CN101337916B - Florfeniol sulfonic acid ester, salt thereof and method for preparing same - Google Patents
Florfeniol sulfonic acid ester, salt thereof and method for preparing same Download PDFInfo
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- CN101337916B CN101337916B CN2008100209863A CN200810020986A CN101337916B CN 101337916 B CN101337916 B CN 101337916B CN 2008100209863 A CN2008100209863 A CN 2008100209863A CN 200810020986 A CN200810020986 A CN 200810020986A CN 101337916 B CN101337916 B CN 101337916B
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- florfenicol
- sulphonate
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- monovalent cation
- acid ester
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Abstract
The invention discloses a florfenicol sulphonic acid ester compound and a method thereof which comprises the following steps: an alkalescent reagent is used as a solvent singly or together with an inert reagent, chlorosulfonic acid is added under anaerobic conditions when the temperature ranges from 0 to 10 DEG C, then florfenicol is added in batches after chlorosulfonic acid is added, a materiel layer is separated after the reaction is performed for 2 to 12 hours, and then florfenicol sulphonic acid ester which is found in the form of acids is obtained; obtained florfenicol sulphonic acid ester which is found in the form of acids is mixed with the alcoholic solution of alkali containing acceptable monovalent cation in pharmacy, the reaction lasts for 2 to 5 hours, and florfenicol sulphonic acid ester salt taking the form of monovalent salt is prepared through filtering, washing and drying. Therefore, the salt form of florfenicol prodrug can be separated, and separated florfenicol prodrug containing acceptable monovalent cation is generated. The product which is obtained by adopting the method has good water-solubility, less stimulation, and high percent conversion for internal hydrolyzation into florfenicol.
Description
Technical field
The present invention relates to a kind of compound and salt and its preparation method for preparing the fluorobenzene niekau series prodrug, particularly a kind of florfenicol sulfonates compounds and preparation method thereof.
Background technology
Florfenicol claims Florfenicol again, be the analog of thiamphenicol, and thiamphenicol is the derivative of paraxin, background technology associated viscera main reference of the present invention U.S.4,235,892 and U.S.5,352,832.
Florfenicol thiamphenicol paraxin
Florfenicol is the special-purpose chloromycetin Broad spectrum antibiotics of a kind of new animal doctor.Its chemical name is that D (+)-Su-1-is to first maple base phenyl-2-dichloro acetamino-3-fluorobenzene alcohol.It has has a broad antifungal spectrum, absorbs characteristics such as good, that the interior distribution of body is wide, safe and efficient, the resistance incidence is low.Florfenicol all has powerful killing action to gram-positive microorganism and negative bacterium, anaerobism gram-positive microorganism and negative bacterium, spirochete, Rickettsiae, ameba etc. all there is stronger anti-microbial effect, can be by hemato encephalic barrier, to the meningitic result of treatment of animal bacteria make other antimicrobial drugs can not than.In vitro tests shows: its anti-microbial activity obviously is better than current antimicrobial drug, as: the quinolones of paraxin, thiamphenicol, terramycin, tsiklomitsin, penbritin and present widespread use.At present, in the Asia, more than 20 country's listings such as Europe, America, be mainly used in the treatment of pig, ox, fish and poultry disease.
Florfenicol mainly extremely can be benefited from the object of its advantage usually by oral or parenteral admin, wherein the latter mainly is intramuscular or intravenous administration.Because it has extremely low water-soluble, solubleness is approximately 1mg/ml, yet, in commercial preparation, expecting 300mg/ml or higher concentration usually, therefore in commercial formulation, organic solvent must be added wherein to obtain the product concentration of expectation.For example, at NUFLOR
, for to be labeled as florfenicol preparation for animals, organic solvent N. methyl-2-pyrrolidone, propylene glycol and/or polyoxyethylene glycol are used so that the solubleness of florfenicol is 300mg/ml in the U.S. and Canada.Yet as injection, these solvents can cause significant local excitation usually when parenteral admin unfortunately.Therefore, need water-soluble better florfenicol form.
Summary of the invention
The strong shortcoming of poorly water-soluble, pungency at the florfenicol compounds that exists in the prior art, the invention provides a kind of florfenicol sulphonate and salt thereof and their preparation method, the florfenicol sulphonate and the salt thereof of the present invention's preparation has good water-solubility, pungency is little, and is hydrolyzed to the transformation efficiency height of florfenicol in the body.
Technical scheme of the present invention is a kind of florfenicol sulphonate, has following structural formula:
More than one florfenicol sulphonates of stating are the salt of the florfenicol sulphonate of prodrug, and structural formula is
M wherein
+Be H
+Perhaps pharmaceutically acceptable monovalent cation.
In one embodiment of the present invention, M
+Can be selected from H
+, Na
+, NH
4 +Perhaps K
+In a specific embodiments of this type, M
+Can be H
+In the specific embodiments of another this type, M
+Be Na
+
In another embodiment of the present invention, M
+Be selected from H
+Perhaps protonated amine.In another embodiment of the present invention, M
+For containing chemical formula NR
1R
2R
3H
+Protonated amine.For containing chemical formula NR
1R
2R
3H
+Protonated amine, R
1, R
2And R
3Be independently selected from respectively H, methyl, ethyl, propyl group, sec.-propyl ,-CH
2CH
2OH and-CH
2C (CH
2OH)
3In one.Alternatively, R
1As above provide, but R
2And R
3Be connected to form five yuan or six-ring.In the specific embodiments of this type, described ring is tetramethyleneimine (pirolidine), piperidines or morpholine.
The example of protonated amine of the present invention includes but not limited to:
In another embodiment, M
+Be 1/2 of the diamines of diprotonization.The example of the diamines of diprotonization of the present invention comprises:
In another embodiment, M
+Monovalent cation form for dibasic aminoacid.In the specific embodiments of this type, the monovalent cation form of dibasic aminoacid comprises in the following chemical formula:
In another embodiment of the present invention, M
+Be selected from meglumine, Benzocaine or PROCAINE HCL, PHARMA GRADE.
Florfenicol sulphonate of the present invention (for example, florfenicol prodrug) and/or its salt can prepare by many methods.In preferred embodiments, the salt of florfenicol prodrug florfenicol sulphonate prepares by the following method: the first step, preparation florfenicol sulphonate: with weakly alkaline reagent separately or and inertia reagent unite and make solvent, in the time of 0～10 ℃, in the oxygen-free environment, add chlorsulfonic acid, add florfenicol after adding again in batches, reacted 2～12 hours, the centrifugate bed of material promptly is able to the florfenicol sulphonate that sour form exists;
Second step, the salt of preparation florfenicol sulphonate: the florfenicol sulphonate that exists with sour form of the first step preparation is mixed with the alkali alcosol that comprises pharmaceutically acceptable monovalent cation, reaction 2～5h, filtration, washing, drying make the salt of the florfenicol sulphonate that is the monovalent salt form.Thus, the salt form of florfenicol prodrug can obtain separating, and produces the separation florfenicol prodrug that has pharmaceutically acceptable monovalent cation.
Described weakly alkaline reagent is any one in triethylamine, pyridine, salt of wormwood, the yellow soda ash, described inertia reagent is any one in toluene, chloroform, methylene dichloride, tetracol phenixin, chlorobenzene, the dimethylbenzene, and described pharmaceutically acceptable monovalent cation or divalent cation are the protonated amine or the amine of diprotonization.
Single or blended reagent suitable in a kind of embodiment of the method for preparing florfenicol prodrug of the present invention comprises triethylamine, pyridine, salt of wormwood (sodium)/toluene, salt of wormwood (sodium)/chloroform, salt of wormwood (sodium)/methylene dichloride, salt of wormwood (sodium)/tetracol phenixin, salt of wormwood (sodium)/chlorobenzene, salt of wormwood (sodium)/dimethylbenzene etc.In another embodiment, pharmaceutically acceptable positively charged ion is Na
+In another embodiment, pharmaceutically acceptable positively charged ion is protonated amine.In another embodiment, pharmaceutically acceptable divalent cation is the diamines of diprotonization.
Beneficial effect of the present invention is:
1. good water solubility, pungency is little.Florfenicol sulphonate of the present invention has good solvability in water, solubleness surpasses 300mg/ml, need not improve solubleness by the strong organic solvent of pungency, and pungency significantly reduces.
2. the present invention can be used for florfenicol and effectively and efficiently sends in vivo.Many possible florfenicol prodrugs such as, florfenicol glutarate for example, all have suitable water-solublely, and promptly solubleness surpasses every milliliter of hundreds of milligram.Yet, many kinds in these prodrugs can not sent florfenicol in the serum at an easy rate, for example, after the administration 4 hours, florfenicol is returned in florfenicol glutarate hydrolysis about only 6% in the bovine serum, and returns florfenicol about only 3% ground florfenicol glutarate hydrolysis in rat blood serum.And florfenicol sulphonate of the present invention can be effectively and is changed into florfenicol quite in large quantities.After the administration 2～3 hours, in mouse serum, rabbit anteserum and sheep blood serum, the degree that the florfenicol sulfonate sodium is transformed is respectively about 60% and 50%.The conversion of external this level is counted as the good indication that treatment effectively transforms.
3. florfenicol sulphonate of the present invention and its salt can be administered to object by the method for any routine, comprise oral or pass through drug administration by injection.
4. the stable storage of the described florfenicol sulphonate of the salt pair of this florfenicol sulphonate provided by the invention is useful.
Description of drawings
Fig. 1 is: the mass spectrum (ESI) of florfenicol sulphonate sodium salt.
Fig. 2 is: the nucleus magnetic resonance figure of florfenicol sulphonate sodium salt.
Fig. 3 is illustrated in mouse serum, rabbit anteserum and the sheep blood serum, and sulphonate of the present invention changes into the graphic representation of the speed and the degree of florfenicol.
After Fig. 4 represented dog intravenous injection florfenicol sulphonate, different time points was gathered blood, recorded the drug-time curve figure of florfenicol concentration in the blood plasma.
After Fig. 5 represented pig intravenous injection florfenicol sulphonate, different time points was gathered blood, recorded the drug-time curve figure of florfenicol concentration in the blood plasma.
After Fig. 6 represented sheep intravenous injection florfenicol sulphonate, different time points was gathered blood, recorded the drug-time curve figure of florfenicol concentration in the blood plasma.
Embodiment
By reference following examples, the present invention can obtain more thorough understanding, and these embodiment are provided as illustration of the present invention.The existence of following examples is for embodiment of the present invention is described, must not regards the restriction to broad range of the present invention as more thoroughly.
A kind of florfenicol sulphonate has following structural formula:
With above-mentioned florfenicol sulphonate is the salt of the florfenicol sulphonate of prodrug, and structural formula is
M wherein
+Be H
+Perhaps pharmaceutically acceptable monovalent cation.Described pharmaceutically acceptable monovalent cation is Na
+, NH
4 +, K
+, protonated amine, dibasic aminoacid monovalent cation form, meglumine, Benzocaine, PROCAINE HCL, PHARMA GRADE in any one; The diamines of diprotonization 1/2, in the divalent cation form 1/2 of dibasic aminoacid any one.Described protonated amine is NR
1R
2R
3H
+, and R wherein
1, R
2And R
3Be independently selected from respectively H, methyl, ethyl, propyl group, sec.-propyl ,-CH
2CH
2OH ,-CH
2C (CH
2OH)
3In any one.Described R
2With R
3Be connected to form five yuan or six-ring.Described five yuan or six-ring are selected from tetramethyleneimine, piperidines or morpholine.Described protonated amine is:
In any one.
A kind of method that is used for the salt of synthetic described florfenicol sulphonate, step is:
The first step, preparation florfenicol sulphonate: with weakly alkaline reagent separately or and inertia reagent unite and make solvent, in the time of 0～10 ℃, in the oxygen-free environment, add chlorsulfonic acid, add florfenicol after adding again in batches, reacted 2～12 hours, the centrifugate bed of material, evaporate to dryness promptly are able to the florfenicol sulphonate that sour form exists;
Second step, the salt of preparation florfenicol sulphonate: the florfenicol sulphonate that exists with sour form of the first step preparation is mixed with the alkali alcosol that comprises pharmaceutically acceptable monovalent cation, reaction 2～5h, filtration, washing, drying make the salt of the florfenicol sulphonate that is the monovalent salt form.
Described weakly alkaline reagent is any one in triethylamine, pyridine, salt of wormwood, the yellow soda ash, described inertia reagent is any one in toluene, chloroform, methylene dichloride, tetracol phenixin, chlorobenzene, the dimethylbenzene, and described pharmaceutically acceptable monovalent cation or divalent cation are the protonated amine or the amine of diprotonization.
Synthesizing of florfenicol sulphonate sodium salt
In the above-mentioned reaction formula 1 is [1R, 2S-1-(4-methylsulfonyl phenyl)-2-(2,2-dichloro-acetyl amino)-3-fluoropropyl] sulphonate
(1) under nitrogen, in three-necked bottle, add pyridine 50ml, the icy salt solution cooling when temperature drops to 0 ℃, drips chlorsulfonic acid 24g (0.21mol), and controlled temperature is no more than 10 ℃, adds in about 1 hour.Naturally be warming up to 15 ℃, add florfenicol 71g (0.2mol) in batches.15～20 ℃ of reactions 8 hours.After the end, add water 300ml, telling oily matter is compound 1.
(2) sodium Metal 99.5 of adding 4.5g in dehydrated alcohol 300ml is cooled to 0 ℃, under agitation, be added drop-wise in the oily matter, in this process, there is small amount of solid to separate out, add, placed 2～5 hours, have a large amount of white solids to separate out, suction filtration is iced washing with alcohol on a small quantity, drying, getting white solid 57.8g compound 2 is the sodium salt of florfenicol sulphonate.Analytical results as shown in Figure 1, 2
HNMR(D
2O，400mHz)：δ7.93(d，2H)，7.69(d，2H)，6.19(d，2H)，5.70(d，1H)，4.77(m，1H)，4.55～4.61(m，2H)，3.21(s，3H)。，MS(m/z)：437.25(M-Na)。
Florfenicol sulphonate of the present invention can be effectively and is changed into florfenicol quite in large quantities.After the administration 3 hours, in mouse serum and bovine serum, the degree that the florfenicol sulfonate sodium is transformed is respectively about 60% and 50%.The stable storage of the described florfenicol sulphonate of the salt pair of this florfenicol sulphonate provided by the invention is useful.
What obtain when changing potassium into sodium in the present embodiment is exactly the sylvite of florfenicol sulphonate.
Synthesizing of florfenicol sulphonate ammonium salt
(1) under nitrogen, in three-necked bottle, add triethylamine 30ml, the icy salt solution cooling when temperature drops to 0 ℃, drips chlorsulfonic acid 24g (0.21mol), and controlled temperature is no more than 10 ℃, adds in about 1 hour.Naturally be warming up to 15 ℃, add florfenicol 71g (0.2mol) in batches.15～20 ℃ of reactions 8 hours.After the end, add water 300ml, telling oily matter is compound 1.
(2) ammonia of feeding 3.5g in dehydrated alcohol 300ml is cooled to 0 ℃, under agitation, be added drop-wise in the oily matter, in this process, there is small amount of solid to separate out, add, placed 2～5 hours, have a large amount of white solids to separate out, suction filtration is iced washing with alcohol on a small quantity, drying gets white solid florfenicol ammonium salt.
The diamines of the protonated amine of florfenicol sulphonate, dibasic aminoacid, diprotonization 1/2, the salt of the divalent cation form 1/2 of dibasic aminoacid synthetic as long as ammonia is replaced accordingly just passable.
Synthesizing of florfenicol sulphonate meglumine salt
(1) under nitrogen, in three-necked bottle, add salt of wormwood 30g/ toluene 80ml, the icy salt solution cooling when temperature drops to 0 ℃, drips chlorsulfonic acid 24g (0.21mol), and controlled temperature is no more than 10 ℃, adds in about 1 hour.Naturally be warming up to 15 ℃, add florfenicol 71g (0.2mol) in batches.15～20 ℃ of reactions 8 hours.After the end, add water 300ml, telling oily matter is compound 1.
(2) in the ethanol 300ml of mass concentration 80%, add the 40g meglumine, be cooled to 0 ℃, under agitation, be added drop-wise in the oily matter, in this process, there is small amount of solid to separate out, add, placed 2～5 hours, have a large amount of white solids to separate out, suction filtration is iced washing with alcohol on a small quantity, drying gets white solid florfenicol meglumine salt.
The synthetic of florfenicol sulphonate Benzocaine, procaine salt also is the same, need only with meglumine replace to Benzocaine, PROCAINE HCL, PHARMA GRADE is just passable.
The prepared compound 1 florfenicol sulphonate of the first step among the embodiment 1～3 is dissolved in respectively in the buffer medium of mouse, rabbit, sheep serum.Respectively 0,0.5,1,2,3,4, behind the 5h, the buffer medium that 100 μ L is contained the florfenicol sulphonate shifts out, mix with 100 μ L acetonitriles, this mixing solutions is passed through column chromatography (Zorbax C8 post, 4.6 * 15cm) analyze, thus determine the transformation efficiency of florfenicol sulphonate to florfenicol.Fig. 3 is illustrated in mouse serum, rabbit anteserum and the sheep blood serum, and sulphonate of the present invention changes into the graphic representation of the speed and the degree of florfenicol.Florfenicol sulphonate as can be seen from the figure of the present invention can be effectively and is changed into florfenicol quite in large quantities.After the administration 3～4 hours, in mouse serum, rabbit anteserum and sheep blood serum, the degree that the florfenicol sulfonate sodium is transformed is about 50%～60%.
With florfenicol sulphonate dissolved in distilled water, being made into concentration is 500mg/mL.Choosing 3 body weight is that dog is used in the healthy test of 12～15kg, presses the dosage intravenous injection of 10mg/kg body weight.Different time points is gathered blood after the administration, and separated plasma is measured florfenicol concentration in the blood plasma.After Fig. 4 represented dog intravenous injection florfenicol sulphonate, different time points was gathered blood, recorded the drug-time curve figure of florfenicol concentration in the blood plasma.From figure, can be good in vivo being converted into florfenicol after the intravenous injection of florfenicol sulphonate as can be seen and absorb.
With florfenicol sulphonate dissolved in distilled water, being made into concentration is 500mg/mL.Choosing 3 body weight is the healthy test pig of 15～18kg, presses the dosage intravenous injection of 10mg/kg body weight.Different time points is gathered blood after the administration, and separated plasma is measured florfenicol concentration in the blood plasma.After Fig. 5 represented pig intravenous injection florfenicol sulphonate, different time points was gathered blood, recorded the drug-time curve figure of florfenicol concentration in the blood plasma.From figure, can be good in vivo being converted into florfenicol after the intravenous injection of florfenicol sulphonate as can be seen and absorb.
With florfenicol sulphonate dissolved in distilled water, being made into concentration is 500mg/mL.Choosing 3 body weight is the healthy sheep of 15～18kg, presses the dosage intravenous injection of 25mg/kg body weight.Different time points is gathered blood after the administration, and separated plasma is measured florfenicol concentration in the blood plasma.After Fig. 6 represented sheep intravenous injection florfenicol sulphonate, different time points was gathered blood, recorded the drug-time curve figure of florfenicol concentration in the blood plasma.From figure, can be good in vivo being converted into florfenicol after the intravenous injection of florfenicol sulphonate as can be seen and absorb.
Claims (9)
1. florfenicol sulphonate is characterized in that having following structural formula:
2. based on the salt of the florfenicol sulphonate of the described florfenicol sulphonate of claim 1, it is characterized in that structural formula is
M wherein
+Be pharmaceutically acceptable monovalent cation.
3. the salt of florfenicol sulphonate as claimed in claim 2 is characterized in that described pharmaceutically acceptable monovalent cation is Na
+, NH
4 +, K
+, protonated amine, dibasic aminoacid monovalent cation form, meglumine, Benzocaine, PROCAINE HCL, PHARMA GRADE in any one; The diamines of diprotonization 1/2, in the divalent cation form 1/2 of dibasic aminoacid any one.
4. the salt of florfenicol sulphonate as claimed in claim 3 is characterized in that described protonated amine is NR
1R
2R
3H
+, and R wherein
1, R
2And R
3Be independently selected from respectively H, methyl, ethyl, propyl group, sec.-propyl ,-CH
2CH
2OH ,-CH
2C (CH
2OH)
3In any one.
5. the salt of florfenicol sulphonate as claimed in claim 3 is characterized in that described protonated amine is NR
1R
2R
3H
+, and R wherein
1Be selected from H, methyl, ethyl, propyl group, sec.-propyl ,-CH
2CH
2OH ,-CH
2C (CH
2OH)
3In any one, described R
2With R
3Be connected to form five yuan or six-ring.
6. the salt of florfenicol sulphonate as claimed in claim 5 is characterized in that described five yuan or six-ring are selected from tetramethyleneimine, piperidines or morpholine.
7. the salt of florfenicol sulphonate as claimed in claim 3 is characterized in that described protonated amine is:
In any one.
8. method that is used for the salt of synthetic florfenicol sulphonate as claimed in claim 2 is characterized in that step is:
The first step, preparation florfenicol sulphonate: with weakly alkaline reagent separately or and inertia reagent unite and make solvent, between 0～10 ℃, in the oxygen-free environment, add chlorsulfonic acid, add florfenicol after adding again in batches, reacted 2～12 hours, centrifugate bed of material oily compound promptly is able to the florfenicol sulphonate that sour form exists;
Second step, the salt of preparation florfenicol sulphonate: the florfenicol sulphonate that exists with sour form of the first step preparation is mixed with the alkali alcosol that comprises pharmaceutically acceptable monovalent cation, reaction 2～5h, filtration, washing, drying make the salt of the florfenicol sulphonate that is the monovalent salt form.
9. the synthetic method that is used to prepare the salt of fluorobenzene niekau series sulphonate as claimed in claim 8, it is characterized in that described weakly alkaline reagent is any one in triethylamine, pyridine, salt of wormwood, the yellow soda ash, described inertia reagent is any one in toluene, chloroform, methylene dichloride, tetracol phenixin, chlorobenzene, the dimethylbenzene, and described pharmaceutically acceptable monovalent cation or divalent cation are the protonated amine or the amine of diprotonization.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4235892A (en) * | 1979-02-05 | 1980-11-25 | Schering Corporation, Patent Dept. | 1-Aryl-2-acylamido-3-fluoro-1-propanols, methods for their use as antibacterial agents and compositions useful therefor |
| US5352832A (en) * | 1992-12-18 | 1994-10-04 | Schering Corporation | Asymmetric process for preparing florfenicol, thiamphenicol chloramphenicol and oxazoline intermediates |
-
2008
- 2008-08-12 CN CN2008100209863A patent/CN101337916B/en not_active Expired - Fee Related
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4235892A (en) * | 1979-02-05 | 1980-11-25 | Schering Corporation, Patent Dept. | 1-Aryl-2-acylamido-3-fluoro-1-propanols, methods for their use as antibacterial agents and compositions useful therefor |
| US5352832A (en) * | 1992-12-18 | 1994-10-04 | Schering Corporation | Asymmetric process for preparing florfenicol, thiamphenicol chloramphenicol and oxazoline intermediates |
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