CN107382855A - A kind of synthetic method of deccox - Google Patents

A kind of synthetic method of deccox Download PDF

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Publication number
CN107382855A
CN107382855A CN201710505078.2A CN201710505078A CN107382855A CN 107382855 A CN107382855 A CN 107382855A CN 201710505078 A CN201710505078 A CN 201710505078A CN 107382855 A CN107382855 A CN 107382855A
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Prior art keywords
deccox
reaction
synthetic method
described step
btc
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CN107382855B (en
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邹晔
张娜
张秋红
陈仁尔
苏为科
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Zhejiang Governor Triangle Biomedical Industry Technology Research Park
Zhejiang Pecno Medical Technology Co Ltd
Zhejiang Glory Biological Polytron Technologies Inc
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Zhejiang Governor Triangle Biomedical Industry Technology Research Park
Zhejiang Pecno Medical Technology Co Ltd
Zhejiang Glory Biological Polytron Technologies Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/48—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C07D215/54—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3
    • C07D215/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen attached in position 3 with oxygen atoms in position 4
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/584—Recycling of catalysts

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a kind of synthetic method of deccox, belong to technology of pharmaceutical engineering field, described method is using 2-ethoxy-phenol as raw material, through being coupled, reducing, being condensed, being etherified, the process such as cyclization deccox is made, reduction process of the present invention reduces azo-compound Imported Ammonia base using environment-friendly hydrazine hydrate as reducing agent, selectivity is good, green, advantageously reduces problem of environmental pollution；Cyclization reagent is made using BTC in cyclization process, mild condition reduces the requirement to equipment, and cost reduces.

Description

A kind of synthetic method of deccox
Technical field
The invention belongs to technology of pharmaceutical engineering field, in particulars relate to a kind of synthesis of quinolines coccidiostat-decoquinate Method.
Background technology
Deccox（DecoquinateEconazole Nitrate）, chemical name be 6- decyloxy -7- ethyoxyls - 4- hydroxyl -3- quinoline carboxylic acid ethyl esters；Deccox is developed into first the 1960s by May-Baker companies of Britain Work(, it is a kind of very effective quinolones livestock and poultry anticoccidial drug, it has wide spectrum coccidiostat activity；Deccox mainly exists The asexual reproductive phase of coccidia plays a role, into after coccidia spore cell, by disturbing DNA synthesis to prevent its development, The early stage of the coccidia history of life starts to play a role, so as to avoid poultry intestinal tract from sustaining damage, therefore, for by various coccidias （Displacement, tender, huge, heap-type, murder by poisoning and Bu Shi etc.）Caused chicken coccidiasis, there is good preventive and therapeutic effect.Due to its effect Fruit is good, toxicity is low, metabolism is fast, better tolerance, and usage time is short at home, the advantages that no resistance to the action of a drug, causes domestic veterinary drug circle Extensive concern, there are good market prospects.
United States Patent (USP) US3485845 is described by being original to nitro guaioxide potassium or to Nitrocatechol sodium etc. Material, reacted by hydro-reduction and pyrocondensation etc., deccox is finally made, but because raw material limits, the technique is at home Production cost is too high, limits its industrialization, large-scale production.The synthetic route of domestic report mainly has two at present：（1）With Catechol is raw material, through being condensed, hydrolyzing, nitrifying, reducing, being condensed again, the technical process such as cyclization deccox is prepared； （2）Using 2-ethoxy-phenol as raw material, through nitrifying, reducing, being condensed, the technical process such as cyclization deccox is prepared.Wherein Reduction process can use palladium charcoal or Raney-Ni catalytic hydrogen reductions（CN 102766094）Or sodium hydrosulfite reduction（CN 102816117）, but palladium charcoal or Raney-Ni prices, not only increase cost, can also cause heavy metal pollution, be unfavorable for reacting It is green；Sodium hydrosulfite is inflammable, explosive, is given off poisonous gas after blast, adds the danger of reaction；Cyclization process is usual Using in high boiling solvent such as diphenyl ether, biphenyl equal solvent high temperature (250oMore than C）Closed loop（CN 102816117）Or cyclisation Reagent phosphorous oxychloride etc. is catalyzed closed loop（CN 103351337）, hot conditions are harsh, and high to equipment requirement, yield is low, adopts at present Cyclization reagent corrosivity is strong, and is unable to one-step synthesis and obtains target product.Therefore, a kind of green life how is designed Production method, reactivity hazard in production process is avoided, turn into production deccox urgent problem.
The content of the invention
It is an object of the invention to overcome prior art when producing deccox, complex operation in production process, production Cost is higher, and reactivity hazard is high, easily causes the technical problem of heavy metal pollution, there is provided a kind of production safety, cost is low, green The method of color environmentally friendly synthesis deccox.
In order to solve the above-mentioned technical problem, the invention provides a kind of synthetic method of deccox, it is characterised in that：Institute The method stated comprises the following steps：
Step A, coupled processes：
Aniline and water are mixed, and are cooled to 0 ~ 10 DEG C, adds concentrated hydrochloric acid, sodium nitrite solution is added dropwise, is kept during dropwise addition Interior temperature continues stirring reaction at 0 ~ 5 DEG C after being added dropwise, and obtains diazonium salt of aniline, standby；
2-ethoxy-phenol is dissolved in ethanol, and pH value is adjusted with saturated sodium carbonate solution, stirring, is cooled to 0 ~ 5 DEG C, then, The diazonium salt of aniline solution of above-mentioned preparation is added dropwise, while saturated sodium carbonate solution regulation pH value, stirring reaction, in must containing is added dropwise The reaction solution of mesosome 3- ethyoxyl -4- hydroxyazobenzenes.
Step B, reduction process：
Catalyst is added in the reaction solution obtained to step A, is stirred, is warming up to backflow, hydrazine hydrate is added dropwise, after reaction terminates, mistake Filter, catalyst is reclaimed, be distilled to recover etoh solvent, obtain crude product, crude product is washed with massive laundering, and vacuum drying obtains product 3- second Epoxide -4- hydroxyanilines.
Step C, condensation course：
3- ethyoxyl -4- hydroxyanilines are mixed with ethoxy methylene fork diethyl malonate, nitrogen protection is passed through, is warming up to 100oC or so, reaction steam the ethanol of generation, after completion of the reaction, are cooled to room temperature simultaneously, obtain being condensed crude product.
Step D, etherification procedure：
Add DMF, Anhydrous potassium carbonate, bromo-decane and water into condensation crude product, temperature reaction, be made etherate 2- (3- ethyoxyls- 4- n-decyloxies anilino-) diethyl methylenemalonate.
Step E, cyclization process：
Etherate is dissolved in toluene, adds appropriate DMF, is stirred, is warming up to 100 ~ 120 DEG C, is slowly dropped into BTC/ toluene solutions, Back flow reaction, after reaction terminates, recovery section toluene is evaporated under reduced pressure, residual reaction liquid is poured into frozen water, it is light yellow heavy to separate out Form sediment, filtering, filter cake is washed with water, and is dried in vacuo, obtains product deccox.
In step B reduction process, due to restoring method of the prior art, reactivity hazard is high, easily produces ring Border is polluted, and therefore, after the present invention is by research, mainly obtains 3- ethyoxyl -4- hydroxyanilines using hydrazine hydrate reduction method, because Hydrazine hydrate reduction method can be used for going back original aromatic nitro compound, aromatic azo-compound, carbonyls, unsaturated acids etc., Effect is preferable, can also use in the present invention, by the use of hydrazine hydrate as reducing agent, reduces azo-compound, so reaction is secondary Product is nitrogen and water, will not produce environmentally harmful product, with selectivity is high, reaction condition is gentle, it is small etc. excellent to pollute Point；Can thus avoid because using sodium hydrosulfite reduction and caused by environmental pollution and unsafe problem；Can also avoid because Using Raney's nickel as hydrogenation catalyst, and complex operation is caused, difficulty is big, the high technical problem of production cost.
But further study show that during using hydrazine hydrate reduction, if being not added with catalyst, the 3- that is obtained by reduction reaction Ethyoxyl -4- hydroxyanilines, yield is relatively low, therefore, appropriate catalyst should be used in reduction process is answered, by adding iron Series catalysts catalytic reaction, FeCl2, FeCl3, FeO (OH) are such as added, yield significantly improves, as further changing for the present invention Enter measure, a kind of synthetic method of above-mentioned deccox, in described step B, catalyst is FeO (OH), using FeO (OH) catalyst is made, the reaction time can shorten, and yield highest can reach 86%.
Preferably, a kind of synthetic method of above-mentioned deccox, in described step B, catalyst Fe O's (OH) Measure 2% ~ 10% of the amount for raw material.
Preferably, a kind of synthetic method of above-mentioned deccox, the catalyst Fe O (OH) in described step B The 4%-5% of the amount for raw material is measured, is found by studying, when FeO (OH) amount is the 4%-5% of amount of raw material, instead Shorter between seasonable, reaction yield is higher, and dosage further reduces the reaction time can be caused to extend, and yield reduces；If further Increase catalyst amount, the reaction time is almost unchanged, and reaction yield increase is less；Therefore, the present invention is used as using FeO (OH) and urged Agent, dosage are the 4%-5% of the amount of raw material, and reaction yield is high.
Preferably, a kind of synthetic method of above-mentioned deccox, in described step B, catalyst Fe O (OH) is returned Reused after receipts, it is 2 to 5 times to reuse number, and after using 5 times, activity has certain decline.
Measure as a further improvement on the present invention, the synthetic method of above-mentioned a kind of deccox, in described step B In, hydrazine hydrate dosage is 2 ~ 6 eq in reduction process.Preferably, hydrazine hydrate dosage is 3 ~ 5 eq.
The synthetic method of above-mentioned a kind of deccox, in described step E, because BTC dosage can influence to react Whether can carry out completely, DMF addition has a certain impact to the time of reaction, therefore as a further improvement on the present invention Measure, BTC dosages are 0.2 ~ 0.7 eq of raw material, and DMF dosages are the 2% ~ 6% of the amount of BTC materials, and the reaction time is 2 ~ 5 hours, So, the step reaction yield can reach more than 64%；Preferably, BTC dosages are 0.3 ~ 0.4 eq of raw material, DMF is used 3% ~ 4% of the amount for BTC materials is measured, the reaction time is 3 hours, and so, the step reaction yield highest can reach 69.3%.
Compared with prior art, the beneficial effects of the present invention are：（1）The present invention uses environment-friendly hydrazine hydrate conduct Reducing agent reduces azo-compound Imported Ammonia base, and this method obviates precious metal palladium charcoal, the hydrogenating reduction, again of Raney-Ni catalysis Metal iron powder acid condition reduces and the reduction of dangerous material sodium hydrosulfite；Using hydrazine hydrate reduction, good, the green, cost of selectivity It is low；（2）The present invention as ring-closure reaction condition, avoids the POCl of highly corrosive using BTC/ toluene3, phosphoric acid use, keep away Pyroreaction condition is exempted from, has reduced to equipment requirement, reduce problem of environmental pollution；（3）Obtained by the method that the present invention uses The high income of product, product content is high, meets the requirement of production, can carry out large-scale production.
Brief description of the drawings
Fig. 1 is the synthetic route chart of the present invention.
Embodiment
The invention will be further described below in conjunction with the accompanying drawings.
A kind of synthetic method of deccox as shown in Figure 1, described method comprise the following steps：Step A, it was coupled Journey；Step B, reduction process；Step C, condensation course；Step D, etherification procedure；Step E, cyclization process.
Embodiment 1：
Step A, coupled processes：27.9 kg aniline are added in the first reactor, the L of water 60, are passed through chilled brine cooling, ice Bath temperature is 0 DEG C, adds the L of concentrated hydrochloric acid 72, adds and treats that temperature drops to less than 2 DEG C, and the kg of 25% sodium nitrite solution 83, drop is added dropwise Temperature is 5 DEG C in being kept during adding, and continues stirring reaction after being added dropwise 1.5 hours, and it is standby to obtain diazonium salt of aniline.
41.4 kg 2-ethoxy-phenols and the L of ethanol 220 are added in the second reactor, are adjusted with saturated sodium carbonate solution PH=7 or so.After cooling, the diazonium salt of aniline solution prepared in the first reactor is added drop-wise in the second reactor, was added dropwise Diazonium salt solution temperature is kept in journey below 5 DEG C, while saturated sodium carbonate solution is added dropwise to keep system pH as 7- 8.Temperature is controlled 8oBelow C, continue stirring reaction, obtain the reaction solution containing intermediate 3- ethyoxyl -4- hydroxyazobenzenes.
Step B, reduction process：1.34 kg FeO (OH) are added in the reaction solution that step A is obtained, stirs, is warming up to back Stream, start that the hydrazine hydrates of 95 kg 80% are added dropwise, hydrazine hydrate dosage is 5 eq, and is dripped in 1 hour, after dripping, is continued Stirring reaction.After reaction terminates, filtering, recovery FeO (OH), etoh solvent is distilled to recover, obtains crude product, crude product massive laundering Wash, vacuum drying obtains product 3- ethyoxyl -4- hydroxyanilines 39.5kg, and reaction yield is 86 %（Relative to raw material neighbour's hydroxyl Phenetole）.
Step C, condensation course：35 kg 3- ethyoxyl -4- hydroxyanilines are added in a kettle, and 49.4 kg ethoxies are sub- Methylene malonic acid diethylester, nitrogen protection, temperature reaction 6 hours are passed through, while steam the ethanol of generation, it is after completion of the reaction, cold But room temperature is arrived, obtains being condensed crude product.
Step D, etherification procedure：250 L DMF, 50 kg Anhydrous potassium carbonates, 64 kg bromo-decanes are added into condensation crude product With 15 kg water, 100 DEG C of reactions are warming up to, after reaction completely, are cooled down, filtering, filter cake is washed with DMF, obtains product 2- (3- second Epoxide -4- n-decyloxies anilino-) 93.2 kg of diethyl methylenemalonate, yield 88.0%（Relative to 3- ethyoxyls -4- Hydroxyanilines）, filtrate is by being evaporated under reduced pressure recovery DMF.
Step E, cyclization process：300 L toluene are added in reactor, by compound 2- (3- ethyoxyl -4- n-decyloxy benzene Amido) diethyl methylenemalonate 70 kg be dissolved in toluene, add 150 mL DMF, mechanical agitation, be warming up to 110 DEG C, delay It is slow to instill BTC (14 kg)/toluene solution, dripped off in 30 minutes, back flow reaction 3 hours, be evaporated under reduced pressure recovery section toluene, knot Shu Hou, reaction solution is poured into 2.5 L frozen water, separate out light-yellow precipitate, filtering, filter cake is washed with water, and is dried in vacuo, is produced The kg of thing deccox 43.7, the step yield are 69.3%.
Embodiment 2：
Step A, coupled processes：18.6 kg aniline are added in the first reactor, the L of water 40, are passed through chilled brine cooling, ice bath Temperature is 0 DEG C, adds the L of concentrated hydrochloric acid 48, adds and treats that temperature drops to 0 DEG C or so, the kg of 25% sodium nitrite solution 57 is added dropwise, is added dropwise During keep in temperature be 0 DEG C, continue stirring reaction 1 hour after being added dropwise, it is standby to obtain diazonium salt of aniline.
27.6 kg 2-ethoxy-phenols and ethanol 150L are added in the second reactor, is adjusted with saturated sodium carbonate solution PH=8 or so, cooling.The diazonium salt of aniline solution prepared in first reactor is added drop-wise in the second reactor, process is added dropwise Middle holding diazonium salt solution temperature is at 4 ~ 5 DEG C, while saturated sodium carbonate solution is added dropwise to keep system pH=7.Control temperature At 8 DEG C, continue stirring reaction, obtain the reaction solution containing intermediate 3- ethyoxyl -4- hydroxyazobenzenes.
Step B, reduction process：0.9 kg FeO (OH) are added in the reaction solution that step A is obtained, stirs, is warming up to back Stream, starting that the hydrazine hydrates of 50 kg 80% are added dropwise, hydrazine hydrate dosage is 4 eq, and is dripped in 40 minutes, after dripping, after Continuous stirring reaction.After reaction terminates, filtering, recovery FeO (OH), etoh solvent is distilled to recover, obtains crude product, a large amount of water of crude product Washing, vacuum drying obtain the kg of product 3- ethyoxyl -4- hydroxyanilines 26.2, reaction yield 85.6%（It is adjacent relative to raw material Hydroxy phenetole）.
Step C, condensation course：25 kg 3- ethyoxyl -4- hydroxyanilines are added in a kettle, and 35.3 kg ethoxies are sub- Methylene malonic acid diethylester, nitrogen protection, temperature reaction are passed through, while steam the ethanol of generation, after completion of the reaction, be cooled to room Temperature, obtain being condensed crude product.
Step D, etherification procedure：200 L DMF, 37 kg Anhydrous potassium carbonates, 48 kg bromo-decanes are added into condensation crude product With 11 kg water, 100 DEG C of reactions are warming up to.After reaction completely, cool down, filtering, filter cake is washed with DMF, obtains product 2- (3- second Epoxide -4- n-decyloxies anilino-) diethyl methylenemalonate 66.2kg, yield 87.5%（Relative to 3- ethyoxyls -4- Hydroxyanilines）, filtrate is by subtracting distillation recovery DMF.
Step E, cyclization process：
200 L toluene are added in reactor, by compound 2- (3- ethoxyl-4-n-decyloxy anilinos) methylene propylmalonic acid two The kg of ethyl ester 46.3 is dissolved in toluene, add 95 mL DMF, mechanical agitation, be warming up to 115 DEG C, be slowly dropped into BTC (11 kg)/ Toluene solution, dripped off in 30 minutes, back flow reaction 3 hours, be evaporated under reduced pressure recovery section toluene, after terminating, reaction solution is poured into 2 In L frozen water, light-yellow precipitate, filtering are separated out, filter cake is washed with water, and is dried in vacuo, obtains product deccox 28.6kg, yield For 68.6%.
Embodiment of the present invention is explained in detail above in conjunction with lot of experimental data, but the present invention is not limited to Data are stated, to those skilled in the art, can be to the present invention under connotation and scope without departing substantially from the present invention Technical scheme carry out some it is rational change, fall within protection scope of the present invention.

Claims (9)

  1. A kind of 1. synthetic method of deccox, it is characterised in that：Described method comprises the following steps：
    Step A, coupled processes：
    Aniline and water are mixed, and are cooled to 0 ~ 10 DEG C, adds concentrated hydrochloric acid, sodium nitrite solution is added dropwise, is kept during dropwise addition Interior temperature continues stirring reaction at 0 ~ 5 DEG C after being added dropwise, and obtains diazonium salt of aniline, standby；
    2-ethoxy-phenol is dissolved in ethanol, and pH value is adjusted with saturated sodium carbonate solution, 0 ~ 5 DEG C is cooled to, then, in dropwise addition The diazonium salt of aniline solution of preparation is stated, while saturated sodium carbonate solution regulation pH value is added dropwise, stirring reaction, is obtained containing intermediate 3- The reaction solution of ethyoxyl -4- hydroxyazobenzenes；
    Step B, reduction process：
    Catalyst is added in the reaction solution obtained to step A, is warming up to backflow, hydrazine hydrate is added dropwise, after reaction terminates, filters, returns Receive catalyst, be distilled to recover etoh solvent, obtain crude product, crude product is washed with massive laundering, vacuum drying obtain product 3- ethyoxyls- 4- hydroxyanilines；
    Step C, condensation course：
    3- ethyoxyl -4- hydroxyanilines are mixed with ethoxy methylene fork diethyl malonate, nitrogen protection is passed through, is warming up to 100oC or so, reaction steam the ethanol of generation, after completion of the reaction, are cooled to room temperature simultaneously, obtain being condensed crude product；
    Step D, etherification procedure：
    Add DMF, Anhydrous potassium carbonate, bromo-decane and water into condensation crude product, temperature reaction, be made etherate 2- (3- ethyoxyls- 4- n-decyloxies anilino-) diethyl methylenemalonate；
    Step E, cyclization process：
    Etherate is dissolved in toluene, adds appropriate DMF, is stirred, is warming up to 100 ~ 120 DEG C, is slowly dropped into BTC/ toluene solutions, Back flow reaction, after reaction terminates, recovery section toluene is evaporated under reduced pressure, residual reaction liquid is poured into frozen water, it is light yellow heavy to separate out Form sediment, filtering, filter cake is washed with water, and is dried in vacuo, obtains product deccox.
  2. A kind of 2. synthetic method of deccox according to claim 1, it is characterised in that：In described step B, urge Agent is FeO (OH).
  3. A kind of 3. synthetic method of deccox according to claim 2, it is characterised in that：In described step B, urge Agent FeO (OH) amount is the 2% ~ 10% of the amount of raw material.
  4. A kind of 4. synthetic method of deccox according to claim 3, it is characterised in that：Urged in described step B Agent FeO (OH) amount is the 4%-5% of the amount of raw material.
  5. A kind of 5. synthetic method of deccox according to any one of claim 2 to 4, it is characterised in that：Described Step B in, catalyst Fe O (OH) recovery after reuse, reuse number be 2 to 5 times.
  6. A kind of 6. synthetic method of deccox according to claim 1, it is characterised in that：In described step B, also Hydrazine hydrate dosage is 2 ~ 6 eq during original.
  7. A kind of 7. synthetic method of deccox according to claim 6, it is characterised in that：In described step B, also Hydrazine hydrate dosage is 3 ~ 5 eq during original.
  8. A kind of 8. synthetic method of deccox according to claim 1, it is characterised in that：In described step E, BTC dosages are 0.2 ~ 0.5 eq of raw material, and DMF dosages are the 2% ~ 5% of the amount of BTC materials, and the reaction time is 2 ~ 5 hours.
  9. A kind of 9. synthetic method of deccox according to claim 8, it is characterised in that：In described step E, BTC dosages are 0.3 ~ 0.4 eq of raw material, and DMF dosages are the 3% ~ 4% of the amount of BTC materials, and the reaction time is 3 hours.
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Publication number Priority date Publication date Assignee Title
CN116003274A (en) * 2022-12-30 2023-04-25 浙江华贝药业有限责任公司 Method for synthesizing catalyst-free 5-aminosalicylic acid

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CN116003274A (en) * 2022-12-30 2023-04-25 浙江华贝药业有限责任公司 Method for synthesizing catalyst-free 5-aminosalicylic acid

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