CN106187823A - A kind of method preparing meta iodobenzyl guanidine - Google Patents

A kind of method preparing meta iodobenzyl guanidine Download PDF

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Publication number
CN106187823A
CN106187823A CN201610518107.4A CN201610518107A CN106187823A CN 106187823 A CN106187823 A CN 106187823A CN 201610518107 A CN201610518107 A CN 201610518107A CN 106187823 A CN106187823 A CN 106187823A
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mibg
sulfate
reducing agent
iodobenzyl guanidine
meta iodobenzyl
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CN106187823B (en
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陈志明
王刚
谢敏浩
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Jiangsu Institute of Nuclear Medicine
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Jiangsu Institute of Nuclear Medicine
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C277/00—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups
    • C07C277/08—Preparation of guanidine or its derivatives, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups of substituted guanidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/05—Isotopically modified compounds, e.g. labelled

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

The present invention relates to one prepare131The method of I MIBG, comprises the steps: meta iodobenzyl guanidine sulfate, stannous sulfate, reducing agent, copper sulfate and Na131I puts in boiling water bath and heats, and reaction stands after terminating, and Aspirate supernatant is crossed microporous filter membrane and get final product.The present invention uses sodium thiosulfate and/or sodium sulfite as reducing agent Marking MIBG sulfate, prepares131I MIBG radiochemical purity is high, good stability, and after placing 48 hours, radiochemical purity is still in higher level.

Description

A kind of method preparing meta iodobenzyl guanidine
Technical field
The present invention relates to radiopharmaceutical field, be specifically related to the preparation method of a kind of meta iodobenzyl guanidine.
Background technology
It is positioned at the tumor that adrenal pheochromocytoma is a kind of secreting hormone, there is adrenal medulla function, at high blood In pressure patient, 0.6%-1.0% is had to be caused by pheochromocytoma.The long-term hypertension of patient Ke Yin causes the serious heart, brain, kidney Infringement or the serious secondary hypertension that happens suddenly, and threat to life.Adrenal medulla pathological changes specifically includes that pheochromocytoma and marrow Matter hypertrophy, mainly shows as paroxysmal or persistence hypertension.Different from essential hypertension, sick by adrenal medulla Hypertension caused by change, as long as surgically after removal of lesions, the blood pressure of Most patients can recover normal, therefore early examines Disconnected, early treatment, then can cure this secondary hypertension sick.
(metaiodobenzylguanidine, MIBG, molecular formula is C to meta iodobenzyl guanidine8H10IN3) it is a kind of epinephrine Energy antipsychotic drugs, similar to norepinephrine structure, can be by medullary epithelium, neuron tumor uptake.Utilize clinically and put The imaging of injectivity isotope iodine label and cytotoxicity, will131I-meta iodobenzyl guanidine (131I-MIBG) swell for neural crest origin Tumor, such as malignant nerve ridge tumor, carcinoid tumor, neuroblastoma, pheochromocytoma, pheochromocytoma and thyroid hyloma etc. Diagnosis and treatment.
Be currently used for pheochromocytoma inspection diagnosis method have: CT, B ultrasonic, 3-methoxy-4-hydroxymelic acid measure and131I-MIBG Radiography imaging etc..Wherein, B ultrasonic can only detect adrenal gland's interior diameter tumor more than 2 centimetres；CT for tumor etiologic diagnosis with And the positive rate of whole body dystopy or metastasis diagnosis is only 70%；In urine the biochemical measurement of VMA can only point out whether have different Often, cannot lesion.But,131The specificity of I-MIBG adrenal medulla scanning is not up to 97.1%-100%, and not False positive rate occur, advantage is notable.
Operation and chemotherapy are also used for pheochromocytoma treatment at present.But owing to pheochromocytoma is often pressed close to big blood vessel, Operation easily causes massive hemorrhage lethal, and postoperative easily stays remaining stove, and causes recurrence, therefore there is certain operative mortality.And change The specificity treated is weak, and toxic and side effects is big.But,131I-MIBG, both can be qualitative due to its isotopic tagging performance of its uniqueness, again may be used Location, strengthens radioactive dosage and can be additionally used in the treatment of pheochromocytoma, highly sensitive, high specificity, thus than other method More welcome by clinic.
131I-MIBG includes for Adrenal medullary imaging: the level diagnosis of (1) pheochromocytoma, determines pernicious thin addicted to chromium The position of born of the same parents' tumor metastasis stove and scope；(2) pheochromocytoma Postoperative Residual focus or the detection of recurrent focus；(3) adrenal gland's marrow The auxiliary diagnosis of matter hypertrophy；(4) CT or ultrasonoscopy have suspicious Adrenal lesion need to further provide for lesion nature and function State person；(5) malignant pheochromocytoma131Follow-up observation after I-MIBG treatment；(6) neuroblastoma, paraganglioma And the auxiliary diagnosis of metastatic lesion；(7) Differential Diagnosis of unknown cause hypertension etc..
131I-MIBG includes for the treatment of adrenal gland neoplasms: (1) can not the pheochromocytoma of excision；(2) operation Rear tumors remaining focus and prophylactic postoperative treatment；(3) transitivity pheochromocytoma；(4) malignant nerve blastoma and taking the photograph Take131Other neuroendocrine tumors of I-MIBG, such as thyroid sample cancer, carcinoid, chemoreceptor etc..
Owing to having safety, noinvasive, sensitive and special,131I-MIBG was recommended for pernicious addicted to chromium in 1980 Glucagonoma, the localization diagnosis of neuroblastoma, nineteen eighty-three is used for clinical treatment, its treatment malignant pheochromocytoma of result Effective percentage reaches more than 50%.Heavy dose of131I-MIBG also can effectively treat, and reduces gross tumor volume, controls being adapted to operation Treat.
At present, meta iodobenzyl guanidine sulfate is synthesis131The important source material of I-MIBG, the earliest by Donald M.W in 1980 Report the method being Material synthesis meta iodobenzyl guanidine sulfate with 3-iodine benzylamine, but raw material 3-iodine benzylamine price, it is difficult to expand Produce.1986, domestic report with m-toluidines for initiation material synthesize between iodine benzyl bromine, then will between iodine benzyl bromine and nitroguanidine Prepare meta iodobenzyl guanidine salt by ullmann reaction, finally prepare target compound meta iodobenzyl guanidine sulfate.
Summary of the invention
It is an object of the invention to provide a kind of meta iodobenzyl guanidine sulfate to prepare131The method of I-MIBG.
For achieving the above object, the present invention is by the following technical solutions:
On the one hand, the present invention provides one to prepare131The method of I-MIBG, comprises the steps: meta iodobenzyl guanidine sulphuric acid Salt, stannous sulfate, reducing agent, copper sulfate and Na131I puts in boiling water bath and heats, and reaction stands after terminating, Aspirate supernatant, mistake Microporous filter membrane, obtains label131I-MIBG, described reducing agent is selected from sodium thiosulfate and/or sodium sulfite.
Preferably, described reducing agent is selected from sodium thiosulfate and sodium sulfite.
It is furthermore preferred that the mol ratio of described sodium thiosulfate and sodium sulfite is 1:1.
Preferably, the consumption of described sodium thiosulfate and/or sodium sulfite is 0.1mmol.
Preferably, the weight ratio of described meta iodobenzyl guanidine sulfate, stannous sulfate and copper sulfate is 1:(0.1-1): (0.1- 1)。
It is furthermore preferred that the weight ratio of described meta iodobenzyl guanidine sulfate, stannous sulfate and copper sulfate is 1: 0.5:0.43.
Preferably, described Na131The radioactivity of I is about 1-10mCi.
It is furthermore preferred that described Na131The radioactivity of I is about 5mCi.
Preferably, the aperture of described microporous filter membrane is 0.22 μm.
On the other hand, the present invention also provides for a kind of using any of the above-described method to prepare131I-MIBG。
The invention have the advantages that:
It is surprising that through repeated tests, present inventors have unexpectedly found that, use sodium thiosulfate and/or sulfurous Acid sodium, as reducing agent Marking MIBG sulfate, prepares131I-MIBG radiochemical purity is high, and good stability is put After putting 48 hours, radiochemical purity is still in higher level.
Detailed description of the invention
Below in conjunction with embodiment, the present invention is further described, but embodiments of the present invention are not limited to this.Under State the experimental technique used in embodiment if no special instructions, be conventional method.
One, the synthesis of meta iodobenzyl guanidine sulfate
1) synthesis of N-(3-iodine benzyl) phthalimide (A)
Weigh 3-iodine benzyl bromine 2.61g (8.8mmol), after dissolving with 30mL anhydrous propanone, add potassium phthalimide 1.66g (9mmol), stirs lower 50 DEG C of water-bath back flow reaction 27 hours, and filtered while hot (avoids solid to separate out), and filtrate water-bath rotates It is evaporated to dryness, solid dehydrated alcohol recrystallization, obtains white needle form crystals (A) 1.3g, yield 41.1%, m.p.145-149 ℃。
2) synthesis of iodine benzylamine hydrochloride (B) between
Weigh (A) 2.0g (5.6mmol), add dehydrated alcohol 20mL, after being heated to 60 DEG C of dissolvings, the most gradually drip Add hydrazine hydrate ethanol solution (be dissolved in 3mL dehydrated alcohol by 0.42g, 8.4mmol hydrazine hydrate and be made into).Insulated and stirred is reacted 20min, has yellow mercury oxide to generate, and stops stirring, and after 70 DEG C of water-baths keep 2.5h, being cooled to RT has a large amount of yellow mercury oxide to separate out.To Reaction bulb adds the hydrochloric acid solution 4mL acidified reaction mixture of 1mol/L, stirs 30min, sucking filtration, be washed with a small amount filter Slag；Merging filtrate, reduction vaporization is concentrated to dryness, vacuum drying, obtains yellow solid (B) 0.539g, yield 35.9%, m.p.184-188℃。
3) synthesis of meta iodobenzyl guanidine bicarbonate (C)
Weigh the lower oil bath of (B) 539mg (2.0mmol) and cyanamide 127mg (3.0mmol) stirring and be heated to 100 DEG C, molten Keep 8 hours under state, be cooled to RT, after the 1mL that adds water dissolves, add potassium bicarbonate 200mg (2.0mmol) and be dissolved in 1mL water, 626mg white solid, yield 92.9%, m.p.124-126 DEG C.
4) preparation of meta iodobenzyl guanidine sulfate (D)
Weigh (C) 539mg (1.6mmol) to be suspended in 5mL water, the sulphuric acid 0.8mL (1.6mmol) of dropping 2mol/L, add Heat is all dissolved, and is cooled to room temperature, separates out white solid, sucking filtration, obtains 515mg, and solid second alcohol and water recrystallization obtains 472mg, receives Rate 91.2%, m.p166-167 DEG C.
Two, prepared by Marking MIBG sulfate131I-MIBG
Embodiment 1: be sequentially added into meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, thiosulfuric acid in teat glass Sodium 0.1mmol, copper sulfate 0.43mg and radioactivity are the Na of 5mCi131I solution, puts in boiling water bath and heats 30 minutes, take It is put into after going out in beaker, stands 30 seconds, Aspirate supernatant, cross 0.22 μm filter membrane, obtain label131I-MIBG。
Embodiment 2: be sequentially added into meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, sodium sulfite in teat glass 0.1mmol, copper sulfate 0.43mg and radioactivity are the Na of 5mCi131I solution, puts in boiling water bath and heats 30 minutes, takes out After be put in beaker, stand 30 seconds, Aspirate supernatant, cross 0.22 μm filter membrane, obtain label131I-MIBG。
Embodiment 3: be sequentially added into meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, thiosulfuric acid in teat glass Sodium 0.05mmol, sodium sulfite 0.05mmol, copper sulfate 0.43mg and radioactivity are the Na of 5mCi131I solution, puts into boiling Water-bath is heated 30 minutes, is put into after taking-up in beaker, stands 30 seconds, Aspirate supernatant, cross 0.22 μm filter membrane, obtain labelling Thing131I-MIBG。
Comparative example: be sequentially added into meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, vitamin in teat glass C0.1mmol, copper sulfate 0.43mg and radioactivity are the Na of 5mCi131I solution, puts in boiling water bath and heats 30 minutes, take It is put into after going out in beaker, stands 30 seconds, Aspirate supernatant, cross 0.22 μm filter membrane, obtain label131I-MIBG。
Three,131I-MIBG radiochemical purity measures and study on the stability
Experiment material: using thin layer chromatography (TLC) method, holder is polyamide film, and developing solvent is dual system: system is 1. Developing solvent be ethyl acetate: ethanol=1:1 (V/V), system developing solvent 2. is normal propyl alcohol: 10% ammonia=3:1 (V/V), Polyamide film cuts into the chromatography strip of 0.5*10cm specification, and it is deep that developing solvent is placed in test tube about 0.5cm.
Experimental technique and result: the marked product of Example 1-3 and comparative example uses capillary tube point sample in polyamide in right amount Thin film one end (distance chromatography strip edge about 1cm), treats that point sample evaporates into naturally in about 1 minute dry, puts into developing solvent at point sample down In saturated test tube, close the lid.Respectively with ethyl acetate: ethanol=1:1 (V/V) and normal propyl alcohol: 10% ammonia=3:1 (V/ V) as developing solvent, launch according to ascending chromatography.To be deployed dose when being expanded to the about 0.5cm away from forward position, is taken out chromatography strip, naturally waves Send to do.
Result shows, 1. ethyl acetate: ethanol=1:1 (V/V) is that each spot and R f value of developing solvent is:131I-MIBG 0.0, free-iodine 0.6.2. developing solvent is normal propyl alcohol: 10% ammonia=3:1 (V/V), and each spot and R f value for developing solvent is:131I- MIBG0.15, to iodine benzylamine 0.35, free-iodine 0.75.
Chromatography strip averagely cuts into 10 parts by the development distance of developing solvent, is respectively put into γ-counting, measures with γ-count Radiocounting, draws in embodiment 1-3 and comparative example free-iodine and to iodine benzylamine purity according to following computing formula, and counts Calculate131I-MIBG radiochemical purity (is shown in Table 1).
Activity meter digit rate summation * 100% of the activity meter digit rate/system one of free-iodine (%)=free-iodine
Activity meter digit rate summation * 100% to iodine benzylamine (%)=to the activity meter digit rate/system two of iodine benzylamine
131I-MIBG (%)=100%-(free-iodine (%)+to iodine benzylamine (%))
Table 1131I-MIBG radiochemical purity is investigated
Sample Embodiment 1 Embodiment 2 Embodiment 3 Comparative example
131I-MIBG radiochemical purity 94.8% 95.4% 98.1% 90.5%
The marked product room temperature of embodiment 1-3 and comparative example will be placed, and respectively at 1h, 4h, 8h, 12h, 24h, 36h And 48h, measure its mark rate with above-mentioned TLC method, investigate131The time dependent radiochemicsl purity of I-MIBG, concrete outcome such as table 2。
Table 2131I-MIBG study on the stability (n=5)
Time 1h 4h 8h 12h 24h 36h 48h
Embodiment 1 94.8% 94.8% 94.5% 94.4% 94.1% 93.9% 93.2%
Embodiment 2 95.4% 95.4% 95.1% 95.0% 94.8% 94.4% 93.7%
Embodiment 3 98.1% 98.1% 97.9% 97.8% 97.8% 97.6% 97.1%
Comparative example 90.5% 90.5% 90.1% 90.1% 89.8% 87.3% 85.4%
From table 1-2, the meta iodobenzyl guanidine sulfate prepared by the present invention is being configured to131After I-MIBG, put in 24 hours Penetrating property purity is almost unchanged, has good stability.Prepare as reducing agent especially with sodium thiosulfate and sodium sulfite131I-MIBG radiochemical purity is higher than preparing using vitamin C as reducing agent131I-MIBG, and its place 24 hours with After stability more preferable, wherein prepare with embodiment 3 method131I-MIBG place after 48 hours radiochemical purity still up to To 97.1%, create unforeseeable excellent effect.

Claims (10)

1. prepare for one kind131The method of I-MIBG, comprises the steps: meta iodobenzyl guanidine sulfate, stannous sulfate, reducing agent, sulfur Acid copper and Na131I puts in boiling water bath and heats, and reaction stands after terminating, and Aspirate supernatant is crossed microporous filter membrane, obtained label131I-MIBG, it is characterised in that described reducing agent is selected from sodium thiosulfate and/or sodium sulfite.
Method the most according to claim 1, it is characterised in that described reducing agent is selected from sodium thiosulfate and sodium sulfite.
Method the most according to claim 2, it is characterised in that the mol ratio of described sodium thiosulfate and sodium sulfite is 1: 1。
4. according to the method described in any one of claim 1-3, it is characterised in that described sodium thiosulfate and/or sodium sulfite Consumption be 0.1mmol.
Method the most according to claim 1, it is characterised in that described meta iodobenzyl guanidine sulfate, stannous sulfate and copper sulfate Weight ratio be 1:(0.1-1): (0.1-1).
Method the most according to claim 5, it is characterised in that described meta iodobenzyl guanidine sulfate, stannous sulfate and copper sulfate Weight ratio be 1:0.5:0.43.
Method the most according to claim 1, it is characterised in that described Na131The radioactivity of I is about 1-10mCi.
Method the most according to claim 7, it is characterised in that described Na131The radioactivity of I is about 5mCi.
Method the most according to claim 1, it is characterised in that the aperture of described microporous filter membrane is 0.22 μm.
10. any one of claim 1-9 method prepares131I-MIBG。
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