1,4,7,10-tetraazadodecane derivative, preparation method and application thereof in synthesizing gadolinium complex

Abstract

The present invention discloses a 1,4,7,10-tetraazadodecane derivative, a preparation method, and its use in the synthesis of gadolinium complexes, belonging to the field of organic synthesis. The method uses compound 1 as a substrate and reacts it with lithium borohydride to produce compound 2. By utilizing a specific selective reduction reaction route and specific intermediates, this method eliminates the need for overprotection / deprotection steps, reduces reaction steps, and improves preparation efficiency.

Description

Technical Field

[0001] The present invention relates to the field of organic synthesis, and in particular to a 1,4,7,10-tetraazadodecane derivative, a preparation method and application thereof in synthesizing a gadolinium complex. Background Art

[0002] 1,4,7,10-Tetraazadodecane derivatives are important raw materials for synthesizing highly effective nuclear magnetic resonance contrast agents. Existing literature (Synthesis of Gadolinium(±)-10-(1-Hydroxypropan-2-yl)-1,4,7,10-tetraazacyclododecane-1,4,7-triyltriacetate via Tribenzyl 1,4,7,10-Tetraazacyclododecane-1,4,7-tricarboxylate. J. Siva Prasad. et al., J. Chem. Soc. Perkin Trans. 1, 1991, 3329.) and U.S. Patent No. 6,432,306 B1 both report that 1,4,7,10-tetraazadodecane derivatives such as Compound 4 can be used to produce highly effective nuclear magnetic resonance contrast agents.

[0003]

[0004] The above-mentioned document (J. Siva Prasad. et al, J. Chem. Soc. Perkin Trans. 1, 1991, 3329.) provides a preparation method of a 1,4,7,10-tetraazadodecane derivative (Compound 12), which is as follows:

[0005]

[0006] As can be seen from the above reaction formula, the prior art preparation of 1,4,7,10-tetraazadodecane derivatives requires selective protection, the introduction of a 1-hydroxy-propane-2-yl group, and subsequent deprotection, followed by the introduction of acetic acid groups on the remaining three nitrogen atoms. This entire preparation process is somewhat lengthy. Summary of the Invention

[0007] In order to solve the above problems, the present invention proposes a new preparation method. By selecting a specific selective reduction reaction route and specific intermediates, no protection / deprotection steps are required, which reduces the reaction steps and improves the preparation efficiency.

[0008] The present invention provides a method for preparing a 1,4,7,10-tetraazadodecane derivative, and the reaction formula is as follows:

[0009]

[0010] In the above formula, R1 is selected from C1-C6 alkyl, R2 is selected from C1-C6 straight chain alkyl,

[0011] The steps include:

[0012] Compound 1 reacts with lithium borohydride to obtain compound 2.

[0013] In one embodiment of the present invention, R1 is methyl, and R2 is methyl or ethyl.

[0014] In one embodiment of the present invention, the molar ratio of compound 1 to lithium borohydride is 1:(2-5); preferably 1:(4-5).

[0015] In one embodiment of the present invention, the reaction is carried out in a solvent, and the solvent can be any one or more of tetrahydrofuran, toluene, 2-methyltetrahydrofuran, methanol or ethanol.

[0016] In one embodiment of the present invention, the concentration of Compound 1 relative to the solvent is 0.1-0.3 g / mL.

[0017] In one embodiment of the present invention, the reaction temperature is -20°C to 0°C, and the reaction time is 6-72 hours, preferably 12-48 hours.

[0018] In one embodiment of the present invention, the steps include:

[0019] Under the protection of inert gas, compound 1 is dissolved in a solvent, cooled to -20-0°C, and lithium borohydride or its solution is added. After the dropwise addition is completed, the reaction is continued at -20-0°C for 6-72 hours. The reaction is quenched, and water and an organic solvent are added for extraction. The organic phase is collected, washed, dried, and purified to obtain compound 2.

[0020] The present invention also provides a method for preparing a 1,4,7,10-tetraazadodecane derivative, and the reaction formula is as follows:

[0021]

[0022] In the above formula, R1 is selected from C1-C6 alkyl, R2 is selected from C1-C6 straight-chain alkyl, X is selected from Br, Cl or OTf,

[0023] The steps include:

[0024] In the presence of an alkaline reagent and a solvent, compound 3 reacts with compound 7 to obtain compound 1.

[0025] In one embodiment of the present invention, the alkaline reagent is selected from any one or more of potassium iodide, sodium carbonate, and potassium carbonate.

[0026] In one embodiment of the present invention, the solvent is selected from any one or more of dichloroethane, acetonitrile, and 2-methyltetrahydrofuran.

[0027] In one embodiment of the present invention, the molar ratio of compound 3 to compound 7 is 1:(1-5); preferably 1:(1.5-2.0).

[0028] In one embodiment of the present invention, the molar ratio of compound 3 to the alkaline reagent is 1:(1-5); preferably 1:(1.5-2.0).

[0029] In one embodiment of the present invention, the concentration of compound 3 relative to the solvent is 0.1-0.5 g / mL; further preferably 0.25-0.35 g / mL.

[0030] In one embodiment of the present invention, the reaction temperature is 70-100° C., the reaction time is 12-48 hours, and the reaction is further carried out at 75-85° C. for 24-48 hours.

[0031] In one embodiment of the present invention, the steps include:

[0032] Dissolve compound 3 in a solvent, add an alkaline reagent and compound 7, heat to 70-100°C and stir to react for 12-48 hours, add water and an organic solvent for extraction, take the organic phase, wash, dry, filter, and purify to obtain compound 1.

[0033] The present invention also provides a 1,4,7,10-tetraazadodecane derivative, the structural formula of which is as follows:

[0034]

[0035] The present invention also provides the use of the above 1,4,7,10-tetraazadodecane derivative as an intermediate in the synthesis of gadolinium complexes.

[0036] In one embodiment of the present invention, the application process includes the following steps:

[0037] S1. Compound 2a is reacted with an acidic reagent to obtain compound 4;

[0038] S2. Compound 4 reacts with a gadolinium salt to obtain a gadolinium complex, or Compound 4 reacts with a gadolinium oxide under alkaline conditions to obtain a gadolinium complex;

[0039] The compound 4 is

[0040] The gadolinium complex is

[0041] In one embodiment of the present invention, the acidic reagent is trifluoroacetic acid or hydrochloric acid.

[0042] In one embodiment of the present invention, S1 specifically comprises: dissolving compound 2a in an organic solvent, then cooling the temperature to -10°C to 5°C, adding an acidic reagent, and then heating the temperature to room temperature for reaction.

[0043] In one embodiment of the present invention, the organic solvent is selected from any one or more of the following: dichloromethane, chloroform, 1,2-dichloroethane, and ethyl acetate.

[0044] In one embodiment of the present invention, the gadolinium salt is gadolinium chloride, and the gadolinium oxide is gadolinium trioxide.

[0045] In one embodiment of the present invention, the molar ratio of compound 4 to gadolinium salt is 1:(0.8-1.5).

[0046] In one embodiment of the present invention, the molar ratio of compound 4 to gadolinium oxide is 1:(0.4-1.0).

[0047] In one embodiment of the present invention, in S2, compound 4 and a gadolinium salt are dispersed in a solvent, mixed and reacted to obtain a gadolinium complex. The reaction temperature is 80-120°C for 8-20 hours, and the reaction time can be 100°C for 12 hours.

[0048] In one embodiment of the present invention, in S2, compound 4, gadolinium oxide, and an alkaline reagent are dispersed in a solvent and mixed and reacted to obtain a gadolinium complex. The reaction temperature is 80-120°C for 8-20 hours, and the reaction time can be 100°C for 12 hours.

[0049] In one embodiment of the present invention, the alkaline reagent is selected from any one or more of the following: triethylamine, diisopropylethylamine, and DABCO.

[0050] In one embodiment of the present invention, the solvent in S2 can specifically be water.

[0051] In one embodiment of the present invention, the molar ratio of the compound 4 to the alkaline agent is 1:(0.8-1.5).

[0052] In one embodiment of the present invention, the S2 specifically comprises: dissolving compound 4 in a solvent, adding gadolinium salt, reacting at 80-120° C. for 8-20 h, filtering, beating, and drying to obtain a gadolinium complex.

[0053] In one embodiment of the present invention, the S2 specifically comprises: dissolving compound 4 in a solvent, adding a gadolinium oxide compound and an alkaline reagent, reacting at 80-120° C. for 8-20 hours, filtering, beating, and drying to obtain a gadolinium complex.

[0054] Functions and effects of the invention:

[0055] According to the method for preparing 1,4,7,10-tetraazadodecane derivatives of the present invention, since lithium borohydride is selected as the reducing agent, when both tert-butyl ester and linear alkyl ester are present in the substrate, the linear alkyl ester can be selectively reduced to the corresponding alcohol while the tert-butyl ester remains unchanged.

[0056] According to the use of 1,4,7,10-tetraazadodecane derivatives in the preparation of gadolinium complexes involved in the present invention, since a specific selective reduction reaction route and specific intermediates are selected, the present invention does not require steps such as overprotection / deprotection, thereby reducing the number of reaction steps and improving the preparation efficiency compared with the prior art. DETAILED DESCRIPTION

[0057] In order to make the technical means, creative features, objectives and effects achieved by the present invention easier to understand, the present invention is described in detail below with reference to the embodiments.

[0058] In the following examples, unless otherwise specified, all raw materials are commercially available products.

[0059] <Example 1>

[0060] Preparation of compound 3

[0061] This embodiment provides a preparation method of compound 3, and the reaction formula is as follows:

[0062]

[0063] The steps include:

[0064] 100 g of compound 5 (100 g, 0.58 mol, 1.0 eq) was dissolved in 1 L of dimethylacetamide, 152 g of sodium acetate (1.85 mol, 3.2 eq) was added, and the temperature was lowered to 0°C. 360 g of compound 6 (1.85 mol, 3.2 eq) was added dropwise. After the addition was completed, the temperature naturally returned to room temperature. The reaction mixture was stirred for 16 h. The reaction solution was concentrated under reduced pressure to one third of the original volume. 1 L of acetonitrile was added and stirred for 30 min. A large amount of solid precipitated. The solid was filtered and dried under reduced pressure to obtain 150 g of compound 3 as a white solid with a yield of 50.2%.

[0065] 1H NMR (400MHz, Methanol-d4) δ3.41(s,4H),3.35(s,2H),3.13(t,J=5.6Hz,4H),2.97(t,J=5. 6Hz, 4H), 2.79 (dd, J=6.6, 3.8Hz, 4H), 2.68 (dd, J=6.5, 3.8Hz, 4H), 1.47 (d, J=3.3Hz, 27H).

[0066] <Example 2>

[0067] Preparation of compound 1a

[0068] This example provides a method for preparing compound 1a, and the reaction formula is as follows:

[0069]

[0070] The steps include:

[0071] 150 g of compound 3 (0.29 mol, 1.0 eq) was dissolved in 500 mL of dichloroethane, 80.04 g of potassium carbonate (0.58 mol, 2.0 eq) was added, and 130.10 g of compound 7a (0.52 mol, 1.8 eq) was added dropwise. After the addition was complete, the temperature was raised to 80° C. and the reaction was stirred for 24 h. 400 mL of water and 200 mL of dichloromethane were added to the reaction system, and extraction was carried out. The organic phase was taken, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 153 g of compound 1a as a gray solid with a yield of 85.8%.

[0072] 1 H NMR(400MHz,Methanol-d4)δ4.29-4.11(m,2H),3.81-3.68(m,1H),3.57-3.42(m,3H),3.27-2 .57(m,11H),2.41-1.82(m,7H),1.66-1.60(m,1H),1.48(d,J=5.1Hz,27H),1.31-1.22(m,6H).

[0073] <Example 3>

[0074] Preparation of compound 1a

[0075] This example provides a method for preparing compound 1a, and the reaction formula is as follows:

[0076]

[0077] The steps include:

[0078] 13 g of compound 3 (25.2 mmol, 1.0 eq) was dissolved in 50 mL of acetonitrile, 5.3 g of sodium carbonate (50.4 mmol, 2.0 eq) was added, and 6.8 g of compound 7b (37.8 mmol, 1.5 eq) was added dropwise. After the addition was complete, the temperature was raised to 80° C. and the reaction was stirred for 24 h. 40 mL of water and 20 mL of dichloromethane were added to the reaction system, and the mixture was extracted. The organic phase was taken, washed with saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, filtered, concentrated under reduced pressure, and purified by column chromatography to obtain 8 g of compound 1a as a gray solid in a yield of 51.6%.

[0079] <Example 4>

[0080] Preparation of compound 2a

[0081] This example provides a method for preparing compound 2a, and the reaction formula is as follows:

[0082]

[0083] The steps include:

[0084] Under nitrogen protection, 50 g of compound 1a (81.3 mmol, 1.0 eq) was dissolved in 300 mL of tetrahydrofuran, and the temperature was lowered to -20°C. 203.3 mL of a tetrahydrofuran solution of lithium borohydride (2 mol / L, 406.5 mmol, 5.0 eq) was added dropwise. After the addition was complete, the reaction was stirred at -20°C for 48 h. 50 mL of methanol was added to quench the reaction, and 400 mL of water and 200 mL of ethyl acetate were added for extraction. The organic phase was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to obtain 30.2 g of compound 2a as a white solid in a yield of 54.9%.

[0085] 1 H NMR(400MHz,Methanol-d4)δ3.60-3.32(m,6H),3.23-2.93(m,5H),2.93-2.72(m,4H),2.67-2 .43(m,3H),2.27-2.14(m,3H),2.13-1.96(m,4H),1.53-1.45(m,27H),0.77(d,J=6.6Hz,3H).

[0086] <Example 5>

[0087] Screening of preparation conditions for compound 2a

[0088] In this example, based on Example 4, the preparation method of compound 2a was screened. The screening method is as follows:

[0089] Under the protection of nitrogen, 200 mg of compound 1a (0.325 mmol, 1.0 eq) was dissolved in 2 mL of solvent, and a 2 mol / L reducing agent solution in tetrahydrofuran was added dropwise at -20°C. The reaction was stirred at a certain temperature for 48 h, and 2 mL of ethanol was added to quench the reaction. 5 mL of water and 5 mL of ethyl acetate were added for extraction. The organic phase was taken and sent for LCMS detection. If the target product was present, the organic phase was concentrated and the target product was collected by column chromatography.

[0090] The screening results are shown in the following table.

[0091] Table 1 Screening of preparation conditions for compound 2a

[0092] Serial number solvent Reducing agent (dosage) Reaction temperature result 1 Methanol Sodium borohydride (2.0 eq) 20℃ No response 2 Tetrahydrofuran Sodium borohydride (4.0 eq) + lithium chloride (4.0 eq) 20℃ No response 3 Tetrahydrofuran Sodium borohydride (4.0 eq) + lithium chloride (4.0 eq) 20℃ No response <![CDATA[4 a ]]> Tetrahydrofuran Lithium aluminum hydride (2.0 eq) 40℃ No target product 5 Toluene DIBAL-H (2.0eq) 20℃ No response <![CDATA[6 b ]]> Tetrahydrofuran Lithium borohydride (2.0 eq) 20℃ 20.5％ 7 Tetrahydrofuran Lithium borohydride (2.0 eq) -20℃ 45.2％ 8 Tetrahydrofuran Lithium borohydride (5.0 eq) 0℃ 67.1％ 9 Tetrahydrofuran Lithium borohydride (4.0 eq) -20℃ 58.6％

[0093] a. The main product of the reaction is an over-reduction product (a compound in which 2-4 ester groups are reduced to the corresponding alcohol); b. In addition to the target product, there is about 30% over-reduction product.

[0094] As can be seen from the above table, not all reducing agents can achieve the technical effect of selective reduction of ethyl ester in the presence of tert-butyl ester and ethyl ester. Among several commonly used reducing agents that can be used to reduce ester groups, only lithium borohydride achieved a relatively ideal yield.

[0095] <Example 6>

[0096] Preparation method of compound 4

[0097] This embodiment provides a preparation method of compound 4, and the reaction formula is as follows:

[0098]

[0099] The steps include:

[0100] 5 g of compound 2a was dissolved in 20 mL of dichloromethane, cooled to 0°C, and 40 mL of trifluoroacetic acid was added. The temperature was naturally raised to room temperature, and the reaction was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure, and 20 mL of water was added. The mixture was suspended on a cation exchange resin and eluted with ammonia water. The eluate was concentrated to obtain 3.5 g of compound 4 as a yellow solid in a yield of 99.2%.

[0101] 1 H NMR (400MHz, Methanol-d4) δ3.66-3.41 (m, 7H), 3.30 (s, 6H), 3.24 (s, 5H), 2.91 (s, 7H), 0.99 (d, J = 6.1Hz, 3H).

[0102] <Example 7>

[0103] Preparation method of compound 4

[0104] This embodiment provides a preparation method of compound 4, and the reaction formula is as follows:

[0105]

[0106] The steps include:

[0107] 2 g of compound 2a was dissolved in 20 mL of ethyl acetate, cooled to 0°C, and 40 mL of 37 wt% hydrochloric acid was added. The temperature was naturally raised to room temperature, and the reaction was stirred at room temperature for 24 h. The mixture was concentrated under reduced pressure, and 20 mL of water was added. The mixture was suspended on a cation exchange resin and eluted with ammonia water. The eluate was concentrated to obtain 1.25 g of compound 4 as a yellow solid in a yield of 88.5%.

[0108] <Example 8>

[0109] Preparation method of gadolinium complex

[0110] This embodiment provides a method for preparing a gadolinium complex, and the reaction formula is as follows:

[0111]

[0112] The steps include:

[0113] 200 mg of compound 4 (0.358 mmol, 1.0 eq) was added to 8 mL of water, and 94.4 mg of gadolinium trichloride (0.358 mmol, 1.0 eq) was added. The temperature was raised to 100°C and the reaction was carried out for 12 h. The mixture was filtered and the filtrate was collected. The solvent was removed and 5 mL of isopropanol was added to slurry. The mixture was filtered and dried to obtain 154.6 mg of compound 8 as a white solid. The yield was 77.3%.

[0114] <Example 9>

[0115] Preparation method of gadolinium complex

[0116] This embodiment provides a method for preparing a gadolinium complex, and the reaction formula is as follows:

[0117]

[0118] The steps include:

[0119] 200 mg of compound 4 (0.358 mmol, 1.0 eq) was added to 8 mL of water, and 64.9 mg of gadolinium trioxide (0.179 mmol, 0.5 eq) and 36.2 mg of triethylamine (0.358 mmol, 1.0 eq) were added. The temperature was raised to 100° C. and the reaction was carried out for 12 h. The mixture was filtered and the filtrate was taken. The solvent was removed and 5 mL of isopropanol was added to slurry. The mixture was filtered and dried to obtain 101.6 mg of compound 8 as a white solid with a yield of 50.8%.

[0120] Functions and Effects of the Embodiments

[0121] According to the preparation method of the 1,4,7,10-tetraazadodecane derivative involved in the above embodiment, because lithium borohydride is selected as the reducing agent, when tert-butyl ester and ethyl ester are present in the substrate at the same time, the ethyl ester can be selectively reduced to the corresponding alcohol while the tert-butyl ester remains unchanged.

[0122] According to the use of 1,4,7,10-tetraazadodecane derivatives in the preparation of gadolinium complexes involved in the above-mentioned embodiments, because a specific selective reduction reaction route and specific intermediates are selected, the present invention does not require steps such as overprotection / deprotection, thereby reducing the number of reaction steps and improving the preparation efficiency compared to the prior art.

[0123] Furthermore, since gadolinium trichloride is selected as the gadolinium source, the gadolinium complex can be prepared with a higher yield than when gadolinium trioxide is used as the gadolinium source.

[0124] The above embodiments are preferred examples of the present invention and are not intended to limit the scope of protection of the present invention.

Claims

1. A method for preparing a 1,4,7,10-tetraazadodecane derivative, characterized in that: The reaction formula is as follows: In the above formula, R1 is selected from C1-C6 alkyl, R2 is selected from C1-C6 straight chain alkyl, The steps include: Compound 1 reacts with lithium borohydride to obtain compound 2.

2. The method for preparing a 1,4,7,10-tetraazadodecane derivative according to claim 1, characterized in that: in, R1 is a methyl group, and R2 is a methyl group or an ethyl group.

3. The method for preparing a 1,4,7,10-tetraazadodecane derivative according to claim 1, characterized in that: in, The molar ratio of compound 1 to lithium borohydride is 1:(2-5).

4. The method for preparing 1,4,7,10-tetraazadodecane derivatives according to claim 1, characterized in that: Compound 1 was prepared by the following method: In the above formula, R1 is selected from C1-C6 alkyl, R2 is selected from C1-C6 straight-chain alkyl, X is selected from Br, Cl or OTf, The steps include: In the presence of an alkaline reagent and a solvent, compound 3 reacts with compound 7 to obtain compound 1.

5. The method for preparing 1,4,7,10-tetraazadodecane derivatives according to claim 4, characterized in that: The alkaline reagent is selected from any one or more of potassium iodide, sodium carbonate, and potassium carbonate.

6. The method for preparing 1,4,7,10-tetraazadodecane derivatives according to claim 4, characterized in that: The solvent is selected from any one or more of dichloroethane, acetonitrile, and 2-methyltetrahydrofuran.

7. The method for preparing 1,4,7,10-tetraazadodecane derivatives according to claim 1, characterized in that: The structural formula of compound 1 is shown in Formula 1a, and the structural formula of compound 2 is shown in Formula 2a: 。 8. Use of the preparation method of 1,4,7,10-tetraazadodecane derivative according to claim 7 in the synthesis of gadolinium complexes, characterized in that: The steps include: According to the preparation method of claim 7, compound 2a is prepared using compound 1a; Compound 2a is reacted with an acidic reagent to obtain compound 4; Compound 4 reacts with a gadolinium salt or compound 4 reacts with a gadolinium oxide under alkaline conditions to obtain a gadolinium complex. The compound 4 is , The gadolinium complex is .

9. The use according to claim 8, characterized in that The acidic reagent is trifluoroacetic acid or hydrochloric acid.

10. The use according to claim 8, characterized in that The gadolinium salt is gadolinium chloride, and the gadolinium oxide is gadolinium trioxide.

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