CN117417369A - Preparation method of penem intermediate 4-BMA - Google Patents
Preparation method of penem intermediate 4-BMA Download PDFInfo
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- CN117417369A CN117417369A CN202311360488.4A CN202311360488A CN117417369A CN 117417369 A CN117417369 A CN 117417369A CN 202311360488 A CN202311360488 A CN 202311360488A CN 117417369 A CN117417369 A CN 117417369A
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- NNANGMFTFSNDLW-GWOFURMSSA-N (2r)-2-[(2s,3s)-3-[(1r)-1-[tert-butyl(dimethyl)silyl]oxyethyl]-4-oxoazetidin-2-yl]propanoic acid Chemical compound CC(C)(C)[Si](C)(C)O[C@H](C)[C@@H]1[C@@H]([C@@H](C)C(O)=O)NC1=O NNANGMFTFSNDLW-GWOFURMSSA-N 0.000 title claims abstract description 21
- HHXMXAQDOUCLDN-RXMQYKEDSA-N penem Chemical compound S1C=CN2C(=O)C[C@H]21 HHXMXAQDOUCLDN-RXMQYKEDSA-N 0.000 title claims abstract description 19
- 238000002360 preparation method Methods 0.000 title claims abstract description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 84
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 34
- 238000006243 chemical reaction Methods 0.000 claims abstract description 23
- 229940080818 propionamide Drugs 0.000 claims abstract description 19
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000006460 hydrolysis reaction Methods 0.000 claims abstract description 9
- 230000007062 hydrolysis Effects 0.000 claims abstract description 6
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 42
- 239000000243 solution Substances 0.000 claims description 38
- WYURNTSHIVDZCO-UHFFFAOYSA-N tetrahydrofuran Substances C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 38
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 33
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 21
- 239000012074 organic phase Substances 0.000 claims description 20
- SUBJHSREKVAVAR-UHFFFAOYSA-N sodium;methanol;methanolate Chemical compound [Na+].OC.[O-]C SUBJHSREKVAVAR-UHFFFAOYSA-N 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 17
- 239000000706 filtrate Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 12
- 239000012071 phase Substances 0.000 claims description 11
- 239000012065 filter cake Substances 0.000 claims description 10
- 238000000967 suction filtration Methods 0.000 claims description 10
- 238000003756 stirring Methods 0.000 claims description 9
- 238000001816 cooling Methods 0.000 claims description 8
- 239000008346 aqueous phase Substances 0.000 claims description 7
- 239000011259 mixed solution Substances 0.000 claims description 7
- 239000011734 sodium Substances 0.000 claims description 7
- 229920002472 Starch Polymers 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 5
- 239000007791 liquid phase Substances 0.000 claims description 5
- 235000019698 starch Nutrition 0.000 claims description 5
- 239000008107 starch Substances 0.000 claims description 5
- 238000001291 vacuum drying Methods 0.000 claims description 5
- 238000005406 washing Methods 0.000 claims description 5
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 230000004913 activation Effects 0.000 claims description 4
- 238000004821 distillation Methods 0.000 claims description 4
- 230000001105 regulatory effect Effects 0.000 claims description 4
- 230000003213 activating effect Effects 0.000 claims description 2
- 238000001704 evaporation Methods 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 238000010791 quenching Methods 0.000 claims description 2
- 230000000171 quenching effect Effects 0.000 claims description 2
- 239000000376 reactant Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims 1
- 239000002904 solvent Substances 0.000 abstract description 4
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 239000007810 chemical reaction solvent Substances 0.000 abstract description 2
- 238000009833 condensation Methods 0.000 abstract description 2
- 230000005494 condensation Effects 0.000 abstract description 2
- 230000009257 reactivity Effects 0.000 abstract description 2
- 239000000126 substance Substances 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 6
- 239000003814 drug Substances 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010348 incorporation Methods 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 239000012266 salt solution Substances 0.000 description 3
- 229910052708 sodium Inorganic materials 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 239000012467 final product Substances 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- OEYMQQDJCUHKQS-UHFFFAOYSA-N (4-oxoazetidin-2-yl) acetate Chemical compound CC(=O)OC1CC(=O)N1 OEYMQQDJCUHKQS-UHFFFAOYSA-N 0.000 description 1
- 101710088194 Dehydrogenase Proteins 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 1
- CBENFWSGALASAD-UHFFFAOYSA-N Ozone Chemical compound [O-][O+]=O CBENFWSGALASAD-UHFFFAOYSA-N 0.000 description 1
- 102000035195 Peptidases Human genes 0.000 description 1
- 108091005804 Peptidases Proteins 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003782 beta lactam antibiotic agent Substances 0.000 description 1
- YZBQHRLRFGPBSL-RXMQYKEDSA-N carbapenem Chemical compound C1C=CN2C(=O)C[C@H]21 YZBQHRLRFGPBSL-RXMQYKEDSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- HPGPEWYJWRWDTP-UHFFFAOYSA-N lithium peroxide Chemical compound [Li+].[Li+].[O-][O-] HPGPEWYJWRWDTP-UHFFFAOYSA-N 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 150000002961 penems Chemical class 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 235000019833 protease Nutrition 0.000 description 1
- 230000036632 reaction speed Effects 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000008096 xylene 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
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
- C07F7/02—Silicon compounds
- C07F7/08—Compounds having one or more C—Si linkages
- C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
- C07F7/1804—Compounds having Si-O-C linkages
- C07F7/1872—Preparation; Treatments not provided for in C07F7/20
- C07F7/1892—Preparation; Treatments not provided for in C07F7/20 by reactions not provided for in C07F7/1876 - C07F7/1888
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the field of chemical intermediate synthesis, in particular to a preparation method of a penem intermediate 4-BMA, which comprises the following steps: (1) Preparing (R) -2- ((2R, 3 s) -3- ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -N- ((R) -1-phenethyl) -N-p-toluenesulfonyl propionamide; (2) hydrolysis to produce 4BMA. The zinc powder is activated by acetic acid for condensation, so that the reactivity of the zinc powder is improved; the hydrolysis reaction selects methanol as a reaction solvent, and the homogeneous reaction is carried out, so that the reaction rate is high; has high yield and purity; the solvent is easy to recycle, the safety is high, and the influence on the environment is small.
Description
Technical Field
The invention relates to the field of chemical intermediate synthesis, in particular to a preparation method of a penem intermediate 4-BMA.
Background
Carbapenem antibiotics (i.e., penems) are novel β -lactam antibiotics, which are known for their broad antimicrobial spectrum and potent antimicrobial activity. The key intermediate used for synthesizing the main ring of the penem medicine is beta-methylazetidin-2-one (4-BMA for short). The introduction of the methyl at the C-1 beta position of the 4-BMA greatly improves the stability of the final product penem drugs to the renal dehydrogenase peptidase (DHP-I), and does not need to be combined with a DHP-I inhibitor, and meanwhile, the antibacterial activity of the final product penem drugs is not influenced. The intermediate 4-BMA is synthesized by the intermediate 4-acetoxyazetidinone (4 AA for short), and then the C-1 beta methyl structure is introduced through the intermediate 4-BMA, so that the method is the most effective and feasible method for synthesizing the penem medicines.
There are various methods for synthesizing 4-BMA, such as: in the patent with publication number of CN106397473B, under the condition that aprotic solvent is one or more of tetrahydrofuran, ethyl acetate, isopropyl ether, benzene, toluene, xylene, chlorobenzene, N-dimethylformamide and dimethyl sulfoxide, hydrogen peroxide is used for hydrolysis reaction under alkaline condition to obtain 4-BMA; patent publication No. CN101973915A, hydrogen peroxide is oxidized in tetrahydrofuran solution under alkaline conditions, which are aqueous solutions of lithium hydroxide, sodium hydroxide or lithium hydroxide/hydrogen peroxide; the patent with publication number CN109970784A uses ozone to perform oxidation reaction; in the patent publication No. CN102491992A, the solvent is ethyl acetate, tetrahydrofuran, toluene or diethyl ether, and hydrogen peroxide is used for oxidation under alkaline condition, and the alkali used under alkaline condition is potassium hydroxide, lithium hydroxide or lithium peroxide, preferably lithium hydroxide. The method has the defects of heterogeneous reaction at different degrees, low reaction speed, low production yield, difficult solvent recovery, high risk, large influence on environment and the like.
Disclosure of Invention
In order to overcome the defects in the prior art, the invention provides a preparation method of a penem intermediate 4-BMA, which comprises the following steps:
(1) Preparation of (R) -2- ((2R, 3S) -3- ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -N- ((R) -1-phenethyl) -N-p-toluenesulfonyl propionamide
Zinc powder is put into THF, acetic acid is added for activation, and then 4AA is added; dropwise adding a mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and THF; after the dripping is finished, 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide is controlled in a liquid phase until the reaction is complete; suction filtration, washing a filter cake with THF, and merging filtrate; adding a saline solution, stirring, and then dropwise adding the hydrochloric acid solution to adjust the pH; standing and layering, and leaving an organic phase; concentrating the organic phase under reduced pressure until no fraction flows out; adding methanol for distillation and concentration until no fraction flows out, and adding methanol for later use;
(2) Hydrolysis to prepare 4BMA
Dropwise adding hydrogen peroxide into the organic phase in the step (1), and then dropwise adding sodium methoxide methanol solution; keeping the temperature after dripping; adding Na 2 SO 3 Quenching the solution until the KI starch test paper does not change blue, and regulating the pH value by using a sodium methoxide methanol solution; suction filtration, methanol leaching of filter cakes and filtrate collection; transferring the water phase into a reaction vessel, and evaporating methanol under reduced pressure; extracting with ethyl acetate, stirring, and separating; the pH of the aqueous phase was adjusted by dropwise addition of hydrochloride water, incubated, filtered to give white crystals of 4BMA and dried in vacuo.
Further, the temperature for activating the zinc powder by acetic acid in the step (1) is 30-35 ℃ and the activation time is 0.5h.
Further, the mass ratio of the zinc powder in the step (1) to the acetic acid is (10-20): 1.
Further, the temperature is controlled to be 5-10 ℃ when the mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and THF is added dropwise in the step (1).
Further, the mass ratio of the 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide to 4AA in the step (1) is (1.8-2.0): 1.
Further, adding a saline solution in the step (1), and stirring for 15min; the aqueous phase was added dropwise to a pH of 6.0 with 4N hydrochloric acid solution.
Further, the organic phase in the step (1) is subjected to reduced pressure distillation and concentration at the temperature of less than or equal to 35 ℃; distilling and adding 5 times of 4-AA into the methanol; and finally, adding methanol, wherein the mass of the reactant is 10 times of that of 4-AA.
Further, the mass ratio of the organic phase to the hydrogen peroxide in the step (2) is (7.5-5): 1; the hydrogen peroxide is hydrogen peroxide with the mass concentration of 30%; the temperature is controlled at-10-0 ℃ when hydrogen peroxide is added dropwise, and the dropwise adding time is 0.5h; the mass ratio of the sodium methoxide methanol solution to the hydrogen peroxide is (2-1) 1, and the mass concentration of the sodium methoxide methanol solution is 25% -29%; the temperature of the sodium methoxide methanol solution is controlled to be 0-5 ℃, the dripping time is 0.5h, and the temperature is maintained for 0.5-1h after dripping.
Further, the step (2) Na 2 SO 3 The mass concentration of the solution is 17%; regulating the pH value to 10-12 by using sodium methoxide methanol solution; the temperature is less than or equal to 35 ℃ when the water phase is decompressed and distilled to remove the methanol.
Further, the extraction temperature of the ethyl acetate in the step (2) is 5-15 ℃; adding ethyl acetate with the volume 4 times of the mass of the hydrogen peroxide; dropwise adding 4N hydrochloride water into the water phase at 3-8 ℃ to adjust the pH to 0.5-1, cooling to 0-5 ℃ and preserving heat for 1h; the vacuum drying temperature is lower than 40 ℃.
The reaction equation is as follows:
compared with the prior art, the invention has the following beneficial technical effects:
1. the condensation of the invention uses acetic acid to activate zinc powder, thereby improving the reactivity of zinc powder.
2. In the hydrolysis reaction, methanol is selected as a reaction solvent, sodium methoxide methanol solution is used for reaction, but not the traditional aprotic solvents such as toluene and the like, and in the reaction process, materials are in homogeneous phase reaction, so that the reaction rate is high. After the dripping is finished, the reaction is completed for 0.5 to 1 hour.
3. Has high yield and purity. Calculated by 4AA, the molar yield of the reaction is more than 94 percent, and the purity is more than 99.00 percent.
4. The solvent is easy to recycle, the safety is high, and the influence on the environment is small.
Detailed Description
The following are specific examples of the present invention, and the technical solutions of the present invention are further described, but the scope of the present invention is not limited to these examples. All changes and equivalents that do not depart from the gist of the invention are intended to be within the scope of the invention.
Example 1
(1) Preparation of (R) -2- ((2R, 3S) -3- ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -N- ((R) -1-phenethyl) -N-p-toluenesulfonyl propionamide
28.0g of zinc powder was poured into 100ml of THF (abbreviated as tetrahydrofuran, hereinafter, the same applies), 1.4g of acetic acid was added and activated at 30 to 35℃for 0.5 hour, and 30g of 4AA was added. After the temperature is reduced, controlling the reaction temperature at 5-10 ℃, dropwise adding 54g of mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and 100ml of THF, and after the dropwise adding, controlling the 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide in a liquid phase until the reaction is complete. Suction filtration, filter cake washing with 40ml THF, and incorporation of filtrate, 320g filtrate. 200g of 26% strength aqueous salt solution are added and stirred for 15min, and 4N hydrochloric acid solution is added dropwise until the pH of the aqueous phase is 6.0. And standing for layering, and leaving an organic phase.
Concentrating the organic phase at 35 ℃ or below under reduced pressure until no fraction flows out, adding 150g of methanol for concentrating until no fraction flows out, and adding 300g of methanol for standby.
(2) Hydrolysis to prepare 4BMA
And (3) dropwise adding 40g of 30% hydrogen peroxide into the organic phase in the step (1), wherein the temperature is controlled at-10 to-5 ℃ after 0.5h, then dropwise adding 40g of 29% sodium methoxide methanol solution at 0 to 5 ℃ after 0.5h, and then preserving the heat for 0.5 to 1h. 17% Na was added 2 SO 3 And (3) the solution is subjected to suction filtration, a filter cake is leached by methanol, and filtrate is collected, wherein the solution is not changed into blue by KI starch test paper, and the pH is adjusted to 10-12 by sodium methoxide methanol solution. Transferring the water phase into a reaction bottle, decompressing and distilling off methanol at the temperature of less than or equal to 35 ℃, adding 160ml of ethyl acetate, cooling to 10-15 ℃, stirring, separating liquid, dripping 4N hydrochloride water at the temperature of 3-8 ℃ until the pH value is 0.5-1, cooling to 0-5 ℃, preserving heat for 4 h, filtering to obtain white crystal 4BMA, and vacuum drying at the temperature of lower than 40 ℃ to obtain 30.2g of finished product, wherein the yield is 95.56%, and the purity is 99.12%.
Example 2
(1) Preparation of (R) -2- ((2R, 3S) -3- ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -N- ((R) -1-phenethyl) -N-p-toluenesulfonyl propionamide
28.0g of zinc powder was poured into 100ml of THF, 2.8g of acetic acid was added and activated at 30-35℃for 0.5h, and 30g of 4AA was added. After the temperature is reduced, controlling the reaction temperature at 5-10 ℃, dropwise adding 60g of mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and 100ml of THF, and after the dropwise adding, controlling the 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide in a liquid phase until the reaction is complete. Suction filtration, filter cake washing with 40ml THF, and incorporation of filtrate, 320g filtrate. 200g of 26% strength aqueous salt solution are added and stirred for 15min, and 4N hydrochloric acid solution is added dropwise until the pH of the aqueous phase is 6.0. And standing for layering, and leaving an organic phase.
Concentrating the organic phase at 35 ℃ or below under reduced pressure until no fraction flows out, adding 150g of methanol for concentrating until no fraction flows out, and adding 300g of methanol for standby.
(2) Hydrolysis to prepare 4BMA
60g of 30% hydrogen peroxide is dripped into the organic phase in the step (1), the dripping is completed within 0.5h, the temperature is controlled at-5-0 ℃, then 120g of 25% sodium methoxide methanol solution is dripped into the organic phase at 0-5 ℃ for 0.5h, and then the temperature is kept for 0.5-1h. 17% Na was added 2 SO 3 And (3) the solution is subjected to suction filtration, a filter cake is leached by methanol, and filtrate is collected, wherein the solution is not changed into blue by KI starch test paper, and the pH is adjusted to 10-12 by sodium methoxide methanol solution. Transferring the water phase into a reaction bottle, decompressing and distilling out methanol at the temperature of less than or equal to 35 ℃, adding 240ml of ethyl acetate, cooling to 5-10 ℃, stirring, separating liquid, dripping 4N hydrochloride water at the temperature of 3-5 ℃ until the pH value is 0.5, cooling to 0 ℃, preserving heat for 1h, filtering to obtain white crystal 4BMA, and vacuum drying at the temperature of less than 40 ℃ to obtain 29.8g of finished product, wherein the yield is 94.60% and the purity is 99.32%.
Example 3
(1) Preparation of (R) -2- ((2R, 3S) -3- ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -N- ((R) -1-phenethyl) -N-p-toluenesulfonyl propionamide
28.0g of zinc powder was poured into 100ml of THF, 2.0g of acetic acid was added and activated at 30-35℃for 0.5h, and 30g of 4AA was added. After the temperature is reduced, controlling the reaction temperature at 5-10 ℃, dropwise adding 56g of mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and 100ml of THF, and after the dropwise adding, controlling the 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide in a liquid phase until the reaction is complete. Suction filtration, filter cake washing with 40ml THF, and incorporation of filtrate, 320g filtrate. 200g of 26% strength aqueous salt solution are added and stirred for 15min, and 4N hydrochloric acid solution is added dropwise until the pH of the aqueous phase is 6.0. And standing for layering, and leaving an organic phase.
Concentrating the organic phase at 35 ℃ or below under reduced pressure until no fraction flows out, adding 150g of methanol for concentrating until no fraction flows out, and adding 300g of methanol for standby.
(2) Hydrolysis to prepare 4BMA
And (3) dropwise adding 56g of 30% hydrogen peroxide into the organic phase in the step (1), wherein the temperature is controlled at-8 to-6 ℃ after 0.5h, then dropwise adding 100g of 25% sodium methoxide methanol solution at 0 to 5 ℃ after 0.5h, and then preserving the heat for 0.5 to 1h. 17% Na was added 2 SO 3 And (3) the solution is subjected to suction filtration, a filter cake is leached by methanol, and filtrate is collected, wherein the solution is not changed into blue by KI starch test paper, and the pH is adjusted to 10-12 by sodium methoxide methanol solution. Transferring the water phase into a reaction bottle, decompressing and distilling off methanol at the temperature of less than or equal to 35 ℃, adding 240ml of ethyl acetate, cooling to 5-10 ℃, stirring, separating liquid, dripping 4N hydrochloride water into the water phase at the temperature of 5-8 ℃ until the PH is 1, cooling to 0-3 ℃, preserving heat for 1h, filtering to obtain white crystal 4BMA, and vacuum drying at the temperature of less than 40 ℃ to obtain 30.1g of finished product with the yield of 95.25% and the purity of 99.42%.
Claims (10)
1. A method for preparing a penem intermediate 4-BMA, which is characterized by comprising the following steps:
(1) Preparation of (R) -2- ((2R, 3S) -3- ((R) -1- (tert-butyldimethylsilyloxy) ethyl) -4-oxoazetidin-2-yl) -N- ((R) -1-phenethyl) -N-p-toluenesulfonyl propionamide
Zinc powder is put into THF, acetic acid is added for activation, and then 4AA is added; dropwise adding a mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and THF; after the dripping is finished, 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide is controlled in a liquid phase until the reaction is complete; suction filtration, washing a filter cake with THF, and merging filtrate; adding a saline solution, stirring, and then dropwise adding the hydrochloric acid solution to adjust the pH; standing and layering, and leaving an organic phase; concentrating the organic phase under reduced pressure until no fraction flows out; adding methanol for distillation and concentration until no fraction flows out, and adding methanol for later use;
(2) Hydrolysis to prepare 4BMA
Step (1)Dropwise adding hydrogen peroxide into the organic phase, and then dropwise adding a sodium methoxide methanol solution; keeping the temperature after dripping; adding Na 2 SO 3 Quenching the solution until the KI starch test paper does not change blue, and regulating the pH value by using a sodium methoxide methanol solution; suction filtration, methanol leaching of filter cakes and filtrate collection; transferring the water phase into a reaction vessel, and evaporating methanol under reduced pressure; extracting with ethyl acetate, stirring, and separating; the pH of the aqueous phase was adjusted by dropwise addition of hydrochloride water, incubated, filtered to give white crystals of 4BMA and dried in vacuo.
2. The method for preparing the penem intermediate 4-BMA according to claim 1, wherein the temperature of activating zinc powder by acetic acid in the step (1) is 30-35 ℃ and the activation time is 0.5h.
3. The preparation method of the penem intermediate 4-BMA according to claim 2, wherein the mass ratio of zinc powder to acetic acid in the step (1) is (10-20): 1.
4. The method for preparing the penem intermediate 4-BMA according to claim 1, wherein the temperature is controlled to be 5-10 ℃ when the mixed solution of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide and THF is added dropwise in the step (1).
5. The method for preparing a penem intermediate 4-BMA according to claim 1, wherein the mass ratio of 2-bromo-N- ((R) -1-phenylethyl) -N-p-toluenesulfonyl propionamide to 4AA in the step (1) is (1.8-2.0): 1.
6. The method for preparing a penem intermediate 4-BMA according to claim 1, wherein the step (1) is carried out by adding a saline solution and stirring for 15min; the aqueous phase was added dropwise to a pH of 6.0 with 4N hydrochloric acid solution.
7. The method for preparing a penem intermediate 4-BMA according to claim 1, wherein the organic phase in the step (1) is concentrated by distillation under reduced pressure at a temperature of 35 ℃ or less; distilling and adding 5 times of 4-AA into the methanol; and finally, adding methanol, wherein the mass of the reactant is 10 times of that of 4-AA.
8. The preparation method of the penem intermediate 4-BMA according to claim 1, wherein the mass ratio of the organic phase to the hydrogen peroxide in the step (2) is (7.5-5) 1; the hydrogen peroxide is hydrogen peroxide with the mass concentration of 30%; the temperature is controlled at-10-0 ℃ when hydrogen peroxide is added dropwise, and the dropwise adding time is 0.5h; the mass ratio of the sodium methoxide methanol solution to the hydrogen peroxide is (2-1) 1, and the mass concentration of the sodium methoxide methanol solution is 25% -29%; the temperature of the sodium methoxide methanol solution is controlled to be 0-5 ℃, the dripping time is 0.5h, and the temperature is maintained for 0.5-1h after dripping.
9. The method for preparing a penem intermediate 4-BMA according to claim 1, wherein the step (2) is Na 2 SO 3 The mass concentration of the solution is 17%; regulating the pH value to 10-12 by using sodium methoxide methanol solution; the temperature is less than or equal to 35 ℃ when the water phase is decompressed and distilled to remove the methanol.
10. The method for preparing the penem intermediate 4-BMA according to claim 1, wherein the extraction temperature of ethyl acetate in the step (2) is 5-15 ℃; adding ethyl acetate with the volume 4 times of the mass of the hydrogen peroxide; dropwise adding 4N hydrochloride water into the water phase at 3-8 ℃ to adjust the pH to 0.5-1, cooling to 0-5 ℃ and preserving heat for 1h; the vacuum drying temperature is lower than 40 ℃.
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