CN1013860B - Ether isonitriles and radiolabeled complexes thereof - Google Patents
Ether isonitriles and radiolabeled complexes thereofInfo
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- CN1013860B CN1013860B CN 86108714 CN86108714A CN1013860B CN 1013860 B CN1013860 B CN 1013860B CN 86108714 CN86108714 CN 86108714 CN 86108714 A CN86108714 A CN 86108714A CN 1013860 B CN1013860 B CN 1013860B
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Abstract
Ether-substituted isonitriles, Tc99m complexes thereof, and processes for myocardial tissue radioimaging using the Tc99m complexes.
Description
The present invention relates to novel ether-substituted isocyanide, i.e. the radiolabeled complexes of these isonitrile and the isonitrile radiolabeled complexes is used for the method that cardiac muscle videotapes.
People such as Jones have narrated the application that various radioactivity isocyanide complex and conduct thereof videotape agent in the 4th, 452, No. 774 patents of the U.S. of publishing on June 5th, 1984.The general formula of the title complexs that the people narrated such as Jones is:
A is the radioactive nuleus that is selected from radio isotope Tc, Ru, Co, Pt, Fe, Os, Ir, W, Re, Cr, Mo, Mn, Ni, Rh, Pd, Nb and Ta in the formula, for example,
99mTc,
99Tc,
97Ru,
51Cr,
57Co,
188Re and
191Os;
(CN)
XR is by the isonitrile of the carbon atom of CN base and radioactive nuleus bonding-close ligand or isonitrile multidentate ligand; R is an organic radical; B and B ' are that being selected from for present technique field professional separately from other is the well-known ligand that generates isocyanide complex, comprising water, chlorine and bromo and comprise one or more donor atoms that can form key with above-mentioned radioactive nuleus; X and Y are by 1 to 8 integer separately; Z and Z ' respectively do for oneself 0 or by 1 to 7 integer; But (XY)+Z+Z ' must be less than or equal to 8; And n represents the valence mumber of title complex, and this valence mumber can equal the 0(electric neutrality) or positive and negative integer, the concrete valence mumber of title complex then depends on the charge number of valence state and R, B and the B ' of A.If when this title complex was prepared to be used for drug disposition, then the existence of any needed counter ion can be determined by the needs of the electric charge on the title complex, still, these counter ions must be the acceptable ions of medicine.
In above-mentioned general formula, R can be aliphatics or aromatic organic radical, and can replace various charged or uncharged bases.When on the above-mentioned organic radical R charged substituting group being arranged, then form charge number on the title complex and be the summation of the charge number of the charge number of ligand (R, B and B ') and radioactive nuleus.The aromatic base R that can exist is phenyl, tolyl, xylyl, naphthyl, phenylbenzene and has substituent aromatic base, and the substituting group on this substituted aromatic base can comprise and resembles halogen, for example, chloro, bromo, iodo or fluorine-based; Hydroxyl, nitro, alkyl, alkoxyl group etc.; The fatty group R that can exist is alkyl, preferably contains the alkyl of 1 to 20 carbon atom, for example, and methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, n-hexyl, 2-ethylhexyl, dodecyl, octadecyl etc.Substituting group on the fatty group can comprise with above-mentioned substituted aroma goes up identical substituting group substantially.
People such as Jones think that title complex that they narrated can be used for thrombus, research pulmonary function, the research renal excretion at the lung observing cardiovascular, check the hemoperfusion shortage and relevant position thereof and takes marrow and hepatobiliary system.
In fact, the technetium complexes of the simple hydrocarbons isonitrile that people such as Jones recommend, for example, tert-butyl isonitrile, liver and the concentration in the lung that has proved the people high slightly (people such as Holman, J.Nucl, Med., 25,1380(1984)).The too early high density of radioactive nuleus requires to postpone the shooting of heart in the lung, so that made the lung functional recovery normal before useful cardiac muscle picture is got in bat.In addition, the concentration height of radioactive nuleus in the liver makes the perfusion shortage of checking position, myocardium tip difficult more.Obviously, need the preparation that the higher cardiac muscle of a kind of selectivity videotapes.
The purpose of this invention is to provide novel ether-substituted isocyanide and diagnostic preparation (diagnostickits), the radiolabeled complexes (preferably Tc99m) of these isonitrile and the diagnostic method of application of radiation title complex.Though people such as Jones are in the U.S. the 4th, 452, the general formula of No. 774 patent disclosures has comprised the isocyanide complex that radiolabeled, ether of the present invention replaces, but concrete openly title complex, people such as the Jones compelling superior characteristic that videotapes also not imagining these ether-substituted isocyanides and had simultaneously resemble the present invention.
More specifically, a content of the present invention provides a kind of novel ether-substituted isocyanide (and preparation) of formula I:
In the formula: A is that straight or branched alkyl and R are the straight or branched alkyl, condition is that the total number of carbon atoms that A adds R equals 4 to 6, another condition is that first carbon atom that is connected with the isonitrile base is a quaternary carbon atom when the total number of carbon atoms that A adds R equals 6, and another condition is that A is not (CH
2)
3
Another content of the present invention relates to these general formulas and is (M(CN-A-O-R)
6) the novel radiolabeled complexes of ether isonitriles, M is a radioactive nuleus in the formula, preferably Tc99m.Another content of the present invention relates to these radio-labeling isocyanide complex videotape agent as cardiac muscle application.
A kind of alkoxylamine formylation of general formula II is generated corresponding methane amide III, is the isonitrile I with its dehydration then, can easily prepare isonitrile of the present invention.
The method that various formylations and dehydration reaction are arranged in the document, these methods all are very familiar to for the professional of organic synthesis.
The amine II can prepare with the whole bag of tricks that those skilled in the art know.Especially can under the situation that has an acidic catalyst to exist, with the open loop of aziridine IV, generate the mixture of the isolating amine V of available distillating method and two kinds of amine of amine VI with a kind of alcohol.
On the other hand, amine can prepare with the alkoxy ester VII, and wherein A ' is the hydrocarbon of 2 or 3 carbon atoms.Alkoxy ester VII and ammonia or ammonium hydroxide reacted generates the acid amides VIII, comes reducing amide can make the amine IX with lithium aluminium hydride or the another kind of reductive agent of knowing then.
The also available alkoxy ester X of amine II prepares.Can generate the acid amides XI by above-mentioned steps.XI is carried out hofmann rearrangement can produce the amine II.
On the other hand, can with the amino alcohol XII at first with a formylating agent, for example ethyl formate or arboxylic acid acid anhydride react, and form methane amide-manthanoate X III and prepare ether isonitriles.Can other methane amides be converted into the method for isonitrile by above-mentioned, methane amide-manthanoate is converted into isonitrile-manthanoate X IV.The appropriateness hydrolysis can produce isonitrile-pure X V, uses sodium hydride and methyl halide resembling then, methyl iodide for example, the standard alkylation conditions under with this isonitrile-pure X V alkylation.
In practice of the present invention, useful ether-substituted isocyanide comprises:
CNCH
2CH
2CH
2OCH
3;CNCH
2CH
2CH
2OCH
2CH
3
CNC（CH
3）
2OCH
2CH
3;CNC（CH
3）
2OCH
3;
CNCH
2C（CH
3）
2OCH
3;CNC（CH
3）
2CH
2OCH
3;
CNCH（CH
3）CH
2OCH
3;CNCH（CH
3）CH
2OCH
2CH
3;
CNCH
2CH（CH
3）OCH
3;CNCH
2CH（CH
3）OCH
2CH
3;
CNCH（CH
3）CH（CH
3）OCH
3;CNCH
2CH（CH
3）CH
2OCH
3;
CNCH
2CH
2CH（CH
3）OCH
3;CNCH
2CH
2OCH（CH
3）
2;
CNCH
2CH
2OCH
2CH
3;CNCH（CH
3）OCH（CH
3）
2;
CNCH
2CH（CH
2CH
3）OCH
3;CNCH（CH
2CH
3）CH
2OCH
3;
CNCH（CH
3）CH
2CH
2OCH
3;CNC（CH
3）
2CH
2CH
2OCH
3.
Details are as follows now will to prepare the specific examples of these ether-substituted isocyanides.
Preparation 1: synthetic 1-methoxyl group-2-methyl-propyl-2-amine and 2-methoxyl group-2-methyl-propyl-1-amine
A. Synthetic 2,2-dimethyl aziridine
In 2-amino-2-methyl-1-propanol (100 grams, 1.12 moles) water-soluble (200 milliliters), and place 1000 milliliters round-bottomed flask.With the vitriol oil (100 gram, 1.12 moles) water-soluble (200 milliliters) and add in the amine aqueous solution.The warm solution of gained is distilled under normal pressure.When temperature rises to 120 ℃, pressure is reduced to aspirator pressure (about 25 mmhg), the temperature that continues to be distilled to distillate reaches 150 ℃.The brown glue of gained placed under the vacuum (about 1 mmhg) and 170 °～200 ℃ heating 1.5 hours down.Some carbonizations are arranged, obtain a kind of solid.Flask is wrapped in the neonychium, and then flask is broken, abandon glass cullet.With mallet solid is smashed, being ground to major part with pestle then becomes fine powder, and wherein the diameter of particle is not more than 1/4 ".Solid is added in water (150 milliliters) solution that contains sodium hydroxide (100 grams, 2.5 moles).With brine bath suspension is heated to 110 ℃, solid promptly slowly dissolves and forms a kind of dark solution.Under 70～88 ℃, from then on product is distilled on the sodium hydrate particle (25 grams, 0.63 mole) in the solution.During to the distillation end, in container, formed a kind of precipitation of white.After filtering with glass fiber, remove water layer and with product sodium hydroxide drying, the sodium Metal 99.5 drying is used in filtration again.Under 70～73 ℃, product is distilled from sodium Metal 99.5, make the clear, colorless product (productive rate 58%) of 46.2 grams.
NMR（CHCl
3）：δ0.1（s，1H，NH）、1.25（s，6H，CH
3）、1.55（s，2H，CH
2）
B. synthetic 1-methoxyl group-2-methyl-propyl-2-amine and 2-methoxyl group-2-methyl-propyl-1-amine
With 2,2-dimethyl aziridine (27.68 grams, 0.39 mole) is dissolved in the new distillatory methyl alcohol (50 gram).This solution is cooled to-10 ℃ in ice/acetone bath.Be dissolved in the two methyl alcohol title complexs of boron trifluoride (58.32 grams, 0.44 mole) in the new distillatory methyl alcohol (50 milliliters) and in ice/acetone bath, be cooled to-10 ℃.Cooled boron trifluoride solution was slowly added in 20 minutes in the cooled aziridine solution.Make resulting solution rise to room temperature at leisure.At room temperature with solution stirring 7 days, and in the product generative process, detect with nucleus magnetic resonance.Liquor capacity is reduced to half of about original volume with rotary evaporation method (25 mmhg, 40 ℃).Add sodium methylate methyl alcohol (25%(w/w of 95.04 grams) solution, 0.594 mole) in solution and white precipitate.Add diethyl ether 300ml and filtering-depositing.Still muddy solution is distilled, and when temperature reaches 60 ℃, it is filtered again.Continue to distill and obtain the mixture (14.24 grams, 35%) of two kinds of amine.Carry out fractionation carefully, two kinds of amine are separated, can make pure 2-methoxyl group-2-methyl-propyl-1-amine (123～124 ℃ of boiling points), NMR(CDCl
3): δ 1.2(s, 8H, NH
2CH
3), 2.7(s, 2H, CH
2), 3.3(s, 3H, CH
3O) and 1-methoxyl group-2-methyl-propyl-2-amine (103～104 ℃ of boiling points), NMR(CDCl
3): δ 1.1(s, 6H, CH
3), 1.6(bs, 2H, NH
2), 3.1(s, 2H, CH
2), 3.4(s, 3H, CH
3O).
Preparation 2: Synthetic 2-methoxyl group-2-methyl-propyl-1-amine
A. Synthetic 2-methoxyl group-2 Methylpropionic acid methyl esters
Dimethyl formamide (100 milliliters) and tetrahydrofuran (THF) (300 milliliters) are placed 1000 milliliters of three mouthfuls of round-bottomed flasks that thermometer, mechanical stirrer and dropping funnel are housed.Add 80% the dispersion (19.80 grams, 0.66 mole) of sodium hydride in oil, form a kind of grey suspension.Suspension is cooled off in ice-water bath.Hydroxy-methyl isobutyl acid (70.8 gram, 0.60 mole) is dissolved in tetrahydrofuran (THF) (50 milliliters) and it is slowly added temperature keep below in 15 ℃ the cooling sodium hydride suspension.Resulting suspension was stirred one hour.The solution that contains methyl-iodide (new distillatory, 108.75 grams, 0.75 mole) in the tetrahydrofuran (THF) (25 milliliters) is slowly added in the cold suspension.Drip with 1.5 hours, temperature keeps below 15 ℃ in the dropping process.Stirred suspension also makes it rise to room temperature and keep 15 hours.In suspension impouring ethyl acetate (300 milliliters) and water (300 milliliters).Separate clear layer and extract water with ethyl acetate (300 milliliters).The organic layer that merges is decoloured with the water (200 milliliters) that contains sodium bisulfite (10 gram).Separate organic phase and carry out drying with sal epsom.Remove most solvent with rotatory evaporator (25 mmhg, 30 ℃).Under normal pressure, resulting solution is distilled and collection product under 137～146 ℃.Contain dimethyl formamide (DMF) in the product, but identify by nucleus magnetic resonance, the output of product is 48.8 grams (61%).
NMR(CHCl
3): δ 1.4(s, 6H, CH
3), 3.3(s, 3H, CH
3O ether), 3.8(s, 3H, CH
3The O ester).
B. Synthetic 2-methoxyl group-2-methyl propanamide
2-methoxyl group-2 Methylpropionic acid methyl esters (42.24 grams, 0.32 mole, and have 10.6 gram DMF) is added ammonium hydroxide (200 milliliters).The biphasic system that obtains was stirred 17 hours down at 25～30 ℃.The transparent homogeneous phase solution that will obtain with rotatory evaporator (25 mmhg, 50 ℃) is concentrated into the generation white precipitate.The solid that will wet is dissolved in methylene dichloride (200ml).Separate water layer and with dichloromethane layer by the silicon-dioxide plug.With methylene dichloride (100 milliliters) wash water layer and with this dichloromethane layer also by the silicon-dioxide plug.At last, methylene dichloride (100 milliliters) is evaporated the methylene dichloride cut that merges by the silicon-dioxide plug and with rotatory evaporator (25 mmhg, 35 ℃), can obtain the crystallization of white.This white crystals is dry in a vacuum, can obtain the 2-methoxyl group-2-methyl propanamide of 29.5 grams (79%).
NMR(CDCl
3): δ 1.4(s, 6H, CH
3), 3.3(9,3H, CH
3O), the extremely wide b of 6.4(, 2H, NH
2).
C. Synthetic 2-methoxyl group-2-methyl-propyl-1-amine
In the dried twoport round-bottomed flask with 250 milliliters of lithium aluminium hydride (3.04 grams, 0.08 mole) addings.At any time flask must remain in the drying nitrogen.Add anhydrous tetrahydro furan (THF) (25ml) and stirred suspension.2-methoxyl group-2-methyl-propyl acid amides (81.9 gram, 0.07 mole) added in 80 milliliters the anhydrous tetrahydro furan and and slowly add lithium aluminium hydride suspension this solution.The control rate of addition makes it be enough to keep carrying out mild backflow.With dripping half an hour, resulting suspension was refluxed one hour again.Make the suspension cooling, under agitation dropwise add 3 ml waters, add 3 milliliter of 15% sodium hydroxide subsequently again.At last, add 9 ml waters and warm suspension was stirred 15 minutes.Filter white precipitate and use the THF washing and precipitating repeatedly with mesopore sintered glass funnel.Under normal pressure, distill the THF that is merged.Remove THF being lower than under 70 ℃.With product in about 124 ℃ of distillations.
Output: 4.19 grams (58%)
NMR（CDCl
3）：δ1.15（s，8H，CH
3，NH
2）、2.6（s，2H，CH
2）、3.2（s，3H，CH
3O）。
Preparation 3: methane amide synthetic N-(2-methoxyl group-2-methyl-propyl)
Formic acid (19.2 gram, 0.40 mole) and diacetyl oxide (40.8 grams, 0.40 mole) are mixed, and 45～50 ℃ of heating one hour down, in ice/acetone bath, be cooled to then and be about 0 ℃.In ice/acetone bath, be cooled to earlier about 0 ℃ 2-methoxyl group-2-methyl-propyl-1-amine (36g, 0.35 mole) and slowly add also and keep the temperature of mixture to be lower than 12 ℃ simultaneously giving.After drip finishing, make mixture slowly rise to room temperature and at room temperature stir and spend the night.Distill under 97～107 ℃/1-2 mmhg pressure with solution evaporation with residuum, can obtain the product of 43.2 grams (94%).
NMR(CDCl
3): δ 1.2(s, 6H, CH
3), 3,3(m, 5H, CH
3O and CH
2), 6.6(b, 1H, NH), 8.2(bs, 1H, HCO).
Preparation 4:N-(2-(1-methoxy-propyl)) methane amide
Formic acid (16.80 gram, 0.35 mole) and diacetyl oxide (37.50 grams, 0.35 mole) mixed being incorporated in 45～50 ℃ of heating one hour down, in ice/acetone bath, be cooled to about 0 ℃ then.2-amino-1-methoxy propane (26.7 gram, 0.30 mole) is cooled in ice/acetone bath is lower than 0 ℃.Formic acid (25 milliliters) is slowly added in the refrigerative amine.Resulting solution further is cooled to is lower than 0 ℃.Amine aqueous solution is added refrigerative formic acid-solution of acetic anhydride, stir resulting solution and make it slowly rise to ambient temperature overnight.Retort solution under low pressure (about 1 mmhg), formic acid, acetate and formic acid-diacetyl oxide be distillation at low temperatures entirely then.At 79～85 ℃ of following product of distillation, obtain clear, colorless oily product.Output is 33.13 grams (94%).
NMR(CDCl
3): δ 1.05(d, 3H, CH
3-C), 3.4(M, 5H, CH
3O and CH
2O), 4.2(M, 1H, CH), 6.8(b, 1H, N-H), 8.0(b, 1H, HC=O).
Synthesizing of isonitrile
The synthetic route of following preparation 2-methoxyl group-2-methyl-propyl-1-isonitrile, 1-methoxycarbonyl propyl-2-isonitrile and 3-isonitrile-3-methyl isophthalic acid-methyl butyl ether also is applicable to other corresponding carbomethoxyisopropyl isonitrates of the ether compound that preparation is described in detail above.
1. prepare 2-methoxyl group-2-methyl-propyl-1-isonitrile
With N-(2-methoxyl group-2-methyl-propyl) methane amide (1.97 gram, 0.015 mole) adds in the ethylene dichloride (23 milliliters).Add triethylamine (4.04 grams, 0.040 mole) and this clear solution is cooled off in ice/water-bath.Trichloromethylchloroformate (superpalite, 1.68 grams, 0.0085 mole) is dissolved in the methylene dichloride (10 milliliters) and slowly adds (45 minutes) in the refrigerative formamide soln.Stirred 2 hours, and made suspension rise to room temperature.Then the suspension impouring is contained in the water (25 milliliters) of SODIUM PHOSPHATE, MONOBASIC (6.90 grams, 0.05 mole).The separate dichloromethane layer is also used the yellow soda ash drying, under decompression (25 mmhg) solution is distilled then, under 56～59 ℃ product is distilled, and can obtain 0.530 gram product (productive rate 31%).
NMR（CDCl
3）：δ1.3（s，6H，CH
3）、3.25（s，3H，CH
3O）、3.4（m，2H，CH
2）。
2. prepare 1-methoxy-propyl-2-isonitrile
With N-(2-(1-methoxy-propyl)) methane amide (11.7 gram, 0.10 mole) is dissolved in the methylene dichloride (125 milliliters).Add triethylamine (30.30 grams, 0.30 mole) and this clear solution is cooled off in ice/water-bath.Trichloromethylchloroformate (11.88 grams, 0.06 mole) is dissolved in the methylene dichloride (40 milliliters).This trichloromethylchloroformate solution is slowly added in the refrigerative formamide soln.Stir resulting suspension and make it slowly rise to room temperature 12 hours.The suspension impouring is contained in the water of yellow soda ash (42.4 grams, 0.40 mole).The separate dichloromethane layer is also used the water washing of phosphoric acid sodium dihydrogen (55.2 grams, 0.40 mole).The separate dichloromethane layer is also used yellow soda ash (anhydrous) drying.
Filtering solution and distillation under pressure of inspiration(Pi) (about 25 mmhg).At 63～66 ℃ of following product of distillation.Product is 5.83 grams (58.8%).
NMR(CDCl
3): δ 1.05(6 identical peak, 3H, CH
3C), 3.0(s, 3H, CH
3-O), 3.1(m, 2H, CH
2), 3.5(m, 1H, CH).
3. synthetic 3-isonitrile-3-methyl isophthalic acid-methyl butyl ether
A. synthetic 3-methane amide-3-methyl isophthalic acid-butanols
3-amino-3-methyl isophthalic acid-butanols (20.60 gram, 0.20 mole) is added ethyl formate (29.60 grams, 0.40 mole), under nitrogen atmosphere,, make it be cooled to room temperature then the clear solution reflux of gained 2 hours.With rotary distillation method (35 ℃, 25 holders) ethyl formate and ethanol byproduct are removed.Oily matter drying with gained under decompression (25 ℃, 0.1 holder) can get product 25.86 grams (99%).
NMR（CDCl
3）：1.4（d，6H，CH
3）、2.0（m，2H，C-CH
2）、3.9（m，2H，O-CH
2）、7.1（bs，1H，NH）、（m，1H，HCO）。
B. the synthetic formic acid (ester of 3-methane amide-3-methyl isophthalic acid-Ding)
Add formic acid (6.90 gram, 0.15 mole) in the diacetyl oxide (15.30 grams, 0.15 mole) and in water-bath, be warmed to 45～50 ℃ 1 hour.In ice/acetone bath, gained solution is cooled to and is lower than 0 ℃.Add 3-methane amide-3-methyl isophthalic acid-butanols (13.10 grams, 0.10 mole) and under constantly stirring (16 hours) make solution slowly rise to room temperature.Under decompression (1 holder, 105～110 ℃),, can obtain product 12.43 grams (78%) with the solution distillation.
NMR（CDCl
3）：1.4（s，6H，CH
3）、2.1（t，2H，C-CH
2）、4.2（t，2H，O-CH
2）、6.0（bs，1H，NH）、8.0（m，2H，HCOO）。
C. the synthetic formic acid (ester of 3-isonitrile-3-methyl isophthalic acid-Ding)
(ester of 3-methane amide-3-methyl isophthalic acid-Ding) (11.13 grams, 0.07 mole) and triethylamine (21.21 restrain 0.21 mole) are dissolved in the methylene dichloride (350 milliliters) with formic acid.Under nitrogen atmosphere, in ice/water-bath, gained solution is cooled off.Superpalite (trichloromethylchloroformate) (8.32 gram, 0.042 mole) is dissolved in methylene dichloride (50 milliliters) and in 30 minutes, dropwise add stir, in the refrigerative formamide soln.Stir gained suspension and make it in 90 minutes, rise to room temperature.Water (250 milliliters) solution adds in this suspension, and the organic layer below separating with yellow soda ash (23 grams, 0.22 mole).With carbonic acid sodium dihydrogen (30 grams, 0.22 mole) water (250 milliliters) the isolating organic layer of solution washing.Organic layer with the dry gained of yellow soda ash (anhydrous, 25 grams).Solution is filtered and distillation under pressure of inspiration(Pi) (25 holder).Be lower than solvent distillation under the room temperature, and, can obtaining 9.22 gram products (93%) at 96～102 ℃ of following product of distillation.
NMR（CDCl
3）：1.5（m，6H，CH
3）、2.0（m，2H，C-CH
2）、4.4（t，2H，O-CH
2）、8.0（s，1H，HCO）。
D. synthetic 3-isonitrile-3-methyl isophthalic acid-butanols
In sodium bicarbonate (8.40 grams, 0.10 mole) and yellow soda ash (10.60 grams, 0.10 mole) water-soluble (200 milliliters).Add formic acid (3-isonitrile-3-methyl isophthalic acid-Ding) ester and vigorous stirring.Make this turbid solution at room temperature place 5 hours.Add sodium-chlor (10 grams, 0.17 mole) and suspension was stirred 15 minutes.Extract suspension with ethyl acetate (3 * 100 milliliters).The organic layer that merges three extractions is used yellow soda ash (25 gram) drying, is filtered and distillation under pressure of inspiration(Pi) (25 hold in the palm).Product 120 ℃ of distillations down, can be obtained product 5.38 grams (74%).
NMR（CDCl
3）：1.5（m.6H，CH
3）、2.0（m.2H，C-CH
2）、3.0（bs，1H，OH）、4.0（t，2H，O-CH
2）。
E. synthetic 3-isonitrile-3-methyl isophthalic acid-methyl butyl ether
3-isonitrile-3-methyl isophthalic acid-methoxybutanol (1.13 grams, 0.01 mole) is dissolved in tetrahydrofuran (THF) (20 milliliters) and the dimethyl sulfoxide (DMSO) (2 milliliters).Add methyl iodide (1.42 grams, 0.01 mole) and solution was at room temperature stirred 5 minutes.Sodium hydride (80% oil dispersion, 0.30 gram, 0.01 mole) was added in 15 minutes one by one in batches.The suspension of gained stirred 90 minutes.Add 15 ml waters and separate organic layer.Extract water layer with ethyl acetate (2 * 20 milliliters),, use yellow soda ash (2 gram) drying, filter and distillation under pressure of inspiration(Pi) (25 hold in the palm) the organic layer merging of second extraction.Product 80～90 ℃ of distillations down, can be obtained product 0.48 gram (38%).
NMR（CDCl
3）：1.5（m，6H，CH
3）、2.0（m，2H，C-CH
2）、3.4（s，3H，CH
3）、3.6（t，2H，O-CH
2）。
By room temperature to reflux temperature or higher temperature, isonitrile is mixed in suitable medium with radioactive metal, can prepare needed radiolabeled ether-substituted isocyanide title complex.Needed mark isocyanide complex is undissolved and can obtains high yield.In some situation, isonitrile itself can be used as a kind of reductive agent, does not therefore need to add reductive agent again.When needs with when wishing accelerated reaction, the additional reductive agent that should add, for the professional, be well-known.The well-known reductive agent of this kind comprises tin salt (using in preparation (kits) mode usually), formamidine sulfinic acid, V-Brite B, sodium bisulfite, azanol, ascorbic acid etc.Reaction generally finished after 1 minute to 2 hours, and the concrete concluding time is then depended on used special reagent and condition.
When usefulness resembles the radioactive nuleus of technetium one class, for example
99TC or
99mTC preferably mixes suitable reductive agent (can reduce technetium) and suitable ether-substituted isocyanide in water-bearing media, and then adds pertechnetate and prepare isocyanide complex.Another kind method is ether-substituted isocyanide is mixed with pertechnetate, and then the adding reductive agent to prepare isocyanide complex.
The isonitrile technetium complexes consistent with the present invention be also available to have the oxidation state technetium, and the prefabricated technetium complexes of routine III valency, IV valency or V valency technetium prepares by these prefabricated title complexs are handled with excessive ether-substituted isocyanide under appropriate condition.
It is excessive up to 100 times or higher excessive ether-substituted isocyanide and excessive reductive agent to use in the complex reaction, to guarantee obtaining production peak from the technetium radioactive nuleus.After the reaction, desirable title complex can be separated from reaction mixture, when needing, for example can be separated by crystallization or precipitation or by conventional chromatogram or ion-exchange chromatography; See the 4th, 452, No. 774 patents of the above-mentioned U.S., disclosed content is listed reference of the present invention in the literary composition.
The preparation consistent with the present invention comprises a kind of aseptic, athermic, ether-substituted isocyanide ligand, in case of necessity, can comprise the reductive agent of a kind of preliminary election radioactive nuleus of reduction of some amount.This kind preparation preferably contains a kind of aseptic, ether-substituted isocyanide ligand and a kind of aseptic reductive agent that pre-determines the preliminary election radioactive nuleus that can reducing of quantity pre-determine quantity of preliminary election set amount.In possible, this kind isonitrile ligand and reductive agent had better be cryodesiccated, to promote stability in storage.Do not sound feasible when feasible as lyophilize, but preparation refrigerated storage or at room temperature store with the solution form.Ether-substituted isocyanide and reductive agent preferably are contained in sterile chamber sealing, athermic.Ether-substituted isocyanide in this kind preparation can be the form of non-radioactive metal adducts, for example awaiting the reply simultaneously with the present invention and the common U.S. Patent application of transferring the possession of 762, in No. 392 and the european patent application of having delivered 183, those adductss of being narrated in No. 555 (publishing on June 24th, 1986), disclosed content is all listed reference of the present invention in these two parts of files.The replaceable metal that is applicable to these metal adductss of preparation is to be selected from Cu, Mo, Pd, Co, Ni, Cr, Ag, Rh(U.S.S.N.672,392) and Zn(European patent 183,555) material, and can be at an easy rate with the title complex of replaceable metal in a kind of suitable medium, with by room temperature to reflux temperature or higher temperature, mix with the ether-substituted isocyanide ligand and to prepare.Reaction was generally finished after 2 hours at 1 minute, and the concrete deadline is depended on used reagent and condition.The selection of radioactive nuleus will be depended on purposes.Certainly, because the validity of Tc99m propellant (generator), so especially preferably use this kind radioactive nuleus.
Illustrate ether-substituted isocyanide of the present invention below and have beyond thought superiority than the simple hydrocarbons isonitrile that people such as Jones (United States Patent (USP) the 4th, 452, No. 774) are recommended.
Example
Prepare following TC99m title complex:
Title complex A:[
99mTc(C X NC(CH
3)
2CH
2OCH
3)
6]
+
Complex B: [
99mTc(C X NCH
2C(CH
3)
2OCH
3)
6]
+
Title complex C:[
99mTc(C X NCH(CH
3) CH
2OCH
3)
6]
+
Tert-butyl isonitrile title complex (comparison):
[
99mTc（C X NC（CH
3）
3）
6]
+
These technetium complexes application class are similar to the standard flag conditions that the people reported such as Jones and prepare.Isonitrile (3～5 milliliters) is dissolved in ethanol (1 milliliter) and phial is sealed adding usefulness then in one 10 milliliters serum phial
99Mo/
99m100～150 microcuries that obtain behind the Tc radioactive nuleus propellant wash-out
99mTeO
- 4Add sodium hyposulfate (0.5 milliliter of aqueous solution that is made into by 20～25 milligrams and 10 ml distilled waters) and phial is placed 100 ℃ of water-baths 15 minutes.After being cooled to room temperature, add 1 ml water and 1 milliliter of methylene dichloride, so product is extracted in the methylene dichloride.Be dissolved in the ethanol with the organic layer evaporation and with product.The purity of finished product can be with the anti-phase plate of thin-layer chromatography whatman C-18 and the alcoholic acid solvent systems using that the solvent mixture contain 22%0.5M ammonium acetate aqueous solution, 66% methyl alcohol, 9% acetonitrile and 3% tetrahydrofuran (THF) is measured or begin in 20 minutes, to have after one minute 0～90% linear gradient with high pressure liquid chromatography Brownlee C-8 reversed-phase column (5 millimeters) and a kind of 0.05M of containing ammonium sulfate solution with when injecting measure.
Distribute by the biology of measuring guinea pig and to estimate title complex.The organ distribution condition of 5,30 and 120 minutes mensuration injection usefulness after injection.At above-mentioned three minute points, with three guinea pigs of vetanarcol (35 milligrams/kilogram, International Pharmacopoeia) anesthesia with by 0.1 milliliter of test of jugular vein injection agent.
99mThe injected dose of Tc isonitrile is 1～2.5 millicurie.When dissected takes out intracorporeal organ and measures radioactivity with Capintec dose calibrator or γ well counter.The weight of the weighing heart, lung and liver.With the radioactive distribution of following table explanation title complex in the heart, lung and liver.Referring to the heart/liver and the heart/lung ratio, can easily find out technetium of the present invention-99m title complex, in the low absorbed dose (and/or eccysis from liver quite promptly) of low absorbed dose that shows lung and liver and keep having significant superiority than simple hydrocarbon isonitrile aspect the high myocardium absorbed dose simultaneously.
Table
The organ ratio
The injected dose % heart/lung * heart/liver * in the heart
5 minutes 30 minutes 2 hours 5 minutes 30 minutes 2 hours 5 minutes 30 minutes 2 hours
a????1.7????1.2????0.8????1.5????2.9????4.8????1.6????1.6????2.7
b????1.4????1.5????1.2????2.3????2.7????5.1????2.0????2.1????5.7
c????1.3????1.4????0.5????3.0????3.8????2.8????2.5????5.0????3.1
d????1.2????1.2????1.0????0.2????0.5????2.0????1.8????1.4????0.8
Annotate: above-mentioned all numerical value are the average trial value of three animals.
* press the ratio calculation of (injected dose %)/(the tissue gram number) of each organ.
a＝[
99mTc（C≡NC（CH
3）
2CH
2OCH
3）
6]
+
b＝[
99mTc（C≡NCH
2C（CH
3）
2OCH
3）
6]
+
c＝[
99mTc（C≡NCH（CH
3）CH
2OCH
3）
6]
+
d＝[
99mTc（C≡NC（CH
3）
3）
6]
+
Claims (20)
1, a kind of method for preparing ether-substituted isocyanide or its metal complexes, the general formula of ether-substituted isocyanide is CN-A-O-R (I), and A is the straight or branched alkyl in the formula, and R is the straight or branched alkyl, condition is that the former sum of carbon that A adds R equals 4 to 6, and another condition is that A is not (CH
2)
3, and another condition is that first carbon atom that is connected with isonitrile is a quaternary carbon atom when the total number of carbon atoms that A adds R equals 6, the preparation method comprises:
(a) formylation of the amine of following general formula
In the formula definition of A and R as mentioned above, from-5 ℃ to reflux temperature, this amine is contacted with ethyl formate or formic acid-acetic anhydride, prepare the methane amide of following general formula:
(b) dehydration of the methane amide of step (a) preparation can in a kind of inert solvent, in the presence of a kind of tertiary amine contact this methane amide or contact with phosphoryl chloride in the presence of a kind of amine alkali under the temperature from-10 ℃ to room temperature with trichloromethylchloroformate, generates ether-substituted isocyanide, or
(c) the isonitrile product that will lead to formula I reacts with the on-radiation metal complexes that is selected from Cu, Mo, Pd, Co, Ni, Cr, Rh and Zn, generates a kind of ether-substituted isocyanide metal adducts.
2, the preparation method of claim 1, the A of its formula of (II) is CH
2C(CH
3)
2, R is CH
3
3, the preparation method of claim 1, the A of its formula of (II) is C(CH
3)
2CH
2, R is CH
3
4, the preparation method of claim 1, the A of its formula of (II) is (CH
2)
3, R is CH
2CH
3
5, the preparation method of claim 1, the A of its formula of (II) is CH(CH
3) CH
2, R is CH
3
6, the preparation method of claim 1, the A of its formula of (II) is CH(CH
3) CH
2, R is CH
2CH
3
7, the preparation method of claim 1, the A of its formula of (II) is CH
2CH(CH
3), R is CH
3
8, the preparation method of claim 1, the A of its formula of (II) is CH
2CH(CH
3), R is CH
2CH
3
9, the preparation method of claim 1, the A of its formula of (II) is CH(CH
3) CH(CH
3), R is CH
3
10, the preparation method of claim 1, the A of its formula of (II) is CH
2CH(CH
3) CH
2, R is CH
3
11, the preparation method of claim 1, the A of its formula of (II) is CH
2CH
2CH(CH
3), R is CH
3
12, the preparation method of claim 1, the A of its formula of (II) is C(CH
3)
2, R is CH
2CH
3
13, the preparation method of claim 1, the A of its formula of (II) is C(CH
3)
2, R is CH
3
14, the preparation method of claim 1, the A of its formula of (II) is (CH
2), R is CH(CH
3)
2
15, the preparation method of claim 1, the A of its formula of (II) is (CH
2)
2, R is CH
2CH
3
16, the preparation method of claim 1, the A of its formula of (II) is CH(CH
2CH
3) CH
2, R is CH
3
17, the preparation method of claim 1, the A of its formula of (II) is CHCH
3, R is CH(CH
3)
2
18, the preparation method of claim 1, the A of its formula of (II) is CH(CH
3) CH
2CH
2, R is CH
3
19, the preparation method of claim 1, the A of its formula of (II) is C(CH
3)
2CH
2CH
2, R is CH
3
20, the preparation method of claim 1, the A of its formula of (II) is CH
2CH(CH
2CH
3), R is CH
3
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US81247085A | 1985-12-23 | 1985-12-23 | |
| US812.470 | 1985-12-23 | ||
| US812,470 | 1985-12-23 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN86108714A CN86108714A (en) | 1987-08-19 |
| CN1013860B true CN1013860B (en) | 1991-09-11 |
Family
ID=25209658
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 86108714 Expired CN1013860B (en) | 1985-12-23 | 1986-12-22 | Ether isonitriles and radiolabeled complexes thereof |
Country Status (3)
| Country | Link |
|---|---|
| CN (1) | CN1013860B (en) |
| SU (1) | SU1542411A3 (en) |
| ZA (1) | ZA869618B (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112457203B (en) * | 2020-11-27 | 2022-08-16 | 苏州亚科科技股份有限公司 | Preparation method of 2-amino-2-methyl-1-propanol |
-
1986
- 1986-12-22 ZA ZA869618A patent/ZA869618B/en unknown
- 1986-12-22 SU SU864028703A patent/SU1542411A3/en active
- 1986-12-22 CN CN 86108714 patent/CN1013860B/en not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| ZA869618B (en) | 1988-08-31 |
| CN86108714A (en) | 1987-08-19 |
| SU1542411A3 (en) | 1990-02-07 |
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