CN103896964A - Method for preparing cephalosporin intermediates - Google Patents
Method for preparing cephalosporin intermediates Download PDFInfo
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- CN103896964A CN103896964A CN201410127279.XA CN201410127279A CN103896964A CN 103896964 A CN103896964 A CN 103896964A CN 201410127279 A CN201410127279 A CN 201410127279A CN 103896964 A CN103896964 A CN 103896964A
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- Prior art keywords
- cephem
- chloromethyl
- amino
- preparation
- reaction
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- 238000000034 method Methods 0.000 title abstract description 9
- 229930186147 Cephalosporin Natural products 0.000 title abstract description 4
- 229940124587 cephalosporin Drugs 0.000 title abstract description 4
- 150000001780 cephalosporins Chemical class 0.000 title abstract description 4
- 239000000543 intermediate Substances 0.000 title abstract 2
- -1 p-methoxy benzyl Chemical group 0.000 claims abstract description 38
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 34
- 239000002253 acid Substances 0.000 claims abstract description 11
- 150000002148 esters Chemical class 0.000 claims abstract description 11
- 239000002904 solvent Substances 0.000 claims abstract description 11
- 239000011230 binding agent Substances 0.000 claims abstract description 9
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 61
- 238000006243 chemical reaction Methods 0.000 claims description 56
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 18
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 16
- 238000002360 preparation method Methods 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical group C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 12
- UHXGEGCCVRMNJH-GUNDQUCTSA-N (6r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid;hydrochloride Chemical compound Cl.S1CC(CCl)=C(C(O)=O)N2C(=O)C(N)[C@H]21 UHXGEGCCVRMNJH-GUNDQUCTSA-N 0.000 claims description 10
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 9
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 8
- 239000001301 oxygen Substances 0.000 claims description 8
- 229910052760 oxygen Inorganic materials 0.000 claims description 8
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 8
- QHTOIDKCEPKVCM-ZCFIWIBFSA-N cepham Chemical compound S1CCCN2C(=O)C[C@H]21 QHTOIDKCEPKVCM-ZCFIWIBFSA-N 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 6
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 claims description 3
- 239000003054 catalyst Substances 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- BUDIODLBJBTUJD-HWZXHQHMSA-N (6r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CCl)=C(C(O)=O)N2C(=O)C(N)[C@H]21 BUDIODLBJBTUJD-HWZXHQHMSA-N 0.000 claims description 2
- 238000013019 agitation Methods 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- YKYONYBAUNKHLG-UHFFFAOYSA-N n-Propyl acetate Natural products CCCOC(C)=O YKYONYBAUNKHLG-UHFFFAOYSA-N 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 238000003756 stirring Methods 0.000 claims description 2
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims 1
- 229940090181 propyl acetate Drugs 0.000 claims 1
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims 1
- 239000002994 raw material Substances 0.000 abstract description 22
- XSBHBYCNRIIYDF-BAFYGKSASA-N (6r)-4-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical class OC(=O)C1=CC(N)S[C@@H]2CC(=O)N21 XSBHBYCNRIIYDF-BAFYGKSASA-N 0.000 abstract description 3
- 101100108853 Mus musculus Anp32e gene Proteins 0.000 abstract description 3
- DYHSDKLCOJIUFX-UHFFFAOYSA-N Di-tert-butyl dicarbonate Substances CC(C)(C)OC(=O)OC(=O)OC(C)(C)C DYHSDKLCOJIUFX-UHFFFAOYSA-N 0.000 abstract 3
- BUDIODLBJBTUJD-CLZZGJSISA-N (6r,7r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid Chemical compound S1CC(CCl)=C(C(O)=O)N2C(=O)[C@@H](N)[C@H]21 BUDIODLBJBTUJD-CLZZGJSISA-N 0.000 abstract 2
- HDYOATPRFNMLSX-KYSFMIDTSA-N benzhydryl (6r,7r)-7-amino-3-(chloromethyl)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate;hydrochloride Chemical compound Cl.S([C@@H]1[C@@H](C(N11)=O)N)CC(CCl)=C1C(=O)OC(C=1C=CC=CC=1)C1=CC=CC=C1 HDYOATPRFNMLSX-KYSFMIDTSA-N 0.000 abstract 1
- 238000006555 catalytic reaction Methods 0.000 abstract 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 18
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 18
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 14
- 238000001035 drying Methods 0.000 description 14
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 0 C*C(C1=C(CCl)CC*C(C2N)N1C2=O)=O Chemical compound C*C(C1=C(CCl)CC*C(C2N)N1C2=O)=O 0.000 description 2
- 125000002252 acyl group Chemical group 0.000 description 2
- 239000003513 alkali Substances 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- OTEKOJQFKOIXMU-UHFFFAOYSA-N 1,4-bis(trichloromethyl)benzene Chemical compound ClC(Cl)(Cl)C1=CC=C(C(Cl)(Cl)Cl)C=C1 OTEKOJQFKOIXMU-UHFFFAOYSA-N 0.000 description 1
- PIZHFBODNLEQBL-UHFFFAOYSA-N 2,2-diethoxy-1-phenylethanone Chemical compound CCOC(OCC)C(=O)C1=CC=CC=C1 PIZHFBODNLEQBL-UHFFFAOYSA-N 0.000 description 1
- 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 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- BXEFQPCKQSTMKA-UHFFFAOYSA-N OC(=O)C=[N+]=[N-] Chemical compound OC(=O)C=[N+]=[N-] BXEFQPCKQSTMKA-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 125000003368 amide group Chemical group 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 238000005660 chlorination reaction Methods 0.000 description 1
- 239000000460 chlorine Substances 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 239000003444 phase transfer catalyst Substances 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000007867 post-reaction treatment Methods 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229960001866 silicon dioxide Drugs 0.000 description 1
- 238000012916 structural analysis Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- MFPWEWYKQYMWRO-UHFFFAOYSA-N tert-butyl carboxy carbonate Chemical compound CC(C)(C)OC(=O)OC(O)=O MFPWEWYKQYMWRO-UHFFFAOYSA-N 0.000 description 1
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 1
- 238000001291 vacuum drying Methods 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
- C07D501/14—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
-
- 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
- C07D501/06—Acylation of 7-aminocephalosporanic acid
Abstract
The invention relates to a method for preparing cephalosporin intermediates. 3-chloromethyl-7beta-amino-3-cephem-4-carboxylic ester hydrochloride (3-chloromethyl-7beta-amino-3-cephem-4-carboxylic p-methoxy benzyl ester hydrochloride (ACLE.HCl) or 3-chloromethyl-7beta-amino-3-cephem-4-carboxylic diphenylmethyl ester hydrochloride (ACLH.HCl) is used as a raw material, neutralized with an acid-binding agent in a solvent and then reacted with di-tert-butyl dicarbonate ester (Boc2O) under a catalysis condition to generate 3-chloromethyl-7beta-tert-butyloxyacyl amino-3-cephem-4-carboxylates (Cpd1 and Cpd2). By adopting the practical method for preparing a cephalosporin mother ring raw material, the yield of the product is 96%, and the purity of the product is 98.5%.
Description
Technical field:
The present invention relates to the preparation method of cepham intermediate; Relate in particular to the preparation method of a kind of 3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-carboxylicesters.
Background technology:
3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-carboxylicesters is the important cepham intermediate feed of a class, synthetic significant for cephalosporins medicine.
Synthetic for 3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-carboxylic acid to methoxybenzyl ester (Cpd1): the people such as Mijoon Lee use the N-(trimethyl silicon based) ethanamide is catalyzer, in the methylene dichloride of ACLE.HCl, with Boc
2o reacts preparation; In literary composition, adopted silicagel column purification yield 51%.(Journal of the American Chemical Society, 125 (52), 16322-16326; 2003) yield is lower, and catalyst n-(trimethyl silicon based) ethanamide of employing is to water sensitive, and is 6 times of molar equivalents of ACLE.HCl consumption, and price is more expensive, thereby causes cost higher, has brought the shortcomings such as post-processing difficulty.
Du Zuyin etc. (CN102827190) adopt and in water, adopt Tetrabutyl amonium bromide is phase-transfer catalyst, at room temperature under property condition, under ACLE.HCl and alkali neutrality condition, with Boc
2target product is prepared in O reaction.Under alkaline condition, tert-Butyl dicarbonate easily decomposes, and in production process, consumption rate is larger, and the process time is longer, yield 80%.
Lin Kaichao (CN101993450B) adopts tetrahydrofuran (THF) to make solvent, and triethylamine is acid binding agent, compd A CLE.HCl and Boc
2o reacts 8h, then obtains target product through aftertreatment.Yield 87.21%.
For synthesizing of 3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-diphenylmethyl carboxylate (Cpd2), it is raw material that the people such as Sakane K adopt 7-ACA, through hydrolysis, Boc
2o amido protecting, the protection of hexichol diazomethane carboxylic acid, then low temperature chlorination reaction target compound.Step is long, complex process, and cost is high.
（EP0307804A2.1988-09;JP92173792,1992-09-09;
J.Antibiotics.1993,46(2):539）。
Based on above bibliographical information and research situation, consider from cost and operational condition, meet the need of market in the urgent need to developing novel process.
Summary of the invention:
The object of the invention is to provide in order to improve the deficiencies in the prior art the preparation method of cepham intermediate, adopt the synthetic cephalo female ring of manufacturing of Simple process, yield is high, product purity is high; Wastage of material and the hidden ring environment pollution of having avoided traditional technology route complexity to bring.
Technical scheme of the present invention is: the preparation method of cepham intermediate, and its concrete steps are as follows: 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and solvent are under agitation condition, and maintenance-5-0 ℃ of cooling bath, adds acid binding agent; Add again catalyzer, drip Boc
2o, 20-25 ℃ of stirring reaction, obtains 3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-carboxylicesters.
Preferably above-mentioned 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride is that 3-chloromethyl-7-amino-3-cephem-4-carboxylic acid is to methoxybenzyl ester hydrochloride or 3-chloromethyl-7-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride.
Preferably above-mentioned solvent is methylene dichloride or 1,2-ethylene dichloride halogenated hydrocarbon solvent; Ethyl acetate or propyl acetate esters solvent; Normal hexane or hexanaphthene alkane solvents; Tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
Preferably above-mentioned acid binding agent is pyridine, triethylamine, powdery sodium carbonate, powdery sodium bicarbonate or potassium carbonate powder.The add-on of preferred described acid binding agent is the pH value 7-8 that is neutralized to reaction soln, and general 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and acid binding agent mol ratio are 1:(1.0-1.1).
Preferably above-mentioned catalyzer is DMAP (DMAP) or 4-diethylin pyridine (DEAP); The add-on of catalyzer is 1:(0.008-0.05 for controlling 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and catalyst molar ratio).
Preferably Boc
2the consumption of O is: 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and Boc
2o mol ratio is 1:(1-1.5).
The consumption of above-mentioned solvent, is advisable with complete solvent raw material and reactant; Reaction times is not done requirement, follows the tracks of reaction according to high performance liquid chromatography or T.C.L point plate, to the time that material concentration no longer changes be the end time.
Beneficial effect:
1. owing to adopting 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride as raw material, obtain according to its structural analysis: 3-position chlorine is active reaction position; 7-bit amino and 4-position carboxyl are all protected, synthesize very convenient to the cynnematin that first carries out the modification of 3-position.
2. this technique normal-temperature reaction, less demanding to acid or alkali environment, the survivable cephalo female ring to heat and soda acid sensitivity, so purity is high, yield is high, is easy to purify.
3. the catalyzer of this process using adopts other product of technical grade, and raw material sources are extensive, is easy to buying.
4. post-reaction treatment is simple, target product yield 96%, and HPLC purity 98.5%, meets the need of market completely.
Embodiment:
Embodiment 1
3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-carboxylic acid is synthetic to methoxybenzyl ester (Cpd1).
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and methylene dichloride 1L, be cooled to-5 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.2g, adds Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5h, till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.45g.Yield 96%; HPLC content 98.5%.
1H-NMR（300MHz，DMSO-d
6）：
δ（ppm）：1.37-1.44（s，9H），3.35（d,2H）,3.48(d,1H),
3.64-3.73(s,3H),4.41(d,1H),4.52(d,1H),5.08(d,1H),5.09(d,1H),5.12-5.23(s,2H),
5.48(q,1H),6.89-6.92(m,2H),7.32-7.34(m,2H).
Embodiment 2
Synthesizing of 3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-diphenylmethyl carboxylate (Cpd2).
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and methylene dichloride 1L, be cooled to-5 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.2g, adds Boc
2o26.2g(0.12mol) 25 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.95g.Yield 96.2%; HPLC content 98.0%.
1H-NMR（300MHz，DMSO-d
6）：
δ（ppm）：1.38-1.44（s，9H），3.35（d,2H）,3.35(d,1H),
3.52-3.72(s,3H),4.40(d,1H),4.42(d,1H),5.12(d,1H),5.14(d,1H),5.56(s,1H),
6.93(q,1H),7.27-7.49(m,11H),8.01-8.04(m,2H).
Embodiment 3
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and ethyl acetate 1L, be cooled to-5 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.2g, adds Boc
2o32.7g(0.15mol) 20 ℃ of reaction 6h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, ethyl acetate layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.40g.Yield 94.9%; HPLC content 98.2%.
Embodiment 4
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and methylene dichloride 1L, be cooled to 0 ℃, drip pyridine 8.6g(0.11mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.2g, adds Boc
2o26.2g(0.12mol) 25 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.42g.Yield 95.3%; HPLC content 98.2%.
Embodiment 5
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and methylene dichloride 1L, be cooled to 0 ℃, drip triethylamine 8.6g(0.11mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.2g, adds Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.43g.Yield 95.6%; HPLC content 98.2%.
Embodiment 6
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and normal hexane 1L, be cooled to 0 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.4g, adds Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5.5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, isolate white solid, use sherwood oil recrystallization, vacuum-drying, obtains 4.2g.Yield 90.6%; HPLC content 98.0%.
Embodiment 7
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and methylene dichloride 2L, be cooled to-5-0 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.3g, adds Boc
2o26.2g(0.12mol) 25 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.43g.Yield 95.5%; HPLC content 98.5%.
Embodiment 8
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and methylene dichloride 1L, be cooled to-5 ℃, add powdery sodium carbonate 10.7g(0.101mol), be neutralized to pH value 7.8, reaction 30min, add DMAP0.3g, add Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.33g.Yield 92.7%; HPLC content 98.0%.
Embodiment 9
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and ethyl acetate 1L, be cooled to-5 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DEAP0.3g, adds Boc
2o30g(0.138mol) 25 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, ethyl acetate layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.7g.Yield 94.9%; HPLC content 98.2%.
Embodiment 10
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and methylene dichloride 1L, be cooled to 0 ℃, drip pyridine 8.6g(0.11mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.3g, adds Boc
2o26.2g(0.12mol) 22 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.72g.Yield 95.3%; HPLC content 98.2%.
Embodiment 11
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and methylene dichloride 1L, be cooled to 0 ℃, drip triethylamine 8.6g(0.11mol), dropwise, be neutralized to pH value 7.2, reaction 30min, add DMAP0.5g, adds Boc2O55g(0.12mol) 20 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.73g.Yield 95.6%; HPLC content 98.2%.
Embodiment 12
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and normal hexane 1L, be cooled to-5 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.3g, adds Boc
2o22.9g(0.105mol) 25 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, white solid sherwood oil recrystallization, obtains 4.48g.Yield 90.6%; HPLC content 98.0%.
Embodiment 13
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and methylene dichloride 2L, be cooled to 0 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DMAP0.1g, adds Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.73g.Yield 95.5%; HPLC content 98.5%.
Embodiment 14
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and methylene dichloride 1L, be cooled to-5 ℃, add powdery sodium carbonate 10.7g(0.101mol), be neutralized to pH value 7.8, reaction 30min, add DEAP0.1g, add Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.6g.Yield 92.7%; HPLC content 98.0%.
Embodiment 15
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride (ACLH.HCl) 45.2g (0.1mol) and 1,2-ethylene dichloride 2L, be cooled to-5 ℃, add potassium carbonate powder 13.9g(0.101mol), be neutralized to pH value 7.8, reaction 30min, adds DMAP0.8g, adds Boc
2o26.2g(0.12mol) 20 ℃ of reaction 5h.Till no longer changing to reaction raw materials content.Pour in 500mL water, separate, ethylene dichloride layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.55g.Yield 91.7%; HPLC content 97.8%.
Embodiment 16
In 3L reactor, add 3-chloromethyl-7 beta-amino-3-cephem-4-carboxylic acid to methoxybenzyl ester hydrochloride (ACLE.HCl) 40.5g (0.1mol) and tetrahydrofuran (THF) 1L, be cooled to 0 ℃, drip triethylamine 10.2g(0.101mol), dropwise, be neutralized to pH value 7.8, reaction 30min, adds DEAP0.1g, adds Boc
2o26.2g(0.12mol) 20 ℃ of reaction 7h, till no longer changing to reaction raw materials content.Be concentrated into dryly, add methylene dichloride 500mL and water 500mL, separate, dichloromethane layer anhydrous sodium sulfate drying, is concentrated into dryly, obtains 4.39g.Yield 94.7%; HPLC content 98.0%.
Claims (7)
1. the preparation method of cepham intermediate, its concrete steps are as follows: 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and solvent are under agitation condition, and maintenance-5-0 ℃ of cooling bath, adds acid binding agent; Add again catalyzer, drip Boc
2o, 20-25 ℃ of stirring reaction, obtains 3-chloromethyl-7 β-tertiary fourth oxygen acyl amino-3-cephem-4-carboxylicesters.
2. preparation method according to claim 1, is characterized in that described 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride is that 3-chloromethyl-7-amino-3-cephem-4-carboxylic acid is to methoxybenzyl ester hydrochloride or 3-chloromethyl-7-amino-3-cephem-4-diphenylmethyl carboxylate hydrochloride.
3. preparation method according to claim 1, is characterized in that described solvent is methylene dichloride, 1,2-ethylene dichloride, ethyl acetate, propyl acetate, normal hexane, hexanaphthene, tetrahydrofuran (THF) or Isosorbide-5-Nitrae-dioxane.
4. preparation method according to claim 1, is characterized in that described acid binding agent is pyridine, triethylamine, powdery sodium carbonate, powdery sodium bicarbonate or potassium carbonate powder.
5. preparation method according to claim 1, is characterized in that the add-on of described acid binding agent is the pH value 7-8 that is neutralized to reaction soln.
6. preparation method according to claim 1, is characterized in that described catalyzer is DMAP (DMAP) or 4-diethylin pyridine (DEAP); The add-on of catalyzer is 1:(0.008-0.05 for controlling 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and catalyst molar ratio).
7. preparation method according to claim 1, is characterized in that Boc
2the consumption of O is: 3-chloromethyl-7-amino-3-cephem-4-carboxylate hydrochloride and Boc
2o mol ratio is 1:(1-1.5).
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106317077A (en) * | 2015-06-24 | 2017-01-11 | 连云港恒运医药科技有限公司 | Novel efficient preparation method of ceftiofur sulfate intermediate |
| CN108033972A (en) * | 2017-12-29 | 2018-05-15 | 山东裕欣药业有限公司 | A kind of synthetic method of Cefprozil |
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| CN106317077A (en) * | 2015-06-24 | 2017-01-11 | 连云港恒运医药科技有限公司 | Novel efficient preparation method of ceftiofur sulfate intermediate |
| CN106317077B (en) * | 2015-06-24 | 2020-07-17 | 连云港恒运药业有限公司 | Novel efficient preparation method of cefoselis sulfate intermediate |
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