TWI241296B - Process for preparing triazolopyrimidine derivatives - Google Patents

Abstract

This invention relates to a novel process for preparing triazolopyrimidine derivatives of the formula (I), wherein R1 represents a hydrogen or an alkyl radical of one to ten carbon atoms, or a cycloalkyl radical of three to six carbon atoms, or an alkenyl radical of up to four carbon atoms; R2 represents a hydrogen, a halogen atoms, a hydroxyalkyl or alkyl radical of one to ten carbon atoms; R3 represents a hydrogen, a hydroxyalkyl or alkyl radical of one to four carbon atoms.

Description

1241296 IX. Description of the invention: [Technical field of the invention] The present invention relates to a novel procedure for preparing a triazolopyrimidine derivative having the following chemical formula (j):

Whitening IR1 represents wind atoms, with dazzling to-ten carbon atoms: earth, cycloalkyl radicals with three to six carbon atoms or dilute radicals with one carbon atom; 1 represents hydrogen atom, :: Original: Two, via radicals with one to ten carbon atoms. From: 时: Atomic radical radical U "represents hydrogen radical Γ i. Four carbon atoms via radical alkyl radical I or have-to An alkyl radical of four carbon atoms. There is a prior art] Compound No. 3,689,488 disclosed in Chemical Formula (〗). They are patented, so they can be used to prevent bronchospasm. Very: related diseases 'For example: asthma or bronchitis. The procedure for making a compound of the Wu State patent described in the Quanguan number is briefly described as follows: <(a) diamine group with chemical formula (I)-! Preparation of 2,4-triazole (shown in # / 令, 1241296 ΝΗ ΗΝ,

R4 S

r4—n = c = s 4 hours R Λ ^ Et H R4-Pr, or Bn 1 N H, N, S &gt; H • HBr several days

N

EtI R4 person S 』t

H

H

3-16 h R 1 Et 1 N H Figure 1 (b) Preparation of triazopyrimidine (shown in Yan 2) HN-N Ά 夂 N, R4 + Η Η R ^ O R2

Rs (II)

Base 2 days 1SU JJ Λ

r2 'R2 + hnX I N 丄, v-Ri 7 i r4 1 Mixture 10 days

when R4 = Bn Hydrogenolysis

Separation Figure 2 There are several disadvantages to the manufacturing in the previous procedure. First, the procedure for preparing diamine-1,2,4-triazole (唑 /) takes several days and is very inefficient. Secondly, the mixture produced by the condensation of diamino-1,2,4-triazole and an α, / 3-unsaturated acid derivative having the formula (Π) to produce an isomer 1241296 is non-selective, 2 ). Thirdly, the hydrogenolysis of methyl sulfonium must be further purified (which is the deprotection of the triazopyrimidine of the chemical formula (I)) to produce a product. From a commercial point of view: == 10 days' very Time-consuming (efficient and expensive.), The program is not as detailed in Figure 1 and Figure 2. [Abstract] The purpose of the ancient ^ 1 is to overcome the aforementioned shortcomings, to provide a τ. The present invention provides a procedure for preparing a triazole pyrimidine derivative having the chemical formula (i). The present invention provides a procedure for preparing a triazole pain bite derivative having the chemical formula (1). This procedure includes at least: Alkyl cyano dithioimino carbonate quickly prepares diamine-1,2,4 · triazoles with the chemical formula (111); effectively protects and deprotects amino groups tecti〇n); and selective blending of α, 10,000 · unsaturated acid derivatives with chemical formula (Π) and imines with chemical formula (VI). Preparation of three salivas with chemical formula (I) according to the present invention. Dense The σ-determining derivative process includes at least four steps. The first step is to effectively prepare The diamine-1,2,4_trisialyl group in the chemical formula (Dish), in which 1 to 2 equivalents of the alkylamine having the chemical formula (IV) is slowly added at room temperature to the dioxane having the chemical formula (V) In a mixture of cyano dithioiminocarbonate (1 equivalent) and a suitable solvent, 1 to 4 equivalents of hydrazine are added dropwise after heating under reflux. 1241296 n2h4

(III) Ν ', CN Rl-NH2-Solvent (IV)

, CN

N meaning

RS ^ SR (V) Fig. 3 Fig. 3 shows a process for preparing a diamino group el, 2,4-triazole having the chemical formula (m), wherein Ri has the same definition as above; r represents an alkane having one to four carbon atoms Radicals; solvents can be water, acetonitrile or alcohol solvents such as methanol, ethanol, propanol or butanol. The second step is to prepare an imine having the chemical formula (VI), where 1 to 7 equivalents of the aldehydes having the chemical formula (VH) and 1 equivalent of the diamine group having the chemical formula (dish) -1,2,4- Trisalene is reacted in an organic solvent at 50 ~ i50 ° C and in the presence of an acid catalyst (0 to i equivalent).

, N H

± 1 丄 &gt;-IN U ΛΝχΝΗ2 + RsAh R H catalyst (III) (VII)

, NH HN—NΛ and n = \ (VI) R8 Figure 4 垸 αΠΙΆ represents nitrile with one to ten carbon atoms, methylbenzyl, -methylbenzyl, ~ substituted base,> ethyl gluten can be used as cereal Qiyanyuan, Dichloromethane, P, from: ―gas ethane or such as: methanol, ethanol, propanol or: the catalyst may not be added '' or the catalyst may be organic such as: U ϊ lithic acid, sulfuric acid or hydrochloric acid Acid or inorganic acid. A1241296 The third step is the condensation of α, n-unsaturated acid derivative with chemical formula (n) and imine with chemical formula (VI), among which 1 to 2 miles is α, / 3 with chemical formula (Π) -Unsaturated acid derivatives are present in the organic solvent at the reflux temperature (~ 150) in the presence of the test (0.1 to 2 equivalents) and the polymer inhibitor (0.05 to 0.2 equivalents), React with 1 equivalent of imine of formula (V!).

Η

R

Rs

Solvent N polymer inhibitor J | base

Figure 5 Figure 5 shows the condensation process of ^, dot-unsaturated acid derivative without chemical formula (jj) and imine with chemical formula (VI), where Ri, R2, R3, and R8 are the same as defined above, and Rs Represents a halogen atom or OR9, where R9 represents an alkyl radical having one to six carbon atoms; and R6 represents an alkyl radical having one to six carbon atoms; solvent = can be acetonitrile, toluene, dibenzobenzene, chlorine Benzene, trichloromethane, dioxane, or 1,2-dioxane; the aforementioned base may be a metal carbonate or a metal carbonate, wherein the aforementioned metal may be lithium, sodium, potassium, thallium, planer, beryllium , Magnesium, calcium, rubidium, or barium; etc .; the aforementioned polymer inhibitors can be hydrogen awakening or monomethyl ether hydroquinone. The last step is to prepare a triazolopyrimidine derivative having the chemical formula (z), wherein the imine having the chemical formula (view) is in the presence of an acid (0.1 to 10 equivalents), water and a solvent at room temperature to reflux temperature. Water 1241296 solution.

(VIII) (I) Figure 6

FIG. 6 shows a process for preparing a sialene derivative with the chemical formula (I), wherein R1, R2, R3, and Rs are the same as the foregoing definitions; the foregoing acids may be inorganic acids such as hydrochloric acid, sulfuric acid, acetic acid, or oxalic acid, etc. Acid bites organic acids; the aforementioned solvents can be water, methanol, ethanol, ethyl acetate, methylbenzyl, dibenzyl, chlorobenzene, chloroform, dichloromethane, or 1,2-dichloro. The following examples are further described. The invention does not limit the scope of the invention. [Embodiment]

Example 1 Preparation of N5-propyl_1H- [1,2,4] triazole-3,5-diamine

In a 10 liter four-necked flask equipped with a reflux concentrator, a thermometer, an injection funnel, and a mechanical stirrer, one of 12,000 g (813 mole) of a sulfanyl-thioimino group ♦ Acid S is intended to be dissolved in 6 Kg of isopropanol. 538 8.94 mole) of n- 10 1241296 propylamine was added dropwise at room temperature over 2 hours. After stirring the reaction mixture for another 20 minutes, the temperature was raised to reflux temperature and 224 g (20.8 mole) of hydrazine was added slowly. (85%), followed by reflux for 2 to 3 hours. Then, 80% isopropanol was distilled off under reduced pressure, and the residue was cooled to 5 to 1 (rc. After filtration and drying, N5-propyl-1H_ [1,2,4] triazole-3 was obtained as a white solid. , 5-diamine. Yield is 1075 g (AI 98%, theoretical value 92%). Melting point is 148 ~ 149 ° C. ^ Example 2 N'benzylidene-N5-propyl_1H_ [1,2, 4] Preparation of triazole_3,5_diamine

HN-N VIII. h Method 1 In a 5 liter flask equipped with a reflux concentrator, thermometer and mechanical stirrer, 251.8 g (1.75 mole) of N5_propyl 2 41 triazole_3,5_ diamine, 1.24 liters of methanol and 1948 g (1 84 m〇'10 of benzaldehyde, followed by heating to reflux for 6 to 10 hours. After the completion of the reaction was determined by Lc (N5-propyl_1Η_Π, 2, 4,] triazole_3,5_diamine peak region ^ 1%), 2/3 volume of solvent was distilled off from the mixture under reduced pressure., The residue was cooled to room temperature, and a yellow solid-n, propyl-mn, 2, 4] was precipitated. Sial_3,5_diamine. Use the data to collect the precipitate, and obtain the desired product 381 ~ 389 98% after drying, theoretical value 93 ~ 95%). g purity When methanol is replaced by ethanol, toluene or acetonitrile, the result of phase 11 I241296 = can also be obtained. When 5.2 g (0.087 mole) of acetic acid is used in these cases or / and the water is removed in an azeotropic state, the reaction time can be reduced to 1 to 4 hours, and the yield and purity are not significantly changed. Method 2 A 5 liter flask equipped with reflux concentration, thermometer and mechanical stirrer was charged with 251.8 g (1.75 mole) of N5-propyl_1H_ [1,2,4] triazole-3,5-diamine, 1.75 liters of toluene, 203.4 g (1.92 m mi′〇 of benzene, and 5.2 g (0.087 mole) of acetic acid, followed by heating under reflux for 1 to 3 hours. In the reaction, the formed water is a by-product, and Removed under azeotropic state. After the reaction was confirmed by LC (N5-propyl_111- [1,2,4] dioxo-3,5- ^ monoamine peak area is less than 1%), the mixture was cooled. And the original N3 · benzylidene-N5 · propyl-1H- [1,2,4] sanjun 3,5-diamine suspension was obtained, which was used in the next stage without purification. Example 3 Preparation of 2- (benzylidene-amino) -6-fluorenyl_4_propyl_4H- [1,2,4] trio-5-a] pyrimidin-5-one

Method 1 A 5-liter flask equipped with a reflux concentrator, a thermometer, and a mechanical stirrer was charged with 401.03 g (1.75 mole) of N3-hytenyl_nl propyl-111- [1,2,4] triazole -3,5-diamine, 253 § (1.83111〇16) potassium carbonate, 250 g (1.92 mole) of methyl 2-ethoxyfluorenyl 12 1241296, Ug (0.009 mole) of p-methoxyphenol and 175. Such as B t: heating and refluxing for 24 to 28 hours. Evaporate under reduced pressure. Add Eyers to ... Product 4tf was removed from the extract and dried to obtain the desired product 406-432 g (77-82% of theory). A similar result was obtained when Tian replaced acetonitrile with methylbenzyl. Method 2: T ^ 1.83 m〇10 potassium carbonate, 250 g (U2 mole) of earth-methoxy-methacrylate and 1.1 g (〇009 鲁 N3_ 亚 ¥ penjia 5 lactol added to the application The soil N_propyl_1] ^ [1,2,4] triazole_3,5_diamine suspended in Example 2 (Method 2) was prepared. After 2 ~ 20 hours, the mixture was cooled. To room temperature, and add methyl-4-propane to collect 2_ (benzylidene-amino) -6_ of the solid by filtration, look at 舲 λ, soil ^^ 1,2,4] The organic layer can be reused in Example 2. The purified horse "-4Η- [1,224", &amp; Methyl benzyl'j ~% Ll, 5_a] pyrimidin_5_one is used in the next stage. 2_ A Example 4 Amine-6-methyl_4_propyl-4h- [i, Preparation of 2,4] triazole [l, 5-a] pyrimidin-5-one

N H2N_, N ^ V &quot; Add 17 5 0 1 2N hydrochloric acid (3.5mole) to the original 2_ (benzylidene_amino) _6_methylpropyl 4 prepared in Example 3 13 1241296 (Method 2) ^ 1 [1,2,4] two saliva [1,5_3]. Sediment 12-5-one. The mixture was heated to ^ ~ 70 C for 30 minutes, and water was removed under reduced pressure in an azeotropic state. Solution, formaldehyde. After the benzaldehyde was completely removed, the mixture was cooled and the pH was adjusted to 7-8 with a 45% aqueous sodium hydroxide solution. The suspension was dried and dried to obtain 2-amino-6-hydroxypropyl-4-H- [1,2,4] bisial [i, 5_a] pyrimid-5_one (purity 98 ') as a pale yellow solid. The yield was 264 to 275 g (73 to 76% of the theoretical value obtained from Example 2). When alcohol,

Similar results were obtained using 1500 ml of methanol as the solvent and hydrolyzing the europium at room temperature.

14

Claims (1)

1241296 X. Scope of patent application: 1. A procedure for preparing trisial alpha-sigma-dine derivatives with the following chemical formula (j): (I) where R1 represents a hydrogen atom and an alkyl radical having one to ten carbon atoms' a cycloalkyl radical having three to six carbon atoms; R2 represents a hydrogen atom and a halogen atom having one to ten carbons Atomic light radical or alkyl radical having one to ten carbon atoms; R3 represents hydrogen atom, hydroxyalkyl radical having one to four carbon atoms or alkyl radical having one to four carbon atoms At least the following steps: (a) reacting an alkyloxymonothioimino carbonate with the chemical formula with an alkylamine of the formula (IV) at room temperature in the presence of a suitable solvent, wherein Represents an alkyl radical having one to four carbon atoms, Ri is the same as defined above, and then, after heating and refluxing, the diamine is dropped to a diamine group of the chemical formula (m) -1, 2, A compound of 4-triazole, wherein R1 is the same as defined above;) A compound having the chemical formula (melon) is reacted with an aldehyde having the chemical formula (VD) in the presence of an organic solvent, wherein Rl 15 1241296 is the same as the foregoing definition, and Rs Department The table has one to ten antiatomic radicals, phenyl groups, or -substituted benzyl groups to obtain an imine compound of formula (vi), where Ri and Rs are the same as previously defined. (〇 At reflux temperature, in an organic solvent in the presence of a base and a polymer inhibitor, selectively condense ", / 5-unsaturated acid derivatives and imines having the chemical formula (shell) with the chemical formula (n), where R2 and Rs are the same as defined above, and R5 represents a halogen atom or OR9, where R has an alkyl radical of-to six carbon atoms, and = represents an alkyl radical of one to six carbon atoms, where Ri And Rs are the same as the foregoing definitions to form an imine having the chemical formula (M), wherein Ri, &amp;, Xin and &amp; are the same as the foregoing definitions. (D) in the presence of an acid, from room temperature to reflux temperature, Three compounds with chemical formula (M) are formed from the compound with chemical formula (M). The derivative of dense σ. 2. The procedure as in the scope of patent application 1, wherein in step (i), it is slowly added at room temperature. An alkylamine having the chemical formula (IV) into a mixture of a dialkylcyanodithioimidocarbonate having the chemical formula (V), and then dripping into the diamine after heating under reflux to obtain and have the chemical formula ( nr) of the diamino group-renrentriazole. / 3. Such as The scope of the patent application, the procedure is to use 2 to 2 equivalents of alkylamines. 4. The procedure of the scope 1 as in the patent, which uses the tf bis 16 1241296 cyanothiocylidene carbonate. 5. If the patent "Fanyuan! Cheng solvent can use water, Γ, spleen 4, /, f, step C a ^ or alcohol solvents. 6. Such as patent application scope 5 diol, ethanol, Propanol or butanol. The alcohol solvent can be 7 · such as the hydrazine of the scope of patent application 1. In order, its _ is used to 4 equivalents 8 · As the scope of patent application 1 is based on 50 ~ 150t: Bottom, right, right, middle, middle In the aforementioned step (b), there is a chemical formula (in an organic solvent, 1 to 5 equivalents of the chemical formula CVH) and the denier- The diamine-yama-trisial reaction has a chemical formula of Tianli (Magic 9 · as in the process of patent application range 1 under acid catalysis. Step (b) can be performed on organic or inorganic acids. * Ma, please apply for the procedures in the range U) 'Among them are acetic acid, toluene sulfonic acid, sulfuric acid or hydrochloric acid. The procedure of the application scope 1 in the 12th chapter, which In the foregoing step, the cereal y uses acetonitrile, monomethylbenzyl, dimethylbenzyl, chlorobenzene, and trichloromethane 11: from monogas oxane, l2-digas ethane, or an alcohol solvent. ^ The procedure of the scope of patent application 12, wherein The aforementioned alcohol solvent may be methanol, ethanol, propanol, or butanol. 14 .: The procedure of the scope of patent application 1, wherein in the foregoing step "), it is 40 to 15 (TC, will be 丄 to 2 equivalents An α, dot-unsaturated acid derivative having (Π) reacts with an equivalent of an imine having the formula (17) 1241296] (w). • As in the sequence of the patent application, where the base uses 0.1 to 2 equivalents. 16 of the 'L V step (C). As in the procedure of the patent application range i, the polymer inhibitor in soybeans uses 0.05 to 02 equivalents of V. Step (C) :: The procedure for applying for the scope i of Jinli, where: 丨: acetonitrile, toluene, dimethylbenzyl, and 'step') :, dichloromethane or U2-digas Burn. Milk, triclosan, and the procedure for applying for scope 1, the prior test in the bean may be A shi _ ^ p 〃 in step (c) "is a metal salt of osmic acid or a metal salt of rhenium carbonate. lc) • If the procedure in the scope of patent application 18, its lithium, sodium, potassium, rubidium, cesium, beryllium, magnesium, calcium, and two 34 metals can be 20, such as patent application agency, pin or barium. sodium. . &quot; Procedure around 8, in which the aforementioned base is carbonic acid 21. As in the procedure in the scope of patent application 1, the above-mentioned procedures can use hydroquinone or monofluorenyl ether hydroquinone. Inventory inhibitors 22. The procedure of patent application scope 21, wherein the prodrug is p-methoxyl age. Polymer inhibition In the aforementioned step (d /, the acid mentioned in the above step can be used in step U) "23. For example, in the procedure of the application scope 1, k may be an inorganic acid or an organic acid. 24 = Procedure for Patent Application Scope 23 Acid, sulfuric acid, acetic acid or oxalic acid. 25. If the agent in the scope of patent application i can use water, methanol, un, Wd) gas! , 7 books, dimethyl milk, dichloromethane, dichloromethane, or 1,2-dichloroethane. 18 1241296 26 · —A procedure for preparing triazole pyrimidine derivatives with the following chemical formula (j) (I) wherein R !, R2, and R3 are the same as defined above, and at least include ... a diamine having the chemical formula (V) is rapidly prepared from a dialkylcyanodithioimide carbonate having the chemical formula (V) The group 4,2,4-triamidine 'wherein Ri and R are the same as defined above; protection and deprotection of glutamine; and -α, / 3 unsaturated acid derivatives having a chemical formula (Π) and having a chemical formula ( VI) Selective condensation of imines, wherein R2, R3, Rs, r6, Ri and R8 are the same as defined above. 19