CN108033971B - Method for synthesizing cefcapene pivoxil hydrochloride - Google Patents
Method for synthesizing cefcapene pivoxil hydrochloride Download PDFInfo
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- 229950004627 cefcapene pivoxil Drugs 0.000 title claims abstract description 26
- 238000000034 method Methods 0.000 title claims abstract description 26
- 230000002194 synthesizing effect Effects 0.000 title claims abstract description 11
- LUXIJPQYUCFVAL-XRLCNELCSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydron;chloride;hydrate Chemical compound O.Cl.N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 LUXIJPQYUCFVAL-XRLCNELCSA-N 0.000 title claims abstract 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 45
- 239000012044 organic layer Substances 0.000 claims abstract description 39
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 35
- 238000006243 chemical reaction Methods 0.000 claims abstract description 32
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims abstract description 22
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims abstract description 16
- 239000002904 solvent Substances 0.000 claims abstract description 16
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 16
- 239000007864 aqueous solution Substances 0.000 claims abstract description 15
- 239000013078 crystal Substances 0.000 claims abstract description 14
- PELJISAVHGXLAL-UHFFFAOYSA-N iodomethyl 2,2-dimethylpropanoate Chemical compound CC(C)(C)C(=O)OCI PELJISAVHGXLAL-UHFFFAOYSA-N 0.000 claims abstract description 13
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims abstract description 11
- 235000019253 formic acid Nutrition 0.000 claims abstract description 11
- 238000001035 drying Methods 0.000 claims abstract description 9
- 238000005406 washing Methods 0.000 claims abstract description 9
- 235000017557 sodium bicarbonate Nutrition 0.000 claims abstract description 8
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims abstract description 8
- 150000001875 compounds Chemical class 0.000 claims abstract description 6
- 239000010410 layer Substances 0.000 claims abstract description 6
- 150000007522 mineralic acids Chemical class 0.000 claims abstract description 6
- 239000002994 raw material Substances 0.000 claims abstract description 6
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims abstract description 5
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims abstract description 5
- 239000007788 liquid Substances 0.000 claims abstract description 4
- 238000001816 cooling Methods 0.000 claims abstract description 3
- 150000007529 inorganic bases Chemical class 0.000 claims abstract description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 21
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 8
- 239000000243 solution Substances 0.000 claims description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 6
- 239000002253 acid Substances 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 4
- 230000035484 reaction time Effects 0.000 claims description 3
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- 229910052500 inorganic mineral Inorganic materials 0.000 claims description 2
- 239000011707 mineral Substances 0.000 claims description 2
- 235000010755 mineral Nutrition 0.000 claims description 2
- XHFLOLLMZOTPSM-UHFFFAOYSA-M sodium;hydrogen carbonate;hydrate Chemical compound [OH-].[Na+].OC(O)=O XHFLOLLMZOTPSM-UHFFFAOYSA-M 0.000 claims description 2
- 238000001914 filtration Methods 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 3
- 239000003814 drug Substances 0.000 abstract description 3
- 238000003786 synthesis reaction Methods 0.000 abstract description 3
- 230000007613 environmental effect Effects 0.000 abstract description 2
- 238000009776 industrial production Methods 0.000 abstract description 2
- WVPAABNYMHNFJG-QDVBXLKVSA-N 2,2-dimethylpropanoyloxymethyl (6r,7r)-7-[[(z)-2-(2-amino-1,3-thiazol-4-yl)pent-2-enoyl]amino]-3-(carbamoyloxymethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate Chemical compound N([C@@H]1C(N2C(=C(COC(N)=O)CS[C@@H]21)C(=O)OCOC(=O)C(C)(C)C)=O)C(=O)\C(=C/CC)C1=CSC(N)=N1 WVPAABNYMHNFJG-QDVBXLKVSA-N 0.000 description 17
- -1 (carbamoyl) oxy Chemical group 0.000 description 11
- 239000000203 mixture Substances 0.000 description 8
- 239000000047 product Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 238000002425 crystallisation Methods 0.000 description 4
- 230000008025 crystallization Effects 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229930186147 Cephalosporin Natural products 0.000 description 3
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 3
- 229940124587 cephalosporin Drugs 0.000 description 3
- 150000001780 cephalosporins Chemical class 0.000 description 3
- 230000001276 controlling effect Effects 0.000 description 3
- 230000032050 esterification Effects 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 238000001308 synthesis method Methods 0.000 description 3
- HSHGZXNAXBPPDL-HZGVNTEJSA-N 7beta-aminocephalosporanic acid Chemical compound S1CC(COC(=O)C)=C(C([O-])=O)N2C(=O)[C@@H]([NH3+])[C@@H]12 HSHGZXNAXBPPDL-HZGVNTEJSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Natural products CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 238000005580 one pot reaction Methods 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 125000006239 protecting group Chemical group 0.000 description 2
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical compound [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 2
- UOCLXMDMGBRAIB-UHFFFAOYSA-N 1,1,1-trichloroethane Chemical compound CC(Cl)(Cl)Cl UOCLXMDMGBRAIB-UHFFFAOYSA-N 0.000 description 1
- SHRCVUQEWNCLJQ-UHFFFAOYSA-N C(C=CCC)(=O)O.NC=1SC=CN1 Chemical compound C(C=CCC)(=O)O.NC=1SC=CN1 SHRCVUQEWNCLJQ-UHFFFAOYSA-N 0.000 description 1
- 238000007112 amidation reaction Methods 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 125000003460 beta-lactamyl group Chemical group 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 229960002966 cefcapene Drugs 0.000 description 1
- 239000007795 chemical reaction product Substances 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 229910052943 magnesium sulfate Inorganic materials 0.000 description 1
- 235000019341 magnesium sulphate Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 229910000160 potassium phosphate Inorganic materials 0.000 description 1
- 235000011009 potassium phosphates Nutrition 0.000 description 1
- 238000004321 preservation Methods 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- WROMPOXWARCANT-UHFFFAOYSA-N tfa trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F.OC(=O)C(F)(F)F WROMPOXWARCANT-UHFFFAOYSA-N 0.000 description 1
- XJDNKRIXUMDJCW-UHFFFAOYSA-J titanium tetrachloride Chemical compound Cl[Ti](Cl)(Cl)Cl XJDNKRIXUMDJCW-UHFFFAOYSA-J 0.000 description 1
- SIOVKLKJSOKLIF-HJWRWDBZSA-N trimethylsilyl (1z)-n-trimethylsilylethanimidate Chemical compound C[Si](C)(C)OC(/C)=N\[Si](C)(C)C SIOVKLKJSOKLIF-HJWRWDBZSA-N 0.000 description 1
- 238000007039 two-step reaction Methods 0.000 description 1
- 239000002699 waste material Substances 0.000 description 1
- 239000002351 wastewater Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/02—Preparation
- C07D501/04—Preparation from compounds already containing the ring or condensed ring systems, e.g. by dehydrogenation of the ring, by introduction, elimination or modification of substituents
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D501/14—Compounds having a nitrogen atom directly attached in position 7
- C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
- C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
- C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
- C07D501/26—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group
- C07D501/34—Methylene radicals, substituted by oxygen atoms; Lactones thereof with the 2-carboxyl group with the 7-amino radical acylated by carboxylic acids containing hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Cephalosporin Compounds (AREA)
Abstract
The invention discloses a method for synthesizing cefcapene pivoxil hydrochloride, and belongs to the technical field of synthesis of cephalo-type medicaments. The method comprises the following steps: (1) BCN is used as an initial raw material, reacts with an inorganic acid aqueous solution in a solvent until the BCN is clear, stands for layering, removes a water layer, collects an organic layer containing a compound I and dries the organic layer; (2) adding formic acid and concentrated hydrochloric acid, reacting at 0-5 ℃, washing with water after the reaction is finished, layering, and collecting an organic layer containing a compound II; (3) adding sodium bicarbonate aqueous solution and iodomethyl pivalate, maintaining pH value at 5-6, layering after reaction, collecting organic layer, adding ethanol, washing with water, layering, adding ethanol into organic layer, adjusting pH value to 7-8 with inorganic base, layering, and collecting organic layer containing compound III; (4) concentrating under reduced pressure until no liquid drops are distilled off, adding a solvent, adding diluted hydrochloric acid to adjust the crystal, cooling to grow the crystal, filtering, and drying to obtain cefcapene pivoxil hydrochloride. The method has the advantages of simple process, mild reaction conditions, environmental friendliness, high yield, high purity and easy industrial production.
Description
Technical Field
The invention belongs to the technical field of synthesis of cephalosporin drugs, and particularly relates to a synthesis method of cefcapene pivoxil hydrochloride.
Background
Cefcapene pivoxil hydrochloride, chemical name: (6R,7R) -3- (((carbamoyl) oxy) methyl) -7- (((2Z) -2- (2-amino-4-thiazolyl) -1-oxo-2-penten) amino) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylic acid 2, 2-dimethylpivaloyloxymethyl ester hydrochloride monohydrate having the formula:
cefcapene pivoxil hydrochloride is a broad-spectrum cephalosporin antibiotic, which was originally developed by Nippon salt-wild-pharmaceutical Co., Ltd, and is marketed in Japan for the first time under the trade name Flomox in 1997, is a semi-synthetic third-generation cephalosporin, and belongs to broad-spectrum antibiotic drugs.
Because a plurality of β -lactam rings in the structure of cefcapene pivoxil hydrochloride are easy to generate degradation reaction, the stability of cefcapene pivoxil hydrochloride is poor, impurities of a finished product become large due to overhigh temperature, overhigh humidity, overhigh acidity, illumination and the like, and in addition, the crystallization temperature, the crystal growing time, the concentration of hydrochloric acid and the selection of a crystallization solvent also have certain influence on the quality of the finished product.
Ishikura K et al (The journal of antibiotics.1994, 466-476) disclose a synthesis method of cefcapene pivoxil, which uses 7-aminocephalosporanic acid as a raw material, firstly modifies The 3-position of 7-aminocephalosporanic acid into carbamoyloxymethyl and 4-position of The compound obtained by ester formation, then reacts with Boc-protected (Z) -2- (2-aminothiazole-4-yl) -2-pentenoic acid, and then hydrolyzes to obtain a key intermediate cefcapene pivoxil, wherein The cefcapene pivoxil is subjected to K-position modification2CO3Forming ester with iodomethyl pivalate under the action, and finally removing Boc group with trifluoroacetic acid (TFA) to obtain cefcapene pivoxil. The TFA used in the method has great influence on the environment, the three wastes are difficult to treat, and in the condensation reaction of carboxylic acid and amino and the ester forming reaction of carboxylic acid and iodomethyl pivalate, the reaction reagents are not well selected, so that the main ring mother nucleus is damaged, the yield is low, and the byproducts are more.
WO 2008155615: the method comprises the steps of protecting 4-carboxyl and 3-hydroxymethyl hydroxyl by using N, O-bis (trimethylsilyl) acetamide, carrying out amidation reaction with amino thiazole pentenoic acid protected by Boc group, directly reacting with CSI without separation, and carrying out esterification and deprotection to obtain a target product. The method has complex operation and higher cost, and is not suitable for large-scale production.
CN 102775425A: discloses a one-pot preparation method of cefcapene diisopropylamine salt serving as a key intermediate of cefcapene pivoxil, which has the advantages that although the operation is simple, the yield is not high, and the purity of a two-step reaction product is only 67 percent under the condition of unknown purity.
CN 105254649A: the patent process discloses the preparation of cefcapene pivoxil by using 7-HACA as a raw material, wherein the esterification process is carried out in the presence of potassium phosphate and acetic acid ketone, and then the esterification process and hydrochloric acid are reacted to remove a protecting group, the total yield of two steps is 68.82 percent, the patent process generates high-salt wastewater, and the total yield of two steps is low.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for synthesizing cefcapene pivoxil hydrochloride, which has the advantages of simple process, mild reaction conditions, environmental friendliness, high yield, high purity and easiness in industrial production.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for synthesizing cefcapene pivoxil hydrochloride comprises the following steps:
(1) reaction with aqueous mineral acid: BCN is used as an initial raw material, reacts with an inorganic acid aqueous solution in a solvent until the BCN is clear, stands for layering, removes a water layer, collects an organic layer containing a compound I, and is dried;
(2) and (3) Boc removal reaction: taking the organic layer containing the compound I obtained in the step (1), adding formic acid and concentrated hydrochloric acid, reacting at 0-5 ℃, washing with water after the reaction is finished, layering, and collecting the organic layer containing the compound II;
(3) reaction with iodomethyl pivalate: controlling the temperature to be 10-30 ℃, adding a sodium bicarbonate aqueous solution and iodomethyl pivalate to the organic layer containing the compound II obtained in the step (2), maintaining the pH value to be 5-6, carrying out layering after the reaction is finished, collecting the organic layer, adding ethanol, washing the organic layer, carrying out layering, adding ethanol to the organic layer, adjusting the pH value to be 7-8 by using inorganic base, layering, and collecting the organic layer containing the compound III;
(4) reaction with dilute hydrochloric acid: taking the organic layer containing the compound III obtained in the step (3), concentrating under reduced pressure until no liquid drops are distilled off, adding a solvent, adding diluted hydrochloric acid to adjust the crystal, cooling to grow the crystal, carrying out suction filtration, and drying to obtain cefcapene pivoxil hydrochloride; the reaction equation is as follows:
preferably, in step (1): the solvent is one or more of methanol, ethanol, isopropanol, tert-butanol, n-butanol, dichloromethane, chloroform, 1-dichloroethane, trichloroethane, acetone, acetonitrile and tetrahydrofuran.
Further preferably, in step (1): the volume milliliter number of the solvent is 2 to 5 times of the mass gram number of the BCN.
Preferably, in step (1): the inorganic acid water solution is one of 5-15% by mass of sulfuric acid and 5-15% by mass of dilute hydrochloric acid.
Preferably, in step (2): the molar ratio of formic acid to concentrated hydrochloric acid is 1: 2-8, wherein the molar ratio of the total mole number of formic acid and concentrated hydrochloric acid to BCN is 5-10: 1; the reaction time is 6 to 8 hours
Preferably, in step (3): the molar ratio of iodomethyl pivalate to BCN is 1: 1; the mass percentage of the sodium bicarbonate water solution is 5-10%.
Preferably, in step (4): the solvent is one of acetone, ethyl acetate, methanol, dichloromethane or 1, 1-dichloroethane.
Preferably, in step (4): the temperature for growing the crystal is controlled to be 0-10 ℃.
Preferably, in step (4): the mol ratio of the addition amount of the dilute hydrochloric acid to the addition amount of the BCN is 1.1-5: 1; the mass percentage content of the dilute hydrochloric acid is 5-10 percent; the time for growing the crystal is 1-3 h.
Further preferably, in step (4): the mol ratio of the addition amount of the dilute hydrochloric acid to the addition amount of the BCN is 1.2: 1; the time for growing the grains is 1.5 h.
Boc is an abbreviation for t-butyloxycarbonyl (t-Butyloxy carbonyl) group, an amino protecting group commonly used in organic synthesis.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
(1) the synthesis method of cefcapene pivoxil hydrochloride firstly carries out Boc removal reaction, adopts mild conditions, avoids the use of trifluoroacetic acid and titanium tetrachloride, then carries out reaction with iodomethyl pivalate, directly carries out post-treatment after the reaction is finished, adds a solvent after the reduced pressure concentration, then dropwise adds dilute hydrochloric acid for crystallization, greatly improves the yield, has simple and easily obtained reaction raw materials, short process period, saves the drying of an intermediate, directly carries out one-pot one-step operation, has mild reaction conditions, is environment-friendly, and is suitable for large-scale popularization and application.
(2) The method uses simple and easily-obtained formic acid and concentrated hydrochloric acid to carry out Boc removal reaction, directly puts the intermediate process into the next reaction in a solution state, greatly shortens the reaction time, saves the drying process, directly adjusts the acid of the product to form salt and separates out, improves the yield, uses a single solvent, can be directly recycled and reused, and reduces the cost.
(3) According to the invention, strong acid is firstly used for removing Boc, and the organic layer is directly esterified, regulated to acid and salified, so that the generation of impurities is reduced, the yield is improved, the operation steps are simplified, and the process period is shortened.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
Example 1
Adding 12.1g (0.0185mol) of BCN solid and 50ml of dichloromethane into a 250ml four-neck flask, adding 9.06g (0.00925mol) of 10 wt% dilute sulfuric acid into the flask to adjust the pH (5.0) to be clear, stirring the mixture at room temperature for 10 minutes, standing the mixture for layering, adding 5g of anhydrous sodium sulfate into an organic layer, standing the organic layer for drying for 8 hours, discarding a water layer, filtering the mixture to remove the anhydrous sodium sulfate, adding 2.7g (0.037mol) of formic acid and 18.76g (0.185mol) of 36 wt% concentrated hydrochloric acid, controlling the temperature to be 0-5 ℃, keeping the temperature and stirring the mixture for 7 hours, adding 30ml of water after the reaction is finished, layering the organic layer, dropwise adding 4.47 g (0.0185mol) of iodomethyl pivalate and maintaining the pH to be 6.0 by using 7 wt% sodium bicarbonate aqueous solution, reacting the mixture for 4 hours at 25 ℃, adding 10ml of ethanol and 30ml of water into the organic layer after the reaction is finished, washing and layering, discarding the aqueous layer, adding 10ml of ethanol into the organic layer, distilling the aqueous solution by using, adding 30ml of acetone at 20-25 ℃, dropwise adding 27g (0.037mol) of 5 wt% hydrochloric acid aqueous solution for crystallization, growing crystals at 5 ℃ for 1.5h, and drying after suction filtration. The product was white powder with a purity of 98.5%, a weight of 7.26g and a yield of 82%.
Example 2
Adding 12.1g (0.0185mol) of BCN solid and 50ml of dichloromethane into a 250ml four-mouth bottle, stirring at room temperature, adding 9.07g of 10 wt% dilute sulfuric acid to adjust the pH (5.01) until the mixture is clear, standing for layering, adding 5g of anhydrous sodium sulfate into an organic layer, standing for 8 hours, removing a water layer, filtering to remove the anhydrous sodium sulfate, adding 2.7g (0.037mol) of formic acid and concentrated hydrochloric acid (22.51 g and 0.222mol), controlling the temperature to be 0-5 ℃, keeping the temperature and stirring for 7 hours, adding 30ml of water, layering, dropwise adding 4.47 g (0.0185mol) of iodomethyl pivalate and 7 wt% of sodium bicarbonate aqueous solution into the organic layer, maintaining the pH to be 6, reacting for 5 hours at 25 ℃, after the reaction is finished, washing the organic layer by 10ml of ethanol and 30ml of water, adding 10ml of ethanol, adjusting the pH to be neutral by 7 wt% of sodium bicarbonate aqueous solution (23g), layering, concentrating the organic layer under reduced pressure until no liquid drops are obtained, adding 30ml of, 5 wt% hydrochloric acid solution is dripped to crystallize, the crystals grow for 1.5h at the temperature of 5 ℃, and the mixture is dried after suction filtration. The product was in the form of a white powder with a purity of 98.7%, a weight of 9.32g (0.015mol) and a yield of 81%.
Example 3
In a 250ml four-neck flask, 12.1g (0.0185mol) of BCN solid and 50ml of dichloromethane are added, stirring is carried out at room temperature, 6.75g (0.0185mol) of 10 wt% diluted hydrochloric acid is added to adjust the pH (5.02) until the mixture is clear, standing and layering are carried out, 5g of magnesium sulfate is added to an organic layer for drying, 2.7g (0.037mol) of formic acid and 24.6g (0.246mol) of concentrated hydrochloric acid are added after the anhydrous magnesium sulfate is removed by filtration, the temperature is controlled to be 0-5 ℃, stirring is carried out for 7 hours under heat preservation, 30ml of water is added to the organic layer for layering, 4.47 g (0.0185mol) of iodomethyl pivalate and 7 wt% sodium bicarbonate aqueous solution (40 ml) are added to the organic layer for reaction at 30 ℃ for 3 hours, after the reaction is finished, 10ml of ethanol and 30ml of water are used for washing and layering, 10ml of ethanol are added, 7 wt% sodium bicarbonate aqueous solution is used for adjusting the pH until the organic layer is neutral, the organic layer is layered, the organic, crystallizing, growing crystal at 0 deg.C for 1.5h, filtering, and drying. The product was in the form of a white powder with a purity of 99%, a weight of 9.55g (0.0153mol) and a yield of 83%.
Claims (6)
1. A method for synthesizing cefcapene pivoxil hydrochloride is characterized by comprising the following steps:
(1) reaction with aqueous mineral acid: BCN is used as an initial raw material, reacts with an inorganic acid aqueous solution in a solvent until the BCN is clear, stands for layering, removes a water layer, collects an organic layer containing a compound I, and is dried;
in the step (1): the solvent is dichloromethane;
the inorganic acid aqueous solution is one of sulfuric acid with the mass percentage of 10% and dilute hydrochloric acid with the mass percentage of 10%;
reacting the solvent with an inorganic acid aqueous solution until the pH value of the solution is 5.0 when the solution is clear;
(2) and (3) Boc removal reaction: taking the organic layer containing the compound I obtained in the step (1), adding formic acid and concentrated hydrochloric acid, reacting at 0-5 ℃, washing with water after the reaction is finished, layering, and collecting the organic layer containing the compound II;
(3) reaction with iodomethyl pivalate: controlling the temperature to be 25-30 ℃, adding a sodium bicarbonate aqueous solution and iodomethyl pivalate to the organic layer containing the compound II obtained in the step (2), maintaining the pH value to be 5-6, carrying out layering after the reaction is finished, collecting the organic layer, adding ethanol, washing the organic layer, carrying out layering, adding ethanol to the organic layer, adjusting the pH value to be 7-8 by using inorganic base, layering, and collecting the organic layer containing the compound III;
(4) reaction with dilute hydrochloric acid: taking the organic layer containing the compound III obtained in the step (3), concentrating under reduced pressure until no liquid drops are distilled off, adding a solvent, adding diluted hydrochloric acid to adjust the crystal, cooling to grow the crystal, carrying out suction filtration, and drying to obtain cefcapene pivoxil hydrochloride;
in the step (4): the solvent is one of acetone, ethyl acetate, methanol, dichloromethane or 1, 1-dichloroethane; growing the crystal at 0-10 deg.C;
the reaction equation is as follows:
2. the method for synthesizing cefcapene pivoxil hydrochloride according to claim 1, wherein in the step (1): the volume milliliter number of the solvent is 2 to 5 times of the mass gram number of the BCN.
3. The method for synthesizing cefcapene pivoxil hydrochloride according to claim 1, wherein in the step (2): the molar ratio of formic acid to concentrated hydrochloric acid is 1: 2-8, wherein the molar ratio of the total mole number of formic acid and concentrated hydrochloric acid to BCN is 5-10: 1; the reaction time is 6-8 hours.
4. The method for synthesizing cefcapene pivoxil hydrochloride according to claim 1, wherein in the step (3): the molar ratio of iodomethyl pivalate to BCN is 1: 1; the mass percentage of the sodium bicarbonate water solution is 5-10%.
5. The method for synthesizing cefcapene pivoxil hydrochloride according to claim 1, wherein in the step (4): the mol ratio of the addition amount of the dilute hydrochloric acid to the addition amount of the BCN is 1.1-5: 1; the mass percentage content of the dilute hydrochloric acid is 5-10 percent; the time for growing the crystal is 1-3 h.
6. The method for synthesizing cefcapene pivoxil hydrochloride according to claim 5, wherein in the step (4): the mol ratio of the addition amount of the dilute hydrochloric acid to the addition amount of the BCN is 1.2: 1; the time for growing the grains is 1.5 h.
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