A preparation method of cyclopentane

Abstract

The present invention discloses a method for preparing cyclopentane. The present invention provides a method for preparing cyclopentane, which comprises the following steps: in an organic solvent, in the presence of a catalyst and a base, triethylenetetramine and ethylene glycol are subjected to a coupling reaction as shown below to prepare cyclopentane; wherein the organic solvent is selected from one or more of an aromatic hydrocarbon solvent, an ether solvent and a halogenated hydrocarbon solvent, the catalyst is nano cobalt ferrite, and the base is an organic base and / or an inorganic base. The preparation method of the present invention is green and environmentally friendly; the entire route is simple to operate, has a high yield, and has few by-products, and the reagents used are cheap, readily available, and non-toxic, and are very suitable for industrial production.

Description

Technical Field

[0001] The invention relates to a preparation method of cyclopentasiloxane. Background Art

[0002] Cyclen, also known as 1,4,7,10-tetraazadodecane, has a strong coordination ability for metal ions and is important in biomedicine, molecular recognition, catalysis, enzyme chemistry, supramolecular chemistry, hydrogen storage materials and other fields. It occupies a very important position in synthetic diagnostic kit therapeutic drugs, and is used as a contrast agent for medical imaging technologies such as magnetic resonance imaging (MRI), X-ray CT, and ultrasound imaging, as well as in the radiopharmaceutical treatment of malignant tumors. For example, the complex drug gadopentetate dimeglumine formed by the structure derived from cyclin and paramagnetic metal gadolinium ions is applied in the field of medical diagnosis, and does not have high toxicity caused by free ions, and has high safety. At present, the market demand for cyclin is increasing, and how to prepare this substance efficiently, environmentally friendly and at a low price is an important issue that needs to be solved.

[0003] The existing technologies for synthesizing cyclopentane are mainly as follows:

[0004] 1. Richman-Atkins synthesis

[0005] This method is a classic method for preparing cyclopentane. Richman and Atkins reported this scheme in 1974 (J.Am.Chem.Soc.1974,96,2268). Diethylenetriamine and diethanolamine are used as starting materials, first toluenesulfonylation is carried out, then the two react to close the ring, and finally the Ts protecting group is removed under strong alkaline conditions to obtain cyclopentane. This method has long been the main way to prepare cyclopentane, but because of the large amount of solvent used, low atomic utilization, high energy consumption, and large amount of wastewater, it has been gradually eliminated in industrial production.

[0006] 2. Weisman synthesis

[0007] Weisman reported a method for synthesizing cyclopentane in 1996 (J.Org.Chem.1996,61,5186). Triethylenetetramine and activated dithiooxamide were cyclized to obtain a tricyclic intermediate, which was then reduced with diisobutylaluminum hydride (DIBALH) and the ring was expanded to obtain cyclopentane. This route is suitable for small-scale preparation in the laboratory, but it is not suitable for large-scale industrial preparation because it uses multiple relatively expensive reagents and requires anhydrous and oxygen-free operation.

[0008] 3. Synthesis of diethyl oxalate

[0009] This method uses triethylenetetramine as a raw material, first condenses with diethyl oxalate to form a ring, and then uses borane or lithium aluminum hydride to reduce the amide to obtain the product. In order to avoid intermolecular cross-condensation, the reaction needs to be carried out at a lower concentration, and the amount of solvent used is large; and the reducing agent used to reduce the amide is expensive, so this method is not suitable for industrial production.

[0010] 4. Glyoxal or diacetyl method

[0011] This is a relatively novel and practical method (Tetrahedron Lett. 1999, 40, 2517), firstly reacting triethylenetetramine with glyoxal or diacetyl to form a rigid tricyclic structure, then reacting with dibromoethane to form a ring, and finally removing the acetal (ketone) under strong acid heating conditions to obtain cyclopentane. The raw materials used in this method are cheap and easy to obtain, and have industrial value, but the disadvantage is that a large amount of acidic wastewater will be generated.

[0012] 5. Imidazolidine method

[0013] Athey reported a unique method for preparing cyclopentane in 2002 (J.Org.Chem.2002,67,4081). Triethylenetetramine is cyclized to a diimidazoline structure by two molecules of N,N-dimethylformamide dimethyl acetal, then cyclized with dibromoethane, and finally hydrolyzed under alkaline conditions to obtain the product. The reaction conditions of this scheme are slightly milder than the above glyoxal / butanedione method, but the reagent price is high and more wastewater will be generated.

[0014]

[0015] In summary, although the synthesis method of cyclopentane has made great progress after years of research and can also be industrialized, it is still constrained by the generation of a large amount of three wastes. Therefore, the development of a short-step, efficient, green and low-cost method for the synthesis of cyclopentane has important industrial significance and application prospects. Summary of the invention

[0016] The technical problem that the present invention intends to solve is to overcome the problems of many three wastes and high cost in the current synthesis of cyclopentane. To this end, the present invention provides a preparation method of cyclopentane, which uses cheap ethylene glycol as a two-carbon unit and triethylenetetramine to prepare cyclopentane by cyclization, and reacts under the action of a cheap, easily available, and reusable metal catalyst; the route is simple to operate, has a high yield, and has few by-products, and the reagents used are cheap, easily available, and non-toxic, and are suitable for industrial production.

[0017] The present invention solves the above technical problems through the following technical solutions.

[0018] The present invention provides a method for preparing cyclopentane, which comprises the following steps: in an organic solvent, in the presence of a catalyst and a base, subjecting triethylenetetramine and ethylene glycol to a coupling reaction as shown below to prepare cyclopentane;

[0019] The organic solvent is selected from one or more of aromatic hydrocarbon solvents, ether solvents and halogenated hydrocarbon solvents; the catalyst is nano-cobalt ferrite; the base is an organic base and / or an inorganic base;

[0020]

[0021] In the present invention, among the organic solvents, the aromatic hydrocarbon solvent is preferably toluene or xylene; the ether solvent is preferably tetrahydrofuran; and the halogenated hydrocarbon solvent is preferably chloroform.

[0022] In the present invention, the volume mass ratio of the organic solvent to the triethylenetetramine can be 1-20 mL / g, preferably 5-10 mL / g, such as 5 mL / g, 8.2 mL / g or 10 mL / g.

[0023] In the present invention, the molar percentage of the catalyst and the triethylenetetramine is preferably 0.1-30 mol%, more preferably 1-20 mol%, such as 1 mol%, 10 mol% or 20 mol%.

[0024] In the present invention, among the bases, the organic base is preferably potassium alkoxide and / or sodium alkoxide, and more preferably potassium tert-butoxide; the inorganic base is preferably an alkali metal salt and / or an alkali metal hydroxide, and more preferably one or more selected from potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate.

[0025] In the present invention, the molar ratio of the base to the triethylenetetramine may be (0.01-5):1, preferably (0.1-2):1, such as 0.1:1, 0.3:1 or 2:1.

[0026] In the present invention, the molar ratio of the base to the triethylenetetramine is preferably (0.1-0.3):1.

[0027] In the present invention, the molar ratio of the ethylene glycol to the triethylenetetramine may be (0.5-2):1, preferably (0.8-1.5):1, such as 0.8:1, 1.05:1 or 1.5:1.

[0028] In the present invention, the molar ratio of the ethylene glycol to the triethylenetetramine is preferably (0.8-1.05):1.

[0029] In the present invention, the reaction temperature of the coupling reaction may be the reflux temperature of the organic solvent.

[0030] In the present invention, the reaction temperature of the coupling reaction is preferably 60-140°C, such as 100-110°C, 130-140°C, 65-70°C or 60-70°C.

[0031] In the present invention, the reaction temperature of the coupling reaction is preferably 100-140°C.

[0032] In the present invention, the coupling reaction is preferably carried out in an anaerobic environment.

[0033] In the present invention, the coupling reaction process is terminated when the triethylenetetramine substantially disappears. Preferably, the triethylenetetramine substantially disappears during the reaction process as detected by GC. The reaction time of the present invention is preferably 12-48h, such as 12h, 24h or 48h.

[0034] In the present invention, after the coupling reaction is completed, post-treatment can be carried out by cooling, removing the catalyst, distilling, cooling, filtering and washing steps;

[0035] The cooling temperature is preferably 25-50°C, such as 25°C or 50°C;

[0036] The catalyst removal is preferably adsorbed by a magnet;

[0037] The cooling temperature is preferably 0-10°C.

[0038] In the present invention, the coupling reaction is to add the triethylenetetramine into the organic solvent, and then sequentially add the catalyst, the ethylene glycol and the base.

[0039] Without violating the common sense in the art, the above-mentioned preferred conditions can be arbitrarily combined to obtain the preferred embodiments of the present invention.

[0040] The reagents and raw materials used in the present invention are commercially available.

[0041] The positive and progressive effects of the present invention are as follows: the preparation method of the present invention uses cheap ethylene glycol as a dicarbon unit and triethylenetetramine for the first time to prepare cyclopentane in a cyclization reaction under the action of a cheap, easily available and reusable metal catalyst; the route is simple to operate, has a high yield and few by-products, and the reagents used are cheap, easily available and non-toxic, and are suitable for industrial production. DETAILED DESCRIPTION

[0042] The present invention is further described below by way of examples, but the present invention is not limited to the scope of the examples. The experimental methods in the following examples without specifying specific conditions are carried out according to conventional methods and conditions, or selected according to the product specifications.

[0043] Example 1

[0044] Triethylenetetramine (14.6 g, 100 mmol) and toluene (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (6.51 g, 1.05 equiv) and sodium hydroxide (1.20 g, 0.3 equiv), and the mixture was heated to 100-110° C. for reflux reaction for 24 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered to 0-10° C., the precipitated solid was filtered, and washed with toluene (15 mL) to obtain 16.5 g of crystalline cyclopentane, with a yield of 96%.

[0045] 1 H NMR (400MHz, CDCl3, ppm): δ=2.07 (s, 4H), 2.64 (s, 16H).

[0046] Example 2

[0047] Triethylenetetramine (14.6 g, 100 mmol) and xylene (146 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (6.51 g, 1.05 equiv) and sodium hydroxide (1.20 g, 0.3 equiv), and the mixture was heated to 130-140 ° C for 12 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50 ° C, and the catalyst was removed by magnetic adsorption. The reaction solution was distilled under reduced pressure to leave 20-25 ml, and the temperature was lowered to 0-10 ° C. The precipitated solid was filtered and washed with xylene (15 mL) to obtain 16.0 g of crystalline cyclopentane, with a yield of 93%. The structure was confirmed by comparing it with the product in Example 1.

[0048] Example 3

[0049] Triethylenetetramine (14.6 g, 100 mmol) and THF (73 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (6.51 g, 1.05 equiv) and sodium hydroxide (1.20 g, 0.3 equiv), and the mixture was heated to 65-70° C. under nitrogen protection for 24 hours. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 25° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered to 0-10° C., the precipitated solid was filtered, and washed with THF (10 mL) to obtain 6.03 g of crystalline cyclopentane, with a yield of 35%. The structure was confirmed by comparing with the product in Example 1.

[0050] Example 4

[0051] Triethylenetetramine (14.6 g, 100 mmol) and chloroform (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (4.70 g, 20 mol%), ethylene glycol (6.51 g, 1.05 equiv) and sodium hydroxide (1.20 g, 0.3 equiv), and the mixture was heated at 60-70° C. for 48 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 25° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered to 0-10° C., the precipitated solid was filtered, and washed with chloroform (15 mL) to obtain 3.79 g of crystalline cyclopentane, with a yield of 22%. The structure was confirmed by comparing with the product in Example 1.

[0052] Example 5

[0053] Triethylenetetramine (14.6 g, 100 mmol) and toluene (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (0.235 g, 1 mol%), ethylene glycol (9.31 g, 1.5 equiv) and sodium hydroxide (8.00 g, 2 equiv), and the mixture was heated at 100-110° C. under nitrogen protection for 48 hours. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered to 0-10° C., the precipitated solid was filtered, and washed with toluene (15 mL) to obtain 6.38 g of crystalline cyclopentane, with a yield of 37%. The structure was confirmed by comparing with the product in Example 1.

[0054] Example 6

[0055] Triethylenetetramine (14.6 g, 100 mmol) and toluene (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (4.97 g, 0.8 equiv) and sodium hydroxide (0.40 g, 0.1 equiv), and the mixture was heated at 100-110° C. for 24 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure, the precipitated solid was filtered, and washed with toluene (15 mL) to obtain 11.5 g of crystalline cyclopentane, with a yield of 67%. The structure was confirmed by comparing it with the product in Example 1.

[0056] Example 7

[0057] Triethylenetetramine (14.6 g, 100 mmol) and toluene (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (6.51 g, 1.05 equiv) and potassium carbonate (0.3 equiv), and the mixture was heated to 100-110° C. for 24 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered by 0-10° C., the precipitated solid was filtered, and washed with toluene (15 mL) to obtain 9.48 g of crystalline cyclopentane, with a yield of 55%. The structure was confirmed by comparing with the product in Example 1.

[0058] Example 8

[0059] Triethylenetetramine (14.6 g, 100 mmol) and toluene (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (6.51 g, 1.05 equiv) and potassium phosphate (0.3 equiv), and the mixture was heated to 100-110° C. for 24 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered to 00-10° C., the precipitated solid was filtered, and washed with toluene (15 mL) to obtain 12.2 g of crystalline cyclopentane, with a yield of 71%, and the structure was confirmed by comparing with the product in Example 1.

[0060] Example 9

[0061] Triethylenetetramine (14.6 g, 100 mmol) and toluene (120 mL) were added to a 500 mL dry round-bottom flask, followed by nano-cobalt ferrite (2.35 g, 10 mol%), ethylene glycol (6.51 g, 1.05 equiv) and potassium tert-butoxide (0.3 equiv), and the mixture was heated under reflux at 100-110° C. for 24 hours under nitrogen protection. The triethylenetetramine was basically eliminated by GC detection. The mixture was cooled to 50° C., the catalyst was removed by magnetic adsorption, the reaction solution was distilled under reduced pressure until 20-25 ml remained, the temperature was lowered to 0-10° C., the precipitated solid was filtered, and washed with toluene (15 mL) to obtain 15.3 g of crystalline cyclopentane, with a yield of 89%, and the structure was confirmed by comparing with the product in Example 1.

Claims

1. A method for preparing cyclopentane, characterized in that: The method comprises the following steps: in an organic solvent, in the presence of a catalyst and a base, subjecting triethylenetetramine and ethylene glycol to a coupling reaction as shown below to prepare cyclopentane; The organic solvent is selected from one or more of aromatic hydrocarbon solvents, ether solvents and halogenated hydrocarbon solvents; the catalyst is nano-cobalt ferrite; the base is an organic base and / or an inorganic base; 2. The method for preparing cyclopentane as claimed in claim 1, characterized in that The aromatic hydrocarbon solvent is toluene or xylene.

3. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The ether solvent is tetrahydrofuran.

4. The method for preparing cyclopentane as claimed in claim 1, characterized in that The halogenated hydrocarbon solvent is chloroform.

5. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The molar percentage of the catalyst and the triethylenetetramine is 0.1-30 mol%.

6. The method for preparing cyclopentane as claimed in claim 5, characterized in that: The molar percentage of the catalyst and the triethylenetetramine is 1-20 mol%.

7. The method for preparing cyclopentane as claimed in claim 6, characterized in that: The molar percentage of the catalyst and the triethylenetetramine is 1 mol%, 10 mol% or 20 mol%.

8. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The inorganic base is an alkali metal salt and / or an alkali metal hydroxide.

9. The method for preparing cyclopentane as claimed in claim 8, characterized in that: The inorganic base is one or more of potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide and potassium phosphate.

10. The method for preparing cyclopentane according to claim 1, characterized in that: The organic base is potassium alkoxide and / or sodium alkoxide.

11. The method for preparing cyclopentane as claimed in claim 10, characterized in that: The organic base is potassium tert-butoxide.

12. The method for preparing cyclopentane according to claim 1, characterized in that: The molar ratio of the base to the triethylenetetramine is (0.01-5):

1.

13. The method for preparing cyclopentane according to claim 12, characterized in that: The molar ratio of the base to the triethylenetetramine is (0.1-2):

1.

14. The method for preparing cyclopentane as claimed in claim 13, characterized in that: The molar ratio of the base to the triethylenetetramine is 0.1:1, 0.3:1 or 2:

1.

15. The method for preparing cyclopentane as claimed in claim 1, characterized in that The volume mass ratio of the organic solvent to the triethylenetetramine is 1-20 mL / g.

16. The method for preparing cyclopentane according to claim 15, characterized in that: The volume mass ratio of the organic solvent to the triethylenetetramine is 5-10 mL / g.

17. The method for preparing cyclopentane according to claim 16, characterized in that: The volume mass ratio of the organic solvent to the triethylenetetramine is 5 mL / g, 8.2 mL / g or 10 mL / g.

18. The method for preparing cyclopentane according to claim 1, characterized in that: The reaction temperature of the coupling reaction is the reflux temperature of the organic solvent.

19. The method for preparing cyclopentane according to claim 18, characterized in that: The reaction temperature of the coupling reaction is 60-140°C.

20. The method for preparing cyclopentane according to claim 19, characterized in that: The reaction temperature of the coupling reaction is 100-110°C, 130-140°C or 60-70°C.

21. The method for preparing cyclopentane as claimed in claim 19, characterized in that: The reaction temperature of the coupling reaction is 65-70°C.

22. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The coupling reaction is carried out in an oxygen-free environment.

23. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The reaction time of the coupling reaction is 12-48h.

24. The method for preparing cyclopentane as claimed in claim 23, characterized in that: The reaction time of the coupling reaction is 12h, 24h or 48h.

25. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The molar ratio of the ethylene glycol to the triethylenetetramine is (0.5-2):

1.

26. The method for preparing cyclopentane as claimed in claim 25, characterized in that: The molar ratio of the ethylene glycol to the triethylenetetramine is (0.8-1.5):

1.

27. The method for preparing cyclopentane as claimed in claim 26, characterized in that: The molar ratio of the ethylene glycol to the triethylenetetramine is 0.8:1, 1.05:1 or 1.5:

1.

28. The method for preparing cyclopentane as claimed in claim 1, characterized in that: After the coupling reaction is completed, post-treatment is performed through cooling, catalyst removal, distillation, temperature reduction, filtration and washing steps.

29. The method for preparing cyclopentane as claimed in claim 28, characterized in that: The cooling is cooling to 25-50°C.

30. The method for preparing cyclopentane as claimed in claim 29, characterized in that: The cooling is cooling to 25°C or 50°C.

31. The method for preparing cyclopentane as claimed in claim 28, characterized in that: The catalyst removal is carried out by magnetic adsorption.

32. The method for preparing cyclopentane as claimed in claim 28, characterized in that: The cooling is to cool to 0-10°C.

33. The method for preparing cyclopentane as claimed in claim 1, characterized in that: The triethylenetetramine is mixed with the organic solvent, and then the catalyst, the ethylene glycol and the base are added.

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