CN110950761A - Synthesis method of latamoxef 7-site side chain - Google Patents
Synthesis method of latamoxef 7-site side chain Download PDFInfo
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- CN110950761A CN110950761A CN201911288231.6A CN201911288231A CN110950761A CN 110950761 A CN110950761 A CN 110950761A CN 201911288231 A CN201911288231 A CN 201911288231A CN 110950761 A CN110950761 A CN 110950761A
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- JWCSIUVGFCSJCK-CAVRMKNVSA-N Disodium Moxalactam Chemical compound N([C@]1(OC)C(N2C(=C(CSC=3N(N=NN=3)C)CO[C@@H]21)C(O)=O)=O)C(=O)C(C(O)=O)C1=CC=C(O)C=C1 JWCSIUVGFCSJCK-CAVRMKNVSA-N 0.000 title claims abstract description 14
- 229960000433 latamoxef Drugs 0.000 title claims abstract description 14
- 238000001308 synthesis method Methods 0.000 title claims abstract description 10
- XQXPVVBIMDBYFF-UHFFFAOYSA-N 4-hydroxyphenylacetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1 XQXPVVBIMDBYFF-UHFFFAOYSA-N 0.000 claims abstract description 50
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 33
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims abstract description 29
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000003054 catalyst Substances 0.000 claims abstract description 15
- 239000001569 carbon dioxide Substances 0.000 claims abstract description 11
- 229910002092 carbon dioxide Inorganic materials 0.000 claims abstract description 11
- 239000000243 solution Substances 0.000 claims abstract description 11
- JDAOUSDBYYNLLA-UHFFFAOYSA-N C(C1=CC=CC=C1)Cl.COC1=CC=C(C(=O)O)C=C1 Chemical compound C(C1=CC=CC=C1)Cl.COC1=CC=C(C(=O)O)C=C1 JDAOUSDBYYNLLA-UHFFFAOYSA-N 0.000 claims abstract description 10
- 239000003444 phase transfer catalyst Substances 0.000 claims abstract description 9
- 239000002253 acid Substances 0.000 claims abstract description 7
- 239000011259 mixed solution Substances 0.000 claims abstract description 7
- 239000011230 binding agent Substances 0.000 claims abstract description 5
- 239000012295 chemical reaction liquid Substances 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 238000000034 method Methods 0.000 claims description 21
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 18
- MZRVEZGGRBJDDB-UHFFFAOYSA-N N-Butyllithium Chemical compound [Li]CCCC MZRVEZGGRBJDDB-UHFFFAOYSA-N 0.000 claims description 12
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 229910052757 nitrogen Inorganic materials 0.000 claims description 9
- -1 methoxybenzoic acid benzyl chloride Chemical compound 0.000 claims description 8
- 239000011736 potassium bicarbonate Substances 0.000 claims description 8
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 8
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 8
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 8
- LZZYPRNAOMGNLH-UHFFFAOYSA-M Cetrimonium bromide Chemical compound [Br-].CCCCCCCCCCCCCCCC[N+](C)(C)C LZZYPRNAOMGNLH-UHFFFAOYSA-M 0.000 claims description 6
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 6
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 235000011181 potassium carbonates Nutrition 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 150000002642 lithium compounds Chemical class 0.000 claims description 4
- YNXURHRFIMQACJ-UHFFFAOYSA-N lithium;methanidylbenzene Chemical compound [Li+].[CH2-]C1=CC=CC=C1 YNXURHRFIMQACJ-UHFFFAOYSA-N 0.000 claims description 4
- 229910052751 metal Inorganic materials 0.000 claims description 4
- 239000002184 metal Substances 0.000 claims description 4
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000007818 Grignard reagent Substances 0.000 claims description 2
- 239000004721 Polyphenylene oxide Substances 0.000 claims description 2
- 150000004795 grignard reagents Chemical class 0.000 claims description 2
- 229920000570 polyether Polymers 0.000 claims description 2
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 2
- 150000003242 quaternary ammonium salts Chemical class 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 235000017550 sodium carbonate Nutrition 0.000 claims description 2
- 239000012970 tertiary amine catalyst Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 2
- MOHYOXXOKFQHDC-UHFFFAOYSA-N 1-(chloromethyl)-4-methoxybenzene Chemical compound COC1=CC=C(CCl)C=C1 MOHYOXXOKFQHDC-UHFFFAOYSA-N 0.000 description 8
- 238000003786 synthesis reaction Methods 0.000 description 7
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000543 intermediate Substances 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007858 starting material Substances 0.000 description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 4
- 239000002699 waste material Substances 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 3
- FVAUCKIRQBBSSJ-UHFFFAOYSA-M sodium iodide Chemical compound [Na+].[I-] FVAUCKIRQBBSSJ-UHFFFAOYSA-M 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- KEGBFXKSTAEIDP-UHFFFAOYSA-N (4-methoxyphenyl)methyl 2-[4-[(4-methoxyphenyl)methoxy]phenyl]acetate Chemical compound C1=CC(OC)=CC=C1COC(=O)CC(C=C1)=CC=C1OCC1=CC=C(OC)C=C1 KEGBFXKSTAEIDP-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 2
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 description 2
- 238000005265 energy consumption Methods 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 230000032050 esterification Effects 0.000 description 2
- 238000005886 esterification reaction Methods 0.000 description 2
- 238000006266 etherification reaction Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 150000002500 ions Chemical class 0.000 description 2
- 239000012452 mother liquor Substances 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- PBVZQAXFSQKDKK-UHFFFAOYSA-N 3-Methoxy-3-oxopropanoic acid Chemical class COC(=O)CC(O)=O PBVZQAXFSQKDKK-UHFFFAOYSA-N 0.000 description 1
- MSHFRERJPWKJFX-UHFFFAOYSA-N 4-Methoxybenzyl alcohol Chemical compound COC1=CC=C(CO)C=C1 MSHFRERJPWKJFX-UHFFFAOYSA-N 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 229930186147 Cephalosporin Natural products 0.000 description 1
- 108090000204 Dipeptidase 1 Proteins 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 1
- 230000002152 alkylating effect Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 102000006635 beta-lactamase Human genes 0.000 description 1
- 230000003115 biocidal effect Effects 0.000 description 1
- 229940124587 cephalosporin Drugs 0.000 description 1
- 150000001780 cephalosporins Chemical class 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000006471 dimerization reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000026030 halogenation Effects 0.000 description 1
- 238000005658 halogenation reaction Methods 0.000 description 1
- 229910000042 hydrogen bromide Inorganic materials 0.000 description 1
- HBMCQTHGYMTCOF-UHFFFAOYSA-N hydroquinone monoacetate Natural products CC(=O)OC1=CC=C(O)C=C1 HBMCQTHGYMTCOF-UHFFFAOYSA-N 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- XGDZEDRBLVIUMX-UHFFFAOYSA-N methyl 2-(4-hydroxyphenyl)acetate Chemical compound COC(=O)CC1=CC=C(O)C=C1 XGDZEDRBLVIUMX-UHFFFAOYSA-N 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000005580 one pot reaction Methods 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 239000012217 radiopharmaceutical Substances 0.000 description 1
- 229940121896 radiopharmaceutical Drugs 0.000 description 1
- 230000002799 radiopharmaceutical effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 235000009518 sodium iodide Nutrition 0.000 description 1
- 239000002912 waste gas Substances 0.000 description 1
- 150000003952 β-lactams Chemical class 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/313—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of doubly bound oxygen containing functional groups, e.g. carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/48—Separation; Purification; Stabilisation; Use of additives
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention provides a synthesis method of latamoxef 7-site side chain, which comprises the following steps: 1) adding a mixed solution of toluene and acetone, p-hydroxyphenylacetic acid, an acid-binding agent, a phase transfer catalyst and p-methoxybenzoic acid benzyl chloride into a reactor to completely react; 2) adding a strong base catalyst into the reaction liquid obtained in the step 1) to adjust the pH value of the solution to be more than 13, introducing carbon dioxide at the temperature of minus 50 ℃ to minus 55 ℃, and concentrating and crystallizing to obtain a product; the synthesis method disclosed by the invention is simple to operate, low in cost, greatly improved in productivity, improved in yield which is more than 90%, higher in product purity which is more than 99%, and capable of obtaining surprising technical effects.
Description
Technical Field
The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of a latamoxef 7-site side chain.
Background
Latamoxef is a novel semi-synthetic β -lactam broad-spectrum antibiotic, has extremely high stability to β -lactamase, and has antibacterial action to penicillinase-resistant strains and cephalosporin-resistant gram-negative bacteria.
At present, the synthesis of 7-position side chain intermediate generally adopts the following 2 routes
Route 1: p-hydroxy phenylacetate is used as a starting material, and is condensed with dimethyl carbonate, p-methoxybenzyl chloride is used for alkylating phenolic hydroxyl, so that the phenolic hydroxyl is protected, and the methyl malonate derivative is partially hydrolyzed under an alkaline condition to obtain a designed intermediate.
The route 2 is that methyl p-hydroxyphenylacetate is used as an initial raw material, and the p-methoxybenzyl chloride is firstly used for protecting phenolic hydroxyl, condensed with dimethyl carbonate and partially hydrolyzed under the alkaline condition to obtain a target product.
Comparing the two synthetic routes, it can be seen that the synthetic process conditions are not significantly different, but in the experimental process, the intermediate 1 in route 2 has a lower melting point and is not easy to crystallize and purify, so route 1 is usually selected as the synthetic route.
The Chinese patent application CN 102718656A discloses that p-methoxybenzyl chloride is used as a starting material, potassium carbonate is used as a catalyst, DMF is used as a solvent, and ice water is added after reaction to separate out a product. The latamoxef 7-side chain chemical synthesis method generally takes p-methoxy benzyl alcohol as a starting material, hydroxymethyl reacts with thionyl chloride or hydrogen chloride (hydrogen bromide) through halogenation to p-methoxy chloro (bromo) benzyl, and then the esterification and etherification reactions are carried out in the next step. The literature Chaudhari, Sachin S.Synlett,1999 mentions that the yield of p-methoxybenzyl chloride prepared by thionyl chloride is relatively high, but the problems of high requirement on reaction equipment, difficult reaction control, serious waste gas pollution and the like exist. While the p-methoxybenzyl chloride is prepared by using hydrogen chloride (20%) in Elbert. journal of laboratory Compounds and radiopharmaceuticals 1994, the reaction conditions are mild, but the environmental protection problem of generating a large amount of waste acid water exists. Meanwhile, the p-methoxybenzyl chloride is very unstable, so that the dimerization reaction of benzyl is easy to occur, and certain influence is exerted on the subsequent reaction of latamoxef 7-side chain chemical synthesis. U.S. Pat. No. 4,4337079 discloses a chemical synthesis method of p-moxalactam 7-side chain, wherein p-methoxybenzyl chloride is used as a starting material, and is subjected to esterification and etherification with p-hydroxyphenylacetic acid, acetone is used as a solvent, and potassium bicarbonate is used as a basic catalyst to prepare 4- (4-methoxybenzyloxy) phenylacetic acid-4-methoxybenzyl ester, wherein the 4- (4-methoxybenzyloxy) phenylacetic acid-4-methoxybenzyl ester is not high in purity and low in yield, and a large amount of potassium bicarbonate waste residues are generated, so that the reaction time is long, the energy consumption is large, and the large-scale production is not facilitated.
Disclosure of Invention
In order to solve the problems, the invention provides a synthesis method of latamoxef 7-position side chain, aiming at overcoming the defects of the prior art, and providing a one-pot synthesis method of latamoxef 7-position side chain, which greatly reduces the use of solvent, avoids the environmental protection problem of generating a large amount of waste acid water and alkaline waste residue, reduces energy consumption, and increases the yield and purity of the product.
The invention provides a synthesis method of latamoxef 7-site side chain, which comprises the following steps:
1) adding a mixed solution of toluene and acetone, p-hydroxyphenylacetic acid, an acid-binding agent, a phase transfer catalyst and p-methoxybenzoic acid benzyl chloride into a reactor to completely react;
2) adding a strong base catalyst into the reaction liquid obtained in the step 1) to adjust the pH value of the solution to be more than 13, introducing carbon dioxide at the temperature of minus 50 ℃ to minus 55 ℃, and concentrating and crystallizing to obtain a product;
wherein the volume ratio of toluene to acetone in the mixed solution is 1:4-1:0.25, the mass ratio of p-glycolic acid to the mixed solution is 0.6:1-0.7:1, and the mass ratio of p-glycolic acid to methoxybenzoic acid benzyl chloride is 0.6: 1-0.8:1.
Further, the acid-binding agent comprises more than one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
Further, the phase transfer catalyst comprises more than one of polyether catalyst, cyclic crown ether catalyst, quaternary ammonium salt catalyst, tertiary amine catalyst and quaternary ammonium base catalyst.
Further, the phase transfer catalyst comprises more than one of tetrabutylammonium bromide, polyethylene glycol and hexadecyl trimethyl ammonium bromide.
Further, the strong base is catalyzed into more than one of organic metal lithium compound, Grignard reagent and alkyl copper lithium.
Further, the organic metal lithium compound comprises more than one of butyl lithium, lithium diisopropylamide and benzyl lithium.
Further, the temperature of the reaction is 60-80 ℃.
Further, the method also comprises a step of stirring in the reaction process, wherein the stirring speed is 400-500 r/min.
Further, the reaction is completely and specifically, the residue of the p-hydroxyphenylacetic acid in the reaction liquid is less than 3 g/L.
Further, the method also comprises a nitrogen protection condition under the reaction condition.
The invention relates to a synthesis method of latamoxef side chains as key intermediates in latamoxef synthesis. P-hydroxyphenylacetic acid and p-methoxybenzyl chloride are reacted in a mixed solvent in the presence of a phase transfer catalyst to obtain p- (p-methoxy) benzyloxy phenylacetic acid (p-methoxy) benzyl ester, then strong base is used as a catalyst to react to generate corresponding negative ions, and the corresponding negative ions are further reacted with carbon dioxide to obtain the latamoxef 7-site side chain. The introduction of the phase transfer catalyst in the first step of the synthesis greatly reduces the dosage of sodium iodide, improves the yield of the product and improves the separation of side chains. The solvent can be mother liquor recycled and reused. The mother liquor is recovered and reused after removing water.
Compared with the prior art, the invention has the following beneficial effects:
1. the method provided by the invention omits the existing benzyl ester separation step, is rapid and simple, and has high product purity.
2. The synthesis method disclosed by the invention is simple to operate, low in cost, greatly improved in productivity and yield, higher in molar yield of more than 92%, higher in product purity of more than 99%, and capable of obtaining surprising technical effects.
3. The method of the invention ensures that the reaction alkalinity is uniformly dispersed by the mutual coordination of the strong basic catalyst and the stirring speed, temperature and the like, thereby greatly improving the yield and purity of the reaction.
Example 1
To a clean reaction flask, 200mL of acetone 800mL of toluene, 63g of p-hydroxyphenylacetic acid, 43.5g of potassium carbonate, 1.3g of tetrabutylammonium bromide and 95g of p-methoxybenzoic acid benzyl chloride were added in this order under nitrogen protection, the reaction was stirred at a rate of 400r/min at 65 ℃ for 5 hours, and a sample was taken to detect that the p-hydroxyphenylacetic acid residue was 2.9 g/L. Adding 3.4g benzyl lithium, introducing carbon dioxide into the solution at the temperature of minus 50 ℃ with the pH =13, concentrating and crystallizing to obtain a white product, wherein the yield is 92% calculated by using p-hydroxyphenylacetic acid, and the purity is 99.5%.
Example 2
Under the protection of nitrogen, 300mL of acetone 700mL of toluene, 63g of p-hydroxyphenylacetic acid, 40g of sodium bicarbonate, 2g of polyethylene glycol and 95g of p-methoxybenzoic acid benzyl chloride are sequentially added into a clean reaction flask, the mixture is stirred and reacted at the temperature of 50 ℃ at the speed of 460r/min for 6 hours, and a sample is taken to detect that the p-hydroxyphenylacetic acid residue is 2.9 g/L. Adding 8g lithium diisopropylamide, introducing carbon dioxide at the solution pH =13 and-55 ℃, concentrating, and crystallizing to obtain a white product, wherein the yield is 93% and the purity is 99.6% by calculating the p-hydroxyphenylacetic acid.
Example 3
500mL of acetone 500mL of toluene, 63g of p-hydroxyphenylacetic acid, 46g of potassium bicarbonate, 4g of cetyltrimethylammonium bromide and 95g of p-methoxybenzoic acid benzyl chloride were sequentially added to a clean reaction flask under nitrogen protection, the reaction was stirred at a speed of 500r/min at 70 ℃ for 5 hours, and a sample was taken to detect that the p-hydroxyphenylacetic acid residue was 2.7 g/L. Adding 6g of butyl lithium, introducing carbon dioxide into the solution at the pH =14 and the temperature of minus 53 ℃, concentrating and crystallizing to obtain 180.7g of white product, wherein the yield is 95 percent calculated by p-hydroxyphenylacetic acid, and the purity is 99.6 percent.
Example 4
To a clean reaction flask, 800mL of acetone 200mL of toluene, 63g of p-hydroxyphenylacetic acid, 46g of potassium bicarbonate, 4g of cetyltrimethylammonium bromide and 95g of p-methoxybenzoic acid benzyl chloride were added in this order under nitrogen protection, the reaction was stirred at a rate of 440r/min at 70 ℃ for 5 hours, and a sample was taken to detect that the p-hydroxyphenylacetic acid residue was 2.7 g/L. Adding 6g of butyl lithium, introducing carbon dioxide into the solution at the pH =14 and the temperature of minus 53 ℃, concentrating and crystallizing to obtain a white product, wherein the yield is 92 percent calculated by p-hydroxyphenylacetic acid, and the purity is 99.8 percent.
Comparative example 1
1000mL of acetone, 63g of p-hydroxyphenylacetic acid, 43.5g of potassium carbonate, 1.3g of tetrabutylammonium bromide and 95g of p-methoxybenzoic acid benzyl chloride were sequentially added to a clean reaction flask under the protection of nitrogen, the reaction was stirred at a speed of 400r/min at 65 ℃ for 5 hours, and a sample was taken to detect that the p-hydroxyphenylacetic acid residue was 2.9 g/L. Adding 3.4g benzyl lithium, introducing carbon dioxide into the solution at the temperature of minus 50 ℃ with the pH =13, concentrating and crystallizing to obtain a white product, wherein the yield is 85 percent calculated by p-hydroxyphenylacetic acid, and the purity is 97.5 percent.
Comparative example 2
To a clean reaction flask, 800mL of acetone 200mL of toluene, 63g of p-hydroxyphenylacetic acid, 46g of potassium bicarbonate, 4g of cetyltrimethylammonium bromide and 95g of p-methoxybenzoic acid benzyl chloride were added in this order under nitrogen protection, the reaction was stirred at a rate of 440r/min at 70 ℃ for 5 hours, and a sample was taken to detect that the p-hydroxyphenylacetic acid residue was 2.7 g/L. Adding 6g of butyl lithium, introducing carbon dioxide into the solution at the pH =10 and the temperature of minus 53 ℃, concentrating and crystallizing to obtain a white product, wherein the yield is 89% and the purity is 97.8% by calculating the p-hydroxyphenylacetic acid.
Comparative example 3
500mL of acetone 500mL of toluene, 63g of p-hydroxyphenylacetic acid, 46g of potassium bicarbonate, 4g of cetyltrimethylammonium bromide and 95g of p-methoxybenzoic acid benzyl chloride were sequentially added to a clean reaction flask under nitrogen protection, the reaction was stirred at a speed of 200r/min at 90 ℃ for 5 hours, and a sample was taken to detect that the p-hydroxyphenylacetic acid residue was 2.7 g/L. 6g of butyllithium were added, the solution was concentrated at pH =14, carbon dioxide was introduced at-53 ℃ and the yield was 89% calculated as p-hydroxyphenylacetic acid and the purity was 95.6%.
The above examples are merely illustrative of several embodiments of the present invention, and the description is specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.
Claims (10)
1. A synthesis method of latamoxef 7-site side chain is characterized in that: the method comprises the following steps:
1) adding a mixed solution of toluene and acetone, p-hydroxyphenylacetic acid, an acid-binding agent, a phase transfer catalyst and p-methoxybenzoic acid benzyl chloride into a reactor to completely react;
2) adding a strong base catalyst into the reaction liquid obtained in the step 1) to adjust the pH value of the solution to be more than 13, introducing carbon dioxide at the temperature of minus 50 ℃ to minus 55 ℃, and concentrating and crystallizing to obtain a product;
wherein the volume ratio of toluene to acetone in the mixed solution is 1:4-1:0.25, the mass ratio of p-glycolic acid to the mixed solution is 0.6:1-0.7:1, and the mass ratio of p-glycolic acid to methoxybenzoic acid benzyl chloride is 0.6: 1-0.8:1.
2. The method of claim 1, wherein: the acid-binding agent comprises more than one of sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
3. The method of claim 1, wherein: the phase transfer catalyst comprises more than one of polyether catalyst, cyclic crown ether catalyst, quaternary ammonium salt catalyst, tertiary amine catalyst and quaternary ammonium base catalyst.
4. The method of claim 1, wherein: the phase transfer catalyst comprises more than one of tetrabutylammonium bromide, polyethylene glycol and hexadecyl trimethyl ammonium bromide.
5. The method of claim 1, wherein: the strong base catalyzes to more than one of organic metal lithium compound, Grignard reagent and alkyl copper lithium.
6. The method of claim 5, wherein: the organic metal lithium compound comprises more than one of butyl lithium, lithium diisopropylamide and benzyl lithium.
7. The method of any of claims 1 to 5, wherein: the temperature of the reaction is 60-80 ℃.
8. The method of any of claims 1 to 5, wherein: the method also comprises the step of stirring in the reaction process, wherein the stirring speed is 50-500 r/min.
9. The method of any of claims 1 to 5, wherein: the reaction is complete, and particularly, the residue of the p-hydroxyphenylacetic acid in the reaction solution is less than 3 g/L.
10. The method of any of claims 1 to 5, wherein: the method also comprises a nitrogen protection condition under the reaction condition.
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| CN201911288231.6A CN110950761A (en) | 2019-12-16 | 2019-12-16 | Synthesis method of latamoxef 7-site side chain |
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| Application Number | Priority Date | Filing Date | Title |
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| CN201911288231.6A CN110950761A (en) | 2019-12-16 | 2019-12-16 | Synthesis method of latamoxef 7-site side chain |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718656A (en) * | 2012-06-15 | 2012-10-10 | 济南诚汇双达化工有限公司 | Preparation method of 2-(4-hydroxyphenyl)-propanedioic acidl-[(4-methoxyphenyl)methyl]ester |
| CN103864610A (en) * | 2012-12-11 | 2014-06-18 | 山东睿鹰先锋制药有限公司 | Preparation method of phenyl malonic acid monoester compound |
| CN110003006A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of sour 7 side chains of latamoxef |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102718656A (en) * | 2012-06-15 | 2012-10-10 | 济南诚汇双达化工有限公司 | Preparation method of 2-(4-hydroxyphenyl)-propanedioic acidl-[(4-methoxyphenyl)methyl]ester |
| CN103864610A (en) * | 2012-12-11 | 2014-06-18 | 山东睿鹰先锋制药有限公司 | Preparation method of phenyl malonic acid monoester compound |
| CN110003006A (en) * | 2019-04-23 | 2019-07-12 | 山西千岫制药有限公司 | A kind of preparation method of sour 7 side chains of latamoxef |
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| Title |
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| 刘相奎等: "4-(4-甲氧基苄基氧基)苯丙二酸-4-甲氧基苄基单酯的工艺改进", 《中国抗生素杂志》 * |
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