Preparation method of cycleanine derivative

Abstract

The invention relates to a preparation method of cycleanine derivatives, and belongs to the technical field of organic synthesis. The preparation method comprises the following steps: S1, reacting cycleanine, benzyl chloroformate and alkali A in a solvent A to obtain an intermediate IM1; s2, reacting the intermediate IM1, tert-butyl bromoacetate and alkali B in a solvent B to obtain an intermediate IM2; s3, reacting the intermediate IM2 and a catalyst Pd / C in a solvent C in a hydrogen atmosphere to obtain an intermediate IM3; s4, the intermediate IM3 and 4, 4-dimethyl-3, 5, 8-trioxabicyclo [5, 1, 0] octane are subjected to a reflux reaction in a solvent D, and an intermediate IM4 is obtained; s5, reacting the intermediate IM4 and acid in a solvent E to obtain an intermediate IM5; s6, the intermediate IM5 and a metal compound react in a solvent F, and the cycleanine derivative # imgabs0 # is obtained. According to the preparation method, raw materials are cheap and easy to obtain, high-pressure preparation liquid phase purification is avoided, equipment investment and industrial wastewater generation are reduced, the reaction is easy to operate, and aftertreatment is relatively simple.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a method for preparing a cyclamenine derivative. Background Art

[0002] In 1973, Lauterbur and Mansfield invented Magnetic Resonance Imaging (MRI) and won the Nobel Prize in Physiology or Medicine. MRI can detect internal tissues without causing damage to the human body. It has been used in hospitals around the world. In magnetic imaging, ionic macrocyclic chelates are the most widely used and safe. In order to improve the water solubility, stability in the body and excretion of contrast agents, macrocyclic ionic chelators are needed.

[0003] Cyclotrimethylenetetramine derivatives are important intermediates in drug research. Most of the existing macrocyclic ionic chelates are derivatives of DOTA and DO3A, and the types are relatively small. Moreover, DOTA, DO3A and their derivatives contain 3 or more carboxylic acids. When complexing a divalent metal ion, the material is acidic, and there will be some free metal ions, which will cause harm to the human body. Therefore, it is difficult to effectively use divalent metals. DO2A derivatives have the characteristics of high water solubility, stable chelates, easy excretion from the body and convenient availability. DO2A derivatives have a unique spatial structure with 10-12 complexing sites. They can form very stable chelates with ions, especially divalent metal ions. The stable chelates formed with metal ions have shown extremely important application value in biochemistry, medicine and other fields, providing more possibilities for the contrast agent market.

[0004] The existing technology is to prepare a small amount of sample by high pressure liquid phase, which is of high cost and only applicable to the synthesis of impurities. Therefore, it is still of certain application value to develop a low cost and high yield route to synthesize cyclopentane derivatives. Summary of the invention

[0005] In order to solve the above technical problems, the present invention provides a method for preparing a cyclopentane derivative. The cyclopentane derivative is synthesized with high yield and high purity by taking cyclopentane as the starting raw material through the processes of adding protecting groups, nucleophilic substitution reaction, deprotecting groups, epoxy-opening reaction, hydrolysis reaction and complexing with metal ions. The raw materials are cheap and easy to obtain, the reaction is easy to operate, the post-treatment is relatively simple, and at the same time, a high purity can be stably obtained, and the method has a good prospect for industrial production.

[0006] The object of the present invention is to provide a method for preparing a cyclamenine derivative, comprising the following steps:

[0007] S1, cyclopentane, benzyl chloroformate and base A react in solvent A to obtain intermediate IM1;

[0008] S2, intermediate IM1, tert-butyl bromoacetate and base B react in solvent B to obtain intermediate IM2;

[0009] S3, under hydrogen atmosphere, the intermediate IM2 and the catalyst Pd / C react in the solvent C to obtain the intermediate IM3;

[0010] S4, intermediate IM3 and 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane are refluxed in solvent D to obtain intermediate IM4;

[0011] S5, intermediate IM4 and acid react in solvent E to obtain intermediate IM5;

[0012] S6, the intermediate IM5 and the metal compound react in a solvent F to obtain the cyclopentane derivative;

[0013] The reaction route is as follows:

[0014]

[0015] Wherein, M is selected from Fe, Ni or Ca.

[0016] In one embodiment of the present invention, in S1, the molar ratio of cyclopentane, benzyl chloroformate and base A is 1:1:2-1:2:3; the reaction temperature is -5°C to 5°C, for example, it can be -5°C, -4°C, -3°C, -2°C, -1°C, 0°C, 1°C, 2°C, 3°C, 4°C, 5, etc.; the reaction time is 6h-15h, for example, it can be 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, etc.

[0017] In one embodiment of the present invention, in S2, the molar ratio of the intermediate IM1, tert-butyl bromoacetate and base B is 1:2:2.5-1:6:9; the reaction temperature is 40°C-80°C, for example, 40°C, 41°C, 42°C, 43°C, 44°C, 45°C, 46°C, 47°C, 48°C, 49°C, 50°C, 51°C, 52°C, 53°C, 54°C, 55°C, 56°C, 57°C, 58°C, 59°C, 60°C, 61°C, 62°C, 63°C, 64°C, 65°C, 66°C, 67°C, 68°C, 69°C, 70°C, 71°C, 72°C, 73°C, 74°C, 75°C, 76°C, 77°C, 78°C, 79°C, 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C ℃, 6h-12h, for example, 6h, 7h, 8h, 9h, 10h, 11h, 12h, etc.

[0018] In one embodiment of the present invention, in S1 and S2, base A and base B are independently selected from one or more of triethylamine, diisopropylamine, potassium carbonate and sodium carbonate; solvent A and solvent B are independently selected from one or more of acetonitrile, dichloromethane, dimethylformamide and dimethyl sulfoxide.

[0019] In one embodiment of the present invention, in S3, the solvent C is selected from one or more of methanol, ethanol, tetrahydrofuran and acetonitrile; the reaction time is 4h-15h, for example, it can be 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, etc.

[0020] In one embodiment of the present invention, in S4, the solvent D is selected from one or more of methanol, ethanol, isopropanol and dimethylformamide.

[0021] In one embodiment of the present invention, in S4, the molar ratio of the intermediate IM3 to 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane is 1:2-1:9; the reflux reaction time is 10h-24h, for example, it can be 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, etc.

[0022] In one embodiment of the present invention, in S5, the acid is selected from one or more of trifluoroacetic acid, hydrochloric acid, acetic acid and sulfuric acid; the solvent E is selected from one or more of water, dichloromethane, acetonitrile, tetrahydrofuran and ethyl acetate; the reaction time is 10h-24h, for example, it can be 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h, etc.

[0023] In one embodiment of the present invention, in S6, the metal compound is selected from one or more of ferrous oxide, ferrous chloride, nickel chloride, calcium carbonate and calcium chloride; and the solvent F is selected from water and / or methanol.

[0024] In one embodiment of the present invention, in S6, the reaction temperature is 80°C-100°C, for example, it can be 80°C, 81°C, 82°C, 83°C, 84°C, 85°C, 86°C, 87°C, 88°C, 89°C, 90°C, 91°C, 92°C, 93°C, 94°C, 95°C, 96°C, 97°C, 98°C, 99°C, 100°C, etc.; the reaction time is 2h-4h, for example, it can be 2h, 2.5h, 3h, 3.5h, 4h, etc.

[0025] The technical solution of the present invention has the following advantages over the prior art:

[0026] The preparation method of the present invention uses cyclopentane as a starting material, and obtains cyclopentane derivatives through the processes of adding protecting groups, nucleophilic substitution reaction, deprotecting groups, epoxy-opening reaction, hydrolysis reaction and complexing metal ions; the raw materials are cheap and easy to obtain, and high-pressure preparation liquid phase purification is avoided, which saves equipment investment and the generation of industrial wastewater; the reaction is easy to operate and the post-treatment is relatively simple; at the same time, stable cyclopentane derivatives with high yield can be obtained, and the method has a good prospect for industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] In order to make the content of the present invention more clearly understood, the present invention is further described in detail below according to specific embodiments of the present invention in conjunction with the accompanying drawings, wherein:

[0028] Figure 1 is the NMR spectrum of the intermediate IM1 of the present invention;

[0029] Figure 2 is the NMR spectrum of the intermediate IM2 of the present invention;

[0030] Figure 3 is the NMR spectrum of the intermediate IM3 of the present invention;

[0031] Figure 4 is the NMR spectrum of the intermediate IM5 of the present invention;

[0032] Figure 5-Figure 6 It is a high-resolution mass spectrum of the cyclopentane derivative TM of the present invention;

[0033] Figure 7 It is the NMR spectrum of the intermediate IM1-1 of the present invention. DETAILED DESCRIPTION

[0034] The present invention is further described below in conjunction with the accompanying drawings and specific embodiments so that those skilled in the art can better understand the present invention and implement it. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of them. It should be understood that the specific embodiments are only used to explain the present invention, but the embodiments are not intended to limit the present invention.

[0035] In the present invention, unless otherwise explained, technical and scientific terms used in the present invention have the same meanings as commonly understood by those skilled in the art to which the present invention belongs.

[0036] In the present invention, unless otherwise stated, the term "and / or" used in the present invention includes any and all combinations of one or more of the associated listed items.

[0037] In the present invention, unless otherwise stated, the experimental methods used in the embodiments of the present invention are conventional methods unless otherwise stated, and the materials, reagents, etc. used are all commercially available unless otherwise stated.

[0038] Example 1

[0039] The preparation method of the cyclopentane derivative of this embodiment specifically comprises the following steps:

[0040] S1. Preparation of intermediate IM1: Under nitrogen atmosphere, add Cyclen (20 g, 116.1 mmol) and dichloromethane (200 mL) to a 500 mL three-necked flask, then add triethylamine (23.5 g, 232.2 mmol), and slowly cool to about 0°C. Slowly drop benzyl chloroformate CbzCl (48.8 mL, 132 mmol); control the temperature at about 0°C and stir the reaction for 12 h; slowly drop purified water (150 mL) to quench, separate the liquids, extract the aqueous phase with dichloromethane (100 mL*2), combine the organic phases, wash once with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase to dryness, separate by rapid column chromatography (silica gel), and use dichloromethane and methanol as eluents to obtain 30.0 g of light yellow solid intermediate IM1 (NMR spectrum as shown in Figure 1 As shown), the yield is 58.7%;

[0041] S2. Preparation of intermediate IM2: In a 500 mL three-necked flask, intermediate IM1 (25 g, 56.8 mmol), potassium carbonate (233.5 g, 170.24 mmol) and acetonitrile (250 mL) were added, the temperature was lowered to about 5°C, and tert-butyl bromoacetate (244.4 g, 124.9 mmol) was slowly added dropwise under this temperature condition, and the reaction was carried out at 5°C for 1.5 h, and the temperature was raised to 60°C and the reaction was carried out for 9 h. After the reaction was completed, the temperature was lowered to room temperature, filtered, and the filtrate was concentrated under reduced pressure to obtain 36.6 g of solid intermediate IM2 (NMR spectrum as shown in FIG. Figure 2 As shown), the yield is 94.9%;

[0042] S3. Preparation of intermediate IM3: In a nitrogen atmosphere, intermediate IM2 (30 g, 44.9 mmol) and methanol (300 mL) were added to a 1 L three-necked flask, and catalyst Pd / C (3 g, 10%) was added. The mixture was replaced with hydrogen three times and reacted at room temperature for 8 h. The palladium carbon was removed by filtration, and the reaction solution was dried by spin drying to obtain 18.1 g of an oily intermediate IM3 (NMR spectrum as shown in FIG. Figure 3 As shown), the yield is 100.71%;

[0043] S4. Preparation of intermediate IM4: In a 500 mL three-necked flask, intermediate IM3 (16 g, 39.9 mmol), 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane (28.8 g, 199.7 mmol) and isopropanol (150 mL) were added, and the mixture was heated under reflux for 18 h. The reaction solution was spin-dried and separated by rapid column chromatography (silica gel). The eluents were dichloromethane and methanol to obtain 19.0 g of light yellow solid intermediate IM4. The yield was 69.1%.

[0044] S5. Preparation of intermediate IM5: In a 500 mL three-necked flask, intermediate IM4 (15 g, 21.8 mmol), dichloromethane (30 mL) and trifluoroacetic acid (60 mL) were added, and the reaction was carried out at room temperature for 18 h. The filtrate was spin-dried, toluene was added to remove the trifluoroacetic acid three times, ethanol (50 mL) was added to slurry for 2.5 h, filtered, and dried to obtain 8 g of off-white solid intermediate IM5 (NMR spectrum as shown in FIG. Figure 4 As shown), the yield is 74.0%;

[0045] S6. Preparation of cyclopentane derivative TM (calcium complex): intermediate IM5 (1 g, 2.01 mmol), calcium carbonate (100.8 mg, 1.01 mmol) and purified water (20 mL) were added to a 100 mL three-necked flask, and the temperature was raised to 90° C. and refluxed for 3 h. A very small amount of insoluble impurities were removed by filtration. The filtrate was spin-dried, ethanol (20 mL) was added and slurried for 1.5 h, filtered, and dried to obtain 0.9 g of white solid cyclopentane derivative TM, with a yield of 83.6%;

[0046] The high-resolution mass spectrum of the cyclopentane derivative TM is shown in Figure 5-Figure 6 As shown, from Figure 5-Figure 6 It can be seen that the peak with M\Z of 535.2275 is the molecular ion peak of the target substance TM complexed with a hydrogen proton; the peak with M\Z of 557.22102 is the molecular ion peak of the target substance TM complexed with a sodium ion; the peak with M\Z of 573.1746 is the molecular ion peak of the target substance TM complexed with a potassium ion, which is consistent with the target structure;

[0047] The reaction route is as follows:

[0048]

[0049] Comparative Example 1

[0050] The same method as in Example 1 is used, except that the intermediate IM1 is prepared by changing the protecting group from Cbz to Boc, and using di-tert-butyl dicarbonate (Boc). 2 O replaces benzyl chloroformate CbzCl, specifically comprising the following steps:

[0051] S1. Preparation of intermediate IM1-1: Under nitrogen atmosphere, add Cyclen (20 g, 116.1 mmol) and dichloromethane (200 mL) into a 500 mL three-necked flask, slowly cool to about 0°C; slowly dropwise add di-tert-butyl dicarbonate (Boc) 2 O (50.7 g, 232.2 mmol); control the temperature at about 0 ° C and stir the reaction for 12 h; slowly add purified water (150 mL) to quench, separate the liquids, extract the aqueous phase with dichloromethane (100 mL*2), combine the organic phases, wash once with saturated brine (200 mL), dry over anhydrous sodium sulfate, filter, concentrate the organic phase to dryness, separate by rapid column chromatography (silica gel), eluents are dichloromethane and methanol, and obtain 32 g of white solid intermediate IM1-1 (NMR spectrum as shown Figure 7 As shown, the main product is the product of the above three Bocs, and it is difficult to control the selection of the reaction site, resulting in the inability to proceed with the subsequent synthesis), with a yield of 58.3%;

[0052] From the results of Example 1 and Comparative Example 1, it can be seen that the para-protecting group of cyclopentane needs to use a protecting group with large steric hindrance, the Cbz protecting group can highly selectively protect the two amino groups at the para position, and the Boc protecting group is difficult to control.

[0053] Obviously, the above embodiments are merely examples for clear explanation and are not intended to limit the implementation methods. For those skilled in the art, other different forms of changes or modifications can be made based on the above description. It is not necessary and impossible to list all the implementation methods here. The obvious changes or modifications derived from these are still within the protection scope of the invention.

Claims

1. A method for preparing a cyclopentane derivative, characterized in that: The following steps are involved: S1, cyclopentane, benzyl chloroformate and base A react in solvent A to obtain intermediate IM1; S2, intermediate IM1, tert-butyl bromoacetate and base B react in solvent B to obtain intermediate IM2; S3, under hydrogen atmosphere, the intermediate IM2 and the catalyst Pd / C react in the solvent C to obtain the intermediate IM3; S4, intermediate IM3 and 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane are refluxed in solvent D to obtain intermediate IM4; S5, intermediate IM4 and acid react in solvent E to obtain intermediate IM5; S6, the intermediate IM5 and the metal compound react in a solvent F to obtain the cyclopentane derivative; The reaction route is as follows: Wherein, M is selected from Fe, Ni or Ca.

2. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S1, the molar ratio of cyclopentane, benzyl chloroformate and base A is 1:1:2-1:2:3; the reaction temperature is -5°C to 5°C, and the reaction time is 6h-15h.

3. The method for preparing the cyclopentane derivative according to claim 1, characterized in that: In S2, the molar ratio of the intermediate IM1, tert-butyl bromoacetate and base B is 1:2:2.5-1:6:9; the reaction temperature is 40°C-80°C, and the reaction time is 6h-12h.

4. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S1 and S2, base A and base B are independently selected from one or more of triethylamine, diisopropylamine, potassium carbonate and sodium carbonate; solvent A and solvent B are independently selected from one or more of acetonitrile, dichloromethane, dimethylformamide and dimethyl sulfoxide.

5. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S3, the solvent C is selected from one or more of methanol, ethanol, tetrahydrofuran and acetonitrile; and the reaction time is 4h-15h.

6. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S4, the solvent D is selected from one or more of methanol, ethanol, isopropanol and dimethylformamide.

7. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S4, the molar ratio of the intermediate IM3 to 4,4-dimethyl-3,5,8-trioxabicyclo[5,1,0]octane is 1:2-1:9; and the reflux reaction time is 10h-24h.

8. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S5, the acid is selected from one or more of trifluoroacetic acid, hydrochloric acid, acetic acid and sulfuric acid; the solvent E is selected from one or more of water, dichloromethane, acetonitrile, tetrahydrofuran and ethyl acetate; and the reaction time is 10h-24h.

9. The method for preparing a cyclopentane derivative according to claim 1, characterized in that: In S6, the metal compound is selected from one or more of ferrous oxide, ferrous chloride, nickel chloride, calcium carbonate and calcium chloride; and the solvent F is selected from water and / or methanol.

10. The method for preparing a cyclamenine derivative according to claim 1, characterized in that: In S6, the reaction temperature is 80°C-100°C, and the reaction time is 2h-4h.

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