Synthetic method of glutarimide compound

Abstract

The invention discloses a synthesis method of a glutarimide compound, which comprises the following steps: by taking a compound pentanediol compound as an initial raw material, firstly activating hydroxyl by a halogenating reagent or a sulfonyl chloride compound, then reacting with sodium cyanide to prepare a glutaronitrile compound, and finally hydrolyzing under the action of Bronsted acid to obtain the glutarimide compound. And carrying out cyclization to generate the glutarimide compound. The synthetic method has the advantages of short steps, low cost and simplicity and convenience in operation, is suitable for large-scale industrial production, and can be used as a drug intermediate or used for researching potential drugs.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical intermediates, and in particular to a synthesis method and a separation method of glutarimide compounds. Background Art

[0002] Glutarimide compounds have important applications in many fields such as chemistry, medicine, and materials science. Especially in the field of medicine, these compounds are often used to develop anti-epileptic drugs, as well as antibacterial and antiviral drugs, and have potential drug development value. There are currently some strategies for synthesizing such glutarimide compounds, and the literature review is as follows:

[0003] Classical synthesis method: 1,3-cyclohexanedione compounds react with sodium hypochlorite to generate glutaric acid compounds (Org.Synth., 1951, 31, 40.) or glutaronitrile is hydrolyzed under alkaline conditions to generate glutaric acid compounds. Glutaric acid compounds are then dehydrated by a dehydrating agent (thionyl chloride, phosphorus oxychloride and acetic anhydride) to remove a molecule of water from the molecule and cyclize to generate glutaric anhydride compounds (Aust.J.Chem., 2019, 72, 860-866.), and then amine nucleophiles (ammonia water, ammonia gas, ammonium acetate and ammonium formate) attack to generate amide acid compounds, and finally high temperature dehydration to generate glutarimide compounds 4 (CN116462627).

[0004]

[0005] However, these synthetic methods have some obvious limitations. First, these routes all require the synthesis of glutaric acid compounds, which will produce a large amount of inorganic salt byproducts that are difficult to remove during the reaction. In addition, glutaric anhydride compounds have poor stability and are easily hydrolyzed to regenerate glutaric acid compounds. Dehydration reactions usually require higher temperatures (120-150°C), which increases the risk and complexity of the reaction and is not conducive to industrial production.

[0006] In order to overcome the above problems, it is necessary to provide a new, safe, environmentally friendly, and easy-to-scale glutarimide compound. Summary of the invention

[0007] In order to overcome the problems existing in the prior art, the present invention has developed a method for synthesizing glutarimide compounds with shorter steps, higher yield, better quality and simple operation.

[0008] In order to achieve the above object, the present invention adopts the following technical solutions:

[0009] The synthetic route of the glutarimide compound 4 in the present invention is as follows:

[0010]

[0011] The above synthetic route uses compound 1 (pentanediol compound) as the starting material, the hydroxyl group is first activated by a halogenating agent or a sulfonyl chloride compound to obtain compound 2, which is then reacted with sodium cyanide (NaCN) to prepare compound 3, and finally hydrolyzed under the action of Bronsted acid and cyclized to form glutarimide compound 4.

[0012] In the above synthetic route, R 1 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 2 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 3 It is selected from the group consisting of chlorine (Cl), bromine (Br), methanesulfonyloxy (OMs) and p-toluenesulfonyloxy (OTs).

[0013] To achieve the above object, the present invention adopts the following technical solution:

[0014] Step S1, using compound 1 as a starting material, activating the hydroxyl group with a halogenating agent or a sulfonyl chloride compound to obtain compound 2;

[0015] Step S2, compound 2 is reacted with sodium cyanide (NaCN) to prepare compound 3;

[0016] Step S3: Compound 3 is hydrolyzed under the action of Bronsted acid and cyclized to generate glutarimide compound 4.

[0017]

[0018] R 1 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 2 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 3 It is selected from the group consisting of chlorine (Cl), bromine (Br), methanesulfonyloxy (OMs) and p-toluenesulfonyloxy (OTs).

[0019] Furthermore, the specific operation steps of step S1 include: reacting compound 1 with a halogenating agent in a first solvent under the promotion of Lewis acid; or reacting compound 1 with a sulfonyl chloride compound in a first solvent under the promotion of a base and an acylation catalyst, the reaction temperature is -20-100°C, and obtaining compound (II) after post-treatment.

[0020] Furthermore, in step S1, the compound 1 is selected from pentylene glycol compounds; preferably, the compound 1 is neopentyl glycol.

[0021] Further, in step S1, the halogenating agent is selected from any one or more of carbon tetrachloride (CCl4), chlorine (Cl2), carbon tetrabromide (CBr4) and bromine (Br2); preferably, the halogenating agent is any one or more of CCl4 and CBr4; more preferably, the halogenating agent is CBr4.

[0022] Further, in step S1, the Lewis acid is selected from any one or more of triphenylphosphine (PPh3), zinc chloride (ZnCl2) and zinc bromide (ZnBr2); preferably, the Lewis acid is selected from PPh3.

[0023] Furthermore, in the step S1, the molar ratio of the compound 1, the halogenating agent and Lewis acid is 1:0.01-5:0.5-10.

[0024] Furthermore, in step S1, the sulfonyl chloride compound is selected from any one or more of methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl); preferably, the sulfonyl chloride compound is TsCl.

[0025] Furthermore, in step S1, the base is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, K2CO3, Na2CO3, NaOH and KOH; preferably, the base is triethylamine.

[0026] Further, in step S1, the acylation catalyst is selected from any one or more of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine and 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine; preferably, the acylation catalyst is DMAP.

[0027] Furthermore, in step S1, the first solvent is selected from tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran; preferably, the first solvent is any one or more of chloroform and dichloromethane (DCM).

[0028] Furthermore, in the step S1, the molar ratio of the compound 1, the sulfonyl chloride compound, the base and the acylation catalyst is 1: 1.0-6.0: 0.5-6.0: 0.01-3.0.

[0029] Furthermore, in the step S1, the reaction temperature is -20-100°C, and the reaction time is 1 to 48 hours; preferably, the reaction temperature is 30-40°C, and the reaction time is 48 hours.

[0030] Furthermore, the specific operation steps of step S2 include: reacting compound 2 and sodium cyanide (NaCN) in a third solvent at a reaction temperature of 20-150° C., and obtaining compound 3 through post-treatment.

[0031] Furthermore, in step S2, the sodium cyanide is selected from any one or more of solid sodium cyanide and aqueous sodium cyanide solution; preferably, the sodium cyanide is solid sodium cyanide.

[0032] Furthermore, in step S2, the second solvent is selected from any one or more of N,N-dimethylformamide, dimethyl sulfoxide (DMSO), tetrahydrofuran and 1,4-dioxane; preferably, the third solvent is dimethyl sulfoxide.

[0033] Furthermore, in step S2, the molar ratio of compound 2 to sodium cyanide is 1:1.0-6.0.

[0034] Furthermore, in step S2, the reaction temperature is 20-150°C and the reaction time is 10-36h; preferably, the reaction temperature is 100-120°C and the reaction time is 24h.

[0035] Furthermore, the specific operation steps of step S3 include: under the action of Bronsted acid, compound 3 is hydrolyzed and cyclized in a third solvent or without solvent, the reaction temperature is 20-150° C., and glutarimide compound 4 is obtained after post-treatment.

[0036] Furthermore, in step S3, the Bronsted acid is selected from any one or more of hydrochloric acid (HCl), sulfuric acid, methanesulfonic acid, formic acid and acetic acid; preferably, the Bronsted acid is hydrochloric acid.

[0037] Furthermore, in step S3, the third solvent is selected from any one or more of ethanol, isopropanol, tetrahydrofuran, acetonitrile and 1,4-dioxane; preferably, the fourth solvent is isopropanol.

[0038] Furthermore, in step S3, the molar ratio of compound 3 to hydrochloric acid is 1:1.0-60.0.

[0039] Furthermore, in step S3, the reaction temperature is 20-150° C., and the reaction time is 12-72 h; preferably, the reaction temperature is 80-90° C., and the reaction time is 48 h.

[0040] Furthermore, in the above-mentioned synthesis method, the products obtained from each reaction need to undergo post-treatment operations.

[0041] Compared with the prior art, the present invention adopts the above technical solution to have the following beneficial effects:

[0042] The present invention provides a method for synthesizing glutarimide compounds: (1) Glutaronitrile compounds can be synthesized by either hydroxyl halogenation or hydroxyl activation, with high reaction efficiency and a wide substrate range; (2) Glutarimide compounds are directly obtained by acidic hydrolysis of cyanide, overcoming the problems of long reaction steps, high reaction temperature and functional group intolerance in traditional methods. BRIEF DESCRIPTION OF THE DRAWINGS

[0043] Attached Figure 1 Compound 2 obtained in Example 1 of the present invention 1 H NMR spectrum;

[0044] Attached Figure 2 Compound 2 obtained in Example 1 of the present invention 13 C NMR spectrum;

[0045] Attached Figure 3 Compound 3 obtained in Example 2 of the present invention 1 H NMR spectrum;

[0046] Attached Figure 4 Compound 3 obtained in Example 2 of the present invention 13 C NMR spectrum;

[0047] Attached Figure 5 The compound 5 obtained in Example 3 of the present invention 1 H NMR spectrum;

[0048] Attached Figure 6 The compound 5 obtained in Example 3 of the present invention 13 C NMR spectrum;

[0049] Attached Figure 7 The compound 6 obtained in Example 4 of the present invention 1 H NMR spectrum;

[0050] Attached Figure 8 The compound 6 obtained in Example 4 of the present invention 13 C NMR spectrum;

[0051] Attached Fig. 9 The compound 7 obtained in Example 5 of the present invention 1 H NMR spectrum;

[0052] Attached Fig.10 The compound 7 obtained in Example 5 of the present invention13 C NMR spectrum;

[0053] Attached Fig.11 Compound 8 obtained in Example 6 of the present invention 1 HNMR spectrum;

[0054] Attached Fig.12 Compound 8 obtained in Example 6 of the present invention 13 C NMR spectrum;

[0055] Attached Fig.13 The compound 3,3-dimethylglutamine obtained in Example 11 of the present invention 1 H NMR spectrum;

[0056] Attached Fig.14 The compound 3,3-dimethylglutamine obtained in Example 11 of the present invention 13 C NMR spectrum;

[0057] Attached Fig.15 The compound glutarimide obtained in Example 13 of the present invention 1 H NMR spectrum;

[0058] Attached Fig.16 The compound glutarimide obtained in Example 13 of the present invention 13 C NMR spectrum. DETAILED DESCRIPTION

[0059] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in the field without creative work belong to the scope of protection of the present invention. The experimental methods without specific conditions in the following embodiments are usually measured according to national standards. The experimental materials without the source indicated in the following embodiments are all commercially available raw materials. The equipment used in each step in the following embodiments is conventional equipment. If there is no corresponding national standard, it is carried out according to the general international standards, conventional conditions, or according to the conditions recommended by the manufacturer. Unless otherwise specified, all parts are weight parts and all percentages are mass percentages. Unless otherwise defined or specified, all professional and scientific terms used in the present invention have the same meaning as those familiar to those skilled in the art. In addition, any methods and materials similar to or equal to the recorded contents can be applied to the method of the present invention. It should be noted that, in the absence of conflict, the features in the embodiments and embodiments of the present invention can be combined with each other. The present invention is further described below in conjunction with specific embodiments, but it is not intended to be limited to the present invention.

[0060] Embodiment 1:

[0061]

[0062] Under nitrogen atmosphere, add 50g of compound 1 neopentyl glycol (480.08mmol, 1.0eq.), 314.80g PPh3 (1.2mol, 2.5eq.) and 200g chloroform to the reaction bottle, and add 184.60g CCl4 (451.7mmol, 2.5eq.) of chloroform (50g) solution dropwise. After the addition is complete, heat to 50-60℃ and keep warm for 24h. After the reaction is completed, filter and concentrate, add 200g n-heptane to beat for 1h, and filter. The filtrate is distilled under reduced pressure to directly obtain compound 21,3-dichloro-2,2-dimethylpropane 50.10g (355.26mmol), a colorless liquid (yield: 74%, purity ≥98%).

[0063] The NMR data are as follows:

[0064] 1 H NMR (400MHz, Chloroform-d): δ3.47 (s, 4H), 1.09 (s, 6H).

[0065] 13 C NMR (100MHz, Chloroform-d): δ52.10, 37.48, 23.58.

[0066] Embodiment 2:

[0067]

[0068] Under nitrogen atmosphere, add 50g of compound 1 neopentyl glycol (480.08mmol, 1.0eq.), 314.80g of PPh3 (1.2mol, 2.5eq.) and 150g of chloroform to the reaction bottle, and add dropwise 398.02g of CBr4 (451.7mmol, 2.5eq.) in chloroform (100g). After the addition is complete, heat to 50-60°C and keep warm for 24h. After the reaction is completed, add 200g of n-heptane for slurrying for 1h and filter. The filtrate is distilled under reduced pressure to directly obtain compound 31,3-dibromo-2,2-dimethylpropane 81.69g (355.26mmol), a light yellow liquid (yield: 67%, purity ≥96%).

[0069] The NMR data are as follows:

[0070] 1H NMR (600MHz, Chloroform-d): δ3.40 (d, J = 2.9 Hz, 4H), 1.17 (d, J = 3.1 Hz, 6H).

[0071] 13 C NMR (151MHz, Chloroform-d): δ43.30, 36.02, 24.78.

[0072] Embodiment 3:

[0073]

[0074] Under nitrogen atmosphere, add 50g of compound 41,3-propylene glycol (657.07mmol, 1.0eq.), 430.86g of PPh3 (1.64mol, 2.5eq.) and 150g of chloroform to the reaction bottle, and dropwise add 544.76g of CBr4 (1.64mol, 2.5eq.) in chloroform (100g). After the dropwise addition is completed, the temperature is raised to 50-60°C and the reaction is kept warm for 24h. After the reaction is completed, add 200g of n-heptane for slurrying for 1h and filter. The filtrate is distilled under reduced pressure to directly obtain compound 51,3-dibromopropane 80.92g (400.81mmol), a light yellow liquid (yield: 61%, purity ≥97%).

[0075] The NMR data are as follows:

[0076] 1 H NMR (600MHz, Chloroform-d): δ3.40 (s, 4H), 1.17 (s, 6H).

[0077] 13 C NMR (150MHz, Chloroform-d): δ43.30, 36.02, 24.79.

[0078] Embodiment 4:

[0079]

[0080] Under nitrogen atmosphere, add 50g of compound 1 neopentyl glycol (480.08mmol, 1.0eq.), 145.74g of TEA (1.44mol, 3.0eq.), 1.17g of DMAP (9.60mmol mol, 0.02eq.) and 150g of DCM to the reaction bottle, cool to 0-5°C, and dropwise add a solution of 126.48g of MsCl (1.10mol, 2.3eq.) in DCM (100g). After the addition is complete, keep warm and react for 2h. After the reaction is completed, add 600g of a mixed solution (5% NaCl and 5% NaHCO3) for extraction, and concentrate the organic phase to 250g-300g. Dropwise add 200g of n-heptane, cool to 0-5°C, keep warm and stir for 1h, and filter. The filter cake was rinsed with 10 g of n-heptane: dichloromethane = 5:1 and dried to directly obtain 118.73 g (456.08 mmol) of compound 62,2-dimethylpropane-1,3-diyl dimethanesulfonate as a light yellow solid (yield: 95%, purity ≥98%).

[0081] The NMR data are as follows:

[0082] 1 H NMR (400MHz, Chloroform-d): δ3.96(s,4H),2.99(s,6H),1.01(s,6H).

[0083] 13 C NMR (100MHz, Chloroform-d): δ73.22, 37.11, 35.38, 21.01.

[0084] Embodiment 5:

[0085]

[0086] Under nitrogen atmosphere, add 50g of compound 1 neopentyl glycol (480.08mmol, 1.0eq.), 145.74g of TEA (1.44mol, 3.0eq.), 1.17g of DMAP (9.60mmol mol, 0.02eq.) and 150g of DCM to the reaction bottle, and dropwise add 210.50g of TsCl (1.10mol, 2.3eq.) in DCM (180g). After the dropwise addition is completed, the temperature is raised to 35°C and kept for reaction for 36h. After the reaction is completed, add 600g of mixed solution (5% NaCl and 5% NaHCO3) for extraction, and the organic phase is concentrated to 350g-400g. Add 200 g of n-heptane dropwise, cool to 0-5°C, keep warm and stir for 1 h, filter, rinse the filter cake with 10 g of n-heptane: dichloromethane = 5:1, and dry to directly obtain compound 72, 182.20 g (441.67 mmol) of 2-dimethyl-1,3-propanediol bis(p-toluenesulfonic acid) ester as a light brown solid (yield: 92%, purity ≥98%).

[0087] The NMR data are as follows:

[0088] 1 H NMR (400MHz, Chloroform-d): δ7.71(d,J=8.0Hz,4H),7.33(d,J=7.9Hz,4H),3.70(s,4H),2.44(s,6H),0.86(s,6H).

[0089] 13 C NMR (100MHz, Chloroform-d): δ145.09,132.52,130.02,127.93,73.78,35.41,21.71,21.06.

[0090] Embodiment 6:

[0091]

[0092] Under nitrogen atmosphere, 50g of compound 21,3-dichloro-2,2-dimethylpropane (354.54mmol, 1.0eq.) and 150g of DMSO were added to the reaction bottle, and 39.96g of NaCN solid (39.96mmol, 2.3eq.) was added in batches, and the temperature was raised to 100°C, and the reaction was kept warm for 24h. After the reaction was completed, 150g of ethyl acetate and 150g of water were added to extract and separate the liquid to obtain organic phase 1 and aqueous phase 1. The aqueous phase 1 was extracted with 150g of ethyl acetate to obtain organic phase 2 and aqueous phase 2. The organic phase 1 and the organic phase 2 were combined and washed with 150g of water for 3 times. The organic phase was concentrated, brushed with a silica gel column (silica gel 42.5g; n-heptane: ethyl acetate = 8:1) and then concentrated. The concentrate was slurried with 5 g of n-heptane:ethyl acetate = 1:1, filtered, and the filter cake was rinsed with 10 g of n-heptane:ethyl acetate = 8:1 to obtain compound 82, 12.15 g (99.74 mmol) of 2-dimethylglutaronitrile as a light yellow solid (yield: 37%, purity ≥98%).

[0093] The NMR data are as follows:

[0094] 1 H NMR (400MHz, Chloroform-d): δ2.42(s,4H),1.25(s,6H).

[0095] 13 C NMR (100MHz, Chloroform-d): δ116.86,76.84,33.10,29.91,26.53.

[0096] Embodiment 7:

[0097]

[0098] Under nitrogen atmosphere, 50g of compound 31,3-dibromo-2,2-dimethylpropane (217.45mmol, 1.0eq.) and 150g of DMSO were added to the reaction bottle, and 24.51g of NaCN solid (500.12mmol, 2.3eq.) was added in batches, and the temperature was raised to 100°C, and the reaction was kept warm for 24h. After the reaction was completed, 150g of ethyl acetate and 150g of water were added to extract and separate the liquid to obtain organic phase 1 and aqueous phase 1. The aqueous phase 1 was extracted with 150g of ethyl acetate to obtain organic phase 2 and aqueous phase 2. The organic phase 1 and the organic phase 2 were combined and washed with 150g of water for 3 times. The organic phase was concentrated, brushed on a silica gel column (silica gel 42.5g; n-heptane: ethyl acetate = 4:1) and then concentrated. The concentrate was slurried with 5 g of n-heptane:ethyl acetate = 1:1, filtered, and the filter cake was rinsed with 10 g of n-heptane:ethyl acetate = 8:1 to obtain compound 82, 12.22 g (100.02 mmol) of 2-dimethylglutaronitrile as a light yellow solid (yield: 46%, purity ≥98%).

[0099] The NMR data are as follows:

[0100] 1 H NMR (600MHz, Chloroform-d): δ2.41 (s, 4H), 1.24 (s, 6H).

[0101] 13 C NMR (150MHz, Chloroform-d): δ116.84,76.82,33.07,29.89,26.50.

[0102] Embodiment 8:

[0103]

[0104] Under nitrogen atmosphere, 50g of compound 62,2-dimethylpropane-1,3-diyl dimethanesulfonate (192.07mmol, 1.0eq.) and 150g of DMSO were added to the reaction bottle, and 72.17g of 30% NaCN aqueous solution (441.77mmol, 2.3eq.) was added in batches, and the temperature was raised to 100°C, and the reaction was kept warm for 24h. After the reaction was completed, 150g of ethyl acetate and 150g of water were added to extract and separate the liquid to obtain organic phase 1 and aqueous phase 1. The aqueous phase 1 was extracted with 150g of ethyl acetate to obtain organic phase 2 and aqueous phase 2. The organic phase 1 and the organic phase 2 were combined and washed with 150g of water for 3 times. The organic phase was concentrated, brushed on a silica gel column (silica gel 42.5g; n-heptane: ethyl acetate = 4:1) and then concentrated. The concentrate was slurried with 5 g of n-heptane:ethyl acetate = 1:1, filtered, and the filter cake was rinsed with 10 g of n-heptane:ethyl acetate = 8:1 to obtain compound 82, 14.78 g (121.01 mmol) of 2-dimethylglutaronitrile as a light yellow solid (yield: 63%, purity ≥98%).

[0105] The NMR data are as follows:

[0106] 1 H NMR (400MHz, Chloroform-d): δ2.43 (s, 4H), 1.25 (s, 6H).

[0107] 13 C NMR (100MHz, Chloroform-d): δ116.89,76.87,33.08,29.93,26.57.

[0108] Embodiment 9:

[0109]

[0110] Under nitrogen atmosphere, 50g of compound 72,2-dimethyl-1,3-propanediol bis(p-toluenesulfonic acid) ester (121.21mmol, 1.0eq.) and 150g of DMSO were added to the reaction bottle, and 13.66g of NaCN solid (278.78mmol, 2.3eq.) was added in batches, and the temperature was raised to 100°C, and the reaction was kept warm for 24h. After the reaction was completed, 150g of ethyl acetate and 150g of water were added to extract and separate the liquid to obtain organic phase 1 and aqueous phase 1. The aqueous phase 1 was extracted with 150g of ethyl acetate to obtain organic phase 2 and aqueous phase 2. The organic phase 1 and the organic phase 2 were combined and washed with 150g of water for 3 times. The organic phase was concentrated, brushed with a silica gel column (silica gel 42.5g; n-heptane: ethyl acetate = 4:1) and then concentrated. The concentrate was slurried with 5 g of n-heptane:ethyl acetate = 1:1, filtered, and the filter cake was rinsed with 10 g of n-heptane:ethyl acetate = 8:1 to obtain compound 82, 10.51 g (86.06 mmol) of 2-dimethylglutaronitrile as a light yellow solid (yield: 71%, purity ≥98%).

[0111] The NMR data are as follows:

[0112] 1 H NMR (400MHz, Chloroform-d): δ2.41 (s, 4H), 1.26 (s, 6H).

[0113] 13 C NMR (100MHz, Chloroform-d): δ116.86,76.89,33.06,29.92,26.52.

[0114] Embodiment 10:

[0115]

[0116] Under nitrogen atmosphere, 50g of compound 51,3-dibromopropane (247.66mmol, 1.0eq.) and 150g of DMSO were added to the reaction bottle, and 27.92g of NaCN solid (569.62mmol, 2.3eq.) was added in batches. The temperature was raised to 100°C and the reaction was kept warm for 24h. After the reaction was completed, 150g of ethyl acetate and 150g of water were added to extract and separate the liquid to obtain organic phase 1 and aqueous phase 1. The aqueous phase 1 was extracted with 150g of ethyl acetate to obtain organic phase 2 and aqueous phase 2. The organic phase 1 and the organic phase 2 were combined and washed with 150g of water for 3 times. The organic phase was concentrated, brushed on a silica gel column (silica gel 42.5g; n-heptane: ethyl acetate = 4:1) and then concentrated. The concentrate was slurried with 5 g of n-heptane:ethyl acetate = 1:1, filtered, and the filter cake was rinsed with 10 g of n-heptane:ethyl acetate = 8:1 to obtain 9.79 g (104.02 mmol) of compound 9 glutaronitrile as a light yellow solid (yield: 42%, purity ≥98%).

[0117] The NMR data are as follows:

[0118] 1 H NMR (400MHz, Chloroform-d): δ2.53 (t, J=7.3Hz, 4H), 3.75 (q, J=7.3Hz, 2H).

[0119] 13 C NMR (100MHz, Chloroform-d): δ117.6, 21.5, 16.3.

[0120] Embodiment 11:

[0121]

[0122] Under nitrogen atmosphere, 50g of compound 82, 2-dimethylglutaronitrile (409.26mmol, 1.0eq.) and 248.68g of 30% HCl aqueous solution (2.06mol, 5.0eq.) were added to the reaction bottle, and the temperature was raised to 80°C, and the reaction was kept warm for 48h. After the reaction, 50g of isopropanol was added, the temperature was lowered to 0-5°C, stirred for 1h, filtered, and the filter cake was rinsed with 5g of isopropanol: water = 1:1 to obtain compound 103, 45.06g (319.22mmol) of 3-dimethylglutamine, a white solid (yield: 78%, purity ≥98%).

[0123] The NMR data are as follows:

[0124] 1 H NMR (400MHz, DMSO-d6): δ2.36 (s, 4H), 0.98 (s, 6H).

[0125] 13 C NMR(100MHz,DMSO-d6)δ173.10,44.87,29.86,27.23.

[0126] Embodiment 12:

[0127]

[0128] Under nitrogen atmosphere, 50g of compound 82, 2-dimethylglutaronitrile (409.26mmol, 1.0eq.) and 122.89g of acetic acid (2.05mol, 5.0eq.) were added to the reaction bottle and heated to 100°C for 48h. After the reaction, the concentrate was concentrated, 100g of isopropanol was added to the concentrate, the temperature was raised to 70°C, and stirred for 1h. The temperature was then lowered to 0-5°C, stirred for 1h, filtered, and the filter cake was rinsed with 10g of isopropanol to obtain compound 103, 41.60g (294.67mmol) of 3-dimethylglutamine, a white solid (yield: 72%, purity ≥98%).

[0129] The NMR data are as follows:

[0130] 1 H NMR (400MHz, DMSO-d6): δ2.35(s,4H),0.97(s,6H).

[0131] 13 C NMR (100MHz, DMSO-d6): δ173.12, 44.86, 29.87, 27.25.

[0132] Embodiment 13:

[0133]

[0134] Under nitrogen atmosphere, 50g of compound 9 glutaronitrile (409.26mmol, 1.0eq.) and 322.81g of 30% HCl aqueous solution (2.66mol, 5.0eq.) were added to the reaction bottle, and the temperature was raised to 80°C, and the reaction was kept warm for 48h. After the reaction, 50g of isopropanol was added, the temperature was lowered to 0-5°C, stirred for 1h, filtered, and the filter cake was rinsed with 5g of isopropanol: water = 1:1 to obtain 44.47g (393.13mmol) of compound 11 glutarimide as a white solid (yield: 74%, purity ≥98%).

[0135] The NMR data are as follows:

[0136] 1 H NMR (600MHz, DMSO-d6): δ11.26 (s, 1H), 3.11 (t, J = 6.7Hz, 4H).

[0137] 13 C NMR (100MHz, DMSO-d6): δ173.92, 31.43, 17.62.

[0138] The specific embodiments of the present invention are described in detail above, but they are only examples, and the present invention is not limited to the specific embodiments described above. For those skilled in the art, any equivalent modifications and substitutions made to the present invention are also within the scope of the present invention. Therefore, the equalization changes and modifications made without departing from the spirit and scope of the present invention should be included in the scope of the present invention.

Claims

1. A method for synthesizing a glutarimide compound, characterized in that: Its synthetic route is as follows: The specific steps include: (1) Step S1, in a first solvent, using compound 1 as a starting material, the hydroxyl group is first activated by a halogenating agent or a sulfonyl chloride compound to obtain compound 2; (2) Step S2, in a second solvent, compound 2 is reacted with sodium cyanide (NaCN) to prepare compound 3; (3) Step S3, in a third solvent, compound 3 is hydrolyzed under the action of Bronsted acid, and cyclized to generate compound 4; R 1 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 2 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 3 It is selected from the group consisting of chlorine (Cl), bromine (Br), methanesulfonyloxy (OMs) and p-toluenesulfonyloxy (OTs).

2. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The halogenating agent in step S1 is selected from any one or more of carbon tetrachloride (CCl4), chlorine (Cl2), carbon tetrabromide (CBr4) and bromine (Br2).

3. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The Lewis acid in step S1 is selected from any one or more of triphenylphosphine (PPh3), zinc chloride (ZnCl2) and zinc bromide (ZnBr2).

4. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The sulfonyl chloride compound in step S1 is selected from any one or more of methanesulfonyl chloride (MsCl) and p-toluenesulfonyl chloride (TsCl).

5. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The base in step S1 is selected from any one or more of triethylamine, trimethylamine, N,N-diisopropylethylamine, 1,8-diazobispiro[5.4.0]undec-7-ene (DBU), pyridine, K2CO3, Na2CO3, NaOH and KOH.

6. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The acylation catalyst in step S1 is selected from any one or more of 4-dimethylaminopyridine (DMAP), 4-pyrrolidinylpyridine and 5,6,9,10-tetrahydro-4H,8H-pyrido[3,2,1-IJ][1,6]naphthyridine.

7. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: In step S1, the first solvent is selected from any one or more of tetrahydrofuran, 2-methyltetrahydrofuran, methyl tert-butyl ether, acetonitrile, 1,4-dioxane, tetrahydrofuran, chloroform and dichloromethane.

8. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The Bronsted acid in step S3 is selected from any one or more of hydrochloric acid (HCl), sulfuric acid, methanesulfonic acid, formic acid and acetic acid.

9. The method for synthesizing glutarimide compounds according to claim 1, characterized in that: The compound 3 in step S3 is a glutaronitrile compound; R 1 is selected from hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl; R 2 Selected from one of hydrogen (H), methyl (Me), ethyl (Et), aryl and C3-C9 alkyl.

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