CN1011588B - Pyridine derivatives and their production - Google Patents
Pyridine derivatives and their productionInfo
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- CN1011588B CN1011588B CN 85106134 CN85106134A CN1011588B CN 1011588 B CN1011588 B CN 1011588B CN 85106134 CN85106134 CN 85106134 CN 85106134 A CN85106134 A CN 85106134A CN 1011588 B CN1011588 B CN 1011588B
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Abstract
The present invention relates to a method for preparing a compound with the molecular formula shown as the specification and pharmacologically qualified salts thereof. The medicines are novel and effective to prevent and treat ulcers of digestive systems (such as gastric ulcer and duodenal ulcer) and gastritis. In the formula, R1 represents hydrogen, methoxy or trifluoromethyl; R2 and R3 respectively represent hydrogen or methyl; R4 represents fluorinated alkyl of C2 to C5; n represents 0 or 1.
Description
The present invention narrates some useful pyridine derivates, as the preparation method of some antiulcer agents.
Though according to the United States Patent (USP) of having announced the 4th, 255, No. 431 (No. the 141783/79th, Japanese uncensored publication) and United States Patent (USP) 4,472, No. 409 (No. the 135881/83rd, Japanese uncensored publications) etc. have known that these pyridine derivates have antiulcer activity.
Yet these compound known have the sour excretory effect of a kind of inhibition, and their gastric mucosal protective effect deficiency is difficult to become satisfactory anti ulcer agent.In addition, the instability of these compounds aspect physicochemical property decomposed with being easy to, and all becomes their shortcoming.
Can think that gastroenteritic ulcer is because of factor of erosion, for example hydrochloric acid, stomach en-and defence factor, for example the imbalance between the blood flow of excretory mucus and mucous membrane causes.So need a kind of medicine, the effect of existing gastric acid inhibitory excretory has the effect that strengthens gastric mucosal protection again.
The objective of the invention is in order to make a kind of not only to the secretion of gastric acid inhibitory, protection stomach mucous membrane and antiulcer agent are all had an anti ulcer agent of good effect simultaneously.Have found that the pyridine derivate of certain pattern meets above-mentioned intention, finish the present invention therefrom.
The present invention's narration:
(1) has the pyridine derivate of chemical formula I
Herein, R
1Be hydrogen, methoxyl group or trifluoromethyl, R
2And R
3Be respectively H or methyl, R
4Be C
2-5Fluorinated alkyl, n represent 0 or 1, or qualified salt on their pharmacology;
(2) have the preparation method of salt qualified on formula I compound or its pharmacology, comprise the compound and the reaction of formula III compound that make following formula II,
R herein
1With above-mentioned definition,
R herein
2, R
3And R
4With above-mentioned definition, X
1And X
2One of them is SH, and another is a kind of leavings group, in case of necessity, resultant of reaction be carried out oxidation.
In above-mentioned chemical formula, with R
4The C of expression
2-5Fluorinated alkyl for example has 2,2,2-trifluoroethyl, 2,2,3,3,3-five fluoropropyls, 2,2,3,3-tetrafluoro propyl group, 1-trifluoromethyl-2,2,2-trifluoroethyl, 2,2,3,3,4,4,4-seven fluorine butyl, 2,2,3,3,4,4,5,5-octafluoro amyl group.
X in the above-mentioned chemical formula
1And X
2Leavings group is exemplified below: halogen, be preferably chlorine, bromine or iodine, or active hydroxyl through esterification, for example aryl-sulfonyl oxygen (is example with benzene sulfonyl oxygen or tosyloxy), perhaps C
1-4Alkylsulfonyloxy group (with methylsulfonyl oxygen example), or the organophosphorus acyl-oxygen is (with hexichol phosphinylidyne oxygen, dibenzyl phosphinylidyne oxygen or two C
1-4Alkyl phosphinylidyne oxygen (for example diformazan phosphinylidyne oxygen) etc. is example).
R
1Can be positioned at the 4th or the 5th, and preferably be positioned at the 5th.
A kind of derivative (I) sulfide (n=0) that the present invention studied can be made by compound (II) and compound (III) reaction.Under the situation that alkali exists, reaction is easy to take place.This alkali is the hydride of basic metal for example, as sodium hydride and potassium hydride KH; Basic metal is as sodium Metal 99.5; Sodium alkoxide is as sodium methylate and sodium ethylate; Alkaline carbonate is as salt of wormwood and yellow soda ash; And organic amine, as triethylamine.React used solvent for example alcohols (as methyl alcohol and ethanol) and dimethyl formamide.This alkali number that reacts used is more excessive slightly than its equivalent usually, but also can be excessive in a large number.Say that clearly required alkali number is about the 1-10 equivalent, preferably about 1-4 equivalent.Range of reaction temperature is about 0 ℃ usually between the boiling point of solvent for use, between preferably about 20 ℃ to 80 ℃.The time range of reaction is about 0.2 to 24 hour, preferably 0.5 to 2 hour.
Sulfinyl derivatives (I) also is the compound that the present invention studied (n=1); can be by (n=0) oxidation and making of compound (I); oxygenant used herein is peracid for example, as metachloroperbenzoic acid, peracetic acid, trifluoroperacetic acid with cross toxilic acid or sodium bromite, clorox, hydrogen peroxide.React for example halohydrocarbon (as trichloromethane and methylene dichloride) of used solvent; Ethers (as tetrahydrofuran (THF) with diox); Acid amides (as dimethyl formamide); Alcohol (as methyl alcohol, ethanol, propyl alcohol and the trimethyl carbinol) or water, these solvents can be used alone or as a mixture.The preferred usage quantity of oxygenant is for approaching compound (I) equivalent (n=0), or more excessive a little.Saying clearly, approximately is the 1-3 equivalent, preferably the 1-1.5 equivalent.Range of reaction temperature be from ice-cooled temperature between the boiling point that is about used solvent, normally from ice-cooled temperature to room temperature, and preferably between about 0 ℃-10 ℃.React the required time, be about 0.1-14 hour usually, preferably about 0.1-4 hour.
By the compound (I) that above-mentioned reaction generated, can emanate and purify with common recrystallize method and chromatography.
The present invention's compound (I) can be made salt qualified on the pharmacology through ordinary method, and these salt for example have hydrochloride, hydrobromate, hydriodate, phosphoric acid salt, nitrate, vitriol, acetate, Citrate trianion.
In all cpds (I), the compound of n=0 is stable salt, though and the compound of n=1 is unstable, can exist with aqueous solution form.
The preparation method of raw material (III) is described below:
Method 1:
Nitro-compound (R herein with chemical formula IV
2And R
3Identical with aforementioned definitions) can be in the presence of alkali and a kind of derivative R of alcohol
4The OH(V) (R herein
4Identical with aforementioned definitions) react and obtain having the alkoxy derivative (R herein of chemical formula VI
2, R
3, R
4All identical) with aforementioned definition.This alkali for example is basic metal (as: lithium, sodium, potassium); The hydride of basic metal (as: sodium hydride, potassium hydride KH); Alkoxide (as: potassium tert.-butoxide, sodium propylate); The carbonate of basic metal or supercarbonate (as: salt of wormwood, Quilonum Retard, yellow soda ash, saleratus, sodium bicarbonate); Or the oxyhydroxide of basic metal (as: sodium hydroxide, potassium hydroxide).
React used solvent, except using R
4Outside the OH, for example ethers (as tetrahydrofuran (THF), diox) and ketone (for example acetone, butanone), acetonitrile, dimethyl formamide and HMPA are example in addition.Temperature of reaction should be selected from the temperature range between the boiling point of the solvent that uses to approaching from ice-cooled temperature, and the reaction times is about 1-48 hour usually.
The above-mentioned compound that makes (VI) in the presence of independent acetic anhydride or with a kind of mineral acid (for example: sulfuric acid and perchloric acid) heating (about 80 ℃ to 120 ℃), is generated a kind of 2-acetyl-o-methyl pyridine derivate (R herein with formula (VII)
2, R
3, R
4All identical) with aforementioned definition.The time range of this reaction is about 0.1 to 10 hour usually.
Then, compound (VII) is carried out alkaline hydrolysis, generate a kind of 2-4-hydroxymethylpiperidine derivative (R herein with formula (VIII)
2, R
3, R
4All identical) with aforementioned definition.This alkali is for example used sodium hydroxide, potassium hydroxide, salt of wormwood, yellow soda ash.The solvent that reaction is used is for example used methyl alcohol, ethanol or water.Range of reaction temperature is about between 20 ℃ to 60 ℃ usually.Reaction times was about between 0.1-2 hour.
Make compound (VIII) further with a kind of chlorizating agent (for example thionyl chloride) or a kind of esterifying agent (for example a kind of organic SULPHURYL CHLORIDE, as methylsulfonyl chloride or Tosyl chloride, or a kind of organic phosphoryl chloride, as diphenyl phosphoryl chloride) reacting generating compound (III).Be used as the amount of the chlorizating agent of this reaction, usually should be than excessive in a large number with respect to the equivalent of compound (VIII).The solvent that reacts used for example is trichloromethane, methylene dichloride, tetrachloroethane.Normally in about 20 ℃ to 80 ℃ scopes, the reaction times is about 0.1 to 2 hour to temperature of reaction.
This reacts the consumption of used organic SULPHURYL CHLORIDE or organophosphorus acyl chlorides, and it is excessive to have slightly than its corresponding equivalent usually, and this reaction is normally carried out under the condition that has alkali to exist.This alkali is organic bases (for example: triethylamine, Tributylamine) or mineral alkali (for example: yellow soda ash, salt of wormwood, sodium bicarbonate) for example.React used alkali number, usually should than corresponding equivalent little have excessive.The solvent that reacts used for example has trichloromethane, methylene dichloride, tetracol phenixin, acetonitrile.Range of reaction temperature usually by with ice-cooled temperature between the boiling point that is about solvent for use.Reaction times is usually by between several minutes to a few hours.Usually preferably the compound III of above-mentioned generation is reacted with compound (II) at once.
Method 2:
Adopt and the aforementioned similar reaction of method (1), with a kind of compound (R herein with formula (IX)
2And R
3All identical with the definition of front) make the compound (R herein of formula (X)
2, R
3, R
4All identical) with aforementioned definition.
Then, compound (X) is carried out methylation reaction with methyl-sulfate, make the compound (R herein of its production (XI)
2, R
3, R
4All identical) with aforementioned definition.This reaction does not need solvent just can carry out usually.Temperature of reaction is in 100 ℃ to 120 ℃ scopes, and the reaction times is in 0.1 to 4 hour scope.
Along with, make the compound (IX) must above-claimed cpd (VIII) with in methyl alcohol, react such as other persulphate of persulfuric acid ammonium source or any.Temperature of reaction is between about 20 ℃ to 80 ℃, and reaction time range is about 0.5 to 4 hour.
The pharmacotoxicological effect of The compounds of this invention is described below:
Because of restraining effect and water logging compressing or the caused stomach ulcer of INDOMETHACIN medicine, and, can use this medicine because of the pure gastric mucosa injury that causes.Yet as what put down in writing in " Gastroenterology " (people such as Satoh, 81 volume P719,1981), the model of the antral ulcer that causes as the anti-inflammatory pain medicine of the stomach ulcer of imitating mankind it is believed that to have as the typical value of experiment.So, list some data of relevant the present invention's compound (I) and some other antiulcer action that can be risen for the ulcer model in the above-mentioned reference of mentioning below as the known compound of representative.
Experimental technique:
Sprague-Dawley male rat fasting 24 hours with some birth seven-star phases.Utilize a kind of stomach tube that these animals are taken the compound of test in stomach.After 30 minutes, do subcutaneous injection with the dosage of 30 milligrams of INDOMETHACIN for mouse by every kg body weight.Give after the INDOMETHACIN during 30-90 minute, these animals can ad lib (Japanese Clea, CE-2).Gave INDOMETHACIN 5 hours afterwards, in tail vein injection was gone into these animal bodies, that continues killed these animals with carbon dioxide with 1 milliliter of 1% T-1824.Stomach is taken out together with reaching duodenum under the esophagus.Esophagus is waled, be instilled in the stomach from duodenum, then duodenum is waled with 10 milliliter 1% formaldehyde solution.Whole stomach all is immersed in 1% the formaldehyde solution.After spending 15 minutes, along stomach being cut than the deep camber position.Appear at the infringement area of antrum; The dissecting microscope that can be placed on a kind of 10 times of eyepieces with the square grid is measured down.The summation of each damage of each animal can be recorded, thereby every group mean value can be calculated.Can record its inhibiting rate according to the difference between the mean value of the mean value of each group and control group.Test compound about INDOMETHACIN is to be suspended in the solution of 5% Sudan Gum-arabic, and its usage is by every kg body weight 2 ml volumes.
Experimental result:
Antiulcer action a)
R
1R
2R
3R
4n （mg/kg，p.o.）
H H H CH
2CF
31 2.4
H CH
3H CH
2CF
31 ＜1.0
H H H CH
2CF
2CF
31 1.3
H CH
3H CH
2CF
2CF
31 ＜1.0
H H H CH
2CF
2CF
2H 1 1.3
H CH
3H CH
2CF
2CF
2H 1 ＜1.0
H CH
3H CH
2CF
2CF
30 3.7
5-OCH
3CH
3CH
3CH
3 ＊121.0
5-CF
3CH
3H CH
3 ＊25.5
* 1 this compound is published in the example 23 of No. 4 255 431, United States Patent (USP).(day not unexamined patent 141783/1979 of the present disclosure).
*2 these compounds are published in the example 3 of No. 4 472 409, United States Patent (USP).(No. 135881/1983, day not unexamined patent of the present disclosure).
A) every group with 6 rats, and the drug regimen of each test compound is each dosage 1,3,10 and 30 mg/kg, to measure ID
50
By above-mentioned data presentation, chemical combination of the present invention and known compound relatively all have 1.5-20 times or above good antiulcer action.In addition, The compounds of this invention (I) is for the secretion of gastric acid inhibitory, and aspects such as protection stomach mucous membrane and pre-ulcer all demonstrate fabulous effect.
The toxicity of relevant The compounds of this invention (I) is described below: giving oral this compound of mouse in order to carry out the antiulcer agent experiment (is R
1=H, R
2=CH
3, R
3=H, R
4=CH
2CF
2CF
3, the compound of n=1), even each dosage is 200 mg/kg, do not have fatal influence, therefore prove that the toxicity of compound (I) is very low.
According to noted earlier, The compounds of this invention (I) has antiulcer action, the effect of the effect of control gastric acid secretion and protection stomach mucous membrane, and in addition, this compound is the low and relatively stable chemical substance of a kind of toxicity.So The compounds of this invention (I) can be used for Mammals (as mouse, rat, rabbit, dog, cat) and human digestive system's the ulcer and the treatment and the prevention of gastritis.
When The compounds of this invention (I) is used for treating the digestive system and ulcer of Mammals as a kind of anti ulcer agent, carrier qualified on it and a kind of pharmacology, vehicle, thinner etc. can be made into the medicament of forms such as capsule for oral use, tablet, granula.Day dosage is about the 0.01-30 mg/kg, preferably about 0.1-3 mg/kg.
In addition, The compounds of this invention (I) is of great use as making compound (I) initial substance (n=1) (n=0).
With the preparation method of the initial compounds that uses and the preparation method of The compounds of this invention (I), all explained clearly in the inventive method by following reference example and embodiment.
Reference example 1
2,2,3, dissolving 2 grams 2 in the 3-C3-Fluoroalcohol (10 milliliters), 3-dimethyl-4-nitropyridine-1-ization oxygen.In room temperature, 1.6 gram potassium tert.-butoxides are added in this solution at leisure.Then this mixture was heated 22 hours 80-90 ℃ of temperature.After the reaction soln dilute with water, use chloroform extraction.The extract dried over mgso concentrates then.This enriched material separates with silica gel (70 gram) chromatographic column.With methyl alcohol and chloroform mixed solution (1: 10) wash-out, recrystallize from the mixed solution of ethyl acetate and hexane, obtain 2.6 the gram fusing points be 138-139 ℃ colourless needle-like crystalline substance 2,3-dimethyl-4-(2,2,3,3-tetrafluoro propoxy-) pyridine-1-ization oxygen.
By similar above-mentioned method, the compound of formula IV can be made the compound of formula VI.
Compound (VI)
R
2R
3R
4Molten point (℃)
H H CH
2CF
3148-150
CH
3CH
3CH
2CF
3138-139
Reference example 2
With 2.0 grams 2,3-dimethyl-4-nitropyridine-1-ization oxygen and butanone (30 milliliters), 2,2,3,3, the mixture of 3-five fluorine propyl alcohol (3.05 milliliters), Anhydrous potassium carbonate (3.29 gram), 2.07 gram HMPA is under stirring state, 70-80 ℃ of temperature heating 4.5 days, then nonsoluble is filtered.Filtrate concentrates.This mixture is used ethyl acetate extraction after adding water.With the extraction liquid dried over mgso, the evaporation that continues removes desolvates.This residuum carries out chromatographic separation with the chromatographic column that contains 50 gram silica gel, mixed solution wash-out with trichloromethane and methyl alcohol (10: 1), recrystallize from the mixed solution of ethyl acetate and hexane, obtain fusing point and be 148-149 ℃ colourless needle-like crystalline substance (2.4 gram) 2,3-dimethyl-4-(2,2,3,3,3-five fluorine propoxy-) pyridine-1-ization oxygen.
By similar aforesaid method, the initial compounds of formula IV can be made the compound with formula VI.
Compound (VI)
R
2R
3R
4Fusing point (℃)
CH
3H CH
2CF
3131.0-131.5
H CH
3CH
2CF
3153-154
H H CH
2CF
2CF
379-81
H CH
3CH
2CF
2CF
3140-142
H H CH
2CF
2CF
2The H oily
H CH
3CH
2CF
2CF
2H 143.5-144.5
CH
3H CH
2CF
2CF
2H 138-139
Reference example 3
Containing 2.6 grams 2,3-dimethyl-4-(2,2,3,3-tetrafluoro propoxy-) in 8 milliliters of acetic anhydrides of pyridine-1-ization oxygen, add 2 vitriol oils.
In 110 ℃ of stirrings 4 hours, it is concentrated in mixture.Residuum is dissolved in 20 ml methanol, add then by 1.2 the gram sodium hydroxide be dissolved in the sodium hydroxide solution that 5 ml waters are made into.Stirring at room 30 minutes, it is concentrated in this mixture.Add water in residuum, use ethyl acetate extraction, use the dried over mgso extract, the evaporation that continues removes and desolvates.Residuum carries out chromatographic separation by the chromatographic column that contains 50 gram silica gel, mixed solution wash-out with trichloromethane and methane (10: 1), recrystallize from isopropyl ether, getting fusing point is the 2-methylol-3-methyl-4-(2 of 67-68 ℃ (1.6 gram), 2,3,3-tetrafluoro propoxy-) pyridine, be yellow crystals.
By similar above-mentioned method, the formula VI compound can be made formula (VIII) compound
Compound (VIII)
R
2R
3R
4Fusing point (℃)
H H CH
2CF
3Oily
CH
3H CH
2CF
393.5-94.0
H H CH
2CF
2CF
3Oily
CH
3H CH
2CF
2CF
3Oily
H CH
3CH
2CF
2CF
387-89
H H CH
2CF
2CF
2H 88-89
H CH
3CH
2CF
2CF
2H 98-99
CH
3H CH
2CF
2CF
2H 67-68
Reference example 4
Containing 2.0 grams 3,10 milliliter 2,2,3,3 of 5-dimethyl-4-nitropyridine-1-ization oxygen in the 3-five fluorine propanol solution, adds 2 at 0 ℃ at leisure with 15 fens clock times and restrains potassium tert.-butoxides.This mixture was stirred 18 hours at 60 ℃.In this reaction mixture, add trichloromethane, then with diatomite with it filtration.Filtrate is carried out chromatographic separation by the chromatographic column that contains 80 gram silica gel, mixed solution wash-out with ethyl acetate and hexane (1: 1), and then with methyl alcohol-eluent ethyl acetate of 20%, recrystallize from the mixed solution of ether and hexane, obtain fusing point and be 89-91 ℃ (2.6 gram) 3,5-dimethyl-4-(2,2,3,3,3-five fluorine propoxy-) pyridine-1-ization oxygen is a kind of crystal.
By similar aforesaid method, formula (IX) compound can be made formula (X) compound.
Compound (X)
R
2R
3R
4Fusing point (℃)
CH
3H CH
2CF
382-94
CH
3CH
3CH
2CF
3138-139
Reference example 5
With 2.5 grams 3,5-dimethyl-4-(2,2,3,3,3-five fluorine propoxy-) mixture of pyridine-1-ization oxygen and 1 milliliter of methyl-sulfate is 120 ℃ of heating 30 minutes, the past methyl alcohol (12.5 milliliters) that wherein adds.At 80 ℃, the methyl alcohol (10 milliliters) and water (20 milliliters) drips of solution that will be dissolved with 4.3 gram ammonium persulphates with 30 minutes add in this mixture restir 30 minutes.Solution concentration with gained.Residuum adds ice cube with after the yellow soda ash neutralization, and that continues uses chloroform extraction.Extract dried over mgso, the evaporation that continues are removed and to be desolvated, draw (2,2 gram) 3,5-dimethyl-2-methylol-4-(2,2,3,3,3-five fluorine methoxyl groups) pyridine, be oily mater.
By similar aforesaid method, compound (X) can be made compound (X III).
Compound (VIII)
R
2R
3R
4Fusing point (℃)
H CH
3CH
2CF
3116-119
CH
3CH
3CH
2CF
362-63
Example 1
Containing 350 milligrams of 2-methylol-3-methyl-4-(2,2,3,3,3-five fluorine propoxy-) add 0.2 milliliter of thionyl chloride in 10 milliliters of trichloromethanes of pyridine.
This mixture was refluxed 30 minutes, then it is concentrated.Residuum is dissolved in 5 ml methanol.Add then in 28% sodium methylate (1 milliliter) of 2-mercaptobenzimidazole (200 milligrams) and the mixing solutions that methyl alcohol (6 milliliters) is formed, refluxed 30 minutes.The methyl alcohol in the resultant is removed in evaporation.Add water toward residuum, use ethyl acetate extraction.Extract is used dried over mgso with after rare sodium hydroxide solution washing.Evaporation removes from resultant and desolvates.Then this residuum is carried out chromatographic separation by the chromatographic column that contains 20 gram silica gel, mixed solution wash-out with ethyl acetate and hexane (2: 1), recrystallize from the mixed solution of ethyl acetate and hexane then, generate 370 milligrams of 2-[3-methyl-4-(2,2,3,3,3-five fluorine propoxy-)-pyridine-2-yl] methylthio group benzo imidazoles 1/2 H
2O, its fusing point are 145-146 ℃, are colourless plates.
By similar above-mentioned method, can make the compound of formula I (n=0) with compound (II) and compound (III).
Compound (I) (n=0)
R
1R
2R
3R
4Fusing point (℃)
H H H CH
2CF
3138-139
H CH
3H CH
2CF
3149-150
H H CH
3CH
2CF
3168-170
H CH
3CH
3CH
2CF
3151.5-152.0
H H H CH
2CF
2CF
3125-126
H H CH
3CH
2CF
2CF
3151-152
H H H CH
2CF
2CF
2The H oily
*3
H CH
3H CH
2CF
2CF
2H 134-135
H H CH
3CH
2CF
2CF
2H 148-149
H CH
3CH
3CH
2CF
2CF
3158-160
＊45-CF
3CH
3H CH
2CF
392-93
5-OCH
3CH
3H CH
2CF
3159-160
5-OCH
3H H CH
2CF
3152-153
* 3 NMR (Nuclear Magnetic Resonance) spectrum (CDCl
3) δ: 4.35(s), 4.39(t, t, J=1.5 and 12Hz), 5.98(1H, t, t, J=52.5 and 4Hz), 6.81(1H, d, d, J=2 and 6Hz), 6.95(1H, d, J=2Hz), 7.1-7.3(2H, m), 7.4-7.7(2H, m), and 8.50(H, d, J=6Hz)
* 4:1/4 H
2The O(crystal water)
Example 2
Toward containing 2.2 gram 2-[3-methyl-4-(2,2,3,3,3-five fluorine propoxy-) pyridine-2-yl] in 20 milliliters of trichloromethanes of methylthio group benzo imidazoles, under with ice-cooled situation dropwise to add 15 milliliters of trichloromethanes that are dissolved with 1.3 gram metachloroperbenzoic acids in 30 minutes.Wash this solution with saturated sodium bicarbonate aqueous solution, with dried over mgso and concentrated.Residuum carries out chromatographic separation by the chromatographic column that contains 50 gram silica gel, use eluent ethyl acetate, recrystallize from the mixed solution of acetone and isopropyl ether then, obtaining fusing point is the 2-[3-methyl-4-(2 of 161-163 ℃ (decomposition) (1.78 gram), 2,3,3,3-five fluorine propoxy-) pyridine-2-yl] the methylsulfinyl benzoglyoxaline, be faint yellow shuttle crystalline substance.
By similar above-mentioned method, the compound of formula I (n=0) can be made the compound of formula I (n=1).
Compound (I) (n=1)
R
1R
2R
3R
4Fusing point (℃)
H H H CH
2CF
3176-177
H CH
3H CH
2CF
3178-182（d）
H H CH
3CH
2CF
3175-177（d）
H CH
3CH
3CH
2CF
3177-178（d）
H H H CH
2CF
2CF
3148-150（d）
H H CH
3CH
2CF
2CF
3145-148（d）
H H H CH
2CF
2CF
2H 132-133
H CH
3H CH
2CF
2CF
2H 147-148（d）
H H CH
3CH
2CF
2CF
2H 136-139（d）
H CH
3CH
3CH
2CF
2CF
3157-159
5-CF
3CH
3H CH
2CF
3161-162（d）
5-OCH
3CH
3H CH
2CF
3140.5-142（d）
5-OCH
3H H CH
2CF
3162-163（d）
Annotate: (d): decompose
Claims (2)
1, the preparation method of acceptable salt on the pyridine derivate of the following chemical formula of a kind of tool or its pharmacology,
R wherein
1Be hydrogen, methoxyl group or trifluoromethyl, R
2And R
3Be respectively hydrogen or methyl, R
4Be C
2-5Fluorinated alkyl, n represent 0 or 1, and this method comprises and with chemical formula is
Compound, R herein
1By aforementioned definition, be with chemical formula
R herein
2, R
3, R
4All by aforementioned definitions, X
1And X
2One of them is SH, and another is a kind of leavings group, in case of necessity, reaction product is carried out oxidation.
2, according to the process of claim 1 wherein X
1Be SH, X
2Be halogen.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85106134 CN1011588B (en) | 1985-07-02 | 1985-08-14 | Pyridine derivatives and their production |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP14639585 | 1985-07-02 | ||
| CN 85106134 CN1011588B (en) | 1985-07-02 | 1985-08-14 | Pyridine derivatives and their production |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85106134A CN85106134A (en) | 1987-03-04 |
| CN1011588B true CN1011588B (en) | 1991-02-13 |
Family
ID=15406730
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85106134 Expired CN1011588B (en) | 1985-07-02 | 1985-08-14 | Pyridine derivatives and their production |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1011588B (en) |
| HU (1) | HU196997B (en) |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109868293A (en) * | 2019-01-22 | 2019-06-11 | 湖南理工学院 | A kind of method that enzymatic transesterification kinetics split 2- chloro mandelic acid enantiomer |
| CN114163419A (en) * | 2021-12-24 | 2022-03-11 | 辰欣药业股份有限公司 | Preparation method of lansoprazole |
-
1985
- 1985-08-14 CN CN 85106134 patent/CN1011588B/en not_active Expired
-
1986
- 1986-07-01 HU HU274586D patent/HU196997B/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| CN85106134A (en) | 1987-03-04 |
| HU196997B (en) | 1989-02-28 |
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