Preparation method of gadoxate disodium key intermediate

Abstract

The invention relates to a preparation method of a gadoxetate disodium key intermediate, which comprises the following steps of: 1, performing ethylation reaction on N-BOC-L-tyrosine methyl ester serving as a raw material and diethyl carbonate under the action of alkali metal carbonate to generate a compound 2; 2, carrying out amine ester exchange reaction on the compound 2 and N-BOC-ethylenediamine to generate a compound 3; 3, deprotecting the compound 3 with hydrochloric acid to generate a compound 4; 4, the compound 4 is reduced through a borane tetrahydrofuran complex and salified through hydrogen chloride to generate a compound 5.

Description

Technical Field

[0001] The present invention relates to a method for preparing a pharmaceutical compound intermediate, and in particular to a method for preparing a key intermediate of gadoxetate disodium. Background Art

[0002] Gadolinium disodium chloride (Gd-EOB-DTPA) is a hepatobiliary-specific MRI contrast agent. Developed by adding a lipid-soluble ethoxybenzyl group (EOB) to the Gd-DTPA molecular structure, Gd-EOB-DTPA exhibits unique biological properties. By shortening tissue T1 relaxation time, Gd-EOB-DTPA produces multiphase dynamic enhancement similar to that of Gd-DTPA, enabling observation of conventional multiphase dynamic enhancement patterns and manifestations of liver lesions. Furthermore, in subjects with normal liver function, 10 to 20 minutes after Gd-EOB-DTPA injection, the liver parenchyma exhibits maximum enhancement, and the biliary system is also visualized. This phase is known as the hepatobiliary-specific phase.

[0003] Gadolinium disodium formula: C 23 H 28 N3O 11 Gd·2Na, chemical name: (4S)-4-(4-ethoxyphenyl)-3,6,9-tris(carboxymethyl)-3,6,9-triazaundecanedioic acid, gadolinium chelate, disodium salt. The chemical structure is:

[0004]

[0005] The gadoxetic acid disodium intermediate with the following structure is a key intermediate for the synthesis of gadoxetic acid disodium (Gd-EOB-DTPA). Its chemical name is ((S)-N1-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine) and its structural formula is as follows:

[0006]

[0007] Existing technology

[0008] 1. Using iodine as the ethylating agent, ethylenediamine as the amine ester exchange agent, trifluoroacetic acid as the deprotection agent, and lithium aluminum tetrahydride for the reduction reaction;

[0009] 2. Use Pd / C as catalyst for deprotection reaction.

[0010] Main defects of existing technology:

[0011] 1. Using iodoethane as the ethylation reagent is highly toxic and costly. Using ethylenediamine as the amine transesterification reagent, due to the high reactivity of the exposed amino groups in the molecule, it easily reacts with another molecule of the raw material to form a dimer impurity (its structural formula is shown below). Trifluoroacetic acid, which is expensive as the reaction solvent and deprotection reagent, requires a large amount of reaction and is difficult to handle, which can easily cause environmental pollution. This route uses lithium aluminum tetrahydride for the reduction reaction, which has high requirements for reaction conditions, high safety requirements, and is dangerous to operate and difficult to handle. Furthermore, the overall process yield and purity are low.

[0012]

[0013] 2. Using N-benzyloxycarbonyl-L-tyrosine ester as the starting material and Pd / C as the catalyst, high-pressure catalytic hydrogenation reduction is carried out at 15 atmospheres, which places high demands on production equipment and has high safety risks.

[0014] In order to overcome the defects of the prior art, the present invention develops a new preparation method of a disodium gadoxetate intermediate ((S)-N1-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine). Summary of the Invention

[0015] The present invention provides a method for preparing a novel gadoxetate disodium intermediate ((S)-N1-(2-aminoethyl)-3-(4-ethoxyphenyl)propane-1,2-diamine). The method and the synthetic route of the method are as follows:

[0016]

[0017] The preparation method of the present invention comprises the following steps:

[0018] Step 1: Using N-BOC-L-tyrosine methyl ester as a raw material, an ethylation reaction is carried out with diethyl carbonate in the presence of an alkali metal carbonate to produce compound 2;

[0019] Step 2, compound 2 undergoes an amine transesterification reaction with N-BOC-ethylenediamine to produce compound 3;

[0020] Step 3, deprotection of compound 3 to generate compound 4;

[0021] In step 4, compound 4 is reduced and salified to generate compound 5.

[0022] Specifically, the alkali metal carbonate in step 1 is potassium carbonate.

[0023] Specifically, the step 1 is as follows: compound 1, N,N-dimethylformamide, anhydrous potassium carbonate and diethyl carbonate are mixed, the temperature is raised to 80-90° C. for reaction, and the compound 2 is obtained by concentration.

[0024] Specifically, the step 2 is as follows: N-BOC-ethylenediamine is added dropwise to compound 2, reacted at 45-55° C., and ethyl acetate is added for crystallization to obtain compound 3.

[0025] Specifically, step 3 is as follows: acid, water, and compound 3 are mixed and reacted at 40-50° C., an alkaline solution is added to adjust the pH, and the organic layer is extracted and separated to obtain compound 4.

[0026] Specifically, the pH is ≥12.

[0027] Specifically, the acid is one of hydrochloric acid, sulfuric acid, and trifluoroacetic acid.

[0028] Specifically, in step 4, the reducing agent is a borane tetrahydrofuran complex, and the salt-forming reagent is a hydrogen chloride ethanol solution. Specifically, step 4 is as follows: tetrahydrofuran and compound 4 are dropwise added with the borane tetrahydrofuran complex under nitrogen protection, reacted at 50-60°C, the reaction is quenched, and then the hydrogen chloride ethanol solution is added. The temperature is lowered to 0-10°C, and the temperature is kept to crystallize to obtain compound 5. Specifically, the molar ratio of compound 4:borane tetrahydrofuran complex is 1:(2.5-4).

[0029] The preparation method of the present invention, its reaction conditions and reaction route are obtained through screening, and the screening process is as follows:

[0030] Advantages of the technical solution of the present invention

[0031] 1. Using diethyl carbonate for ethylation reaction has low cost, low toxicity and little environmental pollution;

[0032] 2. Using N-BOC-ethylenediamine for amine transesterification can avoid the formation of dimer impurities;

[0033] 3. Using hydrochloric acid for deprotection reaction has low cost, simple post-processing and little environmental pollution;

[0034] 4. Borane tetrahydrofuran complex is used for the reduction reaction, which can be carried out under normal pressure, has no special requirements for equipment, and the post-processing operation is simple and safe;

[0035] 5. The quality and yield of compound 5 can be improved, wherein the purity can reach 99.8% and the total yield can reach 81%. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 HPLC spectrum of compound 5

[0037] Figure 2 5H-NMR spectrum of compound

[0038] Figure 3 C-NMR spectrum of compound 5 DETAILED DESCRIPTION

[0039] The present invention is further illustrated by the following examples, but is not intended to limit the present invention.

[0040] Example 1

[0041] Step 1: 8 g of compound 1 (0.027 mol), 40 g of N,N-dimethylformamide, 4.5 g of anhydrous potassium carbonate, and 6.4 g of diethyl carbonate (0.054 mol) were added separately into a 250 ml three-necked flask, heated to 80-90°C, kept warm for 12 h, filtered, and the filtrate was concentrated to dryness to obtain 8.4 g of compound 2 with a yield of 96% and a purity of 99.9%.

[0042] Step 2: Add 33.6 g of methanol and 8.4 g of compound 2 (0.026 mol) into a 250 ml three-necked flask, stir to dissolve, and slowly add dropwise to a 250 ml three-necked flask containing 16.7 g of N-BOC-ethylenediamine (0.104 mol). Heat to 45-55 ° C and react for 20 h. Concentrate under reduced pressure. Add 15.8 g of ethyl acetate to the residue. After the addition is complete, keep warm and crystallize for 4 h. Continue to cool to 0-10 ° C, keep warm and crystallize for 4 h. Filter, wash, and dry in vacuo to obtain 11.3 g of compound 3 with a yield of 96% and a purity of 99.8%.

[0043] Step 3: Add 20 g of hydrochloric acid, 20 g of water, and 11.3 g of compound 3 (0.025 mol) to a 250 ml three-necked flask, heat to 40-50 ° C and react for 4 h, add 10% sodium hydroxide solution to adjust the system pH to ≥12, then add 40 g of dichloromethane for extraction, separate the layers, and concentrate the obtained organic layer under reduced pressure to obtain 6.1 g of compound 4, with a yield of 98% and a purity of 99.4%. Step 4: Add 20 g of tetrahydrofuran and 6.1 g of compound 4 (0.024 mol) into a 250 ml three-necked flask, stir to dissolve, slowly add 69 g of borane tetrahydrofuran complex (0.07 mol) into the system under nitrogen protection, heat to 50-60 ° C and react for 16 h, cool to 0-10 ° C, quench the reaction with 15 g of methanol, and concentrate under reduced pressure. Add 24.4 g of hydrogen chloride ethanol solution to the residue, cool to 0-10 ° C, keep warm for crystallization for 4 h, filter, wash, and dry in vacuo to obtain 7.6 g of compound 5 with a yield of 90% and a purity of 99.8%.

[0044] Example 2

[0045] Step 1: 8 g of compound 1 (0.027 mol), 40 g of N,N-dimethylformamide, 4.5 g of anhydrous potassium carbonate, and 8.4 g of iodoethane (0.054 mol) were added separately into a 250 ml three-necked flask, heated to 80-90°C, kept warm for 12 h, filtered, and the filtrate was concentrated to dryness to obtain 8.2 g of compound 2 with a yield of 94% and a purity of 97.3%.

[0046] Example 3

[0047] Step 1: 8 g of compound 1 (0.027 mol), 40 g of N,N-dimethylformamide, 4.5 g of KOH, and 6.4 g of diethyl carbonate (0.054 mol) were added separately into a 250 ml three-necked flask, heated to 80-90°C, and kept warm for 12 h. The mixture was filtered and the filtrate was concentrated to dryness to obtain 8.1 g of compound 2 with a yield of 92% and a purity of 93.2%.

[0048] Example 4

[0049] Step 1: 8 g of compound 1 (0.027 mol), 40 g of N,N-dimethylformamide, 4.5 g of anhydrous potassium carbonate, and 6.4 g of diethyl carbonate (0.054 mol) were added separately into a 250 ml three-necked flask. The mixture was kept warm at room temperature for 12 h. The mixture was filtered and the filtrate was concentrated to dryness to obtain 8.0 g of compound 2 with a yield of 91% and a purity of 80.5%.

[0050] Example 5

[0051] Step 1: 8 g of compound 1 (0.027 mol), 40 g of N,N-dimethylformamide, 10 g of sodium ethoxide ethanol solution, and 5.9 g of bromoethane (0.054 mol) were added separately into a 250 ml three-necked flask, heated to 80-90°C, kept warm for 12 h, filtered, and the filtrate was concentrated to dryness to obtain 8.1 g of compound 2 with a yield of 90% and a purity of 70.3%.

[0052] Example 6

[0053] Step 1: 8 g of compound 1 (0.027 mol), 40 g of N,N-dimethylformamide, 10 g of sodium ethoxide ethanol solution, and 8.4 g of iodine (0.054 mol) were added to a 250 ml three-necked flask, heated to 80-90°C, and kept warm for 12 h. The mixture was filtered and the filtrate was concentrated to dryness to obtain 8.3 g of compound 2 with a yield of 93% and a purity of 74.5%.

[0054] Example 7

[0055] Step 2: Add 33.6 g of methanol and 8.4 g of compound 2 (0.026 mol) into a 250 ml three-necked flask, stir to dissolve, and slowly add dropwise to a 250 ml three-necked flask containing 6.3 g of ethylenediamine (0.104 mol). Heat to 45-55 ° C and react for 20 hours. Concentrate under reduced pressure, add 15.8 g of ethyl acetate to the residue, and after the addition is complete, keep warm and crystallize for 4 hours. Continue to cool to 0-10 ° C, keep warm and crystallize for 4 hours, filter, wash, and dry in vacuo to obtain 7.3 g of an analogue of compound 3 with a yield of 80% and a purity of 95.0%.

[0056] Example 8

[0057] Step 2: Add 33.6 g of methanol and 8.4 g of compound 2 (0.026 mol) into a 250 ml three-necked flask, stir to dissolve, and slowly add dropwise to a 250 ml three-necked flask containing 10.6 g of N-acetylethylenediamine (0.104 mol). Heat to 45-55 ° C and react for 20 h. Concentrate under reduced pressure. Add 15.8 g of ethyl acetate to the residue. After the addition is complete, keep warm and crystallize for 4 h. Continue to cool to 0-10 ° C, keep warm and crystallize for 4 h. Filter, wash, and dry in vacuo to obtain 9.5 g of compound 3 with a yield of 81% and a purity of 98.2%.

[0058] Example 9

[0059] Step 3: Add 20 g of sulfuric acid, 20 g of water, and 11.3 g of compound 3 (0.025 mol) to a 250 ml three-necked flask, heat to 40-50 ° C and react for 4 h, add 10% sodium hydroxide solution to adjust the system pH to ≥12, then add 40 g of dichloromethane for extraction, separate the layers, and concentrate the obtained organic layer under reduced pressure to obtain 5.5 g of compound 4, with a yield of 87% and a purity of 97.2%.

[0060] Example 10

[0061] Step 3: 20 g of hydrochloric acid, 20 g of water, and 9.5 g of the product of Example 8 (0.024 mol) were added to a 250 ml three-necked flask, the temperature was raised to 40-50 ° C, and the reaction was carried out for 4 h. 10% sodium hydroxide solution was added to adjust the pH of the system to ≥12, and then 40 g of dichloromethane was added for extraction. The layers were separated and the obtained organic layer was concentrated under reduced pressure to obtain 5.3 g of compound 4 with a yield of 87% and a purity of 97.2%.

[0062] Example 11

[0063] Step 3: Add 20 g of trifluoroacetic acid, 20 g of water, and 11.3 g of compound 3 (0.025 mol) to a 250 ml three-necked flask, heat to 40-50 ° C and react for 4 h, add 10% sodium hydroxide solution to adjust the system pH to ≥12, then add 40 g of dichloromethane for extraction, separate the layers, and concentrate the obtained organic layer under reduced pressure to obtain 5.6 g of compound 4, with a yield of 89% and a purity of 97.1%.

[0064] Example 12

[0065] Step 4: Add 20 g of tetrahydrofuran and 6.1 g of compound 4 (0.024 mol) to a 250 ml three-necked flask, stir to dissolve, slowly add 4.6 g of LiAlH4 (0.12 mol) to the system under nitrogen protection, heat to 50-60 ° C and react for 16 h, cool to 0-10 ° C, quench the reaction with 15 g of methanol, filter, and concentrate the filtrate under reduced pressure. Add 24.4 g of hydrogen chloride ethanol solution to the residue, cool to 0-10 ° C, keep warm for 4 h, filter, wash, and dry in vacuo to obtain 5.1 g of compound 5 with a yield of 61% and a purity of 95.8%.

[0066] Example 13

[0067] Step 4: Add 15 g (0.4 mol) of LiAlH4 and 250 mL of tetrahydrofuran to a 1000 mL three-necked flask equipped with a dropping funnel and reflux system. Dissolve 20.1 g (0.08 mol) of compound 4 in 150 mL of tetrahydrofuran and slowly add the mixture dropwise to the flask, maintaining a slight boil. React at 50°C for 3 h. After addition, cool the reaction mixture to room temperature. Filter, wash the filter cake twice with tetrahydrofuran, and combine the filtrates, evaporating to dryness under reduced pressure to yield 21.1 g (0.06 mol) of a white solid, with a yield of 76% and a purity of 70.2%.

[0068] Example 14

[0069] Step 4: Compound 4 (143 g, 569 mmol) was dissolved in 4.8 L (4.8 mol) of borane-tetrahydrofuran complex (1.0 M in tetrahydrofuran). The solution was concentrated under reduced pressure to a volume of approximately 2 L and refluxed at 80°C for 32 hours. The solution was then cooled to 0°C and 250 mL of methanol was slowly added over 30 minutes. After standing at 0°C for 2 hours, hydrogen chloride gas was passed through the solution until the pH became distinctly acidic. The resulting suspension was stirred for 2 hours, and the precipitate was collected by filtration, washed with a total of 2.5 L of tetrahydrofuran, and then dried under vacuum over phosphorus pentoxide at room temperature to yield 31.2 g (0.09 mol) of a white solid, a yield of 46% and a purity of 95.1%.

[0070] Example 15

[0071] Step 4: Compound 4 (143 g, 0.569 mol) was subjected to high-pressure catalytic hydrogenation reduction using Pd / C as a catalyst at 15 atmospheres. The mixture was filtered and concentrated. 572.0 g of ethanolic hydrogen chloride solution was added to the residue, and the temperature was lowered to 0-10°C. The mixture was kept warm for 4 h for crystallization. The residue was filtered, washed, and dried in vacuo to obtain 29.6 g (0.09 mol) of a white solid with a yield of 15% and a purity of 78.1%.

[0072] Example 16

[0073] Step 4: Add 20 g of tetrahydrofuran and 6.1 g of compound 4 (0.024 mol) into a 250 ml three-necked flask, stir to dissolve, and slowly add 69 g of borane tetrahydrofuran complex (0.07 mol) dropwise to the system under nitrogen protection. Heat to 50-60 ° C and react for 16 h. Cool to 0-10 ° C, quench the reaction with 15 g of methanol, pass hydrogen chloride gas into the solution until the pH is obviously acidic, cool to 0-10 ° C, keep warm for 4 h, filter, wash, and dry in vacuo to obtain 4.2 g of compound 5 with a yield of 50% and a purity of 94.2%.

[0074] Example 17

[0075] Step 4: 10 g of compound 3 was first reduced with borane tetrahydrofuran complex, and then the deprotection of step 3 was performed. The remaining reaction conditions were the same as those in Example 1 to obtain 3.7 g of compound 5 with a total yield of 48% and a purity of 88.3%.

[0076] Example 18

[0077] Step 4: 20 g of tetrahydrofuran and 6.1 g of compound 4 (0.024 mol) were added to a 250 ml three-necked flask, stirred and dissolved, and palladium chloride (PdCl2, 10 mol%) as a catalyst and PMHS (5 equivalents of [H - ]) as a hydride source, heat to 50-60 ° C for 16 hours, cool to 0-10 ° C, quench the reaction with 15 g of methanol, and concentrate under reduced pressure. Add 24.4 g of ethanolic hydrogen chloride solution to the residue, cool to 0-10 ° C, keep warm for 4 hours, filter, wash, and dry in vacuo to obtain 3.5 g of compound 5 with a yield of 42% and a purity of 50.2%.

[0078] Example 19

[0079] Step 4: 20 g of tetrahydrofuran and 6.1 g of compound 4 (0.024 mol) were added to a 250 ml three-necked flask, stirred and dissolved, palladium carbon was added, and chlorobenzene (0.012 mol) and PMHS (5 equivalents of [H -]) as a hydride source, heat to 50-60 ° C for 16 hours, cool to 0-10 ° C, quench the reaction with 15 g of methanol, and concentrate under reduced pressure. Add 24.4 g of hydrogen chloride ethanol solution to the residue, cool to 0-10 ° C, keep warm for 4 hours, filter, wash, and dry in vacuo to obtain 3.1 g of compound 5 with a yield of 37% and a purity of 60.1%.

[0080] Example 20

[0081] Step 4: Add 6.1 g of compound 4 (0.024 mol), 16.7 g of triethylsilane (0.144 mol) and 30.1 g of trifluoroacetic acid (0.264 mol) into a 250 ml three-necked flask, stir and dissolve, heat to 80-90°C and react for 28 h, concentrate under reduced pressure, add 24.1 g of ethanol solution to the residue, stir and dissolve, add 20.9 g of n-heptane dropwise to the solution, keep warm at 20-30°C for crystallization for 12 h, filter, wash and dry in vacuo to obtain 1.7 g of compound 5 with a yield of 20% and a purity of 30.6%.

[0082] Example 21

[0083] Step 4: 10.9 g of compound 3 (0.024 mol), 16.7 g of triethylsilane (0.144 mol) and 30.1 g of trifluoroacetic acid (0.264 mol) were added to a 250 ml three-necked flask, stirred and dissolved, cooled to 20-30 ° C, 10% sodium hydroxide solution was added to adjust the system pH to ≥12, and then 40 g of dichloromethane was added for extraction. The layers were separated and the obtained organic layer was concentrated under reduced pressure. After concentration under reduced pressure, 24.1 g of ethanol solution was added to the residue, stirred and dissolved, and 20.9 g of n-heptane was added dropwise to the solution. The mixture was kept at 20-30 ° C for crystallization for 12 h, filtered, washed, and dried in vacuo to obtain 3.2 g of compound 5 with a yield of 38% and a purity of 32.3%.

Claims

1. A method for preparing a key intermediate of gadoxetate disodium, wherein the synthetic route is as follows: Step 1: Using N-BOC-L-tyrosine methyl ester as a raw material, an ethylation reaction is carried out with diethyl carbonate in the presence of an alkali metal carbonate to produce compound 2; Step 2, compound 2 undergoes an amine transesterification reaction with N-BOC-ethylenediamine to produce compound 3; Step 3, deprotection of compound 3 to generate compound 4; In step 4, compound 4 is reduced and salified to generate compound 5.

2. The method according to claim 1, wherein: The alkali metal carbonate in step 1 is potassium carbonate.

3. The method according to claim 2, wherein: The step 1 is as follows: Compound 1, N,N-dimethylformamide, anhydrous potassium carbonate and diethyl carbonate are mixed, the temperature is raised to 80-90° C. for reaction, and the mixture is concentrated to obtain Compound 2.

4. The method according to claim 1, wherein: The step 2 is as follows: N-BOC-ethylenediamine is added dropwise to compound 2, reacted at 45-55° C., and ethyl acetate is added for crystallization to obtain compound 3.

5. The method according to claim 1, wherein: The step 3 is as follows: acid, water and compound 3 are mixed and reacted at 40-50° C., an alkaline solution is added to adjust the pH, and the organic layer is extracted and separated to obtain compound 4.

6. The method according to claim 5, wherein: The pH is ≥12.

7. The method according to claim 5, wherein: The acid is one of hydrochloric acid, sulfuric acid and trifluoroacetic acid.

8. The method according to claim 1, wherein: In step 4, the reducing agent is a borane tetrahydrofuran complex, and the salt-forming reagent is a hydrogen chloride ethanol solution.

9. The method according to claim 8, wherein: The step 4 is as follows: tetrahydrofuran and compound 4 are dropwise added with borane tetrahydrofuran complex under nitrogen protection, and the reaction is carried out at 50-60° C., after quenching the reaction, a hydrogen chloride ethanol solution is added, the temperature is lowered to 0-10° C., and the temperature is kept to crystallize to obtain compound 5.

10. The method according to claim 8, wherein: The molar ratio of the compound 4 to the borane tetrahydrofuran complex is 1:(2.5-4).

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