Preparation method of alpha-aminoketone compound

Abstract

The invention discloses a preparation method of alpha-aminoketone compounds, which is characterized in that in the presence of water as a reaction solvent and inorganic base, iodine as an accelerant, propiophenone compounds and amine compounds are subjected to sp3 C-H amination reaction to prepare a series of alpha-aminoketone compounds at high yield. Compared with the prior art, the method has the advantages that the use of an organic solvent and organic alkali is avoided, the production cost and the operation difficulty are remarkably reduced, and meanwhile, the atom economy and the production safety of the preparation process are also remarkably improved. The method disclosed by the invention has good substrate universality, can be carried out at room temperature, is simple in preparation and post-treatment operation and pollution-free, conforms to the green chemical development concept, and is suitable for industrial production.

Description

Technical Field

[0001] The present application belongs to the technical field of pharmaceutical chemistry, and specifically relates to a method for preparing an α-amino ketone compound. Background Art

[0002] α-Aminoketone compounds are important pharmaceutical compounds, pharmaceutical synthesis intermediates, and organic synthesis intermediates. For example, amfepramone is a stimulant and appetite suppressant, and is mainly used clinically to treat various degrees of simple obesity and obese patients with coronary heart disease, hypertension, and diabetes. N-pyrrolidino norephedrine is a key intermediate in the synthesis of the anti-AIDS drug efavirenz. As a new drug compound, for example, a series of α-aminoketone compounds reported in US2022056029A1 are used as mAChR antagonists.

[0003] Traditional methods for synthesizing α-amino ketone compounds are mainly divided into the following categories: using brominated substrates as raw materials and coupling with NH-containing compounds under alkaline conditions; or using ketone compounds as raw materials and reacting with NH-containing compounds in the presence of bromine and NBS (US2022056029A1; US2019389842A1; Biomol. Ther., 2017, 25, 122-129; Org. Lett., 2017, 19, 2548-2551; EP3002592A1; CN104 805148A); and / or directly prepared by reacting aromatic ketone compounds with NH compounds in the presence of tetrabutylammonium iodide / peroxide or a strong oxidant such as LiClO4 (Chem.Sci., 2021, 12(46), 15318-15328; J.Org.Chem., 2016, 81(23), 11565-11573); and / or directly prepared by reacting aromatic ketone compounds with NH compounds under transition metal catalysis (CN105272936A; CN103848854A). However, the above methods have the disadvantages of using expensive substrates and / or reagents, multi-step reactions, harsh reaction conditions, poor production safety and greater operational difficulty. At the same time, the above methods all require the presence of organic solvents to proceed smoothly. Chang Junbiao et al. reported the sp-catalysis of phenylacetone compounds and morpholine promoted by iodine. 3 C H amination reaction can only be carried out at room temperature in the presence of an organic base DBU and an organic solvent DMSO (Asian J. Org. Chem., 2022, 11, e202200268).

[0004] Considering the concept of green chemistry development and atom economy, it is clear that water has great advantages as a solvent for organic reactions. It is widely available, economical, environmentally friendly, easy to handle, and using water as a solvent in production can also reduce the risk of fire and explosion. Therefore, using water instead of organic solvents as a reaction solvent has a good development prospect. The inventors found through experimental research that for the sp-iodine reaction of phenylacetone and morpholine promoted by iodine, 3 The CH amination reaction can prepare α-amino ketone in high yield under the condition of water as solvent by appropriately controlling the reaction conditions, thereby completing the present invention. Summary of the invention

[0005] The object of the present invention is to provide a method for preparing α-amino ketone compounds, wherein water is used as a reaction solvent and an inorganic base is present, iodine is used as a promoter, a phenylacetone compound and an amine compound are reacted by sp 3 The CH amination reaction is used to prepare a series of α-amino ketone compounds with high yield. Compared with the prior art, the method avoids the use of organic solvents and organic bases, significantly reduces the production cost and operation difficulty, and also significantly improves the atom economy and production safety of the preparation process. In addition, the method of the present invention has good substrate universality, can be carried out under room temperature, and has simple preparation and post-treatment operations, no pollution, conforms to the concept of green chemistry development, and is suitable for industrial production.

[0006] A method for preparing an α-amino ketone compound provided by the present invention comprises the following steps:

[0007] The phenylacetone compound shown in Formula 1, the amine compound shown in Formula 2, an inorganic base, elemental iodine and water are sequentially added to the reactor, and then the reaction mixture is stirred at room temperature until the reaction is complete, and the α-amino ketone compound shown in Formula 3 is prepared by post-treatment; the reaction formula is as follows:

[0008]

[0009] In the above reaction formula, m=an integer of 0, 1, 2, 3, 4, 5; R1 represents a substituent on the benzene ring, and each R1 is independently selected from hydrogen, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Aryl, C 1-6 Haloalkyl, C 1-6 Acyl, C 6-20 Aryl-C 1-6 Alkyl, C 2-20Heteroaryl; and / or two adjacent R1 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing heteroatoms, wherein the heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally selected from halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Aryl, C 1-6 The alkyl group is substituted with a haloalkyl substituent.

[0010] R2 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl.

[0011] R3 and R4 are independently selected from C 1-6 Alkyl; and / or R3, R4 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing other heteroatoms, wherein the other heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally selected from halogen, oxo (=O), -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Aryl, C 1-6 The alkyl group is substituted with a haloalkyl substituent.

[0012] In any part of the present invention, the alkyl group and / or alkyl moiety include straight chain and branched alkyl groups, and examples of alkyl groups having the stated number of carbon atoms include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and the like.

[0013] In any part of the present invention, the aryl group with the number of carbon atoms includes, but is not limited to, phenyl, naphthyl, anthracenyl, indenyl, phenanthryl, etc. The aryl group with the number of carbon atoms includes, but is not limited to, furanyl, pyridyl, thienyl, indolyl, pyrazinyl, pyridazinyl, benzofuranyl, carbazolyl, etc.

[0014] In any part of the present invention, the cyclic group is saturated or unsaturated.

[0015] Preferably, m=an integer of 1 or 2; R1 represents a substituent on the benzene ring, and each R1 is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, trifluoromethyl, acetyl, benzyl, furyl, thienyl, pyridyl; and / or two adjacent R1 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing heteroatoms, wherein the heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally substituted by a substituent selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, and trifluoromethyl.

[0016] R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0017] R3 and R4 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, and n-hexyl; and / or R3 and R4 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing other heteroatoms, wherein the other heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally substituted by a substituent selected from fluorine, chlorine, bromine, iodine, oxo (=O), -CN, -NO2, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, and trifluoromethyl.

[0018] Most preferably, the compound of Formula 1 has the following structure:

[0019]

[0020] The compound of formula 2 has the following structure:

[0021]

[0022] According to the aforementioned method of the present invention, the inorganic base is selected from one or more of K2CO3, Na2CO3, Cs2CO3, KHCO3, NaHCO3, NaOH and KOH; preferably K2CO3, Na2CO3, NaOH and KOH; most preferably K2CO3.

[0023] According to the aforementioned method of the present invention, the molar ratio of compound 1 of formula 1, compound 2, inorganic base and elemental iodine is 1:(1-3):(0.5-2):(0.5-2); preferably 1:2:1:1.

[0024] According to the aforementioned method of the present invention, the time for the reaction to be complete is 12 to 48 hours, preferably 24 hours.

[0025] According to the aforementioned method of the present invention, the post-treatment operation is as follows: the reaction solution is extracted with ethyl acetate, the organic phases are combined, and then washed with a saturated sodium thiosulfate solution, the organic phases are dried, filtered, and concentrated to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the α-amino ketone compound shown in Formula 3.

[0026] Compared with the prior art, the method of the present invention has the following advantages:

[0027] The method for preparing α-aminoketone compounds provided by the present invention avoids the use of organic solvents and organic bases, significantly reduces production costs and operational difficulties, and also significantly improves the atom economy and production safety of the preparation process. The method of the present invention has good substrate universality, can be carried out at room temperature, and has simple preparation and post-processing operations, is pollution-free, conforms to the concept of green chemistry development, and is suitable for industrial production. DETAILED DESCRIPTION

[0028] The present invention is further described in detail below in conjunction with specific examples. In the following, unless otherwise specified, the methods used are all conventional methods in the art, and the raw materials and / or reagents used are all purchased from conventional commercial channels without further purification.

[0029] Example 1-14 Reaction Condition Optimization Test

[0030] Using phenylacetone 1a and morpholine 2a as template substrates, the effects of different synthetic process conditions on the yield of the target product 3a were explored. The results are shown in Table 1. The reaction formula is as follows:

[0031]

[0032] Table 1:

[0033]

[0034] a Reaction conditions: 1a (0.3 mmol), 2a and solvent (1 mL) were reacted at room temperature (RT) for 24 h. The excess 2a could be recycled. b Isolated yield. c Increased by-products.

[0035] Taking Example 13 as an example, the typical test operation is as follows:

[0036] To a 25 mL sealed tube reactor, 0.3 mmol of phenylacetone 1a, 0.6 mmol of morpholine 2a, 0.3 mmol of potassium carbonate, 0.3 mmol of elemental iodine and 1.0 mL of purified water were added in sequence, and finally a magnetic bar was added. The reaction mixture was stirred at room temperature for 24 h. The reaction was complete after monitoring by TLC. The reaction solution was extracted three times with ethyl acetate (30 mL each time), and the organic phases were combined and washed with 10 mL of saturated sodium thiosulfate solution. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to remove the solvent to obtain a residue. The residue was separated by silica gel column chromatography (eluting solvent was petroleum ether / ethyl acetate = 6:1 to 4:1) to obtain the target product 3a as a colorless oil with a yield of 80%. 1 H NMR (500MHz, CDCl3) δ8.05(d,J=7.3Hz,2H),7.52(t,J=7.4Hz,1H),7.41(t,J=7.8Hz,2H),4.04( q,J=6.8Hz,1H),3.68–3.61(m,4H),2.61–2.57(m,2H),2.55–2.51(m,2H),1.26(d,J=6.8Hz,3H); 13 C NMR (125MHz, CDCl3) δ200.1,136.0,132.9,128.6,128.3,67.0,64.6,49.9,11.5.

[0037] In Examples 1-12 and 14, except that the reaction variables shown in Table 1 are different from those in Example 13, the remaining reaction conditions and operations are the same as those in Example 13. As can be seen from Table 1, the reaction of the present invention cannot be carried out without adding alkali and promoter I2 (Example 1-2). When the alkali is replaced by an inorganic alkali such as NaOH and KOH with a stronger alkalinity, it is found by TLC detection that the by-products are significantly increased (Examples 5 and 6). When the alkali is replaced by an organic alkali such as DBU, only trace amounts of the target product can be obtained (Example 7). Using the inorganic alkali Na2CO3 can also obtain a good target product yield (Example 8). I2 is used as a promoter in the reaction of the present invention, and its dosage has a significant effect on the yield of the target product. The feed ratio study shows that the optimal feed ratio of phenylacetone, morpholine, potassium carbonate and iodine is 1:2:1:1. Under this feed ratio condition, a relatively high target product yield can be obtained, while saving the dosage of the raw material morpholine, which helps to further reduce the production cost (Examples 3-4, 9-10, 13-14). Under the mixed solvent conditions of organic solvent and / or water and organic solvent such as acetonitrile, the target product yield is significantly reduced (Example 11). In addition, when the reaction temperature is raised, TLC shows that by-products increase significantly and the yield of the target product decreases (Example 12).

[0038] In order to improve the yield, reduce the cost of raw materials and facilitate the purification of the product, the reaction conditions of Example 13 were selected as the optimal reaction conditions. On the basis of obtaining the optimal reaction conditions, the universality of the optimal reaction conditions for the reaction substrate substituents was further explored, and the reaction formula and results are as follows:

[0039]

[0040] Structural characterization of the product:

[0041] Compound 3b:

[0042] 1 H NMR (500MHz, CDCl3) δ8.07(d,J=8.9Hz,2H),6.90(d,J=8.9Hz,2H),3.99(q,J=6.8Hz,1H),3 .84(s,3H),3.70–3.63(m,4H),2.63–2.59(m,2H),2.54–2.50(m,2H),1.26(d,J=6.8Hz,3H); 13 C NMR (125MHz, CDCl3) δ198.8,163.4,131.1,128.9,113.5,67.0,64.6,55.4,50.1,12.1.

[0043] Compound 3c:

[0044] 1 H NMR (400MHz, CDCl3) δ8.06–8.03(m,2H),7.58–7.54(m,1H),7.48–7.43(m,2H),3.91(dd,J=9.1,4.8Hz,1H),3.65(t ,J=4.7Hz,4H),2.69–2.64(m,2H),2.60–2.55(m,2H),1.96–1.85(m,1H),1.80–1.70(m,1H),0.86(t,J=7.4Hz,3H); 13 C NMR (100MHz, CDCl3) δ199.8,137.4,133.0,128.5,128.5,70.2,67.3,50.3,19.5,10.9.

[0045] Compound 3d:

[0046] 11H NMR (600 MHz, CDCl3) δ 8.10 (d, J = 7.7 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 4.11 (q, J = 6.8 Hz, 1H), 2.91 (d, J = 10.9 Hz, 1H), 2.76 (d, J = 11.1 Hz, 1H), 2.42 (td, J = 11.5, 2.6 Hz, 1H), 2.14 (td, J = 11.5, 2.6 Hz, 1H), 1.61 (d, J = 12.5 Hz, 1H), 1.55 (d, J = 12.8 Hz, 1H), 1.27–1.10 (m, 6H), 0.88 (d, J = 6.4 Hz, 3H); 13 13C NMR (150 MHz, CDCl3) δ 201.1, 136.5, 132.8, 128.9, 128.3, 64.7, 51.6, 48.7, 34.7, 34.4, 30.8, 21.8, 11.5.

[0047] Compound 3e:

[0048] 1 1H NMR (400 MHz, CDCl3) δ 7.93 (d, J = 8.3 Hz, 2H), 7.22 (d, J = 7.8 Hz, 2H), 4.10 (q, J = 6.7 Hz, 1H), 2.84 (ddd, J = 6.0, 4.2, 1.9 Hz, 4H), 2.63–2.52 (m, 4H), 2.39 (s, 3H), 1.22 (d, J = 6.7 Hz, 3H); 13 13C NMR (100 MHz, CDCl3) δ 199.6, 143.5, 133.6, 128.9, 128.9, 64.9, 51.5, 28.3, 21.6, 10.0.

[0049] Compound 3f:

[0050] 1 1H NMR (500 MHz, CDCl3) δ 8.11 (d, J = 8.0 Hz, 2H), 7.54 (t, J = 7.4 Hz, 1H), 7.44 (t, J = 7.7 Hz, 2H), 7.06 (d, J = 5.2 Hz, 1H), 6.72 (d, J = 5.1 Hz, 1H), 4.39 (q, J = 6.8 Hz, 1H), 3.84 (d, J = 14.2 Hz, 1H), 3.74 (d, J = 14.2 Hz, 1H), 2.93 (t, J = 5.6 Hz, 2H), 2.87–2.75 (m, 2H), 1.39 (d, J = 6.8 Hz, 3H);13 C NMR (125MHz, CDCl3) δ200.5,136.1,133.6,133.3,133.0,128.8,128.4,125.2,122.6,63.5,49.3,47.1,25.8,11.7.

[0051] Compound 3g (bupropion):

[0052] 1 H NMR (600MHz, CDCl3) δ8.09(d,J=7.4Hz,2H),7.51(d,J=7.5Hz,1H),7.43(t,J=7.6Hz,2H),4.39(q,J=6.7Hz,1 H),2.64(dd,J=13.2,7.2Hz,2H),2.56(dd,J=13.4,6.8Hz,2H),1.23(d,J=6.7Hz,3H),1.01(t,J=7.1Hz,6H); 13 C NMR (150MHz, CDCl3) δ202.0,136.8,132.5,128.9,128.2,60.3,44.3,13.6,10.2.

[0053] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Although the present invention is described in detail with reference to the aforementioned embodiments, those skilled in the art can still modify the technical solutions described in the aforementioned embodiments or replace some of the technical features therein by equivalents. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A method for preparing an α-amino ketone compound, characterized in that The following steps are involved: The phenylacetone compound shown in Formula 1, the amine compound shown in Formula 2, an inorganic base, elemental iodine and water are sequentially added to the reactor, and then the reaction mixture is stirred at room temperature until the reaction is complete, and the α-amino ketone compound shown in Formula 3 is prepared by post-treatment; the reaction formula is as follows: In the above reaction formula, m=an integer of 0, 1, 2, 3, 4, 5; R1 represents a substituent on the benzene ring, and each R1 is independently selected from hydrogen, halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Aryl, C 1-6 Haloalkyl, C 1-6 Acyl, C 6-20 Aryl-C 1-6 Alkyl, C 2-20 Heteroaryl; and / or two adjacent R1 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing heteroatoms, wherein the heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally selected from halogen, -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Aryl, C 1-6 Substituted by a haloalkyl substituent; R2 is selected from C 1-6 Alkyl, C 3-12 Cycloalkyl; R3 and R4 are independently selected from C 1-6 Alkyl; and / or R3, R4 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing other heteroatoms, wherein the other heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally selected from halogen, oxo (=O), -CN, -NO2, C 1-6 Alkyl, C 1-6 Alkoxy, C 6-20 Aryl, C 1-6 The alkyl group is substituted with a haloalkyl substituent.

2. The preparation method according to claim 1, characterized in that: m=an integer of 1 or 2; R1 represents a substituent on the benzene ring, and each R1 is independently selected from hydrogen, fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, trifluoromethyl, acetyl, benzyl, furyl, thienyl, pyridyl; and / or two adjacent R1 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing heteroatoms, wherein the heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally substituted by a substituent selected from fluorine, chlorine, bromine, iodine, -CN, -NO2, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, and trifluoromethyl; R2 is selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; R3 and R4 are independently selected from methyl, ethyl, n-propyl, isopropyl, n-butyl, n-pentyl, and n-hexyl; and / or R3 and R4 substituents are connected to each other to form a cyclic group containing 3 to 8 carbon atoms and optionally containing other heteroatoms, wherein the other heteroatoms are selected from one or more of O, S, and N, and the cyclic group is optionally substituted by a substituent selected from fluorine, chlorine, bromine, iodine, oxo (=O), -CN, -NO2, methyl, ethyl, tert-butyl, methoxy, ethoxy, tert-butoxy, phenyl, and trifluoromethyl.

3. The preparation method according to claim 2, characterized in that: The compound of formula 1 has the following structure: The compound of formula 2 has the following structure:

4. The preparation method according to any one of claims 1 to 3, characterized in that: The inorganic base is selected from one or more of K2CO3, Na2CO3, Cs2CO3, KHCO3, NaHCO3, NaOH and KOH.

5. The preparation method according to claim 4, characterized in that: The inorganic base is selected from one or more of K2CO3, Na2CO3, NaOH and KOH.

6. The method according to claim 5, characterized in that The inorganic base is selected from K2CO3.

7. The preparation method according to any one of claims 1 to 3, characterized in that: The molar ratio of the phenylacetone compound shown in Formula 1, the amine compound shown in Formula 2, the inorganic base and elemental iodine is 1:(1-3):(0.5-2):(0.5-2).

8. The preparation method according to claim 7, characterized in that: The molar ratio of the phenylacetone compound shown in Formula 1, the amine compound shown in Formula 2, the inorganic base, and elemental iodine is 1:2:1:

1.

9. The preparation method according to any one of claims 1 to 3, characterized in that: The time required for the reaction to be completed is 12 to 48 hours.

10. The preparation method according to any one of claims 1 to 3, characterized in that: The post-treatment operation is as follows: the reaction solution is extracted with ethyl acetate, the organic phases are combined, and then washed with a saturated sodium thiosulfate solution. The organic phase is dried, filtered, and concentrated to obtain a residue, and the residue is separated by silica gel column chromatography to obtain the α-amino ketone compound shown in formula 3.

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