
Preparating example 2
The steps included are as follows for the synthesis of the cefalexin impurity of this example.
Step a, in the reaction flask of dried and clean, 10ml methylene chloride, 30ml chloroform and 5g7- amino is added and goes
Acetoxyl group cephalosporanic acid is cooled to 4 DEG C, and 3.2g tetramethylguanidine is added into reaction flask, and control reaction temperature is not higher than 10 DEG C,
Reaction 40 minutes, obtains 7-aminodesacetoxycephalosporanic acid salting liquid.
Step b, 2g pivaloyl chloride is added into reaction flask in the case where temperature control is no more than 10 DEG C, after charging, controls temperature
At 4 DEG C, react 3 hours.
Step c, the hydrochloric acid 70ml that mass concentration is 2.84% is added into hydrolysis bottle, adjusts the temperature to 35 DEG C, it will
The product of step b after reaction, which pours into hydrolysis bottle, to be sufficiently stirred 40 minutes, is stood 30 minutes, is taken lower layer's organic phase,
Organic phase be evaporated under reduced pressure crystallizing and obtains (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl) amino] -3- methyl -8-
Oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 2.5822g.Measuring its yield is 51.95%, and purity is
98.52%, and its nuclear-magnetism Structural Identification result is as follows:
1H NMR(500MHz,CDCl3) δ: 6.45~6.43 (d, J=8.3Hz, 1H), 5.76~5.73 (dd, J=
8.3Hz, J=4.6Hz, 1H), 5.03~5.02 (d, J=4.6Hz, 1H), 3.59~3.55 (d, J=18.6Hz, 1H), 3.24
~3.28 (d, J=18.6Hz, 1H), 2.21 (s, 2H), 1.25 (s, 9H).
Preparating example 3
The steps included are as follows for the synthesis of the cefalexin impurity of this example.
Step a, in the reaction flask of dried and clean, 20ml methylene chloride, 20ml DMF and 5g 7- aminodeacetoxy is added
Oxygroup cephalosporanic acid is cooled to 7 DEG C, and 4g tetramethylguanidine is added into reaction flask, and control reaction temperature is not higher than 10 DEG C, reaction 50
Minute, obtain 7-aminodesacetoxycephalosporanic acid salting liquid.
Step b, 3.4g pivaloyl chloride is added into reaction flask in the case where temperature control is no more than 10 DEG C, after charging, control temperature
Degree reacts 2 hours at 9 DEG C.
Step c, the hydrochloric acid 70ml that mass concentration is 7% is added into hydrolysis bottle, 25 DEG C are adjusted the temperature to, by step
The product of b after reaction, which pours into hydrolysis bottle, to be sufficiently stirred 50 minutes, is stood 30 minutes, is taken lower layer's organic phase, will have
Machine, which mutually carries out being evaporated under reduced pressure crystallizing, obtains (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl) amino] -3- methyl -8- oxygen
Generation -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid 5.0118g.Measuring its yield is 71.84%, and purity is
98.26%, and its nuclear-magnetism Structural Identification result is as follows:
1H NMR(500MHz,CDCl3) δ: 6.45~6.43 (d, J=8.3Hz, 1H), 5.76~5.73 (dd, J=
8.3Hz, J=4.6Hz, 1H), 5.03~5.02 (d, J=4.6Hz, 1H), 3.59~3.55 (d, J=18.6Hz, 1H), 3.24
~3.28 (d, J=18.6Hz, 1H), 2.21 (s, 2H), 1.25 (s, 9H).
The hydrogen nuclear magnetic spectrogram of the cefalexin impurity of the present embodiment synthesis is as shown in fig. 1, and can be with by above each example
Find out that the purity of the cefalexin impurity as synthesized by the synthetic method of the present embodiment is greater than 98%, cephalo can be met well
The miscellaneous Quality Research of ammonia benzyl, and have good realistic meaning.
The foregoing is merely illustrative of the preferred embodiments of the present invention, is not intended to limit the invention, all in essence of the invention
Within mind and principle, any modification, equivalent replacement, improvement and so on be should all be included in the protection scope of the present invention.
Claims (10)
1. a kind of synthetic method of cefalexin impurity, it is characterised in that: this method comprises the following steps that
A, 7-aminodesacetoxycephalosporanic acid is reacted to obtain 7-aminodesacetoxycephalosporanic acid salt with tetramethylguanidine；
B, 7-aminodesacetoxycephalosporanic acid salt is reacted to obtain (6R, 7R) -7- [(2,2- diformazan with pivaloyl chloride
Base -1- oxopropyl) amino] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylate；
C, dilute hydrochloric acid and step b products therefrom are sufficiently mixed, reaction are hydrolyzed, after reaction stratification, take lower layer
Simultaneously crystallization is evaporated under reduced pressure in taken organic phase by organic phase, to obtain (6R, 7R) -7- [(2,2- dimethyl -1- oxopropyl) ammonia
Base] -3- methyl -8- oxo -5- thia -1- azabicyclo [4.2.0] oct-2-ene -2- carboxylic acid.
2. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: step a is at 0~10 DEG C
It is reacted, step b is to be reacted at 0~25 DEG C, and step c is to be reacted at 15~40 DEG C.
3. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: the 7- amino in step a is gone
The molar ratio of acetoxyl group cephalosporanic acid and tetramethylguanidine is 1:(1~1.5).
4. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: the reaction time in step a
It is 0.5~1 hour.
5. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: the reaction institute in step a and b
Solvent is one or both of methylene chloride, chloroform and DMF.
6. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: the 7- amino in step b is gone
The molar ratio of acetoxyl group cephalosporanic acid salt and pivaloyl chloride is 1:(0.5~1.5).
7. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: the reaction time 2 in step b
~5 hours.
8. the synthetic method of cefalexin impurity according to claim 1, it is characterised in that: the matter of dilute hydrochloric acid in step c
Measuring concentration is 1%~15%.
9. the synthetic method of cefalexin impurity according to claim 8, it is characterised in that: dilute hydrochloric acid used in step c
Mass concentration is 2.5%~10%, and the molar ratio of hydrogen chloride contained in the dilute hydrochloric acid being added and step b products therefrom
For 1:(1.0~2.0).
10. the synthetic method of cefalexin impurity according to any one of claim 1 to 9, it is characterised in that: step c
The temperature of middle hydrolysis is 25~35 DEG C, and the time of hydrolysis is 10~60 minutes.
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
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