CN105315299B - A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 - Google Patents
A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 Download PDFInfo
- Publication number
- CN105315299B CN105315299B CN201510609572.4A CN201510609572A CN105315299B CN 105315299 B CN105315299 B CN 105315299B CN 201510609572 A CN201510609572 A CN 201510609572A CN 105315299 B CN105315299 B CN 105315299B
- Authority
- CN
- China
- Prior art keywords
- anca
- ceftizoxime
- synthetic method
- compound
- parent nucleus
- 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.)
- Active
Links
- 0 CCC(*)=C(C(*Cc1ccc(C)cc1)=*)N(C(C1*C(Cc2ccccc2)=O)S)C1=* Chemical compound CCC(*)=C(C(*Cc1ccc(C)cc1)=*)N(C(C1*C(Cc2ccccc2)=O)S)C1=* 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N c1ccccc1 Chemical compound c1ccccc1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7.With CHS as initiation material, sequentially pass through hydroxyl reduction, removing 7 on amino protecting group phenylacetyl group and 4 carboxyls on protection group to nitrobenzyl be obtained 7 ANCA.The price of initiation material CHS of the invention is compared with 3 hydroxy-cephams, and price is lower, and the operating procedure of reaction is simple, total moles yield is 81.3%, and 7 ANCA for producing are white solid powder, and purity is more than 99.0%, the quality of product preferably, is suitable for industrialized production.
Description
Technical field
The invention belongs to medicine intermediate synthesis technical field, it is related to a kind of synthesis side of Ceftizoxime parent nucleus 7-ANCA
Method.
Background technology
7-Amino-3-cep-hem-4-carboxylic acid (abbreviation 7-ANCA), English is entitled：7-Amino-3-nor-3-
Cephem-4-carboxylic acid, molecular formula：C7H8N2O3S, molecular weight：200.22, outward appearance is white or off-white color crystallization
Powder, structure is as follows：
7-ANCA is the parent nucleus for synthesizing Ceftizoxime, and its synthesis step is more, and difficulty is larger, to actual production technique and skill
Art level is required to higher, and price is up to 2900 yuan/kg.How Ceftizoxime bulk drug price, the system of parent nucleus 7-ANCA are reduced
Standby technique is particularly important.
The synthesis route of current 7-ANCA mainly has two classes：
(1) with 7-ACA as raw material, 7-ANCA is obtained by amido protecting, hydrolysis, cracking and deaminizating protection group.
(2) with 3- hydroxy-cephams as raw material, protected by sodium borohydride reduction, methylsufonyl chloride esterification, elimination, decarboxylation
Base and deaminizating protection group obtain 7-ANCA.
Above route is analyzed, 7-ACA is that fermented product head satisfies rhzomorph C through hydrolysis, and itself possesses
The hexatomic ring of cynnematin, it is necessary to transformation is only the group of C-3, therefore with 7-ACA be the road of Material synthesis 7-ANCA
Line reactions steps are less, but are disadvantageous in that 7-ACA prices for 700 yuan/kg, the high cost of initiation material, in recent years
Be not suitable for industrialized production, gradually abandoned by each manufacturer.Synthesize the road of 7-ANCA as initiation material with 3- hydroxy-cephams
Line, although the price of 3- hydroxy-cephams is low with respect to 7-ACA, but synthesis step is more, operation requires height, causes the price of 7-ANCA
It is high.
In sum, because the synthesis difficulty of existing 7-ANCA is larger, step is more, and one initiation material of exploitation is cheap
Be easy to get, reactions steps are shorter, it is simple to operate, be adapted to industrialized production 7-ANCA process route highly significant.
The content of the invention
The present invention solves the technical problem of providing, a kind of initiation material is cheap and easy to get, reactions steps are shorter, operation
Simply, product yield is high, lower-cost Ceftizoxime parent nucleus 7-ANCA synthetic method.
In order to solve the above technical problems, one aspect of the present invention is：A kind of Ceftizoxime parent nucleus 7- is provided
The synthetic method of ANCA, in turn includes the following steps：
Step (a)：With CHS as raw material, in diphenyl chlorosilane (Ph2) and aluminium chloride (AlCl SiHCl3) in the presence of it is anti-
Should, obtain compound A：
Step (b) compound A, with imidazoles as acid binding agent, removes 7 in the presence of diisooctyl phenyl phosphite and bromine
Amino protecting group phenylacetyl group on position, then with hydrochloric acid into salt, obtains compound B：
Protection groups of step (c) the compound B on 4 carboxyls of removing under bromotrimethylsilane effect is obtained to nitrobenzyl
7-ANCA：
A kind of synthetic method of described Ceftizoxime parent nucleus 7-ANCA, step (a) reaction dissolvent is halide or halogen
For ethane, preferably chloromethane or chloric ethane, further preferred dichloromethane.
In step (a), CHS and diphenyl chlorosilane (Ph2SiHCl mol ratio) is 1:1.0~1.5, aluminium chloride
(AlCl3) it is catalyst, consumption is 3~6% (" % " represents molar percentage) of substrate CHS, and the reaction time is 3~4h, instead
It is 15~25 DEG C to answer temperature.
In step (b), with dichloromethane as reaction dissolvent, temperature is -10~-15 DEG C, is being added without compound A and imidazoles
In the case of, diisooctyl phenyl phosphite and bromine first stir the color fade of 2~3h to bromine.
In step (b), after the color fade of bromine, temperature is down to -40~-45 DEG C, adds imidazoles and compound A, changes
Compound A is 1 with the mol ratio of diisooctyl phenyl phosphite, bromine, imidazoles:1.0~1.5:1.0~1.5:1.0~1.5, it is excellent
Select 1:1.0~1.2:1.0~1.2:1.0~1.2, the reaction time is 4~5h.
In step (b), after completion of the reaction, washed by with 10% aqueous hydrochloric acid solution, compound B is deposited with hydrochloride form
.
In step (c), protection group on compound B and bromotrimethylsilane reaction 4 carboxyls of removing to nitrobenzyl, instead
It is 20~25 DEG C to answer temperature, and the reaction time is 4~5h, and compound B is 1 with the mol ratio of bromotrimethylsilane:2.0~2.5.
Beneficial effect：
The invention provides a kind of new Ceftizoxime parent nucleus 7-ANCA synthetic methods, compared with prior art, the present invention
The price of initiation material CHS is cheaper than 3- hydroxy-cepham, reactions steps are shorter, simple to operate, cost is relatively low, and total moles are received
Rate is 81.3%, and the 7-ANCA for producing is white solid powder, and purity is more than 99.0%, and the quality of product preferably, is fitted
Together in industrialized production.
Specific embodiment
Present invention is further explained and described by the following examples, but the examples of implementation for being provided should not be understood
It is that the scope of the present invention is construed as limiting.
The synthesis of the compound A of embodiment 1
1000mL four-hole boiling flasks input 600mL dichloromethane, 46.95g (0.10mol) CHS, stirring and dissolving, then put into
24.06g(0.11mol)Ph2SiHCl, 0.67g (0.005mol) AlCl3, 15~25 DEG C of temperature control, stirring reaction 4h obtains compound
1, HPLC detection CHS<1%, reaction is finished.
Add 10% sodium-chloride water solution agitator treatings of 250mL 10 minutes, organic layer adds 20.0g anhydrous magnesium sulfates to stir
Mix drying.Filtering, filter cake is washed with 100mL dichloromethane.Merging filtrate and washing lotion, temperature is no more than 20 DEG C in control, depressurizes dense
It is reduced to without dichloromethane outflow, adds 150mL methyl alcohol, is stirred 30 minutes at 20~25 DEG C, then be cooled to -10~-15 DEG C of stirrings
2h, suction filtration, filter cake methyl alcohol (- 10~-15 DEG C) drip washing of 50mL precoolings, filter cake is vacuum dried 4h, obtains at 40~50 DEG C
44.48g compound A, molar yield is 98.1%, and purity is 99.2%.
The synthesis of the compound B of embodiment 2
1000mL four-hole boiling flasks input 600mL dichloromethane, 42.08g (0.11mol) diisooctyl phenyl phosphites and
17.58g (0.11mol) bromine, temperature control -10~-15 DEG C, the color fade of stirring 3h to bromine, then it is cooled to -40~-45 DEG C,
Add 7.49g (0.11mol) imidazoles, 45.35g (0.10mol) compound A, temperature control -40~-45 DEG C, stirring reaction 5h, HPLC
Detection compound A<1%, reaction is finished.
The methyl alcohol (- 40~-45 DEG C) of 200mL precoolings is added, 2h is stirred, the aqueous hydrochloric acid solutions of 300mL 10% are added, stirred
Mix 30 minutes, separate organic layer, with 10% sodium-chloride water solution agitator treatings of 300mL 10 minutes, organic layer add 20.0g without
Water magnesium sulfate stirs drying.Filtering, filter cake wash with 100mL dichloromethane, merging filtrate and washing lotion, and temperature is no more than 20 in control
DEG C, it is concentrated under reduced pressure into without dichloromethane outflow.150mL acetonitriles are added, is stirred 30 minutes at 20~25 DEG C, then be cooled to -5~0
DEG C stirring 2h, suction filtration, filter cake acetonitrile (- 5~0 DEG C) drip washing of 50mL precoolings, filter cake is vacuum dried 4h, obtains at 40~50 DEG C
To 34.61g compound B, molar yield is 93.1%, and purity is 98.6%.
The synthesis of the 7-ANCA of embodiment 3
1000mL four-hole boiling flasks input 500mL dichloromethane, 37.18g (0.10mol) compound B, 20~25 DEG C of temperature control,
32.15g (0.21mol) bromotrimethylsilane was added dropwise in 30 minutes, drop finishes, 20~25 DEG C of temperature control, stirring reaction 5h, HPLC inspection
Survey compound B<1%, reaction is finished.
- 5~0 DEG C is cooled to, the aqueous hydrochloric acid solutions of 300mL 10% (0~5 DEG C) of precooling, 0~5 DEG C of temperature control, stirring is added
30 minutes, water phase is separated, with 100mL dichloromethane agitator treating 10 minutes, separate water phase, add the stirring of 1.00g activated carbons
Decolouring 30 minutes, suction filtration, the filter cake hydrochloric acid drip washing of 100mL 10%, merging filtrate and washing lotion.0~5 DEG C of temperature control, is added dropwise 28%
Ammoniacal liquor adjusts pH value between 3.5~4.0.After pH value regulation in place, 0~5 DEG C of temperature control stirs 1h, suction filtration, filter cake 100mL
Purifying water wash, filter cake is vacuum dried 6h, obtains 17.82g 7-ANCA at 40~50 DEG C, and outward appearance is white solid powder, is rubbed
Your yield is 89.0%, and purity is 99.1%.
Embodiments of the invention are the foregoing is only, the scope of the claims of the invention is not thereby limited, it is every to utilize this hair
Equivalent structure or equivalent flow conversion that bright description is done, or directly or indirectly it is used in other related technology necks
Domain, is included within the scope of the present invention.
Claims (9)
1. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA, it is characterised in that in turn include the following steps：
Step (a)：With CHS as raw material, in diphenyl chlorosilane Ph2SiHCl and aluminium chloride AlCl3In the presence of react, obtain chemical combination
Thing A：
Step (b)：Compound A, with imidazoles as acid binding agent, removes 7 in the presence of diisooctyl phenyl phosphite and bromine
On protection group phenylacetyl group, then with hydrochloric acid into salt, obtain compound B：
Step (c)：Protection groups of the compound B on 4 carboxyls of removing under bromotrimethylsilane effect obtains 7- to nitrobenzyl
ANCA：
2. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA according to claim 1, it is characterised in that step (a)
Reaction dissolvent is halide or halothane.
3. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA according to claim 2, it is characterised in that step (a)
Reaction dissolvent is chloromethane or chloric ethane.
4. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA according to claim 3, it is characterised in that step (a)
Reaction dissolvent is dichloromethane.
5. a kind of synthetic method of the Ceftizoxime parent nucleus 7-ANCA according to any one of Claims 1 to 4, its feature exists
In, in step (a), CHS and diphenyl chlorosilane Ph2The mol ratio of SiHCl is 1:1.0~1.5, aluminium chloride AlCl3It is catalysis
Agent, consumption is the 3~6% of substrate CHS mole percent concentrations, and the reaction time is 3~4h, and reaction temperature is 15~25 DEG C.
6. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA according to claim 1, it is characterised in that step (b)
In, with dichloromethane as reaction dissolvent, temperature is -10~-15 DEG C, in the case where compound A and imidazoles is added without, phosphorous acid
One benzene di-isooctyl and bromine first stir the color fade of 2~3h to bromine.
7. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA according to claim 6, it is characterised in that step (b)
In, after the color fade of bromine, temperature is down to -40~-45 DEG C, adds imidazoles and compound A, reacts 4~5h；Wherein, chemical combination
Thing A is 1 with the mol ratio of diisooctyl phenyl phosphite, bromine, imidazoles:1.0~1.5:1.0~1.5:1.0~1.5.
8. a kind of synthetic method of the Ceftizoxime parent nucleus 7-ANCA according to any one of claim 1,6 or 7, its feature
It is in step (b), after completion of the reaction, to be washed by with 10% aqueous hydrochloric acid solution, compound B exists with hydrochloride form.
9. a kind of synthetic method of Ceftizoxime parent nucleus 7-ANCA according to claim 1, it is characterised in that step (c)
In, compound B reacts the protection group removed on 4 carboxyls with bromotrimethylsilane to nitrobenzyl, and reaction temperature is 20~25
DEG C, the reaction time is 4~5h, and compound B is 1 with the mol ratio of bromotrimethylsilane:2.0~2.5.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510609572.4A CN105315299B (en) | 2015-09-22 | 2015-09-22 | A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510609572.4A CN105315299B (en) | 2015-09-22 | 2015-09-22 | A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN105315299A CN105315299A (en) | 2016-02-10 |
| CN105315299B true CN105315299B (en) | 2017-06-27 |
Family
ID=55243692
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201510609572.4A Active CN105315299B (en) | 2015-09-22 | 2015-09-22 | A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN105315299B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107722042B (en) * | 2017-10-19 | 2019-11-01 | 盐城开元医药化工有限公司 | A kind of synthetic method of Flomoxef parent nucleus |
Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4081595A (en) * | 1975-11-11 | 1978-03-28 | Shionogi & Co., Ltd. | Reduction giving 3-cephem compounds |
| GB2025933A (en) * | 1978-06-13 | 1980-01-30 | Fujisawa Pharmaceutical Co | >Cephem and cepham compounds |
| US4822888A (en) * | 1977-03-14 | 1989-04-18 | Fujisawa Pharmaceutical Company, Limited | New cepham compounds and processes for the production thereof |
| WO2001083492A1 (en) * | 2000-05-02 | 2001-11-08 | Newbiotics, Inc. | Improved beta-lactam antibiotics |
| CN101357927A (en) * | 2008-07-29 | 2009-02-04 | 浙江普洛得邦制药有限公司 | 7-amino-3-non-3-cephalosporin-4-carbosylic acid preparation method |
| CN102021211A (en) * | 2010-11-18 | 2011-04-20 | 浙江普洛得邦制药有限公司 | Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid |
| CN102180888A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method for 7-amino-3-non-3-cephem-4-carboxylic acid(7-ANCA) |
| CN102219794A (en) * | 2011-08-03 | 2011-10-19 | 天津华药医药有限公司 | Preparation method of ceftizoxime sodium |
| WO2015070394A1 (en) * | 2013-11-13 | 2015-05-21 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing penem antibiotic intermediate |
-
2015
- 2015-09-22 CN CN201510609572.4A patent/CN105315299B/en active Active
Patent Citations (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4081595A (en) * | 1975-11-11 | 1978-03-28 | Shionogi & Co., Ltd. | Reduction giving 3-cephem compounds |
| US4822888A (en) * | 1977-03-14 | 1989-04-18 | Fujisawa Pharmaceutical Company, Limited | New cepham compounds and processes for the production thereof |
| GB2025933A (en) * | 1978-06-13 | 1980-01-30 | Fujisawa Pharmaceutical Co | >Cephem and cepham compounds |
| WO2001083492A1 (en) * | 2000-05-02 | 2001-11-08 | Newbiotics, Inc. | Improved beta-lactam antibiotics |
| CN101357927A (en) * | 2008-07-29 | 2009-02-04 | 浙江普洛得邦制药有限公司 | 7-amino-3-non-3-cephalosporin-4-carbosylic acid preparation method |
| CN102021211A (en) * | 2010-11-18 | 2011-04-20 | 浙江普洛得邦制药有限公司 | Method for preparing 7-amino-3-nor-3-cephalo-4-carboxylic acid |
| CN102180888A (en) * | 2011-03-02 | 2011-09-14 | 河北科技大学 | Preparation method for 7-amino-3-non-3-cephem-4-carboxylic acid(7-ANCA) |
| CN102219794A (en) * | 2011-08-03 | 2011-10-19 | 天津华药医药有限公司 | Preparation method of ceftizoxime sodium |
| WO2015070394A1 (en) * | 2013-11-13 | 2015-05-21 | 凯莱英医药集团（天津）股份有限公司 | Method for preparing penem antibiotic intermediate |
Non-Patent Citations (2)
| Title |
|---|
| 7-氨基-3-无-3-头孢-4-羧酸的合成改进;齐永斌 等;《精细化工原料及中间体》;20091008(第10期);第31－32页 * |
| Studies of β-lactam antibiotics. 1. Structure-activity relations of sodium 7β-[(Z)-2-(2-amino-4-thiazolyl)-2-(methoxyimino)acetamido]-3-cephem-4-carboxylate (ceftizoxime) and its RELATED COMPOUNDS;T. TAKAYA et al.;《Nippon Kagaku Kaishi》;19811231(第5期);第785-804页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN105315299A (en) | 2016-02-10 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106699570A (en) | Synthesis method for (2-chloro-5-iodophenyl)(4-fluorophenyl)ketone | |
| CN111362939B (en) | Preparation method of palbociclib parent nucleus structure compound | |
| CN105315299B (en) | A kind of synthetic method of the ANCA of Ceftizoxime parent nucleus 7 | |
| CN105541801B (en) | The synthetic method of EZH2 methyltransferase inhibitors GSK126 | |
| CN104402909A (en) | Synthetic method of cefoxitin acid | |
| CN110003274A (en) | Phosphonylation dihydro-isoquinoline ketone compounds and preparation method thereof | |
| CN103588765B (en) | The synthetic method of the synthetic method of Azilsartan or its salt and intermediate and intermediate | |
| CN103373960B (en) | A kind of tolvaptan intermediate and preparation method thereof | |
| CN108586493A (en) | A kind of preparation method of crystal type CEFUROXIME AXETIL | |
| CN105566260B (en) | A kind of preparation method of frusemide | |
| CN102757350A (en) | Preparation method of erlotinib intermediate, i.e., 3-aminobenzeneacetylene | |
| CN105037059A (en) | Preparation method of alpha-(4-substituted phenyl)isobutyric acid | |
| CN109836425B (en) | Preparation process of synthetic pemetrexed | |
| CN104478768B (en) | A kind of fluoroform sulfo group fluorophenyl compound | |
| CN107011347A (en) | A kind of synthetic method of 4 chlorine 7H pyrrolo-es [2,3 d] pyrimidines | |
| CN103387584A (en) | Synthetic method of 7-amino-3-chloro-3-cephem-4-carboxylic acid | |
| CN103450172A (en) | Preparation method of antipsychotic drug lurasidone | |
| CN113372286A (en) | Method for preparing 1-phenyl-5-mercapto tetrazole by one-step method | |
| CN102491992A (en) | Method for preparing carbapenem type antibiotic key intermediate 4-BMA | |
| CN103274943B (en) | 4-[1-(2-propinyl)-3, 4-dioxo-n-butyl] benzoate and preparation method thereof | |
| CN105348197A (en) | Preparation method of lorcaserin hydrochloride | |
| CN110294694A (en) | A kind of improved preparation method of intermediate DAS of paratonere 177 | |
| CN104530015B (en) | A kind of preparation method of avanaphil | |
| CN104672180A (en) | Chiral preparation method of [(1S)-3-methyl-1-[[(2R)-2-methylepoxyethyl]carbonyl]butyl]tert-butyl carbamate | |
| CN102391170A (en) | Method for preparing N,N-diallyl-5-methoxytryptamine hydrochlorides |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |