Synthesis method of gadoxate disodium intermediate

Abstract

The invention discloses a gadoxetate disodium intermediate synthesis method, which comprises: S1, carrying out a reaction on an organic alkali and a compound A according to a molar ratio of 2-10: 1 and thionyl chloride in a reaction solvent at a temperature of-5-0 DEG C for 2 h, adding water for extraction, and separating out a dichloromethane phase to obtain a dichloromethane solution of a compound B; s2, the dichloromethane solution of the compound B reacts for 10-12 h at the temperature of 25 DEG C in the presence of an oxidizing agent, sodium sulfite is added for quenching reaction, extraction is conducted, a dichloromethane phase is separated out, a solvent is distilled out under reduced pressure, and a compound C is obtained; s3, adding ethylenediamine into the compound C, reacting at 25 DEG C for 10-12 hours, adding water and a dichloromethane phase for extraction, and drying an organic phase by distillation under reduced pressure to obtain a compound D; the preparation method comprises the following steps: generating a five-membered ring of sulfoxide from a compound C alcohol and an amino group by using thionyl chloride, oxidizing the sulfoxide into sulfone, and recrystallizing and purifying; and then the raw materials are put into the subsequent reaction to control the total yield and purity, the total yield of the reaction is up to 90%, and the production cost is effectively reduced.

Description

Technical Field

[0001] This invention relates to a method for synthesizing a disodium gadoxetate intermediate, belonging to the field of compound reaction technology. Background Technology

[0002] Disodium gadoxetate is a novel magnetic resonance contrast agent. Disodium gadoxetate injection shortens the T1 relaxation time of tissues, allowing for observation of the conventional multi-phase dynamic enhancement patterns and manifestations of liver lesions. Furthermore, in individuals with normal liver function, 10-20 minutes after injection of disodium gadoxetate, the liver parenchyma shows enhancement, and the biliary system also becomes visible; this phase is known as the hepatobiliary-specific phase.

[0003] Gadoxate disodium injection is administered intravenously. It enters hepatocytes via the organic anion transport polypeptide 1B3 on the sinusoidal surface of the hepatocyte membrane, and is then excreted into the biliary system via multidrug resistance protein 2, primarily located on the biliary tract surface of the hepatocyte membrane (approximately 50%), without altering its chemical structure. The remaining 50% is excreted via the kidneys. Gadoxate disodium injection has a detection rate of over 90% for hepatocellular carcinoma, higher than that of 64-slice enhanced CT and ultrasound, especially for hepatocellular carcinomas <1 cm in size. For both primary and secondary liver lesions, gadoxate disodium injection with contrast-enhanced MRI is superior to enhanced CT and conventional contrast agents.

[0004] With its widespread use both domestically and internationally, gadoxetine disodium injection has evolved from simply diagnosing localized intrahepatic lesions to evaluating diffuse liver lesions (such as non-alcoholic fatty liver disease, cholestatic liver disease, liver fibrosis, and cirrhosis). It has also shown initial advantages in predicting liver function and liver dysfunction after liver transplantation, but its value still needs to be confirmed by further clinical research.

[0005] S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride is a key raw material for the synthesis of disodium gadoxetate, so there is an urgent need to develop an intermediate that meets GMP requirements. Currently, the following synthetic methods are available in the literature:

[0006] Method 1: Patent CN101007775A discloses a method for preparing S-1-(4-ethoxy)-3-azapentane-1,5-diamine. This route uses amino-protected L-tyrosine ester as the starting material, and proceeds through alkylation, amino substitution, deamination, and reduction with lithium aluminum hydride (LiAlH) to obtain S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine. However, this route uses iodoethane, a highly carcinogenic and toxic reagent, as the alkylating agent, posing a high risk. Furthermore, this method uses expensive trifluoroacetic acid as the reaction solvent and deprotecting agent, requiring large quantities, making post-processing difficult, and easily causing environmental pollution. Moreover, this route uses lithium aluminum hydride for the reduction reaction, which requires anhydrous and oxygen-free conditions, posing high safety requirements, and presents significant operational hazards and post-processing difficulties, resulting in an overall yield of only 53%. This synthetic method is not suitable for industrial-scale production.

[0007] Method 2: Inorg. Chem. 1999.38.1134-1144 discloses a method using N-oxycarbonyl (Cbz)-L-tyrosine ester as the starting material, employing the highly carcinogenic and toxic reagent iodoethane, and using Pd / C as a catalyst for high-pressure catalytic hydrogenation reduction. This method has strict requirements on production equipment and operating conditions, posing a high safety risk. In addition, this route uses flammable, explosive, and highly toxic diborane, making transportation, storage, and operation extremely dangerous. The reaction time is as long as 32 hours, resulting in low equipment efficiency, difficult waste liquid post-treatment, and significant environmental impact. The overall yield of this route is only 55%, therefore it is also unsuitable for industrial production.

[0008] Method 3: According to the literature reported in Inorg.Chem.1999.38.1134-1144, this synthesis method also uses the highly toxic reagent iodoethane and high-pressure catalytic hydrogenation in the process, which is harsh on the reaction conditions, has high safety risks, and is not conducive to industrial production.

[0009] Method 4: Patent CN103896788A discloses a method using N-oxycarbonyl (Cbz)-L-tyrosine ester as the starting material, alkylating it with bromoethane, reducing it with sodium borohydride in a mixed solvent of tetrahydrofuran and methanol to obtain compound 3. Compound 3 then reacts with p-toluenesulfonic acid chloride and methanesulfonic acid chloride to generate intermediate 4. Intermediate 4 then reacts with ethylenediamine, and finally deprotects it with hydrochloric acid and methanol to generate S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride. This route uses sodium borohydride in a mixed solvent of tetrahydrofuran and methanol to obtain compound 3, which is costly and presents difficulties in subsequent solvent recycling. This invention uses a single solvent for the reaction, making subsequent recycling easier and more environmentally friendly. In the preparation of compound 4, compound 3 is reacted with p-toluenesulfonic acid chloride and methanesulfonic acid chloride to generate the key intermediate sulfonate 4, which is then reacted with ethylenediamine to produce the product after deprotection. However, intermediate sulfonate 4 is unstable, posing a very high risk during subsequent storage, transportation, and use, making it difficult to control the quality of the intermediate. This batch-to-batch inconsistency in stability poses challenges to GMP production.

[0010] Through long-term experimental research, the inventors have creatively found a simple and mild method for preparing the key intermediate of S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride, avoiding the defects of the prior art. Summary of the Invention

[0011] In view of the shortcomings of the existing technology, the purpose of this invention is to provide a method for synthesizing disodium gadoxetate intermediate.

[0012] To achieve the above objectives, the present invention provides the following technical solution: a method for synthesizing a disodium gadoxetate intermediate, wherein the disodium gadoxetate intermediate is S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride, and its synthetic route is as follows:

[0013]

[0014]

[0015] S1: Organic base and compound A are reacted with thionyl chloride in a reaction solvent at a molar ratio of 2-10:1 and at -5-0℃ for 2 hours. Water is added for extraction, and the dichloromethane phase is separated to obtain a dichloromethane solution of compound B.

[0016] S2: The dichloromethane solution of compound B was reacted at 25°C for 10-12 h in the presence of an oxidant. The reaction was quenched by adding sodium sulfite, and the mixture was extracted to separate the dichloromethane phase. The solvent was then evaporated under reduced pressure to obtain compound C.

[0017] S3: Add ethylenediamine to compound C, react at 25°C for 10-12 h, add water, extract with dichloromethane phase, and evaporate the organic phase under reduced pressure to obtain compound D.

[0018] Using the above technical solution, starting with amino-protected L-tyrosine (SM1), compound B is obtained by acylation with sulfoxide, followed by oxidation with ruthenium trichloride to obtain compound C, which then reacts with ethylenediamine to obtain compound D. Subsequent deprotection of compound D yields the key intermediate S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride for gadoxetate disodium salt.

[0019] Preferably, step S1 specifically includes:

[0020] S11: Mix an organic base with dichloromethane at a mass-to-volume ratio of 1:2-3 to obtain a dichloromethane solution of the organic base; mix sulfoxide with dichloromethane at a mass-to-volume ratio of 1:1.4-2 to obtain a dichloromethane solution of sulfoxide; mix BOC-protected L-tyrosine with dichloromethane at a mass-to-volume ratio of 1:3-5 to obtain a dichloromethane solution of L-tyrosine.

[0021] S12: Add the dichloromethane solution of thionyl chloride dropwise to the dichloromethane solution of the organic base, stir at -5 to 0℃ for 1-2 h to obtain the organic base-thionyl chloride system;

[0022] S13: Add a dichloromethane solution of L-tyrosine alcohol dropwise to an organic base-thionyl chloride system, stir at -5 to 0°C for 1-2 h, then add water for extraction, separate the dichloromethane phase, and obtain a dichloromethane solution of compound B.

[0023] Preferably, the organic base in step S1 is one or two of imidazole, pyridine, triethylamine, N-methylpiperidine, and N-methylmorpholine.

[0024] Preferably, the organic base in step S1 is imidazole.

[0025] Preferably, in step S1, the molar ratio of the organic base to compound A is 5-7:1, and the molar ratio of compound A to thionyl chloride is 2-5:1.

[0026] Preferably, the molar ratio of compound A to sulfoxide in step S1 is 1.5-2:1.

[0027] Preferably, the oxidant in step S2 is one or two of ruthenium trichloride, sodium periodate, hydrogen peroxide, and m-chloroperoxybenzoic acid.

[0028] Preferably, the oxidant in step S2 is ruthenium trichloride and sodium periodate, with a molar ratio of 0.5-5:1.

[0029] Preferably, the volume ratio of ethylenediamine to compound C in step S3 is 2-10:1.

[0030] Preferably, the volume ratio of ethylenediamine to compound C in step S3 is 2-5:1.

[0031] By employing the above technical solution and using BOC-protected L-complexanol as a raw material, the use of highly toxic reagents such as diborane and lithium aluminum hydride in the process is avoided, thus improving the safety of the reaction. This significantly improves the yield and purity of the key intermediate in the production of S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride, with an HPLC purity exceeding 99%.

[0032] The beneficial effects of this invention are:

[0033] (1) This invention addresses the problems of existing technologies by using thionyl chloride to generate a five-membered ring sulfoxide from compound C, then oxidizing the sulfoxide to a sulfone, followed by recrystallization purification; this is then incorporated into subsequent reactions to control the overall yield and purity. This controls the risks of intermediates during subsequent storage, transportation, and use, precisely controls the quality of intermediates, reduces batch-to-batch variations, and utilizes subsequent GMP production.

[0034] (2) The present invention uses a continuous feeding process with fewer impurities, which reduces the impurities generated during production; the solvent used is simple and easy to recycle, which greatly improves the environmental friendliness.

[0035] (3) The present invention greatly improves the reaction yield, with a total reaction yield of up to 90%, effectively reducing production costs. At the same time, the process uses a novel leaving group, which is original. Detailed Implementation

[0036] To make the technical means, creative features, objectives and effects of this invention easier to understand, the invention will be further described below in conjunction with specific embodiments.

[0037] Example 1

[0038] A method for synthesizing a disodium gadoxetate intermediate includes the following steps:

[0039] S1: Preparation of dichloromethane solution of compound B

[0040] S11: Dissolve 20.4 kg of triethylamine (202 mol) in 30 L of dichloromethane to obtain a dichloromethane solution of triethylamine; dissolve 7.2 kg of thionyl chloride (60.5 mol) in 10 L of dichloromethane to obtain a dichloromethane solution of thionyl chloride; dissolve 10 kg of BOC-protected L-tyrosine (33.8 mol) in 30 L of dichloromethane to obtain a dichloromethane solution of L-tyrosine.

[0041] S12: Add the dichloromethane solution of thionyl chloride dropwise to the dichloromethane solution of triethylamine, stir at -5 to 0℃ for 2 h to obtain the triethylamine-thionyl chloride system;

[0042] S13: A dichloromethane solution of L-tyrosine was added dropwise to the triethylamine-thionyl chloride system. The mixture was stirred at -5 to 0°C for 1 hour. After the reaction was complete, 30 L of water was added to the system for separation. The aqueous phase was then extracted twice with dichloromethane (10 L each time). The organic phases were combined to obtain a dichloromethane solution of compound B, which was directly used in the next reaction. The yield was 100%, and the HPLC purity was 94.6%.

[0043] S2: Preparation of compound C

[0044] A mixture of 90 L of dichloromethane solution (33.8 mol) of compound B and 30 L of water was added to the above reaction mixture. 66 g (0.29 mol) of ruthenium trichloride hydrate was added dropwise to the mixture. 10 kg (58 mol) of m-chloroperoxybenzoic acid was dissolved in 20 L of water and added dropwise to the system while maintaining a temperature of 20-30 °C. After the addition was complete, the reaction was maintained at this temperature for 12 h. After the reaction was complete, 20 L of saturated sodium sulfite solution was added to the system. The mixture was separated, and the aqueous phase was extracted twice with dichloromethane (20 L each time). The solvent was removed under reduced pressure, and column purification was performed to obtain 0.9 kg of compound C1, with a yield of 90.2% and an HPLC purity of 97.6%.

[0045] S3: Preparation of compound D

[0046] 10 kg (30.0 mol) of compound C obtained in step S2 was dissolved in 100 L of ethylenediamine, and the reaction was carried out at 10-20 °C for 12 h. After the reaction was completed, 500 L of water was added to the system, and the mixture was extracted twice with dichloromethane (50 L each time). The solvent was evaporated under reduced pressure to give 9.2 kg of compound D, with a yield of 97.4% and an HPLC purity of 99.1%. MS [M+H]+: 338.3.

[0047] Example 2

[0048] A method for synthesizing a disodium gadoxetate intermediate includes the following steps:

[0049] S1: Preparation of dichloromethane solution of compound B

[0050] S11: Dissolve 13.8 kg imidazole (202 mol) in 30 L dichloromethane to obtain an imidazole dichloromethane solution; dissolve 7.2 kg thionyl chloride (60.5 mol) in 10 L dichloromethane to obtain a thionyl chloride dichloromethane solution; dissolve 10 kg BOC-protected L-tyrosine (33.8 mol) in 30 L dichloromethane to obtain an L-tyrosine dichloromethane solution.

[0051] S12: Add the dichloromethane solution of thionyl chloride dropwise to the dichloromethane solution of imidazole, stir at -5 to 0℃ for 2 h to obtain the imidazole-thionyl chloride system;

[0052] S13: A dichloromethane solution of L-tyrosine was added dropwise to the imidazole-thionyl chloride system. The mixture was stirred at -5 to 0°C for 1 hour. After the reaction was complete, 30 L of water was added to the system for separation. The aqueous phase was then extracted twice with dichloromethane (10 L each time). The organic phases were combined to obtain a dichloromethane solution of compound B, which was directly used in the next reaction. The yield was 100%, and the HPLC purity was 99.3%.

[0053] S2: Preparation of compound C

[0054] A mixture of 90 L of dichloromethane solution (33.8 mol) of compound B and 30 L of water was added to the above reaction mixture. 66 g (0.29 mol) of ruthenium trichloride hydrate was added dropwise to the mixture. 12.5 kg (58 mol) of sodium periodate was dissolved in 20 L of water, and the solution was added dropwise to the system while maintaining a temperature of 20-30 °C. After the addition was complete, the reaction was maintained at this temperature for 12 h. After the reaction was complete, 20 L of saturated sodium sulfite solution was added to the system. The mixture was separated, and the aqueous phase was extracted twice with dichloromethane (20 L each time). The solvent was removed under reduced pressure to obtain 11.5 kg of compound C1, with a yield of 95.0% and an HPLC purity of 98.2%.

[0055] 1H HNMR (400MHz, CDCl3) δ = 7.13 (d, J = 8Hz, 2H), 6.86 (d, J = 8Hz, 2H), 4.3-4.5 (m, 3H), 4.04 (q, J=8Hz,2H),3.29(dd,J=4,16Hz,1H),2.82-2.90(m,1H),1.57(s,9H),1.42(t,J=12Hz,3H).

[0056] S3: Preparation of compound D

[0057] 10 kg (30.0 mol) of compound C obtained in step S2 was dissolved in 20 L of ethylenediamine and reacted at 10-20 °C for 12 h. After the reaction was complete, 200 L of water was added to the system, and the mixture was extracted twice with dichloromethane (10 L each time). The solvent was evaporated under reduced pressure to give 9.2 kg of compound D, with a yield of 97.4% and an HPLC purity of 99.3%. MS [M+H]+: 338.3.

[0058] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from its spirit or basic characteristics. Therefore, the embodiments should be considered exemplary and non-limiting in all respects, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0059] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing a disodium gadoxetate intermediate, characterized in that: The intermediate of gadoxetate disodium salt is S-1-(4-ethoxybenzyl)-3-azapentane-1,5-diamine trihydrochloride, and its synthetic route is as follows: S1: Organic base and compound A are reacted with thionyl chloride in a reaction solvent at a molar ratio of 2-10:1 and at -5-0℃ for 1-2 h. Water is added for extraction, and the dichloromethane phase is separated to obtain a dichloromethane solution of compound B. S2: The dichloromethane solution of compound B was reacted at 20-30℃ for 10-12h in the presence of an oxidant. The reaction was quenched by adding sodium sulfite, and the mixture was extracted to separate the dichloromethane phase. The solvent was then evaporated under reduced pressure to obtain compound C. S3: Add ethylenediamine to compound C, react at 10-20℃ for 10-12 h, add water, extract with dichloromethane phase, and evaporate the organic phase under reduced pressure to obtain compound D.

2. The method for synthesizing a disodium gadoxetate intermediate as described in claim 1, characterized in that: Step S1 is as follows: S11: Mix an organic base with dichloromethane at a mass-to-volume ratio of 1:2-3 to obtain a dichloromethane solution of the organic base; mix sulfoxide with dichloromethane at a mass-to-volume ratio of 1:1.4-2 to obtain a dichloromethane solution of sulfoxide; mix BOC-protected L-tyrosine with dichloromethane at a mass-to-volume ratio of 1:3-5 to obtain a dichloromethane solution of L-tyrosine. S12: Add the dichloromethane solution of thionyl chloride dropwise to the dichloromethane solution of the organic base, stir at -5 to 0℃ for 1-2 h to obtain the organic base-thionyl chloride system; S13: Add a dichloromethane solution of L-tyrosine alcohol dropwise to an organic base-thionyl chloride system, stir at -5 to 0°C for 1-2 h, then add water for extraction, separate the dichloromethane phase, and obtain a dichloromethane solution of compound B.

3. The method for synthesizing a disodium gadoxetate intermediate as described in claim 2, characterized in that: The organic base in step S1 is one or two of imidazole, pyridine, triethylamine, N-methylpiperidine, and N-methylmorpholine.

4. The method for synthesizing a disodium gadoxetate intermediate as described in claim 2, characterized in that: In step S1, the molar ratio of the organic base to compound A is 5-7:1, and the molar ratio of compound A to thionyl chloride is 2-5:

1.

5. The method for synthesizing a disodium gadoxetate intermediate as described in claim 4, characterized in that: In step S1, the molar ratio of compound A to sulfoxide is 1.5-2:

1.

6. The method for synthesizing a disodium gadoxetate intermediate as described in claim 1, characterized in that: The oxidant in step S2 is one or two of ruthenium trichloride, sodium periodate, hydrogen peroxide, and m-chloroperoxybenzoic acid.

7. The method for synthesizing a disodium gadoxetate intermediate as described in claim 6, characterized in that: The oxidizing agents in step S2 are ruthenium trichloride and sodium periodate, with a molar ratio of 0.5-5:

1.

8. The method for synthesizing a disodium gadoxetate intermediate as described in claim 1, characterized in that: In step S3, the volume ratio of ethylenediamine to compound C is 2-10:

1.

9. The method for synthesizing a disodium gadoxetate intermediate as described in claim 8, characterized in that: The volume ratio of ethylenediamine to compound C in step S3 is 2-5:1.

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