CN103755725A - Preparation method of 7beta-phenylacetyl amino-3-free-3-cephem-4-carboxylic acid benzyl ester - Google Patents

Preparation method of 7beta-phenylacetyl amino-3-free-3-cephem-4-carboxylic acid benzyl ester Download PDF

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CN103755725A
CN103755725A CN201310731208.6A CN201310731208A CN103755725A CN 103755725 A CN103755725 A CN 103755725A CN 201310731208 A CN201310731208 A CN 201310731208A CN 103755725 A CN103755725 A CN 103755725A
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cephem
phenylacetylamino
diphenylmethyl carboxylate
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CN103755725B (en
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孙楠
胡宝祥
莫卫民
顾士崇
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Zhejiang University of Technology ZJUT
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    • 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
    • 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
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Abstract

The invention provides a method for preparing a 7beta-phenylacetyl amino-3-free-3-cephem-4-carboxylic acid benzyl ester from 7beta-phenylacetyl amino-3-methylol-3-cephem-4-carboxylic acid benzyl ester by adopting a catalytic oxidation and catalytic formylation two-step method. The method disclosed by the invention has the characteristics of being available in raw materials, short in reaction step, mild in reaction condition, fewer in three wastes, good in purity of a target product, high in atom economy and the like.

Description

7 β-phenylacetylamino-3-is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate
(1) technical field
The present invention relates to a kind of preparation method of cephalosporins medicine intermediate, be specifically related to 7 β-phenylacetylamino-3-without the preparation method of-3-cephem-4-diphenylmethyl carboxylate.
(2) background technology
7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate is a kind of important intermediate of preparing cephalosporins medicine, particularly can be used for the preparation of ceftizoxime sodium (Ceftizoxime sodium) and Ceftibuten (Ceftibuten).These two medicines all belong to third generation cephalosporin analog antibiotic, are current clinical conventional cephalosporins medicines.7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate is for No. CAS: 36923-19-0, and its chemical structural formula is as follows:
Figure BDA0000446973390000011
Bibliographical information is prepared 7 β-phenylacetylamino-3-and is mainly contained following two kinds without the method for-3-cephem-4-diphenylmethyl carboxylate.
(1) take 7 β-phenylacetylamino-3-hydroxyl-3-cephem-4-diphenylmethyl carboxylate is raw material, passes through NaBH 4the method three-step reaction that reduction, methylsulfonyl and alkali promote to eliminate alkylene obtains 7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate (CN102617600, US4647658), and reaction process as shown in Figure 1.
Although this technological process yield is higher, every step reaction all needs to use greatly excessive reaction reagent.As the NaBH of reduction process needs 2～5 equivalents 4, the methylsulfonyl chloride of methylsulfonyl process need 4～5 equivalents, organic amines more than elimination alkylene process need 10 equivalents is alkali etc.Use these greatly excessive reaction reagents not only to cause reaction process to produce a large amount of three wastes, also make product separation complicated, need complicated post-processing step.In addition, the preparation process of this technological process starting raw material 7 β-phenylacetylamino-3-hydroxyl-3-cephem-4-diphenylmethyl carboxylate is complicated.This raw material generally needs to obtain through 9 step reactions by penicillin K salt, and reaction process relates to a large amount of poisonous and harmful reagent, and severe reaction conditions (Organic Process Research & Development2002,6,152-157).In a word, this technique just exists reactions steps long from source, and quantity of three wastes is large, the shortcoming that Atom economy is poor.
(2) take 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate is raw material; by oxidation, de-formylated method two-step reaction, obtain 7 β-phenylacetylamino-3-without-3-cephem-4-diphenylmethyl carboxylate (US4269977; CN101463039), reaction process as shown in Figure 2.
This technological process step is short, and required raw material 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate can make (CN101570544) through three-step reaction by the amino cephalo alkane olefin(e) acid of 7-(7-ACA), compare with operational path (1), there is significant advantage.Wherein existing many bibliographical informations 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate be oxidized to the method for intermediate 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate, as Anelli method (US5631366), Dess-Martin method (US5510538) and MnO 2methods (CN101463039) etc., yield is between 70～96%.This oxide compound or the current Prozef of preparing, Cefixime Micronized, Cefdinir, the key intermediate of the cephalosporins medicines such as Cefditoren pivoxil Cephalosporins.Yet; to be 7 β-phenylacetylamino-3-there is significant shortcoming without the method for-3-cephem-4-diphenylmethyl carboxylate to 3 formyl radicals that remove 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate of existing report, greatly limited the actual application value of this technique.As US4269977 is used the Wilkinson reagent (triphenylphosphine rhodium chloride) of equivalent costliness, remove 3 formyl radicals, greatly increased production cost, and the document does not provide yield data.CN101463039 has reported that take the metal of 0.1 equivalent is catalyzer, adopt the method for catalytic hydrogenation to remove 3 formyl radicals, but the kind of concrete metal catalyst is not provided, and the yield of report is only 50%.
In a word, there is the shortcomings such as quantity of three wastes is large, yield is low, production efficiency is low, cost is higher, complex operation in the technique of existing report.
(3) summary of the invention
The object of the invention is to overcome now methodical shortcoming, provide a kind of and through catalyzed oxidation, catalysis piptonychia acidylate two step method, prepare 7 β-phenylacetylamino-3-without the novel method of-3-cephem-4-diphenylmethyl carboxylate by 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate.The reaction equation the present invention relates to is as follows:
Figure BDA0000446973390000031
The technical solution used in the present invention is:
7 β-phenylacetylamino-3-is without a preparation method for-3-cephem-4-diphenylmethyl carboxylate, and described preparation method is:
7 β-phenylacetylamino shown in modus ponens (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate, with anhydrous RhCl 3for catalyzer, bidentate organic phosphine reagent (P-P) is part, sulfonyl azide compounds (RSO 2n 3) be CO trapping agent, in anhydrous ether kind solvent, under nitrogen protection, at 20～80 ℃, carry out piptonychia acylation reaction, HPLC follows the tracks of detection, after reaction finishes, reaction solution separation obtains the 7 β-phenylacetylamino-3-shown in target product formula (III) without-3-cephem-4-diphenylmethyl carboxylate, and the piptonychia acylation reaction time is 12～24h conventionally; 7 β-phenylacetylamino shown in described formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate and RhCl 3, bidentate organic phosphine reagent, sulfonyl azide compounds feed intake amount of substance than being 1:0.03～0.1:0.03～0.1:1.0～1.5.
β-phenylacetylamino-3-of the present invention is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, wherein said bidentate type organic phosphine reagent is selected from (2R, 3S)-2, two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene (BINAP), 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene (XantPhos), two [(2-diphenyl phosphine) phenyl] ether (DPEPhos), 1, two (diphenylphosphine) propane (DPPP) of 3-or two (diphenylphosphine) ethane (DPPE) of 1,3-; Wherein take XantPhos as best.
In preparation method of the present invention, described sulfonyl azide compounds (RSO 2n 3) be selected from sulfonyl azide, phenyl sulfonyl azide or p-toluene sulfonyt azide that C1～C12 alkyl replaces; Wherein take p-toluene sulfonyt azide as best.
In preparation method of the present invention, described ether solvent is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane or glycol dimethyl ether; The mass ratio that feeds intake of 7 β-phenylacetylamino shown in described formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate and ether solvent is 1:3～7; Being more preferably this mass ratio that feeds intake is 1:5.
In preparation method of the present invention, the particularly preferably formyl radical-3-cephem-4-diphenylmethyl carboxylate of 7 β-phenylacetylamino-3-shown in described formula (II) and RhCl 3, bidentate organic phosphine reagent, sulfonyl azide feed intake amount of substance than being 1:0.05:0.05:1.1.
In preparation method of the present invention, the separation method of described reaction solution is: after reaction finishes, reaction solution is cooled to room temperature, adds water, uses CH 2cl 2extraction, the organic phase of merging is successively through the HCl aqueous solution, saturated NaCl solution washing, activated carbon decolorizing, anhydrous Na 2sO 4dry, filter, filtrate decompression reclaims solvent, residue obtained ether/normal hexane mixed solvent the recrystallization that is 1:1 by volume ratio, the solid of recrystallization gained vacuum decompression at 40 ℃ is dry, obtain the 7 β-phenylacetylamino-3-shown in formula (III) without-3-cephem-4-diphenylmethyl carboxylate, through HPLC area normalization method, measure, content is greater than 99%.。
7 β-phenylacetylamino-3-of the present invention is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate; 7 β-phenylacetylamino shown in wherein said formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate makes as follows: 7 β-phenylacetylamino shown in formula (I)-3-methylol-3-cephem-4-diphenylmethyl carboxylate of take is raw material, the Losantin that effective chlorine content is 60% (Ca (OCl) 2) be oxygenant, 2,2,6,6-tetramethyl piperidine oxide compound (TEMPO) is catalyzer, in the buffered soln that is 8.5～11 in pH value and the mixed solvent of halohydrocarbon, at-5～10 ℃, carry out oxidizing reaction 2～4h, HPLC follows the tracks of detection, and after reaction finishes, reaction mixture is isolated to the 7 β-phenylacetylamino shown in formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate; 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephem-4-diphenylmethyl carboxylate and Losantin, 2,2,6, the amount of substance ratio that feeds intake of 6-tetramethyl piperidine oxide compound is 1:1.1～1.5:0.01～0.1; The mass ratio that feeds intake of 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephem-4-diphenylmethyl carboxylate and buffered soln, halohydrocarbon is 1:4～10:4～10.
Figure BDA0000446973390000051
β-phenylacetylamino-3-shown in formula of the present invention (II) is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, and the buffer reagent of wherein said buffered soln is selected from NaHCO 3/ Na 2cO 3, NaHCO 3/ Na 2cO 3, KHCO 3/ K 2cO 3, KHCO 3/ KOH or NH 4cl/NH 3h 2o; The pH value of preferred described buffered soln is 9.5～10; Described halohydrocarbon is selected from methylene dichloride, 1,2-ethylene dichloride or trichloromethane; Particularly preferably the mass ratio that feeds intake of the methylol-3-cephem-4-diphenylmethyl carboxylate of 7 β-phenylacetylamino-3-shown in described formula (I) and buffered soln, halohydrocarbon is 1:6:6.
β-phenylacetylamino-3-shown in formula of the present invention (II) is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, particularly preferably methylol-3-cephem-4-the diphenylmethyl carboxylate of 7 β-phenylacetylamino-3-shown in described formula (I) and Losantin, 2,2, the amount of substance ratio that feeds intake of 6,6-tetramethyl piperidine oxide compound is 1:1.1:0.03; And, preferably at 0～5 ℃, react 2～4h.
β-phenylacetylamino-3-shown in formula of the present invention (II) is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, the method of wherein said reaction mixture separation is: after reaction finishes, in reaction mixture, dripping the HCl aqueous solution to pH value is 6～7, separate organic layer, water layer is used when reacting halogenated hydrocarbon solvent extraction identical in mixed solvent, merge organic phase, organic phase is used the 5wt% vat powder aqueous solution (being SODIUM HYDROSULPHITE sodium water solution), saturated NaCl solution washing, anhydrous Na successively 2sO 4dry, to filter, filtrate decompression reclaims solvent, the residue obtaining acetonitrile recrystallization, the solid of recrystallization gained vacuum decompression at 40 ℃ is dry, obtains the 7 β-phenylacetylamino shown in formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate.
Beneficial effect of the present invention is mainly reflected in:
1, to take 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate be starting raw material to this technique; adopt oxidation, de-formylated method to prepare 7 β-phenylacetylamino-3-without-3-cephalo-4-diphenylmethyl carboxylate; having raw material is easy to get; reactions steps is short; reaction conditions is gentle; quantity of three wastes is few, and target product purity is high, Atom economy high.
2, this technique, in the piptonychia acylation process of 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate, be take cheap sulfonyl azide reagent as CO trapping agent, has greatly reduced precious metal RhCl 3consumption, make reaction under catalytic condition, can carry out, thereby greatly reduce production cost; Under the effect of bidentate organophosphorus ligand, greatly improved catalyzer RhCl simultaneously 3activity, reaction is carried out under relatively lower temp, thereby has been improved the selectivity of reaction and the purity of product.
3, this technique is in the oxidising process of 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate, with solid Ca (OCl) 2for oxygenant, accurate measurement, easy and simple to handle, safe to use.The reaction conditions that the NaOCl aqueous solution that the mass concentration of take with bibliographical information is 17.9g/ml is oxygenant is compared, not needing to add KBr is cocatalyst, can avoid owing to adding the NaOCl aqueous solution, the dilution effect of generation causes the variation of system pH simultaneously, thus the carrying out of impact reaction.
(4) accompanying drawing explanation
Fig. 1 is CN102617600, and the 7 β-phenylacetylamino-3-reporting in US4647658 is without the synthetic route chart of-3-cephem-4-diphenylmethyl carboxylate;
Fig. 2 is US4269977, and the 7 β-phenylacetylamino-3-reporting in CN101463039 is without the synthetic route chart of-3-cephem-4-diphenylmethyl carboxylate.
(5) embodiment
Below in conjunction with specific embodiment, the present invention is described further, but protection scope of the present invention is not limited in this:
The preparation of embodiment 1:7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate
In 150mL four-hole boiling flask, add successively 30g CH 2cl 2, the buffered soln of 30g saturated sodium bicarbonate and sodium carbonate (pH=9.5), 0.047g TEMPO(0.3mmol) and 5.14g7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate (10mmol).At 0 ℃, in 10min, adding 2.62g effective chlorine content is 60% Ca (OCl) 2(11mmol) solid, finishes, and continues stirring reaction 2h.After reaction finishes, it is 6.5 that the hydrochloric acid soln that is 10% with massfraction is adjusted to pH by reaction solution, separates organic layer, water CH 2cl 2(15mL * 2) extraction.The safety powder solution that the organic phase obtaining is 5% with massfraction successively, saturated NaCl solution washing, anhydrous Na 2sO 4dry.Remove by filter siccative, decompression and solvent recovery, the solid obtaining acetonitrile recrystallization, vacuum decompression is dry at 40 ℃.Finally obtain faint yellow solid 4.73g, yield 92.4%.HPLC detects purity 98.6%(HPLC area normalization method).M.p.143-144℃(dec.); 1H?NMR(DMSO-d 6)δ3.35(s,2H),3.39-3.61(m,2H),4.61-4.64(m,1H),4.77-4.4.80(m,1H),7.70(s,1H),7.18-7.51(m,15H),9.22(s,1H),13.18(s,1H); 13C?NMR(125Hz,DMSO-d 6)δ21.7,41.6,59.4,60.0,80.0,122.8,126.52,126.63,127.12,128.11,128.21,128.23,128.50,128.56,128.98,135.60,138.20,138.91,139.15,159.8,165.7,170.9,187.6.ESI-MS(m/z):535.1[M+Na] +。
Embodiment 2:
The preparation of 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate: except the pH value of saturated sodium bicarbonate and sodium carbonate buffered soln is 8.5; other operational condition is all identical with embodiment 1; obtain faint yellow solid 4.35g, yield 85.0%, purity 98.0%.Embodiment 3:
The preparation of 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate: except replacing outside methylene dichloride with 1,2-ethylene dichloride, other operational condition is all identical with embodiment 1, obtains faint yellow solid 4.62g, yield 90.4%, purity 98.8%.
Embodiment 4:
The preparation of 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate: replace sodium bicarbonate and sodium carbonate buffered soln except take ammonium chloride and the ammoniacal liquor buffered soln that pH value is 9.5; other operational condition is all identical with embodiment 1; obtain faint yellow solid 4.58g; yield 89.5%, purity 98.0%.
Embodiment 5:
The preparation of 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate: the charging capacity of raw material 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate is identical with embodiment 1, except 7 β-phenylacetylamino-3-methylol-3-cephem-4-diphenylmethyl carboxylate, Ca (OCl) 2with the ratio of the amount of substance that feeds intake of TEMPO be outside 1:1.3:0.02, other operational condition is all identical with embodiment 1, obtains faint yellow solid 4.12g, yield 80.5%, purity 98.1%.
Embodiment 6:7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate
In tri-mouthfuls of reaction flasks of 50mL, under nitrogen protection, add successively the anhydrous RhCl of 0.10g 3(0.5mmol), 0.29g XantPhos(0.5mmol) and 25g anhydrous tetrahydro furan, N 2under protection, after stirring at room 10min, then add 5.12g7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate (10mmol) and 2.17g p-toluene sulfonyt azide (11mmol).Reaction solution is warming up to 45 ℃, stirring reaction 12h.After reaction finishes, reaction solution is cooled to room temperature, adds 50mL water, water CH 2cl 2(25mL * 2) extraction.The salt acid elution that the organic phase merging is 5% through massfraction successively, saturated NaCl solution washing, activated carbon decolorizing, anhydrous Na 2sO 4dry.Remove by filter siccative, decompression and solvent recovery, ether/normal hexane recrystallization that the dope obtaining is 1:1 by volume ratio, vacuum decompression is dry at 40 ℃.Finally obtain white solid 4.22g, yield 87.2%.HPLC detects purity 99.2%(HPLC area normalization method).M. p.169-170℃(dec.); 1H?NMR(500Hz,DMSO-d 6)δ3.51-3.61(m,2H),3.64-3.71(m,2H),5.09(d,J=5.5Hz),5.11(d,J=5.0Hz,1H),5.18(t,J=5.5Hz,1H),5.81(dd,J 1=5.0Hz,J 2=8.5Hz1H),6.78(dd,J 1=3.5Hz,J 2=6.0Hz1H),6.92(s,1H),7.23-7.58(m,15H),9.17(d,J=8.5Hz,1H); 13C?NMR(125Hz,DMSO-d 6)δ23.7,41.6,57.1,59.3,78.1,122.6,126.21,126.44,126.62,126.77,127.69,127.91,128.18,128.43,128.54,128.98,135.8,139.9,140.5,160.2,164.7,170.9.ESI-MS(m/z):507.2[M+Na] +。
Embodiment 7:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except replacing XantPhos with BINAP, other operational condition is all identical with embodiment 6, obtains white solid 3.15g, yield 65.1%, purity 98.2%.
Embodiment 8:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except replacing XantPhos with DPEPhos, other operational condition is all identical with embodiment 6, obtains white solid 3.48g, yield 71.9%, purity 98.0%.
Embodiment 9:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except replacing XantPhos with DPPP, other operational condition is all identical with embodiment 6, obtains white solid 4.02g, yield 83.1%, purity 98.7%.
Embodiment 10:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: except replacing p-toluene sulfonyt azide with methylsulfonyl nitrine, other operational condition is all identical with embodiment 6, obtains white solid 4.10g, yield 84.7%, purity 98.2%.
Embodiment 11:
7 β-phenylacetylamino-3-is without the preparation of-3-cephalo-4-diphenylmethyl carboxylate: the charging capacity of raw material 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate is in the same manner as in Example 6, except 7 β-phenylacetylamino-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate, RhCl 3, bidentate organophosphorus ligand, sulfonyl azide the ratio of the amount of substance that feeds intake be outside 1:0.03:0.03:1.2, other operational condition is all identical with embodiment 6, obtains white solid 3.52g, yield 72.8%, purity 97.0%.

Claims (10)

1. 7 β-phenylacetylamino-3-, without a preparation method for-3-cephem-4-diphenylmethyl carboxylate, is characterized in that described preparation method is:
7 β-phenylacetylamino shown in modus ponens (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate, with anhydrous RhCl 3for catalyzer, bidentate organic phosphine reagent is part, sulfonyl azide compounds is CO trapping agent, in anhydrous ether kind solvent, under nitrogen protection, at 20～80 ℃, carry out piptonychia acylation reaction, HPLC follows the tracks of detection, and after reaction finishes, reaction solution separation obtains the 7 β-phenylacetylamino-3-shown in target product formula (III) without-3-cephem-4-diphenylmethyl carboxylate; 7 β-phenylacetylamino shown in described formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate and RhCl 3, bidentate organic phosphine reagent, sulfonyl azide compounds feed intake amount of substance than being 1:0.03～0.1:0.03～0.1:1.0～1.5
Figure FDA0000446973380000011
2. β-phenylacetylamino-3-as claimed in claim 1 is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, it is characterized in that described bidentate type organic phosphine reagent is selected from (2R, 3S)-2, two diphenyl phosphine-1 of 2'-, 1'-dinaphthalene, 4, two diphenylphosphine-9 of 5-, 9-dimethyl oxa-anthracene, two [(2-diphenyl phosphine) phenyl] ether, 1, two (diphenylphosphine) propane of 3-or two (diphenylphosphine) ethane of 1,3-.
3. β-phenylacetylamino-3-as claimed in claim 1, without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, is characterized in that described sulfonyl azide compounds is selected from sulfonyl azide, phenyl sulfonyl azide or p-toluene sulfonyt azide that C1～C12 alkyl replaces.
4. β-phenylacetylamino-3-as claimed in claim 1, without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, is characterized in that described ether solvent is selected from ether, isopropyl ether, methyl tertiary butyl ether, tetrahydrofuran (THF), dioxane or glycol dimethyl ether.
5. β-phenylacetylamino-3-as claimed in claim 1, without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, is characterized in that the mass ratio that feeds intake of 7 β-phenylacetylamino shown in described formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate and ether solvent is 1:3～7.
6. β-phenylacetylamino-3-as claimed in claim 1, without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, is characterized in that the separation method of described reaction solution is: after reaction finishes, reaction solution is cooled to room temperature, adds water, uses CH 2cl 2extraction, the organic phase of merging is successively through the HCl aqueous solution, saturated NaCl solution washing, activated carbon decolorizing, anhydrous Na 2sO 4dry, filter, filtrate decompression reclaims solvent, the residue obtained ether/normal hexane mixed solvent recrystallization that is 1:1 by volume ratio, the solid of recrystallization gained vacuum decompression at 40 ℃ is dry, obtains the 7 β-phenylacetylamino-3-shown in formula (III) without-3-cephem-4-diphenylmethyl carboxylate.
7. 7 β-phenylacetylamino-3-as claimed in claim 1 is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, it is characterized in that 7 β-phenylacetylamino shown in described formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate makes as follows: 7 β-phenylacetylamino shown in formula (I)-3-methylol-3-cephem-4-diphenylmethyl carboxylate of take is raw material, effective chlorine content is that 60% Losantin is oxygenant, 2, 2, 6, 6-tetramethyl piperidine oxide compound is catalyzer, in the buffered soln that is 8.5～11 in pH value and the mixed solvent of halohydrocarbon, at-5～10 ℃, carry out oxidizing reaction, HPLC follows the tracks of detection, after reaction finishes, reaction mixture is isolated to the 7 β-phenylacetylamino shown in formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate, 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephem-4-diphenylmethyl carboxylate and Losantin, 2,2,6, the amount of substance ratio that feeds intake of 6-tetramethyl piperidine oxide compound is 1:1.1～1.5:0.01～0.1, the mass ratio that feeds intake of 7 β-phenylacetylamino shown in described formula (I)-3-methylol-3-cephem-4-diphenylmethyl carboxylate and buffered soln, halohydrocarbon is 1:4～10:4～10
Figure FDA0000446973380000031
8. β-phenylacetylamino-3-as claimed in claim 7, without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, is characterized in that the buffer reagent of described buffered soln is selected from NaHCO 3/ Na 2cO 3, NaHCO 3/ Na 2cO 3, KHCO 3/ K 2cO 3, KHCO 3/ KOH or NH 4cl/NH 3h 2o.
9. β-phenylacetylamino-3-as claimed in claim 7, without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, is characterized in that described halohydrocarbon is selected from methylene dichloride, 1,2-ethylene dichloride or trichloromethane.
10. β-phenylacetylamino-the 3-as described in one of claim 7～9 is without the preparation method of-3-cephem-4-diphenylmethyl carboxylate, the method that it is characterized in that described reaction mixture separation is: after reaction finishes, in reaction mixture, dripping the HCl aqueous solution to pH value is 6～7, separate organic layer, water layer is used when reacting halogenated hydrocarbon solvent extraction identical in mixed solvent, merge organic phase, organic phase is used the 5wt% vat powder aqueous solution, saturated NaCl solution washing, anhydrous Na successively 2sO 4dry, to filter, filtrate decompression reclaims solvent, the residue obtaining acetonitrile recrystallization, the solid of recrystallization gained vacuum decompression at 40 ℃ is dry, obtains the 7 β-phenylacetylamino shown in formula (II)-3-formyl radical-3-cephem-4-diphenylmethyl carboxylate.
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