CN107118224A - A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof - Google Patents
A kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method thereof Download PDFInfo
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- CN107118224A CN107118224A CN201710454606.6A CN201710454606A CN107118224A CN 107118224 A CN107118224 A CN 107118224A CN 201710454606 A CN201710454606 A CN 201710454606A CN 107118224 A CN107118224 A CN 107118224A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/10—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D505/12—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7
- C07D505/14—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 substituted in position 7 with hetero atoms directly attached in position 7
- C07D505/16—Nitrogen atoms
- C07D505/18—Nitrogen atoms further acylated by radicals derived from carboxylic acids or by nitrogen or sulfur analogues thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D505/00—Heterocyclic compounds containing 5-oxa-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. oxacephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D505/02—Preparation
- C07D505/06—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
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Abstract
The invention discloses a kind of preparation method of oxygen cephalosporin nucleus intermediate, its solvated compounds and preparation method.The present invention prepares the oxygen cephalosporin nucleus intermediate using chlorination, selects specific catalyst, and being not required to additionally to add organic base just can be in fast reaction, and reaction temperature is low, and accessory substance is few, products obtained therefrom quality height.Crystallized the invention further relates to the intermediate in the solution containing acetonitrile, a kind of new solvated compoundses can be formed with acetonitrile, crystalline particle is big, and stability is good, is easy to filter and stores, and product yield is high, is adapted to industrialized production.
Description
Technical field
The present invention relates to antibiotic medicine preparing technical field, more particularly to a kind of preparation side of oxygen cephalosporin nucleus intermediate
Method and its solvated compounds and preparation method, belong to technical field of medicine synthesis.
Background technology
Oxacephems antibiotic such as latamoxef, Flomoxef etc. are because of its special structure, to a variety of gram-negative bacterias
There is good antibacterial action.Further, since the performance of such resistance to beta-lactamase of antibiotic is strong, the product seldom occur microorganism
Drug resistance.Oxacephems antibiotic such as latamoxef compound, relates generally to key intermediate 3- chloromethyl compounds (IV)
Synthesis.
Wherein, R is H or methyl.
The complete synthetic method of the key intermediate 3- chloromethyl compounds (IV) of existing oxacephems antibiotic, only
Have in US4366316 and Tetrahedron Letters 1980, Vol 21, have relevant report in 351-354, its route is all
The first addition chloro under low temperature/illumination condition, then acted on organic or inorganic alkali and eliminate the chlorine of 3, so as to generate 3- chloromethyls
Compound (IV), is shown below：
Wherein, R1The acyl residue commonly used for cephalosporin chemistry field, R2For carboxyl-protecting group.
The route first step addition chloro needs to complete under illumination condition, and light reaction generally requires special expensive
Light reaction equipment, and energy can decay light in a solvent, cause that reaction is uneven and speed is very slow, and raw material is difficult to convert
Entirely, it is also easy to occur allylic substitution, produces more accessory substance.On the other hand, two-step reaction must maintain -30 DEG C of low temperature
~-20 DEG C, energy consumption is big, and yield is relatively low (50%-55%).
In addition, recrystallisation solvent aspect patent US4366316's is methanol, non-patent literature Tetrahedron
It is that first column chromatography is recrystallized again in Letters 1980, Vol 21,351-354, and without the specific recrystallisation solvent of explanation, but it is produced
The nuclear-magnetism of product1There is no the related H of acetonitrile chemical shift in H-NMR data, it may be determined that its product is crystallized with acetonitrile
's.Under the conditions of this, products obtained therefrom is that, without solvated compoundses, it, which has problem, has crystallization loss big, the low (60%- of yield
65%).And crystalline particle is very thin, the rate of filtration is very slow during filtering, filtration difficulty.It is unfavorable for industrialized production.
Patent JPS5967289A and CN1980939A is improved the chloro technique of the first step, with catalyst and tiing up
Sour agent instead of illumination, and specific route is as follows：
Compared to illumination condition, reaction condition is gentle a lot, catalyst used is simply reacted, selected from triphenylphosphine, three
The organic matters such as benzene phosphine oxide, triethyl phosphite, hydroquinones.Organic impurities can be introduced in subsequent product, product quality is influenceed.
In addition, needing to add the acid binding agents such as organic base (pyridine, piperidines, 2 picolines etc.) in course of reaction, chlorine is with organic base one
Determine to produce side reaction in degree, organic impurities, influence product quality and increase waste water can be also introduced in subsequent product and waste water
Treating capacity.
The content of the invention
The invention provides a kind of preparation method of the high oxygen cephalosporin nucleus intermediate of yield and product quality and its solvent
Compound and preparation method.This method environmental protection and economy, the solvated compoundses stability of generation is good, is readily transported and stores, is suitable to
Industrialized production.
A kind of preparation method of oxygen cephalosporin nucleus intermediate, comprises the following steps：
A) in organic solvent, 3- methylene compounds (I) are generated in the middle of chloro with chlorine in the presence of catalyst
Body；
The chloro intermediate contains compound of dichloro (III) and three chlorinated compounds (II), wherein, dichloro- chemical combination
Thing (III) is primary product, and three chlorinated compounds (II) are a small amount of；
B) three chlorinated compounds (II) in chloro intermediate reduce to obtain compound of dichloro (III) through reducing agent；
C) compound of dichloro (III) generation oxygen cephalosporin nucleus intermediate (IV) under alkali effect；
The general structure of the oxygen cephalosporin nucleus intermediate (IV) is：
Wherein, R is H or methyl.
Specific reaction equation is as follows：
Wherein, R is H or methyl.
Catalyst described in step (a), selected from including cobalt, iron, copper, silver, nickel, zinc, ferrous iron, cuprous halide, sulphur
One or more in compound, sulfate, the organophosphorus ligand compound of oxide or halide.Wherein, organophosphorus ligand
Organophosphor ligand can be phosphorous acid di tert butyl carbonate, methyl triphenyl phosphine ethyl ester, diphenylphosphine, triphenylphosphine, double in compound
(triphenylphosphine), three (triphenylphosphines), diphenyl phosphine oxide, triphenylphosphine oxide, ethyltriphenyl phosphonium chloride phosphorus, tributyl cetyl
Phosphonium bromide, phenyl phosphonyl chloride, diphenyl -2- pyridine radicals phosphines, three (o-tolyl) phosphines, dichlorophenyl phosphine, two (diphenylphosphines
Base) methane, double (diphenylphosphine) ethane of 1,2-, 1,3- bis- (diphenylphosphine) propane, 1,4- double (diphenylphosphine) butane, 1,5- bis-
(diphenylphosphino) pentane, diphenyl phosphorus chloride, BPP, methyltriphenylphospbromide bromide phosphorus, (1- butyl) triphen
One kind in base phosphorus chloride, normal-butyl tri-phenyl-phosphorus bromide, tributylphosphine oxide.
Catalyst described in step (a), wherein, halide can be cobalt chloride, iron chloride, copper chloride, silver chlorate, chlorine
Change nickel, zinc chloride, frerrous chloride, stannous chloride, cobaltous bromide, ferric bromide, copper bromide, silver bromide, nickelous bromide, zinc bromide, bromination
In ferrous iron, cuprous bromide, cobaltous iodide, ferric iodide, cupric iodide, silver iodide, nickel iodide, zinc iodide, iron iodide, cuprous iodide
It is a kind of；
Sulfide can be cobalt sulfide, ironic sulfide, copper sulfide, silver sulfide, nickel sulfide, zinc sulphide, ferrous sulfide, sulphur
One kind during change is cuprous；
Sulfate can be sub- for cobaltous sulfate, ferric sulfate, copper sulphate, silver sulfate, nickel sulfate, zinc sulfate, ferrous sulfate, sulfuric acid
One kind in copper；
Oxide can be sub- for cobalt oxide, iron oxide, cupric oxide, silver oxide, nickel oxide, zinc oxide, ferrous oxide, oxidation
One kind in copper；
The organophosphorus ligand compound of halide can be phosphorous acid di tert butyl carbonate complex, the first of above-mentioned halide
Base triphenylphosphine ethyl ester complex, diphenylphosphine complex, triphenylphosphine complex, double (triphenylphosphines) are matched somebody with somebody
Position compound, three (triphenylphosphine) complexes, diphenyl phosphine oxide complex, triphenylphosphine oxide complex, second
Base triphenylphosphonium chloride complex, tributyl cetyl phosphonium bromide complex, phenyl phosphonyl chloride ligand compound
Thing, diphenyl -2- pyridine radicals phosphines complex, three (o-tolyl) phosphine complexes, dichlorophenyl phosphine complex,
Double (diphenylphosphine) the ethane complexes of two (diphenylphosphino) methane complexes, 1,2-, 1,3- bis- (diphenylphosphine)
Double (diphenylphosphine) the butane complexes of propane complex, 1,4-, 1,5- bis- (diphenylphosphino) pentane ligand compound
Thing, diphenyl phosphorus chloride complex, BPP complex, methyltriphenylphospbromide bromide phosphorus ligand compound
Thing, (1- butyl) triphenylphosphonium chloride complex, normal-butyl tri-phenyl-phosphorus bromide complex, tributylphosphine oxide are matched somebody with somebody
One kind in the compound of position.
The consumption of catalyst described in step (a) is 0.01~0.2 parts by weight relative to compound (I).Preferably,
The consumption of catalyst described in step (a) is 0.03~0.1 parts by weight relative to compound (I).It is used as further preferred, step
Suddenly the consumption of the catalyst described in (a) is 0.04~0.07 parts by weight relative to compound (I).
Addition reaction temperature described in step (a) is -40 DEG C~10 DEG C, preferably -10 DEG C~0 DEG C.
Chlorine consumption described in step (a) is 1.0~3.0 molar equivalents relative to compound (I), preferably 1.5~
2.5 molar equivalent.
One or more of the organic solvent in halogenated alkane, ester, ether described in step (a).Described alkyl halide
One or more of the hydrocarbon in dichloromethane, chloroform, carbon tetrachloride, trichloroethanes；Described ester is selected from ethyl acetate, acetic acid
One or more in propyl ester；One or more of the described ether in glycol dimethyl ether, tetrahydrofuran.Preferably,
Described organic solvent comprises at least the one or more in dichloromethane, chloroform.
Reducing agent described in step (b) can be in sodium sulfite, sodium hydrogensulfite, sodium thiosulfate, dimethyl sulfide
One or more, preferably sodium sulfite or sodium thiosulfate.The reducing agent is preferably added in form of an aqueous solutions, and concentration is excellent
Elect 5wt%~10wt% as.
In the present invention, step (a)~(c) can be carried out in identical solvent, can after the reaction of step (a) is completed
To be directly added into the reaction that reducing agent carries out step (b)；After the reaction of step (b) terminates, step can be entered after washing
Suddenly (c) is reacted.
The invention further relates to a kind of oxygen cephalosporin nucleus intermediate solvated compoundses, its general structure is：Its X diffraction is characterized as below：
Present invention also offers the preparation method of described oxygen cephalosporin nucleus intermediate solvated compoundses (V), including：Change
Compound (IV) is crystallized in acetonitrile or organic solvent containing acetonitrile, forms single acetonitrile solvent compound (V).
Reaction equation is as follows：
Wherein, R is H or methyl.
Above-mentioned compound (IV) can be obtained using the method described in this patent, or be obtained using method disclosed in prior art
Arrive, the compound that chloro is obtained under illumination condition (IV) as disclosed in US4366316.
The above-mentioned organic solvent containing acetonitrile is dichloromethane, chloroform, n-hexane, ethyl acetate, petroleum ether, isopropyl
Ether, methyl acetate, methanol, ethanol, the one or more of isopropanol.
Above-mentioned acetonitrile and mol ratio >=1 of compound (IV).
Compared with the existing technology, beneficial effects of the present invention are embodied in：
(1) catalyst of chlorination selection, is not required to additionally add organic base just energy fast reaction.Reaction temperature is low, secondary
Product is few, and products obtained therefrom quality is high.
(2) patent technique of the present invention uses the solvent crystallization containing acetonitrile, and final products are acetonitrile solvent compound, its benefit
It is exactly that small, high income (90%-95%) is lost in crystallization, product purity >=99.0%, filtering is convenient.Acetonitrile solvent compound is stable
Property is good, and 25 DEG C of room temperature can be preserved more than 6 months, be readily transported and stored, beneficial to industrialized production.
Brief description of the drawings
Fig. 1 is that single acetonitrile solvent compound (V) that embodiment 1 is obtained parses obtained crystal knot after X diffraction sign
Composition.
Embodiment
The present invention is further illustrated by the following examples, but not as limitation of the present invention.
Embodiment 1
7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclos [4.2.0] oct-2-ene -2- formic acid two
The preparation method of benzene methyl list acetonitrile solvent compound (V)：
Chemical equation
1st, 7- benzamidos -3- chloromethyls -8- oxos -5- oxa- -1- azabicyclos [4.2.0] oct-2-ene -2- formic acid
The preparation method of benzhydryl ester：
Wherein, R is H
2nd, 7- benzamidos -3- chloromethyls -8- oxos -5- oxa- -1- azabicyclos [4.2.0] oct-2-ene -2- formic acid
The preparation method of benzhydryl ester list acetonitrile solvent compound
Wherein, R is H
Operating process：
In having churned mechanically 100mL there-necked flasks, by 5.0g (10.68mmol) compound (I), 0.25g frerrous chlorides
With the mixing of 10ml dichloromethane, -20 DEG C are cooled to, 10% chlorine/dichloromethane solution 17.6g (2.3eq) is added, continue anti-
60min is answered, HPLC detection reactions are complete, add 7% sodium sulfite aqueous solution 70mL (3.6eq), separate organic layer, use carbonic acid
Hydrogen sodium water solution is washed, and adjusts PH to 7-8.
Organic layer obtained above is cooled to 0 DEG C, piperidines 0.97g (1.07eq) is added, HPLC detection reactions are complete, plus
Enter watery hydrochloric acid and adjust PH to 5-7, with water 50mL water washings 1 time, aqueous phase is extracted 1 time with 20ml dichloromethane, merges organic layer.Decompression
Dry solvent is concentrated, concentrate (IV) is obtained.
Acetonitrile is added in concentrate obtained above (IV), 0 DEG C of crystallization is cooled to after dissolving.Obtain single acetonitrile solvent
Compound (V) (R=H) 5.36g, yield 92.0%, HPLC detection purity 99.3%.
The structure obtained after the parsing of X diffraction characterize data is as shown in Figure 1.
According to the method for embodiment 1, the bar such as feed change structure, catalyst and its consumption, chlorine consumption, recrystallisation solvent
Part, according to the process of embodiment 1, obtain a series of intermediate 3- chloromethyls list acetonitrile solvent compounds (V) (R=H or
Methyl).Specific data are as shown in the table：
Comparative example 1
Compound 7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-enes -2-
The preparation method of formic acid benzhydryl ester (IV)：
Wherein, R=H.
5.0g (10.68mmol) compound (II) and 0.25g triphenylphosphines are dissolved in 10mL dichloromethane, 3 DEG C are cooled to,
Constant temperature is stirred 5 minutes, is added after 2- picolines 1.0g (1.01eq), 20min, and 10% chlorine/dichloromethane solution is added dropwise
After 25g (3.3eq), 3 DEG C of reaction 2h, after HPLC detection reactions completely, 7% sodium sulfite solution 50mL (2.6eq) is added, point
Go out organic layer, washed with sodium bicarbonate aqueous solution.
Organic layer obtained above is cooled to 0 DEG C, piperidines 0.97g (1.07eq) is added, maintains 0 DEG C to react 3 hours,
After HPLC detection reactions completely,
Add watery hydrochloric acid and adjust PH to 5-7, with water 50mL water washings 1 time, aqueous phase is extracted 1 time with 20ml dichloromethane, is merged
Organic layer.Be concentrated under reduced pressure dry solvent, obtains concentrate (IV) 4.34g, product purity 80.7%, yield 65.3%.
The result of comparative example 1 shows, using acid binding agent/catalyst system of the prior art, obtained product yield and
Purity is substantially reduced.
Embodiment 33
The 4.34g concentrates (IV) that comparative example 1 is obtained add crystallization in acetonitrile and obtain single acetonitrile solvent compound (V)
3.23g, crystallization yield 92%, HPLC detection purity 99.1%.
Comparative example 2
According to the method for comparative example 1, when R=methyl, using pyridine as acid-binding agent, triethylamine is used as step
2 use alkali, according to the process of comparative example 1, obtain compound (IV) (R=methyl) addition methanol and are crystallized, obtain chemical combination
Thing (IV) 3.51g, yield 60.1%, HPLC detection purity 98.2%.
Comparative example 3
Compound 7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-enes -2-
The preparation method of formic acid benzhydryl ester (IV)：
Wherein, R=H.
5.0g (10.68mmol) compound (II) is dissolved in 50mL dichloromethane, -10 DEG C are cooled to, 10% chlorine is added
Gas/dichloromethane solution 30g (3.96eq).Open after illumination, -10 DEG C of reaction 1h, after HPLC detection reactions completely, stop light
According to the sodium sulfite solution 58mL (3.0eq) of addition 7% separates organic layer, washed with sodium bicarbonate aqueous solution.
Organic layer obtained above is cooled to 0 DEG C, piperidines 0.97g (1.07eq) is added, maintains 0 DEG C to react 3 hours,
After HPLC detection reactions completely,
Add watery hydrochloric acid and adjust PH to 5-7, with water 50mL water washings 1 time, aqueous phase is extracted 1 time with 20ml dichloromethane, is merged
Organic layer.Be concentrated under reduced pressure dry solvent, obtains concentrate (IV) 3.78g, product purity 72.9%, yield 52.1%.
The result of comparative example 3 shows that, using illumination system of the prior art, obtained product yield and purity substantially drops
It is low.
Embodiment 34
The 3.78g concentrates (IV) that comparative example 3 is obtained add crystallization in acetonitrile and obtain single acetonitrile solvent compound (V)
2.75g, crystallization yield 90%, HPLC detection purity 99.0%,
Comparative example 4
Compound 7- benzamido -3- chloromethyl -8- oxo -5- oxa- -1- azabicyclo [4.2.0] oct-2-enes -2-
The preparation method of formic acid benzhydryl ester (IV)：
Wherein, R=H.
5.0g (10.68mmol) compound (I) and 0.25g (0.05 weight ratio) triphenylphosphine are dissolved in 50mL dichloromethanes
Alkane, is cooled to 3 DEG C, constant temperature is stirred 5 minutes, adds after 2- picolines 1.0g (1.01eq), 20min, add iodine monochloride
After 5.7g (3.3eq), 3 DEG C of reaction 1h, HPLC detection reactions are complete, add 7% sodium sulfite solution 50mL (2.6eq) reactions
After 30min, separate organic layer and washed with sodium bicarbonate aqueous solution.
Organic layer obtained above is cooled to 0 DEG C, piperidines 0.97g (1.07eq) is added, maintains 0 DEG C to react 3 hours,
After HPLC detection reactions completely, add watery hydrochloric acid and neutralize, with water 50mL water washings 1 time, aqueous phase extracts 1 with 20ml dichloromethane
It is secondary, merge organic layer.Be concentrated under reduced pressure dry solvent, obtains concentrate (IV) 5.5g, product purity 85.4%, yield 87.5%.
According to the method for comparative example 4, the condition such as feed change structure, catalyst, acid binding agent, according to the technique of comparative example 4
Method, obtains a series of halogenating reaction data.Specific data are as shown in the table：
The result of comparative example 4 shows that the catalyst system of the present invention is applied to chlorine as chlorinating agent, when with monochlor(in)ate
When iodine is as chlorinating agent, reaction effect is not good.
Embodiment 35
Crystalline product and the crystalline product of compound (IV) respectively to single acetonitrile solvent compound (V) does stability and ground
Study carefully, as a result find that crystallization of the stability significantly better than compound (IV) of the crystalline product of single acetonitrile solvent compound (V) is produced
Product.Specific data are as follows：
Claims (13)
1. a kind of preparation method of oxygen cephalosporin nucleus intermediate, it is characterised in that comprise the following steps：
A) in organic solvent, 3- methylene compounds (I) generate chloro intermediate with chlorine in the presence of catalyst；
Wherein chloro intermediate contains compound of dichloro (III) and three chlorinated compounds (II)；
B) three chlorinated compounds (II) in chloro intermediate reduce to obtain compound of dichloro (III) through reducing agent；
C) compound of dichloro (III) generation oxygen cephalosporin nucleus intermediate (IV) under alkali effect；
The general structure of the oxygen cephalosporin nucleus intermediate (IV) is：
Wherein, R is H or methyl.
2. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 1, it is characterised in that described in step (a)
Catalyst, selected from comprising cobalt, iron, copper, silver, nickel, zinc, ferrous iron, cuprous halide, sulfide, sulfate, oxide or
One or more in the organophosphorus ligand compound of halide.
3. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 2, it is characterised in that described halide can
Think one kind in chloride, bromide, iodide；
Organophosphor ligand can be phosphorous acid di tert butyl carbonate, methyl triphenyl phosphine in the organophosphorus ligand compound of the halide
Ethyl ester, diphenylphosphine, triphenylphosphine, double (triphenylphosphines), three (triphenylphosphines), diphenyl phosphine oxide, triphenylphosphine oxide, ethyl three
Tetraphenylphosphonium chloride phosphorus, tributyl cetyl phosphonium bromide, phenyl phosphonyl chloride, diphenyl -2- pyridine radicals phosphines, three (o-tolyls)
Phosphine, dichlorophenyl phosphine, two (diphenylphosphino) methane, 1,2- double (diphenylphosphine) ethane, 1,3- bis- (diphenylphosphine) propane, 1,
4- double (diphenylphosphine) butane, 1,5- bis- (diphenylphosphino) pentane, diphenyl phosphorus chloride, BPP, methyl
One kind in tri-phenyl-phosphorus bromide, (1- butyl) triphenylphosphonium chloride, normal-butyl tri-phenyl-phosphorus bromide, tributylphosphine oxide.
4. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 1, it is characterised in that described in step (a)
Catalyst consumption relative to compound (I) be 0.01~0.2 parts by weight.
5. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 1, it is characterised in that described in step (a)
Addition reaction temperature be -40 DEG C~10 DEG C.
6. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 1, it is characterised in that described in step (a)
Chlorine consumption relative to compound (I) be 1.0~3.0 molar equivalents.
7. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 1, it is characterised in that described in step (a)
One or more of the organic solvent in halogenated alkane, ester, ether；Described halogenated alkane is selected from dichloromethane, chloroform, four
One or more in chlorination carbon, trichloroethanes；
One or more of the described ester in ethyl acetate, propyl acetate；
One or more of the described ether in glycol dimethyl ether, tetrahydrofuran.
8. the preparation method of oxygen cephalosporin nucleus intermediate according to claim 1, it is characterised in that described in step (b)
Reducing agent includes the one or more in sodium sulfite, sodium hydrogensulfite, sodium thiosulfate, dimethyl sulfide.
9. a kind of oxygen cephalosporin nucleus intermediate solvated compoundses, it is characterised in that structure is such as shown in (V)：
Wherein, R is H or methyl；
Its X diffraction is characterized as:
10. a kind of preparation method of oxygen cephalosporin nucleus intermediate solvated compoundses as claimed in claim 9, it is characterised in that
Including：Compound (IV) is crystallized in acetonitrile or organic solvent containing acetonitrile, forms single acetonitrile solvent compound
(Ⅴ)。
11. the preparation method of oxygen cephalosporin nucleus intermediate solvated compoundses according to claim 10, it is characterised in that institute
The compound (IV) stated is prepared according to the Fang Fang described in any one of claim 1~8.
12. the preparation method of oxygen cephalosporin nucleus intermediate solvated compoundses according to claim 10, it is characterised in that institute
The organic solvent containing acetonitrile stated be dichloromethane, chloroform, n-hexane, ethyl acetate, petroleum ether, isopropyl ether, methyl acetate,
One or more in methanol, ethanol, isopropanol.
13. the preparation method of the oxygen cephalosporin nucleus intermediate solvated compoundses according to any one of claim 10~12, its
It is characterised by, described acetonitrile and mol ratio >=1 of compound (IV).
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Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4042585A (en) * | 1976-03-22 | 1977-08-16 | Eli Lilly And Company | Process for preparation of 3-halomethylcephems |
| US4048163A (en) * | 1976-03-22 | 1977-09-13 | Eli Lilly And Company | Process for preparation of 7-alkoxy-3-chloromethylcephems |
| US4354022A (en) * | 1981-06-05 | 1982-10-12 | Fujisawa Pharmaceutical Co., Ltd. | Process for preparing 3-methylenecepham compounds or a salt thereof |
| US4366316A (en) * | 1977-02-15 | 1982-12-28 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds and process for producing said compounds |
| JPS5967289A (en) * | 1982-10-08 | 1984-04-16 | Shionogi & Co Ltd | N-haloacylaminooxacepham derivative |
| CN101538274A (en) * | 2009-02-23 | 2009-09-23 | 上海医药工业研究院 | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives |
| CN102295655A (en) * | 2011-07-05 | 2011-12-28 | 山东睿鹰先锋制药有限公司 | Oxacephem antibiotic intermediate solvate and preparation method thereof |
| CN102443013A (en) * | 2010-10-10 | 2012-05-09 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefprozil dimethyl formamide solvate |
| CN1980939B (en) * | 2004-07-08 | 2012-05-30 | 盐野义制药株式会社 | Process for producing 1-oxacephalosporin-7alpha-methoxy-3-chloromethyl derivative |
| CN106749335A (en) * | 2016-11-29 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of preparation method and application of halo oxygen cephalo-type intermediate |
-
2017
- 2017-06-15 CN CN201710454606.6A patent/CN107118224B/en active Active
Patent Citations (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4042585A (en) * | 1976-03-22 | 1977-08-16 | Eli Lilly And Company | Process for preparation of 3-halomethylcephems |
| US4048163A (en) * | 1976-03-22 | 1977-09-13 | Eli Lilly And Company | Process for preparation of 7-alkoxy-3-chloromethylcephems |
| US4366316A (en) * | 1977-02-15 | 1982-12-28 | Shionogi & Co., Ltd. | 1-Oxadethiacepham compounds and process for producing said compounds |
| US4354022A (en) * | 1981-06-05 | 1982-10-12 | Fujisawa Pharmaceutical Co., Ltd. | Process for preparing 3-methylenecepham compounds or a salt thereof |
| JPS5967289A (en) * | 1982-10-08 | 1984-04-16 | Shionogi & Co Ltd | N-haloacylaminooxacepham derivative |
| CN1980939B (en) * | 2004-07-08 | 2012-05-30 | 盐野义制药株式会社 | Process for producing 1-oxacephalosporin-7alpha-methoxy-3-chloromethyl derivative |
| CN101538274A (en) * | 2009-02-23 | 2009-09-23 | 上海医药工业研究院 | Method for preparing 1-oxacephalosporin-3-chloromethyl derivatives |
| CN102443013A (en) * | 2010-10-10 | 2012-05-09 | 石药集团中奇制药技术（石家庄）有限公司 | Method for preparing cefprozil dimethyl formamide solvate |
| CN102295655A (en) * | 2011-07-05 | 2011-12-28 | 山东睿鹰先锋制药有限公司 | Oxacephem antibiotic intermediate solvate and preparation method thereof |
| CN106749335A (en) * | 2016-11-29 | 2017-05-31 | 浙江新和成股份有限公司 | A kind of preparation method and application of halo oxygen cephalo-type intermediate |
Non-Patent Citations (2)
| Title |
|---|
| TSUNEO OKONOGI,等: "Synthesis and antibacterial activity of novel 2-methyl-1-oxacephalosporins", 《THE JOURNAL OF ANTIBIOTICS》 * |
| 邵波: "氟氧头孢母核的合成", 《重庆医科大学硕士学位论文》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108409785A (en) * | 2018-03-12 | 2018-08-17 | 江苏富比亚化学品有限公司 | A kind of method that reduction prepares triphenylphosphine |
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