CN114213255A - Synthetic method of six-membered ring benzylamine compound - Google Patents
Synthetic method of six-membered ring benzylamine compound Download PDFInfo
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- C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
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- C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
- C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
- C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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- C07C2601/14—The ring being saturated
Abstract
The application relates to the field of organic matter synthesis, and particularly discloses a synthetic method of a six-membered ring benzylamine compound, which comprises the following steps: taking a compound D, a compound E and potassium tert-butoxide as raw materials, taking dimethyl sulfoxide as a solvent, reacting at 5-10 ℃ for 1-2h, then heating to 20 ℃ for reaction, and after the reaction is finished, purifying and separating to obtain a compound A; taking the compound A, potassium carbonate and hydrogen peroxide as raw materials, taking dimethyl sulfoxide as a solvent, reacting at 50-65 ℃, adding ice water after the reaction is finished to separate out a product, filtering and washing to obtain a compound B; and dissolving the compound B in acetonitrile, adjusting the pH value to be within the range of 13-14, adding a saturated sodium hypochlorite solution for reaction, and purifying and washing after the reaction is finished to obtain a compound C. The method has the effect of overcoming the defect that the synthesis process of the hexatomic ring benzylamine compound is not suitable for industrial production.
Description
Technical Field
The application relates to the field of organic matter synthesis, in particular to a synthetic method of a six-membered ring benzylamine compound.
Background
The six-membered ring benzylamine compound refers to a benzylamine compound with a six-membered heterocyclic ring or a six-membered carbocyclic ring on a molecular chain besides a benzene ring. The six-membered ring benzylamine compound and the derivative thereof are the core mother nucleus of ACY-775 of an HDAC6 inhibitor, are used for treating malignant tumors, and have a remarkable effect of improving IC 50. In addition, the six-membered ring benzylamine compound can also be applied to preventing diseases with pathological characteristics of metabolic pathways, such as cardiovascular diseases, Alzheimer's disease and the like.
The six-membered ring benzylamine compound has wide application prospect as a drug intermediate, however, in the related technology, the compound is usually synthesized by using a format reagent as a raw material, the synthesis method is limited, the synthesis cost is high, the synthesis process is complicated, and the six-membered ring benzylamine compound is not suitable for industrial production. In recent years, although new synthesis methods have appeared, the overall yield is low, taking 1- (3-fluorophenyl) cyclohexylamine as an example, in the related art, 1- (3-fluorophenyl) cyclohexanecarbonitrile is converted into 1- (3-fluorophenyl) cyclohexanecarboxamide by polyphosphoric acid, and then the 1- (3-fluorophenyl) cyclohexanecarboxamide is reacted with sodium hypochlorite to obtain a product. Wherein, the polyphosphoric acid and the 1- (3-fluorophenyl) cyclohexanecarbonitrile need to react at a high temperature of 110 ℃, the post-treatment operation is complicated, the polyphosphoric acid and the 1- (3-fluorophenyl) cyclohexanecarbonitrile need to be quenched by sodium bicarbonate aqueous solution, bubbles are continuously generated in the quenching process, the reaction yield is low, and the polyphosphoric acid and the 1- (3-fluorophenyl) cyclohexanecarbonitrile are not suitable for industrial production.
Disclosure of Invention
In order to overcome the defect that the synthesis process of the six-membered ring benzylamine compound is not suitable for industrial production, the application provides a synthesis method of the six-membered ring benzylamine compound.
The synthesis method of the hexatomic ring benzylamine compound adopts the following technical scheme:
a synthetic method of a six-membered ring benzylamine compound comprises the following steps:
s1, taking a compound A, potassium carbonate and hydrogen peroxide as raw materials, taking dimethyl sulfoxide as a solvent, reacting at 50-65 ℃, wherein the mass fraction of the hydrogen peroxide is 30% -35%, the mass ratio of the compound A to the potassium carbonate is 1 (2.05-2.15), the feeding ratio of the compound A to the hydrogen peroxide is (5-7) mol:1L, adding ice water to precipitate a product after the reaction is finished, and filtering and washing to obtain a compound B;
s2, dissolving the compound B in acetonitrile, adjusting the pH value to be 13-14, adding a saturated sodium hypochlorite solution for reaction, wherein the feeding ratio of the compound B to the saturated sodium hypochlorite solution is (4.2-4.9) mol:1L, and purifying and washing after the reaction is finished to obtain a compound C;
the compound A is represented by the following chemical formula I:
the chemical formula is as follows:
wherein R is selected from one of hydrogen, fluorine, chlorine, bromine and methoxy, and X is selected from one of the following groups:
(1) x is one of carbon, nitrogen and oxygen;
or (2) X is represented by the following formula two:
the chemical formula II:
or (3) X is represented by the following formula three:
the chemical formula III:
the compound B is represented by the following formula iv:
chemical formula four:
the compound C is represented by the following chemical formula five:
the chemical formula is five:
by adopting the technical scheme, in a dimethyl sulfoxide-potassium carbonate-hydrogen peroxide system, the cyano group in the compound A is hydrolyzed into an amide group, only ice water is needed to be added after the reaction is finished to separate out the solid, and the product can be obtained after filtering and washing, so that the post-treatment operation is simple and convenient, the yield is higher, compared with the process using polyphosphoric acid as a raw material, the process has the advantages of simplifying the process steps, improving the yield and being suitable for industrial production;
the saturated sodium hypochlorite solution in the application refers to a saturated sodium hypochlorite solution at the temperature of 20 ℃ and under the standard atmospheric pressure, the compound B is better in solubility in acetonitrile, the acetonitrile is a water-soluble solvent and is suitable for forming a reaction system with the compound B and the saturated sodium hypochlorite solution, the compound C can be obtained by purification and washing after the reaction is finished, the operation is simple and convenient, the yield is higher, and the possibility is provided for the industrial production of the hexatomic ring benzylamine compound.
Optionally, in the step S1, the compound a is dissolved in dimethyl sulfoxide, potassium carbonate is added, and hydrogen peroxide is added at a rate of 0.5 to 1 ml/min.
By adopting the technical scheme, heat is generated in the reaction process of the compound A, the potassium carbonate and the hydrogen peroxide, and the hydrogen peroxide is slowly added at the rate of 0.5-1ml/min, so that the concentrated heat release is reduced, and the influence of temperature change on the reaction is reduced.
Optionally, in the step S1, hydrogen peroxide is added at 20 ℃, and then the temperature is increased to 60 ℃ at a rate of 5-20 ℃/min for reaction.
By adopting the technical scheme, the reaction is violent in the process of adding hydrogen peroxide, hydrogen peroxide is added at 20 ℃, and then the temperature is raised to 60 ℃ for reaction, so that the reaction temperature is convenient to control, and the possibility of side reaction caused by violent initial reaction is reduced.
Optionally, in the step S2, a saturated sodium hypochlorite solution is added at a rate of 1-2 ml/min.
By adopting the technical scheme, the saturated sodium hypochlorite solution is slowly added at the rate of 1-2ml/min, so that the temperature of a reaction system can be controlled, and the possibility of side reaction caused by concentrated heat release of the reaction is reduced.
Optionally, in the step S2, a saturated sodium hypochlorite solution is added at 0-5 ℃, and then the temperature is raised to 20 ℃ for reaction.
By adopting the technical scheme, the reaction is violent in the process of adding the saturated sodium hypochlorite solution, the saturated sodium hypochlorite solution is added at 0-5 ℃, and the temperature is raised to 20 ℃ for reaction, so that the reaction temperature is convenient to control, and the influence of temperature change on the reaction is reduced.
Optionally, in the step S2, the purification washing step includes the following steps:
acid washing: adding hydrochloric acid to adjust the pH value of the solution to 5, and performing primary extraction by ethyl acetate;
alkali washing: the aqueous solution obtained by the primary extraction was taken, added with sodium hydroxide to adjust the solution to pH 9, and subjected to secondary extraction with ethyl acetate to obtain compound C.
By adopting the technical scheme, in the acid washing process, the compound C is converted into salt to be dissolved in water, impurities such as residual raw materials, solvents and the like are removed by ethyl acetate extraction, the compound C is obtained again by alkali washing, and the compound C with higher purity is obtained after the impurities such as inorganic salt and the like are removed by extraction.
Optionally, the compound a is prepared by the following steps:
preparation stage of compound a: taking a compound D, a compound E and potassium tert-butoxide as raw materials, taking dimethyl sulfoxide as a solvent, reacting at 5-20 ℃, wherein the mass ratio of the compound D, the compound E and the potassium tert-butoxide is 1:1:2.1, and purifying and separating after the reaction is finished to obtain a compound A;
the compound D is represented by the following formula six:
chemical formula six:
the compound E is represented by the following formula seven:
a seventh chemical formula:
by adopting the technical scheme, compared with the compound A, the compound D and the compound E are easily available raw materials, so that the compound A is prepared from the compound D and the compound E, and is suitable for industrial production; the common synthesis method takes a compound D, a compound E and sodium hydride as raw materials, the raw materials react in N, N-dimethylformamide, the sodium hydride is easy to burn, the heat is violently released during the reaction in the N, N-dimethylformamide, the safety risk exists, and the yield is low; the compound D, the compound E and potassium tert-butoxide are used as raw materials to react in dimethyl sulfoxide, hydrogen on a bivalent methyl group of the compound D has acidity, and the potassium tert-butoxide is alkaline, so that the hydrogen on the bivalent methyl group of the compound D can be captured to form carbocation, and then the compound D and the compound E react to form a six-membered ring.
Optionally, in the preparation stage of the compound a, the reaction solution is stirred, and the reaction is performed for 1-2 hours at 5-10 ℃, and then the temperature is raised to 20 ℃ for reaction.
By adopting the technical scheme, in the process of reacting at 5-10 ℃ for 1-2h, raw materials are uniformly mixed by stirring, the reaction can be fully carried out after the temperature is raised to 20 ℃, and meanwhile, the reaction is carried out at a lower temperature and then the temperature is raised, so that the heat release in the initial stage of the reaction can be reduced, and the side reaction is not easy to occur.
Optionally, in the preparation stage of the compound a, the compound D is dissolved in dimethyl sulfoxide, the solution is cooled to 0-5 ℃, potassium tert-butoxide is added, the compound E is added at a rate of 1-2ml/min, and the temperature is controlled at 5-20 ℃ for reaction.
By adopting the technical scheme, the potassium tert-butoxide and the compound E are added at a lower temperature, so that the heat release at the initial stage of the reaction is reduced, and the possibility of side reaction caused by heat generated by violent reaction is reduced.
Optionally, in the preparation stage of the compound a, the purification and separation comprises the following steps:
and (3) extraction: extracting the reacted solution by ethyl acetate;
washing: taking an organic phase obtained by extraction, and washing the organic phase by using a saturated sodium chloride solution;
and (3) spin-drying: the solvent was removed by rotary evaporation to give compound a.
By adopting the technical scheme, the saturated sodium chloride solution in the application refers to a saturated sodium chloride solution at the temperature of 20 ℃ and under the standard atmospheric pressure, impurities such as inorganic salts in the reaction solution are removed through extraction, and the solvent is dried in a spinning mode after washing, so that the compound A with high purity can be obtained.
In summary, the present application includes at least one of the following beneficial technical effects:
1. in a dimethyl sulfoxide-potassium carbonate-hydrogen peroxide system, cyano in the compound A is hydrolyzed into an amide group, only ice water is needed to be added after the reaction is finished to separate out solids, and the product can be obtained after filtration and washing, so that the post-treatment operation is simple and convenient, the yield is higher, compared with a process using polyphosphoric acid as a raw material, the process not only simplifies the process steps, but also improves the yield, and the process is suitable for industrial production; the compound B has good solubility in acetonitrile, the acetonitrile is a water-soluble solvent, and is suitable for forming a reaction system with the compound B and a saturated sodium hypochlorite solution, and the compound C can be obtained by purification and washing after the reaction is finished, so that the operation is simple and convenient, the yield is high, and the possibility is provided for the industrial production of the hexatomic ring benzylamine compound;
2. in the acid washing process, converting the compound C into salt, dissolving the salt in water, extracting by ethyl acetate, removing impurities such as residual raw materials, solvents and the like, obtaining the compound C again by alkali washing, and extracting to remove impurities such as inorganic salt and the like to obtain the compound C with higher purity;
3. compared with the compound A, the compound D and the compound E are easily available raw materials, so that the compound A is prepared from the compound D and the compound E and is suitable for industrial production; the compound D, the compound E and potassium tert-butoxide are used as raw materials to react in dimethyl sulfoxide, hydrogen on a bivalent methyl group of the compound D has acidity, and the potassium tert-butoxide is alkaline, so that the hydrogen on the bivalent methyl group of the compound D can be captured to form carbocation, and then the compound D and the compound E react to form a six-membered ring.
Detailed Description
Source of raw materials
Unless otherwise specified, the starting materials in the following examples and comparative examples were purchased from Hadamard reagent, wherein the polyphosphoric acid is available under the designation 84132C, P2O5The content is 85 percent.
Examples
Example 1
A method for synthesizing 1- (3-fluorophenyl) cyclohexylamine has the following reaction equation:
table 1 example 1 the raw materials used and their charge amounts
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 3-fluorophenylacetonitrile | C8H6FN | 135.14 | 100g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 174.4g |
| 1, 5-dibromopentane | C5H10Br2 | 229.94 | 170.2g |
| Potassium carbonate | K2CO3 | 138.21 | 186g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 100ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 50ml |
The method comprises the following steps:
p1, weighing 100g of 3-fluorobenzonitrile into a three-neck flask, adding 500ml of dimethyl sulfoxide for dissolving, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 800r/min until the reaction is finished, adding 174.4g of potassium tert-butoxide, dropping 170.2g of 1, 5-dibromopentane at the rate of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 1h, removing the ice-water bath, heating at 20 deg.C, reacting at 20 deg.C for 16h, adding 1L ice water to quench the reaction, the organic phases were combined after extraction was complete, washed with saturated sodium chloride solution (20 ℃, saturated solution at standard atmospheric pressure) and the solvent was spin dried by rotary evaporator to give 1- (3-fluorophenyl) cyclohexanecarbonitrile.
P2, weighing 130g of 1- (3-fluorophenyl) cyclohexanecarbonitrile obtained in the step P1, adding 500ml of dimethyl sulfoxide to dissolve, adding 186g of potassium carbonate, adding 100ml of hydrogen peroxide at the speed of 1ml/min under the condition of 20 ℃, heating the hydrogen peroxide to 60 ℃ at the speed of 10 ℃/min to react for 2h, cooling the mixture at the temperature of 20 ℃ after the reaction is finished, adding ice water to separate out a product, filtering, and washing with water to obtain the 1- (3-fluorophenyl) cyclohexanecarboxamide.
P3, weighing 50g of 1- (3-fluorophenyl) cyclohexanecarboxamide obtained in the step P2, adding 250ml of acetonitrile to dissolve the 1- (3-fluorophenyl) cyclohexanecarboxamide, adjusting the pH to 13 by using 5mol/L of sodium hydroxide solution, cooling the solution to 0 ℃ under the condition of ice water bath, dropwise adding 50ml of saturated sodium hypochlorite solution (20 ℃, saturated solution under standard atmospheric pressure) at the rate of 1ml/min, heating the solution at the environment of 20 ℃, controlling the temperature to be 20 ℃ to react for 12 hours, adding 1mol/L of hydrochloric acid to adjust the pH of the solution to 5 after the reaction is finished, performing primary extraction by using 200ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L of sodium hydroxide solution to adjust the pH to 9, and performing secondary extraction by using 200ml of ethyl acetate to obtain the 1- (3-fluorophenyl) cyclohexaneamine.
Through detection, the purity of the 1- (3-fluorophenyl) cyclohexanecarbonitrile in the step P1 is 95%, and the yield is 88%;
the purity of 1- (3-fluorophenyl) cyclohexanecarboxamide in the P2 step was 95%, and the yield was 95%;
the purity of 1- (3-fluorophenyl) cyclohexylamine in the P3 step was 97%, the yield was 90%, and the detection data was LCMS ═ 176.1(M + H)+.NMR(400MHz,CDCl3)δ8.43(s,2H),7.39-7.35(m,1H),7.09-7.05(m,2H),6.97(t,J＝7.7Hz,1H),1.70-1.43(m,9H),1.37-1.25(m,1H)。
Example 2
A method for synthesizing 1-phenylcyclohexylamine comprises the following reaction equation:
table 2 raw materials and their amounts used in example 2
| Reagent | Molecular formula | Molecular weight | Feed amount |
| Benzyl cyanide | C8H6FN | 117.15 | 10g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 20.1g |
| 1, 5-dibromopentane | C5H10Br2 | 229.94 | 19.62g |
| Potassium carbonate | K2CO3 | 138.21 | 20.3g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 10ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 5ml |
The method comprises the following steps:
p1, weighing 10g of phenylacetonitrile into a three-neck flask, adding 50ml of dimethyl sulfoxide for dissolving, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 600r/min until the reaction is finished, adding 20.1g of potassium tert-butoxide, dropping 19.62g of 1, 5-dibromopentane at the rate of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 1h, removing the ice-water bath, heating at 20 deg.C, reacting at 20 deg.C for 16h, adding 100ml ice water to quench reaction, extracting with ethyl acetate twice, using 50ml ethyl acetate for each extraction, combining the organic phases after the extraction is completed, washing with saturated sodium chloride solution (20 deg.C, saturated solution under standard atmospheric pressure), the solvent was spin-dried by a rotary evaporator to give 1-phenyl-1-cyclohexanecarbonitrile.
P2, weighing 13g of 1-phenyl-1-cyclohexanecarbonitrile obtained in the step P1, adding 50ml of dimethyl sulfoxide to dissolve, adding 20.3g of potassium carbonate, adding 10ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the speed of 10 ℃/min to react for 2.5h, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 1-phenylcyclohexanecarboxamide.
P3, weighing 5g of 1-phenylcyclohexanecarboxamide obtained in the step P2, adding 25ml of acetonitrile for dissolving, adjusting the pH to 13 by using 5mol/L sodium hydroxide solution, cooling the solution to 0 ℃ under the condition of ice water bath, dropwise adding 5ml of saturated sodium hypochlorite solution (20 ℃, saturated solution under standard atmospheric pressure) at the rate of 1ml/min, heating at the environment of 20 ℃, controlling the temperature to 20 ℃ for reacting for 8 hours, adding 1mol/L hydrochloric acid to adjust the pH of the solution to 5 after the reaction is finished, performing primary extraction by using 30ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L sodium hydroxide solution to adjust the pH to 9, and performing secondary extraction by using 30ml of ethyl acetate to obtain the 1-phenylcyclohexylamine.
Through detection, the purity of the 1-phenyl-1-cyclohexanecarbonitrile in the step P1 is 96%, and the yield is 85%;
the purity of the 1-phenylcyclohexanecarboxamide in the P2 step is 95%, and the yield is 92%;
the purity of 1-phenylcyclohexylamine in P3 step was 96%, the yield was 92%, and the detection data was LCMS 158.1(M + H)+.NMR(400MHz,CDCl3)δ8.42(s,2H),7.56-7.50(m,2H)，7.35(t,J＝7.7Hz,2H),7.25-7.19(m,1H),1.73-1.46(m,9H),1.40-1.28(m,1H)
Example 3
A method for synthesizing 1-Boc-4-phenyl-4-piperidylamine has the following reaction equation:
table 3 raw materials and their amounts charged in example 3
| Reagent | Molecular formula | Molecular weight | Feed amount |
| Benzyl cyanide | C8H6FN | 117.15 | 50g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 100.5g |
| N-Boc-N, N-bis (2-bromoethyl) amine | C9H17Br2NO2 | 331.04 | 141.3g |
| Potassium carbonate | K2CO3 | 138.21 | 91.7g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 50ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 35ml |
The method comprises the following steps:
p1, weighing 50g of phenylacetonitrile into a three-neck flask, adding 250ml of dimethyl sulfoxide for dissolution, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 800r/min until the reaction is finished, adding 100.5g of potassium tert-butoxide, adding 141.3g of N-Boc-N, N-bis (2-bromoethyl) amine dropwise at the rate of 1ml/min, controlling the temperature at 5-10 ℃ for reaction for 1h, removing the ice water bath, heating up under the environment of 20 ℃, controlling the temperature at 20 ℃ for reacting for 16h, adding 600ml of ice water to quench the reaction after the reaction is finished, extracting with ethyl acetate twice (250 ml for each extraction), mixing the organic phases after extraction, washing with saturated sodium chloride solution (20 deg.C, saturated solution at standard atmospheric pressure), the solvent was spin dried by rotary evaporator to give 1-Boc-4-cyano-4-phenylpiperidine.
P2, weighing 90g of 1-Boc-4-cyano-4-phenylpiperidine obtained in the step P1, adding 300ml of dimethyl sulfoxide to dissolve the 1-Boc-4-cyano-4-phenylpiperidine, adding 91.7g of potassium carbonate, adding 50ml of hydrogen peroxide at the rate of 1ml/min at the temperature of 20 ℃, heating the hydrogen peroxide at the rate of 10 ℃/min to 60 ℃ to react for 2h, cooling the mixture at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering the product, and washing the product with water to obtain the 1-Boc-4-phenylpiperidine-4-formamide.
P3, weighing 50g of 1-Boc-4-phenylpiperidine-4-carboxamide obtained in the step P2, adding 160ml of acetonitrile to dissolve, adjusting pH to 14 by 5mol/L sodium hydroxide solution, the solution was cooled to 0 ℃ under ice-water bath conditions, 35ml of a saturated sodium hypochlorite solution (20 ℃, saturated solution at standard atmospheric pressure) was added dropwise at a rate of 1ml/min, heating at 20 deg.C, reacting at 20 deg.C for 10h, adding 1mol/L hydrochloric acid to adjust pH to 5, performing primary extraction by 200ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L of sodium hydroxide solution to adjust the pH value to 9, a second extraction was performed with 200ml of ethyl acetate to obtain 1-Boc-4-phenyl-4-piperidinamine.
Through detection, the purity of the 1-Boc-4-cyano-4-phenylpiperidine in the step P1 is 97%, and the yield is 75%;
the purity of 1-Boc-4-phenylpiperidine-4-carboxamide in the P2 step was 95%, and the yield was 89%;
the purity of 1-Boc-4-phenyl-4-piperidinamine in P3 step was 95% with a yield of 93%, and the detection data was LCMS ═ 259.1(M + H)+.NMR(400MHz,DMSO-d6)δ＝8.42(s.,2H),7.64(d,J＝7.2Hz,2H),7.56-7.39(m,3H),3.80-3.63(m,2H),3.01(d,J＝7.3Hz,2H),2.42(d,J＝14.1Hz,2H),2.08-1.92(m,2H),1.40(s,9H)。
Example 4
A method for synthesizing 1-methyl-4-phenyl-4-piperidylamine has the following reaction equation:
table 4 example 4 raw materials and their amounts charged
| Reagent | Molecular formula | Molecular weight | Feed amount |
| Benzyl cyanide | C8H6FN | 117.15 | 10g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 20.1g |
| 2-bromo-N- (2-bromoethyl) -N-methylethylamine | C5H11Br2N | 244.96 | 20.9g |
| Potassium carbonate | K2CO3 | 138.21 | 14.5g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 9ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 5ml |
The method comprises the following steps:
p1, weighing 10g of phenylacetonitrile into a three-neck flask, adding 50ml of dimethyl sulfoxide to dissolve, cooling the solution to 0 ℃ under the condition of ice-water bath, stirring at the speed of 700r/min until the reaction is finished, adding 20.1g of potassium tert-butoxide, dropwise adding 20.9g of 2-bromo-N- (2-bromoethyl) -N-methylethylamine at the speed of 1ml/min, controlling the temperature to be 5-10 ℃ to react for 1.5h, removing the ice-water bath, heating at the temperature of 20 ℃, controlling the temperature to react for 16h, adding 100ml of ice water to quench the reaction after the reaction is finished, extracting twice through ethyl acetate, using 50ml of ethyl acetate for each extraction, combining organic phases after the extraction is finished, washing through a saturated sodium chloride solution (20 ℃, a saturated solution under the standard atmospheric pressure), spin-drying the solvent through a rotary evaporator, to obtain 4-cyano-1-methyl-4-phenylpiperidine.
P2, weighing 10g of 4-cyano-1-methyl-4-phenylpiperidine obtained in the step P1, adding 50ml of dimethyl sulfoxide to dissolve, adding 14.5g of potassium carbonate, adding 9ml of hydrogen peroxide at the rate of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the rate of 10 ℃/min to react for 2.5h, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 1-methyl-4-phenylpiperidine-4-formamide.
P3, weighing 5g of 1-methyl-4-phenylpiperidine-4-formamide obtained in the step P2, adding 25ml of acetonitrile to dissolve the 1-methyl-4-phenylpiperidine-4-formamide, adjusting the pH to 13 by using 5mol/L sodium hydroxide solution, cooling the solution to 0 deg.C in ice water bath, adding 5ml of saturated sodium hypochlorite solution (20 deg.C, saturated solution under standard atmospheric pressure) dropwise at a rate of 1ml/min, heating at 20 deg.C, reacting at 20 deg.C for 11h, adding 1mol/L hydrochloric acid to adjust pH to 5, extracting with 30ml ethyl acetate, taking the water solution obtained by the extraction, adding 1mol/L sodium hydroxide solution to adjust the pH value to 9, the mixture was subjected to secondary extraction with 30ml of ethyl acetate to give 1-methyl-4-phenyl-4-piperidinamine.
Through detection, the purity of the 4-cyano-1-methyl-4-phenylpiperidine in the step P1 is 95%, and the yield is 80%;
the purity of 1-methyl-4-phenylpiperidine-4-carboxamide in step P2 was 97%, and the yield was 94%;
the purity of 1-methyl-4-phenyl-4-piperidinamine in P3 step was 94%, the yield was 90%, and the assay data was LCMS 173.1(M + H)+.NMR(400MHz,DMSO-d6)δ＝8.42(s.,2H),7.64(d,J＝7.2Hz,2H),7.56-7.39(m,3H),2.51-2.41(m,4H),2.18(s,3H),2.13(t,J＝7.3Hz,2H),1.88(t,J＝14.1Hz,2H)。
Example 5
A method for synthesizing 4-phenyltetrahydropyran-4-amine has the following reaction equation:
table 5 example 5 raw materials and their amounts charged
| Reagent | Molecular formula | Molecular weight | Feed amount |
| Benzyl cyanide | C8H6FN | 117.15 | 20g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 40.2g |
| Bis (2-bromoethyl) ether | C4H8Br2O | 231.91 | 39.6g |
| Potassium carbonate | K2CO3 | 138.21 | 20.2g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 10ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 10ml |
The method comprises the following steps:
p1, weighing 20g of benzyl cyanide in a three-neck flask, adding 100ml of dimethyl sulfoxide for dissolving, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 1000r/min until the reaction is finished, adding 40.2g of potassium tert-butoxide, dripping 39.6g of bis (2-bromoethyl) ether at the speed of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 1h, removing the ice water bath, heating up under the environment of 20 ℃, controlling the temperature at 20 ℃ for reacting for 16h, adding 200ml of ice water to quench the reaction after the reaction is finished, extracting with ethyl acetate twice, using 100ml of ethyl acetate for each extraction, combining the organic phases after the extraction is completed, washing with saturated sodium chloride solution (20 deg.C, saturated solution at standard atmospheric pressure), the solvent was spin-dried by rotary evaporator to give 4-phenyl-4-cyanotetrahydropyran.
P2, weighing 13g of 4-phenyl-4-cyano tetrahydropyran obtained in the step P1, adding 50ml of dimethyl sulfoxide to dissolve, adding 20.2g of potassium carbonate, adding 10ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the speed of 10 ℃/min to react for 3 hours, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 4-phenyl tetrahydropyran-4-formamide.
P3, weighing 10g of 4-phenyltetrahydropyran-4-formamide obtained in the step P2, adding 50ml of acetonitrile for dissolving, adjusting the pH to 13 by using 5mol/L sodium hydroxide solution, cooling the solution to 0 deg.C in ice water bath, adding 10ml saturated sodium hypochlorite solution (20 deg.C, saturated solution under standard atmospheric pressure) dropwise at a rate of 1ml/min, heating at 20 deg.C, reacting at 20 deg.C for 12h, adding 1mol/L hydrochloric acid to adjust pH to 5, performing primary extraction by 60ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L sodium hydroxide solution to adjust the pH value to 9, secondary extraction was performed with 60ml of ethyl acetate to obtain 4-phenyltetrahydropyran-4-amine.
Through detection, the purity of the 4-phenyl-4-cyano tetrahydropyran in the step P1 is 95%, and the yield is 82%;
the purity of 4-phenyltetrahydropyran-4-carboxamide in step P2 was 96% with a yield of 90%;
the purity of 4-phenyltetrahydropyran-4-amine in step P3 was 96%, the yield was 91%, and the assay data was LCMS 160.1(M + H)+.NMR(400MHz,DMSO-d6)δ＝8.41(s.,2H),7.64(d,J＝7.2Hz,2H),7.56-7.39(m,3H),3.46-3.36(m,4H),1.99(t,J＝7.3Hz,2H),1.95(t,J＝14.1Hz,2H)。
Example 6
A method for synthesizing 4- (3-fluorophenyl) tetrahydropyran-4-amine comprises the following reaction equation:
table 6 example 6 raw materials and their amounts charged
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 3-fluorophenylacetonitrile | C8H6FN | 135.14 | 10g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 17.4g |
| Bis (2-bromoethyl) ether | C4H8Br2O | 231.91 | 17.16g |
| Potassium carbonate | K2CO3 | 138.21 | 18.4g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 10ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 10ml |
The method comprises the following steps:
p1, weighing 10g of 3-fluorobenzonitrile into a three-neck flask, adding 50ml of dimethyl sulfoxide for dissolving, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 800r/min until the reaction is finished, adding 17.4g of potassium tert-butoxide, dropwise adding 17.16g of bis (2-bromoethyl) ether at the rate of 1ml/min, controlling the temperature at 5-10 ℃ for reaction for 1.5h, removing the ice water bath, heating at 20 deg.C, reacting at 20 deg.C for 16h, adding 100ml ice water to quench reaction, extracting with ethyl acetate twice, using 50ml ethyl acetate for each extraction, combining the organic phases after the extraction is completed, washing with saturated sodium chloride solution (20 deg.C, saturated solution under standard atmospheric pressure), the solvent was dried by rotary evaporator to give 4- (3-fluorophenyl) -4-cyanotetrahydropyran.
P2, weighing 13g of 4- (3-fluorophenyl) -4-cyano tetrahydropyran obtained in the step P1, adding 50ml of dimethyl sulfoxide to dissolve, adding 18.4g of potassium carbonate, adding 10ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the speed of 10 ℃/min to react for 2h, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 4- (3-fluorophenyl) tetrahydropyran-4-formamide.
P3, weighing 10g of 4- (3-fluorophenyl) tetrahydropyran-4-carboxamide obtained in the step P2, adding 50ml of acetonitrile to dissolve, adjusting the pH to 13 by using 5mol/L sodium hydroxide solution, cooling the solution to 0 deg.C in ice water bath, adding 10ml saturated sodium hypochlorite solution (20 deg.C, saturated solution under standard atmospheric pressure) dropwise at a rate of 1ml/min, heating at 20 deg.C, reacting at 20 deg.C for 10h, adding 1mol/L hydrochloric acid to adjust pH to 5, performing primary extraction by 60ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L sodium hydroxide solution to adjust the pH value to 9, secondary extraction was performed with 60ml of ethyl acetate to give 4- (3-fluorophenyl) tetrahydropyran-4-amine.
Through detection, the purity of the 4- (3-fluorophenyl) -4-cyano tetrahydropyran in the step P1 is 95%, and the yield is 88%;
the purity of 4- (3-fluorophenyl) tetrahydropyran-4-carboxamide in step P2 was 97% with a yield of 95%;
the purity of 4- (3-fluorophenyl) tetrahydropyran-4-amine in step P3 was 95%, the yield was 90%, and the detection data was LCMS ═ 178.1(M + H)+.NMR(400MHz,DMSO-d6)δ＝8.45(s,2H),7.42-7.38(m,1H),7.17-7.09(m,2H),6.99(t,J＝7.7Hz,1H),3.47-3.37(m,4H),2.00(t,J＝7.3Hz,2H),1.93(t,J＝14.1Hz,2H)。
Example 7
A method for synthesizing 1-Boc-4- (3-fluorophenyl) -4-piperidylamine has the following reaction equation:
table 7 raw materials and their amounts charged in example 7
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 3-fluorophenylacetonitrile | C8H6FN | 135.14 | 50g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 87.2g |
| N-Boc-N, N-bis (2-bromoethyl) amine | C9H17Br2NO2 | 331.04 | 122.5g |
| Potassium carbonate | K2CO3 | 138.21 | 85.8g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 50ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 35ml |
The method comprises the following steps:
p1, weighing 50g of 3-fluorophenylacetonitrile in a three-neck flask, adding 250ml of dimethyl sulfoxide to dissolve the 3-fluorophenylacetonitrile, cooling the solution to 0 ℃ under the condition of ice-water bath, stirring the solution at the speed of 1000r/min until the reaction is finished, adding 87.2g of potassium tert-butoxide, dropwise adding 122.5g of N-Boc-N, N-bis (2-bromoethyl) amine at the speed of 1ml/min, controlling the temperature to be 5-10 ℃ to react for 1.5h, removing the ice-water bath, heating the solution at the temperature of 20 ℃ to react for 16h, adding 600ml of ice water to quench the reaction, extracting the solution twice by using 250ml of ethyl acetate after each extraction, combining organic phases after the extraction is finished, washing the organic phases by using a saturated sodium chloride solution (20 ℃, a saturated solution under the standard atmospheric pressure), and spin-drying the solvent by using a rotary evaporator to obtain the 1-Boc-4-cyano-4- (3-fluorophenyl) piperazine Pyridine.
P2, weighing 90g of 1-Boc-4-cyano-4- (3-fluorophenyl) piperidine obtained in the step P1, adding 300ml of dimethyl sulfoxide to dissolve the 1-Boc-4-cyano-4- (3-fluorophenyl) piperidine, adding 85.8g of potassium carbonate, adding 50ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating the hydrogen peroxide at the speed of 10 ℃/min to 60 ℃ to react for 3h, cooling the mixture at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product after the cooling, filtering the product, and washing the product with water to obtain the 1-Boc-4- (3-fluorophenyl) piperidine-4-formamide.
P3, weighing 50g of 1-Boc-4- (3-fluorophenyl) piperidine-4-carboxamide obtained in the step P2, adding 160ml of acetonitrile to dissolve, adjusting pH to 13 by 5mol/L sodium hydroxide solution, the solution was cooled to 0 ℃ under ice-water bath conditions, 35ml of a saturated sodium hypochlorite solution (20 ℃, saturated solution at standard atmospheric pressure) was added dropwise at a rate of 1ml/min, heating at 20 deg.C, reacting at 20 deg.C for 12h, adding 1mol/L hydrochloric acid to adjust pH to 5, performing primary extraction by 200ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L of sodium hydroxide solution to adjust the pH value to 9, a second extraction was performed with 200ml of ethyl acetate to obtain 1-Boc-4- (3-fluorophenyl) -4-piperidinamine.
Through detection, the purity of the 1-Boc-4-cyano-4- (3-fluorophenyl) piperidine in the step of P1 is 96%, and the yield is 86%;
the purity of 1-Boc-4- (3-fluorophenyl) piperidine-4-carboxamide in P2 step was 95% with a yield of 93%;
the purity of 1-Boc-4- (3-fluorophenyl) -4-piperidinamine in P3 step was 96% and the yield was 86%, as determined by LCMS 277.1(M + H)+.NMR(400MHz,DMSO-d6)δ＝8.40(s.,2H),7.36(dd,J＝7.2Hz,1H),7.09-7.05(m,2H),6.96(s,1H),3.80-3.63(m,2H),3.01(d,J＝7.3Hz,2H),2.42(d,J＝14.1Hz,2H),2.08-1.92(m,2H),1.40(s,9H)。
Example 8
A method for synthesizing 1- (3-methoxyphenyl) cyclohexylamine has the following reaction equation:
table 8 raw materials and their amounts charged in example 8
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 3-Methoxyphenylacetonitrile | C9H9NO | 147.17 | 50g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 80.05g |
| 1, 5-dibromopentane | C5H10Br2 | 229.94 | 78.1g |
| Potassium carbonate | K2CO3 | 138.21 | 20.2g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 10ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 10ml |
The method comprises the following steps:
p1, weighing 50g of 3-methoxy benzyl cyanide in a three-neck flask, adding 250ml of dimethyl sulfoxide to dissolve, cooling the solution to 0 ℃ under the condition of ice-water bath, stirring at the speed of 800r/min until the reaction is finished, adding 80.05g of potassium tert-butoxide, dripping 78.1g of 1, 5-dibromopentane at the speed of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 1.5h, removing the ice-water bath, heating at 20 deg.C, reacting at 20 deg.C for 17h, adding 500ml ice water to quench reaction, extracting with ethyl acetate twice (250 ml for each extraction), mixing the organic phases after extraction, washing with saturated sodium chloride solution (20 deg.C, saturated solution at standard atmospheric pressure), the solvent was spin-dried by rotary evaporator to give 1- (3-methoxyphenyl) -1-cyclohexanecarbonitrile.
P2, weighing 15g of 1- (3-methoxyphenyl) -1-cyclohexanecarbonitrile obtained in the step P1, adding 50ml of dimethyl sulfoxide to dissolve, adding 20.2g of potassium carbonate, adding 10ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the speed of 10 ℃/min to react for 2.5h with the mass fraction of the hydrogen peroxide being 31%, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 1- (3-methoxyphenyl) cyclohexanecarboxamide.
P3, weighing 10g of 1- (3-methoxyphenyl) cyclohexanecarboxamide obtained in the step P2, adding 50ml of acetonitrile for dissolving, adjusting the pH to 13 by 5mol/L of sodium hydroxide solution, cooling the solution to 0 deg.C in ice water bath, adding 10ml saturated sodium hypochlorite solution (20 deg.C, saturated solution under standard atmospheric pressure) dropwise at a rate of 1ml/min, heating at 20 ℃, controlling the temperature at 20 ℃ for reaction for 8h, adding 1mol/L hydrochloric acid to adjust the pH value of the solution to 5 after the reaction is finished, extracting with 50ml ethyl acetate, taking the water solution obtained by the extraction, adding 1mol/L sodium hydroxide solution to adjust the pH value to 9, secondary extraction was performed with 50ml of ethyl acetate to give 1- (3-methoxyphenyl) cyclohexylamine.
Through detection, the purity of the 1- (3-methoxyphenyl) -1-cyclohexanecarbonitrile in the step P1 is 95%, and the yield is 80%;
the purity of 4- (3-fluorophenyl) tetrahydropyran-4-carboxamide in step P2 was 97% with a yield of 94%;
the purity of 1- (3-methoxyphenyl) cyclohexylamine in the P3 step was 97%, the yield was 79%, and the detection data was LCMS 188.1(M + H)+.NMR(400MHz,CDCl3)δ8.44(s,2H),7.30(t,J＝7.7Hz,1H),6.99(s,1H),6.96-6.88(m,2H),3.70(s,1H),1.73-1.46(m,9H),1.40-1.28(m,1H)。
Example 9
A method for synthesizing 1- (3-chlorphenyl) cyclohexylamine comprises the following reaction equation:
TABLE 9 raw materials and their amounts charged in example 9
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 3-Chlorobenzeneacetonitrile | C8H6ClN | 151.59 | 30g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 46.6g |
| 1, 5-dibromopentane | C5H10Br2 | 229.94 | 45.5g |
| Potassium carbonate | K2CO3 | 138.21 | 52.8g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 30ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 25ml |
The method comprises the following steps:
p1, weighing 30g of 3-chlorobenzonitrile into a three-neck flask, adding 150ml of dimethyl sulfoxide for dissolution, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 700r/min until the reaction is finished, adding 46.6g of potassium tert-butoxide, dripping 45.5g of 1, 5-dibromopentane at the speed of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 1h, removing the ice-water bath, heating up under the environment of 20 ℃, controlling the temperature at 20 ℃ for reacting for 16h, adding 300ml of ice water to quench the reaction after the reaction is finished, extraction was performed twice with ethyl acetate using 150ml of ethyl acetate for each extraction, the organic phases were combined after the extraction was completed, washed with saturated sodium chloride solution (20 ℃, saturated solution at standard atmospheric pressure), and the solvent was spin-dried by rotary evaporator to give 1- (3-chlorophenyl) cyclohexanecarbonitrile.
P2, weighing 40g of 1- (3-chlorophenyl) cyclohexanecarbonitrile obtained in the step P1, adding 150ml of dimethyl sulfoxide to dissolve, adding 52.8g of potassium carbonate, adding 30ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the speed of 10 ℃/min to react for 3h, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 1- (3-chlorophenyl) cyclohexanecarboxamide.
P3, weighing 25g of 1- (3-chlorophenyl) cyclohexanecarboxamide obtained in the step P2, adding 130ml of acetonitrile to dissolve the 1- (3-chlorophenyl) cyclohexanecarboxamide, adjusting the pH to 13 by using 5mol/L sodium hydroxide solution, cooling the solution to 0 ℃ under the condition of ice water bath, dropwise adding 25ml of saturated sodium hypochlorite solution (20 ℃, saturated solution under standard atmospheric pressure) at the rate of 1ml/min, heating the solution at the environment of 20 ℃, controlling the temperature to be 20 ℃ to react for 14 hours, adding 1mol/L hydrochloric acid to adjust the pH of the solution to 5 after the reaction is finished, performing primary extraction by using 100ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L sodium hydroxide solution to adjust the pH to 9, and performing secondary extraction by using 100ml of ethyl acetate to obtain the 1- (3-chlorophenyl) cyclohexylamine.
Through detection, the purity of the 1- (3-chlorophenyl) cyclohexanecarbonitrile in the P1 step is 94%, and the yield is 76%;
the purity of the 1- (3-chlorophenyl) cyclohexanecarboxamide in the P2 step was 96%, and the yield was 85%;
the purity of 1- (3-chlorophenyl) cyclohexylamine in P3 step was 95%, the yield was 82%, and the detection data was LCMS ═ 192.1(M + H)+.NMR(400MHz,CDCl3)δ8.42(s,2H),7.46(s,1H),7.35(t,J＝7.7Hz,2H),7.20(m,1H),1.75-1.49(m,9H),1.45-1.33(m,1H)。
Example 10
A method for synthesizing 1- (4-fluorophenyl) cyclohexylamine has the following reaction equation:
TABLE 10 raw materials and their amounts used in example 10
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 4-Fluorophenylacetonitrile | C8H6FN | 135.14 | 100g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 174.4g |
| 1, 5-dibromopentane | C5H10Br2 | 229.94 | 170.2g |
| Potassium carbonate | K2CO3 | 138.21 | 186g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 100ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 50ml |
The method comprises the following steps:
p1, weighing 100g of 4-fluorobenzonitrile into a three-neck flask, adding 500ml of dimethyl sulfoxide for dissolving, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 800r/min until the reaction is finished, adding 174.4g of potassium tert-butoxide, dropping 170.2g of 1, 5-dibromopentane at the rate of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 1.5h, removing the ice-water bath, heating at 20 deg.C, reacting at 20 deg.C for 12h, adding 1L ice water to quench the reaction, the organic phases were combined after extraction was complete, washed with saturated sodium chloride solution (20 ℃, saturated solution at standard atmospheric pressure) and the solvent was spin dried by rotary evaporator to give 1- (4-fluorophenyl) cyclohexanecarbonitrile.
P2, weighing 130g of 1- (4-fluorophenyl) cyclohexanecarbonitrile obtained in the step P1, adding 500ml of dimethyl sulfoxide to dissolve, adding 186g of potassium carbonate, adding 100ml of hydrogen peroxide at the speed of 1ml/min under the condition of 20 ℃, heating to 65 ℃ at the speed of 10 ℃/min to react for 1.5h, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to precipitate a product, filtering, and washing with water to obtain the 1- (4-fluorophenyl) cyclohexanecarboxamide.
P3, weighing 50g of 1- (4-fluorophenyl) cyclohexanecarboxamide obtained in the step P2, adding 250ml of acetonitrile to dissolve the 1- (4-fluorophenyl) cyclohexanecarboxamide, adjusting the pH to 13 by using 5mol/L of sodium hydroxide solution, cooling the solution to 0 ℃ under the condition of ice water bath, dropwise adding 50ml of saturated sodium hypochlorite solution (20 ℃, saturated solution under standard atmospheric pressure) at the rate of 1ml/min, heating the solution at the environment of 20 ℃, controlling the temperature to be 20 ℃ to react for 16 hours, adding 1mol/L of hydrochloric acid to adjust the pH of the solution to 5 after the reaction is finished, performing primary extraction by using 200ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L of sodium hydroxide solution to adjust the pH to 9, and performing secondary extraction by using 200ml of ethyl acetate to obtain the 1- (4-fluorophenyl) cyclohexaneamine.
Through detection, the purity of the 1- (4-fluorophenyl) cyclohexanecarbonitrile in the step P1 is 96%, and the yield is 80%;
the purity of 1- (4-fluorophenyl) cyclohexanecarboxamide in the P2 step was 95%, and the yield was 95%;
the purity of 1- (4-fluorophenyl) cyclohexylamine in the P3 step was 96%, the yield was 92%, and the detection data was LCMS ═ 176.1(M + H)+.NMR(400MHz,CDCl3)δ8.44(s,2H),7.30-7.26(dd,2H),7.24-7.19(dd,2H),1.72-1.45(m,9H),1.41-1.27(m,1H)。
Example 11
A method for synthesizing 1- (3-methoxyphenyl) cyclohexylamine has the following reaction equation:
TABLE 11 raw materials and their amounts charged in example 11
| Reagent | Molecular formula | Molecular weight | Feed amount |
| 4-Methoxybenzene acetonitrile | C9H9NO | 147.17 | 25g |
| Potassium tert-butoxide | C4H9KO | 112.21 | 40g |
| 1, 5-dibromopentane | C5H10Br2 | 229.94 | 39g |
| Potassium carbonate | K2CO3 | 138.21 | 20.2g |
| Hydrogen peroxide solution | H2O2 | 34.01 | 10ml |
| Saturated sodium hypochlorite solution | NaClO | 74.44 | 20ml |
The method comprises the following steps:
p1, weighing 25g of 4-fluorobenzonitrile into a three-neck flask, adding 125ml of dimethyl sulfoxide for dissolving, cooling the solution to 0 ℃ under the condition of ice water bath, stirring at the speed of 600r/min until the reaction is finished, adding 40g of potassium tert-butoxide, dripping 39g of 1, 5-dibromopentane at the rate of 1ml/min, controlling the temperature to be 5-10 ℃ for reaction for 2h, removing the ice-water bath, heating up at 20 ℃, controlling the temperature at 20 ℃ for reaction for 15h, adding 250ml of ice water to quench the reaction after the reaction is finished, extracting with ethyl acetate twice (130 ml each time), mixing the organic phases after extraction, washing with saturated sodium chloride solution (20 deg.C, saturated solution at standard atmospheric pressure), the solvent was rotary dried by rotary evaporator to give 1- (4-methoxyphenyl) -1-cyclohexanecarbonitrile.
P2, weighing 14g of 1- (4-methoxyphenyl) -1-cyclohexanecarbonitrile obtained in the step P1, adding 50ml of dimethyl sulfoxide to dissolve, adding 20.2g of potassium carbonate, adding 10ml of hydrogen peroxide at the speed of 1ml/min at the temperature of 20 ℃, heating to 60 ℃ at the speed of 10 ℃/min to react for 3h with the mass fraction of the hydrogen peroxide being 31%, cooling at the temperature of 20 ℃ after the reaction is finished, adding ice water to separate out a product, filtering, and washing with water to obtain the 1- (4-methoxyphenyl) cyclohexanecarboxamide.
P3, weighing 20g of 1- (4-methoxyphenyl) cyclohexanecarboxamide obtained in the step P2, adding 100ml of acetonitrile for dissolving, adjusting the pH to 13 by 5mol/L sodium hydroxide solution, cooling the solution to 0 deg.C in ice water bath, adding dropwise 20ml of saturated sodium hypochlorite solution (20 deg.C, saturated solution at standard atmospheric pressure) at a rate of 1ml/min, heating at 20 deg.C, reacting at 20 deg.C for 16h, adding 1mol/L hydrochloric acid to adjust pH to 5, performing primary extraction by 120ml of ethyl acetate, taking the aqueous solution obtained by the primary extraction, adding 1mol/L of sodium hydroxide solution to adjust the pH value to 9, secondary extraction was performed with 120ml of ethyl acetate to give 1- (3-methoxyphenyl) cyclohexylamine.
Through detection, the purity of the 1- (4-methoxyphenyl) -1-cyclohexanecarbonitrile in the step P1 is 95%, and the yield is 85%;
the purity of the 1- (4-methoxyphenyl) cyclohexanecarboxamide in the P2 step was 97%, and the yield was 91%;
the purity of 1- (3-methoxyphenyl) cyclohexylamine in the P3 step was 95%, the yield was 76%, and the detection data was LCMS 188.1(M + H)+.NMR(400MHz,CDCl3)δ8.43(s,2H),7.30-7.26(d,2H),6.91-6.87(d,2H),3.81(s,3H),1.72-1.45(m,9H),1.41-1.27(m,1H)。
Comparative example
Comparative example 1
A method for synthesizing 1- (3-fluorophenyl) cyclohexylamine has the following reaction equation:
q1, weighing 100g of 3-fluorophenylacetonitrile, dissolving in 1L of N, N-dimethylformamide, adding 170g of 1, 5-dibromopentane, dropwise adding 65g of sodium hydride under the condition of ice-water bath, stirring at the temperature of 50 ℃ after dropwise adding, reacting for 12h, quenching with ice water after the reaction is finished, extracting with ethyl acetate for three times, using 500ml of ethyl acetate each time, combining organic phases obtained by extraction, and purifying by a chromatographic column to obtain the 1- (3-fluorophenyl) cyclohexanecarbonitrile.
Q2, weighing 100g of 1- (3-fluorophenyl) cyclohexanecarbonitrile obtained in the Q1 step, dissolving in 500ml of polyphosphoric acid, reacting at 110 ℃ for 6h, after the reaction is finished, dropwise adding a saturated sodium bicarbonate solution (20 ℃, saturated solution under standard atmospheric pressure) until the pH is 8, collecting the precipitate, and washing with 1L of water to obtain 1- (3-fluorophenyl) cyclohexanecarboxamide.
Q3, weighing 95g of 1- (3-fluorophenyl) cyclohexanecarboxamide obtained in the step Q2, dissolving in 800ml of n-butanol, adding 260ml of saturated sodium hypochlorite solution (20 ℃, saturated solution under standard atmospheric pressure), cooling the solution to 0 ℃ under the condition of ice water bath, adjusting the pH of the solution to 13 by 3mol/l of sodium hydroxide, removing the ice water bath, heating at 20 ℃, controlling the temperature to 20 ℃, stirring at the speed of 600r/min, reacting for 12 hours, extracting twice by ethyl acetate after the reaction is finished, extracting by 500ml of ethyl acetate each time, combining the extracted organic phases, washing by saturated sodium chloride solution (20 ℃, saturated solution under standard atmospheric pressure), and drying to obtain 1- (3-fluorophenyl) cyclohexylamine.
Through detection, the yield of the 1- (3-fluorophenyl) cyclohexanecarbonitrile in the step Q1 is 67%;
the yield of 1- (3-fluorophenyl) cyclohexanecarboxamide in the Q2 step was 87%;
the yield of 1- (3-fluorophenyl) cyclohexylamine in the Q3 step was 73%.
By combining the example 1 and the comparative example 1, it can be seen that in the preparation process of 1- (3-fluorophenyl) cyclohexanecarbonitrile, the milder potassium tert-butoxide is selected to replace sodium hydride, and the solvent is replaced by dimethyl sulfoxide from N, N-dimethylformamide, so that not only is the reaction safety improved, but also the yield is greatly improved;
in the preparation process of the 1- (3-fluorophenyl) cyclohexanecarboxamide, a dimethyl sulfoxide-potassium carbonate-hydrogen peroxide system is selected to hydrolyze the cyano group of the 1- (3-fluorophenyl) cyclohexanecarbonitrile, so that the post-treatment operation is simple and convenient, and the yield is greatly improved;
in the preparation process of the 1- (3-fluorophenyl) cyclohexylamine, acetonitrile is selected as a solvent, and the reaction is carried out by firstly adjusting the pH value and then dropwise adding a saturated sodium hypochlorite solution, so that the yield can be improved by about 17%;
the method provides possibility for the industrial production of the hexatomic ring benzylamine compound by simplifying the post-treatment of each step, improving the safety and greatly increasing the yield.
The above embodiments are preferred embodiments of the present application, and the protection scope of the present application is not limited by the above embodiments, so: all equivalent changes made according to the structure, shape and principle of the present application shall be covered by the protection scope of the present application.
Claims (10)
1. A synthetic method of a six-membered ring benzylamine compound is characterized by comprising the following steps:
s1, taking a compound A, potassium carbonate and hydrogen peroxide as raw materials, taking dimethyl sulfoxide as a solvent, reacting at 50-65 ℃, wherein the mass fraction of the hydrogen peroxide is 30% -35%, the mass ratio of the compound A to the potassium carbonate is 1 (2.05-2.15), the feeding ratio of the compound A to the hydrogen peroxide is (5-7) mol:1L, adding ice water to precipitate a product after the reaction is finished, and filtering and washing to obtain a compound B;
s2, dissolving the compound B in acetonitrile, adjusting the pH value to be 13-14, adding a saturated sodium hypochlorite solution for reaction, wherein the feeding ratio of the compound B to the saturated sodium hypochlorite solution is (4.2-4.9) mol:1L, and after the reaction is finished, purifying and washing to obtain a compound C;
the compound A is represented by the following chemical formula I:
the chemical formula is as follows:
wherein R is selected from one of hydrogen, fluorine, chlorine, bromine and methoxy, and X is selected from one of the following groups:
(1) x is one of carbon, nitrogen and oxygen;
or (2) X is represented by the following formula two:
the chemical formula II:
or (3) X is represented by the following formula three:
the chemical formula III:
the compound B is represented by the following formula iv:
chemical formula four:
the compound C is represented by the following chemical formula five:
the chemical formula is five:
2. the method for synthesizing a six-membered ring benzylamine compound according to claim 1, wherein: in the step S1, the compound A is firstly dissolved in dimethyl sulfoxide, potassium carbonate is added, and finally hydrogen peroxide is added at the rate of 0.5-1 ml/min.
3. The method for synthesizing a six-membered ring benzylamine compound according to claim 2, wherein: in the step S1, hydrogen peroxide is added under the condition of 20 ℃, and then the temperature is raised to 60 ℃ for reaction.
4. The method for synthesizing a six-membered ring benzylamine compound according to claim 1, wherein: in the step S2, a saturated sodium hypochlorite solution is added at a rate of 1-2 ml/min.
5. The method for synthesizing a six-membered ring benzylamine compound according to claim 4, wherein: in the step S2, a saturated sodium hypochlorite solution is added at the temperature of 0-5 ℃, and then the temperature is raised to 20 ℃ for reaction.
6. The method for synthesizing a six-membered ring benzylamine compound according to claim 1, wherein the step of S2, the purification and washing step comprises the following steps:
acid washing: adding hydrochloric acid to adjust the pH value of the solution to 5, and performing primary extraction by ethyl acetate;
alkali washing: the aqueous solution obtained by the primary extraction was taken, added with sodium hydroxide to adjust the solution to pH 9, and subjected to secondary extraction with ethyl acetate to obtain compound C.
7. The method for synthesizing a six-membered ring benzylamine compound according to claim 1, wherein the compound A is prepared by the following steps:
preparation stage of compound a: taking a compound D, a compound E and potassium tert-butoxide as raw materials, taking dimethyl sulfoxide as a solvent, reacting at 5-20 ℃, wherein the mass ratio of the compound D, the compound E and the potassium tert-butoxide is 1:1:2.1, and purifying and separating after the reaction is finished to obtain a compound A;
the compound D is represented by the following formula six:
chemical formula six:
the compound E is represented by the following formula seven:
a seventh chemical formula:
8. the method for synthesizing a six-membered ring benzylamine compound according to claim 7, wherein: in the preparation stage of the compound A, reaction liquid is stirred, firstly reacted for 1-2h at 5-10 ℃, and then heated to 20 ℃ for reaction.
9. The method for synthesizing a six-membered ring benzylamine compound according to claim 7, wherein: in the preparation stage of the compound A, the compound D is firstly dissolved in dimethyl sulfoxide, the solution is cooled to 0-5 ℃, then potassium tert-butoxide is added, finally the compound E is added at the rate of 1-2ml/min, and the temperature is controlled at 5-20 ℃ for reaction.
10. The method for synthesizing six-membered ring benzylamine compounds according to claim 7, wherein the purification and separation in the preparation stage of compound A comprises the following steps:
and (3) extraction: extracting the reacted solution by ethyl acetate;
washing: taking an organic phase obtained by extraction, and washing the organic phase by using a saturated sodium chloride solution;
and (3) spin-drying: the solvent was removed by rotary evaporation to give compound a.
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| US20150239869A1 (en) * | 2014-02-26 | 2015-08-27 | Acetylon Pharmaceuticals, Inc. | Pyrimidine hydroxy amide compounds as hdac6 selective inhibitors |
| US20160137630A1 (en) * | 2014-10-08 | 2016-05-19 | Acetylon Pharmaceuticals, Inc. | Induction of gata2 by hdac1 and hdac2 inhibitors |
| TW201840556A (en) * | 2017-03-10 | 2018-11-16 | 美商Ｖｐｓ ３股份有限公司 | Metalloenzyme inhibitor compounds, pharmaceutical compositions and methods by using the metalloenzyme inhibitor compounds |
| WO2021143680A1 (en) * | 2020-01-16 | 2021-07-22 | 浙江海正药业股份有限公司 | Heteroaryl derivative, preparation method therefor, and use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20150239869A1 (en) * | 2014-02-26 | 2015-08-27 | Acetylon Pharmaceuticals, Inc. | Pyrimidine hydroxy amide compounds as hdac6 selective inhibitors |
| US20160137630A1 (en) * | 2014-10-08 | 2016-05-19 | Acetylon Pharmaceuticals, Inc. | Induction of gata2 by hdac1 and hdac2 inhibitors |
| TW201840556A (en) * | 2017-03-10 | 2018-11-16 | 美商Ｖｐｓ ３股份有限公司 | Metalloenzyme inhibitor compounds, pharmaceutical compositions and methods by using the metalloenzyme inhibitor compounds |
| WO2021143680A1 (en) * | 2020-01-16 | 2021-07-22 | 浙江海正药业股份有限公司 | Heteroaryl derivative, preparation method therefor, and use thereof |
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