CN115197241B - Preparation method of 6, 6-dibromopenicillanic acid - Google Patents
Preparation method of 6, 6-dibromopenicillanic acid Download PDFInfo
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- CN115197241B CN115197241B CN202110378040.XA CN202110378040A CN115197241B CN 115197241 B CN115197241 B CN 115197241B CN 202110378040 A CN202110378040 A CN 202110378040A CN 115197241 B CN115197241 B CN 115197241B
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- OSORMYZMWHVFOZ-UHFFFAOYSA-N phenethyl benzoate Chemical compound C=1C=CC=CC=1C(=O)OCCC1=CC=CC=C1 OSORMYZMWHVFOZ-UHFFFAOYSA-N 0.000 title claims abstract description 23
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 61
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 42
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims abstract description 36
- 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 claims abstract description 29
- NGHVIOIJCVXTGV-UHFFFAOYSA-N 6beta-amino-penicillanic acid Natural products OC(=O)C1C(C)(C)SC2C(N)C(=O)N21 NGHVIOIJCVXTGV-UHFFFAOYSA-N 0.000 claims abstract description 29
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 28
- WKBOTKDWSSQWDR-UHFFFAOYSA-N Bromine atom Chemical compound [Br] WKBOTKDWSSQWDR-UHFFFAOYSA-N 0.000 claims abstract description 27
- GDTBXPJZTBHREO-UHFFFAOYSA-N bromine Substances BrBr GDTBXPJZTBHREO-UHFFFAOYSA-N 0.000 claims abstract description 27
- 229910052794 bromium Inorganic materials 0.000 claims abstract description 27
- 235000010288 sodium nitrite Nutrition 0.000 claims abstract description 18
- 238000000034 method Methods 0.000 claims abstract description 17
- 239000002904 solvent Substances 0.000 claims abstract description 8
- 239000000243 solution Substances 0.000 claims description 15
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 12
- 239000003960 organic solvent Substances 0.000 claims description 11
- 238000003756 stirring Methods 0.000 claims description 11
- DWAQJAXMDSEUJJ-UHFFFAOYSA-M Sodium bisulfite Chemical compound [Na+].OS([O-])=O DWAQJAXMDSEUJJ-UHFFFAOYSA-M 0.000 claims description 10
- 235000010267 sodium hydrogen sulphite Nutrition 0.000 claims description 10
- 239000007864 aqueous solution Substances 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 8
- 230000008569 process Effects 0.000 claims description 6
- 238000010791 quenching Methods 0.000 claims description 2
- 239000004289 sodium hydrogen sulphite Substances 0.000 claims description 2
- 239000002253 acid Substances 0.000 abstract description 14
- 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 abstract description 6
- NKZMPZCWBSWAOX-IBTYICNHSA-M Sulbactam sodium Chemical compound [Na+].O=S1(=O)C(C)(C)[C@H](C([O-])=O)N2C(=O)C[C@H]21 NKZMPZCWBSWAOX-IBTYICNHSA-M 0.000 abstract description 6
- 229960000614 sulbactam sodium Drugs 0.000 abstract description 6
- 229960000373 tazobactam sodium Drugs 0.000 abstract description 6
- 239000006227 byproduct Substances 0.000 abstract description 5
- 238000007142 ring opening reaction Methods 0.000 abstract description 5
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 239000002699 waste material Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 3
- 150000003952 β-lactams Chemical class 0.000 abstract description 2
- 239000000047 product Substances 0.000 description 17
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 10
- 239000012074 organic phase Substances 0.000 description 10
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 7
- BMYNFMYTOJXKLE-UHFFFAOYSA-N 3-azaniumyl-2-hydroxypropanoate Chemical compound NCC(O)C(O)=O BMYNFMYTOJXKLE-UHFFFAOYSA-N 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 239000012071 phase Substances 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 4
- 239000000706 filtrate Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 239000012445 acidic reagent Substances 0.000 description 3
- 125000003460 beta-lactamyl group Chemical group 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000009471 action Effects 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 238000006193 diazotization reaction Methods 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 238000011065 in-situ storage Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000003781 beta lactamase inhibitor Substances 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 229940126813 beta-lactamase inhibitor Drugs 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 239000007810 chemical reaction solvent Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 125000000950 dibromo group Chemical group Br* 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 238000011010 flushing procedure Methods 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- YTJSFYQNRXLOIC-UHFFFAOYSA-N octadecylsilane Chemical compound CCCCCCCCCCCCCCCCCC[SiH3] YTJSFYQNRXLOIC-UHFFFAOYSA-N 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 229960005256 sulbactam Drugs 0.000 description 1
- 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 1
- 238000001308 synthesis method Methods 0.000 description 1
- 229960003865 tazobactam Drugs 0.000 description 1
- 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 description 1
- 230000002485 urinary effect Effects 0.000 description 1
- 229940126085 β‑Lactamase Inhibitor 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
- C07D499/04—Preparation
- C07D499/10—Modification of an amino radical directly attached in position 6
-
- 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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 6, 6-dibromopenicillanic acid. The preparation method of the application takes water and ethyl acetate as solvents, and bromine, sodium nitrite and 6-APA are added for reaction to obtain 6, 6-dibromopenicillanic acid. The preparation method can reduce the occurrence of the ring-opening reaction of the beta-lactam in the reaction, thereby reducing the amount of byproducts and improving the yield of the reaction. On the other hand, strong acid is not used in the preparation method, so that the raw material cost can be reduced, the emission of three wastes is reduced, and the preparation method is more environment-friendly. The method has good application prospect in the synthesis of sulbactam sodium and tazobactam sodium.
Description
Technical Field
The application belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 6, 6-dibromopenicillanic acid.
Background
Sulbactam sodium and tazobactam sodium are commonly used together with penicillin and cephalosporin medicines, so that the sulbactam sodium and tazobactam sodium are prevented from being damaged by beta-lactamase, the antibacterial activity is enhanced, and the sulbactam sodium and tazobactam sodium are suitable for infections of respiratory systems, urinary systems and the like. The 6, 6-dibromo penicillanic acid is a key intermediate in the synthesis process of beta-lactamase inhibitor sulbactam and tazobactam, and is prepared by taking 6-APA as a starting material through a dibromo reaction. The reaction formula of the preparation process is as follows:
in the existing preparation process, the reaction needs to be carried out under the condition of strong acid. Therefore, in most literature reports, the conditions of this reaction require the addition of strong acids such as sulfuric acid or hydrobromic acid, for example: the patent applications WO03087105A1, CN106699774A, CN109705142A, CN109438475A and CN111808122A are added with sulfuric acid as diazotizing reaction reagent or solvent; WO2004039776A2, CN104262359A and CN104910184A all use hydrobromic acid as a reactant; the rest of the published literature or patents are also partly modified on the basis of this.
However, the chemical structure of 6-APA contains a β -lactam ring, which is unstable under strong acid conditions and is prone to ring opening, yielding a by-product of β -lactam ring opening. Although the reaction yields are reported in the literature to be relatively high, the products necessarily contain a large amount of by-products of the beta-lactam ring opening. The existing technology generally directly puts the above products into the next reaction without purification, which can adversely affect the total synthetic yield of sulbactam sodium and tazobactam sodium. On the other hand, the amount of waste acid generated by the reaction is large, so that the environment is protected, the cost is greatly increased, and the commercial production is not facilitated.
Disclosure of Invention
Aiming at the defects of the prior art, the application provides a preparation method of 6, 6-dibromopenicillanic acid, which aims at: the synthesis of the 6, 6-dibromo penicillanic acid is realized by optimizing the solvent and the process condition under the condition of not adding any strong acid reagent or solvent.
A preparation method of 6, 6-dibromopenicillanic acid takes water and an organic solvent as solvents, bromine, sodium nitrite and 6-APA are added for reaction, and then the 6, 6-dibromopenicillanic acid is obtained.
6-APA means 6-aminopenicillanic acid. The preparation method of 6, 6-dibromo penicillanic acid directly uses water and an organic solvent as reaction solvents, does not add strong acid, utilizes bromine, water and a substrate to generate hydrobromic acid in situ, and carries out diazotization reaction under the action of sodium nitrite. Preferably, the organic solvent is selected from ethyl acetate or dichloromethane, and/or the ratio of the amount of the 6-APA, water and the organic solvent is 1g (0.8-1.2) ml (6-10) ml, and/or the ratio of the amount of the 6-APA, bromine and sodium nitrite is 1 (2-4): 0.8-1.2.
Preferably, the dosage ratio of the 6-APA, the water and the organic solvent is 1g to 1ml to 6ml, and/or the dosage ratio of the 6-APA, the bromine and the sodium nitrite is 1 to 3 to 1.05.
Preferably, the reaction temperature of the reaction is 0-10 ℃.
Preferably, the reaction temperature of the reaction is 0-5 ℃.
Preferably, the method specifically comprises the following steps:
(1) Taking water and an organic solvent as solvents, adding bromine and sodium nitrite, then adding 6-APA in batches, and continuing the reaction;
(2) And adding sodium bisulphite solution to quench after the reaction is finished, and separating to obtain a 6, 6-dibromopenicillanic acid product.
Preferably, in step (1), the time for continuing the reaction is from 0.5 to 3 hours, preferably 1 hour.
Preferably, in the step (1), the batch mode is that 6-APA is divided into 8-12 parts and added every 3-10 minutes; preferably, the components are divided into 10 parts, and the components are added every 5 minutes; the exothermic heat of the reaction is obvious after the 6-APA is fed, and the batch feeding can prevent the flushing;
and/or, the process of adding reagents and continuing the reaction is performed under stirring.
Preferably, in step (2), the sodium bisulfite solution is 10-50wt.% aqueous solution, preferably 30wt.% aqueous solution, and/or the equivalent ratio of the bromine to sodium bisulfite solution is 1 (0.5-1.0), preferably 1:0.8.
The application also comprises the 6, 6-dibromopenicillanic acid prepared by the preparation method. The purity of the 6, 6-dibromo penicillanic acid prepared by the method is higher.
According to the technical scheme, hydrobromic acid is generated in situ by utilizing bromine, water and a substrate under the condition of omitting strong acid, diazotization reaction is carried out under the action of sodium nitrite, and the occurrence of beta-lactam ring-opening reaction in the reaction can be reduced, so that the amount of byproducts is reduced, and the reaction yield is improved. Experiments prove that after the method omits strong acid, the yield and purity of the product are slightly higher than those of the process of adding strong acid, and the method can completely replace the existing synthesis method of adding strong acid.
On the other hand, the application does not use strong acid, can reduce the cost of raw materials, can greatly improve economic benefit, can reduce the emission of three wastes, and is more environment-friendly.
It should be apparent that, in light of the foregoing, various modifications, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
The above-described aspects of the present application will be described in further detail below with reference to specific embodiments in the form of examples. It should not be understood that the scope of the above subject matter of the present application is limited to the following examples only. All techniques implemented based on the above description of the application are within the scope of the application.
Drawings
FIG. 1 is a chromatogram of the product of example 1;
FIG. 2 is a chromatogram of the product of example 2;
FIG. 3 is a chromatogram of the product of example 3;
FIG. 4 is a chromatogram of the product of example 4;
FIG. 5 is a chromatogram of the product of comparative example 1;
FIG. 6 is a chromatogram of the product of comparative example 2.
Detailed Description
The reagents used in the following examples and comparative examples were as follows:
6-APA: inner Mongolia is a very popular pharmaceutical Co.Ltd;
ethyl acetate: city chemical Co., ltd;
bromine: city chemical Co., ltd;
sodium nitrite: city chemical Co., ltd;
NaHSO 3 : city chemical Co., ltd;
sodium chloride: city chemical Co., ltd;
anhydrous sodium sulfate: city chemical Co., ltd;
n-hexane: city chemical Co., ltd;
hydrobromic acid: city chemical Co., ltd;
sulfuric acid: chemicals Inc. of Goldmountain chemical Co., chengdu City.
In the following examples and comparative examples, the yield was calculated as:
yield = actual yield/theoretical yield x 100%
The purity detection method is high performance liquid chromatography detection, and the chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filler; mobile phase A is 5.44g/L potassium dihydrogen phosphate solution (pH value is adjusted to 4.0 by 1mol/L phosphoric acid solution), mobile phase B is acetonitrile, and linear gradient elution is carried out according to the following table; the detection wavelength is 215nm; the sample volume was 20. Mu.l, the column temperature was 40℃and the flow rate was 1.0ml per minute.
| Time (minutes) | Mobile phase A% | Mobile phase B% |
| 0 | 98 | 2 |
| 7.5 | 50 | 50 |
| 8.5 | 50 | 50 |
| 9 | 98 | 2 |
| 13 | 98 | 2 |
Example 1
20ml of water is added into a reaction bottle, 120ml of ethyl acetate, 44g of bromine and 6.7g of sodium nitrite are added into the reaction bottle in sequence under stirring, the reaction bottle is cooled to 0 ℃, 20g of 6-APA is added into the reaction bottle in batches at the temperature, and the reaction is carried out for 1h at the temperature after the addition. After the reaction, the residual bromine is quenched by dropwise adding 30% NaHSO3 water solution, separating the solution, extracting the water phase once again by using 100ml of ethyl acetate, merging the organic phases, washing the organic phases with water and saturated sodium chloride once respectively, drying the organic phases by using anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, adding 100ml of n-hexane, stirring and washing the filtrate to obtain 27g of 6, 6-dibromopenicillanic acid, wherein the yield is 81%, and the purity is 95.3%. The chromatogram of the obtained product is shown in FIG. 1.
Example 2
20ml of water is added into a reaction bottle, 120ml of dichloromethane, 44g of bromine and 6.7g of sodium nitrite are added into the reaction bottle in sequence under stirring, the reaction bottle is cooled to 0 ℃, 20g of 6-APA is added into the reaction bottle in batches at the temperature, and the reaction is carried out for 1h at the temperature after the addition. After the reaction, the residual bromine is quenched by dropwise adding 30% NaHSO3 water solution, separating the solution, extracting the water phase once again by using 100ml of dichloromethane, combining the organic phases, washing the organic phases once by using water and saturated sodium chloride respectively, drying the organic phases by using anhydrous sodium sulfate, filtering, concentrating the filtrate to dryness, adding 100ml of n-hexane, stirring and washing the filtrate to obtain 26g of 6, 6-dibromopenicillanic acid, wherein the yield is 78%, and the purity is 94.7%. The chromatogram of the resulting product is shown in figure 2.
Example 3
20ml of water is added into a reaction bottle, 120ml of ethyl acetate, 59g of bromine and 6.7g of sodium nitrite are added into the reaction bottle in sequence under stirring, the reaction bottle is cooled to 0 ℃, 20g of 6-APA is added into the reaction bottle in batches at the temperature, and the reaction is carried out for 1h at the temperature after the addition. After the reaction, 30% NaHSO was added dropwise 3 The residual bromine is quenched by aqueous solution, separated, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, washed once by water and saturated sodium chloride respectively, dried by anhydrous sodium sulfate, filtered, concentrated to dryness, added with 100ml of normal hexane and stirred for washing, filtered to obtain 25g of 6, 6-dibromopenicillanic acid, the yield is 76%, and the purity is 92.5%. The chromatogram of the resulting product is shown in FIG. 3.
Example 4
20ml of water is added into a reaction bottle, 120ml of ethyl acetate, 44g of bromine and 7.1g of sodium nitrite are added into the reaction bottle in sequence under stirring, the reaction bottle is cooled to 0 ℃, 20g of 6-APA is added into the reaction bottle in batches at the temperature, and the reaction is carried out for 1h at the temperature after the addition. After the reaction, 30% NaHSO was added dropwise 3 The residual bromine is quenched by aqueous solution, separated, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, washed once by water and saturated sodium chloride respectively, dried by anhydrous sodium sulfate, filtered, concentrated to dryness, added with 100ml of normal hexane for stirring and washing, and filtered to obtain 24g of 6, 6-dibromopenicillanic acid with the yield of 72 percent and the purity of 93.0 percent. The chromatogram of the resulting product is shown in FIG. 4.
Comparative example 1 use of hydrobromic acid as diazotising agent
20ml of water was added to the reaction flask, and 48% of hydrogen bromide was added sequentially with stirring20ml of acid, 120ml of ethyl acetate, 44g of bromine, 6.7g of sodium nitrite, cooling to 0 ℃, adding 20g of 6-APA in batches at the temperature, and reacting for 1h at the temperature. After the reaction, 30% NaHSO was added dropwise 3 The residual bromine is quenched by aqueous solution, separated, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, washed once by water and saturated sodium chloride respectively, dried by anhydrous sodium sulfate, filtered, concentrated to dryness, added with 100ml of normal hexane for stirring and washing, and filtered to obtain 24g of 6, 6-dibromopenicillanic acid with the yield of 72 percent and the purity of 90.3 percent. The chromatogram of the resulting product is shown in FIG. 5.
Comparative example 2 use sulfuric acid as diazotizing agent
20ml of water, 20ml of 2.5N sulfuric acid, 120ml of ethyl acetate, 44g of bromine and 6.7g of sodium nitrite are added into a reaction bottle in sequence under stirring, the mixture is cooled to 0 ℃, 20g of 6-APA is added in batches at the temperature, and the mixture is reacted for 1h at the temperature. After the reaction, 30% NaHSO was added dropwise 3 The residual bromine is quenched by aqueous solution, separated, the aqueous phase is extracted once by 100ml of ethyl acetate, the organic phases are combined, washed once by water and saturated sodium chloride respectively, dried by anhydrous sodium sulfate, filtered, concentrated to dryness, added with 100ml of normal hexane and stirred for washing, and filtered to obtain 23g of 6, 6-dibromopenicillanic acid with the yield of 70 percent and the purity of 91.4 percent. The chromatogram of the resulting product is shown in FIG. 6.
The experimental examples and examples show that the yield of the preparation process is 81%, the purity of the product is 95.3%, and the application requirements of the practical production of sulbactam sodium and tazobactam sodium can be met. After the strong acid reagent is added in the process, the yield and purity are reduced, and the application can reduce the generation of byproducts under the condition of not adding strong acid. In addition, the raw material cost can be effectively reduced without using strong acid reagent, and the emission of waste acid is reduced. Therefore, the application has good application prospect in industry.
Claims (10)
1. A preparation method of 6, 6-dibromopenicillanic acid is characterized by comprising the following steps: taking water and an organic solvent as solvents, adding bromine, sodium nitrite and 6-APA for reaction, and obtaining 6, 6-dibromopenicillanic acid;
the method specifically comprises the following steps:
(1) Taking water and an organic solvent as solvents, adding bromine and sodium nitrite, then adding 6-APA in batches, and continuing the reaction;
(2) Adding sodium bisulphite solution to quench after the reaction is completed, and separating to obtain a 6, 6-dibromopenicillanic acid product;
the organic solvent is selected from ethyl acetate or dichloromethane, the dosage ratio of the 6-APA, water and the organic solvent is 1g (0.8-1.2) ml (6-10) ml, and the dosage ratio of the 6-APA, bromine and sodium nitrite is 1 (2-4) in molar ratio (0.8-1.2).
2. The method of manufacturing according to claim 1, wherein: the dosage ratio of the 6-APA, the water and the organic solvent is 1g to 1ml to 6ml, and/or the dosage ratio of the 6-APA, the bromine and the sodium nitrite is 1 to 3 to 1.05.
3. The method of manufacturing according to claim 1, wherein: the reaction temperature of the reaction is 0-10 ℃.
4. A method of preparation according to claim 3, characterized in that: the reaction temperature of the reaction is 0-5 ℃.
5. The method of manufacturing according to claim 1, wherein: in the step (1), the time for continuing the reaction is 0.5-3h.
6. The method of manufacture of claim 5, wherein: in the step (1), the time for continuing the reaction is 1h.
7. The method of manufacturing according to claim 1, wherein: in the step (1), the batch mode is that 6-APA is divided into 8-12 parts uniformly and added every 3-10 minutes; and/or, the process of adding 6-APA and continuing the reaction is carried out under stirring.
8. The method of preparing as claimed in claim 7, wherein: in step (1), the batch mode is to divide the 6-APA equally into 10 parts and add every 5 minutes.
9. The method of manufacturing according to claim 1, wherein: in the step (2), the sodium bisulfite solution is 10-50wt.% of an aqueous solution, and/or the equivalent ratio of the bromine solution to the sodium bisulfite solution is 1 (0.5-1.0).
10. The method of preparing as claimed in claim 9, wherein: in step (2), the sodium bisulfite solution is a 30wt.% aqueous solution, and/or the equivalent ratio of the bromine to sodium bisulfite solution is 1:0.8.
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| GB2042520A (en) * | 1979-01-10 | 1980-09-24 | Schering Corp | 2-penem compounds and a method for preparing them |
| CN104262359A (en) * | 2014-09-29 | 2015-01-07 | 江西富祥药业股份有限公司 | Synthetic method of salbactam acid |
| CN109160919A (en) * | 2017-07-28 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/10 water sulbactam sodium compound of one kind and its drug combination preparation |
| CN111808122A (en) * | 2020-07-20 | 2020-10-23 | 青岛科技大学 | Method for synthesizing sulbactam acid |
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- 2021-04-08 CN CN202110378040.XA patent/CN115197241B/en active Active
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|---|---|---|---|---|
| GB2042520A (en) * | 1979-01-10 | 1980-09-24 | Schering Corp | 2-penem compounds and a method for preparing them |
| CN104262359A (en) * | 2014-09-29 | 2015-01-07 | 江西富祥药业股份有限公司 | Synthetic method of salbactam acid |
| CN109160919A (en) * | 2017-07-28 | 2019-01-08 | 海南美兰史克制药有限公司 | 1/10 water sulbactam sodium compound of one kind and its drug combination preparation |
| CN111808122A (en) * | 2020-07-20 | 2020-10-23 | 青岛科技大学 | Method for synthesizing sulbactam acid |
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