CN106187823B - A kind of method for preparing meta iodobenzyl guanidine - Google Patents
A kind of method for preparing meta iodobenzyl guanidine Download PDFInfo
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- CN106187823B CN106187823B CN201610518107.4A CN201610518107A CN106187823B CN 106187823 B CN106187823 B CN 106187823B CN 201610518107 A CN201610518107 A CN 201610518107A CN 106187823 B CN106187823 B CN 106187823B
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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
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- 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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- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract
It is prepared the present invention relates to a kind of131The method of I MIBG, includes the following steps：By meta iodobenzyl guanidine sulfate, stannous sulfate, reducing agent, copper sulphate and Na131I is put into boiling water bath and heats, and stands after reaction, Aspirate supernatant, crosses miillpore filter to obtain the final product.The present invention, as reducing agent Marking MIBG sulfate, is prepared using sodium thiosulfate and/or sodium sulfite131I MIBG radiochemical purities are high, and stability is good, and radiochemical purity is still in higher level after placing 48 hours.
Description
Technical field
The present invention relates to radiopharmaceutical fields, and in particular to a kind of preparation method of meta iodobenzyl guanidine.
Background technology
It is a kind of tumour of secreting hormone positioned at adrenal pheochromocytoma, there is adrenal medella, in high blood
It presses in patient, 0.6%-1.0% is as caused by pheochromocytoma.The long-term hypertension of patient Ke Yin causes the serious heart, brain, kidney
It damages or happens suddenly serious secondary hypertension, and threat to life.Adrenal medella lesion mainly includes：Pheochromocytoma and marrow
Matter hyperplasia is clinically mainly shown as paroxysmal or duration hypertension.It is different from essential hypertension, by adrenal medella disease
Hypertension caused by becoming, as long as surgically after removal of lesions, the blood pressure of Most patients can restore normal, therefore early diagnosis
Disconnected, early treatment can then cure secondary hypertension disease.
Meta iodobenzyl guanidine (metaiodobenzylguanidine, MIBG, molecular formula C8H10IN3) it is a kind of adrenaline
Energy antipsychotic drugs, it is similar to norepinephrine structure, it can be by medullary epithelium, neuron tumor uptake.Clinically using putting
The imaging of injectivity isotope iodine label and cytotoxicity, will131I- meta iodobenzyl guanidines (131I-MIBG it) swells for neural crest origin
Knurl, such as malignant nerve ridge knurl, carcinoid tumor, neuroblastoma, pheochromocytoma, Chromaffionoma and thyroid gland hyloma etc.
Diagnose and treat.
Method currently used for pheochromocytoma inspection diagnosis has：CT, B ultrasound, vanilmandelic acid measure and131I-MIBG
Radiography imaging etc..Wherein, B ultrasound can only detect the tumour that adrenal gland interior diameter is more than 2 centimetres；CT for tumour etiologic diagnosis with
And whole body dystopy or the positive rate of transfer stove diagnosis are only 70%；Whether the biochemical measurement of VMA can only prompt to have different in urine
It often, can not lesion.However,131The reachable 97.1%-100% of specificity of I-MIBG adrenal medellas scanning, and not
There is false positive rate, advantage is notable.
Operation and chemotherapy are also used for pheochromocytoma treatment at present.But due to pheochromocytoma often with big blood vessel close to,
It is lethal that operation easily causes massive haemorrhage, and it is postoperative easily stay remaining stove, and cause recurrence, therefore there are certain operative mortality rates.And change
The specificity for the treatment of is weak, and toxic side effect is big.However,131I-MIBG, not only can be qualitative due to its its unique isotopic tagging performance, but also can
Positioning increases radioactive dosage and can be additionally used in the treatment of pheochromocytoma, high sensitivity, high specificity, thus than other methods
More welcome by clinic.
131I-MIBG includes for Adrenal medullary imaging：(1) level diagnosis of pheochromocytoma determines that pernicious thermophilic chromium is thin
The position of born of the same parents' tumor metastasis stove and range；(2) detection of pheochromocytoma Postoperative Residual lesion or recurrent focus；(3) adrenal gland marrow
The auxiliary diagnosis of matter hyperplasia；(4) CT or ultrasonoscopy have suspicious Adrenal lesion that need to further provide for lesion nature and function
State person；(5) malignant pheochromocytoma131Follow-up observation after I-MIBG treatments；(6) neuroblastoma, paraganglioma
And its auxiliary diagnosis of metastatic lesion；(7) antidiastole of unknown cause hypertension etc..
131I-MIBG includes for the treatment of adrenal tumor：(1) cannot perform the operation the pheochromocytoma of excision；(2) it performs the operation
Tumors remaining lesion and prophylactic postoperative treatment afterwards；(3) metastatic pheochromocytoma；(4) it malignant nerve blastoma and can take the photograph
It takes131Other neuroendocrine tumors of I-MIBG, such as thyroid gland sample cancer, class cancer, chemocepter.
It is safe, noninvasive, sensitive and special due to having the characteristics that,131I-MIBG was recommended for pernicious thermophilic chromium in 1980
The localization diagnosis of cytoma, neuroblastoma, nineteen eighty-three are used for clinical treatment, and as a result it treats malignant pheochromocytoma
Effective percentage is up to more than 50%.Large dosage131I-MIBG also can be treated effectively, reduced gross tumor volume, controlled with being adapted to operation
It treats.
At present, meta iodobenzyl guanidine sulfate is synthesis131The important source material of I-MIBG, earliest by Donald M.W in 1980
Report the method using 3- iodine benzylamine as Material synthesis meta iodobenzyl guanidine sulfate, but raw material 3- iodine benzylamine prices, it is difficult to expand
Production.1986, the country report using m- toluidines as starting material synthesize between iodine benzyl bromine, then will between iodine benzyl bromine and nitroguanidine
Meta iodobenzyl guanidine salt is prepared by ullmann reaction, target compound meta iodobenzyl guanidine sulfate is finally prepared.
Invention content
The object of the present invention is to provide a kind of preparations of meta iodobenzyl guanidine sulfate131The method of I-MIBG.
To achieve the above object, the present invention uses following technical scheme：
On the one hand, the present invention provides a kind of prepare131The method of I-MIBG, includes the following steps：By meta iodobenzyl guanidine sulfuric acid
Salt, stannous sulfate, reducing agent, copper sulphate and Na131I is put into boiling water bath and heats, and stands after reaction, Aspirate supernatant, mistake
Miillpore filter is to get marker131I-MIBG, the reducing agent are selected from sodium thiosulfate and/or sodium sulfite.
Preferably, the reducing agent is selected from sodium thiosulfate and sodium sulfite.
It is furthermore preferred that the molar ratio of the sodium thiosulfate and sodium sulfite is 1：1.
Preferably, the dosage of the sodium thiosulfate and/or sodium sulfite is 0.1mmol.
Preferably, the weight ratio of the meta iodobenzyl guanidine sulfate, stannous sulfate and copper sulphate is 1：(0.1-1)：(0.1-
1)。
It is furthermore preferred that the weight ratio of the meta iodobenzyl guanidine sulfate, stannous sulfate and copper sulphate is 1: 0.5：0.43.
Preferably, the Na131The radioactive activity of I is about 1-10mCi.
It is furthermore preferred that the Na131The radioactive activity of I is about 5mCi.
Preferably, the aperture of the miillpore filter is 0.22 μm.
On the other hand, it is prepared the present invention also provides a kind of using any of the above-described method131I-MIBG。
The invention has the advantages that：
It is surprising that by repeated tests, present inventors have unexpectedly found that, using sodium thiosulfate and/or sulfurous
Sour sodium is prepared as reducing agent Marking MIBG sulfate131I-MIBG radiochemical purities are high, and stability is good, puts
Radiochemical purity is still in higher level after putting 48 hours.
Specific embodiment
The present invention is further described, but the implementation of the present invention is not limited to this with reference to embodiment.Under
It states experimental method used in embodiment unless otherwise specified, is conventional method.
First, the synthesis of meta iodobenzyl guanidine sulfate
1) synthesis of N- (3- iodine benzyl) phthalimide (A)
3- iodine benzyl bromine 2.61g (8.8mmol) are weighed, after being dissolved with 30mL anhydrous propanones, add in potassium phthalimide
1.66g (9mmol), stirs lower 50 DEG C of water-bath back flow reactions 27 hours, filters (solid is avoided to be precipitated) while hot, filtrate water-bath rotation
It is evaporated to dryness, solid is recrystallized with absolute ethyl alcohol, obtains white needle form crystals (A) 1.3g, yield 41.1%, m.p.145-149
℃。
2) synthesis of iodine benzylamine hydrochloride (B) between
(A) 2.0g (5.6mmol) is weighed, adds in absolute ethyl alcohol 20mL, after being heated to 60 DEG C of dissolvings, is gradually dripped under stiring
Add hydrazine hydrate ethanol solution (by 0.42g, 8.4mmol hydrazine hydrates are dissolved in 3mL absolute ethyl alcohols and are made into).Insulated and stirred is reacted
20min has yellow mercury oxide generation, stops stirring, and after 70 DEG C of water-baths keep 2.5h, being cooled to RT has a large amount of yellow mercury oxides to be precipitated.To
The hydrochloric acid solution 4mL acidified reaction mixtures of 1mol/L are added in reaction bulb, stir 30min, filters, filter is washed with a small amount
Slag；Merging filtrate, reduction vaporization are concentrated to dryness, and vacuum drying obtains yellow solid (B) 0.539g, yield 35.9%,
m.p.184-188℃。
3) synthesis of meta iodobenzyl guanidine bicarbonate (C)
The lower oil bath heating of (B) 539mg (2.0mmol) and cyanamide 127mg (3.0mmol) stirrings is weighed to 100 DEG C, molten
It is kept for 8 hours under state, is cooled to RT, after water 1mL is added to dissolve, added in saleratus 200mg (2.0mmol) and be dissolved in 1mL water, obtain
626mg white solids, yield 92.9%, m.p.124-126 DEG C.
4) preparation of meta iodobenzyl guanidine sulfate (D)
It weighs (C) 539mg (1.6mmol) to be suspended in 5mL water, the sulfuric acid 0.8mL (1.6mmol) of 2mol/L is added dropwise, adds
Hot all dissolvings, are cooled to room temperature, white solid are precipitated, filter, and obtain 515mg, and solid is recrystallized with second alcohol and water, obtains 472mg, is received
Rate 91.2%, m.p166-167 DEG C.
2nd, prepared by Marking MIBG sulfate131I-MIBG
Embodiment 1：Meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, thiosulfuric acid are sequentially added into teat glass
Sodium 0.1mmol, copper sulphate 0.43mg and the Na that radioactive activity is 5mCi131I solution is put into boiling water bath and heats 30 minutes, takes
It is put into beaker after going out, stands 30 seconds, Aspirate supernatant crosses 0.22 μm of filter membrane to get marker131I-MIBG。
Embodiment 2：Meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, sodium sulfite are sequentially added into teat glass
0.1mmol, copper sulphate 0.43mg and the Na that radioactive activity is 5mCi131I solution is put into boiling water bath and heats 30 minutes, takes out
After be put into beaker, stand 30 seconds, Aspirate supernatant, cross 0.22 μm of filter membrane to get marker131I-MIBG。
Embodiment 3：Meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, thiosulfuric acid are sequentially added into teat glass
Sodium 0.05mmol, sodium sulfite 0.05mmol, copper sulphate 0.43mg and the Na that radioactive activity is 5mCi131I solution is put into boiling
It heats 30 minutes in water-bath, is put into beaker after taking-up, stand 30 seconds, Aspirate supernatant crosses 0.22 μm of filter membrane to get label
Object131I-MIBG。
Comparative example：Meta iodobenzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, vitamin are sequentially added into teat glass
C0.1mmol, copper sulphate 0.43mg and the Na that radioactive activity is 5mCi131I solution is put into boiling water bath and heats 30 minutes, takes
It is put into beaker after going out, stands 30 seconds, Aspirate supernatant crosses 0.22 μm of filter membrane to get marker131I-MIBG。
3rd,131I-MIBG radiochemical purities measure and study on the stability
Experiment material：Using thin-layer chromatography (TLC) method, support is polyamide film, and solvent is dual system：System is 1.
Solvent be ethyl acetate：Ethyl alcohol=1:1 (V/V), the solvent of system 2. are normal propyl alcohol：10% ammonium hydroxide=3:1 (V/V),
Polyamide film is cut into the chromatography strip of 0.5*10cm specifications, solvent is placed in test tube about 0.5cm depths.
Experimental method and result：Example 1-3 and the marked product of comparative example are in right amount with capillary point sample in polyamide
Film one end (apart from chromatography strip edge about 1cm), it is dry to treat that point sample evaporates into naturally in about 1 minute, is put into solvent at point sample downward
In the test tube of saturation, close the lid.Respectively with ethyl acetate：Ethyl alcohol=1:1 (V/V) and normal propyl alcohol：10% ammonium hydroxide=3:1(V/
V) as solvent, it is unfolded according to ascending chromatography.To be deployed dose when being expanded to away from forward position about 0.5cm, is taken out chromatography strip, waved naturally
It is sent to dry.
The results show that 1. ethyl acetate：Ethyl alcohol=1:1 (V/V) is that each spot and R f value of solvent is：131I-MIBG
0.0, free-iodine 0.6.2. solvent is normal propyl alcohol：10% ammonium hydroxide=3:1 (V/V), each spot and R f value for being solvent are：131I-
MIBG0.15, to iodine benzylamine 0.35, free-iodine 0.75.
Chromatography strip averagely cuts into 10 parts by the development distance of solvent, is respectively put into γ-counting, is measured with γ-count
Radiocounting obtains in embodiment 1-3 and comparative example free-iodine and to iodine benzylamine purity, and count according to following calculation formula
It calculates131I-MIBG radiochemical purities (are shown in Table 1).
The activity meter digit rate summation * 100% of activity meter digit rate/system one of free-iodine (%)=free-iodine
To iodine benzylamine (%)=to the activity meter digit rate summation * 100% of activity meter digit rate/system two of iodine benzylamine
131I-MIBG (%)=100%- (free-iodine (%)+to iodine benzylamine (%))
Table 1131I-MIBG radiochemical purities are investigated
| Sample | Embodiment 1 | Embodiment 2 | Embodiment 3 | Comparative example |
| 131I-MIBG radiochemical purities | 94.8% | 95.4% | 98.1% | 90.5% |
The marked product of embodiment 1-3 and comparative example will be placed at room temperature for, and respectively 1h, 4h, 8h, 12h, for 24 hours, 36h
And 48h, its mark rate is measured in above-mentioned TLC methods, is investigated131The radiochemicsl purity that I-MIBG is changed over time, 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% |
As table 1-2 it is found that 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.It is prepared especially with sodium thiosulfate and sodium sulfite as reducing agent131I-MIBG radiochemical purities are higher than what is prepared using vitamin C as reducing agent131I-MIBG, and its place 24 hours with
Stability afterwards is more preferable, wherein prepared in 3 method of embodiment131Radiochemical purity is still reachable after I-MIBG is placed 48 hours
To 97.1%, unexpected excellent effect is produced.
Claims (3)
1. a kind of prepare131The method of I-MIBG, which is characterized in that include the following steps：Iodine is sequentially added into teat glass
Benzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, sodium thiosulfate 0.1mmol, copper sulphate 0.43mg and radioactive activity are 5mCi
Na131I solution is put into boiling water bath and heats 30 minutes, is put into beaker after taking-up, stands 30 seconds, Aspirate supernatant, mistake
0.22 μm of filter membrane is to get marker131I-MIBG。
2. a kind of prepare131The method of I-MIBG, which is characterized in that include the following steps：Iodine is sequentially added into teat glass
Benzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, sodium sulfite 0.1mmol, copper sulphate 0.43mg and radioactive activity are 5mCi's
Na131I solution is put into boiling water bath and heats 30 minutes, is put into beaker after taking-up, stands 30 seconds, and Aspirate supernatant crosses 0.22 μ
M filter membranes are to get marker131I-MIBG。
3. a kind of prepare131The method of I-MIBG, which is characterized in that include the following steps：Iodine is sequentially added into teat glass
Benzyl guanidine sulfate 1mg, stannous sulfate 0.5mg, sodium thiosulfate 0.05mmol, sodium sulfite 0.05mmol, copper sulphate 0.43mg
And the Na that radioactive activity is 5mCi131I solution is put into boiling water bath and heats 30 minutes, is put into beaker after taking-up, stands 30
Second, Aspirate supernatant crosses 0.22 μm of filter membrane to get marker131I-MIBG。
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| CN101137326B (en) * | 2003-12-01 | 2010-10-20 | 医疗物理有限公司 | Adrenergic imaging agent and its uses and related kit |
| CN100404131C (en) * | 2005-08-17 | 2008-07-23 | 中国石油天然气股份有限公司 | Preparation method of silicon-copper contact for synthesizing organic chlorosilane |
| CN100408234C (en) * | 2005-10-27 | 2008-08-06 | 中南大学 | Production of cuprous oxide powder and bronze powder using sulfur dioxide reduction method |
| CN100431699C (en) * | 2006-05-23 | 2008-11-12 | 淮海工学院 | Activated carbon carried cuprous iodide catalyst, and its preparing method and use |
| CN104761421B (en) * | 2014-01-06 | 2018-01-16 | 江苏省原子医学研究所 | A kind of carrier-free [* X] MXBG preparation method |
| CN103908684B (en) * | 2014-01-24 | 2017-02-15 | 江苏省原子医学研究所 | Drug box for labeling carrier-free [＜*＞I] metaiodobenzylguanidine (MIBG) and preparation method thereof |
| CN104496856A (en) * | 2014-12-22 | 2015-04-08 | 北京智博高科生物技术有限公司 | Preparation method of metaiodobenzylguanidine (MIBG) sulphate |
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