CN104530111A - Compound trimethyl (3-(trimethylsilyl) benzyloxyl) silane as well as preparation method and application thereof - Google Patents

Abstract

The invention relates to a compound trimethyl (3-(trimethylsilyl) benzyloxy) silane and a preparation method and application thereof. The trimethyl (3-(trimethylsilyl) benzyloxy) silane provided by the present invention can be used as a raw material for preparing radiopharmaceuticals for in vivo imaging or in vivo radiotherapy, especially for the treatment and diagnosis of human chromaffin Provide intermediate raw materials for the labeling precursor of the radiopharmaceutical inter-iodobenzylguanidine (*I-MIBG) used in neuroendocrine tumors such as cell tumors and neuroblastoma, thus providing a new labeling precursor for carrier-free inter-iodobenzylguanidine , so that it reduces toxicity compared to the existing carrier-free *I-MIBG labeling precursor, improves safety, and then facilitates clinical use and reduces side effects on patients; in addition, the trimethyl (3-(three The preparation method of methylsilyl)benzyloxy)silane is simple and easy to operate, has high yield and low economic cost, and is suitable for large-scale industrial production.

Description

Compound trimethyl(3-(trimethylsilyl)benzyloxy)silane and its preparation method and application

technical field

The invention relates to a compound trimethyl (3-(trimethylsilyl) benzyloxy) silane and a preparation method and application thereof.

Background technique

The radioactive labeling of compounds refers to the addition of radionuclides to compounds or the substitution of one or several atoms in compound molecules in order to achieve the purpose of tracing. Generally speaking, when a compound is radiolabeled, the biological and chemical properties are unchanged, but the nuclear properties are changed. Nuclear medicine uses this feature to carry radionuclides to the lesion site through compounds, and use the radiation released by nuclides to diagnose or treat diseases. Among them, radioactive iodine-labeled MIBG is a drug used in nuclear medicine for diagnosis and treatment. Inter-iodobenzylguanidine (MIBG) is a guanethidine derivative, structurally similar to norepinephrine, is a blocker of adrenal neurons, can specifically bind to adrenergic receptors, and can be distributed by sympathetic nerves Abundant organs such as adrenal medulla, myocardium, spleen, liver and salivary glands take up and store it. Meanwhile, the radionuclides ¹²³ I and ¹³¹ I have excellent nuclear properties. The 160keV single photon emitted by ¹²³ I is particularly suitable for single photon emission tomography (SPECT), while the β and γ rays emitted by ¹³¹ I can realize the effects of diagnosis and treatment at the same time. Therefore, radioactive iodine-labeled MIBG ( ^* I-MIBG) is used as an adrenal medulla imaging agent for the diagnosis and treatment of adult pheochromocytoma and children's neuroblastoma.

According to whether there is a carrier after radiolabeling, the radiopharmaceutical m-iodobenzylguanidine ^* I-MIBG is divided into two types: carrier and carrier-free. Most of the early reports are directed at the synthesis method of the carrier-labeled precursor MIBG sulfate, such as the method of two-step synthesis of MIBG using m-iodobenzylamine and nitrile amine [DMWieland et al., J.Nucl.Med., 21, 349 (1980) ], this method has been a classic method for synthesizing MIBG for many years and has been widely used. Carrier-free ^* I-MIBG is prepared by labeling trimethyltin (or silicon) benzylguanidine as a precursor. With the development of clinical application and scientific research, it has been found that carrier-free ^* I-MIBG has more excellent characteristics than carrier ^* I-MIBG, and carrier-free ^* I-MIBG is more effective than carrier ^* I-MIBG in treatment and imaging. The chemical dose used in the drug is less, the chemical dose received by the patient is reduced, the side effects on the patient are reduced, and the drug use is safer [Friedrich, H.; Herbert, K.; Anna, S.; Kurt, M.; Reingard, M. SYNTHESIS., 2012, 44:3387-3391]. In recent years, there have been reports of carrier-free ^* I-MIBG-labeled precursor synthesis methods, such as using tributyltin or silicon as a substituent [Vaidyanathan, G.; Zalutsky, MRAppl.Radiat.Isot.1992,44,621.]; 2003, Chinese scholars reported the preparation of 3-trimethylsilylbenzylguanidine using 3-bromotoluene as a starting material through a five-step reaction; in 2012, Austrian scholars reported a five-step synthesis of N,N' using 3-bromobenzyl alcohol -(tert-butyloxycarbonyl)-N-(3-trimethyltinbenzyl)guanidine method [Friedrich, H.; Herbert, K.; Anna, S.; Kurt, M.; Reingard, M. SYNTHESIS ., 2012, 44:3387-3391]. However, in terms of application, the cost of synthesizing MIBG according to the above method is relatively high, and the synthesis process is relatively complicated, which is difficult for industrialization or industrialization transformation. In addition, the tin element is highly toxic to the human body, and the risk of using tin as a substituent of the labeling precursor as a drug for the human body is relatively high, resulting in the fact that the carrier-free labeling precursor is currently in the scientific research stage and has no clinical application support.

Therefore, there is an urgent need for research and improvement in this field to increase yield, reduce cost, reduce toxicity, and improve safety, so as to be suitable for clinical use and industrial scale production.

Contents of the invention

The object of the present invention is to provide the compound trimethyl(3-(trimethylsilyl)benzyloxy)silane and its preparation method and application, aiming at the problems existing in the prior art.

The technical scheme for solving the problem of the present invention is: provide compound trimethyl (3-(trimethylsilyl) benzyloxy) silane, as shown in general formula (I):

The compound trimethyl (3-(trimethylsilyl) benzyloxy) silane represented by general formula (I) of the present invention includes its single isomer, diastereoisomer, tautomer, Enantiomers, E-isomers and Z-isomers.

The present invention also provides a preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane shown in general formula (I): comprising the steps of:

(1) In the reactor, first take 3-bromobenzyl alcohol and dissolve it in anhydrous tetrahydrofuran, then add n-butyllithium dropwise to the resulting solution, and stir to complete the reaction;

(2) Add dropwise a tetrahydrofuran solution of pre-dissolved trimethylchlorosilane to the reaction solution obtained in step (1), and the reaction is complete;

(3) Separating the product to obtain the compound trimethyl(3-(trimethylsilyl)benzyloxy)silane represented by the formula (I).

Preferably, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in said step (1), the mixture of 3-bromobenzyl alcohol and n-butyllithium The molar ratio is 1:4 to 1:2; in the step (2), the amount of trimethylchlorosilane added, in terms of 3-bromobenzyl alcohol, the moles of 3-bromobenzyl alcohol and trimethylchlorosilane The ratio is 2:5 to 1:2.

Preferably, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in said step (1), n-butyllithium is added dropwise under nitrogen protection, - Carry out under the condition of 70°C～-85°C, add n-butyllithium dropwise and then stir for 30 minutes to 50 minutes; Add the pre-dissolved trimethylchlorosilane tetrahydrofuran solution dropwise into the reaction liquid, react at -70°C to -85°C for 20 minutes to 40 minutes, then raise the temperature to room temperature, and continue the reaction at room temperature for 50 minutes to 90 minutes to The response is complete.

Preferably, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in said step (2), after the reaction is complete, add water to quench the reaction; In the step (3), the reaction solution obtained in the step (2) is extracted with dichloromethane, the organic phase obtained by the extraction is dried and concentrated by distillation under reduced pressure, and the crude product is then separated by column chromatography to obtain the product trimethyl ( 3-(Trimethylsilyl)benzyloxy)silane.

Preferably, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in said step (3), the solvent used for column chromatography separation is petroleum ether and acetic acid mixture of ethyl esters.

Preferably, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in said step (3), column chromatographic separation of used petroleum ether and ethyl acetate In the prepared mixture solvent, the volume ratio of petroleum ether to ethyl acetate is 5:1.

The present invention also provides the use of methyl(3-(trimethylsilyl)benzyloxy)silane represented by general formula (I) for preparing radiopharmaceuticals for in vivo imaging or in vivo radiotherapy, preferably for Preparation of radiopharmaceutical carrier-free meta-iodobenzylguanidine (*I-MIBG) labeled precursor can help improve the specific activity of the final product ^* I-MIBG, and reduce the toxic and side effects of drugs, thereby reducing the risk of drug use.

The methyl (3-(trimethylsilyl) benzyloxy) silane provided by the present invention can be used as a raw material for preparing radiopharmaceuticals for in vivo imaging or in vivo radiotherapy, especially for the treatment and diagnosis of human chromaffin cells It provides intermediate raw materials for the labeling precursor of the radiopharmaceutical inter-iodobenzylguanidine (*I-MIBG) used in neuroendocrine tumors such as neoplasms and neuroblastoma, thus providing a new labeling precursor for carrier-free inter-iodobenzylguanidine, Compared with the existing tin-labeled precursors and other labeling precursors without carrier *I-MIBG, the toxicity is reduced, the safety is improved, and then it is beneficial to clinical use and reduces side effects on patients; in addition, the methyl ( The preparation method of 3-(trimethylsilyl)benzyloxy)silane is simple and easy to operate, has high yield and low economic cost, and is suitable for large-scale industrial production.

Detailed ways

In the present invention, the compound trimethyl(3-(trimethylsilyl)benzyloxy)silane represented by the general formula (I) is provided, including its single isomers, diastereoisomers, and interconversion isomers, enantiomers, E-isomers and Z-isomers,

The preparation synthetic reaction scheme of trimethyl (3-(trimethylsilyl) benzyloxy) silane shown in above-mentioned general formula (I) is as follows:

The preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane shown in above-mentioned general formula (I), carries out following steps:

(1) In the reactor, first take 3-bromobenzyl alcohol and dissolve it in anhydrous tetrahydrofuran, then add n-butyllithium dropwise to the resulting solution, and stir to complete the reaction;

(2) Add dropwise a tetrahydrofuran solution of pre-dissolved trimethylchlorosilane to the reaction solution obtained in step (1), and the reaction is complete;

(3) Carry out product separation, obtain the compound trimethyl (3-(trimethylsilyl) benzyloxy) silane shown in formula (I);

In order to ensure the yield, rate and stability of the reaction, preferably, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in the step (1) , the mol ratio of 3-bromobenzyl alcohol and n-butyllithium is 1:4 to 1:2; - The molar ratio of bromobenzyl alcohol to trimethylchlorosilane is 2:5 to 1:2.

Preferably, in order to ensure sufficient and efficient reaction between reactants, in the preparation method of trimethyl(3-(trimethylsilyl)benzyloxy)silane of the present invention, in the step (1), The dropwise addition of n-butyllithium is carried out under the protection of nitrogen at -70°C to -85°C, and the reaction is stirred for 30 minutes to 50 minutes after the dropwise addition of n-butyllithium; in the step (2), at -70°C to Add the pre-dissolved tetrahydrofuran solution of trimethylchlorosilane dropwise to the reaction solution obtained in step (1) at -85°C, react at -70°C to -85°C for 20 minutes to 40 minutes, then warm up to room temperature, Continue the reaction at room temperature for 50 minutes to 90 minutes until the reaction is complete.

Preferably, in order to improve the purity of the target product, in the preparation method of trimethyl (3-(trimethylsilyl) benzyloxy) silane of the present invention, in the step (2), after the reaction is complete, add water to quench In the step (3), the reaction solution obtained in the step (2) is extracted with dichloromethane, the organic phase obtained by the extraction is dried and concentrated by distillation under reduced pressure, and the crude product is then separated by column chromatography, namely The product trimethyl(3-(trimethylsilyl)benzyloxy)silane is obtained. In order to efficiently guarantee the separation effect of column chromatography, preferably, the solvent used for column chromatography separation is a mixture of petroleum ether and ethyl acetate; preferably, in the mixture solvent of petroleum ether and ethyl acetate used for column chromatography separation, petroleum ether and The volume ratio of ethyl acetate is 5:1.

The present invention also provides the use of methyl(3-(trimethylsilyl)benzyloxy)silane represented by general formula (I) for preparing radiopharmaceuticals for in vivo imaging or in vivo radiotherapy, preferably for Preparation of labeled precursor of radiopharmaceutical carrier-free inter-iodobenzylguanidine (*I-MIBG) can help improve the specific activity of the final product ^* I-MIBG, greatly improve the quality of medicines, reduce the side effects of medication for patients, and reduce the risk of hypertension phase risk; in addition, adopting silicon element to replace tin element can abandon the risk that tin element remains in the final product, also reduced the toxic and side effect of medicine equally; Use the methyl (3-(trimethylsilyl) benzyl) Compared with the traditional isotope exchange labeling method, the carrier-free labeling precursor prepared by oxy)silane has simplified operation process, simple labeling method, easy operation, can reduce the operating cost and technical cost of the production enterprise, and improve the enterprise benefit. Therefore, A yl(3-(trimethylsilyl)benzyloxy)silane is the key compound for the preparation of unsupported labeling precursors, and it is beneficial to the implementation of industrialization.

Each compound prepared by the present invention is characterized and identified by Bruker Avance III NMR spectrometer instrument nuclear magnetic resonance (NMR).

The present invention will be further described below in conjunction with specific examples, but the protection scope of the present invention is not limited thereto.

The experimental methods used in the following examples are conventional methods unless otherwise specified.

The materials and reagents used in the following examples can be obtained from commercial sources unless otherwise specified.

Example 1

Synthesize compound trimethyl (3-(trimethylsilyl) benzyloxy) silane as shown in formula (I),

The synthesis reaction is as follows:

The preparation method is as follows:

(1) Take 12 mmol of 3-bromobenzyl alcohol, dissolve it in 54 mL of anhydrous tetrahydrofuran, slowly add 30 mmol of n-butyl lithium dropwise to the obtained solution under nitrogen protection at -78°C, and stir for 40 minutes;

(2) Add trimethylchlorosilane solution dropwise to the reaction solution obtained in step (1) at -78°C, the added trimethylchlorosilane solution is formed by dissolving 25.2mmol trimethylchlorosilane in 22.5mL tetrahydrofuran, After dropping the trimethylchlorosilane solution, keep the reaction at -78°C for 30 minutes, then raise the temperature to room temperature, and continue the reaction at room temperature for 1 hour. After the reaction is complete, add water to quench the reaction;

(3) Extract the reaction solution obtained in step (2) with dichloromethane, dry the obtained organic phase and concentrate it by distillation under reduced pressure, and carry out column chromatography separation of the gained crude product, the solvent used for column chromatography separation adopts petroleum ether and ethyl acetate The mixture with a volume ratio of 5:1 was separated to obtain a light yellow oily liquid with the structure shown in formula (I), and the yield was 20.5%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.48(s, 1H), 7.42 (s,1H),7.33(s,2H),4.72(s,2H),0.28(s,9H),0.17(s,9H).

Application example

The methyl (3-(trimethylsilyl) benzyloxy) silane prepared by the present invention is used to prepare radiopharmaceuticals for in vivo imaging or in vivo radiotherapy, so that it can be used for the preparation of radiopharmaceutical carrier-free m-iodobenzyl The labeling precursor of guanidine (*I-MIBG) and its intermediate are described as examples, but the present invention is not limited thereto.

Application example 1

The method for preparing the labeled precursor of carrier-free m-iodobenzylguanidine (*I-MIBG) is as follows:

(1) Dissolve the compound trimethyl (3-(trimethylsilyl) benzyloxy) silane in anhydrous tetrahydrofuran, then add tetrabutylammonium fluoride to the resulting solution, stir and react completely, and obtain intermediate Among them, the molar ratio of trimethyl(3-(trimethylsilyl)benzyloxy)silane to tetrabutylammonium fluoride is preferably 1:2 to 3:2; after adding tetrabutylammonium fluoride, mix The solution is preferably stirred and reacted at room temperature, and the reaction time is preferably 1.5 hours to 2.5 hours;

(2) take and triphenylphosphine, dissolved in toluene, then, in the resulting solution, diethyl azodicarboxylate was added dropwise, the reaction was complete, and the labeled precursor compound of carrier-free m-iodobenzylguanidine (*I-MIBG) was obtained; in, and The molar ratio of is preferably 2:5 to 3:5, The molar ratio to triphenylphosphine is preferably 3:5 to 4:5, The molar ratio to diethyl azodicarboxylate is preferably 3:5 to 4:5; nitrogen is continuously passed into the reaction flask, so that the dropwise addition of diethyl azodicarboxylate is preferably carried out under nitrogen protection and ice bath conditions; After adding diethyl azodicarboxylate dropwise, it is preferable to react the mixed solution at room temperature under the protection of nitrogen, so that the reaction can be completely separated from oxygen, which is beneficial to increase the yield. The reaction time is preferably 4 hours to 7 hours.

The specific examples of application example 1 are used to illustrate the effect of compound trimethyl (3-(trimethylsilyl) benzyloxy) silane shown in the formula (I) provided by the invention on the synthesis of drug intermediates. High efficiency and stability, and the intermediates synthesized by the compound represented by formula (I) have significant effects on the toxicity, safety, yield and process optimization of the labeled precursors of synthetic target radiopharmaceuticals, but the application of the present invention does not limited to this.

Specific embodiment of application example 1

The preparation method of the silicon-labeled precursor for carrier-free m-iodobenzylguanidine (*I-MIBG) is as follows:

(1) Take 1.58 mmol of the compound shown in formula (I) prepared in Example 1, dissolve it in 10 mL of anhydrous tetrahydrofuran, add 1.58 mmol of tetrabutylammonium fluoride to the resulting solution, and stir and react at room temperature for 2 hours; then, The solvent was distilled off under reduced pressure, extracted with dichloromethane and water, the resulting organic phase was dried, and then separated by column chromatography. The solvent used for column chromatography was a mixture of petroleum ether and ethyl acetate with a volume ratio of 5:1. The target product was isolated as a colorless oily liquid with the structure shown in the following formula (II), and the yield was 58.2%; ¹ H NMR (400MHz, CDCl ₃ ) δ7.53(s, 1H), 7.50–7.44(m, 1H) ,7.37(d,J=4.0Hz,2H),4.70(s,2H),1.83(s,1H),0.29(s,9H);

(2) get the intermediate compound shown in the formula (II) of step (1) synthesis 0.577mmol, 1.154mmol and 0.866mmol of triphenylphosphine were dissolved in 5mL of toluene, and 0.866mmol of diethyl azodicarboxylate was added dropwise to the resulting solution under nitrogen protection and ice bath conditions, and the mixed solution was kept at room temperature under nitrogen protection. React for 5 hours; after the reaction is complete, first carry out suction filtration, then distill the concentrated solution under reduced pressure, and then carry out column chromatography separation. The volume ratio to ethyl acetate was 6:1, and a colorless oily liquid product was isolated with the structure shown in formula (I), and the yield was 78.7%. ; ¹ H NMR (400MHz, CDCl ₃ ) δ7.47(s, 1H), 7.39(d, J=6.4Hz, 1H), 7.32–7.26(m, 2H), 5.19(s, 2H), 1.49(s ,9H),1.35(s,9H),0.25(s,9H).

The present invention is not limited to the above-mentioned embodiments, and any obvious improvements or changes made by those skilled in the art to the above-mentioned embodiments will not exceed the concept of the present invention and the scope of protection of the appended claims.

Claims (9)

1. The compound trimethyl (3- (trimethylsilyl) benzyloxy) silane is shown as a general formula (I):

2. trimethyl (3- (trimethylsilyl) benzyloxy) silane according to claim 1, characterized in that the compound of general formula (i) trimethyl (3- (trimethylsilyl) benzyloxy) silane comprises its single isomers, diastereomers, tautomers, enantiomers, E-isomers and Z-isomers.

3. A process for the preparation of trimethyl (3- (trimethylsilyl) benzyloxy) silane as defined in claim 1 or 2, comprising the steps of:

(1) in a reactor, dissolving 3-bromobenzyl alcohol in anhydrous tetrahydrofuran, then dropwise adding n-butyl lithium into the obtained solution, and stirring for completely reacting;

(2) dripping a tetrahydrofuran solution of pre-dissolved trimethylchlorosilane into the reaction liquid obtained in the step (1) to completely react;

(3) and (3) separating a product to obtain the compound trimethyl (3- (trimethylsilyl) benzyloxy) silane shown as the formula (I).

4. The method for preparing trimethyl (3- (trimethylsilyl) benzyloxy) silane according to claim 3, characterized in that in said step (1), the molar ratio of 3-bromobenzyl alcohol to n-butyllithium is from 1:4 to 1: 2;

in the step (2), the trimethylchlorosilane is added in an amount of 2:5 to 1:2 of molar ratio of 3-bromobenzyl to trimethylchlorosilane based on 3-bromobenzyl.

5. The method for preparing trimethyl (3- (trimethylsilyl) benzyloxy) silane as recited in claim 3, wherein in said step (1), n-butyllithium is added dropwise under nitrogen protection at-70 ℃ to-85 ℃, and after n-butyllithium is added dropwise, the reaction is stirred for 30 to 50 minutes;

in the step (2), a tetrahydrofuran solution of pre-dissolved trimethylchlorosilane is dropwise added into the reaction liquid obtained in the step (1) at the temperature of-70 to-85 ℃, the mixture is reacted for 20 to 40 minutes at the temperature of-70 to-85 ℃, then the temperature is increased to room temperature, and the reaction is continued for 50 to 90 minutes at the room temperature until the reaction is complete.

6. The method for preparing trimethyl (3- (trimethylsilyl) benzyloxy) silane as set forth in claim 3, wherein in said step (2), water is added after completion of the reaction to quench the reaction;

and (3) extracting the reaction liquid obtained in the step (2) by using dichloromethane, drying an organic phase obtained by extraction, carrying out reduced pressure distillation and concentration to obtain a crude product, and then carrying out column chromatography separation to obtain a product trimethyl (3- (trimethylsilyl) benzyloxy) silane.

7. The method for preparing trimethyl (3- (trimethylsilyl) benzyloxy) silane as set forth in claim 6, wherein the solvent used for column chromatography in step (3) is a mixture of petroleum ether and ethyl acetate.

8. The method for preparing trimethyl (3- (trimethylsilyl) benzyloxy) silane as recited in claim 7, wherein in said step (3), the volume ratio of petroleum ether to ethyl acetate is 5:1 in the solvent mixture of petroleum ether and ethyl acetate used for column chromatography.

9. Use of trimethyl (3- (trimethylsilyl) benzyloxy) silane as defined in claim 1 for the preparation of a radiopharmaceutical for in vivo imaging or in vivo radiotherapy.