Preparation method of a bicyclic-substituted pyrazolone azo derivative and intermediate thereof

Abstract

Provide a preparation method of a bicyclic-substituted pyrazolone azo derivative and an intermediate thereof. #imgabs0#

Description

Technical Field

[0001] The present invention relates to a preparation method of a bicyclic substituted pyrazolone azo derivative and an intermediate thereof. Background Art

[0002] Platelets are cells that play an important role in the process of hemostasis and repair of damaged blood vessels. Severe deficiency of platelets, namely thrombocytopenia, may cause serious consequences or even death. Thrombocytopenia includes idiopathic thrombocytopenic purpura (ITP), and thrombocytopenia caused by chemotherapy (interferon IFN, heparin, etc.), radiotherapy, bacterial or viral infections (HIV, hepatitis C, etc.) and liver diseases.

[0003] Thrombopoietin (TPO) is a hematopoietic growth factor that stimulates platelet production in vivo. By binding to a specific receptor (c-Mpl), it can regulate the proliferation, differentiation, and maturation of megakaryocytes, thereby forming platelets and increasing the number of platelets in the circulating blood. Recombinant human thrombopoietin (rhTPO) and polyethylene glycolylated recombinant human megakaryocyte growth factor (PEG-rHuMGDF) are the first-generation platelet growth factors that have entered clinical trials. The two have similar pharmacological properties and can both effectively increase platelet levels. However, it was found in clinical trials that PEG-rHuMGDF can induce the production of IgG neutralizing antibodies, causing or exacerbating thrombocytopenia. Therefore, the research and development work on platelet growth factors has turned to non-immunogenic TPO mimetics. In particular, small molecule non-peptide TPO mimetics have been favored due to their advantages such as convenient administration and low price.

[0004] GlaxoSmithKline (GSK) disclosed the thrombopoietin analogue eltrombopag in patents WO2001089457A2 and WO2006064957A1, and it showed considerable activity; the preparation method of azo compounds was disclosed in WO2001017349A1.

[0005] WO2009092276A1 protects a class of novel bicyclic substituted pyrazolone azo derivatives and their uses as TPO mimetics and TPO receptor agonists; WO2010142137A1 disclosed a pharmaceutically acceptable salt form of a series of bicyclic substituted pyrazolone azo derivatives, which are more effective TPO mimetics and TPO receptor agonists.

[0006] Examples 1, 3, 6, 9, and 15 of WO2009092276A1 disclosed the preparation method of compound 15, with a total of nine reaction steps, and the specific reactions are as follows:

[0007]

[0008] The method finally obtains the target product through HPLC purification, with a yield of only 39.8%. This method has problems such as a relatively large number of reaction steps, a long reaction time, and a low yield, which is not conducive to industrial scale-up production. Summary of the Invention

[0009] The technical problem to be solved by the present invention is to provide a method for preparing the compound shown in formula (V) that is completely different from the prior art. By changing the starting materials and intermediates to prepare the target product, the preparation method is optimized through shortening the reaction steps, the starting materials and other reactants being simple to purchase, the reaction conditions being simple and controllable, and the post-reaction treatment method being simple, etc., to improve the yield and facilitate industrial scale-up production.

[0010] The technical solution of the present invention is as follows:

[0011] The present invention provides a method for preparing the compound shown in formula (V), which is characterized in that the method is the reaction of the compound shown in formula (III) with the compound shown in formula (IV) or its salt to obtain the compound shown in formula (V),

[0012]

[0013] Wherein,

[0014] A is selected from a carbon atom or an oxygen atom;

[0015] R is selected from a hydrogen atom or an alkyl group;

[0016] R1, R2, R3, R4 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, an optionally substituted aryl group or a heteroaryl group, and the substituents are selected from an alkyl group, a halogen, a hydroxyl group, a tetrazolyl group, an imidazolyl group, a dihydroimidazolyl group, a carboxyl group or an alkoxycarbonyl group;

[0017] R5, R6, R7 are each independently selected from a hydrogen atom, an alkyl group, an alkoxy group, a halogen, a hydroxyl group, an amino group, a nitro group, a cyano group, a carboxyl group or an alkoxycarbonyl group;

[0018] R8, R9, R 10 , R 11 are each independently selected from a hydrogen atom or an alkyl group;

[0019] n is selected from 0, 1 or 2.

[0020] Preferably, the method further includes,

[0021]

[0022] Wherein, R, R1, R2, R3, R4 are as defined in formula (V).

[0023] More preferably, the method further includes,

[0024]

[0025] Among them, R1, R2, R3, and R4 are as defined in formula (V).

[0026] The present invention provides a method for preparing a compound of formula (III), and the method is as follows.

[0027]

[0028] Among them, R, R1, R2, R3, and R4 are as defined in formula (V).

[0029] The method for preparing the compound of formula (III) further includes

[0030]

[0031] Among them, R1, R2, R3, and R4 are as defined in formula (V).

[0032] Preferably in the above solution, the method for preparing the compound of formula (III-1) is as follows.

[0033]

[0034] The method for preparing the compound of formula (III-1) further includes

[0035]

[0036] The present invention further provides a compound as shown in formula (II).

[0037]

[0038] Among them, R1, R2, R3, and R4 are as defined in formula (V).

[0039] Preferably, the compound has the structure shown in formula (IIA).

[0040]

[0041] Among them, R2, R3, and R4 are as defined in formula (V);

[0042] R a is selected from a hydrogen atom, a halogen, a hydroxyl group, an amino group, a cyano group, a carboxyl group, a tetrazolyl group, an alkyl group, an alkoxy group, or an alkoxycarbonyl group;

[0043] m is selected from 0, 1, 2, or 3;

[0044] X is selected from an N, O, or S atom.

[0045] More preferably, the compound has the structure shown in formula (IIB).

[0046]

[0047] Among them, R2, R3, and R4 are defined as in formula (V).

[0048] More preferably, the compound has the structure shown in formula (II-1),

[0049]

[0050] The present invention also provides a method for preparing a compound of formula (II), characterized in that the method is

[0051]

[0052] Among them, R1, R2, R3, and R4 are defined as in formula (V).

[0053] The method for preparing the compound of formula (II-1) in the present invention is

[0054]

[0055] The present invention also provides a compound as shown in formula (IV) or a salt thereof,

[0056]

[0057] Among them, R5, R6, R7, R8, R9, R 10 , R 11 , n, and A are defined as in formula (V).

[0058] Preferably, the compound has the structure shown in formula (IVA),

[0059]

[0060] Among them, R5, R6, and R7 are defined as in formula (V);

[0061] The salt is preferably hydrochloride, sulfate, phosphate, acetate, trifluoroacetate, oxalate, tartrate, maleate, fumarate, citrate, p-toluenesulfonate, benzenesulfonate, ethanesulfonate, or methanesulfonate.

[0062] More preferably, the compound has the structure shown in formula (IV-1),

[0063]

[0064] The present invention also provides a method for preparing a compound of formula (IV) or a salt thereof, characterized in that the method is

[0065]

[0066] Among them, R5, R6, R7, R8, R9, R 10 , R 11 , n, and A are defined as in formula (V).

[0067] Preferably in the above solution, the method is

[0068]

[0069] The present invention further provides a method for preparing a compound represented by formula (V-1), characterized in that the method is

[0070]

[0071] The compound represented by formula (III-1) is reacted in an aqueous acid solution under low temperature conditions and the action of sodium nitrite to form a diazo compound, and the diazo compound is then subjected to a condensation reaction with the compound represented by formula (IV-1) under alkaline conditions, and then filtered and dried to obtain a solid; the acid is preferably hydrochloric acid or sulfuric acid, the low temperature is selected from -4 to 5 °C, preferably -4 to -1 °C; the base is selected from sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate or sodium hydroxide, preferably sodium hydroxide.

[0072] The present invention also provides a method for preparing the compound represented by formula (III-1)

[0073]

[0074] The compound represented by formula (II-1) is added to an alkaline solution, heated to reflux for reaction, cooled, acidified to crystallize, filtered, washed and dried to obtain a product; the alkaline solution is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide solution, preferably sodium hydroxide solution; the acid is preferably hydrochloric acid.

[0075] The present invention also provides a method for preparing the compound represented by formula (II-1)

[0076]

[0077] The compound represented by formula (I) is reacted in an aqueous acid solution under low temperature conditions and the action of sodium nitrite to form a diazo compound; furoic acid and copper dichloride dihydrate are added to a solvent, and the above diazo compound is added dropwise, and a condensation reaction is carried out, and then filtered, washed and dried to obtain a product; the acid is preferably hydrochloric acid or sulfuric acid, the solvent is preferably water or acetone, and the low temperature is selected from -6 to 5 °C, preferably -6 to -3 °C.

[0078] The present invention also provides a method for preparing the compound represented by formula (IV-1)

[0079]

[0080] The compound shown in formula (IV-A-1) and ethyl acetoacetate are added to an organic solvent, and the reaction is carried out under heating and reflux. After the reaction solution is cooled, it is filtered and washed to obtain the product; the organic solvent is preferably an ester solvent, and the ester solvent is preferably ethyl acetate.

[0081] The present invention also provides a method for preparing a pharmaceutically acceptable salt of the compound shown in formula (V-1), including the steps in the above-mentioned scheme, and the step of reacting the compound shown in formula (V-1) with a base in an organic solvent to prepare its pharmaceutically acceptable salt. The base is selected from sodium hydroxide, lysine, arginine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, tromethamine, tetramethylammonium, tetraethylammonium or choline hydroxide, preferably ethanolamine; the organic solvent is preferably an ether solvent, an alcohol solvent, or a mixed solvent of an ether solvent and an alcohol solvent. Detailed description of the invention

[0083] For a better understanding of the present invention, certain technical and scientific terms are specifically defined below. Unless otherwise clearly defined elsewhere in this document, all other technical and scientific terms used herein have the meanings commonly understood by those of ordinary skill in the art to which the present invention pertains.

[0084] As used in the present invention, "halogen or halogen atom" refers to a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.

[0085] As used in the present invention, "alkyl" refers to a straight-chain or branched-chain alkyl containing 1-20 carbon atoms, including, for example, "C 1-6 alkyl", "C 1-4 alkyl", etc. Specific examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2,3-dimethylbutyl, 2-ethylbutyl, 1,2-dimethylpropyl, etc.

[0086] As used in the present invention, "aryl" refers to a 6- to 14-membered fully carbon monocyclic or fused polycyclic (that is, rings sharing adjacent carbon atom pairs) group having a conjugated π-electron system, preferably a 6- to 8-membered aryl group, more preferably a phenyl group, an anthryl group, a phenanthryl group, and most preferably a phenyl group.

[0087] As used herein, the term "heteroaryl" refers to a 5- to 15-membered fully carbon monocyclic or fused polycyclic group having a conjugated π-electron system and further containing 1 to 4 heteroatoms selected from one or more of oxygen, sulfur, or nitrogen. Preferred heteroaryl groups are 5- to 8-membered, and more preferably 5- to 6-membered. Specific examples include, but are not limited to, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, pyridyl, 2-pyridone, 4-pyridone, pyrimidinyl, pyridazinyl, pyrazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, azepine, 1,3-diazepine, azocine, etc.; the heteroaryl group may also be fused to an aryl group, a heterocyclic group, or a cycloalkyl ring.

[0088] As used herein, the term "alkoxy, alkoxycarbonyl" refers to a group connected in the form of alkyl-O- or alkyl-O-C(O)-, where "alkyl" is as defined above.

[0089] As used herein, the term "ester solvent" refers to a combination of a lower organic acid having 1 to 4 carbon atoms and a lower alcohol having 1 to 6 carbon atoms. Specific examples include, but are not limited to: ethyl acetate, isopropyl acetate, or butyl acetate.

[0090] As used herein, the term "alcohol solvent" refers to a group derived by replacing one or more hydrogen atoms on an "alkyl" group with one or more "hydroxyl" groups, where "alkyl" is as defined above. Specific examples include, but are not limited to: methanol, ethanol, ethylene glycol, n-propanol, or 2-propanol.

[0091] As used herein, the term "ether solvent" refers to a chain or cyclic compound containing an ether bond -O- and having 1 to 10 carbon atoms. Specific examples include, but are not limited to: propylene glycol methyl ether, tetrahydrofuran, or 1,4-dioxane.

[0092] As used herein, the term "mixed solvent" refers to a solvent formed by mixing one or more different types of organic solvents in a certain proportion, or a solvent formed by mixing an organic solvent and water in a certain proportion.

[0093] Advantages of the Invention

[0094] Compared with the prior art, the technical solution for preparing the compound shown in formula (V) of the present invention has the following advantages:

[0095] (1) The number of reaction steps is reduced. The number of reaction steps disclosed in the prior art is 9 steps, while the number of reaction steps of the present invention is 4 steps.

[0096] (2) Compared with the prior art, the starting materials and intermediates of the present invention are different, providing a synthetic method with a completely different idea, and both the starting materials and reactants are simple and easy to purchase.

[0097] (3) The yield is increased. The yield of the end product disclosed in the prior art is 39.8%, while the yield of the end product of the present invention is 95%.

[0098] (4) The post-treatment of the reaction is simple and easy to scale up for industrial production. Detailed implementation manners

[0099] The following examples are used to further describe the present invention, but these examples do not limit the scope of the present invention.

[0100] For the experimental methods without specific conditions in the embodiments of the present invention, they are usually carried out under conventional conditions, or according to the conditions recommended by the raw material or commodity manufacturers. The reagents without specific sources are conventional reagents purchased from the market.

[0101] Examples

[0102] The structure of the compound is determined by nuclear magnetic resonance (NMR) or / and mass spectrometry (MS). The NMR chemical shift (δ) is given in units of 10 -6 (ppm). The NMR measurement is performed using a Bruker AVANCE-500 nuclear magnetic resonance spectrometer, the measurement solvent is deuterium oxide plus sodium hydroxide (D2O + NaOH), and the internal standard is tetramethylsilane (TMS).

[0103] The MS measurement is performed using a Waters Q-Tofmicro TM quadrupole-time-of-flight mass spectrometer.

[0104] The HPLC measurement is performed using a Waters Alliance 2695 high performance liquid chromatograph or an Agilent 1200 series liquid chromatograph, with octadecylsilane-bonded silica gel as the chromatographic column packing material.

[0105] Example 1. Preparation of 3-methyl-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1H-pyrazol-5-ol hydrochloride

[0106]

[0107] (5,6,7,8 - Tetrahydronaphthalen - 2 - yl)hydrazine hydrochloride (1.3 kg, which can be prepared according to the method in patent application WO2009092276A1), ethyl acetoacetate (1.17 L), were added to ethyl acetate (5.2 L). The reaction was heated to reflux for 2 hours. The reaction solution was cooled to room temperature, then cooled to 0 - 5 °C, stirred for 1 hour, filtered, and the solid was washed with a small amount of ethyl acetate to obtain a white solid product (1.4 kg, yield 81%).

[0108] MS m / z(ESI): 229.26[M - HCl + H]

[0109] Example 2. Preparation of (Z)-5-(2 - hydroxy - 3-(2-(3 - methyl - 5 - oxo - 1-(5,6,7,8 - tetrahydronaphthalen - 2 - yl)-1,5 - dihydro - 4H - pyrazol - 4 - yl)hydrazino)phenyl)furan - 2 - carboxylic acid (V - 1)

[0110]

[0111] The first step. Synthesis of intermediate (II - 1)

[0112] Purified water (14.80 kg), 7 - aminobenzoxazol - 2(3H)-one (2.00 kg, which can be prepared according to the method in patent application WO2005016898A2), hydrochloric acid (5.33 kg) were added to the reaction kettle, heated to 40 - 45 °C, stirred for 10 min, cooled to - 3 - 5 °C, and an aqueous sodium nitrite solution (940 g of sodium nitrite, 3.20 kg of water) was added dropwise, keeping the internal temperature not exceeding 5 °C, controlling the end point with starch - potassium iodide test paper, and continuing to stir for 15 min;

[0113] Acetone (28 L) was added to the reaction kettle, furoic acid (4.57 kg) and copper(II) chloride dihydrate (232 g) were added in turn, stirred at 35 - 40 °C until dissolved, and the diazonium salt solution was added dropwise, keeping the internal temperature at 35 - 40 °C during this period, and continuing to stir for 1.5 h. Purified water (60 L) was added, heated to 35 - 40 °C and stirred for 30 min. Filtered, the filter cake was washed with purified water at 45 - 50 °C. The filter cake was added to purified water (40 kg), the pH was adjusted to 8 - 9 with 15% aqueous sodium hydroxide solution, filtered, the filtrate was adjusted to pH 3 - 4 with 6 mol / L hydrochloric acid, filtered, the filter cake was washed with purified water and dried to obtain a solid (1.63 kg, yield 50%).

[0114] The second step. Synthesis of intermediate (III - 1)

[0115] The product from the previous step (1.4 kg), 15% aqueous sodium hydroxide solution (9.7 kg), under argon protection, was heated to reflux and reacted for 28 h. The reaction solution was poured into ice water (5 - 6 kg), and hydrochloric acid (6 N, 3 L) was slowly added to adjust the pH value to 5 - 6 while maintaining the temperature below 20 °C. During this period, ethyl acetate was added to eliminate bubbles. After filtration, it was washed with purified water and dried to obtain a solid (1.18 kg, yield 94%).

[0116] Step 3. Synthesis of Intermediate (V-1)

[0117] To the reaction kettle were successively added the product from the previous step (1.10 kg), purified water (27.5 kg), and hydrochloric acid (2.92 kg). After stirring and dissolving, it was cooled to -4 to -1 °C, and an aqueous sodium nitrite solution (346 g of sodium nitrite and 5.5 kg of water) was added dropwise. After the addition was complete, the reaction continued for 15 min. The temperature was lowered to -8 to -5 °C. Sodium hydroxide (1.48 kg) was dissolved in purified water (13.2 kg) to obtain a 10% aqueous sodium hydroxide solution. 5-Methyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)-2H-pyrazol-3-ol hydrochloride (1.26 kg) was added to the above-mentioned aqueous sodium hydroxide solution (10 kg) for dissolution, and the resulting solution was added to the diazonium salt solution at one time while maintaining the temperature not higher than 10 °C. The remaining 10% aqueous sodium hydroxide solution was added to adjust the pH to 8 - 9, and the temperature was naturally raised to 8 - 12 °C for reaction for 4 h. 6N hydrochloric acid was added to adjust the pH = 2 - 3 while maintaining the temperature not exceeding 20 °C. After filtration, the filter cake was washed with water until the pH = 6 - 7. The filter cake was added to 50% aqueous tetrahydrofuran solution (19 kg), and slurried at room temperature for 2 h. After filtration, it was washed with 50% aqueous tetrahydrofuran solution and then with water, and dried. The solid was added to ethyl acetate (20 kg), and slurried at 40 - 45 °C for 2 h under argon protection. After cooling to room temperature, it was filtered, washed with ethyl acetate. The solid was added to ethyl acetate (20 kg), and slurried at 40 - 45 °C for 2 h under argon protection. After cooling to room temperature, it was filtered, washed with ethyl acetate, and dried to obtain a solid (2.18 kg, yield 95%, purity 99.5%).

[0118] MS m / z(ESI): 457.1[M - 1]

[0119] Example 3. Preparation of (Z)-5-(2-Hydroxy-3-(2-(3-methyl-5-oxo-1-(5,6,7,8-tetrahydronaphthalen-2-yl)-1,5-dihydro-4H-pyrazol-4-ylidene)hydrazino)phenyl)furan-2-carboxylic acid ethanolamine salt (1:2)

[0120]

[0121] Preparation of the crude product

[0122] At room temperature, the compound of formula (V-1) (1.8 kg) was suspended in a mixed solvent of tetrahydrofuran / ethanol (14.5 kg, V / V = 2:1), stirred for 0.5 h, cooled to 10 - 15 °C, and a tetrahydrofuran / ethanol solution of ethanolamine (479.6 g) (tetrahydrofuran 91 g and ethanol 41 g) was added dropwise. The temperature was naturally raised to room temperature and the reaction was carried out for 20 h. The mixture was filtered, washed with a tetrahydrofuran / ethanol (V / V = 2:1) mixed solvent, washed with ethyl acetate, filtered, and dried to obtain a dark red solid (1.73 kg, yield 76%, purity 99.7%).

[0123] 1 H-NMR (500 MHz, D2O + NaOH) δ 7.725 - 7.741 (d, 1H), 7.298 - 7.316 (d, 3H), 7.183 - 7.198 (d, 1H), 7.131 - 7.149 (m, 2H), 6.612 - 6.643 (t, 1H), 3.574 - 3.596 (t, 4H), 2.759 - 2.778 (br, 4H), 2.698 - 2.721 (t, 4H), 2.428 (s, 3H), 1.772 (br, 4H).

Claims

1. A method for preparing a compound represented by formula (V-1), characterized in that, The method is as follows: The compound shown in Formula III-1 generates the corresponding diazo compound, and the diazo compound reacts with the compound shown in Formula IV-1 under alkaline conditions, and the base is sodium hydroxide.

2. The method according to claim 1, wherein The method further includes:

3. The method according to claim 2, wherein The method further includes:

4. The method according to claim 1, wherein The method further includes:

5. A method for preparing a pharmaceutically acceptable salt of the compound shown in Formula (V-1), which includes the steps described in any one of claims 1-4, and the step of preparing its pharmaceutically acceptable salt by reacting the compound shown in Formula (V-1) with a base, and the base is selected from sodium hydroxide, lysine, arginine, methylamine, dimethylamine, trimethylamine, ethylamine, diethylamine, triethylamine, ethanolamine, piperazine, dibenzylethylenediamine, meglumine, tromethamine, tetramethylammonium, tetraethylammonium or choline hydroxide.

6. The method according to claim 5, wherein the base is ethanolamine.

Images