A process for the preparation of 1,4,8,11-tetraazacyclotetradecane

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of 1,4,8,11-tetraazacyclotetradecane. The preparation method is characterized in that 1,3-dibromopropane and cycloethylamine are used as starting materials to react, and then the obtained intermediate is subjected to ring opening, ring expansion and cyclization by 1,3-propanediamine to obtain 1,4,8,11-tetraazacyclotetradecane. The process effectively avoids the introduction and removal of Ts-protecting groups by changing the reaction conditions, is simple to operate, shortens the reaction steps, and reduces the production time. The whole synthesis method is simple to operate and suitable for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical synthesis technology, specifically relating to a method for preparing 1,4,8,11-tetraazacyclotetradecane. Background Technology

[0002] Plerixafor, developed by Genzyme Corporation, is a small-molecule monoclonal antibody targeted therapy. In December 2008, it was first approved by the FDA as an orphan drug. Clinical studies have shown that plerixafor significantly increases white blood cell counts and promotes the flow of hematopoietic stem cells from the bone marrow into the bloodstream, exhibiting synergistic effects with granulocyte colony-stimulating factor (G-CSF). It has been used in the clinical treatment of multiple myeloma and non-Hodgkin's lymphoma patients undergoing stem cell transplantation. Its chemical structure is as follows:

[0003]

[0004] There are many publicly available methods for the preparation of pleroxafer, most of which use 1,4,8,11-tetraazacyclotetradecane as a raw material. After triple protection with N1, N4, and N8, the mixture is bridged with 1,4-di(halomethyl)benzene and deprotected to obtain the final product. R can be p-toluenesulfonyl, methanesulfonyl, trifluoroacetyl, tert-butoxycarbonyl, etc. While this method has fewer steps, the use of p-toluenesulfonyl as a protecting group easily generates multi-site protected byproducts, requiring column purification and separation, and the p-toluenesulfonyl group is difficult to remove. Similarly, using trifluoroacetyl also generates multi-site protected byproducts, requiring separation with a fast silica gel column, making it unsuitable for large-scale industrial production. Furthermore, due to the strong polarity of the trifluoroacetyl group, the activity of the fourth unprotected -NH group is reduced, often resulting in incomplete reaction in subsequent steps. This leads to the introduction of the difficult-to-remove impurity 1,4,8,11-tetraazacyclotetradecane after further deprotection. When using other protecting agents such as p-toluenesulfonyl, the deprotection step is a critical step because the deprotecting agents (such as hydrobromic acid / glacial acetic acid, concentrated sulfuric acid, etc.) often induce side reactions. The synthetic route is as follows:

[0005]

[0006] References Tetrahedron Letters, 1996, 37(43), 7711-7714 and Synth. Commun., 1998, 28(15): 2903-2906 describe a process using 1,4,8,11-tetraazacyclotetradecane as a starting material. Under anhydrous and oxygen-free conditions, the 1,4-bis(halomethyl)benzene is protected by an intracyclic phosphoryl group and then bridged with 1,4-bis(halomethyl)benzene, followed by deprotection to obtain plerusore. This process also uses 1,4,8,11-tetraazacyclotetradecane as a starting material, but this material is difficult to prepare and expensive if purchased directly. Furthermore, the route requires high levels of anhydrous and oxygen-free conditions, demanding reaction conditions. Incomplete deprotection makes the reaction process difficult to monitor, intermediates require multiple purifications, resulting in low overall yields and high costs. The synthetic route is as follows:

[0007]

[0008] In addition to the strategies described above, US Patent 5047527A also uses Cr(CO)6 to protect related materials before preparation; however, chromium compounds are highly toxic and unsuitable for industrial production. The synthetic route is as follows:

[0009]

[0010] References J.Org.Chem., 2003, 68(16), 6435-6436, Improved Synthesis Process of CXCR4 Antagonist Plexafor, Chemical Research, 2017, 28(5): 584-588, and Chinese patent application CN107417636A use methyl acrylate and ethylenediamine as raw materials. The process involves Michael addition and aminolysis, followed by cyclization with dimethyl malonate, bridging with 1,4-bis(halomethyl)benzene, and then reduction to obtain plexafor. Although this process uses common raw materials or reagents such as methyl acrylate and ethylenediamine, resulting in low cost, the final reduction step uses a borane-dimethyl sulfide complex as a reducing agent, which is expensive and potentially hazardous. The reaction solvent requires strict anhydrous treatment and argon protection, or the single-step cyclization yield is low (11.4%). The synthetic route is as follows:

[0011]

[0012] The literature on the improved synthesis process of plexafor, *Chinese Journal of Medicinal Chemistry*, 2010, 20(6):511-513, describes an improvement to the above process. Using diethyl malonate as a starting material, 1,4,8,11-tetraaza-5,7,12-trioxo-cyclotetradecane is obtained through aminolysis, Michael addition, and cyclization. This is then bridged with 1,4-dibromotoluene and reduced to obtain plexafor. This route is an improvement on the above route, but the intermediates in several subsequent steps require recrystallization, which directly affects the overall yield. The synthetic route is as follows:

[0013]

[0014] The synthetic process of the antitumor drug praxavir was studied in the Journal of Suzhou University, 2018, 33(10):107-109. Using DMF-DMA as a protecting group, selective triprotection of 1,4,8,11-tetraazacyclotetradecane was achieved at N1, N4, and N8-, without the need for column separation. The deprotection conditions were mild, and the overall yield was 60.37%. However, this process requires strict anhydrous treatment of the reaction solvent and argon protection during the addition of the protecting group, making the operation relatively cumbersome. The synthetic route is as follows:

[0015]

[0016] The literature New J. Chem., 2001, 25, 1168-1174 and WO2017037639A1 describes a synthetic route that uses N,N'-bis(2-aminoethyl)-1,3-propanediamine and glyoxal as starting materials, followed by reaction with 1,4-dibromomethylbenzene and hydrolysis to obtain the target product. The synthetic route is as follows:

[0017]

[0018] The literature J.Org.Chem. 2005, 70, 7042-7053 describes a process using N,N'-bis(2-aminoethyl)-1,3-propanediamine and acetone aldehyde as starting materials. The reaction proceeds to 1,3-dibromopropane, followed by a final reaction with 1,4-dibromomethylbenzene and hydrolysis to obtain the target product, with an overall yield of 25%. However, this process was only validated on a small-scale (1.0 g) test, and the target product was a yellow oil. The synthetic route is as follows:

[0019]

[0020] The literature Org. Prep. Proced. Int., 50:588-591, 2018 directly uses 1,4,8,11-tetraazacyclotetradecane and 1,4-dibromomethylbenzene as raw materials to obtain the target product with a high yield of 92% and a high purity of 99.6% under the action of a phase transfer catalyst, but this process has not been scaled up for verification. The synthetic route is as follows:

[0021]

[0022] As shown above, 1,4,8,11-tetraazacyclotetradecane (cyclam) is used as a key intermediate in the preparation of plexafor in various synthetic strategies. Therefore, cyclam can directly affect the production of this drug. Currently, the main methods for preparing cyclam include the following:

[0023] Method 1: Patent US5811544A describes a method using 1,3-diaminopropane as a starting material. First, it reacts with 2 equiv of chloroacetyl chloride to generate an amide, which is then cyclized with 1 equiv of 1,3-diaminopropane. The cyclized product is then reduced with 65% red aluminum toluene solution to obtain cyclam. While the literature describes only three steps, the second step, the high-temperature cyclization of 1,3-diaminopropane with the amide generated in the first step, requires a long time (24 hours), and the cyclized product is impure, producing numerous impurities as shown below. This necessitates column chromatography purification, limiting its industrial application. The synthetic route is as follows:

[0024]

[0025] Method 2: Patent WO9705123A1 uses bis-(3-aminopropyl)ethylenediamine as a starting material. First, it undergoes a sulfonation reaction with p-toluenesulfonyl chloride, followed by cyclization with 1,2-bis(p-toluenesulfonyloxy)ethane. The protection is then removed by reaction with 48% hydrobromic acid and glacial acetic acid, and finally, alkalization yields cyclam. The advantages of this method are high yields in the first substitution step and the second cyclization step, and a significantly shortened cyclization time in the second step. However, the use of a 48% hydrobromic acid / glacial acetic acid system for Ts removal results in a yield of only 72.0%, affecting the overall yield. The synthetic route is as follows:

[0026]

[0027] Method 3: In the literature Tetrahedron Letters, 1992, 33(38): 5505-5508, bis-(3-aminopropyl)ethylenediamine was used as a raw material. It was first sulfonated with trifluoromethanesulfonic anhydride, then cyclized with 1,2-dibromoethane in the presence of potassium carbonate, and finally the protecting group was removed with sodium / liquid ammonia to obtain cyclam. The first step of this method uses trifluoromethanesulfonic anhydride as the sulfonating agent, resulting in a low yield; the second step requires a cyclization temperature of 110℃, which is too high and easily causes side reactions; the third step, the removal of the trifluoromethanesulfonyl group, uses sodium / liquid ammonia and requires dropwise addition at -33℃, making the operation complicated and unsuitable for industrial application; the combined yield of the second and third steps is only 57.2%. The synthetic route is as follows:

[0028]

[0029] Method 4: In the literature Bulletin of the Academy of Sciences of the USSR Division of Chemical Science, 36(2):372-376, ethylenediamine is used as a raw material. It undergoes a substitution reaction with 1,3-dibromopropane to generate di(2-aminoethyl)propanediamine. Then, it undergoes sulfonation with p-toluenesulfonyl chloride under the action of sodium ethoxide. Then, it undergoes cyclization with 1,3-bis(p-toluenesulfonyloxy)propane. Finally, it is deprotected by concentrated sulfuric acid and alkalized to obtain cyclam.

[0030] However, this method uses ethylenediamine as a starting material, which undergoes a substitution reaction with 1,3-dibromopropane to generate di(2-aminoethyl)propanediamine. The yield of this step is low, only 42.0%. Sulfonation with p-toluenesulfonyl chloride under the action of sodium ethoxide yields only 52.1%. Cyclolysis with 1,3-bis(p-toluenesulfonyloxy)propane yields 65.3%. Finally, deprotection with concentrated sulfuric acid yields 81.0%. As can be seen, the overall yield of this method is not high. The synthetic route is as follows:

[0031]

[0032] Method 5: Arkivoc, 2006(4):212-233. Using 1,3-propanediamine as a starting material, cyclization with diethyl oxalate to form an amide, followed by reduction with borane, and finally acidification followed by alkalization, yields cyclam. This method uses ultrasound during the borane reduction process after cyclization with 1,3-propanediamine and diethyl oxalate, resulting in a total yield of only 19.0%, making it unsuitable for industrial scale-up. The synthetic route is as follows:

[0033]

[0034] Given the many shortcomings in the current preparation of cyclam, finding a simple, mild, safe, and easy-to-operate preparation process suitable for industrial-scale cyclam production, with high product yield and purity, remains a problem that needs to be solved. Summary of the Invention

[0035] To address the numerous problems existing in the current preparation of 1,4,8,11-tetraazacyclotetradecane, a key intermediate for plexamethonium, this invention provides a novel method for preparing 1,4,8,11-tetraazacyclotetradecane. This method features mild reaction conditions, a safe and simple operation, and yields a target product with high purity and yield.

[0036] The specific technical solution of the present invention is as follows:

[0037] A method for preparing 1,4,8,11-tetraazacyclotetradecane, a key intermediate of plexamethoxy, characterized by the following steps:

[0038] Step 1: Add compound SM-1, compound SM-2, acid-binding agent, and organic solvent A to a sealed reaction apparatus, and control the temperature T. A After the reaction was completed, the reaction solution was poured into purified water, extracted with dichloromethane, washed with saturated brine, and concentrated under reduced pressure to dryness to obtain compound I-1;

[0039] Step 2: Add compound I-1 and compound SM-3 to an alcohol-water mixed solvent, add a catalyst, and control the temperature T. B After the reaction is completed, the pH is adjusted to weakly alkaline by adding alkali. Toluene is added to the reaction solution, and the mixture is extracted at 70-75°C. The organic phases are combined, washed with saturated sodium carbonate solution, washed with saturated brine solution, and concentrated under reduced pressure to dryness to obtain the target product I.

[0040] The synthesis route is as follows:

[0041]

[0042] Preferably, the acid-binding agent mentioned in step 1 is selected from one of triethylamine, N,N-diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide, with potassium carbonate being the most preferred.

[0043] Preferably, the molar ratio of compound SM-1, compound SM-2, and acid-binding agent in step 1 is 1:2.4-3.6:2.6-4.0, more preferably 1:2.8:3.2.

[0044] Preferably, the organic solvent A in step 1 is selected from one or a combination of N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, and dimethyl sulfoxide, with N,N-dimethylformamide being the most preferred.

[0045] Preferably, the reaction temperature T in step 1 A The temperature range is 50–100℃, with 80–85℃ being preferred.

[0046] Preferably, the alcohol-water mixed solvent in step 2 is selected from one or a combination of tert-butanol-water, isopropanol-water, and ethanol-water, with isopropanol-water being the most preferred.

[0047] Preferably, the catalyst in step 2 is selected from formic acid, acetic acid, trifluoroacetic acid, and benzenesulfonic acid.

[0048] Preferably, the molar ratio of compound I-2, compound SM-3, and catalyst in step 2 is 1:1.3-2.0:0.8-1.2, more preferably 1:1.5:1.0.

[0049] Preferably, the alkali mentioned in step 2 is selected from one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate solid or their aqueous solutions.

[0050] Preferably, the reaction temperature T in step 2 B The temperature should be 70–80℃, preferably 75–80℃.

[0051] The beneficial effects of this invention are:

[0052] 1. This invention provides a simple and efficient method for preparing the key intermediate 1,4,8,11-tetraazacyclotetradecane for plexafor. The intermediate I-1 is prepared by starting with 1,3-dibromopropane and cycloethylamine, and then cyclized by ring-opening and ring-expansion with 1,3-propanediamine to obtain the target product.

[0053] 2. This process effectively avoids the introduction and removal of protecting groups such as Ts- by changing the reaction conditions. It is simple to operate, shortens the reaction steps, and reduces production time.

[0054] 3. The target product obtained by this process has a high yield and purity. Detailed Implementation

[0055] The present invention will be further illustrated by the following embodiments. It should be understood that the embodiments of the present invention are merely for illustrating the present invention and are not intended to limit the present invention. Therefore, any simple improvements to the present invention under the premise of the method of the present invention are within the scope of protection of the present invention.

[0056] This invention uses HPLC to determine the purity of 1,4,8,11-tetraazacyclotetradecane. The chromatographic conditions are as follows:

[0057] Column: Kromasil 100-5-C 18 A 4.6×250mm or equivalent chromatographic column and a ghost peak trapping column (Welch Ghost-Buster Column 4.6×50mm is recommended);

[0058] Column: Supelco LC-ABE C 18 Column (4.6 mm × 150 mm, 5 μm) or equivalent chromatographic column;

[0059] Mobile phase A: 0.1% aqueous phosphoric acid solution; Mobile phase B: acetonitrile;

[0060] Acetonitrile: 25 mmol / L ammonium dihydrogen phosphate (adjusted to pH 5.0 with sodium hydroxide) (25:75);

[0061] Gradient elution:

[0062]

[0063] Column temperature: 30℃;

[0064] Detection wavelength: 200nm;

[0065] Flow rate: 1.2 ml / min;

[0066] Injection volume: 10 μl.

[0067] The structural confirmation data of compound I-1 obtained in this invention are as follows:

[0068]

[0069] ESI-HRMS (m / z): 127.1228 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ: 2.22~2.30(m,4H), 1.67~1.72(m,4H), 1.03~1.12(m,6H); 13 C NMR (125MHz, CDCl3) δ: 60.64, 30.73, 26.06.

[0070] The structural confirmation data for compound I obtained in this invention are as follows:

[0071]

[0072] ESI-HRMS (m / z): 201.2043 [M+H] + ; 1 H NMR (600MHz, CDCl3) δ: 2.82 (t, J = 6.4Hz, 8H), 2.73 (s, 8H), 2.20 (s, 4H), 1.73 ~ 1.76 (m, 4H); 13 C NMR (125MHz, CDCl3) δ: 51.46, 48.72, 31.63.

[0073] In the following embodiments, the various processes and methods not described in detail are conventional methods known in the art.

[0074] Synthesis of I-1:

[0075] Example 1

[0076] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (12.06 g, 0.28 mol), potassium carbonate (44.23 g, 0.32 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 80–85 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 98.9% and an HPLC purity of 99.98%.

[0077] Example 2

[0078] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (10.34 g, 0.24 mol), potassium carbonate (44.23 g, 0.32 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 90–95 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 94.3% and an HPLC purity of 99.72%.

[0079] Example 3

[0080] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (9.47 g, 0.22 mol), potassium carbonate (44.23 g, 0.32 mol), and dimethyl sulfoxide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 95–100 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 88.3% and an HPLC purity of 98.85%.

[0081] Example 4

[0082] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (15.50 g, 0.36 mol), triethylamine (32.38 g, 0.32 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 60–65 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 95.2% and an HPLC purity of 99.58%.

[0083] Example 5

[0084] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (16.37 g, 0.38 mol), N,N-diisopropylethylamine (41.36 g, 0.32 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 50–55 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 89.3% and an HPLC purity of 98.74%.

[0085] Example 6

[0086] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (12.06 g, 0.28 mol), sodium hydroxide (10.40 g, 0.26 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 85–90 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 94.3% and an HPLC purity of 99.71%.

[0087] Example 7

[0088] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (12.06 g, 0.28 mol), potassium hydroxide (13.46 g, 0.24 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 45–50 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 85.3% and an HPLC purity of 98.92%.

[0089] Example 8

[0090] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (12.06 g, 0.28 mol), sodium carbonate (42.40 g, 0.40 mol), and N,N-dimethylformamide (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 65–70 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 95.5% and an HPLC purity of 99.57%.

[0091] Example 9

[0092] Compound SM-1 (20.19 g, 0.1 mol), compound SM-2 (12.06 g, 0.28 mol), pyridine (33.22 g, 0.42 mol), and acetonitrile (200 ml) were added to a closed reaction apparatus and reacted at a controlled temperature of 55–60 °C. After the reaction was detected to be complete, the reaction solution was poured into purified water (200 ml), extracted with dichloromethane (50 ml), washed with saturated brine (50 ml), and concentrated under reduced pressure to dryness to obtain compound I-1 with a yield of 87.5% and an HPLC purity of 98.42%.

[0093] Synthesis of I

[0094] Example 10

[0095] Compound I-1 (6.31 g, 0.05 mol) and 1,3-propanediamine (5.56 g, 0.075 mol) were added to a mixed solvent of isopropanol-water (V:V = 8:1, 60 ml). Anhydrous formic acid (2.30 g, 0.05 mol) was added, and the reaction was carried out at 75–80 °C. After the reaction was detected to be complete, sodium hydroxide was added to adjust the pH to slightly alkaline. Toluene (20 ml × 4) was added to the reaction solution, and the mixture was extracted at 70–75 °C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine solution (20 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 98.6% and an HPLC purity of 99.95%.

[0096] Example 11

[0097] Compound I-1 (6.31 g, 0.05 mol) and 1,3-propanediamine (4.82 g, 0.065 mol) were added to a mixed solvent of isopropanol-water (V:V = 8:1, 60 ml). Trifluoroacetic acid (4.56 g, 0.04 mol) was added, and the reaction was carried out at a controlled temperature of 75–80 °C. After the reaction was detected to be complete, potassium hydroxide was added to adjust the pH to slightly alkaline. Toluene (20 ml × 4) was added to the reaction solution, and the mixture was extracted at 70–75 °C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine solution (20 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 92.8% and an HPLC purity of 99.62%.

[0098] Example 12

[0099] Compound I-1 (6.31 g, 0.05 mol) and 1,3-propanediamine (3.71 g, 0.05 mol) were added to a mixed solvent of tert-butanol and water (V:V = 7:1, 60 ml). Anhydrous formic acid (1.38 g, 0.03 mol) was added, and the reaction was carried out at a controlled temperature of 75–80 °C. After the reaction was detected to be complete, sodium carbonate was added to adjust the pH to slightly alkaline. Toluene (20 ml × 4) was added to the reaction solution, and the mixture was extracted at 70–75 °C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine solution (20 ml), and concentrated under reduced pressure to dryness to obtain the target product. The yield was 84.2%, and the HPLC purity was 98.88%.

[0100] Example 13

[0101] Compound I-1 (6.31 g, 0.05 mol) and 1,3-propanediamine (7.41 g, 0.1 mol) were added to an ethanol-water mixture (V:V = 9:1, 60 ml), and acetic acid (3.60 g, 0.06 mol) was added. The reaction was carried out at 70–75 °C. After the reaction was completed, sodium hydroxide was added to adjust the pH to slightly alkaline. Toluene (20 ml × 4) was added to the reaction solution, and the mixture was extracted at 70–75 °C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine solution (20 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 93.8% and an HPLC purity of 99.42%.

[0102] Example 14

[0103] Compound I-1 (6.31 g, 0.05 mol) and 1,3-propanediamine (7.78 g, 0.105 mol) were added to a mixed solvent of isopropanol-water (V:V = 8:1, 60 ml), and benzenesulfonic acid (11.07 g, 0.07 mol) was added. The reaction was carried out at 70–75 °C. After the reaction was detected to be complete, sodium hydroxide was added to adjust the pH to slightly alkaline. Toluene (20 ml × 4) was added to the reaction solution, and the mixture was extracted at 70–75 °C. The organic phases were combined, washed with saturated sodium carbonate solution (20 ml), washed with saturated brine solution (20 ml), and concentrated under reduced pressure to dryness to obtain the target product I, with a yield of 86.3% and an HPLC purity of 97.23%.

Claims

1. A method for preparing 1,4,8,11-tetraazacyclotetradecane, characterized in that, The preparation method includes the following steps: Step 1: Add compound SM-1, compound SM-2, acid-binding agent, and organic solvent A to a sealed reaction apparatus, and control the temperature T. A After the reaction was completed, the reaction solution was poured into purified water, extracted with dichloromethane, washed with saturated brine, and concentrated under reduced pressure to dryness to obtain compound I-1; Step 2: Add compound I-1 and compound SM-3 to an alcohol-water mixed solvent, add a catalyst, and control the temperature T. B After the reaction was detected to be complete, the pH was adjusted to weakly alkaline by adding alkali. Toluene was added to the reaction solution, and the mixture was extracted at 70-75°C. The organic phases were combined, washed with saturated sodium carbonate solution, washed with saturated brine solution, and the organic phase was concentrated to dryness under reduced pressure to obtain the target product I. The catalyst mentioned in step 2 is selected from one of formic acid, acetic acid, trifluoroacetic acid, and benzenesulfonic acid; The synthesis route is as follows: 。 2. The preparation method according to claim 1, characterized in that, The acid-binding agent mentioned in step 1 is selected from triethylamine, N , N - One of diisopropylethylamine, pyridine, potassium carbonate, sodium carbonate, potassium hydroxide, and sodium hydroxide.

3. The preparation method according to claim 1, characterized in that, The molar ratio of compound SM-1, compound SM-2, and acid-binding agent mentioned in step 1 is 1:2.4~3.6:2.6~4.

0.

4. The preparation method according to claim 1, characterized in that, The organic solvent A mentioned in step 1 is selected from N , N - Dimethylformamide, acetonitrile, N , N - One or a combination of dimethylacetamide, dimethyl sulfoxide.

5. The preparation method according to claim 1, characterized in that, The reaction temperature T mentioned in step 1 A The temperature is 50~100℃.

6. The preparation method according to claim 1, characterized in that, The alcohol-water mixed solvent mentioned in step 2 is selected from one or a combination of tert-butanol-water, isopropanol-water, and ethanol-water.

7. The preparation method according to claim 1, characterized in that, The molar ratio of compound I-1, compound SM-3, and catalyst in step 2 is 1:1.3~2.0:0.8~1.

2.

8. The preparation method according to claim 1, characterized in that, The alkali mentioned in step 2 is selected from one or a combination of sodium hydroxide, potassium hydroxide, sodium carbonate solid or their aqueous solutions.

9. The preparation method according to claim 1, characterized in that, The reaction temperature T mentioned in step 2 B The temperature is 70~80℃.

Images