CN1023479C - Process for preparation of ethylenediamine monoamide derivatives - Google Patents
Process for preparation of ethylenediamine monoamide derivatives Download PDFInfo
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- CN1023479C CN1023479C CN 85107182 CN85107182A CN1023479C CN 1023479 C CN1023479 C CN 1023479C CN 85107182 CN85107182 CN 85107182 CN 85107182 A CN85107182 A CN 85107182A CN 1023479 C CN1023479 C CN 1023479C
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Abstract
An ethylenediamine monoamide derivative in conformity with a general formula (I) is accidentally discovered; in the formula, R represents an aromatic five-membered or six-membered heterocyclic group defined in claim of right I. In addition, the ethylenediamine monoamide derivative is useful in pharmacy, all salts generated by the ethylenediamine monoamide derivative and acid have the property of inhibiting monoamine oxidase interested by people, and have low toxicity so that the ethylenediamine monoamide derivative can be used for treating depression and Parkinson's syndrome. Compounds in formula (I) are all new compounds except for N-(2-aminoethyl) pyridine-2-formamide, and can be synthesized by a known method.
Description
The invention relates to the monoamide derivatives of quadrol, especially have the monoamide class of quadrol of following general formula and the salt that useful they and acid generate in pharmacy:
In the formula, R represents one of following groups:
Above-listed various in, R
1, R
2, R
3And R
4In have two expression hydrogen at least, all can represent hydrogen, halogen, nitro, amino, hydroxyl, lower alkoxy, low alkyl group or the phenoxy group or the benzyloxies that replace arbitrarily respectively for all the other two; R
5, R
6And R
7All can represent hydrogen or halogen respectively; R
8, R
9And R
10All can represent hydrogen, halogen or low alkyl group respectively, its condition is R
8, R
9And R
10In have at least one not to be hydrogen; R
11, R
12And R
13All can represent hydrogen or halogen respectively, its condition is R
11, R
12And R
13In have at least one not to be hydrogen; R
14, R
15, R
16, R
18And R
19All can represent hydrogen, halogen or low alkyl group: R respectively
17The expression hydrogen or halogen; And R
20And R
21All can represent hydrogen or low alkyl group respectively.
It seems that from classification these compounds once saw: as United States Patent (USP) 4,034,106, and we are surprised to find that these compounds are interesting, and have useful drug effect character and low toxicity in treatment.Find according to experimentation on animals, the compound of above-mentioned formula I and in pharmacy useful they have a series of character of inhibition monoamine oxidase (MAO) with the salt that acid generates.
The objective of the invention is: the compound of general molecular formula I and the salt that generates with acid in they that use in the pharmacy thereof as being the material of therapeutic activity to be arranged and they are made the various medicaments of a kind of compound of containing formula I or its useful they and the salt of acid generation in pharmacy; Introduce the manufacture method of this medicine and point out the compound of general molecular formula I and useful they and acid generate in pharmacy salt in control or preventing disease or improve health, the use aspect control or prevention depressive state and Parkinsonism especially.
Remove at the existing N-(2-aminoethyl of recording and narrating in " Acta Polon.Pharm.39; 41(1982) ") outside the pyridine-2-carboxamide, the all cpds that comprises in the above-mentioned formula I, promptly meeting the salt that the quadrol monoamide derivatives of following general formula and they and acid generate all is novel compound, points out that this point equally also is an one object of the present invention:
One of R ' expression following groups among the formula I a:
Above-mentioned various in, R
1 ', R
2 ', R
3 'And R
4 'In have two expression hydrogen atoms at least, all can represent hydrogen, halogen, nitro, amino, hydroxyl, lower alkoxy, low alkyl group or the phenoxy group or the benzyloxies that replace arbitrarily respectively for all the other two, its condition is R
1 ', R
2 ', R
3 'And R
4 'Can not represent hydrogen simultaneously; R
5, R
6And R
7All can represent hydrogen or halogen respectively; R
8, R
9And R
10All can represent hydrogen, halogen or low alkyl group respectively, its condition is R
8, R
9And R
10In have at least one not to be hydrogen; R
11, R
12And R
13All can represent hydrogen or halogen respectively, its condition is R
11, R
12And R
13In have at least one not to be hydrogen; R
14, R
15, R
16, R
18And R
19All can represent hydrogen, halogen or low alkyl group respectively; R
17The expression hydrogen or halogen; And R
20And R
21All can represent hydrogen or low alkyl group respectively.
Last purpose of the present invention provides a kind of method of the salt that these useful in the compound of manufacturing general molecular formula/I a and pharmacy compounds and acid generates.
Term " low alkyl group " expression of using in this paper describes has 1～3 carbon atom straight chain and branched hydrocarbyl, i.e. methyl, ethyl, n-propyl and sec.-propyl.Term " lower alkoxy " expression low alkyl group ether group, term herein " low alkyl group " has above-mentioned meaning.Term " halogen " refers to fluorine, chlorine, bromine and four kinds of halogens of iodine.Be meant such phenyl for the phenoxy group or the used term " phenyl of replacement " of benzyloxy that replace: its one or more hydrogen atoms are replaced by halogen, low alkyl group, lower alkoxy, nitro or hydroxyl.Known within the scope of the invention those groups of term " leavings group " expression are as halogen (chlorine or bromine is better), arylsulfonyloxy (as tolysulfonyl oxygen base), alkane sulfonyloxy (as mesyloxy) or the like.
Term " the useful salt that generates with acid in the pharmacy " comprises the salt that generates with following mineral acid and organic acid: example hydrochloric acid, Hydrogen bromide, nitric acid, sulfuric acid, phosphoric acid, citric acid, formic acid, vest acid, acetate, succsinic acid, tartrate, methylsulfonic acid, tosic acid or the like.Any one skilled person in this field as long as he had both understood the present situation in this field, understands the character that this compounds is converted to a kind of salt again, and he just can easily make this salt so.
In the compound of general molecular formula I, R representative (a), (f), (g) or those compounds (h) are reasonable compounds.
In the compound of general molecular formula I, substituent R
1, R
2, R
3And R
4In have three expression hydrogen at least, and the compound of the 4th expression hydrogen, halogen, amino, hydroxyl or lower alkoxy is preferential especially.
In the compound of general molecular formula I, substituent R
16And R
17Or R
18And R
19In have one the expression hydrogen or halogen compound also be preferential especially.
According to top as can be known described: in the compound that meets the formula I, all to satisfy following compound be particularly preferred compound: its R represent group (a), (f), (g) and (h) in one, substituent R
1, R
2, R
3And R
4In have three expression hydrogen and the 4th substituting group represented hydrogen, halogen, amino, hydroxyl or lower alkoxy, substituent R at least
16And R
17, or R
18And R
19In an expression hydrogen and another substituting group is represented hydrogen or halogen is arranged.
The particularly preferred compound that meets the formula I is:
The N-(2-aminoethyl)-4-methoxypyridine-2-methane amide,
The N-(2-aminoethyl) thiazole-2-methane amide,
The N-(2-aminoethyl)-4-bromopyridine-2-methane amide,
The N-(2-aminoethyl)-2-chloropyridine-2-methane amide,
The N-(2-aminoethyl)-2-chloropyridine-4-methane amide,
The N-(2-aminoethyl)-5-methyl-isoxazole-3-methane amide,
The N-(2-aminoethyl)-6-bromopyridine-2-methane amide,
The N-(2-aminoethyl)-6-chloropyridine-2-methane amide,
The N-(2-aminoethyl)-5-bromo thiazole-4-methane amide,
The N-(2-aminoethyl)-3-aminopyridine-2-methane amide,
The N-(2-aminoethyl) pyridine-2-carboxamide and
The N-(2-aminoethyl)-5-chloropyridine-2-methane amide.
According to the present invention, can meet the salt that useful they and acid generate in the compound of formula I a and the pharmacy by following method manufacturing.
A) make the compound that meets following general formula with free acid or can be because of the form and the reacting ethylenediamine of derivative with its active official:
R in the formula
1Has aforementioned meaning
Or
B) make compound and the ammonia react that meets following general formula:
R in the formula
1Has aforementioned meaning, R
22Expression hydrogen, and R
23Represent a kind of leavings group,
Or
C) will meet radicals R in the compound of following general formula
24Change amino into:
R in the formula
1Have aforementioned meaning, and R
24
Expression can change amino a kind of group into
Or
D) phenmethyl in the compound that meets following general formula is dissociated:
Substituent R in the formula
2 ", R
3 "And R
4 "In have two expression hydrogen at least, the 3rd expression hydrogen, halogen, nitro, amino, hydroxyl, lower alkoxy, low alkyl group or the phenoxy group that replaces arbitrarily, and R
1 "The expression benzyloxy
And, if desired, can be with the compound of gained by changing salt useful in a kind of pharmacy into acid-respons.
Derivative as the active function groups of the acid that meets the formula II, can consider to adopt, for example, halogenide (for example muriate), symmetry or mixed acid anhydride, ester (for example methyl esters, p-nitrophenyl ester or N-hydroxy-succinamide ester), stacked oxide and acid amides (for example imidazoles thing or amber ester imide).
As stated above a), meeting the reactive derivative of a kind of acid of II or it and the reaction of quadrol can carry out according to ordinary method.For example, in the presence of certain condensing agent, a kind of free acid that meets the formula II can be in a kind of inert solvent and reacting ethylenediamine.If carbodiimide such as dicyclohexylcarbodiimide are used as condensing agent, then reaction can be carried out in following solvents: a kind of chain alkyl carboxylic acid ester (as ethyl acetate), a kind of ether (as tetrahydrofuran (THF) or dioxane), a kind of hydrochloric ether (as methylene dichloride or chloroform), a kind of aromatic hydrocarbon (as benzene, toluene or dimethylbenzene), acetonitrile or dimethyl formamide under a temperature between-20 ℃ of pacts and the room temperature (better about 0 ℃) easily.If phosphorus trichloride is used as condensing agent, then reaction can be in a kind of solvent such as pyridine, carries out easily under a temperature between the reflux temperature of about 0 ℃ and reaction mixture.In preceding method another specific examples a), be that quadrol is reacted with one of active functional derivative of the aforesaid a kind of acid that meets the formula II.For example, a kind of halogenide, as meet the muriate of a kind of acid of formula II, can in the presence of a kind of solvent such as the ether in about 0 ℃ and quadrol react.
The compound that meets the formula III is, for example, N-(2-halogenated ethyl) methane amide, concrete example such as N-(2-chloroethyl) methane amide, N-(2-methylsulfonyl ethyl) methane amide or N-(2-tolysulfonyl ethyl) or the like.
According to foregoing method b), meeting a kind of compound of formula III can be by a kind of currently known methods and ammonia react, temperature of reaction is between approximately-40 ℃ and 50 ℃, and if desired, reaction can be carried out in the presence of a kind of solvent such as dimethyl formamide, N,N-DIMETHYLACETAMIDE, dimethyl sulfoxide (DMSO) etc.This is reflected at about room temperature and has under a kind of solvent existence and can carry out easily.
According to aforesaid method c), with radicals R
24Change amino reaction into, also can carry out, and used this method is by radicals R according to a kind of original known method
24Character decision.If R is a kind of amide group, then conversion reaction can be carried out easily by acidity or alkaline hydrolysis.Use a kind of solution of mineral acid, for example: hydrochloric acid, Hydrogen bromide, sulfuric acid, phosphoric acid etc., acidic hydrolysis just can carry out in a kind of inert solvent easily.The example of inert solvent has a kind of alcohol (as methyl alcohol or ethanol) or a kind of ether (as tetrahydrofuran (THF) or dioxane).Alkaline hydrolysis can be carried out under the condition of using alkali metal hydroxide aqueous solution (as potassium hydroxide solution or sodium hydroxide solution).Some organic solvent inert such as top those solvents of mentioning about acidic hydrolysis can be used as the solubilising solvent and add.Acid and alkaline hydrolysis can be carried out in the temperature range from about room temperature to reflux temperature, at the boiling point of reaction mixture or be lower than slightly under the temperature of this boiling point and compare.If R
24Be phthalimido, then this group can not only be converted into amino by acid and alkaline hydrolysis, can also separate by ammonia with the aqueous solution of a kind of low-grade alkylamine (as methylamine or ethamine) and be converted into amino.A kind of low-level chain triacontanol can be used as organic solvent.This is reflected under the temperature and compares.Changing benzene imide base into amino the third method comprises: the compound (R wherein that will meet the formula IV
24Be benzene imide base) react in mixture, tetrahydrofuran (THF) or the aqueous ethanol of a kind of inert solvent such as ethanol, ethanol and chloroform with hydrazine.Temperature of reaction can change in about 100 ℃ scope from room temperature, compares at the boiling point of selected solvent.Last product can extract by diluted mineral acid, and and then alkalization gained acidic solution obtain.No matter exist still not have a kind of inert solvent, at room temperature, amino available trifluoroacetic acid of tertiary butyloxycarbonyl or formic acid change amino easily into, and trichlorine ethoxy carbonyl amino changes amino reaction into and will use zinc or cadmium to carry out under acidic conditions.Acidic conditions can carry out in the acetate and reaches easily by allowing be reflected at, and whether a kind of additional inert solvent exists and all can as alcohol (for example methyl alcohol).Use a kind of method of the known top acidic hydrolysis of being mentioned or pass through hydrogenolysis, benzyloxy carbonyl amino group can be converted into amino.According to known method, for example in the presence of a kind of catalyzer such as palladium charcoal, Raney nickel, platinum oxide etc., use element hydrogen, azido-can be reduced to amino.According to being known method equally, hexa-methylene four ammoniums can transform into amino by acidic hydrolysis.
According to aforesaid method d), dissociating of phenmethyl can be carried out easily according to known method itself, and these methods are in the presence of platinum.Carry out hydrogenolysis in room temperature, perhaps inert solvent whether exist all can situation under, (relatively good 50 ℃ of left and right sides) is hydrolyzed with trifluoroacetic acid in the temperature range of room temperature to 100 ℃.
Being used as the compound that meets the formula II of raw material and active functional derivative thereof in a) in aforesaid method is compound known or can be with the compound that makes with preparation known compound similar methods.
At preceding method b) in be used as raw material formula III compound also be compound known or with the similar compound of known compound, they can prepare with known method itself.For example, a kind of compound or its active functional derivative that meet the formula II can react with thanomin under the reaction conditions of a) stipulating for aforesaid method, resulting N-(2-hydroxyethyl) methane amide can change the formula III compound that needs into known method itself, and this currently known methods is to make the N-(2-hydroxyethyl) methane amide and a kind of halogenating agent (as phosphorus trichloride, phosphorus tribromide, phosphorus pentachloride, phosphoryl chloride or the like), a kind of aryl sulfonyl halides (as Tosyl chloride) or a kind of alkane sulfonic acid halide (as methylsulfonyl chloride) react.
At aforesaid method c) in be used as raw material formula IV compound also be known or with the similar compound of known compound, they can prepare by known method itself.For example, a kind of compound of formula II or its active functional derivative can for preceding method a) under the defined terms and a kind of compound of following general formula react:
R in the formula
24Has aforementioned meaning
The compound of formula V is a known compound, maybe can be with preparing with preparation known compound similar methods.
According to a kind of alternative method, R
24The formula IV compound of expression benzene imide phenyl, azido-or hexa-methylene four ammoniums also can through type III compound and phthalimide potassium, a kind of an alkali metal azide or hexa-methylene four ammoniums react and make, this reaction is to be preceding method b by a kind of known method itself) carry out under the reaction conditions of regulation.
At aforesaid method d) in be used as raw material formula I b compound belong to the compound of formula I a, thereby can make according to the method for the preparation formula I a compound of having stated.
As described in the text, the salt pair monoamine oxidase (MAO) that useful they and acid generate in formula I compound and the pharmacy has and suppresses active.According to this activity, formula I compound and in pharmacy the useful salt that generates with acid can be used for treating depressive state and Parkinsonism.
The MAO of the compound among the present invention suppresses activity and can adopt standard method to measure.For example, give the oral compound to be measured of rat.After two hours, mouse is killed, according to the method for in " Biochem Pharmacol.12(1963) 1439-1441 ", recording and narrating, MAO is carried out in the homogenate of its cerebral tissue suppress determination of activity, but use phenylethylamine (2 * 10
-5Rub/liter) replace tyrasamine as substrate (substrate).Activity that some compounds of the present invention record with aforesaid method and toxicity thereof are respectively from following ED
50(median effective dose) data (little rubbing/kg body weight, oral, for rat) and LD
50(medium lethal dose) data (milligram/kg body weight, oral, for mouse) be fully aware of.(table 1 is seen the literary composition back)
Meet the compound of formula I and in pharmacy useful they can be used as medicament with the salt that acid generates, for example, use with the form of pharmaceutical preparation, these pharmaceutical preparations can be oral with tablet, coated tablet, drageeing, form hard or soft gelatin capsule, solution, emulsion or suspension.Also can, for example, carry out rectal administration or carry out the parenteral canal drug administration with the injection liquid form with suppository form.
Be to make tablet, coated tablet, drageeing and hard gelatin capsule, meeting useful they and acid generate in the compound of formula I and the pharmacy thereof salt can together process with inert on the medicine, inorganic or organic excipients.Have more such vehicle to use here, for example concerning tablet, drageeing and hard gelatin capsule, lactose, W-Gum or derivatives thereof, talcum, stearic acid or its salt or the like can be used as vehicle.For soft gelatin capsule, the example of suitable vehicle has vegetables oil, wax, fat, semisolid and liquid polyol or the like.
For making solution and syrup, the example of suitable vehicle has water, polyvalent alcohol, sucrose, Nulomoline, glucose or the like.
For injection solution, the example of suitable vehicle has water, alcohol, polyvalent alcohol, glycerine, vegetables oil or the like.
For suppository, the example of suitable vehicle has natural oil or winterized stearin, wax, fat, semiliquid or liquid polyol or the like.
Salt, buffer reagent, finishing agent or the oxidation inhibitor that can contain in addition, sanitas, solubilizing agent, stablizer, wetting agent, sugar-coat agent, sweetening agent, tinting material, sweetener, adjusting osmotic pressure in these pharmaceutical preparations.They can also contain other treatment and go up useful material.
According to the present invention, the compound of general molecular formula I and in pharmacy useful they can be used for control or prevent various dysthymia disorders and Parkinsonism with the salt that acid generates.Its taking dose can change in the grace period very much, and certainly, this dosage is by every kind of needs decision of each patient in particular cases.Although the day taking dose of formula I compound can surpass 100 milligrams, in general, under oral situation, the day taking dose of formula I compound is about 10 to 100 milligrams and is fit to that this point be should give and pointed out.
Following Example is for the present invention is described, rather than limits the present invention by any way.The unit of all temperature datas all is degree centigrade.
Example 1
With 42 milliliters of (0.3 mole) triethylamines in the suspension of 250 milliliters of methylene dichloride that splash into 24.6 gram (0.2 mole) 2-Pyridinecarboxylic Acids and 19.9 milliliters of (0.21 mole) Vinyl chloroformates below 0 °.Be added dropwise to complete back (1 hour), with the 22.4(0.22 mole) the single acetyl quadrol dissolves in 50 milliliters of methylene dichloride, and in 0～5 ° temperature range, splash into this solution in the above-mentioned solution, 5 ° of restir reaction mixtures 30 minutes, regulate pH to 2 filter reaction mixture in 0 ° of hydrochloric acid then with 37%, isolate the water-soluble liquid phase of tart, at every turn should be mutually twice with 200 milliliters of washed with dichloromethane.
Then with sodium hydroxide solution alkalization this water-soluble liquid phase, and with the dichloromethane extraction several.With dried over mgso dichloro extracting solution, it is concentrated.The residue re-crystallizing in ethyl acetate.Obtain N-(2-kharophen ethyl)-the 2-pyridine carboxamide, 96～99 ° of fusing points.
With 12.0 gram (0.058 mole) N-(2-kharophen ethyls)-the 2-pyridine carboxamide is suspended in 200 milliliters of ethanol and the 116 milliliters of 2N hydrochloric acid, and reflux suspension spends the night.The concentrating under reduced pressure reaction mixture boils solid residue with methyl alcohol then, cooling, suction filtration, drying.Obtain the N-(2-aminoethyl) pyridine-2-carboxamide dihydrochloride white crystal, fusing point: 262 ° (decomposition).
The single acetyl diamines be according to people such as J.Hill in the preparation of method described in " JACS61(1939), 822 ", boiling point 124～127 °/4 crust.
Example 2
In 60 ° of temperature are bathed, with 6.0 gram (35.7 mmole) 4-nitro-2-Pyridinecarboxylic Acids 300 milliliters of absolute thfs and 5.9 gram (36.4 mmoles) 1,1 '-stirred 4 hours in the carbonyl dimidazoles.Then, in wherein adding 6.0 gram (36.1 mmole) (2-aminoethyl) t-butyl carbamates, reflux mixture 4 hours.The concentrating under reduced pressure compound of reaction distributes it then between ethyl acetate and water.The organic phase dried over mgso that merges concentrates.Resistates ethyl acetate crystallization, obtain thus [2-(4-nitropyridine-2-formamido group) ethyl] the t-butyl carbamate white crystals, 130～131 ° of fusing points.
According to above-mentioned similar methods,
-be raw material with 4.0 gram (23.8 mmole) 5-nitro-2-Pyridinecarboxylic Acids, can make [2-(5-nitropyridine-2-formamido group) ethyl] t-butyl carbamate, 141～142 ° of fusing points;
-be raw material with 4.0 gram (19.8 mmole) 4-bromo-2-Pyridinecarboxylic Acids, can make [2-(4-bromopyridine-2-formamido group) ethyl] t-butyl carbamate, 134 ° of fusing points
-be raw material with 8.0 gram (39.6 mmole) 5-bromo-2-Pyridinecarboxylic Acids, can make [2-(5-bromopyridine-2-formamido group) ethyl] t-butyl carbamate, 118 ° of fusing points;
-be raw material with 16.0 gram (79.2 mmole) 6-bromo-2-Pyridinecarboxylic Acids, can make [2-(6-bromopyridine-2-formamido group) ethyl] t-butyl carbamate, 108～109 ° of fusing points;
-be raw material with 10.0 gram (63.5 mmole) 6-chloro-2-Pyridinecarboxylic Acids, can make [2-(6-chloropyridine-2-formamido group) ethyl] t-butyl carbamate, 114～115 ° of fusing points;
-with 1.4 gram (7.3 mmoles) 4,6-two chloro-2-Pyridinecarboxylic Acids are raw material, can make [2-(4,6-dichloropyridine-2-formamido group) ethyl] t-butyl carbamate, 126～127 ° of fusing points;
-be raw material with the mixtures of 5.9 gram (22.3 mmole) 3-chloro-5-benzyloxy-2-Pyridinecarboxylic Acids and 5-chloro-3-benzyloxy-2-Pyridinecarboxylic Acids, subsequently crude mixture being carried out silica gel chromatography separates, can make [2-(3-chloro-5-benzyloxy-2-formamido group) ethyl] t-butyl carbamate, 127～130 ° of fusing points, [2-(5-chloro-3-benzyloxy-2-formamido group) ethyl] t-butyl carbamate, 130～133 ° of fusing points;
-be raw material with 1.6 gram (6.7 mmole) 3-methoxyl group-2-Pyridinecarboxylic Acids, can make [2-(3-methoxypyridine-2-formamido group) ethyl] t-butyl carbamate, 115 ° of fusing points;
-be raw material with 3.7 gram (24.2 mmole) 4-methoxyl group-2-Pyridinecarboxylic Acids, can make [2-(4-methoxypyridine-2-formamido group) ethyl] t-butyl carbamate, 106～107 ° of fusing points;
-with 28.2 the gram (206 mmole) 6-methyl-2-Pyridinecarboxylic Acids be raw material, can make 2-(6-methoxypyridine-2-formamido group) ethyl] t-butyl carbamate, 94～95 ° of fusing points;
-with 6.8 gram (60 mmole) oxazole-4-carboxylic acids are raw material, can make [2-(oxazole-4-formamido group) ethyls] and t-butyl carbamate, 148～150 ° of fusing points;
-be raw material with 9.8 gram (75.9 mmole) thiazole-4-carboxylic acids, can make [2-(thiazole-4-formamido group) ethyl] t-butyl carbamate, 112～118 ° of fusing points;
-be raw material with 6.55 gram (40 mmole) 2-chlorine thiazole-4-carboxylic acids, can make [2-(2-diuril azoles-4-formamido group) ethyl] t-butyl carbamate, 127～129 ° of fusing points
-bromo thiazole-the 4-carboxylic acid is a raw material with 7.0 gram (33.6 mmole) 5-, can make [2-(5-bromo thiazole-4-formamido group) ethyl] t-butyl carbamate, 108～111 ° of fusing points;
-bromo thiazole-the 4-carboxylic acid is a raw material with 7.3 gram (30 mmole) 2-chloro-5-, can make [2-(2-chloro-5-bromo thiazole-4-formamido group) ethyl] t-butyl carbamate, 142～144 ° of fusing points.
In room temperature 7.0 gram (22.6 mmole) [2-(4-nitropyridine-2-formamido group) ethyl] t-butyl carbamates are stirred together with 9 milliliters of methylene dichloride and 9 milliliters of trifluoroacetic acids.Concentrating under reduced pressure reaction mixture then.Residue changes hydrochloride into ethanol solution of hydrogen chloride, this salt ethanol/ether recrystallization.Obtain the N-(2-aminoethyl)-4-nitropyridine-2-carboxamide hydrochloride white crystal, 193～194 ° of fusing points.
At (2-aminoethyl) t-butyl carbamate that is used as raw material described in this example first paragragh is preparation like this:
Under room temperature and argon shield, stir 600 milliliters of (8.98 moles) quadrols, 3 liters of dioxane, 1.5 premium on currency and the magnesian mixtures of 90 grams.The solution that 327 gram di-t-butyl carbonic ethers (di-t-butyl dicarbonate) is dissolved in 1.5 liters of dioxane gained splashed in the above-mentioned mixture in 20 minutes, stirring at room reaction mixture 16 hours, subsequently at Dicalit(trade(brand)name Y filter precoated layer) last suction filtration, concentrating under reduced pressure then.With sludge shape resistates and 500 milliliters of ether reflux together, reflux altogether five times at every turn, all solution is drained drying, suction filtration on Dicalit at every turn.After ethereal solution concentrated, remaining yellow oily resistates with its distillation, obtained (2-aminoethyl) t-butyl carbamate colorless oil under high vacuum, boiling point 84～86 °/46.5 crust.
Press with above-mentioned identical method, with 5.7 gram (0.018 mole) [2-(5-nitropyridine-2-formamido group) ethyl] t-butyl carbamates is raw material, its fusing point is 141～142 °, can get the N-(2-aminoethyl)-5-nitropyridine-2-carboxamide hydrochloride, fusing point 249～250.
Example 3
With 10 gram (49.5 mmole) 3-bromo-2-Pyridinecarboxylic Acids (wherein containing 20% 5-bromo-2-Pyridinecarboxylic Acid) 600 milliliters of absolute thfs and 8.1 gram (50 mmoles) 1,1 '-carbonyl dimidazoles in reflux 2 hours.In wherein adding 8.4 gram (52.4 mmole) (2-aminoethyl) t-butyl carbamates, again mixture heating up was refluxed 4 hours then.The concentrating under reduced pressure reaction mixture.Resistates is distributed between methylene dichloride and water.The organic phase that washing merges, drying also concentrates it.With two kinds of mixtures of methylene dichloride and methylene dichloride and ethyl acetate (7: 3 with 6: 4) is that eluent carries out silica gel chromatography to resistates (9.7 gram) and separates.Collect and concentrate the part of deviating from that contains desired product, resistates ethyl acetate/normal hexane recrystallization.Obtain [2-(3-bromopyridine-2-formamido group) ethyl] the t-butyl carbamate white crystal, 125～130 ° of fusing points.
With 3.2 gram (9.3 mmole) [2-(3-bromopyridine-2-formamido group) ethyl] t-butyl carbamates with 3.5 milliliters of methylene dichloride and 3.5 milliliters of trifluoroacetic acids reflux together 4 hours.The concentrating under reduced pressure reaction mixture is dissolved in ethanol with resistates, and solution is handled with the ethanol solution of hydrogen chloride of equimolar amount.Hydrochloride methanol recrystallization obtains the N-(2-aminoethyl thus)-3-bromopyridine-2-formyl amine salt white crystal, 279 ° of fusing points.
The content that is used as raw material is that 80% 3-bromo-2-Pyridinecarboxylic Acid is in method described in " J.Prakt.Chem.133(1932) " the 33rd page according to R.Graf, by oxidation 3-bromine 2-picoline preparation, and the latter according to J.Abblard in method preparation described in " Bull.Soc.Chim.France(1972) " the 2466th page.
Press with above-mentioned similar methods
-be raw material with 4.4 gram (0.013 mole) [2-(4-bromopyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 134 °, can make the N-(2-aminoethyl)-4-bromopyridine-2-carboxamide hydrochloride, 224～225 ° of fusing points;
-be raw material with 9.2 gram (0.027 mole) [2-(5-bromopyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 118 °, can make the N-(2-aminoethyl)-5-bromopyridine-2-carboxamide hydrochloride, 220～221 ° of fusing points;
-be raw material with 8.0 gram (0.023 mole) [2-(6-bromopyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 108～109 °, can make the N-(2-aminoethyl)-6-bromopyridine-2-carboxamide hydrochloride, 214～215 ° of fusing points.
Embodiment 4
With making 8.0 gram (50.8 mmole) 4-chloro-2-Pyridinecarboxylic Acids and the reaction of (2-aminoethyl) t-butyl carbamate with similar methods described in the example 3.The resistates that obtains after the processing (12.6 gram) is with ethyl acetate/normal hexane recrystallization, obtains the beige crystals of [2-(4-chloropyridine-2-formamido group) ethyl] t-butyl carbamate thus, 120～123 ° of fusing points.
With with similar methods described in 3 second sections of the examples, 10.6 grams (35.4 mmole) [2-(4-chloropyridine-2-formamido group) ethyl] t-butyl carbamate and trifluoroacetic acid are reacted.To change the hydrochloride that forms methanol recrystallization by resistates, obtain the N-(2-aminoethyl thus)-beige crystals of 4-chloropyridine-2-carboxamide hydrochloride, 228～229 ° of fusing points.
The 4-chloro-2-Pyridinecarboxylic Acid that is used as raw material by people such as E.Matsumura in method preparation described in " Bull.Chem.Sco.Jap.43(1970) " the 3210th page.
Press and above-mentioned similar methods,
-be raw material with 10.5 gram (0.035 mole) [2-(6-chloropyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 114～115, can make the N-(2-aminoethyl)-6-chloropyridine-2-carboxamide hydrochloride, 223～224 ° of fusing points;
-with 1.7 grams (0.005 mole) [2-(4,6-dichloropyridine-2-formamido group) ethyl]
T-butyl carbamate is a raw material, and its fusing point is 126～127 °, can make the N-(2-aminoethyl)-4,6-dichloropyridine-2-carboxamide hydrochloride, 197～199 ° of fusing points;
-be raw material with 1.6 gram (5.34 moles) [2-(5-chloropyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 104～105 °, can make the N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride, 193～195 ° of fusing points.
The 5-chloro-2-Pyridinecarboxylic Acid that is used as raw material by people such as J.Oehlke at " Pharmazie38(9) (1983) " the 591st page and R.Graf in " J.prakt.Chemie133(1932) " the 31st page of described method preparation.
Example 5
70 ° with 40.4 gram (0.138 mole) 3-benzyloxy-2-Pyridinecarboxylic Acid hydrochloride sesquialter hydrates and 30.0 gram (0.185 moles) 1,1 '-carbonyl dimidazoles stirred 1 hour in 600 milliliters of tetrahydrofuran (THF)s.With 29.7 gram (0.185 mole) N-(tertbutyloxycarbonyls) quadrol is dissolved in 100 milliliters of tetrahydrofuran (THF)s, then it splashed in the above-mentioned solution, in 70 ° of restir mixtures 2 hours.
Subsequently reaction mixture is cooled to room temperature, under reduced pressure with rotatory evaporator it is concentrated into 1/4 volume, water is with its dissolving and with chloroform extraction three times.Chloroform extraction liquid with dried over mgso after with its complete evaporation, resistates is with chloroform/normal hexane recrystallization, obtains [2-(3-benzyloxy pyridine-2-formamido group) ethyl] carbamyl tert-butyl ester thus, 145～147 ° of fusing points.
8.0 gram (0.022 mole) [2-(3-benzyloxy pyridine-2-formamido group) ethyl] t-butyl carbamates are dissolved in 100 milliliters of trifluoroacetic acids, and the solution of gained was stirred 1/2 hour at 20 °.Extremely do with the rotatory evaporator evaporating mixture then, resistates is dissolved in ethanol, solution is handled with the methanol solution (6N) of hydrogenchloride.Behind the methanol/ethanol recrystallization, obtain the N-(2-aminoethyl)-3-benzyloxy pyridine-2-carboxamide dihydrochloride, 139～142 ° of fusing points.
Press with above-mentioned similar methods,
-be raw material with 2.25 gram (0.0055 mole) [2-(3-chloro-5-benzyloxy pyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 127～130 °.Can make the N-(2-aminoethyl)-3-chloro-5-benzyloxy pyridine-2-carboxamide hydrochloride, 223～225 ° of fusing points;
-be raw material with 2.0 gram (0.0049 mole) [2-(3-{ 4-chlorine benzyloxy } pyridine-2-formamido group) ethyl] t-butyl carbamates, can make the N-(2-aminoethyl)-3-(4-chlorine benzyloxy) the pyridine-2-carboxamide dihydrochloride, 152～154 ° of fusing points;
-be raw material with 3.8 gram (0.0099 mole) [2-(3-{ 4-methyl benzyloxy } pyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 139～141 °, can make the N-(2-aminoethyl)-3-(4-methyl benzyloxy) the pyridine-2-carboxamide dihydrochloride, 227～228 ° of fusing points;
-be raw material with 5.0 gram (0.012 mole) [2-(3-benzyloxy-6-picoline-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 145～150 °, can make the N-(2-aminoethyl)-3-benzyloxy-6-picoline-2-methane amide dihydrochloride, 174～175 ° of fusing points.
Example 6
With with similar methods described in the example 3,8.0 gram (37.2 mmole) 3-phenoxy group-2-Pyridinecarboxylic Acids and (2-aminoethyl) t-butyl carbamates are reacted.The resistates that obtains after the processing (12 gram) is used the ether recrystallization, obtain thus [2-(3-phenoxypyridines-2-formamido group) ethyl] the t-butyl carbamate white crystal, 97～98 ° of fusing points.
With with similar methods described in second paragragh of example 3,8.7 grams (24.3 mmole) [2-(3-phenoxypyridines-2-formamido group) ethyl] t-butyl carbamate and trifluoroacetic acid are reacted.Resistates is changed into behind the hydrochloride with ethanol/ether recrystallization twice, obtains the N-(2-aminoethyl thus)-3-phenoxypyridines-2-carboxamide hydrochloride white crystal, 180～186 ° of fusing points.
3-phenoxy group-the 2-Pyridinecarboxylic Acid that is used as raw material is by preparing 3-phenoxy group-2-pyridine nitrile in propyl carbinol with the potassium hydroxide saponification.And 3-phenoxy group-2-pyridine nitrile is by United States Patent (USP) 4,212, makes described in 980, and its fusing point is 120～121 ° (getting with after ethyl acetate/normal hexane crystallization).
According to above-mentioned similar methods,
-with 5.0 grams (20 mmole) [the 3-(2-chlorophenoxy) pyridine-2-carboxylic acids is raw material, can make [the 2-(3-(2-chlorophenoxy) pyridine-2-formamido group) ethyl] t-butyl carbamate, 86～87 ° of fusing points, again it is changed into the N-(2-aminoethyl)-the 3-(2-chlorophenoxy) pyridine-2-carboxamide hydrochloride (1.3 moles) white crystal, 117～123 ° of fusing points;
-with 5.0 gram (20 mmole) 3-(3-chlorophenoxies) pyridine-2-carboxylic acids is raw material, can make [the 2-(3-(3-chlorophenoxy) pyridine-2-formamido group) ethyl] the carboxylamine tertiary butyl ester, 86～87 ° of fusing points, again it is changed into the N-(2-aminoethyl)-the 3-(3-chlorophenoxy) the pyridine-2-carboxamide hydrochloride, be white crystal, 160～161 ° of (in ethanol, crystallizing out) fusing points;
-with 5.0 gram (20 mmole) 3-(4-chlorophenoxies) pyridine-2-carboxylic acids is raw material, can make [the 2-(3-(4-chlorophenoxy) pyridine-2-formamido group) ethyl] the carboxylamine tertiary butyl ester, 120～122 ° of～fusing points, again it is changed into the N-(2-aminoethyl)-the 3-(4-chlorophenoxy) pyridine-2-carboxamide hydrochloride (1.8 moles), be white crystal, (ethanol), 226～229 ° of fusing points;
-with 5.0 gram (20.4 mmole) 3-(3-methoxyl group phenoxypyridines)-the 2-carboxylic acid is a raw material, can make [2-(3-(3-methoxyl group phenoxy group) pyridine-2-formamido group) ethyl] t-butyl carbamate, 81～82 ° of fusing points, again it is changed into the N-(2-aminoethyl)-3-(3-methoxyl group phenoxy group) the pyridine-2-carboxamide hydrochloride, be white crystal, (ethanol/ether), 142～143 ° of fusing points.
Being used as 3-phenoxy group-2-pyridine nitrile saponification in propyl carbinol that the 3-phenoxy group-2-Pyridinecarboxylic Acid of the replacement of raw material will replace accordingly with potassium hydroxide prepares.The corresponding 3-phenoxy group-2-pyridine nitrile that replaces then is that method makes described in 981 according to United States Patent (USP) 4,212:
-3-(2-chlorophenoxy) pyridine-2-carboxylic acids, 122～123 ° of fusing points (ethyl acetate/normal hexane);
-3-(3-chlorophenoxy) pyridine-2-carboxylic acids, 126～127 ° of fusing points (ethyl acetate/normal hexane);
-3-(4-chlorophenoxy) pyridine-2-carboxylic acids, fusing point 136～137 ° (ethyl acetate/normal hexane) and
-3-(3-methoxyl group phenoxy group) pyridine-2-carboxylic acids, fusing point 126(ethyl acetate/normal hexane)
Example 7
70 ° with 4.0 gram (0.024 mole) 3-oxyethyl group-2-Pyridinecarboxylic Acids and 4.1 gram (0.025 moles) 1,1 '-carbonyl dimidazoles stirred 2 hours in 250 milliliters of tetrahydrofuran (THF)s.With 4.1 gram (0.025 mole) N-(tertbutyloxycarbonyls) quadrol is dissolved in 20 milliliters of tetrahydrofuran (THF)s, and gained solution is splashed in the above-mentioned solution, continued to stir the mixture 2 hours in 70 °.
Then reaction mixture is cooled to room temperature, with rotatory evaporator it is evaporated to 1/4 volume, the concentrated solution water dissolution is used chloroform extraction three times again.Chloroform extraction liquid with dried over mgso after, with its complete evaporation, resistates is that eluent carries out the silica gel chromatography separation with the dichloroethane solution of 2～5% methyl alcohol, and with methylene dichloride/normal hexane recrystallization, can get thus [2-(3-ethoxy pyridine-2-formamido group) ethyl] t-butyl carbamate, 125～126 ° of fusing points.
In 0 ° of solution stirring 1 hour that 5.1 gram (0.016 mole) [2-(3-ethoxy pyridine-2-formamido group) ethyl] t-butyl carbamates is dissolved in gained in 45 milliliters of trifluoroacetic acids.With rotatory evaporator mixture is evaporated to driedly then, resistates is dissolved in ethanol and handling with the ethanolic soln (6N) of hydrogenchloride.Behind ethanol/ether recrystallization, get the N-(2-aminoethyl)-3-ethoxy pyridine-2-methane amide dihydrochloride, 188～190 ° of fusing points.
Press with above-mentioned similar methods
-with 0.7 gram (0.0024 mole) [2-(3-methoxypyridine-2-formamido group) the ethyl carbamic acid tert-butyl ester is raw material, its fusing point is 115 °, can make the N-(2-aminoethyl)-3-Methoxy Pyridine-2-methane amide dihydrochloride, 181～183 ° of fusing points.
-be raw material with 5.3 gram (0.018 mole) [2-(4-methoxypyridine-2-formamido group) ethyl] t-butyl carbamates, its fusing point is 106～107 °, can make the N-(2-aminoethyl)-the 4-methoxypyridine dihydrochloride, 109～211 ° of fusing points;
-be raw material with 1.7 gram (11.1 mmole) 6-methoxypyridine carboxylic acids, can make [2-(6-methoxypyridine-2-formamido group) ethyl] t-butyl carbamate, 104～105 ° of fusing points, again it is changed into the N-(2-aminoethyl)-6-methoxypyridine-2-carboxamide hydrochloride, the lenticular (ethanol/ether) that is white in color, 124～125 ° of fusing points.
6-methoxyl group-the 2-Pyridinecarboxylic Acid that is used as raw material be by E.V.Brown and M.B.Shamhu in method preparation described in " J.Org.Chem., 36(14) (1971) " the 2002nd page, 129～130 ° of fusing points.
Example 8
70 ° with 4.4 gram (0.025 mole) 3-methyl-2-Pyridinecarboxylic Acids and 4.4 gram (0.027 moles) 1,1 '-carbonyl dimidazoles is added in 300 milliliters of tetrahydrofuran (THF)s and stirred 3 hours.With 8.6 gram (0.054 mole) N-(tertbutyloxycarbonyls) quadrol is dissolved in 50 milliliters of tetrahydrofuran (THF)s, and the drips of solution of gained is added in the above-mentioned solution, continued to stir the mixture 3 hours in 70 °.
Then reaction mixture is cooled to room temperature, it is evaporated to 1/4 volume on rotatory evaporator, water is with its dilution and with chloroform extraction three times.Use the dried over mgso chloroform extracted solution, then with its complete evaporation, resistates diisopropyl ether crystallization, obtain thus [2-(3-picoline-2-formamido group) ethyl] t-butyl carbamate, 81～82 ° of fusing points.
In 20 ° of solution stirring 1 hour that 5.0 gram (0.018 mole) [2-(3-picoline-2-formamido group) ethyl] t-butyl carbamates are dissolved in 50 milliliters of trifluoroacetic acid gained.On rotatory evaporator, mixture is evaporated to dried then.Resistates is dissolved in the methyl alcohol, and solution is handled with the ethanolic soln (6N) of hydrogenchloride.Behind the methanol recrystallization, obtain the N-(2-aminoethyl)-3-picoline-2-carboxamide hydrochloride, 254～256 ° of fusing points.
According to above-mentioned similar methods, with 2.0 gram (0.007 mole) [2-(6-picoline-2-formamido group) ethyl] t-butyl carbamates is raw material, its fusing point is 94～95 °, can make the N-(2-aminoethyl)-6-picoline-2-methane amide dihydrochloride, 218～222 ° of fusing points.
Example 9
With with similar methods described in the example 2,10.0 gram (54.9 mmole) 3-methyl-4-nitro-2-Pyridinecarboxylic Acids and (2-aminoethyl) t-butyl carbamate are reacted.The resistates re-crystallizing in ethyl acetate that obtains after the processing, obtain thus [2-(3-methyl-4-nitropyridine-2-formamido group) ethyl] the t-butyl formate white crystal, 133～134 ° of fusing points.
With with similar methods described in second paragragh of example 2,14.6 grams (45 mmole) [2-(3-methyl-4-nitropyridine-2-formamido group) ethyl] t-butyl carbamate and trifluoroacetic acid are reacted.Change resulting resistates into hydrochloride, this hydrochloride methanol recrystallization can get the N-(2-aminoethyl thus)-3-methyl-4-nitropyridine-2-carboxamide hydrochloride white crystal, 204～205 ° of fusing points.
3-methyl-4-nitro-the 2-Pyridinecarboxylic Acid that is used as raw material by people such as E.Matsumara in method preparation described in " Bull.Chem.Soc.Jap.43(1970) " the 3210th page.
Example 10
With with similar methods described in the example 2,9.2 gram (53.6 mmole) 4-chloro-3-methyl-2-Pyridinecarboxylic Acids are reacted with (2-aminoethyl) t-butyl carbamate.The resistates that obtains after the processing (14.7 gram) is used re-crystallizing in ethyl acetate, therefore can get [2-(4-chloro-3-picoline-2-formamido group) ethyl] the t-butyl carbamate white crystal, 134～135 ° of fusing points.
With with similar methods described in second paragragh of example 2,12.5 grams (39.8 mmole) [2-(4-chloro-3-picoline-2-formyl nitrogen base) ethyl] t-butyl carbamate and trifluoroacetic acid are reacted.Change resistates into hydrochloride, this hydrochloride can get the N-(2-aminoethyl thus with ethanol/ether recrystallization)-4-chloro-3-picoline-2-carboxamide hydrochloride white crystal, 180～181 ° of fusing points.
The 4-chloro-3-methyl-2-Pyridinecarboxylic Acid that is used as raw material is in the preparation of method described in " Bull.Chem.Sco.Jap., 43(1970) " the 3210th page by people such as E.Matsumura.
Use similar methods, with 3.3 gram (17.59 mmole) 4-chloro-5-methoxyl group-2-Pyridinecarboxylic Acids is raw material, can make 2-(4-chloro-5-methoxypyridine-2-formamido group) ethyl] t-butyl carbamate light yellow crystal (in ethyl acetate/normal hexane crystallization and get), 132～133 ° of fusing points, again it is changed into N-(2-aminoethyl-4-chloro-5-methoxypyridine-2-carboxamide hydrochloride, the lenticular (crystallization in methanol) that is white in color, 256～257 ° of fusing points.
The 4-chloro-5-methoxyl group-2-Pyridinecarboxylic Acid that is used as raw material is prepared as follows:
Kojic acid (5-hydroxyl-2-methylol-4H-pyrans-4-ketone) is methylated in " J.Org.Chem.; 15(1950) " the 221st page the above method according to people such as K.N.Campbell, generate 2-methylol-5-methoxyl group-4H-pyrans-4-ketone, change resultant into 2-methylol-5-methoxyl group-4-pyridone according to J.W.Armit and T.J.Nolan in " J.Chem.Sco.(1931) " the 3023rd page the above method then.This compound carries out oxidation in " Ber., 87(1954) " the 13rd page of the above method with nitric acid according to K.Heyns and G.Vogelsang, generates 5-methoxyl group-4-pyridone-2-carboxylic acid, then resultant is boiled together resaponifying with thionyl chloride.Obtain the orange crystal of 4-chloro-5-methoxyl group-2-Pyridinecarboxylic Acid, 209 ° of fusing points.
Example 11
With 5.5 gram (0.040 mole) 3-aminopyridine-2-carboxylic acids and 6.8 gram (0.042 moles) 1,1 '-carbonyl dimidazoles adds in 120 milliliters of tetrahydrofuran (THF)s, at 70 ° it stirred 1 hour.With 6.75 gram (0.042 mole) N-(tertbutyloxycarbonyls) quadrol is dissolved in 10 milliliters of tetrahydrofuran (THF)s, and this solution is splashed in the above-mentioned solution, continued to stir the mixture 2 hours in 70 °.
Subsequently reaction mixture is cooled to room temperature, again with its reduction vaporization to 1/4 volume on rotatory evaporator, dilute with water is also used chloroform extraction three times.The chloroform extracted solution dried over mgso makes its evaporation fully then, and resistates is that eluent carries out the silica gel chromatography separation with the chloroform.Obtain [2-(3-aminopyridine-2-formamido group) ethyl] t-butyl carbamate, 103～105 ° of fusing points.
0 ° of solution stirring 1 hour that 2.8 gram (0.010 mole) [2-(3-aminopyridine-2-formamido group) ethyl] t-butyl carbamates is dissolved in 50 milliliters of trifluoroacetic acid gained.On rotatory evaporator, mixture is evaporated to dried then.Resistates is dissolved in methyl alcohol, and solution is handled with the hydrogen chloride methanol solution of 6N.Behind the methanol recrystallization, obtain the N-(2-aminoethyl)-3-aminopyridine-2-methane amide dihydrochloride, 222～225 ° of fusing points.
Example 12
Under 20 ° and normal pressure, with 0.5 gram palladium carbon (10% palladium) with 4.9 gram (0.014 mole) N-(2-aminoethyls)-hydrogenation 1 hour in 1: 1 mixture of 70 milliliters of second alcohol and waters of 3-benzyloxy pyridine-2-carboxamide dihydrochloride.Elimination catalyzer subsequently, filtrate is evaporated to 1/2 volume on rotatory evaporator, add ether after, the constipation partial crystallization goes out the N-(2-aminoethyl)-3-hydroxyl-2-pyridine carboxamide dihydrochloride, 256～258 ° of fusing points.
Employing is with above-mentioned similar methods, with 0.6 gram (0.0016 mole) N-(2-aminoethyl)-3-benzyloxy-6-picoline-2-methane amide dihydrochloride is a raw material, its fusing point is 174～175 ° (examples 5), can make the N-(2-aminoethyl)-3-hydroxyl-6-picoline-2-methane amide dihydrochloride, 237～243 ° of fusing points.
Example 13
With the 1.95(0.0048 mole) fusing point is that [2-(3-benzyloxy-5-chloropyridine-2-formamido group) ethyl] t-butyl carbamate of 130～133 ° is fused in 30 milliliters of trifluoroacetic acids, stirs these solution 7 hours at 50 °.Evaporating mixture is dissolved in methyl alcohol to doing with resistates on rotatory evaporator then, and solution is handled with the methanol solution (6N) of hydrogenchloride.After recrystallizing methanol, obtain the N-(2-aminoethyl)-3-carboxyl-5-chloropyridine-2-carboxamide hydrochloride, 220～223 ° of fusing points.
Example 14
25.0 gram (0.2 mole) pyrazine carboxylic acids are dissolved in 300 milliliters of methylene dichloride and 20.1 milliliters of (0.21 mole) chloro ethyl formates, then 31 milliliters of (0.22 mole) triethylamines are splashed in the above-mentioned solution in 0 ° and 1/2 hour.After 1/2 hour, at 0 ° the gained drips of solution is added to 68 milliliters of (1 mole) quadrols and is dissolved in the solution of 200 milliliters of methylene dichloride gained, and under the condition of no exterior cooling restir mixture 1 hour.After this, the throw out elimination, reduction vaporization filtrate is to doing on rotatory evaporator.Resistates obtains the N-(2-aminoethyl with Virahol recrystallization twice) pyrazine-2-carboxamide hydrochloride, 205～207 ° of fusing points.
Example 15
2.1 gram (0.013 mole) 5-chloropyrazine-2-carboxylic acids and 2.3 gram (0.014 mole) 1,1 ' carbonyl dimidazoles are dissolved in 10 milliliters of tetrahydrofuran (THF)s; At 70 ° with this solution stirring 3/4 hour.In this solution, splashing into 2.2 gram (0.014 mole) N-(tertbutyloxycarbonyls then) quadrol is dissolved in the solution of 5 milliliters of tetrahydrofuran (THF) gained, in 70 ° of restir mixtures 1 hour.
Subsequently the reaction mixture cool to room temperature, and on rotatory evaporator, carry out concentrating under reduced pressure, the reaction mixture after concentrating is dissolved in dilute hydrochloric acid (0.1N) and with dichloromethane extraction three times.The dichloromethane extract that uses dried over mgso to cross evaporates fully, and resistates is that eluent carries out the silica gel chromatography separation with the methylene dichloride, obtain thus [2-(5-chloropyrazine-2-formamido group) ethyl] t-butyl carbamate.
1.6 gram (0.0053 mole) [2-(5-chloropyrazine-2-formamido group) ethyl] t-butyl carbamates are dissolved in 6 milliliters of trifluoroacetic acids, and stirred these solution 20 minutes at 20 °.Evaporating mixture is extremely done on rotatory evaporator then.Resistates is dissolved in methyl alcohol, and solution is handled with the methanol solution (6N) of hydrogenchloride.After the methanol recrystallization, obtain the N-(2-aminoethyl)-5-chloropyrazine-2-carboxamide hydrochloride, 225 ° of fusing points.
Example 16
21.0 gram (0.11 mole) 5-bromo-pyromucic acid are suspended in 650 milliliters of toluene and 40 milliliters of (0.55 mole) thionyl chloride reflux suspension 2 hours.Then reaction soln is concentrated, obtain 5-bromo-2-furans carbonyl chloride resistates thus.
In 0～8 °, 20 minutes, the drips of solution that 22.6 gram (0.108 mole) 5-bromo-2-furans carbonyl chlorides are dissolved in 100 milliliters of methylene dichloride gained is added to 11.0 gram (0.108 mole) the single acetyl quadrols that are cooled to 0 ° in advance and is dissolved in the solution of 250 milliliters of methylene dichloride and 18 milliliters of (0.129 mole) triethylamine gained.At room temperature reaction mixture is stirred and spend the night, suction filtration is also used washed with dichloromethane.Obtain N-(2-kharophen ethyl)-the light beige crystals of 5-bromo-2-furoylamide, 175～176 ° of fusing points.
With 22.2 gram (0.08 mole) N-(2-kharophen ethyls)-5-bromo-2-furoylamide, 150 milliliters of ethanol and 160 milliliters of 2N hydrochloric acid reflux 22 hours together.Concentrating under reduced pressure reaction mixture then.Obtain 214 grammeter look crystal.This crystal is carried out reflux in the mixed solution of 750 milliliters of ethanol and 100 ml methanol.Regulate the pH to 2 of suspension then with alcohol hydrochloric acid, filtering suspension liquid.Concentrating under reduced pressure filtrate to its volume is about 300 milliliters, carries out crystallization operation then.Mixture is cooled to 5 ° and carry out suction filtration.After the drying, obtain 5-bromo-N-(2-aminoethyl)-the light beige crystals of 2-furoyl amine hydrochlorate, 174～175 ° of fusing points.
Example 17
With with similar methods described in the example 16, be raw material with 43 gram (0.2 mole) 5-bromo-2-Thiophene Carboxylic Acids, can make the white crystals thing.With this crystallization reflux in 500 milliliters of ethanol, and 2 ° of cool overnight.After filtration under diminished pressure and the drying, obtain N-(2-kharophen ethyl)-5-bromo-2-thenoyl amine white crystal, 244～245 ° of fusing points.
By with similar methods described in the 3rd section of example 1, make N-(2-kharophen ethyl)-5-bromo-2-thenoyl amine and hydrochloric acid reaction.Resistates is dissolved in ethanol (pH1), and solution is evaporated to about 300 milliliters after filtering.After being cooled to 5 °, suction filtration goes out product, drying, carry out recrystallization with ethanol after, obtain 5-bromo-N-(2-aminoethyl)-2-thenoyl amine hydrochlorate white crystal, 221～222 ° of fusing points.
Example 18
According to similar methods described in the example 2, make 10.0 gram (70.3 mmole) 5-methyl-2-Thiophene Carboxylic Acids and (2-aminoethyl) t-butyl carbamate reactions.Obtain a kind of faint yellow oily resistates (20.6 gram) after handling, resistates is dissolved in ethyl acetate, on 100 gram silica gel, filter.Merge each pure fraction, concentrate.Resistates (15.9 gram oily matter) carries out crystallization with ethyl acetate/normal hexane, thus [2-(5-thiotolene-2-formamido group) ethyl] the t-butyl carbamate white crystal, 109～110 ° of fusing points.
According to the similar methods described in second paragragh of example 2,14.9 grams (52.4 mmole) [2-(5-thiotolene-2-formamido group) ethyl] t-butyl carbamate and trifluoroacetic acid are reacted.After resistates is changed into hydrochloride,, obtain the N-(2-aminoethyl thus with ethanol/ether recrystallization) thiotolene-2-carboxamide hydrochloride oldlace crystallization, 161～162 ° of fusing points.
Example 19
70 ° with 3.1 gram (0.024 mole) 5-Jia Ji oxazole-4-carboxylic acids and 4.0 gram (0.024 moles) 1,1 '-carbonyl dimidazoles stirred 1 hour.In this solution, splashing into 3.9 gram (0.024 mole) N-(tertbutyloxycarbonyls then) quadrol is dissolved in the solution of 15 milliliters of tetrahydrofuran (THF) gained, continued to stir the mixture 1/2 hour.
Reaction mixture is to room temperature subsequently, and on rotatory evaporator it is evaporated to 1/4 volume, and the raffinate dilute with water is with chloroform extraction three times.Will be complete through the chloroform extracted solution evaporation of dried over mgso, resistates carries out crystallization with chloroform/normal hexane, can get thus [2-(5-first base oxazole-4-formyl radical) ethyl] t-butyl carbamate.
20 ° of solution stirring 1/4 hour that 4.5 gram (0.017 mole) [2-(5-Jia Ji oxazole-4-formamido group) ethyl] t-butyl carbamates are dissolved in 20 milliliters of trifluoroacetic acid gained.Again with rotatory evaporator with the mixture evaporate to dryness, resistates is dissolved in methyl alcohol, solution is handled with the methanol solution of hydrogenchloride.After recrystallizing methanol, obtain the N-(2-aminoethyl)-5-Jia Ji oxazole-4-carboxamide hydrochloride, 225 ° of fusing points.
Adopt and above-mentioned similar methods, with 9.6 gram (0.037 mole) [2-oxazole-4-formamido group) ethyl] t-butyl carbamates is raw material, its fusing point is 148～150, can make N-(2-aminoethyl) oxazole-4-carboxamide hydrochloride, 222～224 ° of fusing points.
Example 20
70 ° with 9.8 gram (0.076 mole) thiazole-2-carboxylic acids and 12.3 gram (0.076 moles) 1,1 '-carbonyl dimidazoles is dissolved in the solution stirring 1 hour of 35 milliliters of tetrahydrofuran (THF) gained.In this solution, splashing into 12.2 gram (0.076 mole) N-(tert-butoxycarbonyls then) quadrol is dissolved in the solution of 20 milliliters of tetrahydrofuran (THF) gained, continued to stir the mixture 1/2 hour at 70 °.
Subsequently reaction mixture is cooled to room temperature, and on rotatory evaporator with its reduction vaporization to about 1/4 volume, the concentrated solution dilute with water is used ethyl acetate extraction three times again.To obtain through the acetic acid ethyl acetate extract evaporate to dryness of dried over mgso [2-(thiazole-2-formamido group) ethyl] t-butyl carbamate.
Stir the solution 1/2 hour that 16.5 grams (0.060 mole) [2-(thiazole-2-formamido group) ethyl] t-butyl carbamate is dissolved in 50 milliliters of trifluoroacetic acid gained at 20 °.Then on rotatory evaporator with the mixture evaporate to dryness, resistates is dissolved in methyl alcohol, this solution is handled with hydrogen chloride methanol solution (6N).After recrystallizing methanol, obtain the N-(2-aminoethyl) thiazole-2-carboxamide hydrochloride, 220 ° of fusing points.
According to above-mentioned similar methods
-be raw material with 11.8 gram (0.043 mole) [2-(thiophene-4-formamido group) ethyl] t-butyl carbamates, its fusing point is 112～118 °, can make the N-(2-aminoethyl) the thiazole-4-carboxamide dihydrochloride, 206～209 ° of fusing points;
-be raw material with 9.15 gram (0.030 mole) [2-(diuril azoles-4-formamido group) ethyl] t-butyl carbamates, its fusing point is 127～129 °, can make the N-(2-aminoethyl)-2-diuril azoles-4-carboxamide hydrochloride, 158～160 ° of fusing points;
-be raw material with 7.0 gram (0.034 mole) [2-(5-bromo thiazole-4-formamido group) ethyl] t-butyl carbamates, its fusing point is 108～111 °, can make the N-(2-aminoethyl)-5-bromo thiazole-4-carboxamide hydrochloride, 281～283 ° of fusing points;
-be raw material with 8.7 gram (0.022 mole) [2-(2-chloro-5-bromo thiazole-4-formamido group) ethyl] t-butyl carbamates, its fusing point is 142～144 °, can make the N-(2-aminoethyl)-2-chloro-5-bromo thiazole-4-carboxamide hydrochloride, 222～225 ° of fusing points;
Example 21
With 1.4 gram (0.011 mole) 5-methyl-isoxazole-3-carboxylic acids and 1.8 gram (0.011 moles) 1,1 '-carbonyl dimidazoles is dissolved in 10 milliliters of tetrahydrofuran (THF)s, stirs these solution 1 hour at 70 °.In this solution, dripping 1.8 gram (0.011 mole) N-(tertbutyloxycarbonyls then) quadrol is dissolved in the solution of 3.5 milliliters of tetrahydrofuran (THF) gained, continued to stir the mixture 1 hour at 20 °.
Then reaction mixture is cooled to room temperature, and on rotatory evaporator it is evaporated to about 1/4 volume, the concentrated solution dilute with water is used chloroform extraction three times.With chloroform extracted solution with dried over mgso after evaporate to dryness, resistates is with chloroform/normal hexane recrystallization, so far, obtains [2-(5-methyl-isoxazole-3-formamido group) ethyl] t-butyl carbamate.
20 ° of solution stirring 1/2 hour that 2.6 gram (0.010 mole) [2-(5-methyl-isoxazole-3-formamido group) ethyl] t-butyl carbamates are dissolved in 14 milliliters of trifluoroacetic acid gained.Then on rotatory evaporator with the mixture evaporate to dryness, resistates is dissolved in methyl alcohol, solution is handled with hydrogen chloride methanol solution (6N).Behind the methanol recrystallization, obtain the N-(2-aminoethyl)-5-methyl-isoxazole-3-carboxamide hydrochloride, 208 ° of fusing points.
Example 22
10.0 gram (81.23 mmole) pyridine-2-carboxylic acids are suspended in 150 milliliters of toluene, and suspension was with 17.7 milliliters of (244 mmole) thionyl chloride and 3 dimethyl formamides reflux together 2 hours.Then, the reduction vaporization mixture is extremely done, the resistates O for toluene, and revaporization is to doing.Obtain pyridine carbonyl acyl chlorides green crystals, it can be directly used in the next step.
Under argon shield, 15.4 milliliters of (254 mmole) thanomins are mixed with 30 milliliters of dimethyl formamides, and it is cooled to 0～5 °.Be dissolved in the solution of 100 milliliters of dimethyl formamide gained at 0～10 ° in wherein splashing into 11.3 gram (63.48 mmole) pyridine carbonyl acyls, mixture at room temperature stirs and spends the night.Under reduced pressure the dimethyl formamide distillation is removed, resistates is dissolved in methylene dichloride, removes insoluble composition, separates eluent in the enterprising circumstances in which people get things ready for a trip spectrum of silicagel column then: methylene dichloride, use methylene chloride (9: 1) then.Obtain the N-(2-hydroxyethyl) the pyridine-2-carboxamide yellow oil.
3 gram (18.0 mmole) N-(2-hydroxyethyls) pyridine-2-carboxamide and 20 milliliters of methylene dichloride and 2.5 milliliters of (17.9 mmole) triethylamines put into a round-bottomed flask, and mixture is cooled to 0～5 °.Under the condition of 0～5 ° of maintenance, be dissolved in the solution of 30 milliliters of methylene dichloride gained in wherein splashing into 1.4 milliliters of (18 mmole) methylsulfonyls.Continue stirred reaction mixture 2 hours in 0～5 °, splash into 30 milliliters of (0.44 mole) strong aquas (25%) at 0～5 ° then.At room temperature reaction mixture is stirred and spend the night, then with its concentrating under reduced pressure.Resistates is dissolved in methylene dichloride, with the 2N hydrochloric acid extraction and wash with water.Merge aqueous extract, with strong caustic (28%) alkalization, and with dichloromethane extraction three times.Organic extracting solution dried over mgso is filtered revaporization.The yellow oil that obtains is carried out silica gel column chromatography separates to be further purified.Earlier use ethyl acetate, use ethyl acetate/alcohol mixture then, use ethanol at last as eluent.Obtain the N-(2-aminoethyl) pyridine-2-carboxamide, according to the evaluation of thin-layer chromatography, this material is identical with example 1 described compound.
Example A contains embedded (interlocking) gelatine capsule weighting material of 5 milligrams of active ingredients and forms
1.N-(2-aminoethyl)-5.75 milligrams of * of 4-bromine)
The pyridine-2-carboxamide hydrochloride
2. lactose powder is 80.25 milligrams
3. W-Gum is 40.00 milligrams
4. talcum is 3.60 milligrams
5. Magnesium Stearate is 0.40 milligram
6. lactose crystal is 110.00 milligrams
Capsule filling weighs 240.00 milligrams
Manufacture method:
To sieve after 1～5 mixing, the mesh size of used sieve is 0.5 millimeter.Then, add 6, with the mixture mixing.Mixed mixture is inserted sizeable embedded gelatine capsule (for example, No. 2 capsules), and the weighting material in each capsule weighs 240 milligrams.
*) be equivalent to 5 milligrams corresponding alkali
Example B contains the tablet of 5 milligrams of active ingredients
Tablet is formed
1.N-(2-aminoethyl)-5.75 milligrams of * of 4-bromine)
The pyridine-2-carboxamide hydrochloride
2. lactose powder is 104.25 milligrams
3. W-Gum is 45.00 milligrams
4. polyvinylpyrrolidone/ K30 is 15.00 milligrams
5. W-Gum is 25.00 milligrams
6. talcum is 4.50 milligrams
7. Magnesium Stearate is 0.50 milligram
Tablet weighs 200.00 milligrams
Method:
To sieve after 1～3 mixing, mesh size is 0.5 millimeter.With wetting this powder mixture of 4 ethanolic soln and with its kneading.With wetting material granulation, drying and make appropriate particles.Then in this dried particles, add 5,6 and 7, the mixture mixing.Press (press) mixture to be pressed into the flap of suitable size last treating, every weight is 200 milligrams.
*) be equivalent to 5 milligrams of corresponding alkali
Example C contains the embedded gelatine capsule of 10 milligrams of active ingredients and forms
1.N-(2-aminoethyl)-11.82 milligrams of * of 4-chlorine)
Pyridine-4-carboxamide hydrochloride
2. lactose powder is 74.18 milligrams
3. W-Gum is 40.00 milligrams
4. talcum is 3.60 milligrams
5. Magnesium Stearate is 0.40 milligram
6. lactose crystal is 110.00 milligrams
The capsule fill weighs 240.00 milligrams
Manufacture method:
To sieve after 1～5 mixing, the mesh size of used sieve is 0.5 millimeter.Then, add 6, the mixture mixing.Mixed mixture is inserted sizeable embedded gelatine capsule (for example, No. 2 capsules), and the weighting material in each capsule weighs 240 milligrams.
*) be equivalent to 10 milligrams corresponding alkali
Example D contains the tablet of 10 milligrams of active ingredients
Form
1.N-(2-aminoethyl)-11.82 milligrams of * of 4-chlorine
The pyridine-2-carboxamide hydrochloride
2. lactose is 103.18 milligrams
3. W-Gum is 40.00 milligrams
4. Polyvinylpyrolidone (PVP) K30 is 15.00 milligrams
5. W-Gum is 25.00 milligrams
6. talcum is 4.50 milligrams
7. Magnesium Stearate is 0.50 milligram
200.00 milligrams of tablet weight
Method:
To sieve after 1～3 mixing, mesh size is 0.5 millimeter.This pulverulent mixture is mediated with wetting this powder mixture of 4 ethanolic soln and with it, wetting material granulation, drying and make appropriate particles.Add 5,6 and 7 then in this dry granules, make the mixture mixing.This mixture is pressed into the tablet of suitable size, and each tablet weight is 200 milligrams.
*) be equivalent to 5 milligrams corresponding alkali
Example E
According to method described in routine A～D, can make capsule or tablet with following compound equally preferably:
The N-(2-aminoethyl)-2-diuril azoles-4-carboxamide hydrochloride,
The N-(2-aminoethyl)-3-aminopyridine-2-methane amide dihydrochloride,
The N-(2-aminoethyl) the pyridine-2-carboxamide dihydrochloride and
The N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride.
Table 1
ED
50LD
50
The N-(2-aminoethyl)-4-bromopyridine-2-carboxamide hydrochloride 4 1000-2000
The N-(2-aminoethyl)-4-chloropyridine-2-carboxamide hydrochloride 5 1250-2500
The N-(2-aminoethyl)-2-diuril azoles-4-carboxamide hydrochloride 6 2500-5000
The N-(2-aminoethyl)-5-methyl-isoxazole-3-carboxamide hydrochloride 20＞4000
The N-(2-aminoethyl)-6-bromopyridine-2-carboxamide hydrochloride 8 1000-2000
The N-(2-aminoethyl)-6-chloropyridine-2-carboxamide hydrochloride 10 625-1250
The N-(2-aminoethyl)-5-bromo thiazole-4-carboxamide hydrochloride 10 1250-2500
The N-(2-aminoethyl)-3-aminopyridine-2-methane amide dihydrochloride 5 2500-5000
The N-(2-aminoethyl) pyridine-2-carboxamide dihydrochloride 1.7＞4000
The N-(2-aminoethyl)-5-chloropyridine-2-carboxamide hydrochloride 0.16 1000-2000
Claims (15)
1, a kind of method of following quadrol monoamide derivatives of preparation general formula and the salt that useful they and acid generate in pharmacy thereof:
R in the formula
1One of expression following groups:
Substituent R in the formula
1 ', R
2 ', R
3 'And R
4 'In have at least two the expression hydrogen atoms, all can represent hydrogen, halogen, nitro respectively for all the other two, hydroxyl, lower alkoxy, low alkyl group or phenoxy group that is optionally substituted or benzyloxy, its condition is R
1 ', R
2 ', R
3 'And R
4 'Do not represent hydrogen, R simultaneously
5, R
6And R
7All can represent hydrogen or halogen, R respectively
8, R
9And R
10In have at least one not to be hydrogen, R
11, R
12And R
13All can represent hydrogen or halogen respectively, its condition is R
11, R
12And R
13In have at least one not to be hydrogen, R
14, R
15, R
16, R
18And R
19All can represent hydrogen, halogen or low alkyl group, R respectively
17Expression hydrogen or halogen, and R
20And R
21All can represent halogen or low alkyl group respectively, present method comprises:
A) make the compound of following general formula
R ' has above-mentioned meaning in the formula
React with free acid or its active functional derivative's form and quadrol, or
B) make the compound of following general formula
R in the formula
1Has above-mentioned meaning, R
22Expression hydrogen, and R
23Represent a kind of leavings group, react with ammonia, or
C) will meet radicals R in the compound of following general formula
24
R in the formula
1Have above-mentioned meaning, and R
24
Represent a kind of amino group that changes into
Change amino into, or
D) phenmethyl in the compound that meets following general formula is left away
Substituent R in the formula
2 ", R
3 "And R
4 "In have two expression hydrogen at least, and the 3rd expression hydrogen, halogen, nitro, amino, hydroxyl, lower alkoxy, low alkyl group or the phenoxy group that is optionally substituted, and R
1 "The expression benzyloxy,
And, if desired, can be with the gained compound, be transformed into the salt that becomes behind useful itself and acid-respons in a kind of pharmacy.
2, according to the R that the process of claim 1 wherein in the reaction raw materials
1Expression group (a '), (f), (g) or (h).
3, according to the method for claim 2, the R ' expression group (a ') in the reaction raw materials wherein, substituent R
1 ', R
2 ', R
3 'And R
4 'In three expression hydrogen are arranged, and the 4th substituting group represented halogen, amino, hydroxyl or lower alkoxy.
4, according to the method for claim 2, the R in the reaction raw materials wherein
1Expression group (f) or (g), and substituent R
16And R
17, or R
18And R
19In an expression hydrogen, and another substituting group is represented hydrogen or halogen.
5, according to the method for claim 1, it is characterized in that: preparation
The N-(2-aminoethyl)-4-methoxypyridine-2-methane amide.
6, according to the method for claim 1, it is characterized in that: thiazole-2-methane amide preparation N-(2-aminoethyl).
7, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-4-bromopyridine-2-methane amide.
8, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-4-chloropyridine-2-methane amide.
9, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-4-diuril azoles-2-methane amide.
10, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-5-methyl-isoxazole-3-methane amide.
11, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-6-bromopyridine-2-methane amide.
12, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-6-chloropyridine-2-methane amide.
13, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-5-bromo thiazole-4-methane amide.
14, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-3-aminopyridine-2-methane amide.
15, according to the method for claim 1, it is characterized in that: preparation N-(2-aminoethyl)-5-chloropyridine-2-methane amide.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85107182 CN1023479C (en) | 1985-09-27 | 1985-09-27 | Process for preparation of ethylenediamine monoamide derivatives |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 85107182 CN1023479C (en) | 1985-09-27 | 1985-09-27 | Process for preparation of ethylenediamine monoamide derivatives |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN85107182A CN85107182A (en) | 1987-04-08 |
| CN1023479C true CN1023479C (en) | 1994-01-12 |
Family
ID=4795504
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 85107182 Expired - Lifetime CN1023479C (en) | 1985-09-27 | 1985-09-27 | Process for preparation of ethylenediamine monoamide derivatives |
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| Country | Link |
|---|---|
| CN (1) | CN1023479C (en) |
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| CN102070518B (en) * | 2011-01-24 | 2012-05-02 | 江苏先声药物研究有限公司 | Synthesis of derivatives of substituted pyridine and azaindole |
| NZ753905A (en) | 2013-06-13 | 2020-07-31 | Akebia Therapeutics Inc | Compositions and methods for treating anemia |
| US11324734B2 (en) | 2015-04-01 | 2022-05-10 | Akebia Therapeutics, Inc. | Compositions and methods for treating anemia |
| WO2019028150A1 (en) | 2017-08-01 | 2019-02-07 | Akebia Therapeutics, Inc. | Compositions for use in methods of treatment of hemoglobin disorders |
| CN115140763B (en) * | 2022-08-04 | 2023-05-30 | 先导薄膜材料有限公司 | Method for removing impurities in ITO (indium tin oxide) tower cleaning powder |
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1985
- 1985-09-27 CN CN 85107182 patent/CN1023479C/en not_active Expired - Lifetime
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| Publication number | Publication date |
|---|---|
| CN85107182A (en) | 1987-04-08 |
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