A process for the preparation of maropintant and intermediates thereof
By combining chiral ruthenium catalysts with chiral ligands, the problems of expensive raw materials and complex processes in the preparation of maropistan have been solved, and efficient and low-cost synthesis of maropistan intermediates and final products has been achieved.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- GENIFARM LAB INC
- Filing Date
- 2024-11-29
- Publication Date
- 2026-05-29
AI Technical Summary
Existing methods for preparing maropitan suffer from problems such as expensive raw materials, long routes, complex processes, and high costs.
Maropitant intermediates were prepared by reacting a chiral ruthenium catalyst with an amine source and hydrogen, followed by condensation with 5-tert-butyl-2-methoxybenzaldehyde and reduction with palladium on carbon or platinum on carbon to achieve the synthesis of maropitant.
This paper provides a method for preparing maropitan that uses inexpensive and readily available raw materials, has a short synthetic route, good selectivity, simple process, and high product yield, thereby reducing production costs.
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Abstract
Description
Technical Field
[0001] This invention belongs to the field of organic synthesis technology. More specifically, it relates to a method for preparing maloppitan and its intermediates. Background Technology
[0002] Maropitant is a quinine NK1 receptor antagonist, developed by Pfizer, and was the first drug approved for the prevention and treatment of canine motion sickness and acute vomiting. It has advantages such as easy absorption, wide distribution, rapid onset of action, high bioavailability, long duration of action, and good safety.
[0003] Currently, there are four preparation routes for malopipant:
[0004] (1) Using 3-quinine cycloketone as the starting material, maloppitan was prepared through a 9-step reaction. The separation and purification were simple, the raw materials were inexpensive and readily available, and the reaction conditions were mild (WO2004035575, WO2005075473, CNCN1914202A). The disadvantages were the numerous steps, low yield (the overall reaction yield was only about 10%), and the involvement of chiral resolution processes and salt crystallization during the reaction, resulting in high overall production costs.
[0005]
[0006] (2) Using 3-oxoquinine ring-2-carboxylic acid ester as the starting material, the free base of maropistan was prepared in 5 steps (CN106977512A). This route avoids the defects of the original patent, which used L-tartaric acid and (R)-10-camphorsulfonic acid for chiral fractionation, salt formation, and low overall yield. The synthetic route is short (only 5 steps), with a high overall yield (approximately 33.78% according to the examples), and the reagents used are readily available for commercial bulk purchase. The process is also simple. The disadvantage is that the starting materials are difficult to purchase commercially or are expensive, requiring multiple steps for separate preparation (CN107721999A, CN110922401A), thus resulting in higher production costs.
[0007]
[0008] (3) Using (S)-2-diphenylmethylquinine-3-one as the starting material, a free base of maropitane was prepared in three steps (CN109320510A). This method has a short synthetic route, high overall yield (approximately 51.2% according to the example), readily commercially available reagents, simple process operation, and does not involve the use of precious metals such as Pd, Ti, and Pt. However, the disadvantage is that the chiral starting material is difficult to purchase commercially and needs to be prepared separately through multiple reaction steps:
[0009]
[0010] (4) Using 3-quinine cycloketone as the starting material (CN112300150A). This route can introduce two chiral centers in high yield, has high selectivity, simplifies the process, and produces products with high purity and high yield (approximately 67.7% in the examples). However, it has poor atom economy, and the 5-step reaction route is still relatively long.
[0011] Summary of the Invention
[0012] The technical problem to be solved by the present invention is to overcome the defects and shortcomings of the existing technology, such as expensive raw materials, long routes, complex processes and high costs, and to provide a method for preparing maropistane intermediates.
[0013] Another object of the present invention is to provide a method for preparing maropitant.
[0014] The above-mentioned objective of this invention is achieved through the following technical solution:
[0015] This invention protects a method for preparing a maropitant intermediate, comprising the following steps: 2-(diphenylmethylene)quinine-3-one of formula (III) is reacted with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a first solvent to obtain the maropitant intermediate (2S,3S)-2-diphenylmethylquinine-3-amine of formula (IV):
[0016]
[0017] The chiral ruthenium catalyst is a combination of a ruthenium catalyst and a chiral ligand.
[0018] This invention protects a method for preparing maloppitan, comprising the following steps:
[0019] sI. The 2-(diphenylmethylene)quinine-3-one shown in formula (III) is reacted with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a first solvent to give (2S,3S)-2-diphenylmethylquinine-3-amine shown in formula (IV);
[0020] sII. The (2S,3S)-2-diphenylmethylquinine-3-amine of formula (IV) undergoes a condensation reaction with 5-tert-butyl-2-methoxybenzaldehyde of formula (V) under the conditions of a second solvent and acid reagent, followed by reduction by palladium on carbon or platinum on carbon and hydrogen to obtain maloppitan of formula (VI):
[0021]
[0022] The chiral ruthenium catalyst is a combination of a ruthenium catalyst and a chiral ligand.
[0023] This invention protects a method for preparing maloppitan, comprising the following steps:
[0024] S1. Under alkaline and third solvent conditions, the 3-quinine cycloketone of formula (I) or its salt reacts with the benzophenone of formula (II) to obtain the 2-(dibenzoyl)quinine-3-one of formula (III);
[0025] S2. The 2-(diphenylmethylene)quinine-3-one shown in formula (III) is reacted with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a first solvent to give (2S,3S)-2-diphenylmethylquinine-3-amine shown in formula (IV);
[0026] S3. The (2S,3S)-2-diphenylmethylquinine-3-amine of formula (IV) undergoes a condensation reaction with 5-tert-butyl-2-methoxybenzaldehyde of formula (V) under acid and second solvent conditions, followed by reduction with palladium on carbon or platinum on carbon and hydrogen to obtain maloppitan of formula (VI):
[0027]
[0028] The chiral ruthenium catalyst is a combination of a ruthenium catalyst and a chiral ligand.
[0029] Furthermore, the chiral ligand is a chiral bisphosphine ligand.
[0030] Preferably, the chiral bisphosphine ligand is a chiral biphenyl bisphosphine ligand or a chiral naphthalene bisphosphine ligand.
[0031] Preferably, the ruthenium catalyst is one or more of p-cymene dichlororuthenium, cyclooctadiene dichlororuthenium, (1,5-cyclooctadiene)(pentamethylcyclopentadiene) ruthenium chloride, ruthenium acetate, ruthenium chloride, and bis(2-methylallyl)(1,5-cyclooctadiene) ruthenium.
[0032] More preferably, the chiral ruthenium catalyst has at least one of the following structures:
[0033]
[0034]
[0035]
[0036] Furthermore, the amine source is one or more of ammonium acetate, ammonium formate, ammonium benzoate, ammonium iodide, ammonium chloride, ammonium trifluoroacetate, ammonium carbonate, ammonium hexafluorophosphate, and ammonia.
[0037] Preferably, the amine source is one or more of ammonium acetate, ammonium formate, and ammonia.
[0038] Furthermore, ammonia can be in a gaseous state or dissolved in a solution, preferably methanol.
[0039] More preferably, the ammonia gas is a methanol solution of ammonia gas.
[0040] Preferably, the additive is one or more of tetraisopropyl titanate, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid. This additive is optional; the intermediate (2S,3S)-2-diphenylmethylquinine-3-amine can still be obtained without it, and adding the additive can further improve its yield and purity.
[0041] Preferably, the first solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, toluene, trifluorotoluene, dimethyl glycol ether (DME), methyl tert-butyl ether, cyclopentyl methyl ether, methyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, and water; and / or
[0042] The second solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, toluene, trifluorotoluene, dimethyl glycol ether (DME), methyl tert-butyl ether, cyclopentyl methyl ether, methyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, and water; and / or
[0043] The third solvent is one or more of the following: diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, tetrahydrofuran, 2-methylfuran, 1,4-dioxane, n-hexane, n-heptane, toluene, benzene, chlorobenzene, dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.
[0044] More preferably, the second solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, and water.
[0045] Further, the alkali is one or more of the following: lithium bis(trimethylsilylamino)amine, sodium bis(trimethylsilylamino)amine, potassium bis(trimethylsilylamino)amine, lithium diisopropylamino, potassium hydroxide, sodium hydroxide, cesium hydroxide, potassium tert-butoxide, sodium tert-butoxide, and lithium tert-butoxide.
[0046] More preferably, the base is one or more of lithium bistrimethylsilylamino, sodium bistrimethylsilylamino, potassium bistrimethylsilylamino, and lithium diisopropylamino.
[0047] Further, in step S3 or step SII, the acid is one or more of hydrochloric acid, formic acid, acetic acid, trifluoroacetic acid, sulfuric acid, and p-toluenesulfonic acid.
[0048] Furthermore, when the raw material is a salt of 3-quininecycloketone, the salt is generated by reacting 3-quininecycloketone with an inorganic or organic acid. During the reaction, the nitrogen atom of the 3-quininecycloketone combines with the acid to form a salt compound. For example, the structural formula of 3-quininecycloketone hydrochloride is as follows:
[0049] Further, the salts of the 3-quinine cycloketone include one or more of the following: hydrochloride, sulfate, nitrate, phosphate, hydrobromide, perchlorate, 4-methylbenzenesulfonate, methanesulfonate, formate, acetate, and citrate.
[0050] Furthermore, the organic acid includes one or more of 4-methylbenzenesulfonic acid, methanesulfonic acid, formic acid, acetic acid, and citric acid.
[0051] Furthermore, the inorganic acid includes one or more of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, hydrobromic acid, and perchloric acid.
[0052] Furthermore, in step S1, the temperature of the reaction is 0–120°C.
[0053] Preferably, in step S1, the reaction temperature is 20–120°C.
[0054] More preferably, in step S1, the reaction temperature is 40–120°C.
[0055] Furthermore, in step S1, the reaction time is 5 min to 2 h.
[0056] Preferably, in step S2 or step S1, the temperature of the reaction is 100–200°C.
[0057] More preferably, in step S2 or step S1, the temperature of the reaction is 120–180°C.
[0058] Furthermore, in step S2 or step S1, the reaction time is 2 to 24 hours.
[0059] Preferably, in step S3 or step SII, the temperature of the condensation reaction is 20–100°C.
[0060] More preferably, in step S3 or step SII, the temperature of the condensation reaction is 40–80°C.
[0061] Preferably, in step S3 or step SII, the reaction temperature for hydrogen reduction is 20–100°C.
[0062] More preferably, in step S3 or step SII, the reaction temperature for hydrogen reduction is 40–80°C.
[0063] Preferably, in step S3 or step SII, the reaction time for hydrogen reduction is 2 to 24 hours.
[0064] Preferably, in step S1, the molar ratio of the 3-quinine cycloketone or its salt to benzophenone and the base is 1:(1-5):(1-5).
[0065] More preferably, in step S1, the molar ratio of the 3-quinine cycloketone or its salt to benzophenone and the base is 1:(1-2):(1-2).
[0066] Preferably, in step S2 or step S1, the molar ratio of 2-(diphenylmethylene)quinine-3-one, chiral ruthenium catalyst, additive, and amine source is 1:(0.01-0.2):(1-20):(1-30).
[0067] More preferably, in step S2 or step S1, the molar ratio of 2-(diphenylmethylene)quinine-3-one, chiral ruthenium catalyst, additive, and amine source is 1:(0.01-0.1):(1-10):(1-10).
[0068] Preferably, in step S3 or step SII, the molar ratio of (2S,3S)-2-diphenylmethylquinine-3-amine, 5-tert-butyl-2-methoxybenzaldehyde, and acid is 1:(1-5):(1-5).
[0069] More preferably, in step S3 or step SII, the molar ratio of (2S,3S)-2-diphenylmethylquinine-3-amine to 5-tert-butyl-2-methoxybenzaldehyde and acid is 1:(1-2):(1-2).
[0070] Furthermore, in the reaction to prepare (2S,3S)-2-diphenylmethylquinine-3-amine or maropistan, the hydrogen pressure can be any suitable pressure.
[0071] Preferably, the pressure of the hydrogen gas is 0.1 to 10 MPa.
[0072] More preferably, the pressure of the hydrogen gas is 1 to 4 MPa.
[0073] Furthermore, in step S1, after the reaction is completed, a post-processing step is included, which includes cooling, filtering, washing, and drying. Further, the drying is performed by baking.
[0074] Furthermore, in step S2 or step S1, after the reaction is completed, a post-processing step is included, which includes separation and purification. This separation and purification is a common operation in the field of organic synthesis.
[0075] Preferably, in step S3 or step SII, after the hydrogen reduction reaction is completed, a post-processing step is included, which includes separation and purification. This separation and purification is a common operation in the field of organic synthesis.
[0076] Compared with the prior art, the present invention has the following beneficial effects:
[0077] This invention discloses a method for preparing maropitant and its intermediates. The preparation method includes the following steps: S1: Under alkaline conditions and a first solvent, 3-quininecycloone or its salt reacts with benzophenone to obtain 2-(dibenzoyl)quininecyclo-3-one; S2: The obtained 2-(dibenzoyl)quininecyclo-3-one reacts with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a second solvent to obtain the intermediate (2S,3S)-2-diphenylmethylquininecyclo-3-amine; S3: The obtained (2S,3S)-2-diphenylmethylquininecyclo-3-amine undergoes a condensation reaction with 5-tert-butyl-2-methoxybenzaldehyde (Formula V) in the presence of acid and a third solvent, followed by reduction with palladium on carbon or platinum on carbon and hydrogen to obtain maropitant. This method uses inexpensive and readily available raw materials, has a short synthetic route, generates bipolar centers in a high yield in a single step, exhibits good selectivity, is simple in process, has high product yield, and low cost. Detailed Implementation
[0078] The present invention will be further illustrated below with reference to specific embodiments, but the embodiments do not limit the present invention in any way. Unless otherwise specified, the reagents, methods and equipment used in the present invention are conventional reagents, methods and equipment in this technical field.
[0079] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.
[0080] Enantiomeric excess, abbreviated as ee, specifically refers to the percentage of the target product (a specific stereoisomer A) minus the percentage of the byproduct (another isomer B) generated in chiral synthesis. The calculation formula is: ee(%) = [n(A) - n(B)] / [n(A) + n(B)] * 100%, where n represents the molar content.
[0081] Example 1
[0082] A method for preparing maloppitan from 3-quininecycloone or its salts as starting materials includes the following steps:
[0083]
[0084] S1: Under a nitrogen atmosphere, 3-quininecycloone (2 mmol, 250 mg, 1.0 eq) and ethylene glycol diethyl ether (6 mL) were added to a 25 mL reaction flask. The mixture was stirred, and lithium diisopropylamino (2.0 eq) was added dropwise at 25 °C. After stirring for 5 minutes, benzophenone (3 mmol, 546 mg, 1.5 eq) was added. The temperature was then raised to 100 °C and maintained for 5 minutes. A large amount of yellow solid was produced, and the reaction was monitored until the reaction was complete. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 2-(dibenzoyl)quininecyclo-3-one (529 mg, 92%).
[0085] S2: Under a nitrogen atmosphere, 2-(diphenylmethylene)quinine-3-one (0.25 mmol, 72 mg, 1.0 eq), catalyst [(S)-(+)-2,2′-bis(di-(3,5-xylyl)phosphino)-1,1′-binaphthyl](P-cymene)ruthenium(II) chloride (Ru-8, 0.01 mmol, 0.04 eq), trifluoroethanol (1 mL), a methanol solution of ammonia (2 M, 10 eq based on ammonia), and additive acetic acid (5 eq) were sequentially added to the reactor. The reactor was purged three times with hydrogen, the hydrogen pressure was adjusted to 5.5 MPa, and the temperature was raised to 165 °C for 24 hours. After separation and purification (eluent: petroleum ether: ethyl acetate: triethylamine = 100:50:2), (2S,3S)-2-diphenylmethylquinine-3-amine (59.3 mg, 81%, ee = 90%) was obtained.
[0086] S3: Under a nitrogen atmosphere, (2S,3S)-2-diphenylmethylquinine-3-amine (0.2 mmol, 58.2 mg), 5-tert-butyl-2-methoxybenzaldehyde (1.7 eq, 65 mg), acetic acid (1.5 eq), and solvents (1 mL isopropanol, 1 mL ethanol, 80 μL water) were sequentially added to a reaction tube. The reaction was carried out at 75 °C for 4 hours. The reaction solution was then transferred to a reaction vessel, and palladium on carbon catalyst (5%) was added. The mixture was purged three times with hydrogen, and the hydrogen pressure was adjusted to 4.0 MPa. The reaction was carried out at 75 °C for 12 hours. After separation and purification (petroleum ether:ethyl acetate:triethylamine = 100:33:2 as developing solvent), maropistan (69.1 mg, 74%, ee = 90%) was obtained.
[0087] Example 2
[0088] A method for preparing maloppitan from 3-quinine cyclic one hydrochloride as a starting material includes the following steps:
[0089]
[0090] S1: Add 3-quinine cyclohexane hydrochloride (2.5 mmol, 404 mg, 1.0 eq) and ethylene glycol diethyl ether (3.5 mL) to a 25 mL reaction flask. Stir and add LDA (3.0 eq) dropwise at 25 °C. After stirring for 5 minutes, add benzophenone (3.75 mmol, 683 mg, 1.5 eq). Then raise the system temperature to 100 °C and maintain for 5 minutes. A large amount of yellow solid is formed. Monitor the reaction for completion. After cooling, add water, filter, and collect.
[0091] The filter cake was collected, washed, and dried to obtain 2-(diphenylmethylene)quinine-3-one (569 mg, 79%).
[0092] S2: 2-(diphenylmethylene)quinine-3-one (0.25 mmol, 72 mg, 1 eq), catalyst Ru-8 (0.015 mmol, 0.06 eq), trifluoroethanol (1 mL), a methanol solution of ammonia (2 M, 15 eq based on ammonia), and additive acetic acid (10 eq) were sequentially added to a reaction vessel. The mixture was purged three times with hydrogen, the hydrogen pressure was adjusted to 3 MPa, and the temperature was raised to 180 °C for 24 hours. After separation and purification, (2S,3S)-2-diphenylmethylquinine-3-amine (60.6 mg, 83%, ee = 89%) was obtained.
[0093] S3: (2S,3S)-2-diphenylmethylquinine-3-amine (0.2 mmol, 58.2 mg), 5-tert-butyl-2-methoxybenzaldehyde (1.7 eq, 65 mg), hydrochloric acid (2 M, 0.1 mL), and solvent (2 mL methanol) were sequentially added to a reaction tube. The reaction mixture was reacted at 75 °C for 4 hours. The reaction solution was then transferred to a reaction vessel, and a platinum-carbon catalyst (5%) was added. The mixture was purged three times with hydrogen gas, and the hydrogen pressure was adjusted to 1.0 MPa. The reaction mixture was then reacted at 70 °C for 15 hours. After separation and purification, maropistan (65 mg, 70%) was obtained.
[0094] Examples 3-26
[0095] Referring to the S1 feeding and process of Example 1, the diisopropylaminolithium and ethylene glycol diethyl ether in Example 1 were replaced with different bases and solvents (Table 1), while other conditions remained the same as in Example 1. The effects on the yield of 2-(diphenylmethylene)quinine-3-one are as follows:
[0096] Table 1 Synthesis conditions and results of Examples 3-26
[0097]
[0098]
[0099] Examples 3-26 demonstrate that the reaction can be carried out in different organic or inorganic bases, with different equivalences, different solvents, and at different temperatures, resulting in the efficient synthesis of 2-(diphenylmethylene)quinine-3-one, with the reaction being even more favorable in organic bases and ether solvents.
[0100] Examples 27-30
[0101] Referring to the S1 feeding and process of Example 1, the molar ratio of 3-quininecycloketone to benzophenone and alkali was changed (as shown in Table 2), while other conditions remained the same as in Example 1. The effects on the yield of 2-(diphenylmethylene)quininecyclo-3-one are as follows:
[0102] Table 2 Synthesis conditions and results of Examples 27-30
[0103] Example Mole ratio Yield (%) Example 27 1：1：1 70 Example 28 1：1.2：1.5 84 Example 29 1：2：2 85 Example 30 1：5：5 73
[0104] Examples 27-30 show that the reaction can proceed normally under different raw material ratios, and 2-(diphenylmethylene)quinine-3-one can be synthesized efficiently.
[0105] Examples 31-33
[0106] Referring to the S1 feeding and process of Example 2, except that different 3-quinine cyclic ketone salts were used instead of 3-quinine cyclic ketone hydrochloride, as shown in Table 3, and other steps and conditions were the same as in Example 2, the effects on the yield of 2-(diphenylmethylene)quinine cyclic-3-one are as follows:
[0107] Table 3 Synthesis conditions and results of Examples 31-33
[0108] Example raw material Yield (%) Example 31 3-Quinine Cycloketone Sulfate 70 Example 32 3-Quinine cycloketone nitrate 70 Example 33 3-Quinine-cyclic ketone hydrobromide 71
[0109] Examples 31-33 show that different salts of 3-quininecycloketones can participate in the reaction normally, and 2-(diphenylmethylene)quininecyclo-3-one can be synthesized efficiently.
[0110] Example 34
[0111] Referring to S1 of Example 2, the order of feeding the raw materials was changed, while other steps and conditions remained the same as in Example 2. The effect on the yield of 2-(diphenylmethylene)quinine-3-one was as follows:
[0112] 3-quininecycloketone hydrochloride (0.5 mmol, 1.0 eq), benzophenone (0.75 mmol, 1.5 eq), and ethylene glycol diethyl ether solvent (1.5 mL) were added to a 25 mL reaction flask. The mixture was stirred, and lithium diisopropylaminol (3.0 eq) was added dropwise at 25 °C. The temperature was then raised to 100 °C and maintained for 2 hours, monitoring for the end of the reaction. After cooling, water was added, the mixture was filtered, the filter cake was collected, washed, and dried to obtain 2-(dibenzoyl)quininecyclo-3-one (97 mg, 68%).
[0113] The above results indicate that changing the order of addition of raw materials does not affect the efficient synthesis of 2-(diphenylmethylene)quinine-3-one.
[0114] Examples 35-51
[0115] Referring to step S2 of Example 1, the amine source was a methanol solution of ammonia, and the additive was acetic acid. The equivalence, pressure, reaction temperature, and reaction time were changed (Table 4), while other conditions remained the same as in Example 1. The effects on the yield and ee of (2S,3S)-2-diphenylmethylquinine-3-amine are as follows:
[0116] Table 4 Synthesis conditions and results of Examples 35-51
[0117]
[0118] The results showed that Examples 35-51 demonstrated that the reaction could proceed normally under different amounts of catalyst, amine source and additives, hydrogen pressure and reaction temperature, and successfully synthesized (2S,3S)-2-diphenylmethylquinine-3-amine.
[0119] Examples 52-63
[0120] Referring to the feeding and process of step S2 in Example 1 (pressure 5.5 MPa, temperature 125 °C, time 12 hours), with different amine sources, additives, and solvents (Table 5), and other conditions being the same as in Example 1, the effects on the yield and ee of (2S,3S)-2-diphenylmethylquinine-3-amine are as follows:
[0121] Table 5 Synthesis conditions and results of Examples 52-63
[0122]
[0123]
[0124] The results of Examples 52-62 show that the reaction can proceed normally under different types of amine sources, additives, and different solvents, with the reaction being better when trifluoroethanol (TFA) and acetic acid are used as additives.
[0125] Examples 63-75
[0126] Referring to step S2 of Example 1, the following conditions were observed: catalyst (1.5%), amine source (10 eq of ammonia-methanol solution), additive (10 eq of acetic acid), solvent (1 mL of TFE), pressure 6.0 MPa, temperature 160 °C, time 8 hours. Different chiral ruthenium catalysts were used (Table 6). Other conditions remained the same as in Example 1. The effects on the yield and ee of (2S,3S)-2-diphenylmethylquinine-3-amine are as follows:
[0127] Table 6 Synthesis conditions and results of Examples 63-75
[0128] Example catalyst Yield / % ee / % Example 63 Ru-1 76 75 Example 64 Ru-2 49 80 Example 65 Ru-3 64 73 Example 66 Ru-4 60 69 Example 67 Ru-5 64 77 Example 68 Ru-6 78 78 Example 69 Ru-7 88 72 Example 70 Ru-8 84 94 Example 71 Ru-9 50 85 Example 72 Ru-10 61 76 Example 73 Ru-11 55 85 Example 74 Ru-12 70 85 Example 75 Ru-13 75 88
[0129] Examples 63-75 show that various common chiral ruthenium catalysts can catalyze the reaction, and the resulting (2S,3S)-2-diphenylmethylquinine-3-amine has a high yield and high purity.
[0130] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.
Claims
1. A method for preparing a maloppitan intermediate, characterized in that, Includes the following steps: The 2-(diphenylmethylene)quinine-3-one shown in formula (III) reacts with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a first solvent to give the maropistan intermediate (2S,3S)-2-diphenylmethylquinine-3-amine shown in formula (IV): The chiral ruthenium catalyst is a combination of a ruthenium catalyst and a chiral ligand.
2. A method for preparing malopiptan, characterized in that, Includes the following steps: sI. The 2-(diphenylmethylene)quinine-3-one shown in formula (III) is reacted with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a first solvent to give (2S,3S)-2-diphenylmethylquinine-3-amine shown in formula (IV); sII. The (2S,3S)-2-diphenylmethylquinine-3-amine of formula (IV) undergoes a condensation reaction with 5-tert-butyl-2-methoxybenzaldehyde of formula (V) under the conditions of a second solvent and acid reagent, followed by reduction by palladium on carbon or platinum on carbon and hydrogen to obtain maloppitan of formula (VI): The chiral ruthenium catalyst is a combination of a ruthenium catalyst and a chiral ligand.
3. A method for preparing maloppitan, characterized in that, Includes the following steps: S1. Under alkaline and third solvent conditions, the 3-quinine cycloketone of formula (I) or its salt reacts with the benzophenone of formula (II) to obtain the 2-(dibenzoyl)quinine-3-one of formula (III); S2. The 2-(diphenylmethylene)quinine-3-one shown in formula (III) is reacted with an amine source and hydrogen under chiral ruthenium catalyst, optional additives, and a first solvent to give (2S,3S)-2-diphenylmethylquinine-3-amine shown in formula (IV); S3. The (2S,3S)-2-diphenylmethylquinine-3-amine of formula (IV) undergoes a condensation reaction with 5-tert-butyl-2-methoxybenzaldehyde of formula (V) under acid and second solvent conditions, followed by reduction with palladium on carbon or platinum on carbon and hydrogen to obtain maloppitan of formula (VI): The chiral ruthenium catalyst is a combination of a ruthenium catalyst and a chiral ligand.
4. The preparation method according to any one of claims 1 to 3, characterized in that, The chiral ligand is a chiral bisphosphine ligand.
5. The preparation method according to claim 4, characterized in that, The chiral bisphosphine ligand is a chiral biphenyl bisphosphine ligand or a chiral naphthalene bisphosphine ligand.
6. The preparation method according to any one of claims 1 to 3, characterized in that, The ruthenium catalyst is one or more of p-cymene dichlororuthenium, cyclooctadiene dichloride, (1,5-cyclooctadiene)(pentamethylcyclopentadiene) ruthenium chloride, ruthenium acetate, ruthenium chloride, and bis(2-methylallyl)(1,5-cyclooctadiene) ruthenium.
7. The preparation method according to any one of claims 1 to 3, characterized in that, The chiral ruthenium catalyst has at least one of the following structures:
8. The preparation method according to any one of claims 1 to 3, characterized in that, The amine source is one or more of the following: ammonium acetate, ammonium formate, ammonium benzoate, ammonium iodide, ammonium chloride, ammonium trifluoroacetate, ammonium carbonate, ammonium hexafluorophosphate, and ammonia.
9. The preparation method according to any one of claims 1 to 3, characterized in that, The first solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, toluene, trifluorotoluene, ethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, dichloromethane, dichloroethane, and water; and / or The second solvent is one or more of methanol, ethanol, isopropanol, trifluoroethanol, toluene, trifluorotoluene, ethylene glycol dimethyl ether, methyl tert-butyl ether, cyclopentyl methyl ether, methyl acetate, tetrahydrofuran, dichloromethane, dichloroethane, and water; and / or The third solvent is one or more of the following: diethyl ether, isopropyl ether, ethylene glycol dimethyl ether, ethylene glycol diethyl ether, ethylene glycol dibutyl ether, tetrahydrofuran, 2-methylfuran, 1,4-dioxane, n-hexane, n-heptane, toluene, benzene, chlorobenzene, dichloromethane, chloroform, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.
10. The preparation method according to any one of claims 1 to 3, characterized in that, The additive is one or more of tetraisopropyl titanate, acetic acid, trifluoroacetic acid, and p-toluenesulfonic acid.