CN115701431A - Preparation method of nonane compound - Google Patents
Preparation method of nonane compound Download PDFInfo
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Abstract
The invention relates to a preparation method of a nonane compound, belonging to the field of pharmaceutical chemistry. The method comprises the steps of carrying out lactamization reaction on initial materials, and then carrying out halogenation, cyclization, hydrogenation, reduction and deprotection reaction, so that a target compound can be simply and conveniently prepared; the method does not need to be split, is economical and efficient in reaction, and is beneficial to industrial application.
Description
Technical Field
The invention relates to the field of medicinal chemistry, in particular to a preparation method of a nonane compound.
Background
(S, S) -2, 8-diazabicyclo- (4, 3, 0) -nonanyl is an important group or fragment in compounds, such as moxifloxacin. Moxifloxacin is an antibacterial drug with broad quinolone antibacterial spectrum, has strong antibacterial activity to common respiratory pathogens, and is clinically used for treating acute sinusitis, acute attack of chronic bronchitis, community-acquired pneumonia, skin and skin soft tissue infection and the like; the structure is shown as the following formula:
(S, S) -2, 8-diazabicyclo- (4, 3, 0) -nonanyl, the presence of 2 chiral centers in its structure, makes its single configuration difficult to obtain. In the prior art, a resolution method is adopted to obtain a single-configuration product, so that the problems of low yield and high cost are easy to exist, and the problems of few raw material sources, high price and high cost are easy to exist in a non-resolution method. Therefore, the simple and convenient acquisition of single-configuration (S, S) -2, 8-diazabicyclo- (4, 3, 0) -nonane has bond and important influence on the preparation of medicaments such as moxifloxacin. The research on the preparation method of (S, S) -2, 8-diazabicyclo- (4, 3, 0) -nonane or the derivative thereof can obtain a target product with a single configuration, is simple and convenient to operate, easy to implement, high in yield, high in purity and low in cost, and has an important effect on the production and preparation of medicaments such as moxifloxacin.
Disclosure of Invention
The invention provides a preparation method which can be used for preparing nonane compounds.
A method for preparing a compound 07, which comprises the following steps of carrying out deprotection reaction on a compound 06 under the action of hydrogen to prepare a compound 07:
wherein R is 2 Hydrogen, tert-butyl, benzyl, (R) -1-phenylethyl, (R) -1-naphthylethyl, substituted benzyl, substituted (R) -1-phenylethyl or substituted (R) -1-naphthylethyl.
In the deprotection reaction, the pressure of hydrogen can be 1MPa to 4MPa. In the deprotection reaction, palladium on carbon or the like may be added as a catalyst.
In the deprotection reaction, the reaction temperature may be 20 ℃ to 80 ℃. In some embodiments, the deprotection reaction is carried out at a temperature of 30 ℃ to 80 ℃. In some embodiments, the deprotection reaction is carried out at a temperature of 35 ℃ to 75 ℃. In some embodiments, the deprotection reaction is carried out at a temperature of 40 ℃ to 70 ℃. In some embodiments, the deprotection reaction is carried out at a temperature of 50 ℃ to 60 ℃. In some embodiments, the deprotection reaction is carried out at a temperature of 60 ℃ to 80 ℃.
In the deprotection reaction, the reaction solvent may be methanol, ethanol or a combination thereof. The reaction solvent may be used in an amount of 3ml to 50ml per gram of compound 06. In some embodiments, the reaction solvent is used in an amount of 8ml to 20ml per gram of compound 06.
In some embodiments, compound 06 is reacted at 35 ℃ to 80 ℃ under the action of palladium carbon and hydrogen in methanol or ethanol, after the reaction is completed, the reaction solution is filtered, and the filtrate is concentrated and distilled to prepare compound 07.
A method of making a compound comprising: under the action of a reducing agent, the compound 05 undergoes reduction reaction and then post-treatment to prepare a compound 06,
wherein R is 2 As defined above.
In the reduction reaction, the reducing agent can be lithium aluminum hydride (LiAlH) 4 ) Sodium borohydride, potassium borohydride and at least one of sodium borohydride and boron trifluoride or a complex combination thereof. In some embodiments, the reducing agent is a combination of sodium borohydride and boron trifluoride. In some embodiments, the reducing agent is a combination of sodium borohydride and boron trifluoride tetrahydrofuran complex, and the addition of boron trifluoride or its complex facilitates the activation reaction and the formation and obtaining of the desired product.
The feed molar ratio of compound 05 to reducing agent can be 1. In some embodiments, the molar ratio of compound 05 to reducing agent charged can be 1.
The reaction temperature of the reduction reaction may be 0 ℃ to 100 ℃. In some embodiments, the reaction temperature of the reduction reaction may be from 50 ℃ to 100 ℃. In some embodiments, the reaction temperature of the reduction reaction may be from 0 ℃ to 40 ℃. In some embodiments, the reaction temperature of the reduction reaction may be from 15 ℃ to 40 ℃.
In the reduction reaction, the reaction solvent may be at least one of Tetrahydrofuran (THF), 2-methyltetrahydrofuran and toluene. In some embodiments, in the reduction reaction, the reaction solvent is a mixed solution of tetrahydrofuran and toluene. In some embodiments, in the reduction reaction, the reaction solvent is a mixed solution of 2-methyltetrahydrofuran and toluene. In some embodiments, in the reduction reaction, the reaction solvent is tetrahydrofuran.
The reaction solvent may be used in an amount of 5ml to 40ml per gram of compound 05. In some embodiments, the reaction solvent is used in an amount of 8ml to 30ml per gram of compound 05 to facilitate the reaction process and product yield.
After the reduction reaction is completed, the post-treatment may include: at-5 deg.C, adding aqueous alkali solution into the reaction solution to adjust pH to be greater than 7, stirring, adding solvent such as ethyl acetate, isopropyl acetate, toluene or dichloromethane, extracting, optionally drying the organic phase with magnesium sulfate, and concentrating to obtain crude compound 06. The aqueous alkali solution may be at least one of an aqueous sodium hydroxide solution, an aqueous potassium hydroxide solution and an aqueous barium hydroxide solution. In some embodiments, after the reduction reaction is completed, the post-treatment comprises adding an acid such as hydrochloric acid, stirring, and then adding an aqueous alkali solution to the reaction solution. In some embodiments, the crude compound 06 is used directly in the next step or is stirred with ethyl acetate or isopropyl acetate, filtered, and the resulting solid is dried to provide compound 06.
A method of making a compound comprising: in the presence of alkali and a catalyst, the compound 04 and a hydrogenation reagent undergo hydrogenation reaction, and after the reaction is finished, the compound 05 is prepared by post-treatment,
wherein R is 2 As defined above.
The base may be at least one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, triethylamine, N-methylmorpholine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine and 1, 8-diazabicyclo [5.4.0] undec-7-ene (DBU). In some embodiments, the base is at least one of sodium carbonate, pyridine, 2-methylpyridine, and 2, 6-dimethylpyridine, facilitating the formation and availability of the desired product. In some embodiments, the base is preferably pyridine, which facilitates the formation and availability of the desired product and control of the manufacturing operation. In some embodiments, the base is preferably sodium carbonate, which facilitates the formation and acquisition of the target product and control of the production operation.
The catalyst may be platinum carbon, palladium carbon or the like. In some embodiments, the catalyst is preferably palladium on carbon.
In the hydrogenation reaction, the hydrogenation reagent may be at least one of hydrogen gas, ammonium formate and sodium formate. In some embodiments, the hydrogenation reagent is preferably hydrogen, which facilitates the production of the product.
In the hydrogenation reaction, the pressure of hydrogen can be controlled to be 1MPa-4MPa. In some embodiments, the pressure of hydrogen in the hydrogenation reaction may be controlled to be 2MPa to 3MPa.
The feed molar ratio of compound 04 to base can be 1. In some embodiments, the charged molar ratio of compound 04 to base is 1.5-1. In some embodiments, the molar ratio of compound 04 to base charged is 1.
In the hydrogenation reaction, the reaction solvent may be methanol, ethanol or a combination thereof.
In the hydrogenation reaction, the reaction temperature can be controlled to be 0-80 ℃. In some embodiments, the reaction temperature during the hydrogenation reaction is from 20 ℃ to 70 ℃. In some embodiments, the reaction temperature during the hydrogenation reaction is from 20 ℃ to 60 ℃. In some embodiments, the reaction temperature during the hydrogenation reaction is from 40 ℃ to 70 ℃. In some embodiments, the reaction temperature during the hydrogenation reaction is from 20 ℃ to 50 ℃.
The reaction solvent may be 3ml to 30ml per gram of compound 04. In some embodiments, the reaction solvent is 5ml to 15ml per gram of compound 04, which facilitates the reaction operation and performance.
In some embodiments, the hydrogenation reaction, after completion of the reaction, the post-treatment comprises: the reaction solution was filtered, and the filtrate was concentrated to obtain a crude compound 05. In some embodiments, the hydrogenation reaction, after completion of the reaction, the post-treatment comprises: and mixing the crude compound 05 with isopropyl acetate, stirring, filtering, and drying the obtained solid to obtain a compound 05 product. In some embodiments, crude compound 05 is dissolved in ethyl acetate or isopropyl acetate, washed with water, and the organic layer is distilled to afford compound 05.
In some embodiments, compound 04 is hydrogenated with hydrogen in ethanol in the presence of an organic base and palladium on carbon as a catalyst, after the reaction is completed, the reaction solution is filtered, the filtrate is concentrated, ethyl acetate or isopropyl acetate is added, stirring and filtering are carried out, and the obtained solid is dried to obtain compound 05.
A method of making a compound comprising: the compound 03 and an amine reagent undergo cyclization reaction, and after the reaction is finished, the compound 04 is prepared through post-treatment,
wherein, X is chlorine, bromine or iodine; r 1 Is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted benzyl; r is 2 As defined above.
The amine reagent may be: ammonia or an ammonia-containing solution such as ammonia water or ammonia in methanol, tert-butylamine, benzylamine, (R) -1-phenylethylamine, (R) -1-naphthylethylamine or other suitable amines. In some embodiments, the amine reagent is at least one of aqueous ammonia, a methanol solution of ammonia, tert-butylamine, benzylamine, (R) -1-phenylethylamine, and (R) -1-naphthylethylamine. In some embodiments, the amine reagent is at least one of aqueous ammonia, a methanol solution of ammonia, benzylamine, and (R) -1-phenylethylamine. In some embodiments, the amine reagent is preferably (R) -1-phenylethylamine, facilitating the production and availability of the desired product.
The molar feed ratio of compound 03 to amine reagent can be 1. In some embodiments, the compound 03 to amine reagent feed molar ratio is 1.05 to 1. In some embodiments, the compound 03 to amine reagent feed molar ratio is 1. In some embodiments, the molar ratio of compound 03 to amine reagent charged is 1. In some embodiments, the dosing mole ratio of compound 03 to amine reagent is 1.01-1. In some embodiments, the compound 03 and amine reagent are dosed at a molar ratio of 1. In some embodiments, the compound 03 to amine reagent feed molar ratio is 1.
In the cyclization reaction, an acid-binding agent can be added, and the acid-binding agent can be the amine reagent, and also can be triethylamine, sodium carbonate, potassium carbonate, sodium bicarbonate or other suitable alkali capable of reacting with acid and the like. In some embodiments, the acid scavenger is triethylamine, which facilitates post-treatment operations. In some embodiments, the acid scavenger is sodium carbonate, which facilitates post-processing operations. The feeding molar ratio of the acid-binding agent to the compound 03 can be 0.5-1.2. In some embodiments, the acid scavenger is triethylamine, and the molar ratio of triethylamine to compound 03 fed is 1. In some embodiments, the acid scavenger is sodium carbonate, and the dosing molar ratio of sodium carbonate to compound 03 is 0.5-0.65.
In the cyclization reaction, the reaction solvent may be methanol, ethanol, isopropanol or acetonitrile, or a mixed solvent of at least one of them and water. In some embodiments, the reaction solvent is ethanol, acetonitrile or a mixture of at least one of them and water in the cyclization reaction, which is favorable for the reaction.
The amount of the reaction solvent used may be 3ml to 40ml, or 5ml to 20ml, per gram of the compound 03.
The reaction temperature of the cyclization reaction can be controlled to be 0-40 ℃. In some embodiments, the reaction temperature of the cyclization reaction is controlled to be 15 ℃ to 35 ℃ or 20 ℃ to 30 ℃.
In some embodiments, after completion of the cyclization reaction, the post-treatment may include: the reaction solution is mixed with water or an aqueous acid solution, stirred, filtered, and the solid is washed with water and then dried to remove the solvent, yielding compound 04.
In some embodiments, after completion of the cyclization reaction, the post-treatment comprises: mixing the reaction solution with water or acid water solution, extracting with ester solvent, removing solvent from the organic phase to obtain compound 04, or concentrating the organic phase, stirring, filtering, and drying to obtain compound 04. The ester solvent may be ethyl acetate, isopropyl acetate, or a combination thereof.
A method of making a compound comprising: the compound 02 and a halogenating reagent are subjected to halogenation reaction, and after the reaction is finished, the compound 03 is prepared through post-treatment,
wherein R is 1 And X are each as defined above.
In some embodiments, X is preferably bromine, which is more favorable for the reaction and product to proceed.
The halogenating agent can be at least one of iodine, bromine, N-bromosuccinimide, N-chlorosuccinimide, N-iodosuccinimide, dibromohydantoin, sodium dibromoisocyanurate, chlorobromoisocyanuric acid and sodium dichloroisocyanurate. In some embodiments, the halogenating agent is at least one of iodine, bromine, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide, dibromohydantoin. In some embodiments, the halogenating agent is at least one of bromine, N-bromosuccinimide, and dibromohydantoin, facilitating the formation and availability of the target product.
The charging molar ratio of the compound 02 to the halogenating agent can be 1. In some embodiments, the feed molar ratio of compound 02 to halogenating agent is 1. In some embodiments, the feed molar ratio of compound 02 to halogenating agent is 1.
In the halogenation reaction, the reaction solvent may be dichloromethane, toluene or a combination thereof.
The reaction solvent may be used in an amount of 3ml to 30ml, or 5ml to 25ml, per gram of compound 02.
The reaction temperature of the halogenation reaction can be controlled to be-5 ℃ to 40 ℃. In some embodiments, the reaction temperature of the halogenation reaction is between 0 ℃ and 35 ℃, or between 15 ℃ and 30 ℃.
In some embodiments, in the halogenation reaction, after the reaction is completed, the post-treatment may comprise: quenching the reaction with saturated aqueous sodium thiosulfate solution, separating the solution, washing the organic phase with water, concentrating, mixing the obtained product with isopropanol, stirring for 0.5-8 hours, filtering, and drying the obtained solid to obtain the compound 03.
A method of making a compound comprising: performing lactamization reaction on the compound 01 and acryloyl chloride, performing post-treatment after the reaction is finished to prepare a compound 02,
wherein R is 1 As defined above.
The feeding molar ratio of the compound 01 to the acryloyl chloride can be 1-1. In some embodiments, the feed molar ratio of compound 01 to acryloyl chloride can be 1.
In the lactamization reaction, the reaction solvent may be N, N-Dimethylformamide (DMF). The reaction solvent may be used in an amount of 5ml to 35ml per gram of compound 01.
In the lactamization reaction, the reaction temperature may be 0 ℃ to 40 ℃. In some embodiments, the reaction temperature in the lactamization reaction is from 20 ℃ to 30 ℃.
After the lactamization reaction is completed, the post-treatment may include: quenching the reaction with saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate or isopropyl acetate, separating the solution, washing the organic phase with water, and removing the solvent from the organic phase to obtain a compound 02. The organic phase obtained after the solvent is removed can be directly used in the next reaction, and can also be purified to obtain the compound 02 with higher quality, and the crude product can be purified by methods such as pulping, crystallization, recrystallization or column chromatography to obtain the compound 02 with higher quality.
Compound 01, as described above, can be prepared by any suitable method. In some embodiments, (R) -1-phenylethylamine is reacted with compound 00 at 50 ℃ to 100 ℃, after the reaction is completed, a solvent such as dichloromethane, toluene, or ethyl acetate is added to dilute, separate, concentrate the organic phase, remove the solvent, and optionally purify to prepare compound 01:
wherein R is 1 As defined above.
In the present invention, the alkyl group may be a methyl group, an ethyl group, a n-propyl group, an isopropyl group, a tert-butyl group, a n-hexyl group or the like.
In the present invention, the cycloalkyl group may be a cyclopropyl group, a cyclobutyl group, a cyclopentyl group or a cyclohexyl group.
The substitution may be any substitution by alkyl, alkoxy or halogen.
In some embodiments, the aforementioned X is chlorine or bromine. In some embodiments, R 1 Preferably methyl or ethyl. In some embodiments, the aforementioned R 2 Preferably hydrogen, tert-butyl, benzyl, (R) -1-phenylethyl or (R) -1-naphthylethyl. In some embodiments, the aforementioned R 2 Preferably hydrogen, benzyl or (R) -1-phenylethyl. In some embodiments, the aforementioned R 2 More preferably (R) -1-phenylethyl. The preferred groups and corresponding reagents and reactions are adopted, so that the target compound is obtained, the cost is reduced, and the industrial production is realized.
The method of the invention prepares the target compound by a brand new route, can simply obtain the target compound with a single configuration, can avoid the loss of chiral resolution, improve the yield, relatively reduce the cost and is beneficial to industrial production.
In the description herein, references to the description of the term "one embodiment," "some embodiments," "an example," "a specific example," or "some examples," etc., mean that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the invention. In this specification, the schematic representations of the terms used above are not necessarily intended to refer to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, various embodiments or examples and features of different embodiments or examples described in this specification can be combined and combined by one skilled in the art without contradiction.
In the present invention, the expression "compound a" and "compound represented by formula a" means the same compound.
In the present invention, optional representation may or may not be performed.
In the invention, the room temperature refers to the ambient temperature and is 15-35 ℃, or 20-30 ℃, or 25-28 ℃.
In the present invention, when the remaining amount of raw materials in the reaction does not exceed 5%, or 2%, or 1%, or 0.5% of the charged amount, it can be regarded as the completion of the reaction, and the remaining amount of raw materials can be detected by high performance liquid chromatography or thin layer chromatography.
Detailed Description
In order to make the technical solutions of the present invention better understood by those skilled in the art, some non-limiting examples are further disclosed below, and the present invention is further described in detail.
The reagents used in the present invention are either commercially available or can be prepared by the methods described herein.
In the present invention, mmol means mmol, h means h, min means min, g means g, ml means ml, DMF means N, N-dimethylformamide, THF means tetrahydrofuran, DCM means dichloromethane, EA means ethyl acetate, bn means benzyl.
ee: enantiomeric excess (enantiomeric excess); dr: diastereomeric excess (diasteromeric processes).
LC-MS: liquid phase-mass spectrometry.
Example 1
Adding 10.00g of ethyl acetoacetate and 9.30g of (R) -1-phenylethylamine into a 250mL single-neck bottle, starting stirring, raising the temperature to 90 ℃ for reaction for 3h, adding 50mL of dichloromethane for dilution after the reaction is finished, separating liquid, and distilling an organic phase at 50 ℃ under reduced pressure to obtain a compound 01-1:19.10g, yellow oil, purity: 98%, yield: 99 percent; and (3) detection:
LC-MS+H + ：234.15；
1 H NMR(400MHz,CDCl 3 )δ8.97(d,J＝6.2Hz,1H),7.36-7.28(m,2H),7.28-7.19(m,3H),4.71-4.57(m,1H),4.47(s,1H),4.13(qd,J＝7.1,1.6Hz,2H),1.76(s,3H),1.51(d,J＝6.8Hz,3H),1.27(s,3H)；
13 C NMR(151MHz,CDCl 3 )δ170.68,161.50,144.98,128.80,127.09,125.42,83.16,58.39,52.84,24.95,19.68,14.67。
example 2
Adding 19.10g of the compound 01-1 into 190ml of DMF, stirring at room temperature under the protection of nitrogen, slowly dropwise adding 7.80g of acryloyl chloride, reacting at room temperature for 3 hours after the addition is finished, and finishing the reaction; adding saturated sodium bicarbonate aqueous solution 100ml for quenching, adding ethyl acetate 200ml for extraction, separating, washing an organic phase twice with water (100ml. Times.2), and evaporating the solvent under reduced pressure to obtain a compound 02-1:26.30g, yellow oil, purity: 85%, yield: 95 percent; and (3) detection:
LC-MS+H + ：288.20；
1 H NMR(400MHz,CDCl 3 )δ7.31(t,J＝7.6Hz,1H),7.25-7.19(m,1H),5.89(q,J＝6.9Hz,1H),4.17(q,J＝7.0Hz,1H),2.66-2.45(m,2H),2.18(s,1H),1.78(d,J＝7.1Hz,1H),1.28(t,J＝7.1Hz,2H)；
13 C NMR(101MHz,CDCl 3 )δ171.48,171.47,167.33,167.32,149.25,141.63,128.49,126.70,125.73,111.33,60.23,51.48,32.36,21.04,18.03,17.71,14.28。
example 3
Adding 26.30g of compound 02-1 (purity: 85%) into 200ml of dichloromethane, stirring at room temperature, adding 13.80g of N-bromosuccinimide in batches, reacting at room temperature for 1h after the addition is finished, adding 20ml of saturated sodium thiosulfate aqueous solution to quench the reaction, separating the solution, washing an organic phase with 150ml of water for 1 time, and concentrating the organic phase to evaporate the solvent; to the resultant was added 160ml of isopropyl alcohol, stirred at room temperature for 3.0 hours, then filtered, and the filter cake was dried under vacuum at 40 ℃ to obtain compound 03-1:21.31g, white solid, purity: 99%, yield: 75 percent.
And (3) product detection: LC-MS + H + ：367.00；
1 H NMR(400MHz,CDCl 3 )δ7.39-7.30(m,2H),7.26(dd,J＝14.0,7.2Hz,3H),5.88(d,J＝7.0Hz,1H),4.69(d,J＝10.7Hz,1H),4.35(d,J＝10.6Hz,1H),4.24(q,J＝7.1Hz,2H),2.75-2.61(m,2H),2.56-2.44(m,2H),1.88(d,J＝7.1Hz,3H),1.32(t,J＝7.1Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ171.31,165.88,148.45,140.69,128.66,127.12,125.95,115.26,61.05,52.07,31.68,25.63,21.26,18.04,14.16。
Example 4-1
Adding 16.00g of the compound 03-1 into 130ml of ethanol, adding 27.00g of ammonia water (28%) into the mixture at room temperature under stirring, and reacting for 1 hour until the reaction is finished; adding 200ml of water for pulping, separating out a large amount of solid, stirring for 3 hours at room temperature, filtering, washing the solid with water, and drying in vacuum at 40 ℃ to obtain a compound 04-1:10.10g, off-white solid, purity: 99%, yield: 90 percent; and (3) detection:
LC-MS+H + ：257.10；
1 H NMR(600MHz,CDCl 3 )δ7.35(t,J＝7.5Hz,2H),7.32–7.27(m,1H),7.25(d,J＝7.7Hz,2H),6.13(d,J＝7.1Hz,1H),3.80(d,J＝18.5Hz,1H),3.12(d,J＝18.5Hz,1H),2.79(dd,J＝12.3,5.1Hz,2H),2.63-2.47(m,2H),2.07-1.98(m,1H),1.68(d,J＝7.2Hz,3H)。
example 4 to 2
Adding 16.00g of the compound 03-1 into 130ml of acetonitrile, adding 14.00g of benzylamine under stirring at room temperature, and reacting for 1 hour to finish the reaction; adding 2mol/l hydrochloric acid aqueous solution to adjust the pH value to 1-3, extracting with 150ml ethyl acetate, concentrating an organic phase to remove the solvent, and obtaining a compound 04-2:14.50g, light yellow solid, purity: 99%, yield: 96 percent; and (3) detection:
LC-MS+H + ：347.10；
1 H NMR(400MHz,CDCl 3 )δ7.26(dd,J＝13.1,6.6Hz,6H),7.17(d,J＝7.6Hz,2H),7.09-7.02(m,2H),5.98(d,J＝7.1Hz,1H),4.43(dd,J＝35.9,15.1Hz,2H),3.62(d,J＝18.1Hz,1H),2.96(d,J＝18.1Hz,1H),2.80-2.72(m,2H),2.59(dd,J＝12.1,4.6Hz,2H),1.61(d,J＝7.2Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ170.10,169.36,150.42,139.35,137.05,128.76,128.70,127.74,127.72,127.47,126.51,111.70,50.32,48.04,45.68,31.80,17.26,16.24。
examples 4 to 3
The method A comprises the following steps: adding 16.00g of the compound 03-1 into 130ml of acetonitrile, adding 15.89g of (R) -1-phenylethylamine into the mixture at room temperature under stirring, and reacting for 1h to finish the reaction; adding 2mol/l hydrochloric acid aqueous solution to adjust the pH value to 1-2, extracting 180ml of ethyl acetate, concentrating an organic phase to remove the solvent, and obtaining a compound 04-3:15.50g, pale yellow viscous semi-solid, purity: 98%, yield: 98 percent.
The method B comprises the following steps: dropwise adding 5.56g of (R) -1-phenylethylamine into 16.00g of compound 03-1, 100ml of ethyl acetate and 4.86g of triethylamine, and reacting at 65 ℃ for 7 hours after the addition is finished to finish the reaction; the reaction system is turned to room temperature, 50ml of water is added, and the mixture is stirred for 30min and then is kept stand for liquid separation; adding 50ml of water and 6mol/l of dilute hydrochloric acid to adjust the pH value of the system to 1-2, stirring for 30min, standing, separating, washing an organic phase once by using 50ml of water, and performing reduced pressure spin drying on the organic phase at 50 ℃ to obtain a compound 04-3:16.06g, reddish brown viscous semisolid with purity 99.11% and yield >100% (containing small amount of solvent).
And (3) product detection: LC-MS + H + ：361.10；
1 H NMR(400MHz,CDCl 3 )δ7.39–7.25(m,6H),7.17(t,J＝8.2Hz,4H),5.99(d,J＝7.1Hz,1H),5.41(d,J＝7.1Hz,1H),3.32(d,J＝18.2Hz,1H),2.95(d,J＝18.2Hz,1H),2.82-2.67(m,2H),2.57(ddd,J＝9.4,5.2,1.6Hz,2H),1.55(d,J＝7.2Hz,3H),1.29(d,J＝7.1Hz,3H)；
13 C NMR(151MHz,CDCl 3 )δ170.08,169.00,150.43,140.78,139.47,128.77,128.66,127.80,127.52,126.85,126.70,111.86,50.27,48.83,44.43,31.78,17.28,17.13,16.16。
Example 5-1
10.00g of Compound 04-1, 1.00g 10% Pd/C was added to 70ml of ethanol, hydrogen gas was charged to 3.0MPa, and the reaction was carried out at 80 ℃ for 20 hours, and after the reaction was completed, detection was carried out to find the dr value of the product: 30/70; filtration, concentration of the filtrate and purification by silica gel column chromatography, eluent ethyl acetate/petroleum ether =1 (volume ratio), yielded compound 05-1:9.10g, colorless oil, purity: 95%, yield: 91 percent(ii) a And (3) detection: MS + H + ：259.10。
Example 5-2
The method A comprises the following steps: 10.00g of the compound 04-2, 0.50g of 10% Pd/C and 10.71g of sodium carbonate were added to 100ml of ethanol, the mixture was charged with hydrogen gas to 2.0MPa, the reaction was carried out at room temperature for 15 hours, and after completion of the reaction, the product dr value was measured: 2/1; filtration, concentration of the filtrate, purification by silica gel column chromatography, eluent ethyl acetate/petroleum ether =1 (volume ratio), to obtain compound 05-2:6.00g, colorless oil, purity: 96%, yield: 60 percent.
The method B comprises the following steps: 5.00g of compound 04-2, 0.50g of 10% palladium on carbon (Pd/C) and 2.74g of pyridine are added into 50ml of ethanol, hydrogen is charged to 2.0MPa, the reaction is carried out for 72h at 45 ℃, and the reaction is finished and detected, and the dr value of a product: 4.4/1; filtration and concentration, the resultant was purified by silica gel column chromatography, eluting with ethyl acetate/petroleum ether =1 (volume ratio), to give compound 05-2:3.90g, yellow oil, purity: 95%, yield: 78 percent.
And (3) product detection: LC-MS + H + ：349.20；
1 H NMR(400MHz,CDCl 3 )δ7.24(dt,J＝9.1,7.0Hz,6H),7.13(dd,J＝6.5,4.6Hz,4H),5.89(q,J＝7.1Hz,1H),4.50(d,J＝14.6Hz,1H),4.25(d,J＝14.6Hz,1H),3.77(td,J＝9.0,5.8Hz,1H),3.51-3.39(m,1H),2.97(dd,J＝10.2,5.8Hz,1H),2.58(t,J＝7.6Hz,1H),2.48-2.33(m,1H),2.23(dd,J＝13.5,3.1Hz,1H),2.08-1.95(m,1H),1.79(tdd,J＝13.2,7.4,3.5Hz,1H),1.36(d,J＝7.2Hz,3H)；
05-2 enantiomer: 1 H NMR(400MHz,CDCl 3 )δ7.19(d,J＝3.6Hz,8H),6.94(dd,J＝6.5,2.8Hz,2H),5.97(q,J＝7.1Hz,1H),4.30(d,J＝14.4Hz,1H),4.08–3.95(m,2H),2.77(t,J＝10.1Hz,1H),2.39(t,J＝4.0Hz,1H),2.27(d,J＝7.2Hz,2H),2.16(ddd,J＝13.3,9.0,4.4Hz,1H),2.03(ddd,J＝16.2,11.9,4.4Hz,1H),1.87-1.79(m,1H),1.42(d,J＝7.1Hz,3H)。
examples 5 to 3
The method A comprises the following steps: adding 10.00g of the compound 04-3, 1.00g 10% Pd/C and 10.30g of sodium carbonate into 100ml of ethanol, charging hydrogen to 2.0MPa, reacting at room temperature for 70h, detecting when the reaction is finished, and obtaining a dr value of a product: 85/15; filtering, concentrating the filtrate to dryness to obtain a crude product, adding 60ml of isopropyl acetate, stirring at room temperature for 3.0h, filtering, and drying to obtain a compound 05-3:7.00g, white solid, purity: 99%, yield: 70 percent.
The method B comprises the following steps: 1.00g of the compound 04-3, 0.30g 10% Pd/C and 1.30g of sodium bicarbonate were added to 15ml of ethanol, the mixture was charged with hydrogen to 3.0MPa, and the reaction was carried out at room temperature for 70 hours, after completion of the reaction, and the product dr value was measured: 83/17; filtering, concentrating the filtrate to dryness to obtain crude product, adding isopropyl acetate 6ml, stirring at room temperature for 3.0h, filtering, and drying to obtain compound 05-3:0.60g, white solid, purity: 99%, yield: 60 percent.
The method C comprises the following steps: 5.00g of Compound 04-3, 0.50g of 10% Pd/C and 3.30g of pyridine were added to 50ml of ethanol, the mixture was charged with hydrogen gas to 2.0MPa, and the reaction was carried out at room temperature for 70 hours, after completion of the reaction, and the product dr value was measured: 92/8; filtering, concentrating the filtrate to dryness to obtain a crude product, adding 50ml of isopropyl acetate, stirring at room temperature for 3.0h, filtering, and drying to obtain a compound 05-2:4.00g, white solid, purity: 99%, yield: 80 percent.
And (3) product detection: LC-MS + H + ：363.20；
1 H NMR(400MHz,CDCl 3 )δ7.26(ddd,J＝9.7,6.0,2.9Hz,4H),7.20(t,J＝7.0Hz,4H),7.13(d,J＝7.6Hz,2H),5.84(q,J＝7.1Hz,1H),5.50(q,J＝7.1Hz,1H),3.76(td,J＝8.9,5.8Hz,1H),3.56-3.44(m,1H),2.67-2.49(m,2H),2.34(d,J＝15.4Hz,1H),2.21(dd,J＝12.8,3.1Hz,1H),1.91-1.66(m,2H),1.41(d,J＝7.2Hz,3H),1.31(d,J＝7.2Hz,3H)；
05-3 enantiomer: 1 H NMR(400MHz,CDCl 3 )δ7.24-7.13(m,8H),6.95(dd,J＝6.5,2.6Hz,2H),6.01(q,J＝7.1Hz,1H),5.25(q,J＝7.1Hz,1H),3.90(td,J＝8.3,6.1Hz,1H),2.77-2.63(m,1H),2.40(dt,J＝17.1,5.4Hz,1H),2.31(dd,J＝10.6,6.0Hz,1H),2.21-2.08(m,2H),1.96(dd,J＝10.6,8.2Hz,1H),1.84(tdd,J＝10.5,9.3,4.5Hz,1H),1.66(s,3H),1.41(d,J＝7.1Hz,3H)。
example 6-1
Adding 6.62g of lithium aluminum hydride into 65ml of dry tetrahydrofuran, stirring at 0 ℃ under the protection of nitrogen, slowly adding 9.00g of tetrahydrofuran (45 ml) solution of a compound 05-1, heating to room temperature after the addition, and reacting for 20 hours to finish the reaction; slowly dropping 10mLH at 0 deg.C 2 Quenching with oxygen, adding 20mL15% sodium hydroxide aqueous solution (mass fraction) and 30mLH 2 And O, stirring for 30min, adding 60ml of ethyl acetate for dilution, drying with anhydrous magnesium sulfate, filtering, concentrating the filtrate under reduced pressure to obtain a crude product, adding 30ml of ethyl acetate, stirring and pulping at room temperature, separating out a solid, filtering, and drying to obtain a compound 06-1:6.42g, off-white solid, purity: 99%, dr value: 99, yield: 80 percent; and (3) detection:
LC-MS+H + ：231.25；
1 H NMR(600MHz,CDCl 3 )δ9.69(s,1H),7.40(d,J＝7.6Hz,2H),7.34-7.27(m,2H),7.22(d,J＝1.8Hz,1H),3.80(d,J＝2.4Hz,1H),3.62(s,1H),3.52(dd,J＝11.4,5.8Hz,1H),3.29(d,J＝3.1Hz,2H),3.20(dd,J＝11.8,6.3Hz,1H),2.38(d,J＝43.7Hz,3H),1.72-1.46(m,3H),1.46-1.27(m,4H)。
example 6 to 2
The method A comprises the following steps: adding 2.62g of lithium aluminum hydride into a dry tetrahydrofuran (16 ml) and toluene (80 ml) mixed solvent, slowly adding 10.00g of tetrahydrofuran (30 ml) solution of a compound 05-3 at 0 ℃ under stirring in the presence of nitrogen, raising the temperature to 90 ℃ after the addition, and reacting for 15 hours to finish the reaction; slowly dropwise adding a solution of 2.76g of sodium hydroxide and 1.24mL of water at 0 ℃ to quench the reaction, stirring for 30min, adding anhydrous sodium sulfate, drying, filtering, and distilling the filtrate under reduced pressure to obtain a compound 06-3:9.00g, yellow oil, purity 92%, yield 98%; dr >99%.
The method B comprises the following steps: adding 10.00g of compound 05-3 into 120ml of tetrahydrofuran, adding 2.62g of sodium borohydride, stirring at 0 ℃ under the protection of nitrogen, slowly adding 19.30g of boron trifluoride tetrahydrofuran solution (50% by mass of tetrahydrofuran solution), heating to room temperature after the addition, reacting for 15 hours, and finishing the reaction; slowly dropwise adding 20ml of 2mol/l dilute hydrochloric acid at 0 ℃, stirring for 30min after the dropwise adding is finished, dropwise adding 10% NaOH aqueous solution to adjust the pH to 8-9, extracting with 100ml of dichloromethane, separating liquid, and concentrating the organic phase under reduced pressure to obtain a compound 06-3:8.90g, yellow oil, 96% purity, 97% yield, dr >99%.
And (3) product detection: MS + H + ：335.50；
1 H NMR(400MHz,DMSO)δ7.23(dt,J＝14.3,10.6Hz,10H),3.55(dd,J＝13.0,6.4Hz,1H),3.55(dd,J＝13.0,6.4Hz,1H),3.32(dd,J＝12.8,6.3Hz,1H),3.00(dd,J＝13.8,6.9Hz,1H),2.75-2.66(m,1H),2.62-2.53(m,1H),2.39(dd,J＝16.6,10.7Hz,2H),2.30(dd,J＝8.5,3.8Hz,1H),1.90(s,1H),1.56(s,1H),1.48-1.35(m,3H),1.29-1.18(m,6H),1.14(d,J＝15.4Hz,1H)；
13 C NMR(101MHz,DMSO)δ146.39(s),143.82(s),128.62(s),128.43(s),127.83(s),127.27(s),127.06(s),126.98(s),65.24(s),60.54(s),58.87(s),56.19(s),50.48(s),42.62(s),36.86(s),25.83(s),24.28(s),23.56(s),20.96(s)。
Example 7-1
Adding 2.00g of the compound 06-1 and 0.30g of 10% Pd/C into 20ml of methanol, filling hydrogen under normal pressure, reacting at 45 ℃ for 15h, and finishing the reaction; cooling to room temperature, filtering, and distilling at 60 ℃ under reduced pressure to obtain a compound 07-1:0.98g, oil, purity: 99%, ee: 99%, yield: 90 percent; and (3) detection:
example 7-2
Adding 20.00g of the Pd/C accounting for 06-3 and 3.00g10 percent of the compound into 200ml of ethanol, filling 2.0MPa of hydrogen, and reacting for 15 hours at 60 ℃ to finish the reaction; cooling to room temperature, filtering, concentrating under reduced pressure to obtain a crude product, and distilling under reduced pressure at 55 ℃ to obtain a compound 07-1:6.80g, oil, purity: 99%, ee: 99%, yield: 90 percent; and (3) detection:
MS+H + ：127.15；
1 H NMR(400MHz,DMSO)δ2.96(t,J＝3.9Hz,1H),2.84–2.64(m,4H),2.58(d,J＝11.0Hz,1H),2.41(td,J＝11.9,2.6Hz,1H),1.91-1.81(m,1H),1.60(dt,J＝9.0,4.5Hz,2H),1.47-1.34(m,1H),1.32-1.22(m,1H)；
13 C NMR(151MHz,DMSO)δ57.78(s),53.53(s),47.89(s),44.91(s),38.15(s),23.82(s),22.15(s)。
the method of the present invention has been described with reference to the preferred embodiments. Those skilled in the art can modify the process parameters appropriately to practice the invention in view of the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to those skilled in the art are deemed to be included within the invention.
Claims (10)
1. A method of preparing a compound comprising at least one of the following a-c:
a) The compound 03 and an amine reagent undergo cyclization reaction, and after the reaction is finished, the compound 04 is prepared by post-treatment,
the amine reagent is at least one of ammonia, ammonia water, methanol solution of ammonia, tert-butylamine, benzylamine, (R) -1-phenylethylamine and (R) -1-naphthylethylamine;
b) In the presence of alkali and a catalyst, the compound 04 and a hydrogenation reagent undergo hydrogenation reaction, and after the reaction is finished, the compound 05 is prepared by post-treatment,
the hydrogenation reagent is at least one of hydrogen, ammonium formate and sodium formate; the alkali is at least one of sodium carbonate, potassium carbonate, sodium bicarbonate, sodium acetate, potassium acetate, triethylamine, N-methylmorpholine, pyridine, 2-methylpyridine, 2, 6-dimethylpyridine and 1, 8-diazabicyclo [5.4.0] undec-7-ene;
c) Under the action of a reducing agent, the compound 05 undergoes reduction reaction and then post-treatment to prepare a compound 06,
the reducing agent is at least one of lithium aluminum hydride, sodium borohydride, potassium borohydride and a combination of sodium borohydride and boron trifluoride or a complex compound thereof;
wherein, X is chlorine, bromine or iodine; r 1 Is substituted or unsubstituted C1-C6 alkyl, substituted or unsubstituted C3-C6 cycloalkyl, or substituted or unsubstituted benzyl; r 2 Hydrogen, tert-butyl, benzyl, (R) -1-phenylethyl, (R) -1-naphthylethyl, substituted benzyl, substituted (R) -1-phenylethyl or substituted (R) -1-naphthylethyl.
2. The method of claim 1, further comprising: the compound 02 and a halogenating reagent are subjected to halogenation reaction, after the reaction is finished, the compound 03 is prepared by post-treatment,
wherein the halogenating agent is iodine, bromine, N-bromosuccinimide, N-chlorosuccinimide, or N-iodosuccinimideAt least one of imide, dibromohydantoin, sodium dibromoisocyanurate, chlorobromoisocyanurate and sodium dichloroisocyanurate; r 1 And X are each as defined in claim 1.
3. The method of claim 2, further comprising: the compound 01 and acryloyl chloride undergo lactamization reaction, after the reaction is finished, the compound 02 is prepared by post-treatment,
4. the method of any of claims 1-3, further comprising: in methanol or ethanol, compound 06 is subjected to deprotection reaction at 20-80 ℃ under the action of palladium carbon and hydrogen to prepare compound 07,
wherein R is 2 As defined in claim 1.
5. The method of any one of claims 1-4, wherein the reduction reaction comprises at least one of the following conditions:
the feeding molar ratio of the compound 05 to the reducing agent is 1;
the reaction solvent is at least one of THF, 2-methyltetrahydrofuran and toluene;
the dosage of the reaction solvent is 5ml-40ml for each gram of the compound 05; or
The post-processing comprises: adding an alkali aqueous solution into the reaction solution at the temperature of-5 ℃, stirring, adding ethyl acetate, toluene or dichloromethane for extraction, and concentrating an organic phase after optionally drying by magnesium sulfate to obtain a crude compound 06; optionally, the crude product is stirred with ethyl acetate, filtered and the solid dried to give compound 06.
6. The process of any of claims 1-4, wherein the hydrogenation reaction comprises at least one of the following conditions:
the catalyst is platinum carbon or palladium carbon;
the feeding molar ratio of the compound 04 to the alkali is 1;
the reaction solvent is methanol, ethanol or the combination thereof;
3ml-30ml of reaction solvent is used for each gram of the compound 04;
the reaction temperature is 0-80 ℃; or
The post-processing comprises: filtering the reaction solution, removing the solvent from the filtrate, mixing the obtained crude product with ethyl acetate or isopropyl acetate, stirring, filtering, and drying the solid to obtain the compound 05.
7. The process of any one of claims 1-4, wherein the cyclization reaction comprises at least one of the following conditions:
the feeding molar ratio of the compound 03 to the amine reagent is 1-1;
the cyclization reaction contains an acid-binding agent, wherein the acid-binding agent is at least one of an amine reagent, triethylamine, sodium carbonate, potassium carbonate and sodium bicarbonate;
the cyclization reaction contains an acid-binding agent, and the feeding molar ratio of the acid-binding agent to a compound 03 is 0.5-1.2;
the reaction solvent is methanol, ethanol, isopropanol, acetonitrile or a mixed solvent of at least one of the methanol, the ethanol, the isopropanol and the acetonitrile and water;
the amount of the reaction solvent is 3ml-40ml for each gram of the compound 03;
the temperature of the cyclization reaction is controlled to be 0-40 ℃; or
The post-processing comprises: mixing the reaction solution with water or an aqueous acid solution, stirring, filtering, washing the solid with water, and drying to remove the solvent to obtain a compound 04; or the post-processing comprises: mixing the reaction solution with an aqueous solution of an acid, adding ethyl acetate, isopropyl acetate or a combination solvent thereof for extraction, and concentrating an organic phase to remove the solvent to obtain a compound 04.
8. The process of claim 2, wherein the halogenation reaction comprises at least one of the following conditions:
the feeding molar ratio of the compound 02 to the halogenating agent is 1.5-1;
the reaction solvent is dichloromethane, toluene or the combination thereof, and the dosage of the reaction solvent is 3ml to 30ml;
the reaction temperature of the halogenation reaction is controlled to be-5-40 ℃; or
The post-processing comprises: quenching the reaction with saturated aqueous solution of sodium thiosulfate, separating the solution, washing the organic phase with water, concentrating, mixing the obtained product with isopropanol, stirring for 0.5-8 hours, filtering, and drying the obtained product to obtain the compound 03.
9. The process of claim 3, wherein the molar ratio of compound 01 to acryloyl chloride fed to the lactamization reaction is 1; the dosage of the reaction solvent is 5ml-35ml for each gram of the compound 01; and after the lactamization reaction is finished, the post-treatment comprises the following steps: quenching the reaction with saturated aqueous sodium bicarbonate solution, extracting with ethyl acetate or isopropyl acetate, separating, washing the organic phase with water, and removing the solvent from the organic phase to obtain the compound 02.
10. The process of any one of claims 1-9, wherein X is bromine; r is 1 Is methyl or ethyl; r 2 Is hydrogen, benzyl or (R) -1-phenylethyl.
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