CN108329220A - A kind of choline carboxylate and preparation method thereof - Google Patents
A kind of choline carboxylate and preparation method thereof Download PDFInfo
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- C07C219/02—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
- C07C219/04—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
- C07C219/14—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having at least one of the hydroxy groups esterified by a carboxylic acid having the esterifying carboxyl group bound to a carbon atom of a six-membered aromatic ring
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- C07C213/04—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reaction of ammonia or amines with olefin oxides or halohydrins
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- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/58—Preparation of carboxylic acid halides
- C07C51/60—Preparation of carboxylic acid halides by conversion of carboxylic acids or their anhydrides or esters, lactones, salts into halides with the same carboxylic acid part
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- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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- C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
- C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen 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
- C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
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Abstract
The present invention provides the compounds that the compound of choline and carboxy-containing acid group are formed in a manner of at ester（Formula I）And preparation method thereof, the compound that especially carboxylic acid-substituted hydroxy benzenes and carboxylic acid-substituted pyridine are formed with choline at ester.The present invention also provides the preparation methods of such compound.By forming cholinester on the basis of reservation compound original feature, its property can be made more mild, adverse reaction can be effectively reduced.
Description
Technical field
The present invention provides the compound that the compound of choline and carboxy-containing acid group are formed in a manner of at ester, the present invention also carries
The preparation method of such compound is supplied.
Background technology
Choline (choline) the i.e. hydroxylate of beta-hydroxyethyl Trimethylamine is a kind of nitrogenous organic basic compound,
It can be ionized completely in aqueous solution, base strength is similar to NaOH.The discovery of choline has 150 years, according to the work of Ensminger
It states, Gobley in 1844 isolates a kind of lecithin (1ecithin) from yolk；1849, Streker divided from pig's bile
A kind of compound is separated out, choline is named as within 1862, Baeyer and Wurtz determine the chemical constitution of choline and synthesize for the first time
Choline.
Effect of the choline in metabolism is various, including the effects that acetylation, phosphorylated, oxidation and hydrolysis.It adds
Speed synthesis and release acetylcholine this important nerve conduction mediator, memory, muscular movement to influence body etc. are a variety of
Function；Choline is the precursor of phosphatidyl choline and sphingomyelin, and the two is the necessary material of composition cell membrane, while being thin again
The precursor substance of intercellular multi-signal；Choline is also the strength activity factor of blood platelet；Choline can be converted into glycine betaine, kidney
Spherulous cell needs glycine betaine to adjust osmotic pressure.
Choline is a main source of unstable methyl.In body, anotherization can be transferred to from a kind of compound
The methyl closed on object is known as unstable methyl, which is known as ester conversion process.Internal ester conversion process has important role, all
Such as participate in the synthesis of the synthesis parahormone critically important to muscle metabolism, adrenaline of creatine and can esterification Cucumber be allowed to
It is discharged from urine.Choline lacks and methyl shortage is often counted as the one thing, because choline lacks the supply for reducing methyl.But
Methyl, which is provided, with glycine betaine, methionine, folic acid or vitamin B12 is not avoided that liver cell is withered by what choline shortage was induced
It dies, therefore, it can be seen that choline has the irreplaceable important specific work(of other methyl donors to regulation and control Apoptosis
Energy.
Choline has affinity to fat, and fat can be promoted to transfer out or improve fat by blood by liver with phospholipid form
Utilization of the fat acid in liver itself, and prevent abnormal accumulation of the fat in liver.If without choline, fat accumulates in liver
There is fatty liver, in morbid state.Clinically, it using choline for treating hepatic sclerosis, hepatitis and other liver diseases, works well.It is another
Aspect, choline and phosphatide have good emulsification property, can prevent cholesterol in the blood vessels the deposition of wall and remove part deposition
Object, while improving the absorption and utilization of fat, have and prevent to cause artery sclerosis since cholesterol deposits in the blood vessels, finally lures
The angiocardiopathy of hair.
Salicylic acid, that is, 2 hydroxybenzoic acid is a kind of fat-soluble organic acid.Early stage makes as antipyretic, analgesic drug
With the later improvement result found to abnormal carbohydrate metabolism.But since it can also bring the pairs such as hypoglycemia, tinnitus, alimentary canal discomfort
Effect.Salicylic acid is used for reducing in clinical test the long-term concurrent cardiopathic risk of diabetic.Newest research is to want
Ask all l diabetes mellitus types for having had heart disease that will take, while salicylic treatment is also proposed as prevention
The method of complication.
Niacin, that is, pyridone-3-carboxylic acid, niacin are used as lipid-regulation medicine.Increase HDL-C and reduction triglycerides because having
It acts on and attracts attention.According to existing domestic and international clinical test evidence and the clinical experience of expert, to niacin class drug
Regulation serum lipids and status are assessed and reach Consensus of experts.Niacin class drug has the Regulation serum lipids of wide spectrum, can be used as single
Or auxiliary treatment medication, it is used for hypertriglyceridemia and combined hyperlipidemia patient, glycerine three is reduced or merge in HDL-C
It is especially suitable when ester increases.
Invention content
The present invention provides one kind choline ester compounds as shown in formula I：
Wherein, A includes one kind in C, N；
Wherein, R1Including-H ,-OH ,-Cl ,-Br ,-I ,-NH2；
Wherein, R2Including-H ,-Cl ,-Br ,-I ,-NH2, R2Further include the substituent group containing 1 to 2 carbon atoms, such as-CH3 ,-
CH2CH3；
Wherein, R3Including-H ,-Cl ,-Br ,-I ,-NH2, R3Further include the substituent group containing 1 to 2 carbon atoms, such as-CH3 ,-
CH2CH3；
Wherein, R4Including-H ,-Cl ,-Br ,-I ,-NH2, R4Further include the substituent group containing 1 to 2 carbon atoms, such as-CH3 ,-
CH2CH3；
Wherein X includes Cl, Br, I.
Particularly, a kind of compound as shown in formula II is we provided：
Wherein X includes Cl, Br, I.
In addition special, we additionally provide a kind of compound as shown in formula III：
Wherein X includes Cl, Br, I, OH.
Choline is as a kind of compound containing quaternary ammonium, and alkalinity is strong, good water solubility, under normal circumstances, with bursine shape
Formula is present in aqueous solution.After bursine is contacted with carboxy-containing acid group, acid-base reaction easily occurs and forms compound salt.And with solid
It is usually halogenation choline, such as choline chloride, choline bromide that body form is existing, halogenation choline solubility in organic solvent
Difference, unique structure cause to be difficult to form ester bond with carboxylic acid group.Under study for action, it has been surprisingly found that, side below can be passed through
Method obtains cholinester.
Explanation is enumerated to the preparation method of compound as shown in formula I, formula II and formula III mentioned by the present invention below.It should
It is interpreted as the description that this method is not limited only to the listed compound enumerated, other carry as described in the present invention is simply taken
For the compound of group, it again may be by similar or identical method and obtain.
Specifically, formula II, III compound represented of formula can be obtained by the following method.Likewise, can also
Other compounds shown in formula I are obtained by similar methods.
The preparation of bromination (2- hydroxyls) benzoic acid cholinester
It takes 2 hydroxybenzoic acid 10g to set in 250ml three-necked flasks, THF 50ml dissolvings, N2 protections, stirring is added.It is added dropwise at 4 DEG C
Phosphorus oxychloride 35g, drop finish, and stir 30 minutes, are slowly warming up to reflux, react 4 hours.Evaporated under reduced pressure.Residue adds acetone
40ml dissolves, and ethylene bromohyrin 20g is added, 60 DEG C are stirred to react 6 hours, evaporated under reduced pressure.Water 20ml is added to dissolve, dichloromethane
100ml extracts (40ml, 30ml, 30ml) in three times, and combined dichloromethane layer is evaporated.Residue column chromatography (80-100 mesh
Silica gel, ethyl acetate-light petrol), eluent is collected, solvent is removed under reduced pressure, THF40ml is added to dissolve, it is molten that 2M trimethylamines THF is added
Liquid 20ml, is stirred at room temperature, be precipitated white solid to get.
1H-NMR(D2O,400MHz):δ ppm8.16 (2H, m), ppm7.47~7.42 δ (2H, m), δ ppm7.68 (1H,
T), ppm3.67~3.62 ppm4.65~4.59 δ (2H, m), δ (2H, m), δ ppm3.28 (9H, s).
The preparation of pyridinium chloride -3- formic acid cholinester
It takes Nicotinicum Acidum 10g to set in 250ml three-necked flasks, anhydrous pyridine 40ml dissolvings is added, lead to N2Protection, stirring.4℃
Lower dropwise addition thionyl chloride 20g, drop finish, and stir 30 minutes, are slowly warming up to reflux, react 4 hours, are concentrated under reduced pressure.Residue adds
Ethylene chlorhydrin 30ml, 40 DEG C are stirred to react 10 hours, are concentrated under reduced pressure, and water 20ml is added to dissolve, and dichloromethane 120ml extracts in four times
(40ml, 30ml, 30ml, 20ml), combined dichloromethane layer is taken to be evaporated.Residue adds THF40ml to dissolve, and 2M trimethylamines are added
THF solution 20ml, 35 DEG C of stirrings, be precipitated white solid to get.
1H-NMR(D2O,400MHz):δ ppm9.75 (1H, m), δ ppm8.69 (1H, m), δ ppm7.76 (1H, m), δ ppm
8.57 (1H, m), ppm4.02~3.96 δ (2H, m), ppm3.55~3.47 δ (2H, m), δ ppm3.13 (9H, s).
Compounds process for production thereof mentioned by the present invention be when preparing the compound as shown in formula 1, formula 2 used by side
Method.
Compounds process for production thereof mentioned by the present invention, feature is mainly reflected in be obtained by following steps:
A. acetyl halide compound is made in carboxy-containing acid group's compound；
B.. carboxylic acid halides is reacted with ethylene halohydrin prepares halogenated carboxylic acid ethyl ester intermediate (IV)；
C. compound shown in Formulas I is obtained by the reaction with trimethylamine in halogenated carboxylic acid ethyl ester intermediate (IV).
By taking compound shown in formula II as an example：
A. by 2 hydroxybenzoic acid, i.e. 2- hydroxybenzoyl chlorides are made in salicylic acid；
B.2- bromo carboxylic acid, ethyl ester intermediate is made with ethylene bromohyrin reaction response in hydroxybenzoyl chloride；
C. formula II is obtained by the reaction with trimethylamine in bromo carboxylic acid, ethyl ester intermediate.
In of the present invention, we are referred to halogenated carboxylic acid ethyl ester, and mentioned halogenated carboxylic acid ethyl ester is shown in formula IV
Compound
Wherein A includes C, N；R1Including H, OH；X includes Cl, Br, I.
The first step is by the way that acyl halide group is made in carboxylic acid group in compounds process for production thereof feature mentioned by the present invention.
Usually, it is to select well acyl chlorides or acylbromide to be made in carboxylic acid.After the completion of prepared by acyl chlorides acylbromides, second step passes through
It reacts to form halogenated carboxylic acid ethyl ester with ethylene halohydrin.In the step, ethylene bromohyrin, ethylene chlorhydrin are to select well.Finally lead to
It crosses and reacts to form halogenated carboxylic acid cholinester with trimethylamine.
In compounds process for production thereof of the present invention, during first step carboxylic acid prepares carboxylic acid halides, it can be used including chlorine
Change sulfoxide, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, tribromo oxygen phosphorus and other reagents that can be used for preparing carboxylic acid halides
As halide reagent.
In the reaction that the carboxylic acid halides of second step participates in, especially acyl chlorides is reacted with ethylene halohydrin prepares halogenated institute's acetoacetic ester mistake
Acyl chlorides is reacted with ethylene halohydrin and is necessary by Cheng Zhong.In general, contain carboxylic acid compound with hydroxy-containing compounds into ester
It is a reaction process being readily appreciated that, and in we study, in accordance with the present invention it has now surprisingly been found that, mentioned carboxy-containing acid groupization
It closes object and (is not doing chloride processing) with the direct reaction process of ethylene halohydrin, the stability of halo groups makes us perplexing.Instead
During answering, there are a variety of side reactions.Attempt under direct acid condition be condensed and be added condensation reagent (such as DCC, EDCI,
DMAP, HATU etc.) catalyzing and condensing at ester during, it is as a result undesirable because side reaction is excessive.And pass through carboxylic acid halides and ethylene halohydrin
Reaction, solves the problems, such as this well.
Obtain halogenated carboxylic acid ethyl ester after, it is subsequent reaction can be selected with trimethylamine (2M trimethylamines tetrahydrofuran solution or
Methanol solution) reaction, which, which reacts, to accelerate reaction speed by suitably increasing temperature, but in organic solvent, excessively high
Temperature is easy to cause the effusion of trimethylamine, this is unfavorable for reaction.The reaction temperature that we select is 0 DEG C~50 DEG C,
Within this range, reaction can be very good to carry out.Another method is the aqueous solution by halogenated carboxylic acid ethyl ester and trimethylamine
Reaction temperature, using the system response, can be increased to 70 DEG C, and the sodium hydroxide of catalytic amount, hydrogen-oxygen can be added by reaction
Change potassium to promote to react.
Compound according to the present invention exists with halide mode under normal conditions, this is because the quaternary ammonium group in structure
Group has compared with caused by strong basicity.And mentioned halogenations object can be handled by simple soda acid and slough halogen group, from
And obtain hydroxide, so its hydroxide also belong to due to the present invention disclosed in a kind of compound.
Compound mentioned by the present invention is as choline carboxylate, on the basis of reservation compound original feature, because of courage
The introducing of alkali can make its property more mild in the feature used as drug, can effectively reduce adverse reaction.
Specifically, Choline Salicylate ester shown in formula II is in experiments it is found that can at least reduce the hair of stomach and intestine side reaction
It is raw.Niacin cholinester shown in formula III at least has the function of having that niacin is same or like in terms of for adjusting blood metabolism,
However its unique metabolic mechanism can effectively reduce niacin directly to the adverse reaction of gastronintestinal system.
Description of the drawings
Attached drawing 1：5 test result table of embodiment；
Attached drawing 2：6 test result table of embodiment.
Specific implementation mode
Embodiment 1
The preparation of bromination (2- hydroxyls) benzoic acid cholinester
It takes 2 hydroxybenzoic acid 10g to set in 250ml three-necked flasks, THF ' 50ml dissolvings, N2 protections, stirring is added.It is added dropwise at 4 DEG C
Phosphorus oxychloride 35g, drop finish, and stir 30 minutes, are slowly warming up to reflux, react 4 hours.Evaporated under reduced pressure.Residue adds acetone
40ml dissolves, and ethylene bromohyrin 20g is added, 60 DEG C are stirred to react 6 hours, evaporated under reduced pressure.Water 20ml is added to dissolve, dichloromethane
100ml extracts (40ml, 30ml, 30ml) in three times, and combined dichloromethane layer is evaporated.Residue fills column, ethyl acetate-pet
Ether (1：15) it elutes, collects eluent, solvent is removed under reduced pressure, residue adds THF40ml to dissolve, and 2M trimethylamine THF solutions are added
20ml is stirred at room temperature, be precipitated white solid to get.
Embodiment 2
The preparation of chlorination (2- hydroxyls -3,5- dichlorophenyl) formic acid cholinester
It takes 2- hydroxyl -3,5- diiodo acids 2g to set in 100ml three-necked flasks, THF ' 10ml dissolvings, N2 protections, stirring is added.4
Oxalyl chloride 7.4g is added dropwise at DEG C, drop finishes, is stirred to react 4 hours.Evaporated under reduced pressure.Ethylene chlorhydrin 10ml is added in residue, and 30 DEG C are stirred
Mix reaction 10 hours, evaporated under reduced pressure.Residue adds THF40ml to dissolve, and 2M trimethylamine THF solution 12ml are added, are stirred at room temperature,
Be precipitated solid, filtering, dry to get.
Embodiment 3
Pyridinium chloride -3- formic acid cholinester
It takes Nicotinicum Acidum 10g to set in 250ml three-necked flasks, anhydrous pyridine 40ml dissolvings is added, lead to N2 protections, stirring. 4℃
Lower dropwise addition phosphorus oxychloride 20g, drop finish, and stir 30 minutes, are slowly warming up to 70 DEG C, react 4 hours, are concentrated under reduced pressure.Residue adds
Ethylene chlorhydrin 30ml, 40 DEG C are stirred to react 10 hours, are concentrated under reduced pressure, and water 20ml is added to dissolve, and dichloromethane 120ml extracts in four times
(40ml, 30ml, 30ml, 20ml), combined dichloromethane layer is taken to be evaporated.Residue adds THF40ml to dissolve, and 2M trimethylamines are added
THF solution 20ml, 35 DEG C of stirrings, be precipitated white solid to get.
Embodiment 4
Pyridinium bromide -4- formic acid cholinester
It takes Nicotinicum Acidum 10g to set in 250ml three-necked flasks, thionyl chloride 40ml dissolvings is added, lead to N2 protections, stirrings 30
Minute, 50 DEG C are slowly warming up to, reacts 4 hours, remaining thionyl chloride is removed under reduced pressure.Residue adds ethylene bromohyrin 20ml, 40 DEG C
Be stirred to react 10 hours, be evaporated under reduced pressure, residue add water 20ml dissolve, dichloromethane 100ml extract in three times (40ml,
30ml, 30ml), combined dichloromethane layer is evaporated.Residue adds THF15ml to dissolve, and 2M trimethylamine THF solution 20ml, room is added
Temperature stirring, be precipitated off-white powder to get.
Embodiment 5
Rat ligatures pylorus type Ulcer Models and prepares
Healthy rat 30 is taken, it is random to divide equally 3 groups, every group 10.Gastric infusion.Negative control group gives 1% carboxymethyl cellulose
Plain sodium 5.0ml/kg.d；Test group gives Choline Salicylate ester (formula II) 80mg/kg.d (equivalent salicylic acid)；Test control group is given
Sodium salicylate 80mg/kg.d (equivalent salicylic acid) is given, is administered once daily, successive administration 7 days.It is fasted after administration in 6th day,
Etherization rat after last 1 administration 3h, by slayShi method surgical ligation pyloruses, suturing them, after 16h fasting for solids and liquids, then
It is anesthetized with ether execution, ligation cardia of cutting open the belly takes stomach to be placed in 1% formalin and impregnates 8min, stomach is cut off along greater curvature, with clear
Stomach lavage to clear is placed on glass plate and is unfolded by water.Examining gastric mucosa face ulcer with anatomical lens, a situation arises.It is sent out with ulcer
Dough product is used as ulcer index, the calculating of ulcer inhibition rate following formula to acquire：Ulcer inhibition rate=(negative control group ulcer surface
Product-test group ulcer area)/negative control group ulcer area × 100%, as a result see attached drawing 1.
As a result
None is dead during test group and test control group animal are administered, and makees pylorus ligation after administration, as a result shows, with
Test control group is compared, and the incidence that Choline Salicylate ester ligatures rat pyloric ulcer is substantially reduced；Test control group animal
5d to 7d dead 1 altogether upon administration, laparotomy inspection dies of gastric perforation.Non- dead animal makees pylorus ligation, ulcer occurring area
It is significantly greater than negative control group and test group with degree.
Embodiment 6
It is prepared by niacin cholinester working solution：Niacin cholinester is taken, methanol is used：Water (1：1) 3500 μ of concentration is made in dilution successively
The a series of activities liquid of mol/L, 350 μm of ol/L, 35 μm of ol/L, 3.5 μm of ol/L.
Take SD rats and Beagle dog plasmas.Two kinds of anti-freezings are selected to handle (anticoagulant heparins：25 μ g heparin sodiums/mL is complete
Blood, anticoagulated whole blood is through 4000rpm × 10min centrifuging and taking upper plasmas；EDTA anti-freezings：1.6mg EDETATE SODIUMs/mL whole bloods resist
Solidifying whole blood is through 4000rpm × 10min centrifuging and takings upper plasma) obtained by blank SD rat plasmas and Beagle dog plasmas, take 45
The working solution that 5 μ l. cholinester containing niacin (formula III) are added in μ l blank plasmas is made a concentration of 3.5 μm of ol/L and 35 μm of ol/L's
Plasma sample, is placed at room temperature for processing after 6h., and LC-MS/MS detects the production quantity (μm ol/L) of niacin in blood plasma.By niacin
The ratio percentage of the addition of production quantity and niacin cholinester is as niacin cholinester to the conversion ratio of niacin hydrolysis
(%) results are shown in attached drawing 2.
Niacin cholinester (formula III) is given birth in SD rat plasmas and Beagle dog plasmas by unspecific cholinesterase hydrolysis
At niacin；Enzyme activity hydrolysis in SD rat plasmas is more active compared with Beagle dogs；Anti-coagulants EDTA (disodium) to SD rats with
The blood plasma unspecific cholinesterase of Beagle dogs has inhibiting effect, and there are the inhibition of concentration dependent enhancings.
Claims (5)
1. a kind of choline ester compounds as shown in formula I：
Ⅰ
Wherein, A includes one kind in C, N；Wherein, R1Including-H ,-OH ,-Cl ,-Br ,-I ,-NH2；
Wherein, R2Including-H ,-Cl ,-Br ,-I ,-NH2, R2Further include the substituent group containing 1 to 2 carbon atoms, such as-CH3 ,-
CH2CH3；Wherein, R3Including-H ,-Cl ,-Br ,-I ,-NH2, R3Further include the substituent group containing 1 to 2 carbon atoms, such as-
CH3、—CH2CH3；Wherein, R4Including-H ,-Cl ,-Br ,-I ,-NH2, R4Further include the substituent group containing 1 to 2 carbon atoms,
Such as-CH3 ,-CH2CH3；Wherein X includes Cl, Br, I.
2. a kind of cholinester compounds process for production thereof as shown in formula I, which is characterized in that obtained by following steps:A. will
Acetyl halide compound is made in carboxy-containing acid group's compound；B. carboxylic acid halides is reacted with ethylene halohydrin prepares halogenated carboxylic acid ethyl ester intermediate
（Ⅳ）；C. halogenated carboxylic acid ethyl ester intermediate（Ⅳ）Compound shown in Formulas I is obtained by the reaction with trimethylamine.
3. compound according to claim 1, which is characterized in that the hexatomic ring in structure includes phenyl ring, substituted benzene ring, pyridine
Ring, substituted pyridines ring.
4. preparation method according to claim 2, which is characterized in that acetyl halide compound step is made in carboxy-containing acid group's compound
Suddenly, used halide reagent includes that thionyl chloride, oxalyl chloride, phosphorus oxychloride, phosphorus trichloride, phosphorus pentachloride, tribromo can be used
Oxygen phosphorus.
5. preparation method according to claim 2, which is characterized in that, which is reacted using carboxylic acid halides with ethylene halohydrin, prepares halogenated carboxylic
Acetoacetic ester intermediate（Ⅳ）.
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