CN108164550A - A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application - Google Patents
A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application Download PDFInfo
- Publication number
- CN108164550A CN108164550A CN201810067248.8A CN201810067248A CN108164550A CN 108164550 A CN108164550 A CN 108164550A CN 201810067248 A CN201810067248 A CN 201810067248A CN 108164550 A CN108164550 A CN 108164550A
- Authority
- CN
- China
- Prior art keywords
- reaction
- parts
- tazobactam
- reaction vessel
- product
- 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.)
- Pending
Links
- 229960000373 tazobactam sodium Drugs 0.000 title claims abstract description 43
- 238000002360 preparation method Methods 0.000 title claims abstract description 35
- -1 Tazobactam Sodium benzhydryl ester Chemical class 0.000 title claims abstract description 29
- 229960003865 tazobactam Drugs 0.000 title claims abstract description 29
- LPQZKKCYTLCDGQ-WEDXCCLWSA-N tazobactam Chemical compound C([C@]1(C)S([C@H]2N(C(C2)=O)[C@H]1C(O)=O)(=O)=O)N1C=CN=N1 LPQZKKCYTLCDGQ-WEDXCCLWSA-N 0.000 title claims abstract description 28
- 238000006243 chemical reaction Methods 0.000 claims abstract description 128
- 238000007142 ring opening reaction Methods 0.000 claims abstract description 36
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 27
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 14
- 230000009977 dual effect Effects 0.000 claims abstract description 12
- 238000006482 condensation reaction Methods 0.000 claims abstract description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 129
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 93
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 48
- 239000000047 product Substances 0.000 claims description 45
- 239000000243 solution Substances 0.000 claims description 44
- NDIURPSCHWTXDC-UHFFFAOYSA-N 2-(4,5-dimethoxy-2-nitrophenyl)acetohydrazide Chemical compound COC1=CC(CC(=O)NN)=C([N+]([O-])=O)C=C1OC NDIURPSCHWTXDC-UHFFFAOYSA-N 0.000 claims description 29
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 26
- 239000008213 purified water Substances 0.000 claims description 26
- 238000003756 stirring Methods 0.000 claims description 25
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 22
- 239000002253 acid Substances 0.000 claims description 21
- 238000010792 warming Methods 0.000 claims description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 15
- 238000004128 high performance liquid chromatography Methods 0.000 claims description 14
- 235000019441 ethanol Nutrition 0.000 claims description 13
- 239000012044 organic layer Substances 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 12
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 12
- 239000007859 condensation product Substances 0.000 claims description 12
- 239000010410 layer Substances 0.000 claims description 12
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 12
- 239000007787 solid Substances 0.000 claims description 12
- 238000013517 stratification Methods 0.000 claims description 12
- 238000004321 preservation Methods 0.000 claims description 11
- 238000001035 drying Methods 0.000 claims description 10
- HPOKESDSMZRZLC-UHFFFAOYSA-N propan-2-one;hydrochloride Chemical compound Cl.CC(C)=O HPOKESDSMZRZLC-UHFFFAOYSA-N 0.000 claims description 10
- 239000000126 substance Substances 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 239000000706 filtrate Substances 0.000 claims description 7
- 239000007788 liquid Substances 0.000 claims description 7
- 239000012286 potassium permanganate Substances 0.000 claims description 7
- 238000005406 washing Methods 0.000 claims description 7
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 claims description 6
- 235000010290 biphenyl Nutrition 0.000 claims description 6
- 239000004305 biphenyl Substances 0.000 claims description 6
- 238000001816 cooling Methods 0.000 claims description 6
- YFMGHVQBAINRBB-UHFFFAOYSA-L disodium hydrogen carbonate chloride hydrate Chemical compound C([O-])(O)=O.[Na+].Cl.[OH-].[Na+] YFMGHVQBAINRBB-UHFFFAOYSA-L 0.000 claims description 6
- 238000001914 filtration Methods 0.000 claims description 6
- 239000012467 final product Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 6
- 150000003839 salts Chemical class 0.000 claims description 6
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 6
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 6
- 235000010288 sodium nitrite Nutrition 0.000 claims description 6
- 239000006188 syrup Substances 0.000 claims description 6
- 235000020357 syrup Nutrition 0.000 claims description 6
- 238000005292 vacuum distillation Methods 0.000 claims description 6
- 230000015572 biosynthetic process Effects 0.000 claims description 5
- 238000003786 synthesis reaction Methods 0.000 claims description 5
- 239000003781 beta lactamase inhibitor Substances 0.000 claims description 4
- 229940126813 beta-lactamase inhibitor Drugs 0.000 claims description 4
- 239000006228 supernatant Substances 0.000 claims description 4
- 239000003643 water by type Substances 0.000 claims description 4
- 229940126085 β‑Lactamase Inhibitor Drugs 0.000 claims description 4
- 150000003952 β-lactams Chemical class 0.000 claims description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 claims description 2
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 claims description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 claims description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 claims description 2
- 239000001099 ammonium carbonate Substances 0.000 claims description 2
- 238000005119 centrifugation Methods 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 239000003112 inhibitor Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 239000002360 explosive Substances 0.000 abstract description 3
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 abstract description 2
- 230000006872 improvement Effects 0.000 abstract description 2
- 231100000614 poison Toxicity 0.000 abstract description 2
- 230000007096 poisonous effect Effects 0.000 abstract description 2
- 208000011117 substance-related disease Diseases 0.000 abstract description 2
- 238000010511 deprotection reaction Methods 0.000 abstract 1
- 239000007858 starting material Substances 0.000 abstract 1
- YXIWHUQXZSMYRE-UHFFFAOYSA-N 1,3-benzothiazole-2-thiol Chemical compound C1=CC=C2SC(S)=NC2=C1 YXIWHUQXZSMYRE-UHFFFAOYSA-N 0.000 description 7
- 241000894006 Bacteria Species 0.000 description 5
- 102000004190 Enzymes Human genes 0.000 description 5
- 108090000790 Enzymes Proteins 0.000 description 5
- RLSSMJSEOOYNOY-UHFFFAOYSA-N m-cresol Chemical compound CC1=CC=CC(O)=C1 RLSSMJSEOOYNOY-UHFFFAOYSA-N 0.000 description 5
- 229940100630 metacresol Drugs 0.000 description 5
- 230000003115 biocidal effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 230000002401 inhibitory effect Effects 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 230000001988 toxicity Effects 0.000 description 3
- 231100000419 toxicity Toxicity 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 0 CC(CN(C=C*)N=C)(C1C(OC(c2ccccc2)c2ccccc2)=*)SC(C2)N1C2=O Chemical compound CC(CN(C=C*)N=C)(C1C(OC(c2ccccc2)c2ccccc2)=*)SC(C2)N1C2=O 0.000 description 2
- HZZVJAQRINQKSD-UHFFFAOYSA-N Clavulanic acid Natural products OC(=O)C1C(=CCO)OC2CC(=O)N21 HZZVJAQRINQKSD-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical compound OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 2
- HSFWRNGVRCDJHI-UHFFFAOYSA-N alpha-acetylene Natural products C#C HSFWRNGVRCDJHI-UHFFFAOYSA-N 0.000 description 2
- 102000006635 beta-lactamase Human genes 0.000 description 2
- HZZVJAQRINQKSD-PBFISZAISA-N clavulanic acid Chemical compound OC(=O)[C@H]1C(=C/CO)/O[C@@H]2CC(=O)N21 HZZVJAQRINQKSD-PBFISZAISA-N 0.000 description 2
- 229960003324 clavulanic acid Drugs 0.000 description 2
- 125000002534 ethynyl group Chemical group [H]C#C* 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 238000005259 measurement Methods 0.000 description 2
- 238000000034 method Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- FKENQMMABCRJMK-RITPCOANSA-N sulbactam Chemical compound O=S1(=O)C(C)(C)[C@H](C(O)=O)N2C(=O)C[C@H]21 FKENQMMABCRJMK-RITPCOANSA-N 0.000 description 2
- 229960005256 sulbactam Drugs 0.000 description 2
- 238000010189 synthetic method Methods 0.000 description 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- NGHVIOIJCVXTGV-ALEPSDHESA-N 6-aminopenicillanic acid Chemical compound [O-]C(=O)[C@H]1C(C)(C)S[C@@H]2[C@H]([NH3+])C(=O)N21 NGHVIOIJCVXTGV-ALEPSDHESA-N 0.000 description 1
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 description 1
- 206010056519 Abdominal infection Diseases 0.000 description 1
- 108700023418 Amidases Proteins 0.000 description 1
- 108020004256 Beta-lactamase Proteins 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 206010024971 Lower respiratory tract infections Diseases 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 102000005922 amidase Human genes 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- LSQZJLSUYDQPKJ-NJBDSQKTSA-N amoxicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=C(O)C=C1 LSQZJLSUYDQPKJ-NJBDSQKTSA-N 0.000 description 1
- 229960003022 amoxicillin Drugs 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 238000013475 authorization Methods 0.000 description 1
- 150000003851 azoles Chemical class 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 210000000349 chromosome Anatomy 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007256 debromination reaction Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 229940125532 enzyme inhibitor Drugs 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000002779 inactivation Effects 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 229920000620 organic polymer Polymers 0.000 description 1
- LSQZJLSUYDQPKJ-UHFFFAOYSA-N p-Hydroxyampicillin Natural products O=C1N2C(C(O)=O)C(C)(C)SC2C1NC(=O)C(N)C1=CC=C(O)C=C1 LSQZJLSUYDQPKJ-UHFFFAOYSA-N 0.000 description 1
- 239000013612 plasmid Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- OSIDZZBISOKIPC-UHFFFAOYSA-N silicon;2h-triazole Chemical class [Si].C=1C=NNN=1 OSIDZZBISOKIPC-UHFFFAOYSA-N 0.000 description 1
- 206010040872 skin infection Diseases 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 150000003852 triazoles Chemical group 0.000 description 1
- 241001148471 unidentified anaerobic bacterium Species 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002132 β-lactam antibiotic Substances 0.000 description 1
- 229940124586 β-lactam antibiotics Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/87—Compounds being unsubstituted in position 3 or with substituents other than only two methyl radicals attached in position 3, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/429—Thiazoles condensed with heterocyclic ring systems
- A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
- A61K31/431—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems containing further heterocyclic rings, e.g. ticarcillin, azlocillin, oxacillin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/04—Preparation
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to a kind of Tazobactam Sodium benzhydryl ester, the preparation process of tazobactam and applications; it prepares path and after ring-opening reaction, chlorination reaction, condensation reaction, dual oxide reaction Tazobactam Sodium benzhydryl ester is prepared as starting material by toluene, 2 mercaptobenzothiazolers and debrominate object, Tazobactam Sodium benzhydryl ester is converted into tazobactam later using deprotection reaction；And the preparation method in this programme makes improvement on the basis of the iodide reaction of the prior art, introduces chlorination, optimizes reaction mass, improves product purity, reduces poisonous and harmful, flammable and explosive substance use in reaction process, makes reaction more green, environmentally friendly；And products collection efficiency may be up to 98% 99.92%, manufacturing cost is also below preparation process of the prior art.
Description
Technical field
The present invention relates to a kind of organic polymer synthesis technology, more particularly to a kind of tazobactam, Tazobactam Sodium hexichol
Methyl esters preparation process and application.
Background technology
Beta-lactam antibiotic has the history of over half a century from being born so far.During this period, as bacterium is to normal
Constantly generate drug resistance with antibiotic, people constantly develop it is more efficient and to drug-fast bacteria more effective antibiotic, same to hour hands
Make this mechanism of the beta-lactamase of beta-lactam enzyme inactivation to drug-fast bacteria generation, develop the β-interior acyl shared with antibiotic
Amine enzyme inhibitor, wherein than it is more typical be exactly Tazobactam Sodium.Tazobactam Sodium is to various types of beta-lactamases even I type enzymes
Also very effectively, act on 10 times stronger than Sulbactam, stability is better than clavulanic acid, to the β of a variety of plasmids and chromosome intermediary-interior
The inhibiting effect of amidase is stronger than clavulanic acid and Sulbactam.With ampicillin, Amoxicillin etc. associated with inside and outside test
Relatively satisfactory effect is achieved, there is the advantages that toxicity is low, and stability is good, and Inhibiting enzyme activity is strong, once in the 30th internationalization
It treats and is cited as most promising beta-lactamase inhibitor in meeting.
At present, relatively conventional preparation process is as follows：
This more conventional preparation process is also the mode of tazobactam/sodium-tazobactam synthesized on the market at present, but
It is since intermediate additive and partial intermediate have inflammable and explosive characteristic or toxicity stronger, such as acetylene, iodine oxidation
The substances such as sodium cause production technology of the prior art more dangerous.
Documents 1：Authorization Notice No. is a kind of Tazobactam Sodium disclosed in the Chinese patent of " CN102020663B "
Synthetic method；
Documents 2：Conjunction of the application publication number for a kind of sodium-tazobactam disclosed in the Chinese patent of " CN102382123A "
Into method.
Since in recent years, increasing to the demand of Tazobactam Sodium in the world, market prospects are very wide, more and more
Laboratory, company starts to study Tazobactam Sodium；As in documents 1 use new-type synthetic method, using 6-APA as
Raw material, by being esterified, aoxidizing, the successive reactions such as reduction-debromination key intermediate 6,6- dihydro penam sulfoxides are made without isolation
Acid benzhydryl ester, then after reacting with 2- triphenyls silicon -1,2,3-triazoles and introducing triazole ring, through potassium permanganate oxidation, middle metacresol
It is deprotected to obtain final product Tazobactam Sodium；It is safer, environmentally friendly although this preparation method is formed relative to the prior art,
Be ultimate yield mean value about between 70%-80%, yield is relatively low.
Thus, we provide a kind of environmental protection and the better preparation process of yield herein.
Invention content
A kind of preparation work of Tazobactam Sodium acid benzhydryl ester higher the object of the present invention is to provide yield and more environmentally friendly
Skill.
The present invention above-mentioned technical purpose technical scheme is that：A kind of tazobactam hexichol first
The preparation process of ester, synthesis step are as follows：
Ring-opening reaction：
Chlorination reaction：
Condensation reaction：
Dual oxide reacts：
Preferably, include the following steps：
Step 1：Ring-opening reaction
Step 1.1：3.0-3.5 parts of part toluene, 0.2-0.4 parts of debrominate objects and 0.1-0.2 parts of MBT are put into reaction vessel A, are risen
Temperature to 70-75 DEG C react 80-100 minutes；
Step 1.2：After completion of the reaction, it is cooled to 58-75 DEG C；
Step 1.3：Product at reduced pressure in step 1.2 is concentrated to dryness, 2.3-2.5 parts of dichloromethane is added in and stirs to being completely dissolved
To supernatant liquid, ring-opening product dichloromethane solution is obtained；
Step 2：Chlorination reaction
Step 2.1：Ring-opening product dichloromethane solution in step 1.3, which is transferred to persistently to stir and cool down into reaction vessel B, to be made
The ring-opening product dichloromethane solution in reaction vessel B is obtained to 0-5 DEG C；
Step 2.2：A concentration of 31% 0.3-0.5 parts of hydrochloric acid solution is slowly added dropwise into reaction vessel B, dropping temperature is less than 0
℃；
Step 2.3：0.5-0.6 parts of the sodium nitrite solution of a concentration of 13-15% is added dropwise into reaction vessel B again, control is added dropwise
Temperature is 5-10 DEG C, and time for adding is 85-100 minutes；
Step 2.4：Reaction vessel B connections wherein substance is placed on after keeping the temperature 10-12 hours at 5-10 DEG C, reaction was completed；
Step 2.5：After centrifuge rejection filter, filtrate is transferred to stratification in another reaction vessel C, water layer is carried with dichloromethane
It takes, is washed repeatedly with water, sodium bicarbonate aqueous solution, purified water successively after merging organic layer；
Step 2.6：Organic layer after washing is transferred in reaction vessel D, is evaporated under reduced pressure to dry, after adding in 1.4-1.5 parts of acetone
It is spare to obtain chloride acetone soln；
Step 3：Condensation reaction
Step 3.1：It is persistently stirred during the chloride acetone soln being prepared in step 2.6 is transferred in reaction vessel E, then to
1,2,3- triazole of 0.4-0.5 parts of purified waters and 0.08-0.10 parts is wherein added in, controlled at 25-30 DEG C, control time is
12-15 hours；
Step 3.2：It is evaporated under reduced pressure after completion of the reaction to dry；
Step 3.3：It puts into 1.3-1.6 parts of dichloromethane and dissolves and obtain clear solution, taken several layers of purified water washes cleans
After be concentrated under reduced pressure into dry, obtain syrup object；
Step 3.4：It stirs after 0.3-0.4 parts of ethyl acetate of input 2.0 hours and is centrifuged to after crystallizing, control whipping temp is 25
DEG C, it is dried after centrifugation and obtains the condensation product with certain humidity；
Step 4：Dual oxide reacts
Step 4.1：It will be stirred to get in the condensation product tide product and dichloromethane that are prepared in step 3.4 input reaction vessel F
Clear solution；
Step 4.2：After being cooled to 10 DEG C, 30-35 DEG C is to slowly warm up to after putting into 0.06-0.07 parts of potassium permanganate, heat preservation 3-4 is small
When after reaction was completed；
Step 4.3：Vacuum distillation to a large amount of solids are precipitated, then put into 0.5-0.6 parts of ethyl acetate and break up solid, are cooled to 0-
After 5 DEG C, centrifuged after standing 1 hour, after ethyl acetate washes clean, drying.
Preferably, being monitored in step 1.1 using HPLC, stop step 1.1 when debrominate object is less than 1.0%；
It is monitored in step 2.3 using HPLC, stops reaction when ring-opening product is less than 0.5%.
Preferably, in step 2.5 after centrifuge rejection filter, filter cake is washed with 0.2-0.25 parts of dichlorotoleune, will be filtered
After liquid merges with organic layer, 2-3 times is washed with water successively, 1.5% ammonium bicarbonate aqueous solution washs 2-3 time, purifies water washing.
A kind of preparation process of tazobactam higher the object of the present invention is to provide yield and more environmentally friendly.
The present invention above-mentioned technical purpose technical scheme is that：It is prepared by the above method
Final product continues to be prepared, and synthesis step is as follows：
Preferably, include the following steps：
Step 5.1：0.2-0.3 parts of Tazobactam Sodium diphenyl ester and 0.5-0.9 parts of metacresols are put into reaction vessel G, are warming up to
7 hours are stood after 80 DEG C；
Step 5.2：1.0-1.2 parts of ethyl acetate are put into reaction vessel H, then the product obtained in step 5.1 cooling is turned
Enter into reaction vessel H, input sodium bicarbonate brine, salt and purified water stir after ten minutes, stratification；
Step 5.3：Adjusting PH to 4.0 after water phase is washed with ethyl acetate, addition EDTA, 0 activated carbon decolorizing, press filtration after decoloration,
The standings of PH to 2.0 are adjusted again keeps the temperature the Tazobactam Sodium acid crude for centrifuging moist after 1 hour, then after adjusting PH to 1.5；
Step 5.4：After being warming up to 70 DEG C after 0.13-0.15 parts of purified waters, 0.2-0.3 parts of highly concentrated ethyl alcohol uniformly mixing, it will walk
It is prepared after Tazobactam Sodium acid crude adds in and dissolves in rapid 5.3；
Step 5.5：After being cooled to less than 0 DEG C, heat preservation centrifuges after 4 hours, is rinsed with ethyl alcohol, dries to obtain tazobactam.
Preferably, the hydrochloric acid solution using a concentration of 10% adjusts PH.
The object of the present invention is to provide a kind of applications of Tazobactam Sodium acid benzhydryl ester.
The present invention above-mentioned technical purpose technical scheme is that：It is prepared by a kind of above-mentioned preparation method
Obtained tazobactam is used for the preparation of beta-lactamase inhibitor.
The object of the present invention is to provide a kind of applications of Tazobactam Sodium acid benzhydryl ester.
The present invention above-mentioned technical purpose technical scheme is that：For beta-lactam inhibitor
It prepares.
In conclusion the invention has the advantages that：
(1) tazobactam is as penicillanic acid sulfones beta-lactamase inhibitor, spy effective to I~VI type 3- lactamases
It is not more effective to I type enzymes；Its toxicity is low, and stability is good, and Inhibiting enzyme activity is strong；Treatment various bacteria is clinically used for including aerobic
It is infected caused by bacterium and anaerobic bacteria, including lower respiratory tract infection, skin and abdominal infection etc.；And the preparation method in this programme exists
Improvement is made on the basis of the iodide reaction of the prior art, introduces chlorination, optimizes reaction mass, improves product purity, drop
Poisonous and harmful during low reaction, flammable and explosive substance use makes reaction more green, environmentally friendly；
(2) using toluene, debrominate object, 2-mercaptobenzothiazole, dichloromethane as raw material, through ring-opening reaction, chlorination, dual oxide
Tazobactam is obtained, and intermediate product Tazobactam Sodium benzhydryl ester can be obtained after the reaction of the steps such as reaction, both the above substance is equal
Product can be used as to sell, reduce production cost, improve profit on sales；And the reaction of ring-opening reaction, chlorination, dual oxide is complete
Cheng Jun is monitored using HPLC, is precisely controlled reaction process, improves products pure degree；
(3) substances such as acetylene, iodine oxidation sodium are not being used in the preparation method provided in this programme, and wherein largely use
The substances such as toluene, dichlorotoleune, acetone, ethyl acetate, ethyl alcohol, phenol can be recycled, further reduction material
Waste, meets environmentally friendly chemistry；
(4) detection can obtain：It is preferable using the tazobactam and Tazobactam Sodium benzhydryl ester optical activity that are prepared in this programme,
And yield may be up to 98%-99.92%, manufacturing cost is also below preparation process of the prior art.
Description of the drawings
Fig. 1 is the preparation technology flow chart of Tazobactam Sodium benzhydryl ester in embodiment；
Fig. 2 is the preparation technology flow chart of tazobactam in embodiment.
Specific embodiment
This specific embodiment is only explanation of the invention, is not limitation of the present invention, people in the art
Member can as needed make the present embodiment the modification of no creative contribution after this specification is read, but as long as at this
It is all protected in the right of invention by Patent Law.
Embodiment 1：
The preparation technology flow chart of tazobactam, as shown in Figure 1, mainly including the following steps that：
Step 1：Ring-opening reaction；
Step 2：Chlorination reaction；
Step 3：Condensation reaction；
Step 4：Dual oxide reacts.
The reaction equation of ring-opening reaction is as follows：
Preparation process is as follows：
Step 1.1：3.0 parts of toluene, 0.2 part of debrominate object and 0.1 part of MBT are put into reaction vessel A, is warming up to 70 DEG C of reactions
80-100 minutes；
Step 1.2：After completion of the reaction, 58 DEG C are cooled to；
Step 1.3：Product at reduced pressure in step 1.2 is concentrated to dryness, 2.3 parts of dichloromethane of addition stir clear to being completely dissolved to obtain
Clear liquid body obtains ring-opening product dichloromethane solution.
The reaction equation of chlorination reaction is as follows：
Preparation process is as follows：
Step 2.1：Ring-opening product dichloromethane solution in step 1.3, which is transferred to persistently to stir and cool down into reaction vessel B, to be made
The ring-opening product dichloromethane solution in reaction vessel B is obtained to 0-5 DEG C；
Step 2.2：A concentration of 31% 0.3 part of hydrochloric acid solution is slowly added dropwise into reaction vessel B, dropping temperature is less than 0 DEG C；
Step 2.3：A concentration of 13% 0.5 part of sodium nitrite solution is added dropwise into reaction vessel B again, control dropping temperature is 5-
10 DEG C, time for adding is 85-100 minutes；
Step 2.4：Reaction vessel B connections wherein substance is placed on after keeping the temperature 10-12 hours at 5-10 DEG C, reaction was completed；
Step 2.5：After centrifuge rejection filter, filtrate is transferred to stratification in another reaction vessel C, water layer is carried with dichloromethane
It takes, is washed repeatedly with water, sodium bicarbonate aqueous solution, purified water successively after merging organic layer.
The reaction equation of condensation reaction is as follows：
Preparation process is as follows：
Step 3.1：It is persistently stirred during the chloride acetone soln being prepared in step 2.6 is transferred in reaction vessel E, then to
0.4 part of purified water and 0.08 part 1 are wherein added in, 2,3- triazoles, controlled at 25-30 DEG C, control time is small for 12-15
When；
Step 3.2：It is evaporated under reduced pressure after completion of the reaction to dry；
Step 3.3：It puts into 1.3 parts of dichloromethane and dissolves and obtain clear solution, subtract after having taken several layers of washes cleans with purified water
Pressure is concentrated to dryness, and obtains syrup object；
Step 3.4：It stirring after 0.3 part of ethyl acetate of input 2.0 hours and is centrifuged to after crystallizing, control whipping temp is 25 DEG C, from
Drying obtains the condensation product with certain humidity after the heart.
The reaction equation of dual oxide reaction is as follows：
Preparation process is as follows：
Step 4.1：It will be stirred to get in the condensation product tide product and dichloromethane that are prepared in step 3.4 input reaction vessel F
Clear solution；
Step 4.2：After being cooled to 10 DEG C, 30 DEG C are to slowly warm up to after putting into 0.06 part of potassium permanganate, heat preservation terminates after 3-4 hours
Reaction；
Step 4.3：Vacuum distillation to a large amount of solids are precipitated, then put into 0.5 part of ethyl acetate and break up solid, are cooled to 0-5 DEG C
Afterwards, it is centrifuged after standing 1 hour, after ethyl acetate washes clean, drying.
Full name is detected using HPLC, in step 1.1, is reacted to after 60 minutes, is monitored using HPLC, works as debrominate
Object starts to cool down when being less than 1.0%；Stop reaction when ring-opening product is less than 0.5% in step 2.3.
Embodiment 2：
Step 1：Ring-opening reaction
Step 1.1：3.5 parts of part toluene, 0.4 part of debrominate object and 0.2 part of MBT are put into reaction vessel A, is warming up to 70-75 DEG C
Reaction 80-100 minutes；
Step 1.2：After completion of the reaction, 75 DEG C are cooled to；
Step 1.3：Product at reduced pressure in step 1.2 is concentrated to dryness, 2.5 parts of dichloromethane of addition stir clear to being completely dissolved to obtain
Clear liquid body obtains ring-opening product dichloromethane solution；
Step 2：Chlorination reaction
Step 2.1：Ring-opening product dichloromethane solution in step 1.3, which is transferred to persistently to stir and cool down into reaction vessel B, to be made
The ring-opening product dichloromethane solution in reaction vessel B is obtained to 0-5 DEG C；
Step 2.2：A concentration of 31% 0.5 part of hydrochloric acid solution is slowly added dropwise into reaction vessel B, dropping temperature is less than 0 DEG C；
Step 2.3：0.6 part of the sodium nitrite solution of a concentration of 13-15% is added dropwise into reaction vessel B again, controls dropping temperature
It it is 5-10 DEG C, time for adding is 85-100 minutes；
Step 2.4：Reaction vessel B connections wherein substance is placed on after keeping the temperature 10-12 hours at 5-10 DEG C, reaction was completed；
Step 2.5：After centrifuge rejection filter, filtrate is transferred to stratification in another reaction vessel C, water layer is carried with dichloromethane
It takes, is washed repeatedly with water, sodium bicarbonate aqueous solution, purified water successively after merging organic layer；
Step 2.6：Organic layer after washing is transferred in reaction vessel D, is evaporated under reduced pressure to doing, chlorine is obtained after adding in 1.5 parts of acetone
Compound acetone soln is spare；
Step 3：Condensation reaction
Step 3.1：It is persistently stirred during the chloride acetone soln being prepared in step 2.6 is transferred in reaction vessel E, then to
0.5 part of purified water and 0.10 part 1 are wherein added in, 2,3- triazoles, controlled at 30 DEG C, control time is 12-15 hours；
Step 3.2：It is evaporated under reduced pressure after completion of the reaction to dry；
Step 3.3：It puts into 1.6 parts of dichloromethane and dissolves and obtain clear solution, subtract after having taken several layers of washes cleans with purified water
Pressure is concentrated to dryness, and obtains syrup object；
Step 3.4：It stirring after 0.4 part of ethyl acetate of input 2.0 hours and is centrifuged to after crystallizing, control whipping temp is 25 DEG C, from
Drying obtains the condensation product with certain humidity after the heart；
Step 4：Dual oxide reacts
Step 4.1：It will be stirred to get in the condensation product tide product and dichloromethane that are prepared in step 3.4 input reaction vessel F
Clear solution；
Step 4.2：After being cooled to 10 DEG C, 30-35 DEG C is to slowly warm up to after putting into 0.07 part of potassium permanganate, after keeping the temperature 3-4 hours
Reaction was completed；
Step 4.3：Vacuum distillation to a large amount of solids are precipitated, then put into 0.6 part of ethyl acetate and break up solid, are cooled to 0-5 DEG C
Afterwards, it is centrifuged after standing 1 hour, after ethyl acetate washes clean, drying.
Full name is detected using HPLC, in step 1.1, is reacted to after 60 minutes, is monitored using HPLC, works as debrominate
Object starts to cool down when being less than 1.0%；Stop reaction when ring-opening product is less than 0.5% in step 2.3.
Embodiment 3：
Step 1：Ring-opening reaction
Step 1.1：3.2 parts of toluene, 0.25 part of debrominate object and 0.14 part of MBT are put into reaction vessel A, is warming up to 70-75 DEG C
Reaction 80-100 minutes；
Step 1.2：After completion of the reaction, 65 DEG C are cooled to；
Step 1.3：Product at reduced pressure in step 1.2 is concentrated to dryness, 2.37 parts of dichloromethane is added in and stirs to being completely dissolved to obtain
Supernatant liquid obtains ring-opening product dichloromethane solution；
Step 2：Chlorination reaction
Step 2.1：Ring-opening product dichloromethane solution in step 1.3, which is transferred to persistently to stir and cool down into reaction vessel B, to be made
The ring-opening product dichloromethane solution in reaction vessel B is obtained to 0-5 DEG C；
Step 2.2：A concentration of 31% 0.37 part of hydrochloric acid solution is slowly added dropwise into reaction vessel B, dropping temperature is less than 0 DEG C；
Step 2.3：0.53 part of the sodium nitrite solution of a concentration of 13-15% is added dropwise into reaction vessel B again, controls dropping temperature
It it is 5-10 DEG C, time for adding is 85-100 minutes；
Step 2.4：Reaction vessel B connections wherein substance is placed on after keeping the temperature 10-12 hours at 5-10 DEG C, reaction was completed；
Step 2.5：After centrifuge rejection filter, filtrate is transferred to stratification in another reaction vessel C, water layer is carried with dichloromethane
It takes, is washed repeatedly with water, sodium bicarbonate aqueous solution, purified water successively after merging organic layer；
Step 2.6：Organic layer after washing is transferred in reaction vessel D, is evaporated under reduced pressure to dry, after adding in 1.4-1.5 parts of acetone
It is spare to obtain chloride acetone soln；
Step 3：Condensation reaction
Step 3.1：It is persistently stirred, then thereto during the chloride acetone soln being prepared in step 2.6 is transferred in container E
0.43 part of purified water and 0.089 part 1 are added in, 2,3- triazoles, controlled at 27 DEG C, control time is 13 hours；
Step 3.2：It is evaporated under reduced pressure after completion of the reaction to dry；
Step 3.3：It puts into 1.4 parts of dichloromethane and dissolves and obtain clear solution, subtract after having taken several layers of washes cleans with purified water
Pressure is concentrated to dryness, and obtains syrup object；
Step 3.4：It stirring after 0.36 part of ethyl acetate of input 2.0 hours and is centrifuged to after crystallizing, control whipping temp is 25 DEG C, from
Drying obtains the condensation product with certain humidity after the heart；
Step 4：Dual oxide reacts
Step 4.1：The condensation product tide product and dichloromethane that are prepared in step 3.4 are put into container F and stir to get clarification
Solution；
Step 4.2：After being cooled to 10 DEG C, 32 DEG C are to slowly warm up to after putting into 0.065 part of potassium permanganate, heat preservation is tied after 3-4 hours
Shu Fanying；
Step 4.3：Vacuum distillation to a large amount of solids are precipitated, then put into 0.53 part of ethyl acetate and break up solid, are cooled to 0-5 DEG C
Afterwards, it is centrifuged after standing 1 hour, after ethyl acetate washes clean, drying.
Full name is detected using HPLC, in step 1.1, is reacted to after 60 minutes, is monitored using HPLC, works as debrominate
Object starts to cool down when being less than 1.0%；Stop reaction when ring-opening product is less than 0.5% in step 2.3.
Embodiment 4：
Step 1：Ring-opening reaction
Step 1.1：3.4 parts of part toluene, 0.35 part of debrominate object and 0.18 part of MBT are put into reaction vessel A, is warming up to 75 DEG C instead
It answers 80-100 minutes；
Step 1.2：After completion of the reaction, 70 DEG C are cooled to；
Step 1.3：Product at reduced pressure in step 1.2 is concentrated to dryness, 2.3-2.5 parts of dichloromethane is added in and stirs to being completely dissolved
To supernatant liquid, ring-opening product dichloromethane solution is obtained；
Step 2：Chlorination reaction
Step 2.1：Ring-opening product dichloromethane solution in step 1.3, which is transferred to persistently to stir and cool down into reaction vessel B, to be made
The ring-opening product dichloromethane solution in reaction vessel B is obtained to 0-5 DEG C；
Step 2.2：A concentration of 31% 0.45 part of hydrochloric acid solution is slowly added dropwise into reaction vessel B, dropping temperature is less than 0 DEG C；
Step 2.3：0.58 part of the sodium nitrite solution of a concentration of 13-15% is added dropwise into reaction vessel B again, controls dropping temperature
It it is 5-10 DEG C, time for adding is 85-100 minutes；
Step 2.4：Reaction vessel B connections wherein substance is placed on after keeping the temperature 10-12 hours at 5-10 DEG C, reaction was completed；
Step 2.5：After centrifuge rejection filter, filtrate is transferred to stratification in another reaction vessel C, water layer is carried with dichloromethane
It takes, is washed repeatedly with water, sodium bicarbonate aqueous solution, purified water successively after merging organic layer；
Step 2.6：Organic layer after washing is transferred in reaction vessel D, is evaporated under reduced pressure to dry, after adding in 1.4-1.5 parts of acetone
It is spare to obtain chloride acetone soln；
Step 3：Condensation reaction
Step 3.1：It is persistently stirred during the chloride acetone soln being prepared in step 2.6 is transferred in reaction vessel E, then to
0.48 part of purified water and 0.09 part 1 are wherein added in, 2,3- triazoles, controlled at 28 DEG C, control time is 12-15 hours；
Step 3.2：It is evaporated under reduced pressure after completion of the reaction to dry；
Step 3.3：It puts into 1.5 parts of dichloromethane and dissolves and obtain clear solution, subtract after having taken several layers of washes cleans with purified water
Pressure is concentrated to dryness, and obtains syrup object；
Step 3.4：It stirring after 0.36 part of ethyl acetate of input 2.0 hours and is centrifuged to after crystallizing, control whipping temp is 25 DEG C, from
Drying obtains the condensation product with certain humidity after the heart；
Step 4：Dual oxide reacts
Step 4.1：It will be stirred to get in the condensation product tide product and dichloromethane that are prepared in step 3.4 input reaction vessel F
Clear solution；
Step 4.2：After being cooled to 10 DEG C, 32 DEG C are to slowly warm up to after putting into 0.068 part of potassium permanganate, heat preservation is tied after 3-4 hours
Shu Fanying；
Step 4.3：Vacuum distillation to a large amount of solids are precipitated, then put into 0.56 part of ethyl acetate and break up solid, are cooled to 0-5 DEG C
Afterwards, it is centrifuged after standing 1 hour, after ethyl acetate washes clean, drying.
Full name is detected using HPLC, in step 1.1, is reacted to after 60 minutes, is monitored using HPLC, works as debrominate
Object starts to cool down when being less than 1.0%；Stop reaction when ring-opening product is less than 0.5% in step 2.3.
Embodiment 5：
Continue to prepare tazobactam by the final product Tazobactam Sodium benzhydryl ester being prepared in embodiment 1- embodiments 4,
As shown in Fig. 2, reaction equation is as follows：
Preparation process is as follows：
Step 5.1：Tazobactam Sodium 0.2 part and 0.5 part metacresol of diphenyl ester is put into reaction vessel G, it is quiet after being warming up to 80 DEG C
It puts 7 hours；
Step 5.2：Into reaction vessel H put into 1.0 parts of ethyl acetate, then by the product obtained in step 5.1 cooling be transferred to
In reaction vessel H, input sodium bicarbonate brine, salt and purified water stir after ten minutes, stratification；
Step 5.3：Adjusting PH to 4.0 after water phase is washed with ethyl acetate, addition EDTA, 0 activated carbon decolorizing, press filtration after decoloration,
The standings of PH to 2.0 are adjusted again and keep the temperature the Tazobactam Sodium acid crude for centrifuging moist after 1 hour, then after adjusting PH to 1.5, and use is dense
The hydrochloric acid spent for 10% adjusts PH；
Step 5.4：After being warming up to 70 DEG C after 0.13 part of purified water, 0.2 part of highly concentrated ethyl alcohol uniformly mixing, it will be made in step 5.3
It is standby to obtain dissolving after Tazobactam Sodium acid crude adds in；
Step 5.5：After being cooled to less than 0 DEG C, heat preservation centrifuges after 4 hours, is rinsed with ethyl alcohol, dries to obtain tazobactam.
Embodiment 6：
Step 5.1：Tazobactam Sodium 0.3 part and 0.9 part metacresol of diphenyl ester is put into reaction vessel G, it is quiet after being warming up to 80 DEG C
It puts 7 hours；
Step 5.2：Into reaction vessel H put into 1.2 parts of ethyl acetate, then by the product obtained in step 5.1 cooling be transferred to
In reaction vessel H, input sodium bicarbonate brine, salt and purified water stir after ten minutes, stratification；
Step 5.3：Adjusting PH to 4.0 after water phase is washed with ethyl acetate, addition EDTA, 0 activated carbon decolorizing, press filtration after decoloration,
The standings of PH to 2.0 are adjusted again and keep the temperature the Tazobactam Sodium acid crude for centrifuging moist after 1 hour, then after adjusting PH to 1.5, and use is dense
The hydrochloric acid spent for 10% adjusts PH；
Step 5.4：After being warming up to 70 DEG C after 0.15 part of purified water, 0.3 part of highly concentrated ethyl alcohol uniformly mixing, it will be made in step 5.3
It is standby to obtain dissolving after Tazobactam Sodium acid crude adds in；
Step 5.5：After being cooled to less than 0 DEG C, heat preservation centrifuges after 4 hours, is rinsed with ethyl alcohol, dries to obtain tazobactam.
Embodiment 7：
Step 5.1：Tazobactam Sodium 0.23 part and 0.7 part metacresol of diphenyl ester is put into reaction vessel G, it is quiet after being warming up to 80 DEG C
It puts 7 hours；
Step 5.2：Into reaction vessel H put into 1.1 parts of ethyl acetate, then by the product obtained in step 5.1 cooling be transferred to
In reaction vessel H, input sodium bicarbonate brine, salt and purified water stir after ten minutes, stratification；
Step 5.3：Adjusting PH to 4.0 after water phase is washed with ethyl acetate, addition EDTA, 0 activated carbon decolorizing, press filtration after decoloration,
The standings of PH to 2.0 are adjusted again keeps the temperature the Tazobactam Sodium acid crude for centrifuging moist after 1 hour, then after adjusting PH to 1.5；
Step 5.4：After being warming up to 70 DEG C after 0.14 part of purified water, 0.25 part of highly concentrated ethyl alcohol uniformly mixing, it will be made in step 5.3
It is standby to obtain dissolving after Tazobactam Sodium acid crude adds in；
Step 5.5：After being cooled to less than 0 DEG C, heat preservation centrifuges after 4 hours, is rinsed with ethyl alcohol, dries to obtain tazobactam.
Embodiment 8：
Step 5.1：Tazobactam Sodium 0.28 part and 0.8 part metacresol of diphenyl ester is put into reaction vessel G, it is quiet after being warming up to 80 DEG C
It puts 7 hours；
Step 5.2：Into reaction vessel H put into 1.1 parts of ethyl acetate, then by the product obtained in step 5.1 cooling be transferred to
In reaction vessel H, input sodium bicarbonate brine, salt and purified water stir after ten minutes, stratification；
Step 5.3：Adjusting PH to 4.0 after water phase is washed with ethyl acetate, addition EDTA, 0 activated carbon decolorizing, press filtration after decoloration,
The standings of PH to 2.0 are adjusted again and keep the temperature the Tazobactam Sodium acid crude for centrifuging moist after 1 hour, then after adjusting PH to 1.5, are used
10% hydrochloric acid is adjusted；
Step 5.4：After being warming up to 70 DEG C after 0.14 part of purified water, 0.28 part of highly concentrated ethyl alcohol uniformly mixing, it will be made in step 5.3
It is standby to obtain dissolving after Tazobactam Sodium acid crude adds in；
Step 5.5：After being cooled to less than 0 DEG C, heat preservation centrifuges after 4 hours, is rinsed with ethyl alcohol, dries to obtain tazobactam.
Measure the final product Tazobactam Sodium benzhydryl ester that is prepared in embodiment 1- embodiments 8, tazobactam
Degree of purity is simultaneously recorded in table 1, and following measurement result is to be averaged after repeatedly measuring.
Table 1：
His azoles bar is prepared into during the final product being prepared in embodiment 1- embodiments 4 is brought into embodiment 5- embodiments 8
Smooth acid, and the tazobactam being prepared is measured, it is recorded in table 2 by measurement standard and after results are averaged.
Table 2：
Claims (9)
1. a kind of preparation process of Tazobactam Sodium acid benzhydryl ester, which is characterized in that synthesis step is as follows：
Ring-opening reaction：
Chlorination reaction：
Condensation reaction：
Dual oxide reacts：
2. a kind of preparation process of Tazobactam Sodium acid benzhydryl ester, which is characterized in that include the following steps：
Step 1：Ring-opening reaction
Step 1.1：3.0-3.5 parts of part toluene, 0.2-0.4 parts of debrominate objects and 0.1-0.2 parts of MBT are put into reaction vessel A, are risen
Temperature to 70-75 DEG C react 80-100 minutes；
Step 1.2：After completion of the reaction, it is cooled to 58-75 DEG C；
Step 1.3：Product at reduced pressure in step 1.2 is concentrated to dryness, 2.3-2.5 parts of dichloromethane is added in and stirs to being completely dissolved
To supernatant liquid, ring-opening product dichloromethane solution is obtained；
Step 2：Chlorination reaction
Step 2.1：Ring-opening product dichloromethane solution in step 1.3, which is transferred to persistently to stir and cool down into reaction vessel B, to be made
The ring-opening product dichloromethane solution in reaction vessel B is obtained to 0-5 DEG C；
Step 2.2：A concentration of 31% 0.3-0.5 parts of hydrochloric acid solution is slowly added dropwise into reaction vessel B, dropping temperature is less than 0
℃；
Step 2.3：0.5-0.6 parts of the sodium nitrite solution of a concentration of 13-15% is added dropwise into reaction vessel B again, control is added dropwise
Temperature is 5-10 DEG C, and time for adding is 85-100 minutes；
Step 2.4：Reaction vessel B connections wherein substance is placed on after keeping the temperature 10-12 hours at 5-10 DEG C, reaction was completed；
Step 2.5：After centrifuge rejection filter, filtrate is transferred to stratification in another reaction vessel C, water layer is carried with dichloromethane
It takes, is washed repeatedly with water, sodium bicarbonate aqueous solution, purified water successively after merging organic layer；
Step 2.6：Organic layer after washing is transferred in reaction vessel D, is evaporated under reduced pressure to dry, after adding in 1.4-1.5 parts of acetone
It is spare to obtain chloride acetone soln；
Step 3：Condensation reaction
Step 3.1：It is persistently stirred during the chloride acetone soln being prepared in step 2.6 is transferred in reaction vessel E, then to
1,2,3- triazole of 0.4-0.5 parts of purified waters and 0.08-0.10 parts is wherein added in, controlled at 25-30 DEG C, control time is
12-15 hours；
Step 3.2：It is evaporated under reduced pressure after completion of the reaction to dry；
Step 3.3：It puts into 1.3-1.6 parts of dichloromethane and dissolves and obtain clear solution, taken several layers of purified water washes cleans
After be concentrated under reduced pressure into dry, obtain syrup object；
Step 3.4：It stirs after 0.3-0.4 parts of ethyl acetate of input 2.0 hours and is centrifuged to after crystallizing, control whipping temp is 25
DEG C, it is dried after centrifugation and obtains the condensation product with certain humidity；
Step 4：Dual oxide reacts
Step 4.1：It will be stirred to get in the condensation product tide product and dichloromethane that are prepared in step 3.4 input reaction vessel F
Clear solution；
Step 4.2：After being cooled to 10 DEG C, 30-35 DEG C is to slowly warm up to after putting into 0.06-0.07 parts of potassium permanganate, heat preservation 3-4 is small
When after reaction was completed；
Step 4.3：Vacuum distillation to a large amount of solids are precipitated, then put into 0.5-0.6 parts of ethyl acetate and break up solid, are cooled to 0-
After 5 DEG C, centrifuged after standing 1 hour, after ethyl acetate washes clean, drying.
3. a kind of preparation process of Tazobactam Sodium acid benzhydryl ester according to claim 1, it is characterised in that：It is adopted in reaction
Reaction process is monitored with HPLC；
It is monitored in step 1.1 using HPLC, stops step 1.1 when debrominate object is less than 1.0%；
It is monitored in step 2.3 using HPLC, stops reaction when ring-opening product is less than 0.5%.
4. a kind of preparation process of Tazobactam Sodium acid benzhydryl ester according to claim 3, it is characterised in that：Step 2.5
After middle centrifuge rejection filter, filter cake is washed with 0.2-0.25 parts of dichlorotoleune, after filtrate is merged with organic layer, uses water successively
Wash 2-3 times, 1.5% ammonium bicarbonate aqueous solution washs 2-3 time, purifies water washing.
5. a kind of preparation process of tazobactam, it is characterised in that：It is prepared by any one of claim 1-3 final
Product continues to be prepared, and synthesis step is as follows：
6. the preparation process of a kind of tazobactam according to claim 3, which is characterized in that include the following steps：
Step 5.1：0.2-0.3 parts of Tazobactam Sodium diphenyl ester and 0.5-0.9 parts of metacresols are put into reaction vessel G, are warming up to
7 hours are stood after 80 DEG C；
Step 5.2：1.0-1.2 parts of ethyl acetate are put into reaction vessel H, then the product obtained in step 5.1 cooling is turned
Enter into reaction vessel H, input sodium bicarbonate brine, salt and purified water stir after ten minutes, stratification；
Step 5.3：Adjusting PH to 4.0 after water phase is washed with ethyl acetate, addition EDTA, 0 activated carbon decolorizing, press filtration after decoloration,
The standings of PH to 2.0 are adjusted again keeps the temperature the Tazobactam Sodium acid crude for centrifuging moist after 1 hour, then after adjusting PH to 1.5；
Step 5.4：After being warming up to 70 DEG C after 0.13-0.15 parts of purified waters, 0.2-0.3 parts of highly concentrated ethyl alcohol uniformly mixing, it will walk
It is prepared after Tazobactam Sodium acid crude adds in and dissolves in rapid 5.3；
Step 5.5：After being cooled to less than 0 DEG C, heat preservation centrifuges after 4 hours, is rinsed with ethyl alcohol, dries to obtain tazobactam.
7. a kind of preparation process of tazobactam according to claim 6, it is characterised in that：Using a concentration of 10%
Hydrochloric acid solution adjusts PH.
8. the tazobactam in a kind of 1-4 as claim described in any one is used for the preparation of beta-lactamase inhibitor.
9. a kind of tazobactam as described in any one of claim 5-7, it is characterised in that：For beta-lactam inhibitor
Preparation.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810067248.8A CN108164550A (en) | 2018-01-23 | 2018-01-23 | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201810067248.8A CN108164550A (en) | 2018-01-23 | 2018-01-23 | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108164550A true CN108164550A (en) | 2018-06-15 |
Family
ID=62515882
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201810067248.8A Pending CN108164550A (en) | 2018-01-23 | 2018-01-23 | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108164550A (en) |
Cited By (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503628A (en) * | 2018-11-28 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of Tazobactam Sodium chiral isomer |
| CN110483498A (en) * | 2019-09-17 | 2019-11-22 | 河北科技大学 | A kind of preparation method of Tazobactam Sodium intermediate |
| CN110804066A (en) * | 2019-06-06 | 2020-02-18 | 联邦制药(内蒙古)有限公司 | Improved preparation method of desoxytazobactam diphenylmethyl ester |
| CN110804065A (en) * | 2019-06-06 | 2020-02-18 | 联邦制药(内蒙古)有限公司 | Method for preparing desoxytazobactam diphenylmethyl ester (M7) by using resin and new application of resin |
| CN111004231A (en) * | 2019-12-18 | 2020-04-14 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of tazobactam intermediate |
| CN111777624A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | A kind of preparation technology of tazobactam acid diphenylmethyl |
| CN111777623A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester and tazobactam acid |
| CN111909177A (en) * | 2020-08-18 | 2020-11-10 | 重庆西米瑞医药技术有限公司 | Tazobactam intermediate, preparation method thereof and method for preparing tazobactam by using intermediate |
| CN113209030A (en) * | 2021-04-27 | 2021-08-06 | 海南通用康力制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium sterile powder injection |
| CN113861222A (en) * | 2021-11-19 | 2021-12-31 | 山东安舜制药有限公司 | Method for synthesizing desoxytazobactam diphenylmethyl ester by adopting novel catalyst |
| CN115246844A (en) * | 2021-04-28 | 2022-10-28 | 苏州朗科生物技术股份有限公司 | Preparation method of tazobactam intermediate |
| CN116836181A (en) * | 2023-07-05 | 2023-10-03 | 山东安信制药有限公司 | Preparation method and control method of tazobactam impurity |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0018305A1 (en) * | 1979-03-26 | 1980-10-29 | Hoechst Uk Limited | Oxapenem derivatives, their preparation, their use, pharmaceutical compositions containing them, diverse initial compounds and their preparation |
| US4496484A (en) * | 1983-04-22 | 1985-01-29 | Taiho Pharmaceutical Company, Limited | Penicillin derivatives |
| JPH07121949B2 (en) * | 1986-12-03 | 1995-12-25 | 大鵬薬品工業株式会社 | 2β-N-Substituted triazolylmethylpenam derivative, its salt and its ester, and their production method |
| CN101048417A (en) * | 2004-10-28 | 2007-10-03 | 大塚化学株式会社 | Process for producing penam compound |
| CN102643292A (en) * | 2012-05-02 | 2012-08-22 | 齐鲁天和惠世制药有限公司 | Tazobactam synthesis method |
| CN105085544A (en) * | 2015-08-19 | 2015-11-25 | 齐鲁天和惠世制药有限公司 | Synthesis method of tazobactam diphenylmethyl ester |
-
2018
- 2018-01-23 CN CN201810067248.8A patent/CN108164550A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0018305A1 (en) * | 1979-03-26 | 1980-10-29 | Hoechst Uk Limited | Oxapenem derivatives, their preparation, their use, pharmaceutical compositions containing them, diverse initial compounds and their preparation |
| US4496484A (en) * | 1983-04-22 | 1985-01-29 | Taiho Pharmaceutical Company, Limited | Penicillin derivatives |
| JPH07121949B2 (en) * | 1986-12-03 | 1995-12-25 | 大鵬薬品工業株式会社 | 2β-N-Substituted triazolylmethylpenam derivative, its salt and its ester, and their production method |
| CN101048417A (en) * | 2004-10-28 | 2007-10-03 | 大塚化学株式会社 | Process for producing penam compound |
| CN102643292A (en) * | 2012-05-02 | 2012-08-22 | 齐鲁天和惠世制药有限公司 | Tazobactam synthesis method |
| CN105085544A (en) * | 2015-08-19 | 2015-11-25 | 齐鲁天和惠世制药有限公司 | Synthesis method of tazobactam diphenylmethyl ester |
Non-Patent Citations (1)
| Title |
|---|
| 胡月华，等: "他唑巴坦的合成新方法", 《安徽师范大学学报(自然科学版)》 * |
Cited By (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109503628A (en) * | 2018-11-28 | 2019-03-22 | 齐鲁天和惠世制药有限公司 | A kind of synthetic method of Tazobactam Sodium chiral isomer |
| CN109503628B (en) * | 2018-11-28 | 2020-07-03 | 山东安信制药有限公司 | Synthetic method of tazobactam chiral isomer |
| CN110804066A (en) * | 2019-06-06 | 2020-02-18 | 联邦制药(内蒙古)有限公司 | Improved preparation method of desoxytazobactam diphenylmethyl ester |
| CN110804065A (en) * | 2019-06-06 | 2020-02-18 | 联邦制药(内蒙古)有限公司 | Method for preparing desoxytazobactam diphenylmethyl ester (M7) by using resin and new application of resin |
| CN110483498B (en) * | 2019-09-17 | 2022-03-04 | 河北科技大学 | A kind of preparation method of tazobactam intermediate |
| CN110483498A (en) * | 2019-09-17 | 2019-11-22 | 河北科技大学 | A kind of preparation method of Tazobactam Sodium intermediate |
| CN111004231A (en) * | 2019-12-18 | 2020-04-14 | 凯莱英医药集团（天津）股份有限公司 | Continuous synthesis method of tazobactam intermediate |
| CN111777623A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester and tazobactam acid |
| CN111777624A (en) * | 2020-06-20 | 2020-10-16 | 常州红太阳药业有限公司 | A kind of preparation technology of tazobactam acid diphenylmethyl |
| CN111777623B (en) * | 2020-06-20 | 2023-03-14 | 常州红太阳药业有限公司 | Preparation process of tazobactam diphenylmethyl ester and tazobactam acid |
| CN111909177A (en) * | 2020-08-18 | 2020-11-10 | 重庆西米瑞医药技术有限公司 | Tazobactam intermediate, preparation method thereof and method for preparing tazobactam by using intermediate |
| CN111909177B (en) * | 2020-08-18 | 2021-09-24 | 重庆西米瑞医药技术有限公司 | Tazobactam intermediate, preparation method thereof and method for preparing tazobactam by using intermediate |
| CN113209030A (en) * | 2021-04-27 | 2021-08-06 | 海南通用康力制药有限公司 | Preparation method of piperacillin sodium and tazobactam sodium sterile powder injection |
| CN115246844A (en) * | 2021-04-28 | 2022-10-28 | 苏州朗科生物技术股份有限公司 | Preparation method of tazobactam intermediate |
| CN113861222A (en) * | 2021-11-19 | 2021-12-31 | 山东安舜制药有限公司 | Method for synthesizing desoxytazobactam diphenylmethyl ester by adopting novel catalyst |
| CN116836181A (en) * | 2023-07-05 | 2023-10-03 | 山东安信制药有限公司 | Preparation method and control method of tazobactam impurity |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108164550A (en) | A kind of tazobactam, Tazobactam Sodium benzhydryl ester preparation process and application | |
| CA1157862A (en) | Amine salts of clavulanic acids, its preparation and use | |
| EP0019345B1 (en) | Process for the preparation of a (d-alpha-amino-(p-hydroxyphenyl)-acetamido) group containing cephalosporanic acid derivatives | |
| CN105753867B (en) | A kind of preparation method of improved AVM hereinafter Batan sodium midbody compound | |
| CN101613359A (en) | Method for synthesizing cefuroxime sodium | |
| CN105399754B (en) | A kind of preparation method of Cefamandole Nafate | |
| CN105017286B (en) | A kind of preparation method of cephalo-type anti-infectives | |
| CN108623618B (en) | A kind of synthetic method of cefminox sodium | |
| CN102234313B (en) | Method for synthesizing pidotimod | |
| CN110003238A (en) | A kind of preparation method of cefotiam | |
| CN105859747B (en) | A kind of preparation method of cefepime Hydrochloride suitable for industrialized production | |
| CN103497203B (en) | The synthetic method of a kind of 2 β-azido-methyl-2 Alpha-Methyl penam-3 α-diphenylmethyl carboxylate | |
| CS215119B2 (en) | Method of making the benzothiazolyldisulphide | |
| CN106222230A (en) | A kind of method of green enzymatic clarification cefaclor | |
| CN102391288B (en) | Preparation methods of cefpirome intermediate and cefpirome | |
| CN104230956B (en) | A kind of preparation method of cefoxitin | |
| EP0053077A2 (en) | Salts of 7-aminocephalosporanic acids, soluble in organic solvents and their use in the preparation of cephalosporins | |
| JPH072750B2 (en) | Process for producing 6-D-α- (4-ethyl-2,3-dioxo-1-piperazinocarbonylamino) -phenylacetamide-penicillanic acid | |
| CN100519564C (en) | Cefradine preparing process | |
| CN114805393A (en) | A kind of preparation method of cefprozil | |
| CN110283187A (en) | A kind of preparation method promoting Cefotaxime Sodium product quality | |
| CN106749410B (en) | A kind of preparation method of Ceftaroline Fosamil in high yield | |
| CN113185538B (en) | Preparation method of cefpodoxime acid | |
| US3985738A (en) | 7-(D-.alpha.-Hydroxy-2-arylacetamido)-3-(tetrazolo-[4,5-b]pyridazin-6-ylthiomethyl)-3-cephem-4-carboxylic acids | |
| JPS63211289A (en) | Intermediates for producing sultamicillin and congeners |
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 | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20180615 |