TW306923B - - Google Patents

Description

Printed by Beigong Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs ---- B7 V. Description of the invention (1) The present invention relates to a new method for preparing imidazolidine derivatives. The general formula of this derivative is as follows:

Where Ri is an alkyl group, cycloalkyl group, aryl group or aralkyl group or a heterocyclic radical,

Ri and IU are completely the same or different, and they are hydrogen, a hydroxyl group, a cyano group, an alkyl group, a cycloalkyl group, an aryl group or an aryl pit group or they are an alkane acetyl group or an alkoxycarbonyl group and , R3 is hydrogen, an alkyl, aryl or aralkyl group or a functional atom. These compounds are used as intermediates in the preparation of angiotensin II antagonists (J. Med. Chem 1991, 34, 2919-2922). The reference cited in this proof describes that by reducing 2-amino-3 · nitropyridine first, and then condensing with an appropriate aliphatic carboxylic acid, the product of Mizugudian can be obtained. In any case, this method of preparation using 2-amino-3-nitro ° i: b pyridine as the starting material is very difficult, because the nitration of the related aminopyridine does not have stereoselectivity when the reaction is carried out. A main goal according to the present invention is to develop a new method to make a simple reaction path possible, which can be used in a large number of preparations in order to obtain the general pillow bite of Formula I. The size of this paper is applicable to the Chinese National Standard (CNS) A4 (210X297mm) -5- ^ Pack „, words · —J (please read the notes on the back before filling in this I) Employee Consumer Cooperative of the Central Bureau of Economics of the Ministry of Economic Affairs Print 3〇6923 ——__ V. Description of the invention (2.) This goal can be achieved by the method described in item 1 of the patent application scope. These are used for individual foundations 1 ^ to 1 ^ 7 and 1. The nomenclature has the following meanings. The alkyl group described is a straight-chain or side-chain pit group, and the most advantageous is to have 1 to 6 carbon atoms, and 1 to 4 carbon atoms is more suitable. Among the examples, methyl, ethyl, n-propyl, iso-propyl, n-butyl and tert-butyl may be mentioned. The most favorable cycloalkyl described is a C3- c6-cycloalkyl, for example, a cyclopropane, a cyclobutane, a cyclopentane, or a ring burned. The aryl group described includes the aromatic group of carboxylic acid, and the most favorable is phenyl or boryl, And the aralkyl described means an aryl-substituted alkyl ', the most advantageous case is a phenyl-take Substituted Cl-C6-alkyl, especially benzyl. An alkane acetyl group is more advantageously represented as a (Ci-Ce) -alkane acetyl group, preferably acetyl. The most advantageous is alkoxy The case is alkoxy, and methoxy or ethoxy is preferred. A heterocyclic type radical is the most favorable case is a heterocyclic ring, which has a 5-component or 6-component ring, and has a nitrogen The original and / or oxygen atom and / or sulfur atom are regarded as heteroatoms. Similarly, the heterocyclic ring system in which they are condensed (dense) may use the Chinese National Standard (CNS) A4 specification on the paper scale (2 丨 0X297mm) (Please read the precautions on the back before filling in this I) H Pack. Book 1 6-5. Invention description (3. A7 B7 system heterocyclic condensed ring systems are included in these Examples of the designated heterocyclic ring having a 5-component ring are thiophene, pyrophene, plutonium, indole, pyrazole, azole, oxazole, isoxazole, thiazole or triazole. It will be mentioned that a heterocyclic ring with a 6-component ring is <4, Lin; Isoquinone, pyridine, pyridazine, pyrimidine, blowing azine, phenocyanine Purine or Pteridine. Ion is fluorine, gas, bromine, or iodine, and the preferred halogen is gas. These designated groups, especially the roots of these rings, can be replaced by a single or Is substituted by many. Suitable radicals are, for example, halogen, nitro, amino, alkylamine, dialkylamine, hydroxy, xylo, alkyl or alkane amide, the explanations above all meanings are applicable In the first stage of the preparation method of the present invention, the general formula of a nitrile is as follows: RiCN 11 where Ri is as defined above, after reacting with a thiol, and the general formula of this thiol is as follows:

SH

III (Please save the notes on the back of stl and fill in the text) fr .if Employee consumption cooperation of the Central Standards Bureau of the Ministry of Economic Affairs. Du Yinzhong-J.VO WA * where IU is alkyl, aryl or aralkyl, in / In the presence of a hydrogen halide, a thioimidazolate hydrohalide will be produced, the general formula of which is as follows:

Ri .S Rs NH HX

IV The paper size is free to use the Chinese National Standard (CNS) A4 specification (210X297 male thin) A7 _ B7 printed by the Employee Consumer Cooperative of the Central Bureau of Standards of the Ministry of Economy V. Invention description (4.) where Ri and Rs are as defined above , And X is a halogen atom. The first stage has been described in detail by Bader et al. In J. chem. Soc. 1% 0 2780. Among the nitriles of general formula II, acetonitrile, propionitrile, butyronitrile or valeronitrile are more advantageous. A particularly suitable nitrile in the above general formula II is propionitrile. Furthermore, 'benzyl mercaptan is more suitable for use as a thiol of general formula 1, and gasified hydrogen is more suitable for use as hydrogen peroxide. In theory, nitriles can be used as a solvent. In any case, the overall use is additionally composed of an inert solvent, such as' dioxane (or dioxane), tetrahydro P Furan, ether, a halogenated hydrocarbon, such as methane or an aromatic hydrocarbon, such as toluene. We have found that in the first stage of the reaction, the more favorable temperature conditions are in the middle. 〇 Between room temperature. The reaction time depends mainly on the amount of functionalized hydrogen, and the best results are obtained, which range from 2 to 3 equivalents of hydrogen halide per equivalent of mercaptan, which is of general formula [II. The final thioimidazolate of formula IV can be separated by a technique known in the art, but it is best to directly react it further with aminoacetonitrile to produce the following formula M:

ΝΗ HX CN This paper; with towel Yunjia County (CNS) Α4 vein (21GX297mm> (Please read the precautions on the back before filling this page}-装 · 、 π —8 —

Printed by the Beigong Consumer Cooperative of the Central Department of Economic Affairs of the Ministry of Economic Affairs. 5. Description of Invention (5) where Ri and X are as defined above. In each case, the aminoethyl ester can be released from a related aminoethyl salt directly before the reaction (removal effect) such as hydrochloric acid or sulfuric acid, by Reactions, such as ammonia. This reaction is usually carried out under the solvent of the preliminary step. The most favorable reaction temperature is between 0 ° C and the reflux temperature of the relevant solvent. This final gland of general formula V can be removed from the reaction mixture in a way that is skilled in the art after the reaction is completed, for example, by filtration, in this example of the general formula V The glands have Ri = ethyl and X = C1. In the final stage, the trampoline of the general formula V can be cyclized with a 1,3-dicarbyl compound of the general formula below in the presence of a base.

Where R3 is as defined above, and R6 and R7 can be completely the same or different, and they are hydrogen, alkyl, aryl, aralkyl, alkoxy or oxyalkyl groups to produce the final product. Suitable 1,3-dicarbon-based compounds have {^ and cadaverine groups, which are alkane diketones such as 2,4-pentanedione (acetoacetone), 3,5-heptanedione, 4 , 6-nonane or R3 == methyl, 3-methyl-2,4-pentanedione (2-methyl-based paper scales are applicable to China National Standards (CNS) A4 specifications (210X 297mm) Q «Μ i III shoulder I-n II n J; (please read the notes on the back before filling this page) 306923 Printed supplementary five, invention description (6) Acetyl acetone printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs. Typical representatives have R6 = alkyl and R7 = pitoxy, and acetyl acetates such as methyl acetoacetate or ethyl acetoacetate. The malonate has Re and R7 == alkoxy, which is also beneficial for use. Among these examples which may be mentioned are methyl malonate and ethyl malonate. Suitable compounds of the general formula VI have 1 ^ and r7 = hydrogen, which are malondiacids or 2-substituted malondiamides. A further suitable formula VI is typically represented by ^ and R7 = alkoxycarbonyl is 2,4-dicarbonylpentane dimethyl ester or 2, and biscarbonylpentane diethyl ester, with Ra and Rf = methoxy Carbonyl and ethoxycarbonyl. The alkali used may be inorganic or organic. Advantageously, cyclization is carried out with organic bases, which are composed of metal alkoxide compounds such as sodium or potassium ethoxide, sodium / potassium methoxide or potassium t-butoxide Substances in related alcohols or a trialkylamine such as triethylamine. Similarly, the inorganic test is better to use alkali metal hydroxide dissolved in a lower aliphatic alcohol, such as sodium oxynitride or potassium oxynitride dissolved in methanol or water 'or other tests Carbonates or bicarbonates of the metal or earth test genus. There is no particular restriction on the choice of solvent. The axis of the lipids, such as formazan, is used to produce good results, but the use of aromatic hydrocarbons, such as toluene, can also produce good results. # ~ This paper scale is applicable to the Chinese National Standard (CNS) Α4 specification (21〇x797 ^ f; ~ 10--------- 4 pack ------ order ------ ·-^ (Please read the precautions on the back before filling this page) Employee consumption cooperation of the Central Bureau of Economics of the Ministry of Economic Affairs. Printed by the company A7 B7 V. Description of the invention (7.> The reaction is carried out at room temperature and used at a more favorable temperature Individual solvents have a reflux temperature, and the preferred temperature is between 50 ° C and the reflux temperature of the solvent. After the reaction is completed, the imidazolidine can be separated from the reaction mixture in a conventional manner. Examples 1 a] Method for preparing S-benzyl propyl sulfonamide • hydrochloric acid 43 g (1.2 mol, 3 equivalents) hydrochloric acid gas is passed through a solution at i °° C containing 50.2 g (0.4 mol) of benzyl The mercaptan and 24.2 grams (0.44 moles) of propionitrile were dissolved in 100 milliliters of dioxane. After the gas flow was completed (about 1 hour), the mixture was warmed to room temperature. After 25 hours After that, a part of dioxane and excess hydrochloric acid are extracted by vacuum evacuation, after which the product will precipitate out , This product can be filtered out, then washed with a little ether, then dried in vacuo, and finally will obtain 82.1 g of white title product (95% yield) &quot; H-NMR (CDC13, 300MHz) β 1.4 (t, 3H) 2.95 (q; 2H)-4.25 (s, 2H) 7.3-7.5 (m, 5H) 12.2 (br.s, 1H) 13.1 (br.s, 1H) b] Preparation of (1-iminopropylamine )-Acetonitrile • Hydrochloric acid method A suspension of 81.5 g (0.38 mol) of the product from the la method is dissolved in 300 ml of dioxane, and then cooled to the temperature icrc, then the next piece of paper is recognized (CNS) A · (210X297mm) ^ ------ 1Τ ------ 0 (please read the notes on the back and then fill out this page) 11 Printed by the Ministry of Economic Affairs Bureau of Central Standards Staff Consumer Cooperative 3〇6θ2 ^ _Βτ ____ V. Description of the invention (8.) Add 23.8 grams (0.42 moles) of aminoacetonitrile (using ammonia to release it from aminoacetonitrile hydrochloric acid). After 2 hours at this temperature This product was filtered off, washed with diethyl ether, and then dried under vacuum. Finally, 52.2 g of white title product was produced (yield 93%).

Melting point: 92-93 ° C &quot; H-NMR (DMSO, 400MHz) ci 1.2 (t, 3H) 2.5 (q, 2H) 4.6 (s, 2H) 9.6 (s, 1H) 10.0 (s, 1H) 10- 6 (s, 1H) c] Method for the preparation of (1-iminopropylamine) -acetonitrile • hydrochloric acid 7.3 g (0.2 mol) of hydrochloric acid was passed into a solution at 10 ° C containing 12.4 g ( 0.1 mol) of benzyl mercaptan and 6.1 g (〇 · π mol) of propionitrile were dissolved in 25 ml of dioxane, and after the step of introducing fluorine was completed, the mixture was mixed at room temperature After stirring continuously for 17 hours, the excess hydrochloric acid was extracted by evacuating under reduced pressure. Finally, a suspension was obtained. 6.16 g (0.11 mol) of aminoacetonitrile (which can be released from aminoacetonitrile hydrochloric acid using ammonia) can be added dropwise at room temperature, and then continuously stirred at this temperature After 2 hours of the mixture, the final solid was filtered off, washed with ether, and then dried in vacuo. As a result, U g of white title product was obtained (yield based on propionitrile: 75%). d] Method for preparing 2-ethyl-5,7-dimethyl-3H-imidazole [4,5-b] pyridine 150 ml of a 1.6M sodium ethoxylate solution dissolved in ethanol (equivalent to this paper) Country @ 家 料 （CNS) Α4 · (2 丨 QX297 Gongen) — —-(Jingxian "Read the notes on the back and then fill out this page) • Click · -12-A 7 B7 5. Description of the invention (9 ·) Sodium ethoxide at 0.24 mol), and then added dropwise to a solution at 0 ° C containing 35.4 g (0.24 mol) of the product from the 1C preparation method dissolved in 150 ml of ethanol. Next, 240 grams (2.4 moles; 10 equivalents) of acetone acetone is added, and then the reaction mixture is slowly heated to 130 ° C, at which temperature water and ethanol will be distilled off, passing at the reflux temperature After half an hour, the mixture was cooled to room temperature, 500 ml of water and 500 ml of ethyl acetate were added and mixed, and then the different phase layers were separated. The organic layer was dried over magnesium sulfate and evaporated to dryness in a rotary evaporator. The resulting residue was recrystallized from ethyl acetate to finally obtain 25.5 g (60%) of the title product as pale yellowish yellow.

Melting point: 148.8-150.4 ° C UMR (400MHz in CD30D) ci 1.4 (t, 3H) 2.55 (s, 6H) 2.9 (q, 2H) 6.9 (s, 1H) (Please note the back of Mtt before filling this page ) -Installation · Line-printed paper copy of the Standardization Bureau of the Ministry of Economic Affairs, Staff and Consumers Cooperative of the Chinese Standard Purlin (CNS} A4 specification (210X297 male thin) 13 —

Claims (1)

Bulletin Α8; Β8 V- "Μ 嶋 ': Ί Λί I 86.3.15 Patent application Fan Gu 3〇β923 ^ 83109360 A method for preparing imidazole pyridine derivatives, the general formula is as follows Among them, Rl is a Ci-C6 burned group, R2 and R4 are completely the same or different, and they are Xinxuan group, Y3 is hydrogen, which is characterized by a kind of riding, and its general formula is as follows: RiCN π where Ri It is as defined above, it will react with a thiol fermentation, the general formula is as follows: RsSH melon where R5 is benzyl 'in the presence of hydrochloric acid, the reaction temperature is between 0 ° C and room temperature, with or without With the addition of an inert solvent, an inseparable thiopyridinium hydrogen salt is produced. Its general formula is as follows: NH HX --------- 1 Pack IT -------- -Subscribe --- .; 一 -J (Please read the notes on the back before filling in this I) Printed by the Central Bureau of Economic Affairs of the Ministry of Economic Affairs, the Consumer Cooperative Cooperative «. This paper scale is based on the national rate of China (CNS &gt; A4 Specifications (2 丨 0XJ9 ^ Xiaoli) 306923 where Rl and R5 are as defined above, and X is a kind of elemental atom. This substance will then be released from a phantom of aminoethine by the action of a base. 〇 ° C reacts with the avoidance temperature of individual solvents to produce a stepping type, the general formula is as follows: V &quot;% v NH HX CN where Ri and X are as defined above, and this substance is in the presence of a base with a The 1,3-dibromidyl compound is finally cyclized in the presence or absence of an inert solvent between it and the reflux temperature, and the general formula of this 13_dicarbon acetyl compound is as follows: I 装 · I- „---: j order (please read the notes on the back before filling this page) The Ministry of Economic Affairs, Central Bureau of Standards and Technology, Beigong Consumer Cooperative Institution, where &amp; as defined above and whose mind is exactly the same as or different from R? And they are CH: 6 alkyl to produce the final product of Formula I. 2. The method according to item〗 of the patent application scope, characterized in that the base used for cyclization is an inorganic or organic base. 3. The method according to item 2 of the patent application scope, characterized in that the alkali used for cyclization is an alkali metal alkoxide or a metal-examining argon oxide dissolved in a lower Of aliphatic alcohols. This paper is suitable for the national standard Feng (CNS) eight four veins (210> c ^ moxibustion)