CN106631872A - Synthesis method of florfenicol analogue intermediate - Google Patents
Synthesis method of florfenicol analogue intermediate Download PDFInfo
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- CN106631872A CN106631872A CN201611146617.XA CN201611146617A CN106631872A CN 106631872 A CN106631872 A CN 106631872A CN 201611146617 A CN201611146617 A CN 201611146617A CN 106631872 A CN106631872 A CN 106631872A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C253/00—Preparation of carboxylic acid nitriles
- C07C253/30—Preparation of carboxylic acid nitriles by reactions not involving the formation of cyano groups
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- C07—ORGANIC CHEMISTRY
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- C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/08—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
- C07D263/10—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
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- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Abstract
The invention relates to a synthesis method of a florfenicol analogue intermediate. The method comprises the following steps that (1) a compound shown as the formula I is dissolved in a polar solvent; a reduction agent is used for performing reduction reaction to obtain a compound shown as the formula II; (2) the compound shown as the formula II obtained in the step (1) and alkali are dissolved in a reaction solvent; a cyclization agent is used for cyclization reaction to obtain a compound shown as the formula III; (3) the compound shown as the formula III obtained in the step (2) is dissolved in the reaction solvent; a fluorinating reagent is continuously added; fluorinating reaction is performed under the pressurization condition; a compound shown as the formula IV is obtained; (4) the compound shown as the formula IV obtained in the step (3) is added into an acid water solution; hydrolysis ring-opening reaction is performed; a compound shown as the formula V is obtained; (5) the compound shown as the formula V obtained in the step (4) and an acylating agent are dissolved in the reaction solvent; acylating reaction is performed; the compound shown as the formula VI is obtained. The synthesis method has the advantages that the process is stable; the operation is simple; the cost is low; the yield is high.
Description
Technical field
The invention belongs to field of medicine and chemical technology, and in particular to a kind of synthetic method of the similar thing intermediate of Florfenicol.
Background technology
Florfenicol (Florfenicol) also known as Florfenicol, with anti-various gram-positive bacteriums and gram
The biologically active of negative bacteria, is a kind of animal specific chloromycetin broad-spectrum antibiotic.Compared with Thiamphenicol, Florfenicol
Antibacterial activity is strong, has a broad antifungal spectrum, good absorbing and bad reaction are few, as many as 10 times up to Thiamphenicol of its antibacterial ability.Fluorobenzene
Buddhist nun examines the bacteriosis and mycoplasma that can be used for ox, pig, fowl etc. and prepares aquatic products medication.
In recent years, it is many category and plant bacteriums start to show some drug resistances to Florfenicol, for example have found with
Lower bacterium has drug resistance:Salmonella (Bolton, L.F. etc., Clin.Microbiol., 1999,37,1348);Escherichia coli
(Keyes, K. etc., Antimicrob.Agents Chemother., 2000,44,421);Friedlander's bacillus
(Cloeckaert, A. etc., Antimicrob.Agents Chemother., 2001,45,2381);And water-borne pathogens, it is beautiful
Mermaid luminous bacillus kill fish subspecies (Kim, E etc., Microbiol.Immunol., 1996,40,665) (CN 1649829A).
The appearance and diffusion danger of Florfenicol drug resistance promote the demand to new antibiotic, and new antibiotic can
Retain or more than the activity of Florfenicol.CN1649829A、US20130237502、US20140088046、
WO2014172443A1 reports Novel florfenicol-type antibiotics, with following chemical constitution:
And the fluoro- 1- propyl alcohol of D- (-)-Su Shi -1- halogen substituted-phenyl -2- haloacetamido -3- is the above-mentioned new fluorine of synthesis
Benzene Buddhist nun examines the important intermediate of class antibiotic, has broad application prospects.
The content of the invention
Present invention aims to the deficiencies in the prior art, there is provided a kind of synthesis of the similar thing intermediate of Florfenicol
Method, the synthetic method craft is stablized, simple to operate, low cost, high income.
Technical scheme provided by the present invention is:
A kind of synthetic method of the similar thing intermediate of Florfenicol, comprises the steps:
1) type I compound is dissolved in into polar solvent, using reducing agent reduction reaction is carried out, obtain the compound of formula II;It is described
One or more of reducing agent in potassium borohydride, sodium borohydride, calcium borohydride and lithium borohydride;
The structural formula of the formula I and the compound of formula II is as follows:
Wherein, R4For C1-6Alkyl;
2) by step 1) in the compound of formula II that obtains and alkali soluble in reaction dissolvent, carry out cyclization using cyclizing agent anti-
Should, obtain the compound of formula III;The cyclizing agent is the one kind in phthalic anhydride, cyanophenyl, chlorobenzoyl chloride or allylic compound;
The structural formula of the compound of the formula III is as follows:
Wherein, R5For protection group;
3) by step 2) in the compound of formula III that obtains be dissolved in reaction dissolvent, and fluorination reagent is continuously added, in pressurization
Under the conditions of carry out fluorination reaction, obtain the compound of formula IV;The fluorination reagent is DAST reagents or Ishikawa reagents;
The structural formula of the compound of the formula IV is as follows:
4) by step 3) in the compound of formula IV that obtains be added to hydrolysis reaction in aqueous acid, obtain the chemical combination of formula V
Thing;
The structural formula of the compound of the formula V is as follows:
5) by step 4) in the compound of formula V that obtains and acylating agent be dissolved in reaction dissolvent, carry out acetylization reaction, obtain
The compound of formula VI;
The structural formula of the compound of the formula VI is as follows:
Wherein, R in formula VI2And R3It is independently selected from halogen;R in the compound of formula I~VI1For halogen, cyano group or amino.
Preferably, the step 1) in reducing agent be potassium borohydride or sodium borohydride.The reducing agent potassium borohydride or
Sodium borohydride can be that solidapowder form adds reaction system, also can wiring solution-forming add reaction system, solvent preferably uses
Water.
Preferably, the step 1) in the mol ratio of type I compound and reducing agent be 1:1~5, reaction temperature 20~80
DEG C, 3~10 hours reaction time.Further preferably, type I compound and the mol ratio of reducing agent are 1:1~2, reaction temperature 40
~60 DEG C, 4~10 hours reaction time.
Preferably, the step 1) in polar solvent be methyl alcohol, ethanol, propyl alcohol, isopropanol, butanol and its mixture,
More preferably methyl alcohol.
Preferably, the step 2) compound of Chinese style II be 1 with the mol ratio of cyclizing agent:1~2, reaction temperature 40
~115 DEG C, 8~20 hours reaction time;The alkali be potassium carbonate, sodium carbonate, ammonium carbonate, sodium acid carbonate, saleratus, acetic acid
One kind in potassium, sodium acetate, trimethylamine or triethylamine, the compound of formula II is 1 with the mol ratio of alkali:0.1~2.Further preferably,
The alkali is potassium carbonate;The compound of formula II be 1 with the mol ratio of cyclizing agent:1~1.6,100~115 DEG C of reaction temperature, formula II
Compound is 1 with the mol ratio of alkali:0.1~1.
Preferably, the step 2) in cyclizing agent be benzonitrile;The reaction dissolvent be methyl alcohol, ethanol, dichloromethane,
One or more in 1,2- dichloroethanes, ethylene glycol, glycerine, further preferably using glycerine.
Preferably, the step 2) in protection group be phthalic anhydride, cyanophenyl, chlorobenzoyl chloride or allylic compound and formula II
The residue obtained after compound ring-closure reaction;The protection group is preferably phenyl.
Preferably, the step 3) mol ratio of the compound of Chinese style III and fluorination reagent is 1:1~3, reaction temperature 80
~110 DEG C, 2~4 hours reaction time.Further preferably, the compound of formula III and the mol ratio of fluorination reagent are 1:1~2, reaction
100~105 DEG C of temperature.
Preferably, the step 3) in reaction dissolvent be dichloromethane, 1,2- dichloroethanes, chloroform or acetonitrile;
Reaction dissolvent is preferably dichloromethane.
Preferably, the step 3) in fluorination reaction carry out under inert gas shielding;The reaction pressure 0.4~
0.8Mpa, preferably 0.6Mpa.
Preferably, the step 4) used in acid be inorganic acid or organic acid.Reaction dissolvent is water, methyl alcohol, second
Alcohol or glacial acetic acid, preferably water.
Preferably, the step 4) used in acid be hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid or right
Toluenesulfonic acid.As one kind preferably, the acid is hydrochloric acid, and concentration of hydrochloric acid is 3~12N.
Preferably, the step 4) compound of Chinese style IV with acid mol ratio be 1:1~100, reaction temperature 60~110
DEG C, 6~20 hours reaction time.Further preferably, 100~110 DEG C of reaction temperature, 16~20 hours reaction time.
Preferably, the step 4) in the compound of formula V that obtains can Jing recrystallization purifyings, recrystallization solvent be methyl alcohol,
One or more in ethanol, isopropanol, n-butanol, n-hexane, normal heptane, petroleum ether, preferably use isopropanol and n-hexane.
Preferably, the step 5) mol ratio of the compound of Chinese style V and acylating agent is 1:1~5, reaction temperature 10~
60 DEG C, 3~15 hours reaction time.Further preferably, the compound of formula V and the mol ratio of acylating agent are 1:1~3, reaction temperature
30~50 DEG C, 6~10 hours reaction time.
Preferably, the step 5) in acylating agent be methyl difluoroacetate, ethyl difluoro, methyl dichloroacetate,
Ethyl dichloroacetate, chlorine methylfluoracetate, chlorine ethyl fluoroacetate, dichloroacetyl chloride, dichloroacetyl bromine, difluoroacetic acid chloride or difluoro
One kind in acetyl bromide.
Preferably, the step 5) in reaction dissolvent be methyl alcohol, ethanol, isopropanol or n-butanol.More preferably
Methyl alcohol.
Preferably, the step 5) in reaction dissolvent add alkali, the alkali be DMAP, pyridine, diethyl
Amine, trimethylamine, triethylamine, sodium methoxide or caustic alcohol;More preferably triethylamine, the reaction is favourable in the presence of a base
In the carrying out of reaction.
Preferably, the step 5) mol ratio of the compound of Chinese style V and alkali is 1:1~3.More preferably 1:1~
1.5。
Preferably, the step 1) and step 2) replace with following concrete steps:Type I compound is dissolved in into polarity molten
Agent, using reducing agent reduction reaction is carried out;Reaction dissolvent is continuously added, after removing polar solvent, adds alkali and cyclizing agent to carry out
Ring-closure reaction, obtains the compound of formula III;The reaction dissolvent is ethylene glycol or one kind or its mixture in glycerine.
Compared with the existing technology, beneficial effects of the present invention are embodied in:
The purity of the similar thing intermediate of Florfenicol that the present invention is prepared is more than 99%, and process stabilizing, operation letter
It is single, low cost, high income, with industrial value.
Specific embodiment
With reference to specific embodiment, the present invention is further illustrated.
Embodiment 1:The synthesis of the compound of formula 2
Take the compound of 50g formulas 1 to be dissolved in 350mL methyl alcohol, be slowly added to 13.3g potassium borohydrides, react 6 hours at 40 DEG C,
Appropriate watery hydrochloric acid is added to stir 30 minutes, evaporated under reduced pressure solvent adds water dissolves, and with 30% sodium hydroxide solution pH > 10 are adjusted,
Dichloromethane extracted several times are used again, merges organic phase, and washed once with saturated common salt, anhydrous sodium sulfate drying, filter, filtrate
Reduced pressure concentration, obtains white solid 39.7g, yield 96%.Crude product is not purified, is directly used in the system of the compound of next step formula 3
It is standby.
Embodiment 2:The synthesis of the compound of formula 2
Take the compound of 50g formulas 1 to be dissolved in 350mL methyl alcohol, be slowly added to 9.3g sodium borohydrides, react 6 hours at 40 DEG C, plus
Enter appropriate watery hydrochloric acid to stir 30 minutes, evaporated under reduced pressure solvent adds water dissolves, with 30% sodium hydroxide solution pH > 10 are adjusted, then
Dichloromethane extracted several times are used, merges organic phase, and washed once with saturated common salt, anhydrous sodium sulfate drying, filtered, filtrate subtracts
Pressure concentration, obtains white solid 39.4g, yield 95.2%.Crude product is not purified, is directly used in the system of the compound of next step formula 3
It is standby.
Embodiment 3:The synthesis of the compound of formula 3
The product 30g that Example 1 is prepared, glycerine 90g, potassium carbonate 6.8g, are warming up to 105 DEG C, and 21.5g benzene is added dropwise
Formonitrile HCN, drips off for 20 minutes, reacts 18 hours at 105 DEG C, cools to 50 DEG C, adds 90g water, stirs 30 minutes at 50 DEG C,
Filter while hot, filter cake is beaten once with ethanol, filter, obtain white solid 41.1g, yield 96%.
Embodiment 4:The synthesis of the compound of formula 3
The product 30g that Example 1 is prepared, ethylene glycol 90g, potassium carbonate 6.8g, are warming up to 105 DEG C, and 21.5g is added dropwise
Benzonitrile, drips off for 20 minutes, reacts 18 hours at 105 DEG C, cools to 50 DEG C, adds 90g water, and at 50 DEG C 30 points are stirred
Clock, filters while hot, and filter cake is beaten once with methyl alcohol, filters, and obtains white solid 40.9g, yield 95.5%.
Embodiment 5:The compound one-step synthesis method of formula 3
Take the compound of 50g formulas 1 to be dissolved in 350mL methyl alcohol, be slowly added to 13.3g potassium borohydrides, react 6 hours at 40 DEG C,
Add 150g glycerine, reduced pressure concentration to be evaporated methyl alcohol, add 11.3g potassium carbonate, be warming up to 105 DEG C, be added dropwise 33.8g benzonitriles, 20
Minute drip off, react 18 hours at 105 DEG C, cool to 50 DEG C, add 150g water, stir 30 minutes at 50 DEG C, while hot mistake
Filter, filter cake is beaten once with ethanol, is filtered, and obtains the compound of formula 3 for white solid 51.4g, two step yields 87%.
Embodiment 6:The synthesis of the compound of formula 4
The product 30g that Example 3 is prepared mixes with 300mL dichloromethane, stirring, protects in room temperature, nitrogen
Under the conditions of 24.7mL (0.136mol) Ishikawa reagents are added dropwise, proceed to autoclave after stirring evenly, reaction pressure 0.6Mpa,
100 DEG C of reaction 2-3 hours, are cooled to room temperature, take out reactant liquor, wash organic phase, and with 30% sodium hydroxide solution pH=6- is adjusted
8, it is washed with water, anhydrous sodium sulfate drying, to filter, filtrate reduced in volume, cooling obtains faint yellow solid, and crude product can not be purified
It is directly used in next step reaction.
Embodiment 7:The synthesis of the compound of formula 4
The product 30g that Example 3 is prepared mixes with 300mL dichloromethane, stirring, protects in room temperature, nitrogen
Under the conditions of 19.4g (0.12mol) Ishikawa reagents are added dropwise, proceed to autoclave after stirring evenly, reaction pressure 0.6Mpa,
100 DEG C of reaction 2-3 hours, are cooled to room temperature, take out reactant liquor, wash organic phase, and with 30% sodium hydroxide solution pH=6- is adjusted
8, it is washed with water, anhydrous sodium sulfate drying, to filter, filtrate reduced in volume, cooling obtains faint yellow solid, and crude product can not be purified
It is directly used in next step reaction.
Embodiment 8:The synthesis of the compound of formula 5
Whole crude products that Example 6 is prepared are added in 300mL 6N hydrochloric acid, are heated to 100-105 DEG C, backflow
Reaction 16 hours, is cooled to room temperature, filters out accessory substance benzoic acid, and filtrate reduced in volume obtains faint yellow solid, adds water-soluble
Solution, with 30% sodium hydroxide solution pH > 12 are adjusted, then are extracted 2 times with dichloromethane, merge organic phase, and are washed with saturated common salt
Once, anhydrous sodium sulfate drying, filters, filtrate decompression solvent evaporated, is recrystallized with isopropanol and n-hexane, obtains white solid
17g, two step yields 80%.
Embodiment 9:The synthesis of the compound of formula 5
Whole crude products that Example 6 is prepared are added in 300mL 6N sulfuric acid, are heated to 100-105 DEG C, backflow
Reaction 16 hours, is cooled to room temperature, filters out accessory substance benzoic acid, and filtrate reduced in volume obtains faint yellow solid, adds water-soluble
Solution, with 30% sodium hydroxide solution pH > 12 are adjusted, then are extracted 2 times with dichloromethane, merge organic phase, and are washed with saturated common salt
Once, anhydrous sodium sulfate drying, filters, filtrate decompression solvent evaporated, is recrystallized with isopropanol and n-hexane, obtains white solid
16.7g, two step yields 78.5%.
Embodiment 10:The synthesis of the compound of formula 6
The product 10g that Example 8 is prepared is dissolved in 350mL methyl alcohol, adds 5g triethylamines, 30.5g difluoroacetic acids
Ethyl ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains white solid 12.7g, yield
92%.
Embodiment 11:The synthesis of the compound of formula 7
The product 10g that Example 8 is prepared is dissolved in 350mL methyl alcohol, adds 5g triethylamines, 38.5g dichloroacetic acid
Ethyl ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 14.4g, yield 93%.
Embodiment 12:The synthesis of the compound of formula 8
The product 10g that Example 8 is prepared is dissolved in 350mL methyl alcohol, adds 3g DMAPs, 34.5g
Chlorine ethyl fluoroacetate, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 13.5g,
Yield 92.4%.
Embodiment 13:The synthesis of the compound of formula 10
Take the compound of 10g formulas 9 to be dissolved in 350mL methyl alcohol, add 2.1g DMAPs, 24.5g chlorine fluoroacetic acid second
Ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 10.9g, yield 91.5%.
Embodiment 14:The synthesis of the compound of formula 11
Take the compound of 10g formulas 9 to be dissolved in 350mL methyl alcohol, add 2.1g DMAPs, 21.6g difluoroacetic acid second
Ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 12.1g, yield 92.1%.
Embodiment 15:The synthesis of the compound of formula 13
Take the compound of 10g formulas 12 to be dissolved in 350mL methyl alcohol, add 2.07g DMAPs, 23.8g chlorine fluoroacetic acids
Ethyl ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 12.1g, yield
91.8%.
Embodiment 16:The synthesis of the compound of formula 15
Take the compound of 10g formulas 14 to be dissolved in 350mL methyl alcohol, add 3.15g DMAPs, 36.2g chlorine fluoroacetic acids
Ethyl ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 13.7g, yield
92.2%.
Embodiment 17:The synthesis of the compound of formula 16
Take the compound of 10g formulas 14 to be dissolved in 350mL methyl alcohol, add 3.15g DMAPs, 31.9g difluoroacetic acids
Ethyl ester, is stirred at room temperature 12 hours, evaporated under reduced pressure solvent, adds isopropyl alcohol and water recrystallization, obtains product 13g, yield 92.8%.
Claims (10)
1. a kind of Florfenicol is similar to the synthetic method of thing intermediate, it is characterised in that comprise the steps:
1) type I compound is dissolved in into polar solvent, using reducing agent reduction reaction is carried out, obtain the compound of formula II;The reduction
One or more of agent in potassium borohydride, sodium borohydride, calcium borohydride and lithium borohydride;
The structural formula of the formula I and the compound of formula II is as follows:
Wherein, R4For C1-6Alkyl;
2) by step 1) in the compound of formula II that obtains and alkali soluble in reaction dissolvent, carry out ring-closure reaction using cyclizing agent, obtain
To the compound of formula III;The cyclizing agent is the one kind in phthalic anhydride, cyanophenyl, chlorobenzoyl chloride or allylic compound;
The structural formula of the compound of the formula III is as follows:
Wherein, R5For protection group;
3) by step 2) in the compound of formula III that obtains be dissolved in reaction dissolvent, and fluorination reagent is continuously added, in pressurized conditions
Under carry out fluorination reaction, obtain the compound of formula IV;The fluorination reagent is DAST reagents or Ishikawa reagents;
The structural formula of the compound of the formula IV is as follows:
4) by step 3) in the compound of formula IV that obtains be added to hydrolysis reaction in aqueous acid, obtain the compound of formula V;
The structural formula of the compound of the formula V is as follows:
5) by step 4) in the compound of formula V that obtains and acylating agent be dissolved in reaction dissolvent, carry out acetylization reaction, obtain formula VI
Compound;
The structural formula of the compound of the formula VI is as follows:
Wherein, R in formula VI2And R3It is independently selected from halogen;R in the compound of formula I~VI1For halogen, cyano group or amino.
2. Florfenicol according to claim 1 is similar to the synthetic method of thing intermediate, it is characterised in that the step 1)
Middle type I compound is 1 with the mol ratio of reducing agent:1~5,20~80 DEG C of reaction temperature, 3~10 hours reaction time.
3. Florfenicol according to claim 1 is similar to the synthetic method of thing intermediate, it is characterised in that the step 2)
The compound of Chinese style II be 1 with the mol ratio of cyclizing agent:1~2,40~115 DEG C of reaction temperature, 8~20 hours reaction time;Institute
It is potassium carbonate, sodium carbonate, ammonium carbonate, sodium acid carbonate, saleratus to state alkali, in potassium acetate, sodium acetate, trimethylamine or triethylamine
One kind, the compound of formula II is 1 with the mol ratio of alkali:0.1~2.
4. Florfenicol according to claim 1 is similar to the synthetic method of thing intermediate, it is characterised in that the step 3)
The compound of Chinese style III is 1 with the mol ratio of fluorination reagent:1~3,80~110 DEG C of reaction temperature, 2~4 hours reaction time.
5. Florfenicol according to claim 1 is similar to the synthetic method of thing intermediate, it is characterised in that the step 4)
Used in acid be hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, methanesulfonic acid or p-methyl benzenesulfonic acid.
6. Florfenicol according to claim 5 is similar to the synthetic method of thing intermediate, it is characterised in that the step 4)
The compound of Chinese style IV is 1 with the mol ratio of acid:1~100,60~110 DEG C of reaction temperature, 6~20 hours reaction time.
7. Florfenicol according to claim 1 is similar to the synthetic method of thing intermediate, it is characterised in that the step 5)
The compound of Chinese style V is 1 with the mol ratio of acylating agent:1~5,10~60 DEG C of reaction temperature, 3~15 hours reaction time.
8. Florfenicol according to claim 7 is similar to the synthetic method of thing intermediate, it is characterised in that the step 5)
Middle reaction dissolvent adds alkali, and the alkali is DMAP, pyridine, diethylamine, trimethylamine, triethylamine, sodium methoxide or second
Sodium alkoxide.
9. Florfenicol according to claim 8 is similar to the synthetic method of thing intermediate, it is characterised in that the step 5)
The compound of Chinese style V is 1 with the mol ratio of alkali:1~3.
10. Florfenicol according to claim 1 is similar to the synthetic method of thing intermediate, it is characterised in that the step
1) with step 2) replace with following concrete steps:Type I compound is dissolved in into polar solvent, using reducing agent reduction reaction is carried out;
Reaction dissolvent is continuously added, after removing polar solvent, adds alkali and cyclizing agent to carry out ring-closure reaction, obtain the compound of formula III;Institute
Reaction dissolvent is stated for the one kind or its mixture in ethylene glycol or glycerine.
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CN108017549A (en) * | 2017-12-07 | 2018-05-11 | 南通常佑药业科技有限公司 | A kind of preparation method of 1- aryl -2- amino -1,3- propanediol hydrochloride derivatives |
WO2020068607A1 (en) | 2018-09-24 | 2020-04-02 | Zoetis Services Llc. | Process for preparing the compound 2,2-difluoro-n-((1r,2s)-3-fluoro-1-hydroxy-1-(4-(6-(s-methylsulfonimidoyl)pyridin-3-yl)phenyl)propan-2-yl)acetamide |
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