CN114315863B - Preparation method of faropenem sodium - Google Patents
Preparation method of faropenem sodium Download PDFInfo
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- CN114315863B CN114315863B CN202111587291.5A CN202111587291A CN114315863B CN 114315863 B CN114315863 B CN 114315863B CN 202111587291 A CN202111587291 A CN 202111587291A CN 114315863 B CN114315863 B CN 114315863B
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- MOGICMVNWAUWMK-HIXRZVNASA-L disodium;(5r,6s)-6-[(1r)-1-hydroxyethyl]-7-oxo-3-[(2r)-oxolan-2-yl]-4-thia-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylate;pentahydrate Chemical compound O.O.O.O.O.[Na+].[Na+].S([C@@H]1[C@H](C(N1C=1C([O-])=O)=O)[C@H](O)C)C=1[C@H]1CCCO1.S([C@@H]1[C@H](C(N1C=1C([O-])=O)=O)[C@H](O)C)C=1[C@H]1CCCO1 MOGICMVNWAUWMK-HIXRZVNASA-L 0.000 title claims abstract description 84
- 229960000379 faropenem Drugs 0.000 title claims abstract description 84
- 238000002360 preparation method Methods 0.000 title claims abstract description 19
- 101710151841 Farnesyl pyrophosphate synthase 1 Proteins 0.000 claims abstract description 33
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 30
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims abstract description 30
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 29
- 101710151842 Farnesyl pyrophosphate synthase 2 Proteins 0.000 claims abstract description 28
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 claims abstract description 25
- 238000002156 mixing Methods 0.000 claims abstract description 21
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 claims abstract description 20
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 claims abstract description 20
- -1 tert-butyldimethylsilyloxy Chemical group 0.000 claims abstract description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims abstract description 15
- CTSLXHKWHWQRSH-UHFFFAOYSA-N oxalyl chloride Chemical compound ClC(=O)C(Cl)=O CTSLXHKWHWQRSH-UHFFFAOYSA-N 0.000 claims abstract description 12
- 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 claims abstract description 11
- 239000011734 sodium Substances 0.000 claims abstract description 11
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 11
- OEOIWYCWCDBOPA-UHFFFAOYSA-N 6-methyl-heptanoic acid Chemical compound CC(C)CCCCC(O)=O OEOIWYCWCDBOPA-UHFFFAOYSA-N 0.000 claims abstract description 10
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims abstract description 10
- MNFORVFSTILPAW-UHFFFAOYSA-N azetidin-2-one Chemical compound O=C1CCN1 MNFORVFSTILPAW-UHFFFAOYSA-N 0.000 claims abstract description 9
- 150000002148 esters Chemical class 0.000 claims abstract description 6
- BDAGIHXWWSANSR-UHFFFAOYSA-N formic acid Substances OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 5
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 165
- 239000000243 solution Substances 0.000 claims description 123
- 238000006243 chemical reaction Methods 0.000 claims description 111
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 99
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 86
- 238000005406 washing Methods 0.000 claims description 86
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 78
- 239000012065 filter cake Substances 0.000 claims description 55
- 239000012074 organic phase Substances 0.000 claims description 46
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 44
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 42
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 33
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 33
- 239000007788 liquid Substances 0.000 claims description 31
- 238000003756 stirring Methods 0.000 claims description 31
- 239000000706 filtrate Substances 0.000 claims description 27
- 238000001914 filtration Methods 0.000 claims description 25
- 238000001816 cooling Methods 0.000 claims description 24
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 23
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 22
- 238000001035 drying Methods 0.000 claims description 22
- 238000010992 reflux Methods 0.000 claims description 22
- 239000011780 sodium chloride Substances 0.000 claims description 22
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 21
- 239000011736 potassium bicarbonate Substances 0.000 claims description 21
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 21
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 21
- 238000002425 crystallisation Methods 0.000 claims description 18
- 230000008025 crystallization Effects 0.000 claims description 18
- QIGBRXMKCJKVMJ-UHFFFAOYSA-N Hydroquinone Chemical compound OC1=CC=C(O)C=C1 QIGBRXMKCJKVMJ-UHFFFAOYSA-N 0.000 claims description 16
- 235000011181 potassium carbonates Nutrition 0.000 claims description 14
- 239000002904 solvent Substances 0.000 claims description 14
- 239000006227 byproduct Substances 0.000 claims description 13
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 11
- 239000011259 mixed solution Substances 0.000 claims description 11
- 229910052757 nitrogen Inorganic materials 0.000 claims description 11
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 11
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- 238000004090 dissolution Methods 0.000 claims description 9
- 238000000034 method Methods 0.000 claims description 8
- 230000001105 regulatory effect Effects 0.000 claims description 8
- 239000007864 aqueous solution Substances 0.000 claims description 7
- 238000000605 extraction Methods 0.000 claims description 7
- 238000010438 heat treatment Methods 0.000 claims description 7
- 238000010791 quenching Methods 0.000 claims description 7
- 238000011001 backwashing Methods 0.000 claims description 6
- 239000013078 crystal Substances 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000008213 purified water Substances 0.000 description 44
- 230000015572 biosynthetic process Effects 0.000 description 21
- 238000003786 synthesis reaction Methods 0.000 description 21
- 238000001514 detection method Methods 0.000 description 20
- 239000000203 mixture Substances 0.000 description 19
- 239000000843 powder Substances 0.000 description 12
- 238000002791 soaking Methods 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000008346 aqueous phase Substances 0.000 description 5
- 230000001276 controlling effect Effects 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 238000007664 blowing Methods 0.000 description 4
- 238000010586 diagram Methods 0.000 description 4
- 238000004821 distillation Methods 0.000 description 4
- 238000011010 flushing procedure Methods 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 238000004321 preservation Methods 0.000 description 4
- 230000000171 quenching effect Effects 0.000 description 4
- 238000007670 refining Methods 0.000 description 4
- 238000010025 steaming Methods 0.000 description 4
- 230000002194 synthesizing effect Effects 0.000 description 4
- 239000000126 substance Substances 0.000 description 3
- HGYMPYIEFATJNC-UHFFFAOYSA-N C(C)(C)(C)[Si](C)C.[O] Chemical group C(C)(C)(C)[Si](C)C.[O] HGYMPYIEFATJNC-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 229960003328 benzoyl peroxide Drugs 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- UHSKFQJFRQCDBE-UHFFFAOYSA-N ropinirole Chemical compound CCCN(CCC)CCC1=CC=CC2=C1CC(=O)N2 UHSKFQJFRQCDBE-UHFFFAOYSA-N 0.000 description 1
- 229960001879 ropinirole Drugs 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of faropenem sodium, which comprises the following steps: mixing potassium carbonate and R- (+) -thiotetrahydrofuran-2-formic acid, (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one, and reacting to obtain FPS-1; mixing the FPS-1, triethylamine and oxalyl chloride monoallyl ester, and reacting to obtain FPS-2; mixing the FPS-2 and triethyl phosphite, and reacting to obtain FPS-3; mixing the FPS-3 and tetrabutylammonium fluoride, and reacting to obtain FPS-4; and mixing the FPS-4, triphenylphosphine, sodium isooctanoate and tetra (triphenylphosphine) palladium, and reacting to obtain the faropenem sodium. The preparation method can obtain the faropenem sodium with high purity and high yield.
Description
Technical Field
The invention belongs to the field of pharmaceutical chemistry, and particularly relates to a preparation method of faropenem sodium.
Background
Faropenem Sodium, chemical name (5R, 6 s) -6- [ (1R) -hydroxyethyl ] -2- [ (2R) -tetrahydrofuran-2-yl ] -penem-3-carboxylic acid monosodium salt di-sesquihydrate. The faropenem sodium has a stable chemical structure, broad-spectrum antibacterial activity, less drug resistance and less adverse reaction.
When the faropenem sodium is prepared, the (3R, 4R) -4-acetoxyl-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one (4 AA) is generally used as a starting material, and the faropenem sodium is prepared through 5 or more steps. Because the related reaction substances are more and the structure is complex, byproducts are generated in the reaction, the requirements of the conditions of each step of reaction are different, the next step of reaction is not influenced because the byproducts or the solvent of the previous step of reaction becomes impurities of the next step of reaction, the intermediates are also required to be extracted after each step of reaction, the preparation steps are more, and if the generation of the byproducts and the loss of the intermediates cannot be effectively reduced, the yield of the final faropenem sodium is greatly influenced.
The existing method for preparing the faropenem sodium has lower product yield and has great lifting space. Therefore, the preparation steps are required to be optimized, and proper reaction raw materials, catalysts, solvents and proper operations are selected to be matched, so that the yield of the faropenem sodium is improved.
Disclosure of Invention
Aiming at the problems, the invention designs a preparation method of the faropenem sodium, which can obtain the faropenem sodium with high purity and high yield.
The invention provides a preparation method of faropenem sodium, which comprises the following steps: mixing potassium carbonate and R- (+) -thiotetrahydrofuran-2-formic acid, (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one, and obtaining (3S, 4R) -3- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -4- [ (2R) -tetrahydrofuranylthio ] azetidin-2-one after reaction, which is marked as FPS-1; mixing the FPS-1, triethylamine and oxalyl chloride monoallyl ester, and obtaining (3S, 4R) -1- [ (1, 2-dioxo-2-allyloxy) ethyl ] -3- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -4- [ (2R) -tetrahydrofuranyl formylthio ] azetidin-2-one, which is marked as FPS-2; mixing FPS-2 and triethyl phosphite, and reacting to obtain (5R, 6S) -6- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -2- [ (2R) -tetrahydrofuranyl ] penem-3-carboxylic acid allyl ester, which is marked as FPS-3; mixing the FPS-3 and tetrabutylammonium fluoride, and reacting to obtain (5R, 6S) -6- [ (1R) -hydroxyethyl ] -2- [ (2R) -tetrahydrofuranyl ] penem-3-carboxylic acid allyl ester, which is marked as FPS-4; and mixing the FPS-4, triphenylphosphine, sodium isooctanoate and tetra (triphenylphosphine) palladium, and reacting to obtain the faropenem sodium.
Preferably, the preparation of said FPS-1 comprises the steps of: dissolving potassium carbonate in water, adding R- (+) -thiotetrahydrofuran-2-formic acid at 10-20 ℃ and reacting for 30-60 min to obtain a solution A; dissolving (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one in acetone to obtain an ethyl solution; adding the solution B into the solution A, and reacting for 4-6 hours at the temperature of 30-35 ℃; after the reaction is completed, toluene is used for extraction, and an organic phase is collected. Further preferably, the organic phase is backwashed with water and dried over anhydrous sodium sulfate; the mixture is filtered, the filter cake is washed with toluene, and the filtrate and the washing liquid are combined to obtain a toluene solution of FPS-1.
Preferably, the molar ratio of potassium carbonate to R- (+) -thiotetrahydrofuran-2-carboxylic acid is 1:1 when preparing the FPS-1.
Preferably, the FPS-1 is prepared such that the molar ratio of R- (+) -thiotetrahydrofuran-2-carboxylic acid to (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one is 1:1.
Preferably, preparing said FPS-2 comprises the steps of: mixing the FPS-1 with triethylamine, adding oxalyl chloride monoallyl ester at the temperature of-5 to 5 ℃ and reacting for 1 to 3 hours at the temperature of-5 to 5 ℃; after the reaction is completed, adding water to quench the reaction, separating liquid, and collecting an organic phase. Further preferably, the organic phase is washed with a mixed solution of potassium bicarbonate and sodium chloride, a sodium chloride solution and dried over anhydrous sodium sulfate; the mixture is filtered, the filter cake is washed with toluene, and the filtrate and the washing liquid are combined to obtain a toluene solution of FPS-2.
Preferably, the preparation of said FPS-3 comprises the steps of: cooling the FPS-2 to below 100 ℃, adding triethyl phosphite under the protection of nitrogen, and carrying out reflux reaction for 5-10 h; after the reaction is completed, the solvent and byproducts are removed. Further preferably, the preparation of said FPS-3 further comprises the steps of: removing solvent and byproducts, adding anhydrous methanol for dissolution, and adding water in a reflux state; cooling to the ambient temperature for crystallization for 4-8 h, cooling to-5 ℃ for crystallization for 1-2 h; filtering, washing the filter cake with aqueous solution of methanol, and drying the filter cake to obtain FPS-3.
Preferably, hydroquinone is also added when preparing said FPS-3.
Preferably, preparing said FPS-4 comprises the steps of: sequentially adding anhydrous acetic acid and ethyl acetate into the FPS-3, controlling the temperature to be 10-20 ℃, adding tetrabutylammonium fluoride and N, N-dimethylformamide, and reacting for 48 hours at the temperature of 10-20 ℃. Further preferably, after the reaction is completed, the aqueous phase is backwashed with ethyl acetate and the organic phases are combined; the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate; the mixture was filtered, and the filter cake was washed with ethyl acetate, and the filtrate and the washings were combined to give a solution of FPS-4.
Preferably, the preparation of said FPS-5 comprises the steps of: sequentially adding triphenylphosphine, sodium isooctanoate and dichloromethane into the FPS-4, stirring, adding tetrakis (triphenylphosphine) palladium, and reacting at 20-30 ℃ for 1-2 h. Further preferably, after the reaction is completed, water is added for crystallization for 1 to 2 hours; filtering, washing the filter cake with acetone, and drying the filter cake to obtain the faropenem sodium.
Preferably, the method further comprises the following steps: mixing the obtained faropenem sodium with water, heating to 45-50 ℃, and adding active carbon after dissolving; filtering, washing filter residues with water, and combining the filtrate and the washing liquid to obtain a faropenem sodium solution; regulating the temperature of the faropenem sodium solution to 40-50 ℃, and adding acetone; cooling to-5 ℃ for crystallization for 1-2 h; filtering, soaking and washing the filter cake with acetone, and drying the filter cake.
Compared with the prior art, the invention has the following beneficial effects:
1. the intermediate (namely FPS-1) is prepared by reacting potassium carbonate with R- (+) -thiotetrahydrofuran-2-carboxylic acid, (3R, 4R) -4-acetoxyl-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidine-2-one, the proportion of the potassium carbonate to the R- (+) -thiotetrahydrofuran-2-carboxylic acid is limited, the prepared FPS-1 has high yield and high purity, and the intermediate is utilized to finally obtain the high-yield and high-purity faropenem sodium.
2. The solution of FPS-1 and the solution of FPS-2 obtained by the method can directly carry out the next reaction without removing the solvent; the continuous yield of FPS-3 is 50% -70%, namely, the yield from (3R, 4R) -4-acetoxyl-3- [ (R) - (tert-butyl dimethyl silica) ethyl ] azetidin-2-ketone to FPS-3 is 50% -70%.
3. The invention can directly carry out the next reaction of removing the carboxyl protecting group without removing the solvent after removing the hydroxyl protecting group; the total yield of the dehydroxy protecting group and the carboxyl protecting group is 85% -95%, namely, the yield from FPS-3 to the faropenem sodium is 85% -95%.
4. The faropenem sodium prepared by the method is further refined to obtain the faropenem sodium with higher purity, and the yield is 70-80%.
Drawings
FIG. 1 is a schematic diagram of the reaction for synthesizing FPS-1 in example 1 of the present invention;
FIG. 2 is a schematic diagram of the reaction for synthesizing FPS-2 in example 1 of the present invention;
FIG. 3 is a schematic diagram of the reaction for synthesizing FPS-3 in example 1 of the present invention;
FIG. 4 is a schematic diagram of the reaction for synthesizing FPS-4 in example 1 of the present invention;
FIG. 5 is a schematic reaction scheme of the synthesis of sodium ropinirole in example 1 of the present invention.
Detailed Description
The following description of the technical solutions in the embodiments of the present invention will be clear and complete, and it is obvious that the described embodiments are only some embodiments of the present invention, but not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
The invention provides a preparation method of faropenem sodium, which comprises the following steps:
s1, mixing potassium carbonate, R- (+) -thiotetrahydrofuran-2-formic acid, (3R, 4R) -4-acetoxyl group-3- [ (R) - (tert-butyl dimethyl silicon oxygen group) ethyl ] azetidin-2-ketone, and obtaining (3S, 4R) -3- [ (1R) - (tert-butyl dimethyl silicon oxygen group) ethyl ] -4- [ (2R) -tetrahydrofuranyl formyl sulfur group ] azetidin-2-ketone after reaction. Wherein the molar ratio of the potassium carbonate to the R- (+) -thiotetrahydrofuran-2-carboxylic acid to the (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one is 1:1:1.
For ease of writing and reading, (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one is designated FPS-SS1, R- (+) -thiotetrahydrofuran-2-carboxylic acid is designated FPS-SS2, and (3S, 4R) -3- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -4- [ (2R) -tetrahydrofuranylthio ] azetidin-2-one is designated FPS-1.
In particular, the method comprises the steps of,
dissolving potassium carbonate in water, adding FPS-SS2 at 10-20 ℃ and reacting for 30-60 min to obtain a solution A; dissolving FPS-SS1 in acetone to obtain a solution B; adding the solution B into the solution A, and reacting for 4-6 hours at the temperature of 30-35 ℃; after the reaction is completed, toluene is used for extraction, and an organic phase is collected; the organic phase is backwashed by water and dried by anhydrous sodium sulfate; the mixture is filtered, the filter cake is washed with toluene, and the filtrate and the washing liquid are combined to obtain a toluene solution of FPS-1. The toluene solution of FPS-1 can be used directly in the next reaction.
The reaction formula of this step is as follows:
s2, mixing the FPS-1, triethylamine and oxalyl chloride monoallyl ester, and reacting to obtain (3S, 4R) -1- [ (1, 2-dioxo-2-allyloxy) ethyl ] -3- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -4- [ (2R) -tetrahydrofuranyl formylthio ] azetidin-2-one.
Oxalyl chloride monoallyl ester is designated as FPS-SS3, and (3S, 4R) -1- [ (1, 2-dioxo-2-allyloxy) ethyl ] -3- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -4- [ (2R) -tetrahydrofuranylthio ] azetidin-2-one is designated as FPS-2.
In particular, the method comprises the steps of,
mixing the FPS-1 with triethylamine, adding the FPS-SS3 at the temperature of between 5 ℃ below zero and 5 ℃ below zero, and reacting for 1 to 3 hours at the temperature of between 5 ℃ below zero and 5 ℃ below zero; after the reaction is completed, adding water to quench the reaction, separating liquid, and collecting an organic phase; the organic phase is washed by a mixed solution of potassium bicarbonate and sodium chloride and a sodium chloride solution in turn, and dried by anhydrous sodium sulfate; the mixture is filtered, the filter cake is washed with toluene, and the filtrate and the washing liquid are combined to obtain a toluene solution of FPS-2. The toluene solution of FPS-2 can be used directly in the next reaction.
The reaction formula of this step is as follows:
s3, mixing the FPS-2, hydroquinone and triethyl phosphite, and reacting to obtain (5R, 6S) -6- [ (1R) - (tert-butyldimethylsilyloxy) ethyl ] -2- [ (2R) -tetrahydrofuranyl ] penem-3-carboxylic acid allyl ester.
(5R, 6S) -6- [ (1R) - (tert-Butyldimethylsiloxy) ethyl ] -2- [ (2R) -tetrahydrofuranyl ] penem-3-carboxylic acid allyl ester was designated FPS-3.
In particular, the method comprises the steps of,
cooling the FPS-2 to below 100 ℃, protecting with nitrogen, adding hydroquinone and triethyl phosphite, and carrying out reflux reaction for 5-10 h; after the reaction is completed, removing the solvent and byproducts; removing solvent and byproducts, adding absolute methanol for dissolution, and adding water while keeping a reflux state; cooling to the ambient temperature for crystallization for 4-8 h, and further cooling to-5 ℃ for crystallization for 1-2 h; filtering, washing the filter cake with aqueous solution of methanol, and drying the filter cake to obtain FPS-3.
The reaction formula of this step is as follows:
s4, mixing the FPS-3 and tetrabutylammonium fluoride, and reacting to obtain (5R, 6S) -6- [ (1R) -hydroxyethyl ] -2- [ (2R) -tetrahydrofuranyl ] penem-3-carboxylic acid allyl ester.
(5R, 6S) -6- [ (1R) -hydroxyethyl ] -2- [ (2R) -tetrahydrofuranyl ] penem-3-carboxylic acid allyl ester was designated FPS-4.
Specifically, anhydrous acetic acid and ethyl acetate are sequentially added into the FPS-3, the temperature is regulated to 10-20 ℃, tetrabutylammonium fluoride and N, N-dimethylformamide are added, and the reaction is carried out for 48 hours at 10-20 ℃; after the reaction is completed, washing by potassium bicarbonate solution, backwashing the water phase by ethyl acetate, and merging organic phases; the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate; the mixture was filtered, and the filter cake was washed with ethyl acetate, and the filtrate and the washings were combined to give a solution of FPS-4. The solution of FPS-4 can be used directly in the next reaction.
The reaction formula of this step is as follows:
s5, mixing the FPS-4, triphenylphosphine, sodium isooctanoate and tetrakis (triphenylphosphine) palladium, and reacting to obtain the faropenem sodium.
Specifically, triphenylphosphine, sodium isooctanoate and methylene dichloride are sequentially added into the FPS-4, tetra (triphenylphosphine) palladium is added after stirring, and the mixture is reacted for 1 to 2 hours at the temperature of 20 to 30 ℃; after the reaction is completed, adding water to separate crystal for 1-2 h; filtering, washing the filter cake with acetone, and drying the filter cake to obtain the faropenem sodium.
The reaction formula of this step is as follows:
s6, mixing the obtained faropenem sodium with water, heating to 45-50 ℃, and adding active carbon after dissolving; filtering, washing filter residues with water, and combining the filtrate and the washing liquid to obtain a faropenem sodium solution; regulating the temperature of the faropenem sodium solution to 40-50 ℃, adding acetone, cooling to-5 ℃ and crystallizing for 1-2 h; filtering, soaking and washing the filter cake with acetone, and drying the filter cake.
Example 1
The embodiment provides a preparation method of faropenem sodium, which comprises the following steps:
s1, synthesis of FPS-1
Dissolving 1.2mol of anhydrous potassium carbonate in 287.43g of purified water, dropwise adding 1.2mol of FPS-SS2 at the temperature of 10-20 ℃, and stirring for reacting for 30-60 min after the addition to obtain a solution A;
287.43g (1 mol) of FPS-SS1 was dissolved in 287.43g of acetone to obtain an ethyl solution;
slowly adding the solution B into the solution A, flushing a container for containing the solution B and an instrument for transferring the solution B with 287.43g of acetone, adding the solution B into the reaction solution, and reacting for 4-6 h at 30-35 ℃;
after the TLC detection reaction was completed, 287.43g of toluene was added for extraction, and an organic phase was collected;
the organic phase was backwashed twice with purified water (287.43 g of purified water for each backwash), and after washing, the organic phase was dried over anhydrous sodium sulfate (mass ratio of anhydrous sodium sulfate for drying to FPS-SS1, described above, was 0.35:1);
the mixture was filtered, and the cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-1, which was directly used for the next reaction.
S2, synthesis of FPS-2
Refluxing and separating the toluene solution of the FPS-1 obtained in the step S1 until no water drops are formed, cooling, adding 1.1mol of triethylamine, dropwise adding 1.1mol of FPS-SS3 at the temperature of-5 ℃, and reacting for 1-3 hours at the temperature of-5 ℃ after the addition;
after the TLC detection reaction is finished, 287.43g of purified water is added for quenching reaction, liquid is separated, and an organic phase is collected;
the organic phase is washed once with a mixed solution containing 10wt% of potassium bicarbonate and 10wt% of sodium chloride in sequence, and twice with a sodium chloride solution having a solute mass fraction of 10% (the mass ratio of the mixed solution containing potassium bicarbonate and sodium chloride for washing to the above-mentioned FPS-SS1 is 3.5:1, and the mass ratio of the sodium chloride solution for washing to the above-mentioned FPS-SS1 is 3.5:1 each time), and dried with anhydrous sodium sulfate (the mass ratio of the anhydrous sodium sulfate for drying to the above-mentioned FPS-SS1 is 0.35:1);
the mixture was filtered, and the filter cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-2, which was directly used for the next reaction.
S3, synthesis of FPS-3
Refluxing and water diversion is carried out on the toluene solution of the FPS-2 obtained in the S2 until no water drops are formed, cooling is carried out to a temperature below 100 ℃, nitrogen protection is carried out, 0.0135mol of hydroquinone and 2.0mol of triethyl phosphite are added, and temperature reflux reaction is controlled for 5-10 h;
after the TLC detection reaction is finished, the solvent and byproducts are removed by reduced pressure distillation, 287.43g of absolute methanol is added for dissolution after steaming, purified water is slowly added under the condition of heat preservation and reflux (the mass ratio of the added purified water to the FPS-SS1 is 1.04:1), after the adding, the temperature is slowly reduced to the ambient temperature for crystallization for 4-8 h, and the temperature is further reduced to-5 ℃ for crystallization for 1-2 h;
filtering, washing the filter cake with an aqueous solution containing 35wt% of methanol, and drying the filter cake to obtain white to pale yellow powder, namely FPS-3, wherein the continuous yield is 50% -70%, namely the total yield of S1, S2 and S3 is 50% -70%.
S4, synthesis of FPS-4
Sequentially adding the FPS-3, the absolute ethyl alcohol and the ethyl acetate obtained in the S3 into a reaction device (wherein the added absolute ethyl alcohol is 5.0mol, the mass ratio of the added ethyl acetate to the FPS-3 is 2.7:1), stirring, controlling the temperature to be 10-20 ℃, adding TBAF 3H2O and N, N-dimethylformamide (wherein the added TBAF 3H2O is 2.0mol, the mass ratio of the added N, N-dimethylformamide to the FPS-3 is 0.95:1), and stirring and reacting for 48 hours at the temperature of 10-20 ℃;
after completion of the TLC detection reaction, the reaction was washed twice with 17% by mass of potassium bicarbonate solution (here, the mass ratio of potassium bicarbonate solution to FPS-3 described above was 4.92:1 each time for washing), the aqueous phase was combined and backwashed twice with ethyl acetate (here, the mass ratio of ethyl acetate to FPS-3 described above was 1:1 each time for backwashing), and the three organic phases were combined;
the combined organic phases were washed three times with saturated brine (the mass ratio of saturated brine to FPS-3 described above was 1.7:1 each time), and dried over anhydrous sodium sulfate (the mass ratio of anhydrous sodium sulfate to FPS-3 described above was 0.75:1).
The mixture was filtered, and the filter cake was washed with ethyl acetate (here, the mass ratio of ethyl acetate used for washing to the above-mentioned FPS-3 was 0.41:1), and the filtrate and the washing liquid were combined to give a solution of FPS-4, which was directly used in the next reaction.
S5, synthesis of faropenem sodium
Sequentially adding the solution of FPS-4 obtained in S4, 0.15mol of triphenylphosphine, 1.1mol of sodium isooctanoate and methylene dichloride into a reaction device (the mass ratio of the methylene dichloride added to the FPS-3 is 6.6:1), stirring, adding 0.0025mol of tetrakis (triphenylphosphine) palladium, and reacting for 1-2 h at 20-30 ℃, wherein the embodiment is taken as a preferable scheme, and adding the tetrakis (triphenylphosphine) palladium under the protection of nitrogen for reaction;
after the TLC detection reaction is finished, adding 2.5mol of purified water, stirring and crystallizing for 1-2 h;
filtering, washing the filter cake twice with acetone (the mass ratio of acetone used for washing each time to FPS-3 is 0.79:1), and drying the filter cake to obtain off-white to pale yellow powder, namely faropenem sodium, wherein the total yield of the dehydroxylated protecting groups and the decarboxylated protecting groups is 85-95%, namely the total yield of S4 and S5 is 85-95%.
S6, refining faropenem sodium
Adding the faropenem sodium obtained in the step S5 and purified water into a reaction device (the mass ratio of the purified water added to the faropenem sodium obtained in the step S5 is 2:1), heating to 45-50 ℃, stirring and dissolving, and adding active carbon after complete dissolution (the mass ratio of the active carbon added to the faropenem sodium obtained in the step S5 is 0.05:1);
filtering, washing filter residues with purified water (the mass ratio of the purified water used for washing to the faropenem sodium obtained in the step S5 is 0.1:1), and combining the filtrate and the washing liquid to obtain a faropenem sodium solution;
regulating the temperature of the faropenem sodium solution to 40-50 ℃, adding acetone (the mass ratio of the added acetone to the faropenem sodium obtained in the step S5 is 5.91:1), cooling to-5 ℃, and stirring for crystallization for 1-2 h;
filtering, soaking and washing the filter cake with acetone (the mass ratio of the acetone used for soaking and washing to the faropenem sodium obtained in the step S5 is 0.79:1), and drying the filter cake by blowing at 25-35 ℃ to obtain white-like powder with the yield of 70-80%.
Example 2
The embodiment provides a preparation method of faropenem sodium, which comprises the following steps:
s1, synthesis of FPS-1
Dissolving 1.2mol of anhydrous potassium carbonate in 287.43g of purified water, dropwise adding 1.2mol of FPS-SS2 at 15 ℃, and stirring for reacting for 45min after the addition to obtain a solution A;
287.43g (1 mol) of FPS-SS1 was dissolved in 287.43g of acetone to obtain an ethyl solution;
slowly adding the solution B into the solution A, flushing a container for containing the solution B and an instrument for transferring the solution B with 287.43g of acetone, adding the solution B into the reaction solution, and reacting for 5 hours at 33 ℃;
after the TLC detection reaction was completed, 287.43g of toluene was added for extraction, and an organic phase was collected;
the organic phase was backwashed twice with purified water (287.43 g of purified water for each backwash), and after washing, the organic phase was dried over anhydrous sodium sulfate (mass ratio of anhydrous sodium sulfate for drying to FPS-SS1, described above, was 0.35:1);
the mixture was filtered, and the cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-1, which was directly used for the next reaction.
S2, synthesis of FPS-2
Refluxing and separating the toluene solution of the FPS-1 obtained in the step S1 until no water drops are formed, cooling, adding 1.1mol of triethylamine, dropwise adding 1.1mol of FPS-SS3 at the temperature of 0 ℃, and reacting for 2 hours at the temperature of 0 ℃;
after the TLC detection reaction is finished, 287.43g of purified water is added for quenching reaction, liquid is separated, and an organic phase is collected;
the organic phase is washed once with a mixed solution containing 10wt% of potassium bicarbonate and 10wt% of sodium chloride in sequence, and twice with a sodium chloride solution having a solute mass fraction of 10% (the mass ratio of the mixed solution containing potassium bicarbonate and sodium chloride for washing to the above-mentioned FPS-SS1 is 3.5:1, and the mass ratio of the sodium chloride solution for washing to the above-mentioned FPS-SS1 is 3.5:1 each time), and dried with anhydrous sodium sulfate (the mass ratio of the anhydrous sodium sulfate for drying to the above-mentioned FPS-SS1 is 0.35:1);
the mixture was filtered, and the filter cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-2, which was directly used for the next reaction.
S3, synthesis of FPS-3
Refluxing and water diversion is carried out on the toluene solution of the FPS-2 obtained in the S2 until no water drops are formed, cooling is carried out to the temperature of 90 ℃, nitrogen protection is carried out, 0.0135mol of hydroquinone and 2.0mol of triethyl phosphite are added, and the temperature reflux reaction is controlled for 8 hours;
after the TLC detection reaction is finished, the solvent and byproducts are removed by reduced pressure distillation, 287.43g of absolute methanol is added for dissolution after steaming, purified water is slowly added under the condition of heat preservation and reflux (the mass ratio of the added purified water to the FPS-SS1 is 1.04:1), after the adding, the temperature is slowly reduced to the ambient temperature for crystallization for 6 hours, and the temperature is further reduced to 0 ℃ for crystallization for 1.5 hours;
the filter cake was washed with an aqueous solution containing 35wt% methanol and dried to give a white to pale yellow powder, i.e., FPS-3.
S4, synthesis of FPS-4
Sequentially adding the FPS-3, the absolute ethyl alcohol and the ethyl acetate obtained in the step S3 into a reaction device (wherein the added absolute ethyl alcohol is 5.0mol, the mass ratio of the added ethyl acetate to the FPS-3 is 2.7:1), stirring, controlling the temperature to be 15 ℃, adding TBAF 3H2O and N, N-dimethylformamide (wherein the added TBAF 3H2O is 2.0mol, the mass ratio of the added N, N-dimethylformamide to the FPS-3 is 0.95:1), and stirring and reacting for 48 hours at the temperature of 15 ℃;
after completion of the TLC detection reaction, the reaction was washed twice with 17% by mass of potassium bicarbonate solution (here, the mass ratio of potassium bicarbonate solution to FPS-3 described above was 4.92:1 each time for washing), the aqueous phase was combined and backwashed twice with ethyl acetate (here, the mass ratio of ethyl acetate to FPS-3 described above was 1:1 each time for backwashing), and the three organic phases were combined;
the combined organic phases were washed three times with saturated brine (the mass ratio of saturated brine to FPS-3 described above was 1.7:1 each time), and dried over anhydrous sodium sulfate (the mass ratio of anhydrous sodium sulfate to FPS-3 described above was 0.75:1).
The mixture was filtered, and the filter cake was washed with ethyl acetate (here, the mass ratio of ethyl acetate used for washing to the above-mentioned FPS-3 was 0.41:1), and the filtrate and the washing liquid were combined to give a solution of FPS-4, which was directly used in the next reaction.
S5, synthesis of faropenem sodium
Sequentially adding the solution of FPS-4 obtained in S4, 0.15mol of triphenylphosphine, 1.1mol of sodium isooctanoate and methylene dichloride into a reaction device (the mass ratio of the methylene dichloride added to the FPS-3 is 6.6:1), stirring, adding 0.0025mol of tetrakis (triphenylphosphine) palladium, and reacting for 1.5h at 25 ℃, wherein the example is taken as a preferable scheme, and adding the tetrakis (triphenylphosphine) palladium under the protection of nitrogen for reacting;
after the TLC detection reaction is finished, adding 2.5mol of purified water, stirring and crystallizing for 1.5h;
the filter cake was filtered, washed twice with acetone (here the mass ratio of acetone to FPS-3 described above was 0.79:1 each time) and the filter cake was dried to give an off-white to pale yellow powder, namely faropenem sodium.
S6, refining faropenem sodium
Adding the faropenem sodium obtained in the step S5 and purified water into a reaction device (the mass ratio of the added purified water to the faropenem sodium obtained in the step S5 is 2:1), heating to 47 ℃, stirring for dissolving, and adding active carbon after complete dissolving (the mass ratio of the added active carbon to the faropenem sodium obtained in the step S5 is 0.05:1);
filtering, washing filter residues with purified water (the mass ratio of the purified water used for washing to the faropenem sodium obtained in the step S5 is 0.1:1), and combining the filtrate and the washing liquid to obtain a faropenem sodium solution;
regulating the temperature of the faropenem sodium solution to 45 ℃, adding acetone (the mass ratio of the added acetone to the faropenem sodium obtained in the step S5 is 5.91:1), cooling to 0 ℃, stirring and crystallizing for 1.5h;
filtering, soaking and washing the filter cake with acetone (the mass ratio of acetone used for soaking and the faropenem sodium obtained in the step S5 is 0.79:1), and drying the filter cake by blowing at 30 ℃ to obtain white-like powder.
Example 3
The embodiment provides a preparation method of faropenem sodium, which comprises the following steps:
s1, synthesis of FPS-1
Dissolving 1.2mol of anhydrous potassium carbonate in 287.43g of purified water, dropwise adding 1.2mol of FPS-SS2 at 10 ℃, and stirring for reacting for 60min after the addition to obtain a solution A;
287.43g (1 mol) of FPS-SS1 was dissolved in 287.43g of acetone to obtain an ethyl solution;
slowly adding the solution B into the solution A, flushing a container for containing the solution B and an instrument for transferring the solution B with 287.43g of acetone, adding the solution B into the reaction solution, and reacting for 6 hours at 30 ℃;
after the TLC detection reaction was completed, 287.43g of toluene was added for extraction, and an organic phase was collected;
the organic phase was backwashed twice with purified water (287.43 g of purified water for each backwash), and after washing, the organic phase was dried over anhydrous sodium sulfate (mass ratio of anhydrous sodium sulfate for drying to FPS-SS1, described above, was 0.35:1);
the mixture was filtered, and the cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-1, which was directly used for the next reaction.
S2, synthesis of FPS-2
Refluxing and separating the toluene solution of the FPS-1 obtained in the step S1 until no water drops are formed, cooling, adding 1.1mol of triethylamine, dropwise adding 1.1mol of FPS-SS3 at the temperature of-5 ℃, and reacting for 1h at the temperature of 5 ℃;
after the TLC detection reaction is finished, 287.43g of purified water is added for quenching reaction, liquid is separated, and an organic phase is collected;
the organic phase is washed once with a mixed solution containing 10wt% of potassium bicarbonate and 10wt% of sodium chloride in sequence, and twice with a sodium chloride solution having a solute mass fraction of 10% (the mass ratio of the mixed solution containing potassium bicarbonate and sodium chloride for washing to the above-mentioned FPS-SS1 is 3.5:1, and the mass ratio of the sodium chloride solution for washing to the above-mentioned FPS-SS1 is 3.5:1 each time), and dried with anhydrous sodium sulfate (the mass ratio of the anhydrous sodium sulfate for drying to the above-mentioned FPS-SS1 is 0.35:1);
the mixture was filtered, and the filter cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-2, which was directly used for the next reaction.
S3, synthesis of FPS-3
Refluxing and water diversion is carried out on the toluene solution of the FPS-2 obtained in the S2 until no water drops are formed, cooling is carried out to the temperature of 95 ℃, nitrogen protection is carried out, 0.0135mol of hydroquinone and 2.0mol of triethyl phosphite are added, and the temperature reflux reaction is controlled for 5 hours;
after the TLC detection reaction is finished, the solvent and byproducts are removed by reduced pressure distillation, 287.43g of absolute methanol is added for dissolution after steaming, purified water is slowly added under the condition of heat preservation and reflux (the mass ratio of the added purified water to the FPS-SS1 is 1.04:1), after the adding, the temperature is slowly reduced to the ambient temperature for crystallization for 4 hours, and the temperature is further reduced to-5 ℃ for crystallization for 2 hours;
the filter cake was washed with an aqueous solution containing 35wt% methanol and dried to give a white to pale yellow powder, i.e., FPS-3.
S4, synthesis of FPS-4
Sequentially adding the FPS-3 obtained in the step S3, absolute ethyl alcohol and ethyl acetate into a reaction device (wherein the added absolute ethyl alcohol is 5.0mol, the mass ratio of the added ethyl acetate to the FPS-3 is 2.7:1), stirring, controlling the temperature to be 10 ℃, adding TBAF 3H2O and N, N-dimethylformamide (wherein the added TBAF 3H2O is 2.0mol, and the mass ratio of the added N, N-dimethylformamide to the FPS-3 is 0.95:1), and stirring and reacting for 48 hours at 20 ℃;
after completion of the TLC detection reaction, the reaction was washed twice with 17% by mass of potassium bicarbonate solution (here, the mass ratio of potassium bicarbonate solution to FPS-3 described above was 4.92:1 each time for washing), the aqueous phase was combined and backwashed twice with ethyl acetate (here, the mass ratio of ethyl acetate to FPS-3 described above was 1:1 each time for backwashing), and the three organic phases were combined;
the combined organic phases were washed three times with saturated brine (the mass ratio of saturated brine to FPS-3 described above was 1.7:1 each time), and dried over anhydrous sodium sulfate (the mass ratio of anhydrous sodium sulfate to FPS-3 described above was 0.75:1).
The mixture was filtered, and the filter cake was washed with ethyl acetate (here, the mass ratio of ethyl acetate used for washing to the above-mentioned FPS-3 was 0.41:1), and the filtrate and the washing liquid were combined to give a solution of FPS-4, which was directly used in the next reaction.
S5, synthesis of faropenem sodium
Sequentially adding the solution of FPS-4 obtained in S4, 0.15mol of triphenylphosphine, 1.1mol of sodium isooctanoate and methylene dichloride into a reaction device (the mass ratio of the methylene dichloride added to the FPS-3 is 6.6:1), stirring, adding 0.0025mol of tetrakis (triphenylphosphine) palladium, and reacting for 2 hours at 20 ℃, wherein the example is taken as a preferable scheme, and adding the tetrakis (triphenylphosphine) palladium under the protection of nitrogen for reaction;
after the TLC detection reaction is finished, adding 2.5mol of purified water, stirring and crystallizing for 1h;
the filter cake was filtered, washed twice with acetone (here the mass ratio of acetone to FPS-3 described above was 0.79:1 each time) and the filter cake was dried to give an off-white to pale yellow powder, namely faropenem sodium.
S6, refining faropenem sodium
Adding the faropenem sodium obtained in the step S5 and purified water into a reaction device (the mass ratio of the added purified water to the faropenem sodium obtained in the step S5 is 2:1), heating to 45 ℃, stirring and dissolving, and adding active carbon after complete dissolution (the mass ratio of the added active carbon to the faropenem sodium obtained in the step S5 is 0.05:1);
filtering, washing filter residues with purified water (the mass ratio of the purified water used for washing to the faropenem sodium obtained in the step S5 is 0.1:1), and combining the filtrate and the washing liquid to obtain a faropenem sodium solution;
regulating the temperature of the faropenem sodium solution to 40 ℃, adding acetone (the mass ratio of the added acetone to the faropenem sodium obtained in the step S5 is 5.91:1), cooling to-5 ℃, stirring and crystallizing for 1h;
filtering, soaking and washing the filter cake with acetone (the mass ratio of acetone used for soaking and the faropenem sodium obtained in the step S5 is 0.79:1), and drying the filter cake by blowing at 25 ℃ to obtain white-like powder.
Example 4
The embodiment provides a preparation method of faropenem sodium, which comprises the following steps:
s1, synthesis of FPS-1
Dissolving 1.2mol of anhydrous potassium carbonate in 287.43g of purified water, dropwise adding 1.2mol of FPS-SS2 at 20 ℃, and stirring for reaction for 30min after the addition to obtain a solution A;
287.43g (1 mol) of FPS-SS1 was dissolved in 287.43g of acetone to obtain an ethyl solution;
slowly adding the solution B into the solution A, flushing a container for containing the solution B and an instrument for transferring the solution B with 287.43g of acetone, adding the solution B into the reaction solution, and reacting for 6 hours at 35 ℃;
after the TLC detection reaction was completed, 287.43g of toluene was added for extraction, and an organic phase was collected;
the organic phase was backwashed twice with purified water (287.43 g of purified water for each backwash), and after washing, the organic phase was dried over anhydrous sodium sulfate (mass ratio of anhydrous sodium sulfate for drying to FPS-SS1, described above, was 0.35:1);
the mixture was filtered, and the cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-1, which was directly used for the next reaction.
S2, synthesis of FPS-2
Refluxing and separating the toluene solution of the FPS-1 obtained in the step S1 until no water drops are formed, cooling, adding 1.1mol of triethylamine, dropwise adding 1.1mol of FPS-SS3 at the temperature of 5 ℃, and reacting for 3 hours at the temperature of-5 ℃;
after the TLC detection reaction is finished, 287.43g of purified water is added for quenching reaction, liquid is separated, and an organic phase is collected;
the organic phase is washed once with a mixed solution containing 10wt% of potassium bicarbonate and 10wt% of sodium chloride in sequence, and twice with a sodium chloride solution having a solute mass fraction of 10% (the mass ratio of the mixed solution containing potassium bicarbonate and sodium chloride for washing to the above-mentioned FPS-SS1 is 3.5:1, and the mass ratio of the sodium chloride solution for washing to the above-mentioned FPS-SS1 is 3.5:1 each time), and dried with anhydrous sodium sulfate (the mass ratio of the anhydrous sodium sulfate for drying to the above-mentioned FPS-SS1 is 0.35:1);
the mixture was filtered, and the filter cake was washed with toluene (here, the mass ratio of toluene used for washing to the above-mentioned FPS-SS1 was 0.3:1), and the filtrate and the washing liquid were combined to obtain a toluene solution of FPS-2, which was directly used for the next reaction.
S3, synthesis of FPS-3
Refluxing and water diversion is carried out on the toluene solution of the FPS-2 obtained in the S2 until no water drops are formed, cooling is carried out to the temperature of 99 ℃, nitrogen protection is carried out, 0.0135mol of hydroquinone and 2.0mol of triethyl phosphite are added, and the temperature reflux reaction is controlled for 10 hours;
after the TLC detection reaction is finished, the solvent and byproducts are removed by reduced pressure distillation, 287.43g of absolute methanol is added for dissolution after steaming, purified water is slowly added under the condition of heat preservation and reflux (the mass ratio of the added purified water to the FPS-SS1 is 1.04:1), after the adding, the temperature is slowly reduced to the ambient temperature for crystallization for 8 hours, and the temperature is further reduced to 5 ℃ for crystallization for 2 hours;
the filter cake was washed with an aqueous solution containing 35wt% methanol and dried to give a white to pale yellow powder.
S4, synthesis of FPS-4
Sequentially adding the FPS-3 obtained in the step S3, absolute ethyl alcohol and ethyl acetate into a reaction device (wherein the added absolute ethyl alcohol is 5.0mol, the mass ratio of the added ethyl acetate to the FPS-3 is 2.7:1), stirring, controlling the temperature to be 20 ℃, adding TBAF 3H2O and N, N-dimethylformamide (wherein the added TBAF 3H2O is 2.0mol, and the mass ratio of the added N, N-dimethylformamide to the FPS-3 is 0.95:1), and stirring and reacting for 48 hours at 10 ℃;
after completion of the TLC detection reaction, the reaction was washed twice with 17% by mass of potassium bicarbonate solution (here, the mass ratio of potassium bicarbonate solution to FPS-3 described above was 4.92:1 each time for washing), the aqueous phase was combined and backwashed twice with ethyl acetate (here, the mass ratio of ethyl acetate to FPS-3 described above was 1:1 each time for backwashing), and the three organic phases were combined;
the combined organic phases were washed three times with saturated brine (here, the mass ratio of saturated brine to FPS-3 was 1.7:1 each time), and dried over anhydrous sodium sulfate (here, the mass ratio of anhydrous sodium sulfate to FPS-3 was 0.75:1);
the mixture was filtered, and the filter cake was washed with ethyl acetate (the mass ratio of ethyl acetate used for washing to FPS-3 described above was 0.41:1), and the filtrate and washings were combined to give a solution of FPS-4, which was used directly in the next reaction.
S5, synthesis of faropenem sodium
Sequentially adding the solution of FPS-4 obtained in S4, 0.15mol of triphenylphosphine, 1.1mol of sodium isooctanoate and methylene dichloride into a reaction device (the mass ratio of the methylene dichloride added to the FPS-3 is 6.6:1), stirring, adding 0.0025mol of tetrakis (triphenylphosphine) palladium, and reacting for 1h at 30 ℃, wherein the example is taken as a preferable scheme, and adding the tetrakis (triphenylphosphine) palladium under the protection of nitrogen for reaction;
after the TLC detection reaction is finished, adding 2.5mol of purified water, stirring and crystallizing for 2 hours;
the filter cake was filtered, washed twice with acetone (here the mass ratio of acetone to FPS-3 described above was 0.79:1 each time) and the filter cake was dried to give an off-white to pale yellow powder, namely faropenem sodium.
S6, refining faropenem sodium
Adding the faropenem sodium obtained in the step S5 and purified water into a reaction device (the mass ratio of the added purified water to the faropenem sodium obtained in the step S5 is 2:1), heating to 50 ℃, stirring for dissolving, and adding active carbon after complete dissolving (the mass ratio of the added active carbon to the faropenem sodium obtained in the step S5 is 0.05:1);
filtering, washing filter residues with purified water (the mass ratio of the purified water used for washing to the faropenem sodium obtained in the step S5 is 0.1:1), and combining the filtrate and the washing liquid to obtain a faropenem sodium solution;
regulating the temperature of the faropenem sodium solution to 50 ℃, adding acetone (the mass ratio of the added acetone to the faropenem sodium obtained in the step S5 is 5.91:1), cooling to 5 ℃, stirring and crystallizing for 2 hours;
filtering, soaking and washing the filter cake with acetone (the mass ratio of acetone used for soaking and the faropenem sodium obtained in the step S5 is 0.79:1), and drying the filter cake by blowing at 35 ℃ to obtain white-like powder.
The above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, those skilled in the art may still make modifications to the technical solutions described in the foregoing embodiments, or may make equivalent substitutions for some or all of the technical features thereof; such modifications and substitutions do not depart from the spirit of the invention, and are intended to be included within the scope of the appended claims and description.
Claims (3)
1. The preparation method of the faropenem sodium is characterized by comprising the following steps of:
s1, dissolving potassium carbonate in water, adding R- (+) -thiotetrahydrofuran-2-formic acid at the temperature of 10-20 ℃ and reacting for 30-60 min to obtain a solution A; dissolving (3R, 4R) -4-acetoxy-3- [ (R) - (tert-butyldimethylsilyloxy) ethyl ] azetidin-2-one in acetone to obtain an ethyl solution; adding the solution B into the solution A, and reacting for 4-6 hours at the temperature of 30-35 ℃; after the reaction is completed, toluene is used for extraction, and an organic phase is collected; the organic phase is backwashed by water and dried by anhydrous sodium sulfate; filtering, washing a filter cake with toluene, and combining the filtrate and the washing liquid to obtain a toluene solution of FPS-1;
s2, mixing the toluene solution of the FPS-1 with triethylamine, adding oxalyl chloride monoallyl ester at the temperature of-5 ℃ and reacting for 1-3 hours at the temperature of-5 ℃; after the reaction is completed, adding water to quench the reaction, separating liquid, and collecting an organic phase; the organic phase is washed by a mixed solution of potassium bicarbonate and sodium chloride and a sodium chloride solution in turn, and dried by anhydrous sodium sulfate; filtering, washing a filter cake with toluene, and combining the filtrate and the washing liquid to obtain a toluene solution of FPS-2;
s3, cooling the toluene solution of the FPS-2 to below 100 ℃, protecting with nitrogen, adding hydroquinone and triethyl phosphite, and carrying out reflux reaction for 5-10 h; after the reaction is completed, removing the solvent and byproducts; removing solvent and byproducts, adding absolute methanol for dissolution, and adding water while keeping a reflux state; cooling to the ambient temperature for crystallization for 4-8 h, and further cooling to-5 ℃ for crystallization for 1-2 h; filtering, washing the filter cake with aqueous solution of methanol, and drying the filter cake to obtain FPS-3;
s4, sequentially adding anhydrous acetic acid and ethyl acetate into the FPS-3, adjusting the temperature to 10-20 ℃, adding tetrabutylammonium fluoride and N, N-dimethylformamide, and reacting for 48 hours at 10-20 ℃; after the reaction is completed, washing by potassium bicarbonate solution, backwashing the water phase by ethyl acetate, and merging organic phases; the organic phase was washed with saturated brine and dried over anhydrous sodium sulfate; filtering, washing a filter cake with ethyl acetate, and combining the filtrate and the washing liquid to obtain a solution of FPS-4;
s5, sequentially adding triphenylphosphine, sodium isooctanoate and methylene dichloride into the FPS-4 solution, stirring, adding tetrakis (triphenylphosphine) palladium, and reacting for 1-2 h at 20-30 ℃; after the reaction is completed, adding water to separate crystal for 1-2 h; filtering, washing the filter cake with acetone, and drying the filter cake to obtain the faropenem sodium.
2. The method of claim 1, wherein the molar ratio of potassium carbonate to R- (+) -thiotetrahydrofuran-2-carboxylic acid is 1:1 when preparing the FPS-1.
3. The method of manufacturing according to claim 1, further comprising the steps of: mixing the obtained faropenem sodium with water, heating to 45-50 ℃, adding active carbon after dissolving, and filtering to obtain a faropenem sodium solution;
and (3) regulating the temperature of the faropenem sodium solution to 40-50 ℃, adding acetone, cooling to-5 ℃ for crystallization for 1-2 h, and filtering to obtain a filter cake.
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| CN101585846A (en) * | 2009-06-11 | 2009-11-25 | 复旦大学 | Preparation method of faropenem sodium |
| CN101585847A (en) * | 2009-07-08 | 2009-11-25 | 成都樵枫科技发展有限公司 | Synthetic method of faropenem sodium |
| CN102964357A (en) * | 2012-11-11 | 2013-03-13 | 苏州二叶制药有限公司 | Faropenem sodium and tablet thereof |
| CN103059046A (en) * | 2013-01-28 | 2013-04-24 | 苏州二叶制药有限公司 | Preparation method of faropenem |
| CN107337684A (en) * | 2017-08-10 | 2017-11-10 | 沈阳三九药业有限公司 | A kind of preparation method of Faropenem sodium |
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| CN101585846A (en) * | 2009-06-11 | 2009-11-25 | 复旦大学 | Preparation method of faropenem sodium |
| CN101585847A (en) * | 2009-07-08 | 2009-11-25 | 成都樵枫科技发展有限公司 | Synthetic method of faropenem sodium |
| CN102964357A (en) * | 2012-11-11 | 2013-03-13 | 苏州二叶制药有限公司 | Faropenem sodium and tablet thereof |
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