CN111039795A - Preparation method of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine - Google Patents
Preparation method of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine Download PDFInfo
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- CN111039795A CN111039795A CN201911306600.XA CN201911306600A CN111039795A CN 111039795 A CN111039795 A CN 111039795A CN 201911306600 A CN201911306600 A CN 201911306600A CN 111039795 A CN111039795 A CN 111039795A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
- C07C209/62—Preparation of compounds containing amino groups bound to a carbon skeleton by cleaving carbon-to-nitrogen, sulfur-to-nitrogen, or phosphorus-to-nitrogen bonds, e.g. hydrolysis of amides, N-dealkylation of amines or quaternary ammonium compounds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/02—Preparation of carboxylic acid amides from carboxylic acids or from esters, anhydrides, or halides thereof by reaction with ammonia or amines
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C231/00—Preparation of carboxylic acid amides
- C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/07—Optical isomers
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/14—The ring being saturated
Abstract
The invention discloses a preparation method of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine. The method comprises the following steps: in a solvent, under the action of alkali, performing methylation reaction on the cyclohexane compound shown in the formula III and a methylation reagent to obtain the cyclohexane compound shown in the formula II. According to the invention, the amino group is protected by the benzoyl group, so that two methyl groups can be prevented from being simultaneously added to the amino group, the methylation reaction condition is mild, the benzoyl group is easy to hydrolyze, the danger of using a large amount of lithium aluminum hydride is avoided, the generation of solid waste is reduced, and the environment protection is facilitated. The method has the advantages of low cost, environmental friendliness and high reaction yield, and is more suitable for industrial safety and large-scale productionAnd (4) production.
Description
Technical Field
The invention relates to a preparation method of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine.
Background
The structure of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine is shown as the formula I:
the (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine can be used as a key raw material for synthesizing a large class of chiral ligands, and the chiral ligands can be used in a plurality of asymmetric reactions. The synthesis of the intermediate generally starts from racemic cyclohexanediamine, obtains chiral cyclohexanediamine by resolution, then reacts with chloroformate, and then uses lithium aluminum hydride to reduce methoxycarbonyl to methyl. The method has the disadvantages that the method uses a large amount of lithium aluminum hydride, has high danger and cannot produce in large scale.
Disclosure of Invention
In order to solve the defects that a large amount of lithium aluminum hydride is needed to be used for preparing (1R,2R) - (-) -N, N '-dimethyl-1, 2-cyclohexanediamine, the danger is high, and the large-scale production cannot be realized in the prior art, the invention provides the preparation method of the (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine, the conditions of the method are mild, the solid waste is less, and the industrial large-scale production is utilized.
The invention provides a preparation method of cyclohexane compounds shown in a formula II, which comprises the following steps:
in a solvent, under the action of alkali, performing methylation reaction on the cyclohexane compound shown in the formula III and a methylation reagent to obtain the cyclohexane compound shown in the formula II;
in the methylation reaction, the solvent may be a solvent commonly used in such methylation reactions in the art, such as dimethylformamide.
In the methylation reaction, the base may be a base commonly used in such methylation reactions in the art, such as an inorganic base, further such as potassium carbonate.
In the methylation reaction, the amount of the base can be an amount commonly used in such methylation reactions in the field, for example, the molar ratio of the base to the cyclohexane compound shown in the formula III is (2-5): 1, e.g. 2:1, 3: 1.
In the methylation reaction, the methylating agent may be a methylating agent commonly used in the art for such methylation reactions, such as methyl iodide.
In the methylation reaction, the amount of the methylation reagent can be an amount commonly used in such methylation reactions in the field, for example, the molar ratio of the methylation reagent to the cyclohexane compound shown in formula III is (2-2.5): 1, e.g. 2: 1.
In the methylation reaction, the temperature of the methylation reaction can be the temperature commonly used in the methylation reaction in the field, such as 0-25 ℃, and further such as 20 ℃.
In the methylation reaction, the progress of the methylation reaction can be monitored according to a detection method (such as TLC, HPLC or GC, and further such as TLC) which is conventional in the art, and generally, the time when the cyclohexane compound shown as formula III disappears is used as an end point of the reaction, and the time of the methylation reaction can be 8-24 hours, for example, 24 hours.
The methylation reaction may also include the following work-up operations: filtering, mixing the filtrate with water (such as ice water), and centrifuging.
In the invention, the preparation method of the cyclohexane compound shown in the formula II can also comprise the following steps: in a solvent, under the action of an acid-binding agent, performing acylation reaction on (1R,2R) - (-) -1, 2-cyclohexanediamine and benzoyl chloride to obtain a cyclohexane compound shown as a formula III;
in the acylation reaction, the solvent may be a solvent commonly used in the art for such acylation reactions, such as a halogenated hydrocarbon solvent, e.g., dichloromethane.
In the acylation reaction, the acid-binding agent may be an acid-binding agent commonly used in the art for such acylation reactions, such as triethylamine.
In the acylation reaction, the acid-binding agent can be used in an amount commonly used in the field of such acylation reactions, for example, the molar ratio of the acid-binding agent to the (1R,2R) - (-) -1, 2-cyclohexanediamine is (2-8): 1, e.g. 3.6: 1.
In the acylation reaction, the benzoyl chloride can be used in an amount commonly used in the art for such acylation reactions, for example, the molar ratio of the benzoyl chloride to the (1R,2R) - (-) -1, 2-cyclohexanediamine is (2-2.5): 1, such as 2: 1.
in the acylation reaction, the temperature of the acylation reaction can be a temperature commonly used in the field for the acylation reaction, such as 0-20 ℃, and further such as 20 ℃.
In the acylation reaction, the progress of the acylation reaction can be monitored according to a detection method (such as TLC, HPLC or GC, and further such as TLC) which is conventional in the art, and the end point of the reaction is generally the time when (1R,2R) - (-) -1, 2-cyclohexanediamine disappears, and the time of the acylation reaction can be 8-24 hours, such as 16 hours.
The acylation reaction may also include the following work-up operations: washing (such as washing with water), separating the phases, and concentrating the organic phase.
The invention also provides a preparation method of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine, which comprises the following steps:
(1) preparing the cyclohexane compound shown in the formula II by adopting the preparation method of the cyclohexane compound shown in the formula II;
(2) sequentially carrying out hydrolysis reaction and neutralization reaction on the cyclohexane compounds shown in the formula II to obtain (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine shown in the formula I;
in step (2), the hydrolysis reaction may be carried out using conditions common to such hydrolysis reactions in the art, such as the addition of an acid. The acid may be an acid commonly used in the art for such hydrolysis reactions, such as hydrochloric acid, again for example concentrated hydrochloric acid with a mass fraction of 37%.
In the step (2), the temperature of the hydrolysis reaction may be a temperature commonly used in the field for such hydrolysis reaction, for example, 100 to 110 ℃.
In the step (2), the progress of the hydrolysis reaction may be monitored according to a conventional detection method in the art (e.g., TLC, HPLC, or GC), and generally, the time when the cyclohexane compound shown in formula II disappears is used as an end point of the reaction, and the time of the hydrolysis reaction may be 16 to 24 hours, for example, 24 hours.
In the step (2), the hydrolysis reaction may further include the following post-treatment steps: cooling, centrifuging, and concentrating the centrifugate.
In the post-treatment step of the hydrolysis reaction of step (2), preferably, benzoic acid obtained by the centrifugation is recovered.
In step (2), the neutralization reaction may be carried out by using conditions common in the art for such neutralization reactions, for example, by adding a base; the base may be a base commonly used in such neutralization reactions in the art, such as sodium hydroxide, and further such as an aqueous sodium hydroxide solution (e.g., 50% by weight aqueous sodium hydroxide).
In the step (2), the neutralization reaction may further include the following post-treatment steps: extracting with organic solvent (such as dichloromethane), and distilling the organic phase (such as vacuum distillation).
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: according to the invention, the amino group is protected by the benzoyl group, so that two methyl groups can be prevented from being simultaneously added to the amino group, the methylation reaction condition is mild, the benzoyl group is easy to hydrolyze, the danger of using a large amount of lithium aluminum hydride is avoided, the generation of solid waste is reduced, and the environment protection is facilitated. During the research, the benzoyl is the best choice, and other protecting groups (especially formate protecting groups such as Boc protecting groups) are easy to close in the molecule at the methylation reaction step, so that methyl cannot be removed.
The method has the advantages of low cost, environmental friendliness and high reaction yield, and is more suitable for industrial safe mass production.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, starting material (1R,2R) - (-) -1, 2-cyclohexanediamine can be synthesized according to the reference J.org.chem.1994,59,7, 1939-.
Example 1
114 kg (1000mol) of raw material (1R,2R) - (-) -1, 2-cyclohexanediamine is dissolved in 1000 l of dichloromethane, 500 l (3600mol) of triethylamine is added, the mixture is frozen and 281 kg (2000mol) of benzoyl chloride is slowly dropped, and the temperature is controlled not to exceed 25 ℃. After the addition, the mixture was stirred at 20 ℃ for 16 hours to complete the reaction, washed with water, and the organic phase was concentrated to give 310 kg of the benzoyl-protected product (compound III) in 96.3% yield.
Dissolving the intermediate obtained in the previous step in 1000L of dimethylformamide, adding 276 kg (2000mol) of solid potassium carbonate powder, dropwise adding 284 kg (2000mol) of methyl iodide, completely adding, stirring for 24 hours at 20 ℃ until the reaction is complete, filtering, pouring the filtrate into 2000L of ice water, separating out a product (compound II), centrifuging, and directly using for next hydrolysis.
Adding 1000 liters of concentrated hydrochloric acid with the mass fraction of 37 percent into the product (compound II) with the upper methyl group obtained by the reaction in the previous step, heating, refluxing and reacting for 24 hours, cooling, centrifuging and recovering benzoic acid after the reaction is finished, concentrating a centrifugal solution to obtain hydrochloride of (1R,2R) - (-) -N, N '-dimethyl-1, 2-cyclohexanediamine, dissolving the hydrochloride in water with one volume, adding a sodium hydroxide aqueous solution with the mass fraction of 50 percent for dissociating, extracting dichloromethane, and distilling under reduced pressure to obtain 120 kg of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine (compound I), wherein the total yield is 85 percent.
1H NMR(500MHz,CDCl3)δ:2.36(s,6H),2.10-2.04(m,2H),2.03-1.96(m,2H),1.47(s,2H),1.25-1.10(m,2H),0.98-0.85(m,2H).
Comparative example 1
114 g (1mol) of the starting material (1R,2R) - (-) -1, 2-cyclohexanediamine was dissolved in 500 ml of water and 500 ml of acetone, 169 g of sodium carbonate solid was added and 480 g of Boc anhydride was added in one portion. Stirring for 16 hours at 20 ℃, filtering, concentrating the filtrate to remove acetone, adding ethyl acetate for extraction, drying and concentrating to obtain 300 g of a product.
Dissolving 31.4 g of the Boc-added product in 250ml of DMF, adding 27.6 g of ground potassium carbonate powder, dropwise adding 30 g of methyl iodide, stirring at 20 ℃ for 16 hours after adding, filtering, pouring the filtrate into 1L of ice water to separate out a product, filtering and drying to obtain 24 g of the product, wherein the yield is 94.5%.
1H NMR(500MHz,CDCl3)δ:3.25-3.15(m,1H),3.75(s,3H),3.74-3.70(m,1H),3.62-3.55(m,1H),2.1-2.05(m,1H),1.96-1.88(m,2H),1.53(s,9H),1.40-1.30(m,4H)。
Claims (10)
1. A preparation method of cyclohexane compounds shown in a formula II is characterized by comprising the following steps:
in a solvent, under the action of alkali, performing methylation reaction on the cyclohexane compound shown in the formula III and a methylation reagent to obtain the cyclohexane compound shown in the formula II;
2. the method according to claim 1, wherein the solvent is dimethylformamide;
and/or, in the methylation reaction, the alkali is inorganic alkali;
and/or in the methylation reaction, the molar ratio of the alkali to the cyclohexane compound shown in the formula III is (2-5): 1;
and/or, in the methylation reaction, the methylating agent is methyl iodide;
and/or in the methylation reaction, the molar ratio of the methylation reagent to the cyclohexane compound shown in the formula III is (2-2.5): 1;
and/or the temperature of the methylation reaction is 0-25 ℃;
and/or the methylation reaction time is 8-24 hours;
and/or, the methylation reaction further comprises the following post-treatment operations: filtering, mixing the filtrate with water, and centrifuging.
3. The method for preparing the cyclohexane compound shown in the formula II according to claim 2, wherein in the methylation reaction, the base is potassium carbonate;
and/or the molar ratio of the base to the cyclohexane compound shown in the formula III is 2:1 or 3: 1;
and/or the molar ratio of the methylating agent to the cyclohexane compound shown in the formula III is 2: 1;
and/or the temperature of the methylation reaction is 20 ℃;
and/or the methylation reaction time is 24 hours.
4. The method for preparing the cyclohexane compound represented by the formula II according to claim 1, wherein the method for preparing the cyclohexane compound represented by the formula II further comprises the following steps: in a solvent, under the action of an acid-binding agent, performing acylation reaction on (1R,2R) - (-) -1, 2-cyclohexanediamine and benzoyl chloride to obtain a cyclohexane compound shown as a formula III;
5. the method for preparing the cyclohexane compound represented by the formula II according to claim 4, wherein the solvent is dichloromethane in the acylation reaction;
and/or in the acylation reaction, the acid-binding agent is triethylamine;
and/or in the acylation reaction, the molar ratio of the acid-binding agent to the (1R,2R) - (-) -1, 2-cyclohexanediamine is (2-8): 1;
and/or, in the acylation reaction, the molar ratio of the benzoyl chloride to the (1R,2R) - (-) -1, 2-cyclohexanediamine is (2-2.5): 1;
and/or the temperature of the acylation reaction is 0-20 ℃;
and/or the time of the acylation reaction is 8-24 hours;
and/or, the acylation reaction also comprises the following post-treatment operations: washing, separating phases, and concentrating the organic phase.
6. The method for preparing the cyclohexane compound represented by the formula II according to claim 5, wherein in the acylation reaction, the molar ratio of the acid-binding agent to the (1R,2R) - (-) -1, 2-cyclohexanediamine is 3.6: 1;
and/or, in the acylation reaction, the molar ratio of the benzoyl chloride to the (1R,2R) - (-) -1, 2-cyclohexanediamine is 2: 1;
and/or the temperature of the acylation reaction is 20 ℃;
and/or the time of the acylation reaction is 16 hours.
7. A preparation method of (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine is characterized by comprising the following steps:
(1) preparing the cyclohexane compound shown in the formula II by adopting the preparation method of the cyclohexane compound shown in the formula II as claimed in any one of claims 1 to 6;
(2) sequentially carrying out hydrolysis reaction and neutralization reaction on the cyclohexane compounds shown in the formula II to obtain (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine shown in the formula I;
8. the process for preparing (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine according to claim 7, wherein in step (2), the hydrolysis is carried out by adding an acid, said acid being hydrochloric acid;
and/or in the step (2), the temperature of the hydrolysis reaction is 100-110 ℃;
and/or in the step (2), the time of the hydrolysis reaction is 16-24 hours;
and/or, in the step (2), the hydrolysis reaction further comprises the following post-treatment steps: cooling, centrifuging, and concentrating the centrifugate.
9. The process for preparing (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine according to claim 8, wherein in step (2), the hydrolysis is carried out by adding an acid, which is concentrated hydrochloric acid with a mass fraction of 37%;
and/or in the step (2), the time of the hydrolysis reaction is 24 hours;
and/or, in the post-treatment step of the hydrolysis reaction in the step (2), recovering the benzoic acid obtained by centrifugation.
10. The process for preparing (1R,2R) - (-) -N, N' -dimethyl-1, 2-cyclohexanediamine according to claim 7, wherein in step (2), the neutralization reaction is carried out by adding a base, wherein the base is sodium hydroxide;
and/or, in the step (2), the neutralization reaction further comprises the following post-treatment steps: extracting with organic solvent, and distilling organic phase.
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| CN102695740A (en) * | 2010-01-07 | 2012-09-26 | 赫克塞尔合成有限公司 | Novel resin curing agents |
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| CN105294997A (en) * | 2015-11-14 | 2016-02-03 | 华玉叶 | High-viscosity curing agent composition |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102695740A (en) * | 2010-01-07 | 2012-09-26 | 赫克塞尔合成有限公司 | Novel resin curing agents |
| CN105237738A (en) * | 2015-11-14 | 2016-01-13 | 华玉叶 | High-viscosity curing agent composition |
| CN105294997A (en) * | 2015-11-14 | 2016-02-03 | 华玉叶 | High-viscosity curing agent composition |
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| HIDEKAZU YAMADA等: "Diastereoselective Imine-Bond Formation through Complementary Double-Helix Formation", 《JOURNAL OF THE AMERICAN CHEMICAL SOCIETY》 * |
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