CN115028604B - Preparation method of cyclohexyl piperazine - Google Patents
Preparation method of cyclohexyl piperazine Download PDFInfo
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- CN115028604B CN115028604B CN202210586853.2A CN202210586853A CN115028604B CN 115028604 B CN115028604 B CN 115028604B CN 202210586853 A CN202210586853 A CN 202210586853A CN 115028604 B CN115028604 B CN 115028604B
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- C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements
- C07D295/027—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements containing only one hetero ring
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Abstract
The invention provides a preparation method of cyclohexyl piperazine. The method comprises the following steps: adding cyclohexylamine and a catalyst A into a reaction container, adding hydroxyacetonitrile, carrying out phase separation after reaction, and washing a lower reaction solution to obtain cyclohexylamine diacetonitrile mother solution; adding solvent and catalyst B into a reaction vessel, at H 2 Adding cyclohexylamino diacetonitrile mother liquor to react in the atmosphere, and obtaining the cyclohexyl piperazine after distillation and purification. The invention prepares the cyclohexyl piperazine by using the cyclohexylamine and the hydroxy acetonitrile as raw materials by a two-step method, so that the raw materials are easy to obtain, the post-treatment process of the product is simpler, the yield of the target product is higher, and the derivative application of the cyclohexylamine is facilitated.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly provides a preparation method of cyclohexyl piperazine.
Background
With the development of the pharmaceutical industry, biomedical intermediates have become an emerging industry in chemical industry, especially the production of heterocyclic pharmaceutical intermediates is more remarkable; wherein piperazine and its derivatives are used as an important branch in heterocyclic drugs, and can be used as raw materials for synthesizing lomefloxacin hydrochloride, sparfloxacin and other drug intermediates. In addition, piperazine and its derivatives can also be used for the synthesis of surfactants, synthetic resins, rubber aids, antioxidants and preservatives, and their comprehensive market demand has a tendency to rise year by year.
At present, the research on piperazine at home and abroad is relatively extensive, and the synthesis mode is countless. The patent with publication number JP4911712 discloses a process for preparing piperazine by taking hydroxyethyl ethylenediamine as a raw material; patent publication No. US368219 discloses a method for preparing piperazine by using diethylenetriamine as raw material; patent publication No. EP16325304 discloses a method for preparing piperazine from aminoethanol; weitamp et al also report a process for the preparation of piperazine from ethylenediamine, and the like; it follows that the process of piperazine synthesis is indeed very common.
At present, the cyclohexylamine piperazine is an emerging piperazine derivative, is also a very critical medical intermediate, and has very few reports on the cyclohexylamine piperazine at home and abroad to date. WO2010051374A1 and CN 112645901A both disclose a process for the preparation of cyclohexylamine piperazine, which comprises adding cyclohexanone or a cyclohexyl halide to 1-Boc-piperazine as starting material to prepare 1-cyclohexylamine piperazine. However, the above-mentioned process for preparing cyclohexylamine piperazine has at least the following problems: as the raw materials are all 1-Boc-piperazine, and the post-treatment needs to remove-Boc, the post-treatment process is complicated, a large amount of acid can be introduced, the corrosion to equipment is extremely strong, the byproducts can be increased, and a large amount of salt-containing wastewater can be generated due to acid-base neutralization, so that the environmental pollution is remarkable, and the industrial production is not facilitated.
In summary, the synthesis process of the cyclohexyl piperazine is few and relatively complex, the process difficulty is high, and the production cost is high, which seriously affects the application and popularization of the piperazine derivative in the chemical industry field, so the preparation process of the cyclohexyl piperazine needs to be further optimized according to the characteristic.
Disclosure of Invention
In view of the above, the present invention provides a method for preparing cyclohexylpiperazine, and mainly aims to provide a novel synthetic route of cyclohexylpiperazine, so as to solve the technical problems of complex post-treatment procedures and more byproducts in the existing synthesis process of cyclohexylpiperazine.
In order to achieve the aim of the invention, the invention adopts the following technical scheme:
a process for the preparation of cyclohexylpiperazine, the process comprising the steps of:
s1: adding cyclohexylamine and a catalyst A into a reaction container, adding hydroxyacetonitrile, carrying out phase separation after reaction, and washing a lower reaction solution to obtain cyclohexylamine diacetonitrile mother solution;
s2: adding solvent and catalyst B into a reaction vessel, at H 2 Adding cyclohexylamino diacetonitrile mother liquor to react in the atmosphere, and obtaining the cyclohexyl piperazine after distillation and purification.
The process route for preparing the cyclohexyl piperazine by taking the cyclohexane and the hydroxyacetonitrile as the main raw materials is schematically shown as follows:
in the invention, the main product cyclohexylpiperazine, possibly residual raw materials cyclohexylamine, byproduct propylamine, monoamine ethyl cyclohexylamine and the like are obtained after the S2 is finished, so that the post-treatment is only carried out by means of rectification and purification. By adopting the preparation route, the product is simple in post-treatment and does not need to introduce impurities, so that the comprehensive yield of the product is higher, and the byproduct aminoethyl cyclohexylamine can be used as an epoxy curing agent.
In the present invention, the catalyst a of S1 is an alkali metal catalyst, preferably an alkali metal hydroxide, more preferably one or more of NaOH, liOH, KOH, rbOH, csOH, most preferably NaOH and/or KOH; preferably, catalyst A is added in an amount of 0.1 to 1wt%, preferably 0.5 to 0.8wt%, of cyclohexylamine.
In the present invention, the molar ratio of hydroxyacetonitrile to cyclohexylamine in S1 is (1.5 to 2.5): 1, and more preferably (2 to 2.2): 1.
In the invention, the hydroxyacetonitrile S1 is a hydroxyacetonitrile aqueous solution; preferably, the aqueous hydroxyacetonitrile solution is added in a semi-continuous manner, preferably at a feed rate of 0.1 to 5g/min, more preferably 1 to 2g/min; the concentration of the aqueous hydroxyacetonitrile solution is 5 to 50% by weight, preferably 10 to 30% by weight.
In the invention, the reaction temperature of the cyclohexylamine and the hydroxyacetonitrile is 50-150 ℃, preferably 100-120 ℃; n (N) 2 The pressure is 0.5-5 MPa absolute pressure, preferably 1-2 MPa absolute pressure; the reaction time is 1 to 5 hours, preferably 2 to 3 hours.
In the invention, the solvent of S2 is one or more of methanol, ethanol, isopropanol, acetonitrile, n-butanol, tetrahydrofuran and acetone, preferably methanol and/or ethanol.
In the invention, the hydrogenation reaction temperature of S2 is 100-280 ℃, preferably 180-230 ℃; h 2 The pressure is 1-8 MPa absolute pressure, preferably 3-6 MPa; the reaction time is 1 to 5 hours, preferably 2 to 4 hours.
In the invention, the distillation and purification temperature of the cyclohexylamine piperazine described in S2 is 60-120 ℃, preferably 80-100 ℃; the pressure is 10 to 50KPa absolute, preferably 20 to 30KPa; the rectification time is 3-10h, preferably 6-8h.
In the invention, the catalyst B described by S2 is [ (M) 1 &M 2 )Cl 2 ](TPPTS) 2 The method comprises the steps of carrying out a first treatment on the surface of the Preferably, the active metal M 1 Is one of group VIII, group IB and group IIB metal elements, preferably Fe, pd, cu, zn, co or Ni; preferably, the auxiliary metal M 2 Is a group IIA, group VIB, group VIIB metal element, preferably one of Cr, mo, mn and Mg; preferably, catalyst B is added in an amount of 1 to 15wt%, preferably 5 to 10wt%, of cyclohexylamine diacetonitrile.
In the invention, the preparation method of the catalyst B described in S2 comprises the following steps:
SS1: adding active metal M1 salt, auxiliary metal M2 salt and PPh into the solution 3 Heating and refluxing, cooling, filtering, washing to obtain viscous solid, and drying to obtain [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 ；
SS2：[(M 1 &M 2 )Cl 2 ](PPh 3 ) 3 Adding THF, heating and refluxing, adding TPPTS, reacting at constant temperature, cooling, collecting water phase and drying to obtain solid product [ (M) 1 &M 2 )Cl 2 ](TPPTS) 2 。
In the present invention, the active metal M as described in SS1 1 With auxiliary metal M 2 The molar ratio of (2) is 5-50:1, preferably 10-20:1.
In the invention, the active metal M1 salt and the auxiliary metal M2 salt of SS1 are hydrochlorides.
In the invention, the solvent of SS1 is methanol; preferably, the active metal M 1 Salt and PPh 3 The mass ratio of (2) is 1:1-10, preferably 1:4-6; reactive metal M 1 The mass ratio of the hydrochloride to the methanol is 1:5-10, preferably 1:5-8.
In the invention, SS1 reacts under the vacuum condition, the vacuum degree is 10-50 KPa, preferably 20-30 KPa; the reaction temperature is 40-80 ℃, preferably 50-60 ℃; the reaction time is 1 to 10 hours, preferably 3 to 5 hours.
In the invention, the vacuum drying of SS1 is absolute pressure of 10-50 KPa, preferably 20-30 KPa; the drying temperature is 60-100 ℃, preferably 70-90 ℃; the drying time is 1 to 10 hours, preferably 4 to 6 hours.
In the present invention, SS2 is described as [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 The mass ratio of the catalyst to THF is 1:10-100, preferably 1:40-60.
In the present invention, SS2 is described as [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 The mass ratio of the catalyst to TPPTS is 1:1-10, preferably 1:2-3.
In the invention, SS2 reacts under vacuum condition, the vacuum degree is 10-50 KPa absolute pressure, preferably 20-30 KPa; the reaction temperature is 40-80 ℃, preferably 50-60 ℃; the reaction time is 1 to 10 hours, preferably 3 to 5 hours.
In the invention, the drying temperature of SS2 is 50-130 ℃, preferably 80-100 ℃; the drying time is 5-10 h, preferably 6-8 h; the vacuum degree is 10 to 50KPa, preferably 20 to 30KPa.
It is another object of the present invention to provide a cyclohexylpiperazine.
The cyclohexyl piperazine is prepared by the preparation method.
Compared with the prior art, the technical scheme of the invention has the beneficial effects that:
(1) Raw materials are easy to obtain, and the post-treatment process of the product is simple;
(2) The product yield is higher, the yield of the cyclohexyl piperazine reaches more than 95%, the yield of the aminoethyl cyclohexylamine is lower than 5%, and the yields of other products are lower than 0.5wt%; and the byproduct aminoethyl cyclohexylamine can be used as an epoxy curing agent.
(3) Expands the modification means and derivative application of the cyclohexylamine, and is favorable for the application and popularization of piperazine derivatives in the chemical industry field.
Detailed Description
The invention will be further illustrated with reference to examples, but the invention is not limited to the examples listed.
The sources of the reaction raw materials are as follows:
cyclohexylamine: purity is more than or equal to 99wt percent, and Wanhua chemistry;
hydroxy acetonitrile: purity is more than or equal to 99.5%, and the Ala is high;
H 2 : purity is more than or equal to 99wt percent, and Wanhua chemistry;
NiCl 2 : purity is more than or equal to 99.9%, and the Ala is high;
CoCl 2 : purity is more than or equal to 99.7%, and the Ala is high;
CrCl 2 : purity is more than or equal to 99.9%, and the Ala is high;
MgCl 2 : purity is more than or equal to 99 percent, and the Ala is provided;
PPh 3 : purity is more than or equal to 99 percent, and the Ala is provided;
THF: purity is more than or equal to 99 percent, and the Ala is provided;
TPPTS: purity is more than or equal to 90%, and the Ala is provided;
cyclohexyl bromide: purity is more than or equal to 90%, and the Ala is provided;
the purity of the 1-Boc-piperazine is more than or equal to 99 percent, and the purity of the aratin is higher than or equal to the purity of the aratin;
potassium carbonate: purity is more than or equal to 98%, and the Ala is provided;
concentrated hydrochloric acid: purity is more than or equal to 30%, and the Ala is provided;
dichloromethane: purity is more than or equal to 99.8%, and the Ala is high;
sodium hydroxide: purity is more than or equal to 96%, and the Allatin;
isopropyl alcohol: purity is more than or equal to 99.7%, and the Ala is high;
the testing method comprises the following steps:
gas chromatography: agilent 7890 and DB-5 (30 mm. Times.0.25 mmID. Times.0.25 μm) were used, the injector temperature was 280℃and the detector temperature was 300 ℃. The temperature program is as follows: the initial column temperature is 50 ℃, and the temperature is kept for 2min; raising the temperature to 80 ℃ at 5 ℃/min, and keeping for 0min; raising the temperature to 300 ℃ at 15 ℃/min, and keeping for 15min. The component content was determined by normalization.
After the addition reaction, the invention can confirm that the cyclohexylamine and the hydroxyacetonitrile react completely when the content of the cyclohexylamine diacetonitrile in the obtained product is basically maintained unchanged through gas chromatography analysis; after the hydrogenation condensation reaction, when the content of the cyclohexylamine piperazine in the obtained product is basically maintained unchanged, the complete reaction of the cyclohexylamine diacetonitrile can be confirmed, and the product is mainly the cyclohexylamine piperazine.
Example 1
Preparing a catalyst:
(1)[(Co&Cr)Cl 2 ](PPh 3 ) 3 is prepared from the following steps: into a three-necked flask, 155.81g of methanol and 25.97g of CoCl were charged 2 、1.83g CrCl 2 103.87g PPh 3 N at absolute pressure 0.4MPa 2 Heating to 50 ℃ under the atmosphere and keeping reflux for 3 hours, cooling to room temperature, filtering to obtain a filter cake, and washing with diethyl ether for 3 times to obtain a viscous solid; continuously drying at 70 ℃ for 5 hours under the absolute pressure of 20KPa to obtain [ (Co)&Cr)Cl 2 ](PPh 3 ) 3 ；
(2)[(Co&Cr)Cl 2 ](TPPTS) 2 Is prepared from the following steps: 200g of THF are passed through N 2 Deoxidizing for 3h, weighing 5g [ (Co)&Cr)Cl 2 ](PPh 3 ) 3 In a 500ml three-neck flask, heating to 50 ℃ under the absolute pressure of 20KPa and refluxing for 30min;then 10g TPPTS was continuously added dropwise into the flask, kept at constant temperature for 3 hours, and then cooled to room temperature. Collecting water phase, vacuum drying at 80deg.C under absolute pressure of 20KPa for 6 hr to obtain solid product [ (Co)&Cr)Cl 2 ](TPPTS) 2 。
The synthesis process comprises the following steps:
s1: 49.6g of cyclohexylamine and 0.25g of NaOH were added to a reaction vessel under N 2 Heating to 100 ℃ under the absolute pressure of 1MPa, stirring, continuously dropwise adding 560.6g of 10wt% hydroxyacetonitrile aqueous solution, continuously carrying out prolonged reaction for 2 hours under the corresponding conditions after the dropwise adding is finished, separating phases to obtain a lower reaction mother solution, and further washing 3 times to obtain a cyclohexylamino diacetonitrile mother solution;
s2: 200g of methanol solvent and 5g of [ (Co)&Cr)Cl 2 ](TPPTS) 2 Adding into a reaction kettle, and adding into H 2 Stirring at the absolute pressure of 3MPa and the temperature of 210 ℃, continuously dropwise adding 100g of cyclohexylamine-based diacetonitrile mother liquor, and continuously prolonging the reaction for 2 hours after the dropwise adding is finished to obtain the cyclohexylpiperazine mother liquor; the cyclohexyl piperazine mother liquor is further subjected to rectification and purification for 6 hours at 80 ℃ and 30KPa absolute pressure to obtain a final product; the corresponding material composition was obtained by GC analysis and mainly comprised of 95.8wt% of piperazine cyclohexylamine, 3.7wt% of cyclohexylamine aminoethyl and 0.5wt% of other by-products.
Example 2
Preparing a catalyst:
(1)[(Ni&Mg)Cl 2 ](PPh 3 ) 3 is prepared from the following steps: into a three-necked flask, 311.04g of methanol and 38.88g of NiCl were charged 2 、0.95g MgCl 2 233.28g PPh 3 N at absolute pressure 0.6MPa 2 Heating to 60 ℃ under the atmosphere and keeping reflux for 7 hours, cooling to room temperature, filtering to obtain a filter cake, and washing with diethyl ether for 3 times to obtain a viscous solid; continuously drying at 90 ℃ for 4 hours under 30KPa absolute pressure to obtain [ (Ni)&Mg)Cl 2 ](PPh 3 ) 3 ；
(2)[(Ni&Mg)Cl 2 ](TPPTS) 2 Is prepared from the following steps: 300g of THF are passed through N 2 Deoxidizing for 3h, weighing 5g [ (Ni)&Mg)Cl 2 ](PPh 3 ) 3 In a 500ml three-necked flask, inHeating to 60 ℃ under the absolute pressure of 30KPa and refluxing for 30min; 15g TPPTS was then added continuously dropwise to the flask, kept at constant temperature for 5 hours, and then cooled to room temperature. Collecting water phase, vacuum drying at 100deg.C under 30KPa absolute pressure for 8 hr to obtain solid product [ (Ni)&Mg)Cl 2 ](TPPTS) 2 。
The synthesis process comprises the following steps:
s1: 49.6g of cyclohexylamine and 0.4g of KOH were added to a reaction vessel, under N 2 Heating to 120 ℃ under the absolute pressure of 2MPa, stirring, continuously dropwise adding 205.6g of 30wt% hydroxyacetonitrile aqueous solution, continuously carrying out prolonged reaction for 3 hours under the corresponding conditions after the dropwise adding is finished, separating phases to obtain a lower reaction mother solution, and further washing 3 times to obtain a cyclohexylamino diacetonitrile mother solution;
s2: 200g of ethanol solvent and 5g of [ (Ni)&Mg)Cl 2 ](TPPTS) 2 Adding into a reaction kettle, and adding into H 2 Stirring at the absolute pressure of 6MPa and the temperature of 180 ℃, continuously dropwise adding 100g of cyclohexylamine-based diacetonitrile mother liquor, and continuously prolonging the reaction for 4 hours after the dropwise adding is finished to obtain the cyclohexylpiperazine mother liquor; the cyclohexyl piperazine mother liquor is further subjected to rectification and purification for 8 hours at the temperature of 100 ℃ and the absolute pressure of 20KPa, so as to obtain a final product; the corresponding material composition was obtained by GC analysis and mainly comprised 96.5wt% of piperazine cyclohexylamine, 3.3wt% of cyclohexylamine aminoethyl and 0.2wt% of other by-products.
Example 3
Preparing a catalyst:
(1)[(Cu&Mg)Cl 2 ](PPh 3 ) 3 is prepared from the following steps: into a three-necked flask, 235.29g of methanol and 33.61g of CuCl were charged 2 、0.95g MgCl 2 168.06g PPh 3 N at absolute pressure 0.5MPa 2 Heating to 55 ℃ under the atmosphere and keeping reflux for 5 hours, cooling to room temperature, filtering to obtain a filter cake, and washing with diethyl ether for 3 times to obtain a viscous solid; continuously drying at 80 ℃ for 6 hours under the absolute pressure of 25KPa to obtain [ (Cu)&Mg)Cl 2 ](PPh 3 ) 3 ；
(2)[(Cu&Mg)Cl 2 ](TPPTS) 2 Is prepared from the following steps: 250g of THF are passed through N 2 Deoxidizing for 3h, weighing 5g [ (Cu)&Mg)Cl 2 ](PPh 3 ) 3 In a 500ml three-neck flask, heating to 55 ℃ under the absolute pressure of 25KPa and refluxing for 30min; then 10g TPPTS was continuously added dropwise into the flask, kept at constant temperature for 4 hours, and then cooled to room temperature. Collecting water phase, vacuum drying at 90 deg.C under 25KPa absolute pressure for 7 hr to obtain solid product&Mg)Cl 2 ](TPPTS) 2 。
The synthesis process comprises the following steps:
s1: 49.6g of cyclohexylamine and 0.3g of LiOH were added to a reaction vessel in N 2 Heating to 100 ℃ under the absolute pressure of 1.5MPa, stirring, continuously dropwise adding 294.32g of 20wt% hydroxyacetonitrile aqueous solution, continuously prolonging the reaction under the corresponding conditions for 2 hours after the dropwise adding is finished, separating phases to obtain a lower reaction mother solution, and further washing 3 times to obtain cyclohexylamine diacetonitrile mother solution;
s2: 200g of isopropanol solvent and 5g of [ (Cu) were dissolved&Mg)Cl 2 ](TPPTS) 2 Adding into a reaction kettle, and adding into H 2 Stirring at the absolute pressure of 4MPa and the temperature of 200 ℃, continuously dropwise adding 100g of cyclohexylamine-based diacetonitrile mother liquor, and continuously prolonging the reaction for 3 hours after the dropwise adding is finished to obtain the cyclohexylpiperazine mother liquor; the cyclohexyl piperazine mother liquor is further subjected to rectification and purification for 7 hours at 90 ℃ and absolute pressure of 25KPa, so as to obtain a final product; the corresponding material composition was obtained by GC analysis and mainly comprised 96.6wt% of piperazine cyclohexylamine, 3.0wt% of cyclohexylamine aminoethyl and 0.4wt% of other by-products.
Example 4
Preparing a catalyst:
(1)[(Fe&Mo)Cl 2 ](PPh 3 ) 3 is prepared from the following steps: into a three-necked flask, 221.9g of methanol and 31.70g of FeCl were charged 2 、1.67g MoCl 2 168.06g PPh 3 N at absolute pressure 0.5MPa 2 Heating to 60 ℃ under the atmosphere, keeping reflux for 6 hours, cooling to room temperature, filtering to obtain a filter cake, and washing with diethyl ether for 3 times to obtain a viscous solid; continuously drying at 70 ℃ for 5 hours under 30KPa absolute pressure to obtain [ (Fe)&Mo)Cl 2 ](PPh 3 ) 3 ；
(2)[(Fe&Mo)Cl 2 ](TPPTS) 2 Is prepared from the following steps: 250g of THF are passed through N 2 Oxygen scavenging3h, weigh 5g [ (Fe)&Mo)Cl 2 ](PPh 3 ) 3 In a 500ml three-neck flask, heating to 60 ℃ under the absolute pressure of 30KPa and refluxing for 30min; 15g TPPTS was then added continuously dropwise to the flask, kept at constant temperature for 5 hours, and then cooled to room temperature. Collecting water phase, vacuum drying at 100deg.C under 30KPa absolute pressure for 7 hr to obtain solid product, i.e., [ (Fe)&Mo)Cl 2 ](TPPTS) 2 。
The synthesis process comprises the following steps:
s1: 49.6g of cyclohexylamine and 0.35g of KOH were added to a reaction vessel, under N 2 Heating to 110 ℃ under the absolute pressure of 2.0MPa, stirring, continuously dropwise adding 224.24g of 25wt% hydroxyacetonitrile aqueous solution, continuously carrying out prolonged reaction for 3 hours under the corresponding conditions after the dropwise adding is finished, carrying out phase separation to obtain a lower reaction mother solution, and further carrying out water washing for 3 times to obtain cyclohexylamine diacetonitrile mother solution;
s2: 200g of isopropanol solvent and 5g of [ (Fe)&Mo)Cl 2 ](TPPTS) 2 Adding into a reaction kettle, and adding into H 2 Stirring at the absolute pressure of 5MPa and the temperature of 230 ℃, continuously dropwise adding 100g of cyclohexylamine-based diacetonitrile mother liquor, and continuously prolonging the reaction for 2 hours after the dropwise adding is finished to obtain the cyclohexylpiperazine mother liquor; the cyclohexyl piperazine mother liquor is further subjected to rectification and purification for 8 hours at the temperature of 100 ℃ and the absolute pressure of 20KPa, so as to obtain a final product; the corresponding material composition was obtained by GC analysis and mainly comprised of 95.5wt% of piperazine cyclohexylamine, 4.2wt% of cyclohexylamine aminoethyl and 0.3wt% of other by-products.
Comparative example 1
The preparation was carried out using cyclohexyl bromide and 1-Boc-piperazine as starting materials and was carried out in accordance with example 1 of the patent CN 112645901A.
Bedding with 4.8Kg of cyclohexyl bromide and 4.1Kg of potassium carbonate, adding 35Kg of 1-Boc-piperazine anhydrous acetonitrile solution with 86wt% concentration by adopting a semi-continuous process, carrying out reaction reflux for 2 hours at 90 ℃, and concentrating the obtained reaction solution to obtain 7.5Kg of intermediate oily substance; continuously dripping 6Kg of concentrated hydrochloric acid with the concentration of 30wt% into the intermediate oily substance at room temperature, keeping the reaction for 4 hours to obtain a reaction liquid, evaporating the solvent to dryness, adding 10Kg of isopropanol to pulp, and continuously stirring for two hours to obtain a white solid; the white solid was dissolved in water, the pH was adjusted to 14 using a 20wt% NaOH solution, and the solution was extracted twice successively with dichlorohexane, and the extract was distilled under reduced pressure at an absolute pressure of 20KPa at 60℃to give 3.5Kg of an oil, the composition of which was determined by GC to include 90.2wt% of piperazine cyclohexylamine and 9.8wt% of other by-products.
Comparative example 2
The procedure of example 1 of the present invention was used, but the catalysts used were different.
S1: 49.6g of cyclohexylamine and 0.25g of NaOH were added to the reaction vessel under N 2 Heating to 100 ℃ under the absolute pressure of 1MPa, stirring, continuously dropwise adding 560.6g of 10wt% hydroxyacetonitrile aqueous solution, continuously carrying out prolonged reaction for 2 hours under the corresponding conditions after the dropwise adding is finished, separating phases to obtain a lower reaction mother solution, and further washing 3 times to obtain a cyclohexylamino diacetonitrile mother solution;
s2: 200g of methanol solvent and 5g of Raney cobalt catalyst are added into a reaction kettle, and the mixture is treated in H 2 Stirring at the absolute pressure of 3MPa and the temperature of 210 ℃, continuously dropwise adding 100g of cyclohexylamine-based diacetonitrile mother liquor, and continuously prolonging the reaction for 2 hours after the dropwise adding is finished to obtain reaction mother liquor; the cyclohexyl piperazine mother liquor is further subjected to rectification and purification for 6 hours at 80 ℃ and 30KPa absolute pressure to obtain a final product; the corresponding material composition was obtained by GC analysis and mainly comprised 2.3wt% of piperazine cyclohexylamine, 93.6wt% of cyclohexylamine aminoethyl and 4.1wt% of other by-products.
The application of the present invention is not limited to the above embodiments, but any modifications or variations within the spirit of the present invention will be included in the scope of the present invention as intended by those skilled in the art.
Claims (15)
1. A process for the preparation of cyclohexylpiperazine, characterized in that it comprises the steps of:
s1: adding cyclohexylamine and a catalyst A into a reaction container, adding hydroxyacetonitrile, carrying out phase separation after reaction, and washing a lower reaction solution to obtain cyclohexylamine diacetonitrile mother solution;
s2: adding solvent and catalyst B into a reaction vessel, at H 2 Adding cyclohexylamine-based diacetonitrile mother liquor to react in the atmosphere, and obtaining cyclohexylpiperazine after distillation and purification;
wherein the catalyst A in S1 is an alkali metal catalyst, and the catalyst B in S2 is [ (M) 1 &M 2 )Cl 2 ](TPPTS) 2 Active metal M 1 Is one of metal elements of VIII, IB and IIB, and is a metal M 2 Is one of metal elements of IIA group, VIB group and VIIB group.
2. The process of claim 1 wherein S1 catalyst a is an alkali metal hydroxide;
and/or the molar ratio of the hydroxyacetonitrile to the cyclohexylamine of S1 is (1.5-2.5): 1;
and/or, S1, wherein the hydroxyacetonitrile is a hydroxyacetonitrile aqueous solution;
and/or the reaction temperature of the cyclohexylamine and the hydroxyacetonitrile is 50-150 ℃ in S1; the pressure is 0.5-5 MPa absolute pressure; the reaction time is 1-5 h.
3. The method of claim 2, wherein S1 the catalyst a is one or more of NaOH, liOH, KOH, rbOH, csOH;
the addition amount of the catalyst A is 0.1-1 wt% of cyclohexylamine;
and/or the molar ratio of the hydroxyacetonitrile to the cyclohexylamine of S1 is (2-2.2): 1;
the hydroxyacetonitrile aqueous solution is added in a semi-continuous mode; the concentration of the hydroxy acetonitrile water solution is 5-50wt%;
and/or the reaction temperature of the cyclohexylamine and the hydroxyacetonitrile is 100-120 ℃ in S1; the pressure is 1-2 MPa absolute pressure; the reaction time is 2-3 h.
4. A process according to claim 3, wherein S1 the catalyst a is NaOH and/or KOH;
the addition amount of the catalyst A is 0.5 to 0.8 weight percent of the cyclohexylamine;
the feeding speed of the hydroxy acetonitrile aqueous solution is 0.1-5 g/min; the concentration of the hydroxy acetonitrile aqueous solution is 10-30wt%.
5. The process according to claim 4, wherein the aqueous hydroxyacetonitrile solution in S1 is fed at a rate of 1 to 2g/min.
6. The preparation method according to claim 1, wherein the solvent of S2 is one or more of methanol, ethanol, isopropanol, acetonitrile, n-butanol, tetrahydrofuran, and acetone;
and/or the S2 hydrogenation reaction temperature is 100-280 ℃; h 2 The pressure is 1-8 MPa absolute pressure; the reaction time is 1-5 h;
and/or the distillation purification temperature of the cyclohexylamine piperazine in the step S2 is 60-120 ℃; the pressure is 10-50 KPa absolute; the rectification time is 3-10h.
7. The method according to claim 6, wherein the solvent S2 is methanol and/or ethanol;
and/or the S2 hydrogenation reaction temperature is 180-230 ℃; h 2 The pressure is 3-6 MPa absolute pressure; the reaction time is 2-4 h;
and/or, the distillation purification temperature of the cyclohexylamine piperazine in the step S2 is 80-100 ℃; the pressure is absolute pressure of 20-30 KPa; the rectification time is 6-8h.
8. The process according to claim 1, wherein S2 is the active metal M 1 One of Fe, pd, cu, zn, co, ni;
the auxiliary metal M 2 One of Cr, mo, mn, mg;
the addition amount of the catalyst B is 1-15wt% of cyclohexylamine diacetonitrile.
9. The process according to claim 1, wherein catalyst B is added in an amount of 5 to 10% by weight of cyclohexylamine diacetonitrile in S2.
10. The preparation method of the catalyst B according to claim 1, wherein the preparation method of the catalyst B according to S2 is as follows:
SS1: adding active metal M1 salt, auxiliary metal M2 salt and PPh into the solution 3 Heating and refluxing, cooling, filtering, washing to obtain viscous solid, and drying to obtain [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 ；
SS2：[(M 1 &M 2 )Cl 2 ](PPh 3 ) 3 Adding THF, heating and refluxing, adding TPPTS, reacting at constant temperature, cooling, collecting water phase and drying to obtain solid product [ (M) 1 &M 2 )Cl 2 ](TPPTS) 2 。
11. The process according to claim 10, wherein SS1 is the active metal M 1 With auxiliary metal M 2 The molar ratio of (2) is 5-50:1;
and/or, the active metal M1 salt and the auxiliary metal M2 salt of the SS1 are hydrochlorides;
and/or, the solvent of SS1 is methanol;
and/or, SS1 reacts under the vacuum condition, the vacuum degree is 10-50 KPa; the reaction temperature is 40-80 ℃; the reaction time is 1-10 h;
and/or drying the SS1 under the absolute pressure of 10-50 KPa; the drying temperature is 60-100 ℃; the drying time is 1-10 h.
12. The process according to claim 11, wherein SS1 is the active metal M 1 With auxiliary metal M 2 The molar ratio of (2) is 10-20:1;
the active metal M 1 Salt and PPh 3 The mass ratio of (2) is 1:1-10; reactive metal M 1 The mass ratio of the salt to the methanol is 1:5-10;
and/or the vacuum degree of the SS1 is 20-30 KPa; the reaction temperature is 50-60 ℃; the reaction time is 3-5 h;
and/or drying the SS1 under the absolute pressure of 20-30 KPa; the drying temperature is 70-90 ℃; the drying time is 4-6 h.
13. The process according to claim 12, wherein SS1 is the active metal M 1 Salt and PPh 3 The mass ratio of (2) is 1:4-6; reactive metal M 1 The mass ratio of the salt to the methanol is 1:5-8.
14. The method of claim 10, wherein SS2 is [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 The mass ratio of the catalyst to THF is 1:10-100;
and/or SS2 [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 The mass ratio of the TPPTS to the TPPTS is 1:1-10;
and/or, SS2 reacts under the vacuum condition, the vacuum degree is 10-50 KPa of absolute pressure; the reaction temperature is 40-80 ℃; the reaction time is 1-10 h;
and/or the drying temperature of SS2 is 50-130 ℃; the drying time is 5-10 h; the vacuum degree is 10-50 KPa absolute.
15. The method of claim 14, wherein SS2 is [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 The mass ratio of the catalyst to THF is 1:40-60;
and/or SS2 [ (M) 1 &M 2 )Cl 2 ](PPh 3 ) 3 The mass ratio of the TPPTS to the TPPTS is 1:2-3;
and/or the vacuum degree of the SS2 is 20-30 KPa absolute; the reaction temperature is 50-60 ℃; the reaction time is 3-5 h;
and/or the drying temperature of SS2 is 80-100 ℃; the drying time is 6-8 hours; the vacuum degree is 20-30 KPa absolute.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010051374A1 (en) * | 2008-10-31 | 2010-05-06 | Pain Therapeutics, Inc. | Analgesic that binds filamin a |
| CN112645901A (en) * | 2020-12-24 | 2021-04-13 | 山东铂源药业有限公司 | Preparation method of 1-cyclohexyl piperazine |
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-
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010051374A1 (en) * | 2008-10-31 | 2010-05-06 | Pain Therapeutics, Inc. | Analgesic that binds filamin a |
| CN112645901A (en) * | 2020-12-24 | 2021-04-13 | 山东铂源药业有限公司 | Preparation method of 1-cyclohexyl piperazine |
Non-Patent Citations (5)
| Title |
|---|
| EDTA及其中间体类似物合成新工艺研究;陈贵华等;《广州化工》;第37卷(第1期);第65-66、72页 * |
| Molecular recognition: minimizing the acid–base interaction of a tunable host–guest system changes the selectivity of binding;Michael Pittelkow et al.;《J Incl Phenom Macrocycl Chem》;第63卷;第257-266页 * |
| New organometallic imines of rhenium(I) as potential ligands of GSK-3β: synthesis, characterization and biological studies;Michelle Muñoz-Osses et al.;《Dalton Transactions》;第47卷;第1233-1242页 * |
| Norio Sakai et al..Copper-Catalyzed Three- Five- or Seven-Component Coupling Reactions: The Selective Synthesis of Cyanomethylamines, N,N-Bis(Cyanomethyl)Amines and N,N'-Bis(Cyanomethyl)Methylenediamines Based on a Strecker-Type Synthesis.《Molecules》.2013,第18卷第12488-12499页. * |
| Sanjib Bhakta et al..Design and Synthesis of 1‑((1,5-Bis(4-chlorophenyl)-2- methyl‑1H‑pyrrol-3-yl)methyl)-4-methylpiperazine (BM212) and N‑Adamantan-2-yl‑N′‑((E)‑3,7-dimethylocta-2,6-dienyl)ethane-1,2- diamine (SQ109) Pyrrole Hybrid Derivatives: Discovery of Potent Antitubercular Agents Effective against Multidrug-Resistant Mycobacteria.《J. Med. Chem.》.2016,第59卷第2780-2793页. * |
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