Preparation and purification method of high-purity cycleanine

Abstract

The invention belongs to the field of medicine preparation and purification, and relates to a preparation and purification method of high-purity cycleanine. The method comprises the following steps: (1) adding triethylene tetramine into a reaction kettle, and slowly adding methylbenzene; (2) adding DMF (Dimethyl Formamide) and TETA.2H2O into a reaction kettle, introducing nitrogen into the reaction kettle, and catalyzing by alkali; (3) carrying out acid hydrolysis on a cyclization product, and filtering and centrifuging; (4) carrying out free reaction on organic alkali and / or inorganic alkali; and (5) refining and purifying. The process is suitable for industrial production, low in cost and easy for batch production.

Description

Technical Field

[0001] The invention belongs to the field of drug preparation and purification, and relates to a preparation and purification method of high-purity cyclopentane. Background Art

[0002] Cyclotrine is also called cyclotine, molecular formula: C 38 H 42 N2O6, molecular weight: 622.75. It is a colorless columnar crystal, melting point 268.5-269.5℃. Optical rotation -6.2° (c= 1.45, chloroform). Cyclotrimethylenetetraazacyclododecane (1,4,7,10-tetraazacyclododecane) is a very important intermediate for the synthesis of diagnostic reagents and therapeutic drugs. Cyclotrimethylenetetraazacyclododecane has the ability to strongly coordinate with a variety of metal ions, and can form a variety of derivatives with side chain groups such as esters, amides, and pyridines, and can be used in different fields such as medicine, enzyme mimics, and molecular recognition.

[0003] The process avoids the step of "adding 1.5-2 times the mass of the triethylenetetramine (I) as solvent I to the solid, heating to reflux, and then concentrating the solution to dryness under reduced pressure at 70-80°C to obtain a refined triethylenetetramine (II)" in the step of purchasing commercially available impure triethylenetetramine as a raw material for refining in the patent CN115785013A; and reduces the step of "intermediate 1 reacts with methylglyoxal to obtain intermediate 2" in the patent CN110698419A. Summary of the invention

[0004] The purpose of the present invention is to provide a method for preparing and purifying high-purity cyclamen.

[0005] In order to achieve the above objectives, the technical solution adopted by the present invention is as follows: A method for preparing and purifying high-purity cyclopentane comprises the following steps: 1) Preparation of TETA.2H2O: After triethylenetetramine and purified water are mixed, they are heated to 65-70 ℃, slowly cooled down, the temperature of the reaction solution is controlled to 25-30 ℃, seed crystals are added, and the reaction is kept at 20-25 ℃ for 1-1.5 hours; toluene is added dropwise at 20-25 ℃, and after the addition of toluene is completed, the temperature of the reaction system is slowly reduced to 10-15 ℃, and the reaction is kept at 10-15 ℃ for 0.5-1 hour; TETA.2H2O is obtained as a white solid wet product; triethylenetetramine is purified by a simple process.

[0006] 2) Ring-closing reaction: add DMF and TETA.2H2O, control the temperature to 0-5℃, add diacetyl dropwise; then add DMF; control the temperature to 0-5℃, keep warm for 0.5-1h; add alkali and 1,2-dibromoethane EDB, control the temperature of the reaction solution at 15-20℃; centrifuge, control the temperature to 55-65℃, concentrate, stop concentrating when there is no solvent dripping from the condenser; the concentrate is the ring-closing product; 3) Hydrolysis reaction: add the cyclized product, and drop concentrated hydrochloric acid at 95-100°C; after the dropwise addition, control the temperature of the reaction solution at 95-100°C for 0.5-1h; slowly cool to 0-5°C, and keep at 0-5°C for 2-3h; centrifuge and wash the filter cake, which is cyclen.4HCl; 4) Free reaction: add cyclen.4HCl, add alkaline solution dropwise, control the temperature to <95℃, and add for 3-4h; after the addition, control the temperature to 90-95℃, stir and react for 0.4-0.6h; slowly cool the reaction solution to 0~5℃, and keep warm for 0.5-1h; centrifuge to obtain the crude product of cyclamenine.

[0007] 5) Refining and purification.

[0008] The above preparation steps can be used to obtain high-purity cyclopentane. In the above steps, regarding the ratio of raw materials, an economical and effective raw material ratio is selected to further improve the yield; regarding the temperature, firstly, a certain temperature must be reached to complete the corresponding reaction, and the temperature cannot be too high to prevent degradation of the raw materials.

[0009] In a preferred embodiment, in step 1), the temperature of the reaction system is slowly lowered to 10-15°C for 1-2 hours, preferably 1 hour. Triethylenetetramine and purified water are mixed at a molar ratio of 1.8-2.5:1.

[0010] In step 1), after the heating temperature is raised to 65-70°C, the temperature is slowly lowered for 2-3 hours.

[0011] Step 5) is specifically as follows: the crude product of cyclopentane is mixed with toluene at 70-90°C and separated into layers; the upper toluene phase is filtered, and the crystals are concentrated under reduced pressure at 40-50°C and a vacuum degree of ≤-0.095 MPa; the temperature is raised to 90-95°C, and the crystals are dissolved again; the temperature is lowered to 60-65°C, and the crystals are slowly separated; the temperature is slowly lowered to 0-5°C, and the temperature is kept for 3-4 hours; centrifugation is performed, and the cyclopentane is dried to obtain the crude product of cyclopentane. The crude product of cyclopentane is mixed with toluene at 70-90°C and separated into layers; and the operation is repeated 3 times.

[0012] In step 2), the diacetyl is added dropwise for 0.5-1 h.

[0013] In step 3), the acid is added dropwise for 0.5-1h. In step 3), the temperature is slowly lowered to 0-5°C, and the cooling process takes 0.5-1.5h.

[0014] In step 4), the reaction was stirred for 0.5 h.

[0015] The invention is beneficial in that the process is suitable for industrial production, has low cost, is easy for batch production, and can prepare cyclopentane with high yield and high purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 This is the gas chromatography detection spectrum of the cyclopentane prepared in Example 1, and the peak with a retention time of 13.440 min is cyclopentane; Figure 2 This is the gas chromatography detection spectrum of the cyclopentane prepared in Example 2, and the peak with a retention time of 13.353 min is cyclopentane. DETAILED DESCRIPTION

[0017] The present invention is described in detail below with reference to specific embodiments.

[0018] The present invention provides a method for preparing and purifying high-purity cyclopentane. The method comprises the following steps: (1) adding triethylenetetramine to a reaction kettle and slowly adding toluene; (2) adding DMF and TETA.2H2O to the reaction kettle, passing nitrogen gas through the reaction kettle, and catalyzing with a base; (3) acid hydrolyzing the ring-closing product, filtering and centrifuging; (4) freeing reaction with an organic base and / or an inorganic base; and (5) refining and purification.

[0019] When preparing TETA.2H2O, after adding triethylenetetramine and purified water, the temperature is slowly lowered for 2-3 hours, the toluene addition process is controlled within 0.5-1 hour, and the cooling time after the toluene addition is controlled within 1-2 hours. During the ring-closing reaction, the mole of DMF is 0.6-0.7 times the mole of TETA.2H2O; potassium carbonate is 1.6-1.8 times the amount of TETA.2H2O (molar multiple); EDB is 1.65-1.85 times the amount of TETA.2H2O (molar multiple). During the hydrolysis reaction, concentrated hydrochloric acid refers to hydrochloric acid with a concentration of 36-38%; concentrated hydrochloric acid is 5.5-6.5 times the amount of TETA.2H2O (molar multiple); in the free reaction, after adding 30% KOH aqueous solution, the temperature is controlled to <95°C (preferably 75-85°C). During the refining process, the amount of toluene added each time is 3-4 times the amount of the crude cyclopentane (mass multiple). The main reason why the temperature in step 1 is higher than that in step 2 and step 3 is to achieve quality control indicators: control the water content <0.5%, thereby improving the purity of cyclopentane; concentrate the filtrate at 40-50°C; and improve the purity of cyclopentane through multiple crystallizations.

[0020] Example 1

[0021] Preparation of TETA.2H2O: (1) Add triethylenetetramine and purified water (molar ratio of triethylenetetramine: purified water: 2.1:1) to the reactor in sequence. Heat to 65°C, slowly cool to 25°C for 2h (to ensure sufficient crystal growth time), control the temperature of the reaction liquid to 25°C, add seed crystals (i.e. TETA.2H2O, the same below) 0.00002 times the weight of triethylenetetramine to improve the crystallization efficiency, and keep the reaction at 25°C for 1h; (2) Add toluene dropwise at a temperature of 25 °C, and the addition process is controlled within 0.5 h; the molar ratio of triethylenetetramine to toluene is 1:2.2; (3) After the addition of toluene is complete, the temperature of the reaction system is slowly lowered to 15°C for 1 hour, and the temperature is kept at 15°C for 1 hour; (4) Centrifuge and dry to obtain TETA.2H2O white solid (wet product).

[0022] Ring Closure Reaction: (1) Start stirring, add DMF and TETA.2H2O to the reactor in sequence, and ventilate the reactor with nitrogen; control the temperature of the reaction solution to 5°C, and add diacetyl dropwise for 0.5 h; the molar ratio of TETA.2H2O to DMF is 1:0.6; the molar ratio of TETA.2H2O to diacetyl is 1:0.5; (2) After the addition is completed, DMF is added to wash the diacetyl dropping tank, and the DMF containing a small amount of diacetyl obtained by washing is added to the reactor; the reaction liquid is temperature controlled to 5°C and kept warm for 1 hour; the DMF added in step (2) is 0.2 times (molar multiple) of the TETA.2H2O added in step (1); (3) Add potassium carbonate and stir for 0.5h; add 1,2- two Ethyl bromide EDB; after the addition is completed, the temperature of the reaction solution is controlled at 20°C; the molar ratio of potassium carbonate to TETA.2H2O in step (1) is 1.6:1; the molar ratio of EDB to TETA.2H2O in step (1) is 1.65:1; (4) Centrifuge and bag the filter cake for solid waste disposal.

[0023] (5) The DMF phase (containing the ring-closure reaction product) was concentrated at a controlled temperature of 55°C until no obvious solvent dripping occurred at the condenser. The concentration was stopped and the concentrate - the crude ring-closure product - was directly used for the next reaction.

[0024] Hydrolysis reaction: (1) Add 36% concentrated hydrochloric acid to the concentrated crude ring-closure product in the reaction kettle at 95°C for 0.5 h. After the addition is complete, the reaction liquid temperature is controlled at 95°C for 1 h. The molar ratio of concentrated hydrochloric acid to TETA.2H2O added in the ring-closure reaction is 6:1. (2) Slowly cool to 5°C within 1 h and keep warm at 5°C for 3 h.

[0025] (3) Centrifugal drying, the filter cake is washed with 5% hydrochloric acid aqueous solution, and the filter cake is cyclen.4HCl-1.

[0026] Free reaction: (1) Add purified water to the reactor and add KOH while stirring; stir to dissolve, control the temperature to 15°C, and prepare a 30% KOH aqueous solution for use; (2) Add cyclen.4HCl under stirring; start to add 30% KOH aqueous solution, control the temperature to 75℃, and add for 3 hours; after the addition is completed, control the temperature to 90℃ and stir to react for 0.5 hours; the mass ratio of cyclen.4HCl to 30% KOH aqueous solution is 1:1.7.

[0027] (3) The reaction solution was slowly cooled to 0°C (cooling time 1 h) and kept warm for 0.5 h; centrifuged to obtain the crude product of cyclopentane.

[0028] refined: (1) Add toluene and crude cyclopentane to a reactor; heat to 90°C, separate the layers, transfer the upper toluene phase to another reactor A, and control the water content of the upper toluene phase to be less than 0.5wt%; the mass ratio of toluene to crude cyclopentane is 3:1; (2) Toluene was added to the reactor again, the temperature was raised to 80°C, and the mixture was stirred for 0.5 h. The layers were separated and the upper toluene phase was transferred to the reactor No. B. The amount of toluene added was the same as that in step (1). (3) Toluene was added to the reactor again, the temperature was raised to 80°C, stirred for 0.5 h, the layers were separated, and the upper toluene phase was transferred to reactor C; the amount of toluene added was the same as in step (1); (4) Filter while hot and transfer the filtrate to reactor D; (5) The filtrate in the D reactor was concentrated under reduced pressure at an internal temperature of 45°C and a vacuum degree of ≤-0.095 MPa to concentrate the toluene phase until crystals precipitated; the concentrated solution was stopped and the temperature was raised to 90°C to dissolve the crystals again; the cooling was started and the temperature was lowered to 60°C to allow slow crystallization (cooling time 0.5 h); the temperature was then slowly lowered to 0°C (cooling time 1.5 h) and the reaction was kept at this temperature for 3 h; the mixture was centrifuged and dried to obtain cyclopentane.

[0029] The detection spectrum of cyclopentane obtained in Example 1 is as follows Figure 1 The total yield of Example 1 is 68%, and the purity is 99.653%.

[0030] Example 2

[0031] Preparation of TETA.2H2O: (1) Add triethylenetetramine and purified water (molar ratio of triethylenetetramine: purified water: 1.8:1) to the reactor in sequence. Heat to 70°C, slowly cool to 30°C for 3h (to ensure sufficient crystal growth time), control the temperature of the reaction liquid to 30°C, add seed crystals 0.00002 times the weight of triethylenetetramine to improve the crystallization efficiency, and keep the reaction at 20°C for 1.5h; (2) Add toluene dropwise at a temperature of 20 °C, and the addition process is controlled within 1 hour; the molar ratio of triethylenetetramine to toluene is 1:2.2; (3) After the addition of toluene is complete, the temperature of the reaction system is slowly lowered to 10°C for 2 hours, and the temperature is kept at 10°C for 1 hour; (4) Centrifuge and dry to obtain TETA.2H2O white solid (wet product).

[0032] Ring Closure Reaction: (1) Start stirring, add DMF and TETA.2H2O to the reactor in sequence, and ventilate the reactor with nitrogen; control the temperature of the reaction solution to 0°C, and add diacetyl dropwise for 1 hour; the molar ratio of TETA.2H2O to DMF is 1:0.7; the molar ratio of TETA.2H2O to diacetyl is 1:0.6; (2) After the addition is completed, DMF is added to wash the diacetyl dropping tank, and the DMF containing a small amount of diacetyl obtained by washing is added to the reactor; the reaction liquid is temperature controlled to 0°C and kept warm for 1 hour; the DMF added in step (2) is 0.2 times (molar multiple) of the TETA.2H2O added in step (1); (3) Add potassium carbonate and stir for 0.5h; add 1,2- two Ethyl bromide EDB; after the addition is completed, the temperature of the reaction solution is controlled at 15°C; the molar ratio of potassium carbonate to TETA.2H2O in step (1) is 1.8:1; the molar ratio of EDB to TETA.2H2O in step (1) is 1.85:1; (4) Centrifuge and bag the filter cake for solid waste disposal.

[0033] (5) Control the temperature at 65°C and start concentrating the DMF phase (containing the ring-closure reaction product) until no obvious solvent dripping occurs at the condenser. Stop concentrating and use the concentrate - the crude ring-closure product - directly in the next reaction.

[0034] Hydrolysis reaction: (1) Add 38% concentrated hydrochloric acid to the concentrated crude ring-closure product in the reaction kettle at 100°C for 1 hour. After the addition is completed, the reaction liquid temperature is controlled at 100°C for 1 hour. The molar ratio of concentrated hydrochloric acid to TETA.2H2O added in the ring-closure reaction is 5.5:1. (2) Slowly cool to 0℃ within 1.5h and keep at 0℃ for 3h.

[0035] (3) Centrifugal drying, the filter cake is washed with 5% hydrochloric acid aqueous solution, and the filter cake is cyclen.4HCl-1.

[0036] Free reaction: (1) Add purified water to the reactor and add KOH while stirring; stir to dissolve, control the temperature to 20°C, and prepare a 30% KOH aqueous solution for use; (2) Add cyclen.4HCl under stirring; start to add 30% KOH aqueous solution, control the temperature to 85℃, and add for 4 hours; after the addition is completed, control the temperature to 95℃ and stir to react for 0.5 hours; the mass ratio of cyclen.4HCl to 30% KOH aqueous solution is 1:1.8.

[0037] (3) The reaction solution was slowly cooled to 5°C (cooling time 0.5 h) and kept warm for 1 h; centrifuged to obtain the crude product of cyclopentane.

[0038] refined: (1) Add toluene and crude cyclopentane to a reactor; heat to 80°C, separate the layers, transfer the upper toluene phase to another reactor A, and control the water content of the upper toluene phase to be less than 0.5wt%; the mass ratio of toluene to crude cyclopentane is 4:1; (2) Toluene was added to the reactor again, the temperature was raised to 70°C, and the mixture was stirred for 0.5 h. The layers were separated and the upper toluene phase was transferred to the reactor No. B. The amount of toluene added was the same as that in step (1). (3) Toluene was added to the reactor again, the temperature was raised to 70°C, stirred for 0.5 h, the layers were separated, and the upper toluene phase was transferred to reactor C; the amount of toluene added was the same as in step (1); (4) Filter while hot and transfer the filtrate to reactor D; (5) The filtrate in the D reactor was concentrated under reduced pressure at an internal temperature of 50°C and a vacuum degree of ≤-0.095 MPa to concentrate the toluene phase until crystals precipitated; the concentrated solution was stopped and the temperature was raised to 95°C to dissolve the crystals again; the cooling was started and the temperature was lowered to 65°C to allow slow crystallization (cooling time 1 h); the temperature was then slowly lowered to 5°C (cooling time 1.5 h) and the reaction was kept at this temperature for 3 h; the mixture was centrifuged and dried to obtain cyclopentane.

[0039] The detection spectrum of cyclopentane obtained in Example 2 is as follows Figure 2 The total yield was 68.02% and the purity was 99.49%.

[0040] The molar ratio of concentrated hydrochloric acid in the hydrolysis reaction to TETA.2H2O added in the ring-closing reaction has a great influence on the yield. Comparative Examples 1 and 2 are basically the same as Example 1, except that only the molar ratio of hydrochloric acid to TETA.2H2O is changed.

[0041] Table 1 Effect of the molar ratio of concentrated hydrochloric acid in the hydrolysis reaction and TETA.2H2O added in the ring-closure reaction on the yield Code <![CDATA[Molar ratio of concentrated hydrochloric acid (HCl) to TETA·2H2O]]> Yield % Comparative Example 1 4.5:1 48.20% Comparative Example 2 5:1 55.31% Example 1 6:1 68.00% Example 2 5.5:1 68.02% The above embodiments are only used to illustrate the technical solutions of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any form, and any technical solutions obtained by equivalent replacement or equivalent transformation shall fall within the protection scope of the present invention.

Claims

1. A method for preparing and purifying high-purity cyclopentane, characterized in that: The steps include: 1) Preparation of TETA.2H2O: After mixing triethylenetetramine and purified water, heat to 65-70 ℃, slowly cool down, control the temperature of the reaction solution to 25-30 ℃, add seed crystals, and keep the temperature at 20-25 ℃ for 1-1.5 hours; control the temperature to be 20-25 ℃ and add toluene dropwise. After the addition of toluene is completed, slowly reduce the temperature of the reaction system to 10-15 ℃, and keep the temperature at 10-15 ℃ for 0.5-1 hour; obtain TETA.2H2O as a white solid wet product; 2) Ring-closing reaction: add DMF and TETA.2H2O, control the temperature to 0-5°C, add diacetyl dropwise; then add DMF; control the temperature to 0-5°C, keep the reaction warm for 0.5-1h; add alkali and 1,2-dibromoethane EDB, and control the temperature of the reaction solution at 15-20°C; Centrifuge and control the temperature at 55-65℃ to concentrate until no solvent drips from the condenser tube. Stop concentrating. The concentrate is the ring-closing product. 3) Hydrolysis reaction: add the ring-closure product, and add concentrated hydrochloric acid dropwise at 95-100°C; after the addition is complete, control the temperature of the reaction solution at 95-100°C for 0.5-1h; slowly cool to 0-5°C, and keep at 0-5°C for 2-3h; Centrifuge and wash the filter cake, which is cyclen.4HCl; 4) Free reaction: add cyclen.4HCl, add alkaline solution dropwise, control the temperature to <95℃, and add for 3-4h; after the addition, control the temperature to 90-95℃, stir and react for 0.4-0.6h; slowly cool the reaction solution to 0~5℃, and keep the temperature for 0.5-1h; Centrifuge to obtain the crude product of cyclopentane; 5) Refining and purification.

2. The method for preparing and purifying high-purity cyclopentane according to claim 1, characterized in that: In step 1), the temperature of the reaction system is slowly lowered to 10-15°C, and the cooling process takes 1-2 hours.

3. The method for preparing and purifying high-purity cyclopentane according to claim 1, characterized in that: Step 5) is specifically as follows: the crude product of cyclopentane is mixed with toluene at 70-90°C and separated into layers; the upper toluene phase is filtered, and the filtrate is concentrated under reduced pressure at 40-50°C and a vacuum degree of ≤-0.095 MPa to precipitate crystals; the temperature is raised to 90-95°C to dissolve the crystals again; the temperature is lowered to 60-65°C to continue to slowly crystallize; the temperature is then slowly lowered to 0-5°C and kept warm for 3-4 hours; centrifuged and dried to obtain cyclopentane.

4. The method for preparing and purifying high-purity cyclopentane according to claim 1, characterized in that: In step 2), the diacetyl is added dropwise for 0.5-1 h.

5. The method for preparing and purifying high-purity cyclopentane according to claim 1, characterized in that: Step 3) Add concentrated hydrochloric acid dropwise for 0.5-1h.

6. The method for preparing and purifying high-purity cyclopentane according to claim 1, characterized in that: In step 3), the temperature is slowly lowered to 0-5°C, and the cooling process takes 0.5-1.5 hours.

7. The method for preparing and purifying high-purity cyclamen according to claim 1, characterized in that: In step 1), triethylenetetramine and purified water are mixed in a molar ratio of 1.8-2.5:

1.

8. The method for preparing and purifying high-purity cyclamen according to claim 3, characterized in that: In step 5), the crude cyclamenine is mixed with toluene at 70-90° C. and separated into layers; this operation is repeated 3 times.

9. The method for preparing and purifying high-purity cyclamen according to claim 1, characterized in that: In step 4), the reaction was stirred for 0.5 h.

10. The method for preparing and purifying high-purity cyclopentane according to claim 1, characterized in that: In step 1), after the heating temperature is raised to 65-70°C, the temperature is slowly lowered for 2-3 hours; after the toluene is added dropwise, the temperature is lowered for 1-2 hours.

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