A process for the preparation of a spiro compound

Abstract

The application relates to a preparation method of a spiro compound, and belongs to the field of pharmaceutical chemistry; the method comprises the following steps: under the condition of a catalyst, raw materials are subjected to a cycloaddition reaction, an amidation reaction and a cyclization reaction to obtain a target compound; the method provided by the application avoids using medicines as raw materials, and high-purity products can be obtained.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, and specifically relates to a method for preparing spirocyclic compounds. Background Technology

[0002] The spirocyclic compound I shown in Formula I is an important impurity that needs to be used as a reference standard in the preparation of the drug tadalafil.

[0003]

[0004] Obtaining compound I, which can be used as a standard reference, i.e., obtaining compound I in high purity, plays a crucial role in drug quality standards. In existing technologies, compound I is typically obtained by reacting tadalafil through a series of reaction steps. This method suffers from problems such as numerous reaction steps, complex processes, and low product purity. Therefore, there is a need to develop a method that avoids using pharmaceutical raw materials and can obtain a high-purity product. Summary of the Invention

[0005] This invention provides a method for preparing compound I. The method provided by this invention avoids the use of pharmaceutical raw materials and yields compound I in high purity.

[0006] A method for preparing compound I includes: reacting compound II with methylamine in a mixed solvent of organic solvent and water at a certain temperature under certain temperature conditions, followed by post-treatment to obtain compound I.

[0007] and / or

[0008] The process includes: in an organic solvent, under the condition of adding a basic reagent, compound III reacts with chloroacetyl chloride via an amidation reaction, followed by post-treatment to prepare compound II.

[0009] and / or

[0010] This includes: under the conditions of adding a catalyst and an inorganic base, compounds 01 and 02 undergo a cycloaddition reaction, followed by post-treatment, to prepare compound III.

[0011]

[0012] In some embodiments, a method for preparing compound I includes: in an organic solvent, under the condition of adding an alkaline reagent, compound III undergoes an amidation reaction with chloroacetyl chloride, followed by post-treatment to prepare compound II; then in a mixed solvent of organic solvent and water, under certain temperature conditions, compound II undergoes a cyclization reaction with methylamine, followed by post-treatment to prepare compound I.

[0013] In some embodiments, a method for preparing compound I includes: cycloaddition reaction of compounds 01 and 02 under the conditions of adding a catalyst and an inorganic base to prepare compound III; and / or amidation reaction of compound III with chloroacetyl chloride in an organic solvent under the conditions of adding a base reagent, followed by post-treatment to prepare compound II.

[0014] In some embodiments, a method for preparing compound I includes: under the conditions of adding a catalyst and an inorganic base, compound O1 and compound O2 undergo a cycloaddition reaction to prepare compound III; in an organic solvent, under the conditions of adding a base reagent, compound III undergoes an amidation reaction with chloroacetyl chloride, followed by post-treatment to prepare compound II; then in a mixed solvent of organic solvent and water, under certain temperature conditions, compound II undergoes a cyclization reaction with methylamine, followed by post-treatment to prepare compound I.

[0015] In the aforementioned cyclization reaction, the organic solvent can be acetonitrile, tetrahydrofuran, isopropanol, DMF, DMSO, or a combination thereof, preferably acetonitrile.

[0016] For each gram of compound II, the amount of the organic solvent used can be 3 ml-50 ml, 5 ml-40 ml, 5 ml-30 ml, or 10-30 ml. In some embodiments, in the aforementioned cyclization reaction, the organic solvent is acetonitrile, and the amount of the organic solvent used for each gram of compound II can be 10 ml-50 ml. In some embodiments, in the aforementioned cyclization reaction, the amount of the organic solvent used for each gram of compound II can be 10 ml-30 ml.

[0017] In the aforementioned cyclization reaction, the reaction temperature can be controlled between 20°C and 80°C. In some embodiments, the reaction temperature can be controlled between 30°C and 60°C. In some embodiments, the reaction temperature is controlled between 40°C and 50°C, which is more conducive to the formation of the target product.

[0018] In the aforementioned cyclization reaction, the molar ratio of compound II to methylamine can be 1:2 to 1:10. In some embodiments, the molar ratio of compound II to methylamine can be 1:2 to 1:7. In some embodiments, the molar ratio of compound II to methylamine can be 1:4 to 1:7, which is beneficial for the formation of the target product. In some embodiments, the molar ratio of compound II to methylamine can be 1:6 or 1:5, which is even more beneficial for the formation of the target product.

[0019] In some embodiments, compound II undergoes a cyclization reaction with methylamine in a mixed solvent of acetonitrile and water at a temperature of 30°C to 60°C. After the reaction is complete, compound I is prepared by post-processing. The molar ratio of compound II to methylamine is 1:2 to 1:7.

[0020] In some embodiments, the post-processing includes: mixing the reaction solution with water, extracting with ethyl acetate or isopropyl acetate, washing the organic phase with a saturated sodium chloride aqueous solution, drying the organic phase and removing the solvent, and preparing the product by chiral column chromatography to obtain compound I; the chiral column chromatography preparation conditions include: instrument: Waters supercritical fluid chromatography (Waters SFC Investigator); Daicel OD column: 10mm*250mm, 5um; flow rate 8mL / min, column temperature 35℃, detection wavelength 210, 254nm, 35% methanol-carbon dioxide isocratic elution.

[0021] In the aforementioned amidation reaction, the organic solvent can be at least one selected from acetonitrile, dichloromethane, tetrahydrofuran, and toluene. The amount of organic solvent used per gram of compound III can be 3 ml to 30 ml. In some embodiments, the amount of organic solvent used per gram of compound III can be 5 ml to 30 ml. In some embodiments, the amount of organic solvent used per gram of compound III can be 8 ml to 20 ml. In some embodiments, the amount of organic solvent used per gram of compound III is 8 ml to 15 ml.

[0022] In the aforementioned amidation reaction, the base reagent can be at least one of triethylamine, N,N-diisopropylethylamine, sodium bicarbonate, sodium carbonate, and potassium bicarbonate; preferably triethylamine, N,N-diisopropylethylamine, or a combination thereof.

[0023] In the aforementioned amidation reaction, the molar ratio of compound III to the base reagent can be 1:2 to 1:3. In some embodiments, the molar ratio of compound III to the base reagent is 1:2 to 1:2.5, which is more conducive to the formation and acquisition of the target product.

[0024] In the aforementioned amidation reaction, the molar ratio of compound III to chloroacetyl chloride can be 1:1.4-1:2. In some embodiments, the molar ratio of compound III to chloroacetyl chloride is 1:1.4-1:1.7 or 1:1.5-1:1.7, which is more conducive to the reaction and the formation and acquisition of the target product.

[0025] The reaction temperature of the amidation reaction can be controlled between 0°C and 35°C. In some embodiments, the reaction temperature of the amidation reaction is controlled between 15°C and 30°C.

[0026] In some embodiments, in acetonitrile, under the condition of adding triethylamine, compound III is subjected to an amidation reaction with chloroacetyl chloride at 15°C-35°C. After the reaction is completed, compound II is prepared by post-treatment.

[0027] The obtained compound II can be separated and purified by any suitable method, or it can be used directly in the next reaction.

[0028] The catalyst may be at least one of nickel acetate (Ni(OAc)2), nickel chloride (NiCl2), nickel trifluoromethanesulfonate (Ni(OTf)2), copper trifluoromethanesulfonate (Cu(OTf)2), zinc trifluoromethanesulfonate (Zn(OTf)2), cobalt chloride (CoCl2), silver acetate (AgOAc), and their hydrates; preferably Ni(OAc)2, its hydrate, or combinations thereof, which are more advantageous for implementation and control.

[0029] The molar ratio of the catalyst to compound O2 can be 0.01:1-0.2:1 or 0.05:1-0.2:1; preferably 0.05:1-0.15:1.

[0030] The cycloaddition reaction can be carried out in methanol, ethanol, isopropanol, acetonitrile, toluene, or combinations thereof. In some embodiments, the cycloaddition reaction is carried out in methanol. For each gram of compound O2, the reaction solvent in the cycloaddition reaction can be 5 ml to 25 ml. In some embodiments, for each gram of compound O2, the reaction solvent in the cycloaddition reaction can be 8 ml to 20 ml.

[0031] The molar ratio of compound 01 to compound 02 can be 1.2:1 to 1:1.

[0032] The inorganic base may include or be sodium carbonate, potassium carbonate, or cesium carbonate or a combination thereof. Potassium carbonate is preferred as the inorganic base. The molar ratio of the inorganic base to compound O2 can be 0.01:1-0.2:1, preferably 0.05:1-0.2:1, which is beneficial for the formation and acquisition of the target product.

[0033] The reaction temperature of the cycloaddition reaction can be controlled between 0°C and 35°C. In some embodiments, the reaction temperature of the amidation reaction is controlled between 15°C and 35°C.

[0034] In some embodiments, under the conditions of adding nickel acetate tetrahydrate (Ni(OAc)2·4H2O) and potassium carbonate, compounds 01 and 02 undergo a cycloaddition reaction at 15°C-35°C. After the reaction is complete, compound III is prepared by post-processing.

[0035] In the aforementioned method, the post-processing may include: mixing the reaction solution with water, extracting with ethyl acetate or isopropyl acetate, washing the organic phase with a saturated sodium chloride aqueous solution, drying the organic phase and removing the solvent, and optionally separating and purifying the product to obtain the target compound.

[0036] The separation and purification can be performed using any suitable method, such as chiral column chromatography, silica gel column chromatography, or solvent slurrying or crystallization. During slurrying or crystallization, the solvent can be at least one selected from ethyl acetate, isopropyl acetate, water, methanol, and DMSO, or a mixture of at least one selected from ethyl acetate, isopropyl acetate, water, methanol, and DMSO with at least one selected from n-hexane, cyclohexane, and n-heptane. During slurrying or crystallization, the solvent used per gram of crude product to be slurried or crystallized can be 3 ml-100 ml, or 3 ml-50 ml, or 5 ml-100 ml, or 5 ml-50 ml, or 10 ml-50 ml, or 10 ml-30 ml. In the aforementioned methods, water or a mixture of water and water can also be used during slurrying or crystallization.

[0037] In some embodiments, the chiral column chromatography separation includes: instrument: Waters supercritical fluid chromatography (Waters SFC Investigator); Daicel OD column: 10mm*250mm, 5um; flow rate 5-10ml / min, preferably 8mL / min, column temperature 35℃, detection wavelength 210 or 254nm, 35% methanol-carbon dioxide isocratic elution.

[0038] In some embodiments, the method for preparing compound I includes: cycloaddition of compounds O1 and O2 under the conditions of adding a catalyst and an inorganic base to prepare compound III; amidation of compound III with chloroacetyl chloride in an organic solvent under the conditions of adding a base reagent to prepare compound II; and cyclization of compound II with methylamine in a mixed solvent of organic solvent and water at a certain temperature to prepare compound I; wherein, after each reaction is completed, each reaction may optionally undergo post-treatment, which may include: quenching the reaction with water, extraction with ethyl acetate or isopropyl acetate, washing the organic phase with saturated brine, drying the obtained organic phase to remove the solvent, and optionally separating and purifying to obtain the target product.

[0039] In some embodiments, the method for preparing compound I includes: cycloaddition reactions of compounds O1 and O2 at 15°C-35°C with the addition of Ni(OAc)₂·4H₂O and potassium carbonate; after completion of the reaction, post-treatment is performed to obtain compound III; amidation reactions of compound III and chloroacetyl chloride at 15°C-35°C with the addition of triethylamine in acetonitrile; after completion of the reaction, post-treatment is performed to obtain compound II; and cyclization reactions of compound II and methylamine in a mixed solvent of acetonitrile and water at 15°C-50°C; after completion of the reaction, post-treatment is performed to obtain compound I. Each reaction is followed by post-treatment, which includes: quenching the reaction with water, extraction with ethyl acetate or isopropyl acetate, washing the organic phase with saturated brine, drying the obtained organic phase to remove the solvent, and optionally separating and purifying to obtain the target product.

[0040] In some embodiments, in the method for preparing compound I, compound II is preferably not separated.

[0041] This invention provides a novel method that eliminates the need for tadalafil active pharmaceutical ingredient; the method provides a high-purity compound I that can be used as a reference standard. Detailed Implementation

[0042] To enable those skilled in the art to better understand the technical solutions of the present invention, some non-limiting embodiments are further disclosed below to provide a more detailed description of the present invention.

[0043] All reagents used in this invention can be purchased commercially or prepared by the methods described in this invention.

[0044] The present invention can use TLC (thin-layer chromatography) or HPLC (high-performance liquid chromatography) to monitor the reaction degree of the raw materials. If HPLC is used, the reaction is considered complete when the peak area of ​​the raw materials is less than 4.0%, 2%, or 1%.

[0045] In this invention, THF represents tetrahydrofuran, NaOH represents sodium hydroxide, Ph represents phenyl, i-Pr represents isopropyl, Et3N represents triethylamine, IPA represents isopropanol, DCM represents dichloromethane, MeOH represents methanol, EA represents ethyl acetate, MeCN represents acetonitrile, DMSO represents dimethyl sulfoxide, h represents hour, min represents minute, ml or mL represents milliliter, g represents gram, and nm represents nanometer.

[0046] The resulting compound I can be detected using methods published in the European Pharmacopoeia or the United States Pharmacopoeia.

[0047] In the description of this specification, the references to terms such as "one embodiment," "some embodiments," "example," "specific example," or "some examples," etc., indicate that a specific feature, structure, material, or characteristic described in connection with that embodiment or example is included in at least one embodiment or example of the present invention. In this specification, the illustrative expressions of the above terms do not necessarily refer to the same embodiment or example. Furthermore, the specific features, structures, materials, or characteristics described may be combined in any suitable manner in one or more embodiments or examples. Moreover, without contradiction, those skilled in the art can combine and integrate the different embodiments or examples described in this specification, as well as the features of different embodiments or examples.

[0048] In this invention, expressions such as "compound A" and "compound represented by formula A" refer to the same compound.

[0049] Example 1

[0050]

[0051] Add 1.55 g Ni(OAc)₂·4H₂O and 150 mL methanol to a 250 mL single-necked flask and stir at room temperature (28 °C). Then add 9.0 g of compound 02 and 14.03 g of compound 01, dissolve completely, and then add 0.86 g of potassium carbonate. Monitor the reaction by TLC, with the developing solvent being ethyl acetate:n-hexane = 1:1 (v / v). After the reaction is complete, add 300 mL of water to the reaction mixture, extract with ethyl acetate, separate the layers, and combine the organic layers. Wash the organic layer with saturated brine, separate the layers, and dry with 16 g of anhydrous sodium sulfate. Filter, rotary evaporate, and purify the residue by silica gel column chromatography with the eluent being ethyl acetate:n-hexane = 1:3 (v / v). Dry the collected eluent of compound III under reduced pressure to obtain 15.8 g of compound III solid with a purity greater than 95% and a yield of 75.7%. Alternatively, compound III can be obtained by crystallization using ethyl acetate and n-hexane.

[0052] Detection of compound III obtained: 1H NMR (400MHz, deuterated chloroform): δ 8.32 (s, 1H), 7.46–7.39 (m, 1H), 7.09 (td, J = 7.7, 1.3Hz, 1H), 6.98 (td, J = 7.6, 1.1Hz, 1H), 6.74 (d, J = 1.7Hz, 1H), 6.73–6.67 (m, 2H), 6.50 (d, J = 8.0Hz, 1H), 5.80 (q, J = 1.5Hz, 2H), 4.79 (s, 1H), 4.35 (dd, J = 8.9, 7.3Hz, 1H), 3.84 (s, 3H), 2.73 (dd, J = 13.2, 7.4Hz, 1H), 2.52 (dd, J = 13.2, 8.9Hz, 1H); LC-MS: [M+H] + =367.

[0053] Example 2

[0054]

[0055] 12.04 g of compound III, 150 mL of acetonitrile, and 6.60 g of triethylamine were added to a 100 mL single-bottle container and stirred at room temperature (24 °C). Then, 6.17 g of chloroacetyl chloride was added, and the reaction continued. The reaction was monitored by TLC with an eluent of ethyl acetate:n-hexane at a volume ratio of 1:1. After the reaction was complete, 300 mL of water was added to quench the reaction mixture, followed by extraction with ethyl acetate and separation. The organic layer was washed with saturated brine, separated, and dried over anhydrous sodium sulfate. The mixture was filtered and rotary evaporated under reduced pressure to obtain compound II: 16.0 g solid. Detection was performed by liquid chromatography-mass spectrometry (LC-MS): [M+H]. + =443.00, yield 110% (containing some impurities), can be used directly in the next reaction; or it can be crystallized from ethyl acetate and n-hexane to give compound II.

[0056] Example 3

[0057]

[0058] Add 56 mL of acetonitrile to a single-bottle container containing 2.26 g of compound II (obtained in Example 2, calculated based on 100% purity) and stir at room temperature (30°C). Then add 2.38 g of aqueous methylamine solution (40%, by mass), heat to 45°C, and monitor the reaction by TLC with ethyl acetate as the developing solvent. After the reaction was complete, 150 mL of water was added to the reaction solution, followed by extraction with 50 mL of EA (4-layer ester), separation, washing the organic layer with 50 mL of saturated sodium chloride solution, separation, drying with 4 g of anhydrous sodium sulfate, filtration, and vacuum distillation to obtain 2.02 g of solid residue. TLC analysis showed that the content of compound I was not less than 60%, with ethyl acetate as the developing solvent. The obtained residue was prepared by chiral column chromatography. The chiral column chromatography conditions were as follows: instrument: Waters supercritical fluid chromatography (Waters SFC Investigator); Daicel OD column: 10 mm * 250 mm, 5 μm; flow rate: 8 mL / min; column temperature: 35 °C; detection wavelengths: 210 nm and 254 nm; isocratic elution with 35% methanol-carbon dioxide to obtain 0.96 g of compound I, with a yield of 46% and a purity of 99.0%.

[0059] Detection of compound I: 1 ¹H NMR (400MHz, deuterated DMSO) δ 10.55 (s, 1H), 7.08 (td, J = 7.7, 1.1Hz, 1H), 6.77 (d, J = 7.7Hz, 1H), 6.70 (td, J = 9.3, 8.4, 4.2Hz, 3H), 6.42 (t, J = 7.0Hz, 2H), 5.94 (d, J = 6.7Hz, 2H). 5.21(s,1H),5.07(t,J=7.6Hz,1H),4.44(dd,J=16.1,1.5Hz,1H),3.81(d,J=16.1Hz ,1H),2.94(s,3H),2.57(dd,J=13.2,6.8Hz,1H),2.42(dd,J=13.2,8.3Hz,1H);[M+H] + =406.1;

[0060] 13 C NMR (151MHz, DMSO) δ179.38,166.75,163.44,147.37,146.63,142.26,132.21,128.72,128.69,12 5.56,121.43,120.08,109.89,108.07,107.58,101.31,67.29,58.90,55.82,53.43,37.84,33.70.

[0061] The method of this invention has been described through preferred embodiments. Those skilled in the art will readily be able to modify or appropriately alter and combine the methods and applications described herein within the scope, spirit, and context of this invention to implement and apply the technology of this invention. Those skilled in the art can refer to the content herein to appropriately improve process parameters. It should be particularly noted that all similar substitutions and modifications are obvious to those skilled in the art and are considered to be included within the scope of this invention.

Claims

1. A method for preparing compound I, comprising: Compound II underwent a cyclization reaction with methylamine in a mixed solvent of acetonitrile and water at 30°C–60°C. After the reaction was complete, compound I was prepared through post-treatment. ； In acetonitrile, with the addition of triethylamine, compound III reacts with chloroacetyl chloride at 15°C-35°C via an amidation reaction. After the reaction is complete and post-processing is performed, compound II is prepared. ； and Compounds 01 and 02 underwent a cycloaddition reaction at 15°C-35°C in the presence of nickel acetate tetrahydrate and potassium carbonate. After the reaction was complete, compound III was prepared following post-treatment. ， The cycloaddition reaction is carried out in methanol, the molar ratio of nickel acetate tetrahydrate to compound O2 is 0.01:1-0.2:1, and the molar ratio of potassium carbonate to compound O2 is 0.01:1-0.2:

1.

2. The method according to claim 1, wherein, In the cyclization reaction, for every gram of compound II, the amount of acetonitrile used is 3 ml to 50 ml.

3. The method according to claim 1 or 2, wherein, In the cyclization reaction, the molar ratio of compound II to methylamine is 1:2 to 1:

10.

4. The method according to claim 1, wherein, In the amidation reaction, for every gram of compound III, the amount of acetonitrile used is 3 ml to 30 ml.

5. The method according to claim 1, wherein, The molar ratio of compound III to triethylamine is 1:2 to 1:

3.

6. The method according to claim 1, wherein, The molar ratio of compound III to chloroacetyl chloride is 1:1.4-1:

2.

7. The method according to claim 1, wherein, For each gram of compound O2, the reaction solvent in the cycloaddition reaction is 5 ml to 25 ml.

8. The method according to claim 1, wherein, The post-processing includes: mixing the reaction solution with water, extracting with ethyl acetate or isopropyl acetate, washing the organic phase with a saturated sodium chloride aqueous solution, drying the organic phase and removing the solvent, and optionally separating and purifying the resulting product. The separation and purification include separation using chiral column chromatography, silica gel column chromatography using a solvent, pulping or crystallization, wherein the solvent is selected from at least one of ethyl acetate, isopropyl acetate, water, methanol and DMSO, or a mixture of at least one of ethyl acetate, isopropyl acetate, water, methanol and DMSO with at least one of n-hexane, cyclohexane and n-heptane.

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