Synthesis method of dialkyl amino alcohol

Abstract

The invention discloses a synthesis method of dialkyl amino alcohol. The dialkyl amino alcohol is obtained by reacting dialkyl amino ester with a Grignard reagent. According to the synthetic route provided by the invention, the overall synthesis condition is mild, the used raw materials are easy to obtain, and the toxicity is relatively low.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing a dialkylamino alcohol. Background Art

[0002] Dialkylamino alcohol compounds are important organic intermediates that can be used in the synthesis of a variety of raw materials and can also be used to synthesize metal amino alcohol salt complexes. They are common precursors that can be used to deposit related metals and their compounds, such as precursors containing dimethylamino-2-propoxy (DMAMP) or dimethylamino-2-butoxy (DMAMB) ligands.

[0003] The most common synthesis method for the synthesis of dialkylamino alcohol compounds is to prepare them by heating epoxide and dialkylamine in an autoclave for reflux, as shown in US Patent No. 3954873 (1976). The main disadvantages of this method are that the reaction temperature is too high and high pressure conditions are required. In the post-treatment, solvent benzene is used for filtration, and benzene is highly toxic. Summary of the invention

[0004] The object of the present invention is to provide a novel method for synthesizing a dialkylamino alcohol having the following general formula (I):

[0005]

[0006] The synthesis method comprises the steps of: reacting a dialkylamino ester represented by the general formula (II) with a Grignard reagent represented by the general formula (III);

[0007]

[0008] wherein R1-R5 independently represent lower alkyl groups, and X1 is halogen.

[0009] Preferably, when R3 and R4 are different, the method further comprises step b: adding a quencher to the reaction solution of step a, quenching and separating to obtain a dialkylaminoketone of general formula (IV), and reacting the quencher with a Grignard reagent of general formula (V) to prepare a dialkylaminoalcohol of general formula (I);

[0010]

[0011] Wherein, X2 is a halogen.

[0012] Preferably, before step a, the method further comprises step c: obtaining a dialkylamino ester represented by general formula (II) by reacting a dialkylamine with a halogenated acetate. The general reaction formula is as follows:

[0013]

[0014] Step a specifically comprises dissolving the dialkylamino ester in solvent A, and adding a Grignard reagent to the reaction system under low temperature conditions. Solvent A is preferably an ether solvent of tetrahydrofuran.

[0015] Step b specifically comprises dissolving the dialkylaminoketone in solvent B, adding a Grignard reagent to the reaction system under low temperature conditions, and continuing the reaction under low temperature conditions. Solvent B is preferably an ether solvent, which can be selected from THF, diethyl ether, 1,4-dioxane, and methyl tert-butyl ether. This step can also refer to the document Tetrahedron Letters No. 41, pp 3625-3628, 1977.

[0016] Step c specifically includes dissolving the dialkylamine in solvent C under low temperature conditions, adding halogenated acetate to the reaction system; after the reaction is completed, dialkylamino ester is obtained by distillation separation. The reaction temperature range is -20 to 0°C. Solvent C can be selected from one of ethyl acetate, toluene, butyl acetate, methyl acetate and isopropyl acetate. The molar ratio of halogenated acetate to dialkylamine is in the range of 1:(2 to 3). The reaction time is 12 to 24 hours. This step can also refer to patent CN113620825A.

[0017] Preferably, R1 and R2 are both methyl.

[0018] Preferably, R3 is methyl or ethyl, and R4 is methyl.

[0019] The invention provides a novel synthesis route of dialkylamino alcohols. The synthesis route adopts dialkylamino esters and Grignard reagents for reaction. The overall synthesis conditions are mild, the raw materials used are easily available, and the toxicity is relatively low. DETAILED DESCRIPTION

[0020] In order to make the above features and advantages of the present invention more clearly understood, the following embodiments are given for detailed description. The methods of the present invention are all conventional methods in the art unless otherwise specified.

[0021] [Example 1]

[0022] This embodiment synthesizes 1-dimethylamino-2-methyl-2-butanol, specifically comprising the steps of:

[0023] (1) Preparation of ethyl N,N-dimethylaminoacetate: dimethylamine is dissolved in toluene cooled to -20 to 0°C, ethyl chloroacetate is added dropwise, and the molar ratio of ethyl chloroacetate to dimethylamine is controlled to be 1:(2 to 3). After stirring for 12 to 24 hours, the formed precipitate is filtered out, the solvent toluene is distilled off, and the product is obtained by vacuum distillation. The ethyl chloroacetate used is easy to obtain and stable at room temperature. Dimethylamine is a gas, and the time for the dimethylamine to be introduced is determined by weighing according to the ventilation size and cooling temperature.

[0024] (2) Preparation of N,N-dimethylamino alcohol: Use ethyl N,N-dimethylaminoacetate to react with methyl and ethyl Grignard reagents in two steps to obtain 1-dimethylamino-2-methyl-2-butanol. At low temperature, add the Grignard reagent dropwise into ethyl dimethylaminoacetate and continue stirring the reaction. The reaction is simple, the conditions are mild, and the Grignard reagent involved is easily available.

[0025] The reaction equation of 1-dimethylamino-2-methyl-2-butanol is shown below:

[0026]

[0027] Wherein N,N-dimethylaminoethyl acetate is synthesized by reacting with methyl and ethyl Grignard reagents in two steps, specifically:

[0028] (2-1) Add N,N-dimethylaminoethyl acetate and solvent tetrahydrofuran into a reaction kettle, cool to -20 to 0°C, slowly drop ethylmagnesium bromide, and control the molar ratio of N,N-dimethylaminoethyl acetate to ethylmagnesium bromide to be 1:(1 to 1.2). After the dropwise addition is completed, continue to stir and react for 1 to 3 hours, add acetic acid solution to quench the reaction system, extract the reaction solution with ether, and obtain 1-(dimethylamino)-2-butanone by distillation. The concentration of the acetic acid solution is 10.4wt%, and the amount of acetic acid added is 1.5 equivalents of ethylmagnesium bromide.

[0029] (2-2) 1-(dimethylamino)-2-butanone and solvent ether are added to a reaction kettle, the temperature is lowered to -10 to 0°C, methylmagnesium bromide is slowly added dropwise, and the molar ratio of 1-(dimethylamino)-2-butanone to methylmagnesium bromide is controlled to be 1:(1 to 1.5). The mixture is stirred at room temperature for 2 to 4 days. After the reaction, it is quenched with a saturated ammonium chloride solution, extracted with ethyl acetate, and distilled to obtain 1-(dimethylamino)-2-methyl-2-butanol.

[0030] The prepared 1-dimethylamino-2-methyl-2-butanol can be used to prepare the corresponding alkylamino alcohol metal complex, such as alkylamino alcohol nickel complex, which specifically comprises the steps of:

[0031] Add 99% pure sodium hydride and solvent tetrahydrofuran into a reaction kettle, cool to -30 to 0°C, slowly add the tetrahydrofuran solution of amino alcohol drop by drop, continue stirring at room temperature for 2 to 8 hours after the addition is complete, filter, and vacuum dry to obtain the sodium salt of amino alcohol;

[0032] The sodium salt is reacted with hexaamminenickel chloride to obtain an alkylamino alcohol nickel complex. The specific steps are: [Ni(NH3)6]Cl2 and toluene are added into a reaction kettle, and the sodium salt of amino alcohol is slowly added. The molar ratio of [Ni(NH3)6]Cl2 to the sodium salt of amino alcohol is controlled to be 1:(2-2.5). The mixture is stirred under reflux for 8 hours. After cooling, the reaction mixture is filtered, and the volatile matter is removed under vacuum to obtain a crude product, which is then sublimated to obtain a pure product.

[0033] [Example 2]

[0034] This embodiment synthesizes 1-dimethylamino-2-methyl-2-propanol, specifically comprising the steps of:

[0035] (1) Preparation of ethyl N,N-dimethylaminoacetate: dimethylamine is dissolved in toluene cooled to -20 to 0°C, ethyl chloroacetate is added dropwise, and the molar ratio of ethyl chloroacetate to dimethylamine is controlled to be 1:(2 to 3), after stirring for 12 to 24 hours, the formed precipitate is filtered off, the solvent toluene is distilled off, and the product is obtained by vacuum distillation. The ethyl chloroacetate used is easily available and stable at room temperature.

[0036] (2) Preparation of N,N-dimethylamino alcohol: Add ethyl N,N-dimethylaminoacetate and solvent tetrahydrofuran into a reaction kettle, cool to -78 to 0°C, slowly drop methylmagnesium bromide, and control the molar ratio of ethyl N,N-dimethylaminoacetate to methylmagnesium bromide to be 1:(2 to 10). After the dropwise addition is complete, slowly warm to room temperature and stir to react for 1 to 48 hours. Add saturated ammonium chloride solution to quench the reaction system, extract the reaction solution with ether, and obtain 1-dimethylamino-2-methyl-2-propanol by distillation.

[0037] The reaction equation of 1-dimethylamino-2-methyl-2-propanol is shown below:

[0038]

[0039] [Example 3]

[0040] This embodiment synthesizes N,N-dimethylamino-2-methyl-2-butanol, specifically comprising the steps of:

[0041] Step 1: Preparation of ethyl N,N-dimethylaminoacetate

[0042] Under the condition of keeping warm at 0℃, 9g of dimethylamine (0.20mol) was introduced into 200mL of toluene solvent, and 12.2g of ethyl chloroacetate (0.10mol) was added dropwise. After keeping warm and stirring for 24h, the precipitate was filtered out, and toluene was distilled off. Vacuum distillation (10Torr) was performed to obtain 10.49g of ethyl N,N-dimethylaminoacetate. The distillation temperature was 55-58℃, and the yield was 80%.

[0043] Step 2: Preparation of N,N-dimethylamino-2-butanone

[0044] Under an inert atmosphere, 10.49 g of ethyl N, N-dimethylaminoacetate (0.08 mol) of step 1 was dissolved in 100 mL of tetrahydrofuran, the temperature was lowered to -15 ° C, 40 mL of ethyl magnesium bromide in tetrahydrofuran solution (2M) was slowly added, and after the addition was completed, the mixture was stirred for 3 h at room temperature, 10.4% acetic acid solution was added, and stirring was continued for 0.5 h. The reaction solution was extracted with ether 3 times, and 6.54 g of 1-(dimethylamino)-2-butanone was obtained by distillation, and the product was 71%.

[0045] Step 3: Preparation of N,N-dimethylamino-2-methyl-2-butanol

[0046] Under an inert atmosphere, 6.54 g of 1-(dimethylamino)-2-butanone (56.8 mmol) obtained in step 2 was dissolved in 60 mL of ether, the temperature was lowered to -10 ° C, 28.5 mL of methylmagnesium bromide ether solution (2M) was added dropwise, and the mixture was slowly heated to room temperature and stirred for 3 days. The mixture was quenched with saturated ammonium chloride solution, extracted with ethyl acetate, and 4.8 g of 1-(dimethylamino)-2-methyl-2-butanol was obtained by distillation, with a yield of 65%.

[0047] The obtained N,N-dimethylamino-2-methyl-2-butanol can be used to prepare the corresponding metal complex, and the specific steps are:

[0048] Step 4: Preparation of N,N-dimethylamino-2-methyl-2-butanol sodium salt

[0049] 0.63 g of sodium hydride (26 mmol, purity 99%) and 50 mL of tetrahydrofuran were added to a three-necked flask, cooled to -10°C, and the tetrahydrofuran solution (26 mmol, 2M) of the amino alcohol obtained in step 3 was slowly added dropwise. After the addition was completed, the temperature was raised to room temperature, and stirring was continued for 6 h. The mixture was filtered and vacuum-dried to obtain 3.6 g of the sodium salt of the amino alcohol, with a yield of 91%.

[0050] Step 5: Preparation of nickel dimethylamino alcohol complex

[0051] Under an inert atmosphere, 2.28 g of [Ni(NH3)6]Cl2 (12 mmol) was dissolved in 30 mL of toluene, and the sodium salt of the amino alcohol obtained in step 4 (24 mmol) was slowly added, and stirred under reflux for 8 h. After cooling, the reaction mixture was filtered, and the volatile substances were removed under vacuum to obtain a crude product, which was then sublimated to obtain 2.64 g of a pure product. The sublimation conditions were 10 -2 Torr, 70°C, yield 66%.

[0052] [Example 4]

[0053] This embodiment synthesizes N,N-dimethylamino-2-methyl-2-propanol, specifically comprising the steps of:

[0054] Step 1: Preparation of ethyl N,N-dimethylaminoacetate

[0055] Under the condition of keeping warm at 0℃, 9g dimethylamine (0.20mol) was introduced into 200mL toluene solvent, and 12.2g ethyl chloroacetate (0.10mol) was added dropwise. After keeping warm and stirring for 24h, the precipitate was filtered out, and toluene was distilled off. Vacuum distillation was performed to obtain 10.49g of ethyl N,N-dimethylaminoacetate, (10Torr) 55-58℃, and the yield was 80%.

[0056] Step 2: Preparation of N,N-dimethylamino-2-methyl-2-propanol

[0057] Under an inert atmosphere, 10.49 g of ethyl N, N-dimethylaminoacetate (0.08 mol) obtained in step 1 was dissolved in 60 mL of tetrahydrofuran, the temperature was lowered to -40 ° C, 80 mL of methyl magnesium bromide solution in tetrahydrofuran (2 M) was added dropwise, and the mixture was slowly heated to room temperature and stirred for 2 days. The mixture was quenched with saturated ammonium chloride solution, extracted with ether, and 7.9 g of 1-(dimethylamino)-2-methyl-2-propanol was obtained by distillation. The yield was 85%.

[0058] [Example 5-6]

[0059] The conditions are the same as those in Example 3, except that the amount of dimethylamine added in step 1 is increased. The specific results are shown in the following table:

[0060] Example Dimethylamine Yield Example 3 9g(0.2mol) 80％ Example 5 11.3g(0.25mol) 85％ Example 6 13.6g(0.30mol) 87％

[0061] [Examples 7-9]

[0062] The conditions were the same as those in Example 3, except that the reaction solvent in step 2 was replaced with diethyl ether, 1,4-dioxane, and methyl tert-butyl ether. The specific results are shown in the following table:

[0063] Example Solvents Yield Example 3 Tetrahydrofuran 71％ Example 7 Ether 70％ Example 8 1,4-Dioxane 65％ Example 9 Methyl tert-butyl ether 68％

[0064] [Examples 10-12]

[0065] The conditions were the same as those in Example 3, except that the amount of ethylmagnesium bromide added in step 2 was controlled to be 50-70 mL, and the data of 1-(dimethylamino)-2-butanone were as follows:

[0066] Example Ethyl magnesium bromide added amount (mL) Yield Example 3 40 71％ Example 10 50 75％ Embodiment 11 60 68％ Example 12 70 55％

[0067] [Examples 13-15]

[0068] The conditions are the same as those in Example 4, and the amount of methylmagnesium bromide added in step 2 is controlled to be 80-140 mL, and the data of 1-(dimethylamino)-2-methyl-2-propanol are as follows:

[0069]

[0070]

[0071] [Example 16]

[0072] All conditions were the same as those in Example 3, except that the stirring time at room temperature in step 3 was controlled to 1 day, and 4.1 g of 1-(dimethylamino)-2-methyl-2-butanol was obtained, with a calculated yield of 55%.

[0073] [Example 17]

[0074] All conditions were the same as those in Example 3, except that the stirring time at room temperature in step 4 was controlled to 2 h, and 3.16 g of the sodium salt of the amino alcohol was obtained, with a calculated yield of 80%.

[0075] [Example 18]

[0076] All conditions were the same as those in Example 3, except that the amount of sodium salt of amino alcohol added in step 5 was controlled to 3.9 g (26 mmol), and 2.8 g of dimethylamino alcohol nickel complex was obtained, with a calculated yield of 70%.

[0077] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made according to the scope of the patent application of the present invention should fall within the scope of the present invention.

Claims

1. A method for synthesizing a dialkylamino alcohol, characterized in that: The dialkylamino alcohol has the following general formula (I): ； The synthesis method comprises the steps of: reacting a dialkylamino ester represented by the general formula (II) with a Grignard reagent represented by the general formula (III); ， R3MgX1 (III), wherein R1-R5 independently represent lower alkyl groups, and X1 is halogen.

2. The method according to claim 1, characterized in that In the case where R3 and R4 are different, the method further comprises step b: adding a quenching agent to the reaction solution of step a, quenching and separating to obtain a dialkylaminoketone represented by general formula (IV), and reacting the quenching agent with a Grignard reagent represented by general formula (V) to prepare a dialkylaminoalcohol represented by general formula (I); ， R4MgX2 (V), Wherein, X2 is a halogen.

3. The method according to claim 1, characterized in that: Step a specifically comprises dissolving the dialkylamino ester in solvent A, and adding a Grignard reagent into the reaction system under low temperature conditions.

4. The method according to claim 3, characterized in that Solvent A is an ether solvent.

5. The method according to claim 2, characterized in that: Step b specifically comprises dissolving the dialkylaminoketone in solvent B, adding a Grignard reagent to the reaction system under low temperature conditions, and continuing the reaction under low temperature conditions.

6. The method according to claim 5, characterized in that Solvent B is one of THF, diethyl ether, 1,4-dioxane, and methyl tert-butyl ether.

7. The method according to claim 1, characterized in that The dialkylamino ester represented by the general formula (II) is obtained by reacting a dialkylamine with a halogenated acetic acid ester. The general reaction formula is as follows: 。 8. The method according to claim 7, characterized in that The preparation of dialkylamino ester specifically comprises: dissolving dialkylamine in solvent C under low temperature conditions, adding halogenated acetate to the reaction system; and obtaining dialkylamino ester by distillation and separation after the reaction is completed.

9. The method according to claim 8, characterized in that In the preparation process of dialkylamino ester, the reaction temperature ranges from -20 to 0°C; the solvent C is one of ethyl acetate, toluene, butyl acetate, methyl acetate and isopropyl acetate; the molar ratio of the halogenated acetate to the dialkylamine ranges from 1:(2 to 3); and the reaction time is 12 to 24 hours.

10. The method according to claim 1, characterized in that R1 and R2 are both methyl; R3 is methyl or ethyl, and R4 is methyl.

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