CN110294756A - GluN2B subunit targeting type central nervous system positive electron tracer and its preparation - Google Patents
GluN2B subunit targeting type central nervous system positive electron tracer and its preparation Download PDFInfo
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Abstract
Although existing GluN2B selectivity positive electron tracer has compared with high-affinity and selectivity, but the property of ideal tracer is not shown in vivo experiment, there is the problems such as too fast metabolism, lower brain capture amount, the distribution of the full brain indifference opposite sex, the too fast decay of C-11 label probe and miss target phenomenon caused by being influenced by the other target spots of brain, limit further Study on Transformation.The present invention designs novel GluN2B subunit targeting type central nervous system positive electron tracer and is not easy the characteristics of being metabolized using methylamino stable structure, reduces the metabolic rate of tracer, extends the up time.Meanwhile tracer of the invention is easy to test detecting and tracking, has preferable electronics tracer effect.In addition, preparation method mild condition of the invention, and it can be quickly obtained the tracer injection liquid of the label of high-purity C 11, effectively solve the problems, such as the too fast decay of C-11 label probe.
Description
Technical field
The present invention relates to the GluN2B targeting type PET probes that carbon -11 marks, and in particular to the design of the radiopharmaceutical,
Exploitation and preparation method.
Background technique
Pidolidone (L-Glutamate) be mammalian central nervous system (Central Nervous System,
CNS principal endogenous excited type neurotransmitter), its receptor (GluRs) can be divided into ionotropic glutamate receptor (iGluRs)
With two class of metabotropic glutamate receptor (mGluRs).The Ligand-gated ion channel that ionotropic glutamate receptor is constituted, root
Three hypotypes can be divided into according to pharmacological property: N-methyl-D-aspartate (NMDA) receptor, alpha-amido -3- hydroxy-5-methyl base are different
Oxazole -4- propionic acid receptor (AMPA) receptor and kainic acid (Kainate) receptor.Wherein nmda receptor (NMDARs) is in excited type
Key player is played during nerve conduction, it is related with nerve synapse development and brain learning and memory function.
GluN2 series subunit has multiple target spots of NMDARs, can regulate and control a series of functions of NMDARs, in full brain domain table
It is very high up to level.Wherein GluN2B antagonist has the function of protection nerve, grinds in the drug for central nervous system disease
It is concerned in hair and diagnosis and treatment application.For alzheimer's disease (Alzheimer's disease, AD) this typical nerve
Degenerative disease has positive evidence to show that the nerve synapse of GluN2B subunit and A beta induced Synaptic dysfunction and AD damage
There is obvious relation between persistence, inhibits GluN2B subunit that can prevent or alleviate some symptoms.In addition, GluN2B antagonist, which has, improves AD trouble
The potential treatment of person's cognitive function is worth.
Currently, being quickly grown by the positive electron tracer of target spot of GluN2B subunit, such as Ifenprodil (Fig. 1) is first
Example be used as GluN2B selective antagonist " prodil " drug, similar structure PET probe-[11C](±)-methoxy-
CP-101606([11C] 2, Fig. 1) mouse brain slice external autography experiment display [11C] 2 there is good spy in forebrain areas
Anisotropic binding ability, but the no specificity increased radioactivity of experiment in vivo deutocerebral region (reference: NuclMedBiol 2002,29,
517-525)；According to the research laboratory Merck report benzenecarboximidamide class compound derived from PET probe ([11C] 3~5, Fig. 1), right
GluN2B compatibility is higher, but brain capture amount is lower and tachytrophism (reference: Appl RadiatIsot2006,64,348-
354)；GluN2B antagonist WMS-1405 PET probe [11C]Me-NB1([11C] 6, Fig. 1) there is good target spot affinity
With preferable selectivity (reference: JNuclMed2018,59,698-703)；The F-18 of non-phenol class GluN2B antagonist, which is marked, to be visited
Needle ([18F] 8 and [18F] 9, Fig. 1) there is high special sexual compatibility to GluN2B subunit enrichment brain area, but can send out in vivo
Raw non-specific binding (reference: Mol Pharmacol, 2016,89,541-551).
In conclusion although the above GluN2B selectivity positive electron tracer has compared with high-affinity and selectivity,
The property of ideal tracer is not shown in experiment in vivo.Too fast metabolism, lower brain capture amount, full brain indifference
Property distribution, the too fast decay of C-11 label probe and the problems such as miss target phenomenon caused by being influenced by the other target spots of brain, limit
Further Study on Transformation (reference: ChemMedChem 2018,13,1058-1068；JClinPharmacol2009,49:856-
864)。
Summary of the invention
The present invention provides GluN2B subunit targeting type central nervous system positive electron tracers, at least to solve existing skill
Electronics tracer tachytrophism in art, problem of non-ideal use.
The present invention provides GluN2B subunit targeting type central nervous system positive electron tracer, the electronics tracer
Structure is shown as follows:
Wherein, R1 is selected from phenyl and its one of derivative or thiophene and derivatives.
Further, the R1 is
Invention additionally discloses the preparation methods of GluN2B subunit targeting type central nervous system positive electron tracer, including step
It is rapid as follows: to take the intermediate 1 with N methyl nitrosourea in solvent, the CH that alkaline reagent and carbon -11 mark is added3I carries out first
Glycosylation reaction obtains product, and reaction equation is as follows:
Further, the intermediate 1 is obtained with the intermediate 3 with boric acid ester group by coupling reaction by intermediate 2,
Reaction equation is as follows:
Further, the intermediate 2 by intermediate 4 under alkaline condition, react and obtain with the methyl halogenated acetamide of N-
, reaction equation is as follows:
Further, the intermediate 1 by intermediate 5 under alkaline condition, react acquisition with the methyl halogenated acetamide of N-,
Reaction equation is as follows:
Further, the intermediate 5 is obtained by intermediate 4 and the intermediate 3 with boric acid ester group by coupling reaction
, reaction equation is as follows:
Further, the intermediate 4 before coupling reaction, is carrying out amido protecting, the intermediate with intermediate 3
4 protect process, acquisition intermediate 5 with deamination after 3 coupling reaction of intermediate, is carried out.
Further, the methyl halogenated acetamide of the N- the preparation method is as follows:
It takes halogenated acetic acids to react with oxalyl chloride, to obtain corresponding haloacetyl chloride, and haloacetyl chloride is instilled into methylamine
To obtain the methyl halogenated acetamide of N- in solution.
Further, the carbon -11 mark iodomethane the preparation method is as follows: the CO marked with carbon -112For raw material, warp
Cross LiAlH4The carbon -11 that reduction and HCl treatment obtain marks iodomethane.
Compared with prior art, the present invention obtaining the compound of C11 label by using the above method, utilizing methylamino
Stable structure is not easy the characteristics of being metabolized, and reduces the metabolic rate of tracer, extends the up time.Meanwhile of the invention showing
Track agent is easy to test detecting and tracking, has preferable electronics tracer effect.In addition, preparation method mild condition of the invention, and
It can be quickly obtained the tracer injection liquid of the label of high-purity C 11, effectively solve the problems, such as the too fast decay of C-11 label probe.
Detailed description of the invention
Fig. 1 is Ifenprodil and part GluN2B selectivity PET probe structure formula；
Fig. 2 is automation labelling experiment operational flowchart；
Fig. 3 is TY-1 product γ detection, UV detection figure；
Fig. 4 is TY-2 product γ detection, UV detection figure.
Specific embodiment
In order to enable those skilled in the art to better understand the solution of the present invention, below in conjunction in the embodiment of the present invention
Attached drawing, technical scheme in the embodiment of the invention is clearly and completely described, it is clear that described embodiment is only
The embodiment of a part of the invention, instead of all the embodiments.Based on the embodiments of the present invention, ordinary skill people
The model that the present invention protects all should belong in member's every other embodiment obtained without making creative work
It encloses.
One, the synthesis of n-compound
1, the synthesis of n-compound TY-1
Step I: setting out from raw material compound 10 (1.39g, 10mmol), at room temperature with oxalyl chloride (1.905g,
15mmol) reaction obtains corresponding acyl chlorides, and reaction is solvent with DCM (20mL) and 2 drop DMF of instillation promote reaction.The acyl that will be obtained
The solvent of chlorine reaction solution removes on a rotary evaporator, and residue is re-dissolved with DCM (10mL), under ice bath temperature, by it
10mL is slowly dropped into dissolved with HNMe2In the DCM solution of (6mL, 12mmol, 2M in THF), reaction solution is to slowly warm up to room temperature simultaneously
Reaction 4 hours, obtains intermediate 11, colorless oil, yield 43%.
Step II: under alkaline condition, raw material 12 (394mg, 2mmol) and intermediate 11 (332mg, 2mmol) is existed
It is reacted at room temperature 2 hours in DMF solvent, obtains intermediate 13, light yellow solid, yield 61%.
Step III: intermediate 13 (282mg, 1mmol) and the 1,4- of substituted boracic acid 14 (170mg, 1.1mmol) at 90 DEG C
Dioxane and water obtain in mixed solvent (10mL), with Pd (dppf) Cl2It is anti-that coupling occurs using cesium carbonate as alkali for catalyst
It should obtain TY-1, gray solid, yield 79%.Product TY-1 molecular information is as follows:1H NMR(300MHz,DMSO)δ8.61(d,
J=1.7Hz, 1H), 8.07 (s, 1H), 7.72-7.38 (m, 3H), 7.35-7.08 (m, 1H), 6.57 (d, J=3.2Hz, 1H),
5.24(s,2H),3.10(s,3H),2.85(s,3H),2.32(s,3H).13C NMR(75MHz,DMSO)δ167.56(s),
160.73 (d, J=243.0Hz), 145.98 (s), 141.59 (s), 135.45 (d, J=3.4Hz), 134.69 (s), 130.52
(d, J=5.1Hz), 130.30 (s), 128.18 (s), 126.59 (d, J=8.0Hz), 125.14 (d, J=17.4Hz),
115.81 (d, J=22.2Hz), 115.55 (s), 101.59 (s), 47.73 (s), 36.29 (s), 35.71 (s), 14.74 (d, J
=3.2Hz)19F NMR(282MHz,DMSO)δ-116.45.HRMS(m/z):[M+Na]+calculated for
334.1332,found 334.1337.
2, the synthesis of n-compound TY-2
Step I: raw material 12 (985mg, 5mmol) is dissolved in DCM (10mL), sequentially adds 4- at room temperature
DMAP(610mg,5mmol)、Et3N (506g, 5mmol) and Boc2O (1.31g, 6mmol) reacts 12 hours, obtains intermediate
17, white solid, yield 82%.
Step II: intermediate 17 (594mg, 2mmol) and the 1,4- of substituted boracic acid ester 18 (263mg, 2mmol) at 90 DEG C
Dioxane and water obtain in mixed solvent (20mL), with Pd (dppf) Cl2It is anti-that coupling occurs using cesium carbonate as alkali for catalyst
The mixture is flowed back 1 hour in 3N aqueous hydrochloric acid solution (40mmol), is obtained pure by the mixture that should obtain compound 19 and 20
Compound 20, white solid, yield 66%.
Step III: being dissolved in DMF (5mL) for intermediate 20 (249mg, 1mmol), delays under condition of ice bath into the solution
Slow be added NaH solid (60mg, 60wt%, 1.5mmol) is simultaneously stirred 30 minutes, be then added intermediate 11 (183mg,
It 1.1mmol) and is gradually warmed to room temperature reaction 10 minutes, obtains TY-2, light yellow solid, yield 36%.Product TY-2 molecule letter
It ceases as follows:1H NMR(300MHz,CDCl3) δ 8.56 (s, 1H), 7.62 (s, 1H), 7.30 (d, J=9.4Hz, 1H), 6.96 (s,
1H),6.71(s,1H),4.90(s,2H),3.08(s,3H),2.98(s,3H),2.19(s,3H).13C NMR(75MHz,
CDCl3)δ166.21,144.54,139.39,137.43,135.59,134.17,130.24,125.28,124.27,123.44,
114.39,102.42,77.45,77.03,76.61,47.99,36.45,35.93,13.61.HRMS(m/z):[M+Na]+
calculated for 356.0600,found 356.0602.
Two, TY-1 and TY-2 corresponds to the synthesis of -11 labelled precursor of carbon
The corresponding monomethyl amide precursor compound TY-1-p of TY-1 and TY-2 skeleton has been synthesized in the embodiment of the present invention (to change
Close object 24) and TY-2-p (compound 25), it is used for subsequent labelling experiment.
1.TY-1-p specific synthetic method:
Step I: setting out from raw material compound 10 (1.39g, 10mmol), the first step first at room temperature with oxalyl chloride
(1.905g, 15mmol) reaction obtains corresponding acyl chlorides, and reaction is solvent with DCM (20mL) and 2 drop DMF of instillation promote reaction.It will
The solvent of obtained acyl chloride reaction liquid removes on a rotary evaporator, and residue is re-dissolved with DCM (10mL), in ice bath temperature
Under, 10mL is slowly dropped into dissolved with H2In the DCM solution of NMe (6mL, 12mmol, 2M in THF), reaction solution slowly heats up
It to room temperature and reacts 4 hours, obtains intermediate 22, colorless oil, yield 23%.
Step II: under alkaline condition, raw material 12 (394mg, 2mmol) and intermediate 22 (304mg, 2mmol) is existed
It is reacted at room temperature 2 hours in DMF solvent, obtains intermediate 23, light yellow solid, yield 52%.
Step III: intermediate 23 (268mg, 1mmol) and the 1,4- of substituted boracic acid 14 (170mg, 1.1mmol) at 90 DEG C
Dioxane and water obtain in mixed solvent (10mL), with Pd (dppf) Cl2It is anti-that coupling occurs using cesium carbonate as alkali for catalyst
It should obtain TY-1-p, light yellow solid, yield 61%.Product TY-1-p molecular information is as follows:1H NMR(300MHz,DMSO)δ
8.62 (d, J=1.6Hz, 1H), 8.06 (d, J=1.2Hz, 2H), 7.82-7.44 (m, 3H), 7.33-7.13 (m, 1H), 6.58
(d, J=3.2Hz, 1H), 4.91 (s, 2H), 2.61 (d, J=4.6Hz, 3H), 2.32 (s, 3H)13C NMR(75MHz,DMSO)δ
168.06 (s), 160.77 (d, J=243.2Hz), 146.04 (s), 141.83 (s), 135.36 (d, J=3.4Hz), 134.37
(s), 130.56 (d, J=5.1Hz), 129.94 (s), 128.34 (s), 126.58 (d, J=8.1Hz), 125.20 (d, J=
17.4Hz), 115.86 (d, J=22.3Hz), 115.42 (s), 101.94 (s), 49.10 (s), 26.05 (s), 1473 (d, J=
3.2Hz).19F NMR(282MHz,DMSO)δ-116.37.HRMS(m/z):[M+Na]+calculated for 320.1175,
found 320.1169.
2.TY-2-p specific synthetic method:
Step I: raw material 12 (985mg, 5mmol) is dissolved in DCM (10mL), sequentially adds 4- at room temperature
DMAP(610mg,5mmol)、Et3N (506g, 5mmol) and Boc2O (1.31g, 6mmol) reacts 12 hours, obtains intermediate
17, white solid, yield 82%.
Step II: intermediate 17 (594mg, 2mmol) and the 1,4- of substituted boracic acid ester 18 (263mg, 2mmol) at 90 DEG C
Dioxane and water obtain in mixed solvent (20mL), with Pd (dppf) Cl2It is anti-that coupling occurs using cesium carbonate as alkali for catalyst
The mixture is flowed back 1 hour in (40mmol) in the aqueous hydrochloric acid solution of 3N, is obtained by the mixture that should obtain compound 19 and 20
It is white solid, yield 66% to pure compound 20.
Step III: being dissolved in DMF (5mL) for intermediate 20 (249mg, 1mmol), delays under condition of ice bath into the solution
Slow be added NaH solid (60mg, 60wt%, 1.5mmol) is simultaneously stirred 30 minutes, be then added intermediate 22 (167mg,
It 1.1mmol) and is gradually warmed to room temperature reaction 10 minutes, obtains TY-2-p, is light yellow solid, yield 29%.Product TY-2-p
Molecular information is as follows:1H NMR(300MHz,DMSO)δ8.58(s,1H),8.03(s,1H),7.65(s,1H),7.39(s,1H),
6.60(s,1H),4.90(s,1H),2.63(s,1H),2.20(s,1H).13C NMR(75MHz,DMSO)δ167.96,146.47,
140.30,138.74,136.20,135.05,129.72,125.82,122.42,122.29,113.91,102.31,49.12,
40.81,40.53,40.25,39.97,39.70,39.42,39.14,26.06,13.84.HRMS(m/z):[M+Na]+
calculated for 342.0444,found 342.0447.
Three, radioactive carbon -11 mark [11C] TY-1 and [11C] TY-2 synthesis
1. automating labelling experiment operating process
Present embodiments provide the TracerLab FX using General Electric (GE) companyFNDevice utilizes TY-1-p and TY-
2-p as precursor, Fully automated synthesis [11C] TY-1 and [11C] TY-2, as shown in Fig. 2, including the following steps:
(1) dry [11C]CH3The preparation of I
[11C]CH3I is passed through with medical cyclotron14N(p,α)11C obtain [11C]CO2For raw material, by LiAlH4
What (0.4M in THF, 300 μ L) reduction and hydrochloric acid (57% aqueous solution, 300 μ L) processing obtained.
(2)[11C] TY-1 and [11C] TY-2 preparation method
It is pre-saturated that the corresponding precursor compound of 1.5mg is dissolved in 300 μ L 6.0mg KOH (85wt% powder) in advance
In anhydrous DMSO, reactor in figure is added；To then generate [11C]CH3I is conveyed by the helium pressure that helium generator generates
Into reactor.Valve v13, v14, v20 and v24 around reaction flask are closed, reaction system is warming up to 130 DEG C and reacts 5 minutes；
It is cooled to 30 DEG C immediately after completion of the reaction, it is whole that reaction system is added in the 2.5mLHPLC mobile phase solvent being previously placed in bottle 4
Only react.
TY-1-p reaction is as follows:
TY-2-p reaction is as follows:
(3)[11C] TY-1 and [11C] TY-2 isolates and purifies
The pure water of 1.5mL is previously added in bottle 14, the complete soln in reaction flask by helium pressure by valve v14 and
V12 is transferred in bottle 14, and all solution in bottle 14 are then injected into half preparation HPLC via valve v12 by helium pressure
In equipment, it is initially separated purifying immediately.
(3.1)[11C] TY-1 isolates and purifies
Machine: U.S.'s water generation high performance liquid chromatograph
Detector: 2487 dual wavelength absorption detector of water generation (Waters 2487Dual λ Absorbance
Detector it) is detected jointly by UV detector (λ=254nm) and radiation amount detector.
Half preparation chromatographic column: 5 μ C of Phenomenex Luna18column(10mm i.d.×250mm)
Column temperature: 23 DEG C
Mobile phase solution (volume ratio): 45%CH3CN, 55%H2O, 0.1%Et3N,pH 10
Flow velocity: 4.5mL/min
Product retention time: 8.50 minutes
(3.2)[11C] TY-2 isolates and purifies
Machine: U.S.'s water generation high performance liquid chromatograph
Detector: 2487 dual wavelength absorption detector of water generation (Waters 2487Dual λ Absorbance
Detector it) is detected jointly by UV detector (λ=254nm) and radiation amount detector.
Half preparation chromatographic column: 5 μ C of Phenomenex Luna18column(10mm i.d.×250mm)
Column temperature: 23 DEG C
Mobile phase solution (volume ratio): 50%CH3CN, 50%H2O, 0.1%Et3N,pH 10
Flow velocity: 5.0mL/min
Product retention time: 8.75 minutes
(4) it extracts, collect
The corresponding part in product peak is collected in big bottle by valve v18,23mL injection has been previously added in big bottle
Sterile water (the United States Pharmacopeia (USP) of rank；Hospira)；Solution in big bottle is in helium pressure
Under effect by be placed in No. 16 positions C18 solid-phase extraction column (i.e. Waters Sep-paklight C18 solid phase extraction column,
Product number WAT023501), and can with removal with the 10mL aseptic water washing C18 solid-phase extraction column 16 being previously added in bottle 7
The impurity such as the remaining salt impurity of energy, HPLC mobile phase.The 0.8mL being previously implanted in bottle 8 is finally utilized under helium pressure
Injection ethanol solution elutes the product on C18 solid-phase extraction column, collects to the 0.9% of the injection rank for having added 20mL in advance
Physiological saline (United States Pharmacopeia (USP)；Hospira in collection of products bottle 17).Solution passes through
0.22 mum syringe filter, obtain can injection [11C] TY-1 and [11C] TY-2 preparation.
After Fully automated synthesis, measurement obtain product [11C] TY-1 and [11C] the correction for attenuation yield of TY-2 is respectively
23% and 21%, specific activity is respectively 15.5GBq/ μm of ol and 14.8GBq/ μm of ol.
(5) radioactive purity detects
(5.1)[11C] TY-1 purity detecting:
Machine: U.S.'s water generation high performance liquid chromatograph
Detector: 2487 dual wavelength absorption detector of water generation (Waters 2487Dual λ Absorbance
Detector it) is detected jointly by UV detector (λ=254nm) and radiation amount detector.
Analytic type chromatographic column: XselectHss T3,4.6mm i.d. × 150mm
Column temperature: 23 DEG C
Mobile phase solution (volume ratio): 50%CH3CN, 50%H2O, 0.1%Et3N,pH 10
Flow velocity: 1.0mL/min；
[11C] TY-1 product retention time (as shown in Figure 3): 5.45min
(5.2)[11C] TY-2 purity detecting:
Machine: U.S.'s water generation high performance liquid chromatograph
Detector: 2487 dual wavelength absorption detector of water generation (Waters 2487Dual λ Absorbance
Detector it) is detected jointly by UV detector (λ=254nm) and radiation amount detector.
Analytic type chromatographic column: XselectHss T3,4.6mm i.d. × 150mm
Column temperature: 23 DEG C
Mobile phase solution (volume ratio): 50%CH3CN, 50%H2O, 0.1%Et3N,pH 10
Flow velocity: 1.0mL/min；
[11C] TY-2 product retention time (as shown in Figure 4): 6.14min
The embodiment of the present invention obtains TY-1, TY-2 compound of C11 label, utilizes methylamino by using the above method
Stable structure is not easy the characteristics of being metabolized, and reduces the metabolic rate of TY-1, TY-2, extends the up time.Meanwhile the present invention
TY-1, TY-2 compound correction for attenuation yield of embodiment are respectively 23% and 21%, and specific activity respectively reaches 15.5GBq/ μ
Mol and 14.8GBq/ μm of ol, is easy to test detecting and tracking, has preferable electronics tracer effect.In addition, the embodiment of the present invention
Preparation method mild condition, and it can be quickly obtained TY-1, TY-2 injection of the label of high-purity C 11, effectively solve C-11 mark
The problem of remembering probe too fast decay.
Finally it should be noted that the above embodiments are merely illustrative of the technical scheme of the present invention and are not intended to be limiting thereof, to the greatest extent
Invention is explained in detail referring to above-described embodiment for pipe, it should be understood by a person of ordinary skill in the art that technology
Personnel read present specification after still can with modifications or equivalent substitutions are made to specific embodiments of the invention, but this
A little modifications are changed within all without departing from the present patent application accompanying claims protection scope.
Claims (10)
1.GluN2B subunit targeting type central nervous system positive electron tracer, which is characterized in that the knot of the electronics tracer
Structure shows as follows:
Wherein, R1 is selected from phenyl and its one of derivative or thiophene and derivatives.
2.GluN2B subunit targeting type central nervous system positive electron tracer, which is characterized in that the R1 is
3. a kind of preparation side of any GluN2B subunit targeting type central nervous system positive electron tracer of claim 1-2
Method, which is characterized in that comprise the following steps that and take the intermediate 1 with N methyl nitrosourea in solvent, alkaline reagent and carbon-is added
The CH of 11 labels3I carries out methylation reaction, obtains product, and reaction equation is as follows:
4. preparation method according to claim 3, which is characterized in that the intermediate 1 is by intermediate 2 and has borate
The intermediate 3 of base is obtained by coupling reaction, and reaction equation is as follows:
5. the preparation method according to claim 4, which is characterized in that the intermediate 2 is by intermediate 4 in alkaline condition
Under, acquisition is reacted with the methyl halogenated acetamide of N-, reaction equation is as follows:
6. preparation method according to claim 3, which is characterized in that the intermediate 1 is by intermediate 5 in alkaline condition
Under, acquisition is reacted with the methyl halogenated acetamide of N-, reaction equation is as follows:
7. preparation method according to claim 6, which is characterized in that the intermediate 5 is by intermediate 4 and has borate
The intermediate 3 of base is obtained by coupling reaction, and reaction equation is as follows:
8. preparation method according to claim 7, which is characterized in that the intermediate 4 with intermediate 3 in coupling reaction
Before, amido protecting is carried out, the intermediate 4 protects process, acquisition intermediate with deamination after 3 coupling reaction of intermediate, is carried out
5。
9. preparation method according to claim 5 or 6, which is characterized in that the preparation side of the methyl halogenated acetamide of N-
Method is as follows:
It takes halogenated acetic acids to react with oxalyl chloride, to obtain corresponding haloacetyl chloride, and haloacetyl chloride is instilled into methylamine solution
In to obtain the methyl halogenated acetamide of N-.
10. preparation method according to claim 3, which is characterized in that the carbon -11 marks the preparation method of iodomethane such as
Under: the CO marked with carbon -112For raw material, by LiAlH4The carbon -11 that reduction and HCl treatment obtain marks iodomethane.
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