WO2008092410A1 - Preparation method of thioureas or salts thereof - Google Patents

Abstract

The invention provides preparation method of thioureas or salts thereof. In particular, the invention provides method of preparing thioureas by reacting cyanamides or salts thereof with thioamides in proper acidic medium. The product can be used to prepare 2-aminothiazoles, such as antimycotic abafungin.

Description

 Method for preparing thiourea compound or salt thereof

 The present invention relates to a process for the preparation of a thiourea compound or a salt thereof. More specifically, the present invention relates to a process for producing a thiourea compound or a salt thereof by reacting an aminonitrile or a salt thereof with a thioamide in a suitable acidic medium. Background technique

A thiazole compound having antifungal activity (such as the compound represented by Formula 1-0) is a broad-spectrum antibacterial agent which has been produced in recent years;

 Among them, Abafungin, chemical name N-[4- [2- (2, 4-diphenylphenoxy)phenyl -2- thiazolyl] -1, 4, 5, 6 - tetrahydro-2-pyrimidinamine, as shown in formula (I), is the first thiazole ring antifungal with novel dual mechanism of action, killing both fungal cells in growth and in quiescence. It has the dual function of inhibiting fungi and killing fungi. This drug is the first drug with this mechanism of action and is expected to be the first line of antifungal products. The drug has a wide spectrum of antibacterial activity. In addition to excellent antifungal effect, this product also has excellent inhibitory effect on yeast and Gram-positive bacteria. It has better effect on Candida than the current marketed varieties, so this product is expected to be used for treatment.曱癣, vaginal candidiasis, vulvovaginitis (especially when bacteria are also involved), and certain bacterial dermatitis and acne.

(I) (ID (III) Thiourea compounds are key intermediates in the preparation of such antifungal 2-aminothiazoles. For example (1, 4, 5, 6-tetrahydro-2-pyrimidinyl) thiourea (Structural as shown in Formula II) is a key intermediate for the preparation of abifene. The preparation method of (1, 4, 5, 6-tetrahydro-2-pyrimidinyl) thiourea (Π) disclosed in the literature is (1, 4, 5, 6-tetrahydro-2-pyrimidinyl) aminonitrile (structure shown in Formula III, can be referred to as "J. Org. Chem., 1973, 38 (1): 155 ~ 156." The preparation method disclosed in the preparation is obtained. ) reacts with hydrogen sulfide (H ₂ S). For example, "Arzneim-Forsh, 1985, 35 (3): 573 - 577." The preparation method of (1, 4, 5, 6-tetrahydro-2-pyrimidinyl) thiourea (II) is as follows: vulcanization (1, 4, 5, 6-tetrahydro-2-pyrimidinyl) aminonitrile (ΙΠ) and potassium hydrogen hydride (KHS) were added to a hydrogen-saturated decyl alcohol solution, and reacted in an autoclave at 70 to 80 for 16 hours. The post-treated product; the preparation method disclosed in US 4,451,453 is: under the hydrogen peroxide in an aqueous solution of (1, 4, 5, 6-tetrahydro-2-pyrimidin) nitrile (111) for 12 hours, then At 65 ~ 70 ° C, hydrogen sulfide is continuously passed for 25 ~ 30 hours, and the product is post-treated; "J. Med. Chem., 1990, 33 (2): 534 - 552." : Underneath, hydrogen sulfide is passed to a solution of (1, 4, 5, 6-tetrahydro-2-pyrimidine) and nitrile (111) and diethylamine in decyl alcohol for 45 minutes, then heated in a steel bomb under 20 Hours, after treatment, the product. It can be seen that the above technologies all have shortcomings such as long reaction time and high requirements for equipment and safeguard measures during industrialization. Summary of the invention

 The present inventors have unexpectedly discovered that by using a conventional reaction apparatus, a suitable amino nitrile or a salt thereof can be reacted with a thioamide in a suitable acidic medium, and a thiourea compound can be smoothly produced in a short period of time. Its salt.

 One aspect of the present invention provides a process for producing a thiourea compound represented by the formula Π-0 or a salt thereof,

Wherein, R, and R "are each independently selected from hydrogen, d_ _2. Alkyl, d_ _2. Alkenyl, Ci.2o alkynyl, cycloalkyl radicals, cycloalkyl radicals -alkyl, C _{6. 1 ( An} aryl group, a 4-8 membered heterocyclic group having 1 to 3 hetero atoms, an aryl group, an alkyl group, an alkoxy group, an alkyl group, or a group represented by the following formula,

Which represents hydrogen, Cwo alkyl, Cwoalkenyl, Cwo alkynyl, C _{3 .10} cycloalkyl

Ci_i. Pit base, 6_ιο aryl base, pit ^ & pit base; R, R3 and R ₄ are independently selected from hydrogen, fluorine, chlorine, bromine, iodine, d_ ₂ . Alkyl, d_ ₂ . Alkenyl, Ci.2o Block base, C-20 pit "? L3⁄4>, C3-10 ring pit base, C3-IO ring pit base Ci-io pit base, C6-10 aryl,

C6-io aryl CJ.JO pit base, CJ.JO pit ·?^3⁄4· CJ.JO pit base,

 The method includes:

 (a), a compound of the formula (III-0) or a salt thereof

 R'- -N- EN

R" ( III - 0)

 Where R, and R" are as defined above,

 The compound of the formula (I 1-0) or its corresponding acid addition salt is obtained by reacting with a compound of the formula (I V-0) in a suitable acidic medium.

Shen, R5 Cl-10 3⁄4 &, . 6-ιο芳&

 (b) optionally, converting the compound of the formula (Π-0) obtained in the step (a) or an acid addition salt thereof to the desired salt or the formula (I 1-0) obtained in the step (a) The acid addition salt of the indicated compound is deacidified to the free compound of the formula (Π-0).

According to some embodiments of the invention, wherein, in the formula (Π-0) and formula (III-0), R, and R" are, independently of each other, selected from the group consisting of hydrogen, alkyl, alkenyl, Cw. Block, C _3--8 cycloalkyl, C _3--8 cycloalkyl - ₆ alkyl, C ₆ - ₈ aryl, 5-6 membered heterocyclyl containing 1-2 heteroatoms, C ₆ - ₈ aryl d- _{a 6} alkyl group, a d- ₆ alkoxy d- ₆ alkyl group, or a group represented by the following formula,

Where ^ represents hydrogen, . Alkyl, . Alkenyl, Cw. Alkynyl group, C ₃ - ₇ cycloalkyl C 1-6 alkyl, C ₆ - ₈ aryl d- ₆ alkyl, d- ₆ alkoxy-d- ₆ alkyl group; R _2, 1 ₃ and ₁₄ to each other Independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, alkyl, alkenyl, and block. Alkoxy 3⁄4L, C3-7 ring C3-7 ring Cl-6

. 6-8 Fang &,. 6-8 aryl & Cl-6 Cl-6

In the formula (IV-0), R ₅ represents. Alkyl, Cwo alkenyl, . Alkynyl, C ₃ - ₇ ring

Cl-6 Ce-8 Fang & Cl-6 Cl-6

According to some preferred embodiments of the invention, wherein in the formula ( Π-0) and formula (III-0), one of R, and R" is hydrogen and the other is hydrogen, (^- ₆ alkyl, D- ₆ alkenyl, d- ₆ a group, a C _{3 -6} cycloalkyl group, a C ₃ - ₆ cycloalkyl d- ₆ alkyl group, a C ₆ - ₇ aryl group, or a group of the formula:

Wherein ^ represents hydrogen, d- ₆ alkyl; R ₂ , R ₃ and R ₄ are independently selected from hydrogen, fluorine,

3⁄4i, Cl Cl

In the formula (IV-0), ₁₅ represents an anthracenyl group, an ethyl group, a n-propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a n-pentyl group, an isopentyl group, an n-hexyl group, an n-octyl group or 2 -ethylhexyl.

 In a more specific embodiment of the present invention, the compound represented by the formula ( Π - 0 ) is a compound represented by the formula (Π) or a salt thereof, and the compound represented by the formula (II I- 0 ) is a compound of the formula (III) a compound or a salt thereof, and the compound represented by the formula (IV-0) is a compound represented by the formula (IV).

 Wherein the compound of the formula (111) or a salt thereof is reacted with a compound of the formula (IV) in a suitable acidic medium to give the corresponding addition salt of the compound of the formula (II). Optionally, the acid addition salt of the compound of formula (I I) can be further converted to the desired salt or deacidified to the free compound of formula (I I).

 Alternatively, in the above process of the present invention, an acid addition salt of the compound of the formula (11-0) is formed in the step (a). The formation of the addition salt advantageously improves the post-treatment process. For example, the acid addition salt of the compound of the formula ((-0) may be cooled, preferably cooled to - more preferably cooled to room temperature, and then filtered, optionally dried, preferably at room temperature or The acid addition salt is obtained by drying at a temperature between room temperature and the decomposition temperature of the acid addition salt of the compound of the formula (I I - 0 ).

 In the process of the present invention, a suitable "acid medium" which can be used in the step (a) may be a liquid acid itself, an acid solution or a solid acid system, etc., which can provide acidic conditions as well as reactants or products. Dispersed among them. The acid moiety in the "acid medium" may be any protic acid (i.e., a donor of protons) that is suitable.

In some embodiments of the invention, a liquid acid can be employed as the acidic medium. "Liquid acid" means an acid which is liquid under the reaction conditions, such as phosphoric acid, polyphosphoric acid, citric acid, acetic acid, hydrazine sulfonic acid, trifluoroacetic acid, or a suitable mixture thereof. In the invention In still other embodiments, an "acid solution" may be used as the acidic medium, and an "acid solution" means an acid solute such as hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, phosphoric acid, sodium hydrogen sulfate, potassium hydrogen sulfate. A solution of citric acid, acetic acid, sulfonic acid, phthalic acid, sodium hydrogen phthalate, hydrogen phthalate, or a suitable mixture thereof.

 In some embodiments, the "acid medium" can be a solid acid system comprising a solid acid as the dispersed or stationary phase and a suitable solvent as the continuous or mobile phase. In the present invention, when referring to a solid acid, it refers to a solid acid, including sulfuric acid, phosphoric acid, boric acid or miscellaneous supported on a carrier of activated carbon, silica, alumina or diatomaceous earth. A polyacid, or an acidic ion exchange resin (such as an acidic ion exchange resin such as 001 x 2 type, 001 x 4 type, 001 x 7 type, or D113 type), which can be used as a dispersed phase or a stationary phase. In the solid acid system, a suitable solvent is also included as a continuous phase or a mobile phase. The solvent in the acid solution and the solid acid system is suitable for the acid solute and the solid acid used, and may be selected from the group consisting of hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dimercaptoacetamide, hydrazine. - mercapto pyrrolidone, decyl alcohol, ethanol, n-propanol, isopropanol, water, ethylene glycol dioxime ether, tetrahydrofuran, diisopropyl ether, ethyl acetate, acetone, cyclohexanone, trichlorodecane, tetrachloro Decane, disulfoxide, citric acid, acetic acid, or a mixture thereof. Those skilled in the art can routinely select "a solvent suitable for the acid solute used" according to the prior art in the prior art. For example, the selected solvent generally has a certain solubility to the acid solute and the reactant, and under the reaction conditions, Acid solutes do not produce chemical changes that affect the main reaction. In some embodiments, the acid solute is selected from the group consisting of hydrogen chloride, hydrogen bromide, hydrogen iodide, sulfuric acid, or phosphoric acid, or a mixture thereof, and the solvent may be selected from the group consisting of hydrazine, hydrazine-dimercaptoamide, hydrazine, hydrazine-dioxin. Acetamide, fluorenyl-pyridyl pyrrolidone, decyl alcohol, ethanol, n-propanol, isopropanol, water, ethylene glycol dioxime ether, tetrahydrofuran, ethyl acetate, diisopropyl ether, citric acid, acetic acid, etc., or A suitable mixed solvent. In other embodiments, the acid solute is selected from the group consisting of citric acid, acetic acid, sulfonic acid or phthalic acid, or a mixture thereof, and the solvent may be selected from the group consisting of hydrazine, hydrazine-dihydrazinamide, hydrazine, hydrazine- Dimercaptoacetamide, fluorenyl-hydrazinopyrrolidone, water, ethylene glycol dioxime ether, tetrahydrofuran, trichlorodecane, disulfoxide, etc., or a suitable mixed solvent thereof. In other embodiments, the acid solute is selected from the group consisting of sodium hydrogen sulfate, potassium hydrogen sulfate, sodium hydrogen phthalate or potassium hydrogen phthalate, or a compound thereof, and the solvent may be selected from the group consisting of ruthenium, osmium-two. Mercaptoamide, hydrazine, hydrazine-dimercaptoacetamide, fluorenyl-hydrazinopyrrolidone, water, disulfoxide, etc., or a suitable mixed solvent thereof.

In still other embodiments of the method of the present invention, the acidic medium is selected from the group consisting of hydrazine of hydrogen chloride, hydrazine-dihydrazinamide solution, hydrazine of hydrogen chloride, hydrazine-dimercaptoacetamide solution, sterol solution of hydrogen chloride, hydrogen chloride Ethanol solution, n-propanol solution of hydrogen chloride, hydrochloric acid, ethyl acetate solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, hydrobromic acid, hydroiodic acid, phosphoric acid and phosphoric acid aqueous solution, sulfuric acid aqueous solution, decyl sulfate solution, sulfuric acid ethanol solution, Polyphosphoric acid, citric acid, acetic acid, trifluoroacetic acid, aqueous acetic acid and tetrahydrofuran acetate solution, preferably a solution of hydrogen chloride, a solution of hydrazine-dihydrazinamide, a solution of hydrogen chloride in tetrahydrofuran, a solution of hydrogen chloride in methanol, an aqueous solution of hydrogen chloride, an aqueous solution of hydrochloric acid, an aqueous solution of hydrobromic acid, an aqueous solution of sulfuric acid, a solution of decyl alcohol or a solution of sulfuric acid, or Its mixture.

 If a "liquid acid" or "acid solution" is used in the present invention as an acidic medium, the amount thereof can be conventionally determined by those skilled in the art. For example, it may be used in an amount of from 2 to 40 times, preferably from 5 to 20 times the weight of the compound of the formula (III-0) or a salt thereof. The acid solutes in the "acid solution" are generally in excess relative to the compound of the formula (IV-0), up to the amount of saturation of the acid in the solvent.

 In some preferred embodiments of the process of the invention, the "salts" of the compounds of formula (?-0) in step (a) include, but are not limited to, hydrochloride, sulfate or hydrobromide, and the like. The compound of the formula (IV-0) is used in an amount of from 1 to 10 mol, preferably from 1 to 3 mol, per mol of the compound of the formula (III-0) or a salt thereof.

 In the above reaction process, the reaction temperature in the step (a) is generally to the boiling point of the medium. For a liquid acid or acid solute or solid acid system which is less volatile under normal pressure, the reaction temperature may preferably be from room temperature to the boiling point of the solution. For larger liquid acids or acid solutes, the lower limit of the reaction temperature may be preferably room temperature, and the upper limit is preferably lower than the reflux temperature. The reaction pressure is preferably atmospheric pressure, but when the required reaction temperature exceeds the atmospheric boiling point of the medium, the boiling point of the medium can be increased to or above the desired reaction temperature by pressurization. The boiling point of the medium at different pressures is common knowledge in the art.

 In the above reaction process, at the end of the reaction of the step (a), the obtained product is generally an acid addition salt formed by the compound represented by the formula (Π-0) and the acid in the medium, and if subjected to a post-treatment operation such as filtration or concentration, The acid addition salt of the compound of the formula (?-0) can be directly obtained; if the post-treatment is carried out by neutralization and re-separation, a compound of the formula (?-0) can be obtained.

 In the above reaction, the step (b) is an optional step, and the presence thereof may be determined as needed. If desired, the acid addition salt of the compound of the formula (I 1-0) obtained in the step (a) is exchanged to the desired salt, or the compound of the formula (Π-0) is formed into a desired compound. When salt, such as hydrochloride, sulfate, hydrobromide, phosphate, sulfonium sulfonate, etc., can be carried out according to conventional salt exchange techniques or salt formation techniques in the art; if it is to be obtained in step (a) When the acid addition salt of the compound of the formula (?-0) is deacidified to a free compound of the formula (?-0), it can also be carried out according to a conventional deacidification technique in the art.

The reaction time is generally 0.5 to 6 hours, which is much longer than the prior art. The reaction time is generally 0.5 to 6 hours, which is much longer than the prior art. shorten. The post-treatment of the method of the invention is simple and convenient, generally can be directly filtered to obtain a product; the obtained product has good quality (HPLC purity is generally greater than 95%), and the yield is high (generally 60-90%), generally no complicated purification operation is required. Can be used directly under One step reaction.

In some embodiments of the present invention, the method further comprises reacting the obtained compound of the formula (Π-0) or a salt thereof with a compound represented by the formula (V-0),

 Where X represents hydroxy, fluoro, chloro, bromo

R ₆ represents a substituent represented by the following formula

Wherein R ₇ , R ₈ , ^ and ^. Respectively represent hydrogen, fluorine, chlorine, bromine, iodine, nitro,

Cl-4 pit foundation, Cl-4 pit ^ L3⁄4^, Cl-4 pit base, - (CH pit base) Ϊ^, Cl-4 pit base, d- ₄ alkylsulfinyl, d- ₄ alkane arylsulfonyl group, or an 1-9 substituents selected from fluoro, chloro, bromo, iodo halogen atom halo ₄ - alkyl, halo-D- ₄ alkoxy group, halo _--4 alkylthio, halo ( ^ _-4 alkylsulfinyl or halo d- ₄ alkylsulfonyl; Y represents oxygen, sulfur, sulfinyl or acyl; Ar represents unsubstituted or substituted by one, two or more substituents Phenyl, oc-naphthyl, P-naphthyl, tetrahydronaphthyl or anthracenyl, wherein the substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine, ( ₈ alkyl, d- ₈ alkoxy, d- ₈ alkoxy, di ((^ - ₈ alkyl) J ^, d- ₈ alkylthio, alkylsulfinyl ₈ D-, D- ₈ alkylsulfonyl group having 1-9 substituents selected from fluoro, chloro a halogenated _4- alkyl group, a halogenated d- ₄ alkoxy group, a halogenated d- ₄ alkylthio group, a halogenated d- ₄ alkylsulfinyl group or a halogenated group of the same or different halogen atoms of bromine or iodine. d- ₄ alkylsulfonyl group, a cycloalkyl group having 3-7 carbon atoms, or a phenyl d- ₄ alkyl group, a phenoxy group or a phenoxy group d- ₄ ,

Producing a compound represented by the formula (1-0),

Wherein, R, and R "are each independently selected from hydrogen, d_ _2. Alkyl group, alkenyl group, C _1-2 o alkynyl. Cycloalkyl,. Cycloalkyl. Group, C _{6. 1 ()} An aryl group, a 4-8 membered heterocyclic group having 1 to 3 hetero atoms, an aryl group, an alkyl group, an alkoxy group, an alkyl group, or a group represented by the following formula,

Wherein represents hydrogen, Cwo alkyl, Cwoalkenyl, Cwo alkynyl, C _{3 .10} cycloalkyl Ci_io pit, 6-10 aryl Ci_io pit, Ci_io pit ^ & Ci_io pit; R, R3 and

R _{4 is} independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, and d_ ₂ . Alkyl, alkenyl, C _1-2 o block, Ci_20 pit &, C3-IO ring pit, C3-IO ring pit based Ci_io pit group, C6-10 aryl, c _{6 .10} arylalkyl, c _M0 alkane C _o alkyl. The practice of the reaction and the preparation of the compound of formula (V-0) can be carried out in accordance with the process disclosed in U.S. Patent 4,956,370.

The entire disclosure of US 4,956,370 is incorporated herein by reference.

In some specific embodiments of the method of the present invention, in the formula (V-0) and the formula (1-0), R ₆ represents a substituent represented by the following formula

Among them, R ₇ , R ₈ , ! ^ and ^. Each independently represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, decyl, ethyl, decyloxy, ethoxy, decyloxy, ethoxy^, bismuth, and diethyl Or thiol, ethylthio, decylsulfinyl, ethanesulfinyl, decylsulfonyl, ethylsulfonyl, or having from 1 to 5 selected from fluorine, chlorine, bromine, Halogenated fluorenyl, haloethyl, halodecyloxy, haloethoxy, halothiol, haloethylthio, halodecylsulfinyl having the same or different halogen atoms of iodine , haloethylsulfinyl, halosulfonylsulfonyl or haloethylsulfonyl, preferably hydrogen, fluorenyl, ethyl, 曱L &ethoxy; X represents oxygen, sulfur, sulfin An acyl or sulfonyl group, preferably an oxygen; Ar represents a phenyl group, a-naphthyl group, P-naphthyl group, tetrahydronaphthyl group or anthracenyl group which is unsubstituted or substituted by one, two or more substituents, wherein The substituent is selected from the group consisting of fluorine, chlorine, bromine, iodine, (^- ₆ alkyl, (^ _-6 alkoxy, d- ₆ alkoxycarbonyl, bis((^- ₆ alkyl)amino, d- ₃ alkane) group, d- ₃ Alkylsulfinyl, d- ₃ alkylsulfonyl group, having the same or different halogen atoms, haloalkyl of 1-7 substituents selected from fluoro, chloro, bromo, iodo d-3 alkyl, halo _--3 alkylthio, Halogenated d- ₃ alkylsulfinyl or halo d- ₃ alkylsulfonyl, cycloalkyl having 3-7, or phenyl d-3 alkyl, phenoxy d-3 Or phenoxy, preferably phenyl, 2-nonylphenyl, 4-nonylphenyl, 2,6-didecylphenyl, 2,4-didecylphenyl, 2, 4, 6-trimethylphenyl, a-naphthyl, β-naphthyl, tetrahydronaphthyl or anthracenyl. In a more specific embodiment of the present invention, the compound of the formula (I 1-0) or a salt thereof is a compound of the formula (II) or a salt thereof, and the compound of the formula (V-0) is a formula (V) Or a compound represented by the formula (VI), and the compound of the formula (1-0) or a salt thereof is a compound of the formula (I) or a salt thereof.

 Suitable times for the reaction in all of the above methods can be determined by one of ordinary skill in the art in accordance with conventional methods known, for example, by monitoring the progress of the reaction by conventional chromatography and spectroscopy techniques such as TLC and HPLC.

 There are hydrogenated aminopyrimidine ring moieties in the structures of some of the above compounds of the formulae (1-0), (Π-0) and (III-0). For example, in the structures of the compounds (1), (Π) and (ΙΠ), there are hydrogenated aminopyrimidine ring moieties, and therefore each of them may exist as an equilibrium mixture of its tautomers, the following The local structural formula represents the part of the structure in which the tautomerism is carried out,

 For the convenience of description, only "(1,4,5,6-tetrahydro-2-pyrimidine) J^" and its related names in the tautomers are discussed in the present specification, but it should be understood that Such description includes the corresponding interconversion "(hexahydro-2-pyrimidinyl)imino", "(3,4,5,6-tetrahydro-2-pyrimidinyl)amino" and the like.

For the structure of (1, 4, 5, 6-tetrahydro-2-pyrimidinyl) thiourea (II), in addition to the tautomerization of the hydrogenated aminopyrimidine moiety, the thiourea moiety also has tautomerism. So The compound (Π) may exist as an equilibrium mixture of tautomers as shown below.

Similarly, for the convenience of description, only the name of "(1, 4, 5, 6-tetrahydro-2-pyribyl) thiourea" in the tautomer is discussed in this specification, but it should be understood Such description includes other mutual deformations.

 In summary, the present invention provides a method for preparing a thiourea compound represented by the formula (?-0), which eliminates the highly toxic malodorous hydrogen sulfide in the prior art, and greatly shortens the reaction time and improves the production efficiency. , simplifies the post-processing process. In addition, the method is simple and convenient to operate, and all operations can be completed in conventional reaction equipment, and the obtained product has good quality and high yield, which is favorable for industrial production. On the basis of this, the present invention further applies the method to the preparation of a 2-thiazole compound (as shown in Formula 1-0), particularly abifene (1). Detailed ways

The invention will now be further described in connection with the examples. The examples are provided for the purpose of illustration only, and are not intended to limit the scope of the invention in any way. The terms and abbreviations used in the examples have the usual meanings. Such as "L", "g", "mol", "% (g/g)", "ml", "^C", "TLC", "h", "HPLC", "Mp", "IR" , "(+) ESI-MS", ^ttl H NMR" means liter, gram, mole, mass percentage, cc, Celsius, TLC, H, HPLC, melting point, infrared absorption spectrum, positive ion mode Electrospray ionization mass spectrometry, proton nuclear magnetic resonance. In NMR data, "s" stands for single peak, "d" stands for doublet, "t" stands for triplet, "quintet" stands for five peak, "dd" stands for double Double peak, "m" stands for multiple peaks. Example 1

 Preparation of (1, 4, 5, 6-tetrahydro- 2-pyrimidine <3⁄4&) thiourea (hydrazine) hydrochloride

Og (1. 4 mol, thioacetamide (IV) 113. Og (1) 5mol) and about 10% (g/g) of hydrogen chloride / hydrazine, 1000 ml of hydrazine-dihydrazinamide solution, reacted at 80 ~ to the starting material (1, 4, 5, 6-tetrahydro- 2-pyrimidine) Disappeared (TLC monitors the progress of the reaction, developing solvent: ethyl acetate: decyl alcohol = 10:1), which takes about 2 hours. After the reaction mixture was cooled, the title compound was obtained. HPLC: 98.66%;

 Mp: 183 - 1851C;

IR (KBr): 3140, 3022, 1687, 1637, 1603, 1573, 1402, 1333 1304, 1055, 986, 961, 686 cm" ¹ : Example 2

 Preparation of (1, 4, 5, 6-tetrahydro- 2-pyrimidine) thiourea (II)

 In a 2 L three-necked flask, 100.0 g of (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (II) hydrochloride obtained in Example 1 was added, and 10% (g/g) of carbonic acid was added. 750 ml of a sodium aqueous solution was stirred at 40 to 45 ° C for 0.5 h, cooled, filtered, and filtered to give the title compound (II) 76.5 g.

 HPLC: 99.25%;

 Mp: 173 - 175 C;

IR (KBr): 3424, 3301, 3104, 3028, 2967, 2870, 1615, 1590, 1457, 1420, 1374, 1324, 1171, 1079, 905, 736, 656 cm- ¹ ;

 (+) ESI-MS: 159 (M+1). Example 3

 Preparation of (1, 4, 5, 6-tetrahydro- 2-pyrimidine) thiourea (II)

 In a 2L three-necked flask, add (1,4,5,6-tetrahydro-2-pyrimidinyl) aminonitrile (III)

124.0 g (1.0 mol), thioacetamide (IV) 90.0 g (1.2 mol) and 1000 ml of a saturated hydrogen chloride/tetrahydrofuran solution under normal pressure, and reacted at a normal pressure of 45 to 501 C to a raw material (1, 4, 5) , 6-tetrahydro- 2-pyrimidine) (III) disappeared (TLC monitors the progress of the reaction, developing solvent: ethyl acetate: decyl alcohol = 10:1), which took about 4 hours. Approximately 20% (g/g) of aqueous sodium hydroxide solution was added to adjust the pH of the mixture to pH </ RTI> </ RTI> </ RTI> <RTIgt;

 HPLC: 98.30%;

 Mp: 172 - 174^C;

IR (KBr): 3425, 3301, 3105, 3028, 2967, 2870, 1618, 1591, 1458, 1422, 1374, 1323, 1172, 1078, 905, 735, 657 cm- ¹ ;

^X H NMR (400 MHz, CDC1 ₃ ) δ (ppm): 1.97 - 2.03 (2H, quintet), 3.43 - 3.46 (4H, t);

 (+) ESI-MS: 159 (M+1). Embodiment 4 ~ Embodiment 13

According to the operation of Example 3 above, (1, 4, 5, 6-tetrahydrogen was produced under the conditions shown in the table below. 2-pyrimidinyl)thiourea (Π), the reactions used were all carried out under normal pressure.

 Example 14

 N-[4-[2-(2,4-Dimercaptophenoxy)phenyl]-2-thiazolyl]-1,4,5,6-tetrahydro-2-pyrimidinamine (I) Hydrochloric acid Preparation of salt

 In a 1 L reaction flask, (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (Π) 79.0 g (0.5 mol), 2-chloro-1- [2- (2, 4-) Dimethylphenol oxy)phenyl]ethanone (V) 137.5 g (0.5 mol) and acetone 600 ml, heated under reflux at normal pressure until the starting material disappeared (TLC monitoring reaction progress, developing solvent: ethyl acetate: decyl alcohol = 10: 1), consuming about 5 h; cooling, filtration, washing the cake with an appropriate amount of acetone, and the filter cake was dried to give the title compound 172.3 g.

 HPLC: 97.52%

Mp: 161~163 Example 15

 N-[4-[2-(2,4-Dimercaptophenoxy)phenyl]-2-thiazolyl]-1,4,5,6-tetrahydro-2-pyrimidinamine (I) Hydrobromo Preparation of acid salt

 In a 1 L reaction flask, (1,4,5,6-tetrahydro-2-pyrimidinyl)thiourea (Π) 79.0 g (0.5 mol), 2-bromo-1- [2- (2, 4-) Dimethyl phenoxy)phenyl ketone Ethyl ketone (VI) 160.0g (0.5mol) and acetone 600ml, heated under reflux at normal pressure until the starting material disappears (TLC monitoring reaction progress, developing solvent: ethyl acetate: decyl alcohol = 10: 1), consuming about 3 h; cooling, filtration, washing the cake with an appropriate amount of acetone, and the filter cake was dried to give the title compound 211.7 g.

 HPLC: 98.74%;

 Mp: 212-214 C;

 Example 16

 N-[4- [2-(2,4-Dimercaptophenoxy)phenyl]-2-thiazolyl]-1,4,5,6-tetrahydro

Preparation of -2 -pyrimidine α)

 In the 5 L reaction flask, Ν-[4-[2-(2,4-dimercaptophenoxy)phenyl]-2-thiazolyl]-1,4,5,6 obtained in Example 14 was added. -100.0g of tetrahydro-2-pyrimidinamine hydrochloride, adding 1000ml of ethanol, heating and dissolving at 60 ~ 65 ° C, adding 2000ml of 1% sodium hydroxide solution, stirring at room temperature for 2h, filtering, The filter cake was washed with an appropriate amount of water, and the cake was dried to give the title compound (83.5 g, white crystals).

 HPLC: 99.08%;

 Mp: 194 - 196^;

IR (KBr): 3215, 3038, 2961, 2859, 1637, 1565, 1492, 1478, 1459, 1449, 1437, 1376, 1348, 1319, 1277, 1250, 1219, 1146, 1122, 1061, 858, 818, 763 , 745, 728, 707, 649 cm- ¹ ;

XH NMR (400MHz, CDC1 ₃ ) δ (ppm): 1.95-2.01 (2H, quintet),

2.21(3H, s), 2.31 (3H, s), 3.44 ~ 3.46 (4H, t), 6.68 ~ 6.70 (1H, dd), 6.79- 6.81 (1H, d), 6.94 - 6.97 (1H, dd) , 7.07 ~ 7.15 (3H, m), 7.23 (1H, s), 7.99-8.01 (1H, m) ;

 (+) ESI-MS: 379 (M+1).

 N-[4-[2-(2,4-dimercaptophenoxy)phenyl]-2-thiazolyl]-1, 4, 5, 6-tetra which was obtained in Example 15 as described above. The title compound can also be obtained from the hydrogen-2-pyrimidinamine (II) hydrobromide salt.

 The method of the invention eliminates the highly toxic malodorous hydrogen sulfide in the prior art, and greatly shortens the reaction time, improves the production efficiency, and simplifies the reaction and the post-treatment process. In addition, the method is simple and convenient to operate, and can be completed in a conventional reaction equipment, and the obtained product has good quality and high yield, which is favorable for industrial production.

Claims

 Rights request

a method for preparing a compound of the formula (Π-0) or a salt thereof,

Wherein, R, and R "are each independently selected from hydrogen, d_ _2. Alkyl group, alkenyl group, C _1-2 o alkynyl, C ₃ .io cycloalkyl, C ₃ .io alkyl cycloalkyl C _M0 a C _{6 .10} aryl group, a 4-8 membered heterocyclic group having 1 to 3 hetero atoms, an aryl dw alkyl group, an alkoxyalkyl group, or a group represented by the following formula,

It represents hydrogen, alkyl, alkenyl, alkynyl, C _3-1 . Cycloalkyl C _io pit group, C6_10 aryl C _io pit base, pit foundation pit; R ,

R ₃ and Rt are independently selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, alkyl, C _1-2 o, C -20, C -20, C 3 - 10 ring, C 3 -IO ring pit base C -io pit base, C6-10 aryl group, C6-10 aryl Ci-io pit base, Ci-io pit base Ci-io pit base, the method includes:

 (a) a compound of the formula (III-O) or a salt thereof

 R'- -N-

R" ( III-0 )

Where R, and R" are as defined above,

The compound of the formula (11-0) or its corresponding acid addition salt is obtained by reacting with a compound of the formula (IV-0) in a suitable acidic medium.

(ΐν-0)

Wherein R ₅ represents d.20 alkyl, d.20 alkenyl, Cwo alkynyl, C _{3 .10} cycloalkyl

a Ci_io pit group, a C6-ioaryl Ci_io pit group, a Ci_io pit Ci_io pit group; and (b) optionally, converting the compound of the formula (II-0) obtained in the step (a) or an acid addition salt thereof The desired salt or the acid addition salt of the compound of the formula (?-0) obtained in the step (a) is deacidified to the compound of the formula (11-0).

The method according to claim 1, wherein in the formula (11-0) and the formula (III-0), R, and R" are independently selected from hydrogen, dw alkyl, alkenyl, block, C _3.8 cycloalkyl, C _3.8 cycloalkyl, d. ₆ alkyl, C _{6. 8} aryl, 5-6 membered heterocyclyl contains 1-2 heteroatoms, C _{6. 8} aryl group d a ₆ alkyl group, a d. ₆ alkoxy group, a d. ₆ alkyl group, or a group represented by the following formula,

Where ^ represents hydrogen, . Alkyl, . Alkenyl, . Alkynyl, c _{3. 7} cycloalkyl C -6 pit group, C6_8 aryl C _ 6 pit group, Ci_6 pit C 6 pit base; R ,

R ₃ and Rt are independently of each other selected from the group consisting of hydrogen, fluorine, chlorine, bromine, iodine, and C _w . Alkyl, C _M0 alkenyl, CMO alkynyl, CMO alkane L &, C ₃ -7 cycloalkyl, C ₃ -7 cycloalkyl Ci. ₆ pit, C6-8 aryl, C6-8 aryl Ci_6 Pit basis, C _6 pit base C _6 pit base; in formula (IV-0 ), R ₅ represents (^ alkyl, Cwo alkenyl, d. alkynyl,

C3-7 ring pit Ci_6 pit 3⁄4^, C6-8 Fang Ci_6 pit 3⁄4^, Cl- 3⁄4-?LS^ Cl-pit &. The method according to claim 1, wherein in the formula (11-0) and the formula (III-0), one of R, and R" is hydrogen, and the other is hydrogen, d- ₆ alkyl, d- ₆ alkenyl , Ci. ₆ ... An alkynyl group, C _{3 6} cycloalkyl, C _{3 6} cycloalkyl d ₆ alkyl, C ₆ - ₇ aryl group, or a group represented by the following formula,

Wherein, represents hydrogen, d ₆ alkyl; R ₂ , R ₃ and Rt are, independently of each other, selected from the group consisting of hydrogen, fluorine, chlorine, d. ₆ alkyl, d. ₆ alkoxy;

In formula (IV-0), R ₅ represents decyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, isopentyl, n-hexyl, n-octyl or 2 -ethylhexyl. The method according to claim 1, wherein the compound represented by the formula (11-0) is a compound represented by the formula (II), the compound represented by the formula (III-0) is a compound represented by the formula (III), and The compound represented by the formula (IV-0) is a compound represented by the formula (IV).

H ₃ C ,: H ₂

(II) (III) (IV). The method according to any one of claims 1 to 4, wherein in the step), an acid addition salt of a compound of the formula (?-0) is formed.

The method according to claim 5, wherein in the step, the acid addition salt of the compound of the formula (11-0) is cooled, precipitated, and optionally dried to obtain the acid addition salt.

A method according to any one of claims 1 to 4, wherein the acidic medium is a liquid acid, an acid solution or a solid acid system. The method according to claim 7, wherein the liquid acid is phosphoric acid, polyphosphoric acid, citric acid, acetic acid, hydrazine sulfonic acid, trifluoroacetic acid, or a suitable mixture thereof; the acid solute in the acid solution is hydrogen chloride, bromine Hydrogen, hydrogen iodide, sulfuric acid, phosphoric acid, sodium hydrogen sulfate, potassium hydrogen sulfate, citric acid, acetic acid, sulfonic acid, phthalic acid, sodium hydrogen phthalate, potassium hydrogen phthalate, Or a suitable mixture thereof; the solvent in the acid solution is compatible with the acid solute used, and is selected from the group consisting of N,N-dimercaptoamide, N,N-dimercaptoacetamide, N-decylpyrrolidone, sterol , ethanol, n-propanol, isopropanol, water, ethylene glycol dioxime ether, tetrahydrofuran, diisopropyl ether, ethyl acetate, acetone, cyclohexanone, trichlorodecane, tetrachlorodecane, disulfoxide , citric acid, acetic acid, or a suitable mixture thereof.

The method according to claim 7, wherein the acid solution is a N,N-dimercaptoamide solution of hydrogen chloride, a N,N-dimercaptoacetamide solution of hydrogen chloride, a sterol solution of hydrogen chloride, and an ethanol of hydrogen chloride. Solution, n-propanol solution of hydrogen chloride, hydrochloric acid, ethyl acetate solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, hydrobromic acid, hydroiodic acid, phosphoric acid and phosphoric acid aqueous solution, aqueous sulfuric acid solution, decyl alcohol solution, ethanolic acid solution, polypolymer Phosphoric acid, citric acid, acetic acid, trifluoroacetic acid, aqueous acetic acid and tetrahydrofuran solution, preferably N,N-dimercaptoamide solution of hydrogen chloride, tetrahydrofuran solution of hydrogen chloride, sterol solution of hydrogen chloride, ethanol solution of hydrogen chloride, aqueous hydrochloric acid solution , aqueous hydrobromic acid solution, aqueous sulfuric acid solution, sterol sulfate solution and sulfuric acid ethanol solution.

0. The method according to claim 7, wherein the solid acid system comprises sulfuric acid, phosphoric acid, boric acid or miscellaneous supported on a carrier of activated carbon, silica, alumina or diatomaceous earth as a dispersed phase or a stationary phase. a polyacid, or an acidic ion exchange resin, and a suitable solvent as a continuous phase or a mobile phase, wherein the solvent is selected from the group consisting of Qualitative: N,N-dimercaptoamide, N,N-dimercaptoacetamide, N-decylpyrrolidone, decyl alcohol, ethanol, n-propanol, isopropanol, water, ethylene glycol diterpene ether, Tetrahydrofuran, diisopropyl ether, ethyl acetate, acetone, cyclohexanone, trichlorodecane, tetrachlorodecane, disulfoxide, citric acid, acetic acid, or a suitable mixture thereof.

The method according to any one of claims 1 to 4, wherein the compound of the formula (IV-0) is used in an amount of from 1 to 10 mol based on 1 mol of the compound of the formula (III-0) or a salt thereof. It is preferably 1 to 3 moles.

The method according to claim 1, further comprising reacting the obtained compound of the formula (11-0) or a salt thereof with a compound represented by the formula (V-0),

 Wherein X represents hydroxy, fluoro, chloro, bromo or iodo;

R ₆ represents a substituent represented by the following formula

Where R ₇ , , and . Each independently represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, (^alkyl, d. ₄ alkane L &, C ₄ alkoxycarbonyl, bis(d. ₄ )^) J^, C" alkane thio, C "alkylsulfinyl, C" alkylsulfonyl group, or an 1-9 substituents selected from fluoro, halo is a halogen atom chlorine, bromine, iodine d_ ₄ alkyl, halo d_ ₄ alkyl! L &, halogenated d ₄ alkylthio, halogenated d ₄ alkylsulfinyl or halogenated d ₄ alkylsulfonyl; Y represents oxygen, sulfur, sulfinyl or sulfonyl; Ar represents unsubstituted or a phenyl group substituted with one, two or more substituents, (X-naphthyl, P-naphthyl, tetrahydronaphthyl or anthracenyl, the one selected from the group consisting of fluorine, chlorine, bromine, iodine, (^alkyl, d. ₈ alkoxy, d. ₈ alkoxy^&, bis((alkyl) &, d- ₈ alkylthio, d- ₈ alkylsulfinyl, d- ₈ alkylsulfonyl, Haloalkyl, haloalkane having 1-9 identical or different halogen atoms selected from fluorine, chlorine, bromine, iodine! L &, halogenated d ₄ alkylthio, halogenated d ₄ alkylsulfinyl or halogenated d_ ₄ alkylsulfonyl group having 3-7 ^^ sub cycloalkyl, Ci.4 alkyl, or phenyl, phenoxy or phenyl group L &,

Producing a compound represented by the formula (1-0),

 Wherein Re is as defined above; R, and R" are as defined in claim 1.

The method according to claim 12, wherein in the formula (V-0) and the formula (1-0), Re represents a substituent represented by the following formula

R«

Among them, R ₇ , , and . Each independently represents hydrogen, fluorine, chlorine, bromine, iodine, nitro, decyl, ethyl, decyloxy, ethoxy, decyloxycarbonyl, ethoxycarbonyl, dimercapto, and diethyl ^, thiol, ethylthio, decylsulfinyl, ethanesulfinyl, decylsulfonyl, ethylsulfonyl, or having 1-5 selected from the group consisting of fluorine, chlorine, bromine, and iodine Halogenated fluorenyl, haloethyl, halodecyloxy, haloethoxy, halothiol, haloethylthio, decylsulfinyl, substituted B, same or different halogen atom a sulfinyl group, a decylsulfonyl group or a haloethylsulfonyl group, preferably hydrogen, decyl, ethyl, decyloxy, ethoxy X represents oxygen, sulfur, sulfinyl or sulfonyl, preferably oxygen; Ar represents unsubstituted or substituted by one, two or more phenyl, a-naphthyl, P-naphthyl, a tetrahydronaphthyl or an anthracenyl group selected from the group consisting of fluorine, chlorine, bromine, and iodine

(^ Alkyl, d. ₆ alkoxy, d. ₆ ^ & alkoxycarbonyl, di (d. ₆ alkyl) &, d_ ₃ alkylthio, d_ ₃ alkylsulfinyl, d_ ₃ alkylsulfonyl group a haloalkyl group having 1 to 7 identical or different halogen atoms selected from the group consisting of fluorine, chlorine, bromine and iodine, a halogenated d ₃ alkylthio group, a halogenated d ₃ alkylsulfinyl group or a halogenated d ₃ alkylsulfonate An acyl group, a cycloalkyl group having 3 to 7 carbon atoms, or a phenyl d- _3- alkyl group, a phenoxy C _1-3 alkyl group or a phenoxy group, preferably a phenyl group, a 2-decylphenyl group, 4 -nonylphenyl, 2,6-dianonylphenyl, 2,4-didecylphenyl, 2,4,6-tridecylphenyl, (X-naphthyl, β-naphthyl, tetra Hydronaphthyl or anthracenyl.

The method according to claim 12, wherein the compound of the formula (11-0) or a salt thereof is a compound represented by the formula (II) or a salt thereof, and the compound represented by the formula (V-0) is a formula (V) Or a compound represented by (VI), and the compound represented by (1-0) or a salt thereof is a compound of the formula (I) or a salt thereof.