CN108358958A - Intermediate, intermediate synthetic method and application - Google Patents
Intermediate, intermediate synthetic method and application Download PDFInfo
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- CN108358958A CN108358958A CN201810066752.6A CN201810066752A CN108358958A CN 108358958 A CN108358958 A CN 108358958A CN 201810066752 A CN201810066752 A CN 201810066752A CN 108358958 A CN108358958 A CN 108358958A
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- dichloromethane
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- 238000010189 synthetic method Methods 0.000 title claims abstract description 21
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims abstract description 111
- 238000006243 chemical reaction Methods 0.000 claims abstract description 78
- 150000001875 compounds Chemical class 0.000 claims abstract description 66
- 229940125782 compound 2 Drugs 0.000 claims abstract description 25
- 230000000269 nucleophilic effect Effects 0.000 claims abstract description 23
- 238000003682 fluorination reaction Methods 0.000 claims abstract description 21
- 238000003786 synthesis reaction Methods 0.000 claims abstract description 17
- 230000015572 biosynthetic process Effects 0.000 claims abstract description 15
- 239000011261 inert gas Substances 0.000 claims abstract description 10
- OIRDBPQYVWXNSJ-UHFFFAOYSA-N methyl trifluoromethansulfonate Chemical compound COS(=O)(=O)C(F)(F)F OIRDBPQYVWXNSJ-UHFFFAOYSA-N 0.000 claims abstract description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 40
- 238000000034 method Methods 0.000 claims description 39
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 33
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000007789 gas Substances 0.000 claims description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 claims description 10
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- 229910052786 argon Inorganic materials 0.000 claims description 5
- 239000001307 helium Substances 0.000 claims description 5
- 229910052734 helium Inorganic materials 0.000 claims description 5
- SWQJXJOGLNCZEY-UHFFFAOYSA-N helium atom Chemical compound [He] SWQJXJOGLNCZEY-UHFFFAOYSA-N 0.000 claims description 5
- 238000004140 cleaning Methods 0.000 claims description 4
- 239000012535 impurity Substances 0.000 claims description 4
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- 230000008030 elimination Effects 0.000 claims 1
- 238000003379 elimination reaction Methods 0.000 claims 1
- 150000002576 ketones Chemical class 0.000 claims 1
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 65
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- 239000000243 solution Substances 0.000 description 53
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 37
- 239000007864 aqueous solution Substances 0.000 description 24
- 229940126214 compound 3 Drugs 0.000 description 24
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 21
- 239000007788 liquid Substances 0.000 description 19
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Substances [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 17
- 229910000027 potassium carbonate Inorganic materials 0.000 description 16
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 15
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- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 14
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- 229940125898 compound 5 Drugs 0.000 description 13
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000002904 solvent Substances 0.000 description 11
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 10
- 229940125904 compound 1 Drugs 0.000 description 10
- 238000010828 elution Methods 0.000 description 9
- 238000002414 normal-phase solid-phase extraction Methods 0.000 description 9
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 description 8
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- 206010018338 Glioma Diseases 0.000 description 7
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- 239000003814 drug Substances 0.000 description 7
- 229910052731 fluorine Inorganic materials 0.000 description 7
- 239000011737 fluorine Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- 239000001257 hydrogen Substances 0.000 description 7
- 229910052739 hydrogen Inorganic materials 0.000 description 7
- SRJQBBLGTWTOEB-UHFFFAOYSA-N 2-(benzhydrylazaniumyl)acetate Chemical compound C=1C=CC=CC=1C(NCC(=O)O)C1=CC=CC=C1 SRJQBBLGTWTOEB-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
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- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 5
- WDBQJSCPCGTAFG-QHCPKHFHSA-N 4,4-difluoro-N-[(1S)-3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-pyridin-3-ylpropyl]cyclohexane-1-carboxamide Chemical compound FC1(CCC(CC1)C(=O)N[C@@H](CCN1CCC(CC1)N1C(=NN=C1C)C(C)C)C=1C=NC=CC=1)F WDBQJSCPCGTAFG-QHCPKHFHSA-N 0.000 description 4
- BWGRDBSNKQABCB-UHFFFAOYSA-N 4,4-difluoro-N-[3-[3-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)-8-azabicyclo[3.2.1]octan-8-yl]-1-thiophen-2-ylpropyl]cyclohexane-1-carboxamide Chemical compound CC(C)C1=NN=C(C)N1C1CC2CCC(C1)N2CCC(NC(=O)C1CCC(F)(F)CC1)C1=CC=CS1 BWGRDBSNKQABCB-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
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- LFZAGIJXANFPFN-UHFFFAOYSA-N N-[3-[4-(3-methyl-5-propan-2-yl-1,2,4-triazol-4-yl)piperidin-1-yl]-1-thiophen-2-ylpropyl]acetamide Chemical compound C(C)(C)C1=NN=C(N1C1CCN(CC1)CCC(C=1SC=CC=1)NC(C)=O)C LFZAGIJXANFPFN-UHFFFAOYSA-N 0.000 description 4
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- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- IQDGSYLLQPDQDV-UHFFFAOYSA-N dimethylazanium;chloride Chemical compound Cl.CNC IQDGSYLLQPDQDV-UHFFFAOYSA-N 0.000 description 4
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- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 4
- NTHWMYGWWRZVTN-UHFFFAOYSA-N sodium silicate Chemical compound [Na+].[Na+].[O-][Si]([O-])=O NTHWMYGWWRZVTN-UHFFFAOYSA-N 0.000 description 4
- 238000002560 therapeutic procedure Methods 0.000 description 4
- 208000003174 Brain Neoplasms Diseases 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 description 3
- 201000011510 cancer Diseases 0.000 description 3
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- 239000002243 precursor Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- 150000003462 sulfoxides Chemical class 0.000 description 3
- ZRNSSRODJSSVEJ-UHFFFAOYSA-N 2-methylpentacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCC(C)C ZRNSSRODJSSVEJ-UHFFFAOYSA-N 0.000 description 2
- ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 description 2
- 0 C**c1cc([*+](C)*)c(C=O)cc1 Chemical compound C**c1cc([*+](C)*)c(C=O)cc1 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000001335 aliphatic alkanes Chemical class 0.000 description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-O ammonium group Chemical group [NH4+] QGZKDVFQNNGYKY-UHFFFAOYSA-O 0.000 description 2
- 229910052796 boron Inorganic materials 0.000 description 2
- 239000012295 chemical reaction liquid Substances 0.000 description 2
- 238000002512 chemotherapy Methods 0.000 description 2
- 239000003245 coal Substances 0.000 description 2
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 2
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 2
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- 238000001704 evaporation Methods 0.000 description 2
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- HMSWAIKSFDFLKN-UHFFFAOYSA-N hexacosane Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCC HMSWAIKSFDFLKN-UHFFFAOYSA-N 0.000 description 2
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- 229910052943 magnesium sulfate Inorganic materials 0.000 description 2
- 235000019341 magnesium sulphate Nutrition 0.000 description 2
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- -1 methyl-trifluoromethyl sulfonic acid Alkane Chemical class 0.000 description 2
- NBVXSUQYWXRMNV-UHFFFAOYSA-N monofluoromethane Natural products FC NBVXSUQYWXRMNV-UHFFFAOYSA-N 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 239000012217 radiopharmaceutical Substances 0.000 description 2
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- 229920006395 saturated elastomer Polymers 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L sodium carbonate Substances [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 description 2
- 239000007790 solid phase Substances 0.000 description 2
- BDHFUVZGWQCTTF-UHFFFAOYSA-M sulfonate Chemical compound [O-]S(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-M 0.000 description 2
- 230000004083 survival effect Effects 0.000 description 2
- NUMQCACRALPSHD-UHFFFAOYSA-N tert-Butyl ethyl ether Natural products CCOC(C)(C)C NUMQCACRALPSHD-UHFFFAOYSA-N 0.000 description 2
- 210000004881 tumor cell Anatomy 0.000 description 2
- XLYOFNOQVPJJNP-NJFSPNSNSA-N ((18)O)water Chemical compound [18OH2] XLYOFNOQVPJJNP-NJFSPNSNSA-N 0.000 description 1
- CVOFKRWYWCSDMA-UHFFFAOYSA-N 2-chloro-n-(2,6-diethylphenyl)-n-(methoxymethyl)acetamide;2,6-dinitro-n,n-dipropyl-4-(trifluoromethyl)aniline Chemical compound CCC1=CC=CC(CC)=C1N(COC)C(=O)CCl.CCCN(CCC)C1=C([N+]([O-])=O)C=C(C(F)(F)F)C=C1[N+]([O-])=O CVOFKRWYWCSDMA-UHFFFAOYSA-N 0.000 description 1
- USFZMSVCRYTOJT-UHFFFAOYSA-N Ammonium acetate Chemical compound N.CC(O)=O USFZMSVCRYTOJT-UHFFFAOYSA-N 0.000 description 1
- 239000005695 Ammonium acetate Substances 0.000 description 1
- 208000014644 Brain disease Diseases 0.000 description 1
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- 206010058467 Lung neoplasm malignant Diseases 0.000 description 1
- 206010028851 Necrosis Diseases 0.000 description 1
- 238000012879 PET imaging Methods 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000019257 ammonium acetate Nutrition 0.000 description 1
- 229940043376 ammonium acetate Drugs 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
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- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
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- PGXWDLGWMQIXDT-UHFFFAOYSA-N methylsulfinylmethane;hydrate Chemical compound O.CS(C)=O PGXWDLGWMQIXDT-UHFFFAOYSA-N 0.000 description 1
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The present invention provides a kind of midbody compound, the synthetic method of midbody compound and applications.This approach includes the following steps：Under inert gas protection, the dichloromethane solution of compound 2 and the dichloromethane solution of methyl trifluoro methyl sulfonate are mixed, is stirred to react 3h~12h, wherein compound 2：The molar ratio of methyl trifluoro methyl sulfonate is 1:1~5；It isolates and purifies to obtain midbody compound after the completion of reaction.The midbody compound is mainly used in the synthesis of F BPA nucleophilic fluorinations.
Description
Technical field
The invention belongs to radiopharmaceutical field, more particularly to a kind of F-BPA nucleophilic fluorinations synthetic method, intermediate synthesis
Method, intermediate and its application.
Background technology
Boron neutron capture therapy (boron neutron capture therapy, BNCT) is a kind of binary radiotheraping method,
It is will to contain10B drugs are introduced in vivo by oral or injecting method, and are allowed to selectively be gathered in cancer cell, are then used
Neutron exposure diseased region, makes10B occurs10B(n,α)7Li nuclear reactions, using resulting α particles and7Li ions are in cell
Cancer cell is killed in range.Mankind's BNCT clinics examination of brain tumor for the first time, which is controlled, starts from the phase at the beginning of the fifties in last century, by decades
It explores, research and clinical trial, BNCT are considered as a kind of method (5 for the treatment of superficial part glioma of effective treatment tumour
Annual survival rate reach 33.3%), with existing surgical operation, radiotherapy chemotherapy, immunization therapy, gene therapy cancer method phase
Than having the characteristics that accurate positioning, significant in efficacy.Currently, other than glioma treatment, treatment liver cancer, joint are also carried out
The research of the diseases such as necrosis, melanoma, lung cancer.This method, which has become treatment malignant glioma and melanoma at present, most to be had
One of method of effect.
Glioma is grown in the nerveous system of regulation and control physical activity, is in infiltrative growth, Tumor cells growth rate pole
Soon, the therapies such as existing surgical resection, chemotherapy, radiotherapy and X knives, γ knives fail the treatment obtained effect
Fruit.After paresthesia epilepsy, the average survival time of patient is only 4~6 months.Oncotherapy most desired effect is both to kill tumour
Cell and do not damage normal cell and tissue.For brain tumor, this target seems more arduous.BNCT technologies can
To be used for treating brain tumor, it has the characteristics that big partial radiation dosage, Small side effects, protection applied widely and easy, but
Realize that ideal BNCT Medications and remedies development level there are much relations.
For BPA since 1987 are applied to clinical test, therapeutic effect is encouraging, is to apply in the world at most
BNCT drugs, validity and safety are all secure.BPA is unquestionable to the validity of glioma, but in experimental study
The BPA for how monitoring patient's body when how to be quickly obtained its internal medicine for pharmacology data, Clinical practice in real time is distributed to select
The problems such as selecting best opportunity progress neutron beam irradiation becomes the direction that scientist makes great efforts research.As (positron emission is disconnected by PET
Layer imaging) technology development and due to its can non-invasively, dynamically under condition of living organism from molecular level body biochemistry
And physiological change, therefore it is not only the optimal tool of early diagnosis and guiding treatment brain diseases, angiocardiopathy and tumour
One of, and the powerful measure of medicine and pharmacology basic theories and practical problems is studied, it is current contact molecular biology and clinical doctor
Bridge, therefore such as with positron nuclide18F labels BPA can not only study the metabolic processes of BPA in vivo, can more lead to
It crosses PET imagings and grasps the bio distribution states of BPA in vivo in real time, this selection of time that BNCT is treated, treatment effectiveness evaluation
It is of great importance.Thus study18The labeling method of F-BPA, optimization flag condition to BNCT technologies it is extensive carry out and other
The meaning of BNCT medicament research and developments also will be more great.
18The common synthetic method of F labeled drugs have using have carrier [18F]F2Electrophilic reaction method and use are DNAcarrier free
[18F]F-Nucleophilic displacement of fluorine method.Electrophilic reaction method labeling method is easy, step is few, but the method uses gas target, product to have carrier, ratio
Activity is low；And nucleophilic displacement of fluorine method uses H2 18O water targets, product carrier-free, specific activity are high, the shortcomings that overcoming parental materials method, no
Foot place is that labeling method is complicated, step is more.Nucleophilic displacement of fluorine method utilization activity [18F]F-Ion with containing the non-of suitable leaving groups
Labelled precursor occurs nucleophilic substitution and prepares Radiopharmaceuticals for PET, which is to prepare suitable non-marked precursor.Mesh
Before, nucleophilic displacement of fluorine method has become in the world18The main direction of development of F labeled PET tracers preparation researches.
Specific to BPA, for BPA electrophilic fluorination methods, BPA's18F directly it is electrophilic label be by Ishiwata etc. first
Report.Currently,18The preparation of F-BPA mostly uses a step electrophilic method label, the method using electrophilic fluorination agent [18F] AcOF passes through
Phenyl ring parental materials can effectively and rapidly by18F is introduced into organic molecule, but mark rate is low, the specific activity at the end of synthesis
For 35-60MBq/ μm of ol.Total generated time is 80min, is more than 95% through HPLC analysis top coal drawings.2004Deng report
Road one kind can obtain compared with high specific activity [18F] BPA method.This process employs [18F]F-To [18F]F2Target after convert
Carry out electrophilic label.4.8 μm of ol can be reduced to from 100 μm of ol with the amount of this method labelled precursor, before greatly reducing label
The dosage of body.The method Radiochemical yield average out to 3.4% (by [18F]F-Initial amount calculate), the specific activity at the end of synthesis
For 0.85-1.52GBq/ μm of ol.Total generated time is 50min, is more than 96% through HPLC analysis top coal drawings.Coderre in 2002
Etc. being prepared for18F-BPA and in vitro being combined it with T98G glioma cells is studied, the results showed that18F-BPA has height
Binding ability, can inference its in vivo glioma imaging validity.In general, BPA electrophilic fluorinations method need to use F2Gas
Body, and F2Gas is very active, corrosivity is extremely strong, has particular/special requirement to reaction vessel, and operation risk factor is larger, to radiation
Property18F2For, the equipment using special substance is both needed to from target system to synthesis module so that manufacturing cost is high, and is prepared into
It arrives18F2It needs with stablizing F2Gas carries out, this makes also there is stable F (carrier) in product prepared by succeeding marker, drops
The low specific activity of product, influences imaging results.
And for the research of BPA nucleophilic fluorine label, it is up to the present showed no relevant report both at home and abroad.
Invention content
Have that carrier, specific activity are low, manufacturing cost is high to solve product existing for the F-BPA made from BPA electrophilic fluorination methods
The problems such as high, the present invention provides a kind of F-BPA nucleophilic fluorinations synthetic method, intermediate synthetic method, intermediate and its applications.
The F-BPA nucleophilic fluorination synthetic methods include the following steps：
(1) synthesis of compound 2
By compound 1, dimethyl ammonium hydrochloride (NH (CH3)2HCl) be added to by dimethyl sulfoxide (DMSO) and water mixing and
At solvent in, K is added points for 2 times or more2CO3, heating reflux reaction 6h~36h；Wherein, compound 1：Dimethyl ammonium hydrochloride：
K2CO3Molar ratio be 1：1~5：1~5；The structural formula of the reaction and the compound 1 that are occurred is as shown in reaction equation 1；Reaction
It isolates and purifies to obtain compound 2 after the completion；
(2) synthesis of compound 3
Under inert gas protection, by the dichloromethane solution of compound 2 and methyl-trifluoromethyl sulfonic acid
(CF3SO3CH3) dichloromethane solution mix, be stirred to react 3h~12h, wherein compound 2：Methyl-trifluoromethane sulfonic acid
The molar ratio of salt is 1:1~5, the reaction occurred is as shown in reaction equation 2；It isolates and purifies to obtain compound 3 after the completion of reaction；
(3) synthesis of compound 4
To K2.2.2 (4,7,13,16,21,24- six oxygen -1,10- diaza-bicyclos [8.8.8] hexacosane), K2CO3And KF
Mixture in be added dimethyl sulfoxide be allowed to dissolve, be stirred to react 0.5h or more at 90-160 DEG C；The diformazan of compound 3 is added dropwise
Sulfoxide solution, the back flow reaction 15min or more at 90~160 DEG C, the reaction occurred is as shown in reaction equation 3；Wherein, compound
3：K2.2.2：The molar ratio of KF is 1：1~2：1~5；Then dimethyl sulfoxide is removed, residue is dissolved with methanol, crosses Sep-Pak
C18 solid-phase extraction columns；Compound 4 is isolated by being eluted on Sep-Pak C18 solid-phase extraction columns；
(4) synthesis of compound 5
TC18 columns are added after compound 4 is dissolved in water, column are rushed with water, then discharge surplus liquid is blown with gas；NaBH is added4
Reactant aqueous solution 2min or more rushes column with water, then blows discharge surplus liquid with gas；HI reactant aqueous solutions 2min or more is added,
Surplus liquid is arranged with gas, the toluene solution dissolved with compound 5 is afforded with toluene；Wherein, compound 4：NaBH4：HI's
Molar ratio is 1：1~5：1~5, the reaction occurred is as shown in reaction equation 4；
(5) synthesis of compound 6
N- (diphenyl methyl)-glycine t-butyl ester is added into the toluene solution dissolved with compound 5
(Ph2CNCH2CO2 tBu it) and Maruoka chiral phase-transfer catalysts and mixes, reacts 5min or more；HI aqueous solutions and KOH is added
Aqueous solution reacts 3min or more at 150~200 DEG C；Wherein, compound 5：N- (diphenyl methyl)-glycine t-butyl ester
Molar ratio be 1：1~5, the reaction occurred is as shown in reaction equation 5；Isolated compound 6 after the completion of reaction, i.e. target are produced
Object；
It is extended according to one, K used by step (1)2CO3It can be by Na2CO3Instead of.
It is extended according to one, dimethyl sulfoxide described in step (1) can be replaced by acetonitrile or dimethylformamide (DMF).
It is extended according to one, the method for isolating and purifying to obtain compound 2 described in step (1) is：Back flow reaction is obtained
Reaction solution is transferred to saturation K2CO3In aqueous solution, K is removed after layering2CO3Layer；Remaining liq is extracted with extractant, it is right
Obtained extract liquor is washed, and compound 2 is obtained after removing moisture removal and extractant.
Further, described that moisture removal is gone to absorb moisture and vacuum drying using water absorbing agent.
Further, the water absorbing agent can be anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.
Further, the extractant can be ether, tetrahydrofuran (THF), ethyl acetate or tertbutyl ether.
Further, inert gas described in step (2) can be nitrogen, helium or argon gas.
It is extended according to one, dichloromethane can be by chloroform, ethyl acetate, acetone or methanol generation described in step (2)
It replaces.
It is extended according to one, the method for isolating and purifying to obtain compound 3 described in step (2) is：By precipitation obtained by the reaction
Object removes impurity with 4 DEG C of dichloromethane below and 4 DEG C of ether cleanings below successively, and compound 3 is obtained after vacuum drying.
It is extended according to one, dimethyl sulfoxide can be by acetonitrile, dimethylformamide (DMF) or tetrahydrochysene described in step (3)
Furans (THF) replaces.
It is extended according to one, methanol can be by ethyl alcohol, isopropanol, acetone, ethyl acetate or dichloromethane described in step (3)
Alkane replaces.
It is extended according to one, the method that separation is eluted described in step (3) is：The salt of ether, 0.1-2mol/L are used successively
Acid, water and dichloromethane elute Sep-Pak C18 solid-phase extraction columns, collect the elution that dichloromethane eluent process generates
Liquid removes moisture and dichloromethane.
Further, the removing moisture absorbs moisture using water absorbing agent.
Further, the water absorbing agent can be anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.
Further, the removing dichloromethane uses rotary evaporation and vacuum drying.
Further, gas described in step (4) can be nitrogen, helium or argon gas.
Further, a concentration of 57wt% or more of HI aqueous solutions described in step (4).
It is extended according to one, toluene can be replaced by benzene, dimethylbenzene or chlorobenzene described in step (4).
Further, a concentration of 57wt% or more of HI aqueous solutions described in step (5).
It is extended according to one, KOH described in step (5) can be replaced by NaOH or LiOH.
It is extended according to one, the separation method of isolated compound 6 described in step (5) is：Evaporation removes toluene, uses
Silican columns are first added in 20~100mmol/L acetic acid residues, acquired solution, with 20~100mmol/L acetic acid aqueous solutions
Then tC18 columns are added in elution, eluted with 20~100mmol/L acetic acid aqueous solutions, and compound 6 is obtained after dry eluent.
Further, KF described in step (3) uses K18F, to synthesize18F-BPA。
It is extended according to one, the present invention also provides a kind of midbody compounds 2, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 2 includes the following steps：Compound 1, dimethyl ammonium hydrochloride are added
Into the solvent mixed by dimethyl sulfoxide and water, divides 2 times or more and K is added2CO3, heating reflux reaction 6h~36h；Wherein,
Compound 1：Dimethyl ammonium hydrochloride：K2CO3Molar ratio be 1：1~5：1~5；It isolates and purifies to obtain intermediate after the completion of reaction
Compound 2.
The application of above-mentioned midbody compound 2：It is synthesized for F-BPA nucleophilic fluorinations.
It is extended according to one, the present invention also provides a kind of midbody compounds 3, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 3 includes the following steps：Under inert gas protection, by compound 2
The dichloromethane solution of dichloromethane solution and methyl-trifluoromethyl sulfonic acid mixes, and is stirred to react 3h~12h, wherein changes
Close object 2：The molar ratio of methyl-trifluoromethyl sulfonic acid is 1:1~5；It isolates and purifies to obtain midbody compound after the completion of reaction
3。
Further, the inert gas can be nitrogen, helium or argon gas.
It is extended according to one, the dichloromethane can be replaced by chloroform, ethyl acetate, acetone or methanol.
It is extended according to one, the method for isolating and purifying to obtain midbody compound 3 is：By sediment obtained by the reaction
Impurity is removed with 4 DEG C of dichloromethane below and 4 DEG C of ether cleanings below successively, midbody compound is obtained after vacuum drying
3。
The application of above-mentioned midbody compound 3：It is synthesized for F-BPA nucleophilic fluorinations.
It is extended according to one, the present invention also provides a kind of midbody compounds 4, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 4 includes the following steps：To K2.2.2, K2CO3And K18In the mixture of F
Dimethyl sulfoxide is added dropwise to be allowed to dissolve, 0.5h or more is stirred to react at 90-160 DEG C；The dimethyl sulfoxide solution of compound 3 is added dropwise,
The back flow reaction 15min or more at 90~160 DEG C；Wherein, compound 3：K2.2.2：K18The molar ratio of F is 1：1~2：1~5；
Then dimethyl sulfoxide is removed, residue is dissolved with methanol, crosses Sep-Pak C18 solid-phase extraction columns；Extracted by Sep-Pak C18 solid phases
Elution on column is taken to isolate midbody compound 4.
The application of above-mentioned midbody compound 4：It is synthesized for F-BPA nucleophilic fluorinations.
It is extended according to one, the present invention also provides a kind of midbody compounds 5, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 5 includes the following steps：TC18 columns are added after compound 4 is dissolved in water,
Column is rushed with water, then discharge surplus liquid is blown with gas；NaBH is added4Reactant aqueous solution 2min or more rushes column with water, then uses gas
Blow discharge surplus liquid；HI reactant aqueous solutions 2min or more is added, arranges surplus liquid with gas, is afforded dissolved in toluene
The toluene solution of intermediate compounds therefor 5；Wherein, compound 4：NaBH4：The molar ratio of HI is 1：1~5：1~5.
The application of above-mentioned midbody compound 5：It is synthesized for F-BPA nucleophilic fluorinations.
The present invention synthesizes F-BPA using nucleophilic displacement of fluorine method, and nucleophilic fluorination process, which uses, stablizes F-Or radioactivity18F-For parent
Nuclear attack reagent, avoids F2The harm of gas.Prepare radioactivity18F-When need not stablize F carrier band, this makes succeeding marker system
Stable F (carrier), i.e. products therefrom carrier-free will not be introduced in standby product, therefore its specific activity is high, can significantly improve PET
Image quality.18The radiosynthesis time of F-BPA preparation process is no more than 100min, and radiochemical purity is up to 98%, energy
It is enough preferably to meet18The requirement of F-BPA clinical applications.
Description of the drawings
Fig. 1 is made from the embodiment of the present invention 218The radiochemistry collection of illustrative plates of F-BPA.
Specific implementation mode
Below with reference to the embodiments and with reference to the accompanying drawing the technical solutions of the present invention will be further described.Below
Detailed description in, for ease of explain, elaborate many concrete details to provide the comprehensive understanding to the embodiment of the present invention.So
And it is apparent that one or more embodiments can also be carried out without these specific details.Although in conjunction with attached drawing
The present invention is described, but embodiment disclosed in attached drawing is intended to carry out exemplary theory to embodiments of the present invention
It is bright, and should not be understood as a kind of limitation to the present invention.
According to embodiment of the present invention, provide a kind of F-BPA nucleophilic fluorinations synthetic method, this method include with
Lower step：
(1) synthesis of compound 2
Compound 1, dimethyl ammonium hydrochloride are added in the solvent mixed by dimethyl sulfoxide and water, points 2 times with
Upper addition K2CO3, heating reflux reaction 6h~36h；Wherein, compound 1：Dimethyl ammonium hydrochloride：K2CO3Molar ratio be 1：1
~5：1~5；The structural formula of the reaction and the compound 1 that are occurred is as shown in reaction equation 1；It is isolated and purified after the completion of reaction
To compound 2.
(2) synthesis of compound 3
Under inert gas protection, by the dichloromethane of the dichloromethane solution of compound 2 and methyl-trifluoromethyl sulfonic acid
Alkane solution mixes, and is stirred to react 3h~12h, wherein compound 2：The molar ratio of methyl-trifluoromethyl sulfonic acid is 1:1~
5, the reaction occurred is as shown in reaction equation 2；It isolates and purifies to obtain compound 3 after the completion of reaction.
(3) synthesis of compound 4
To K2.2.2, K2CO3It is allowed to dissolve with dimethyl sulfoxide is added in the mixture of KF, be stirred to react at 90-160 DEG C
0.5h or more；The dimethyl sulfoxide solution of compound 3 is added dropwise, the back flow reaction 15min or more at 90~160 DEG C, what is occurred is anti-
It should be as shown in reaction equation 3；Wherein, compound 3：K2.2.2：The molar ratio of KF is 1：1~2：1~5；Then dimethyl sulfoxide is removed,
Residue is dissolved with methanol, crosses Sep-Pak C18 solid-phase extraction columns；It is isolated by being eluted on Sep-Pak C18 solid-phase extraction columns
Compound 4.
(4) synthesis of compound 5
TC18 columns are added after compound 4 is dissolved in water, column are rushed with water, then discharge surplus liquid is blown with gas；NaBH is added4
Reactant aqueous solution 2min or more rushes column with water, then blows discharge surplus liquid with gas；HI reactant aqueous solutions 2min or more is added,
Surplus liquid is arranged with gas, the toluene solution dissolved with compound 5 is afforded with toluene；Wherein, compound 4：NaBH4：HI's
Molar ratio is 1：1~5：1~5, the reaction occurred is as shown in reaction equation 4；
(5) synthesis of compound 6
Be added into the toluene solution dissolved with compound 5 N- (diphenyl methyl)-glycine t-butyl ester and
Maruoka chiral phase-transfer catalysts simultaneously mix, and react 5min or more；HI aqueous solutions and KOH aqueous solutions is added, in 150~200
3min or more is reacted at DEG C；Wherein, compound 5：The molar ratio of N- (diphenyl methyl)-glycine t-butyl ester is 1：1~5,
The reaction occurred is as shown in reaction equation 5；Isolated compound 6, i.e. target product after the completion of reaction.
According to an example, K used by step (1)2CO3It can be by Na2CO3Instead of.
According to an example, dimethyl sulfoxide described in step (1) can be replaced by acetonitrile or dimethylformamide.
According to an example, the method for isolating and purifying to obtain compound 2 described in step (1) is：Back flow reaction is obtained
Reaction solution is transferred to saturation K2CO3In aqueous solution, K is removed after layering2CO3Layer；Remaining liq is extracted with extractant, it is right
Obtained extract liquor is washed, and compound 2 is obtained after removing moisture removal and extractant.
Further, described that moisture removal is gone to absorb moisture and vacuum drying using water absorbing agent.
Further, the water absorbing agent can be anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.
Further, the extractant can be ether, tetrahydrofuran, ethyl acetate or tertbutyl ether.
Further, inert gas described in step (2) can be nitrogen, helium or argon gas.
According to an example, dichloromethane can be by chloroform, ethyl acetate, acetone or methanol generation described in step (2)
It replaces.
According to an example, the method for isolating and purifying to obtain compound 3 described in step (2) is：By precipitation obtained by the reaction
Object removes impurity with 4 DEG C of dichloromethane below and 4 DEG C of ether cleanings below successively, and compound 3 is obtained after vacuum drying.
According to an example, dimethyl sulfoxide can be by acetonitrile, dimethylformamide or tetrahydrofuran described in step (3)
Instead of.
According to an example, methanol can be by ethyl alcohol, isopropanol, acetone, ethyl acetate or dichloromethane described in step (3)
Alkane replaces.
According to an example, the method that separation is eluted described in step (3) is：The salt of ether, 0.1-2mol/L are used successively
Acid, water and dichloromethane elute Sep-Pak C18 solid-phase extraction columns, collect the elution that dichloromethane eluent process generates
Liquid removes moisture and dichloromethane.
Further, the removing moisture absorbs moisture using water absorbing agent.
Further, the water absorbing agent can be anhydrous magnesium sulfate, anhydrous sodium sulfate, anhydrous calcium chloride or molecular sieve.
Further, the removing dichloromethane uses rotary evaporation and vacuum drying.
Further, gas described in step (4) can be nitrogen.
Further, a concentration of 57wt% or more of HI aqueous solutions described in step (4).
According to an example, toluene described in step (4) can be replaced by benzene, dimethylbenzene or chlorobenzene.
Further, a concentration of 57wt% or more of HI aqueous solutions described in step (5).
According to an example, KOH described in step (5) can be replaced by NaOH or LiOH.
According to an example, the separation method of isolated compound 6 described in step (5) is：Evaporation removes toluene, uses
Silican columns are first added in 20~100mmol/L acetic acid residues, acquired solution, with 20~100mmol/L acetic acid aqueous solutions
Then tC18 columns are added in elution, eluted with 20~100mmol/L acetic acid aqueous solutions, and compound 6 is obtained after dry eluent.
Further, KF described in step (3) uses K18F, to synthesize18F-BPA。
According to an example, the present invention also provides a kind of midbody compounds 2, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 2 includes the following steps：Compound 1, dimethyl ammonium hydrochloride are added
Into the solvent mixed by dimethyl sulfoxide and water, divides 2 times or more and K is added2CO3, heating reflux reaction 6h~36h；Wherein,
Compound 1：Dimethyl ammonium hydrochloride：K2CO3Molar ratio be 1：1~5：1~5；It isolates and purifies to obtain intermediate after the completion of reaction
Compound 2.
The application of above-mentioned midbody compound 2：It is synthesized for F-BPA nucleophilic fluorinations.
According to an example, the present invention also provides a kind of midbody compounds 3, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 3 includes the following steps：Under inert gas protection, by compound 2
The dichloromethane solution of dichloromethane solution and methyl-trifluoromethyl sulfonic acid mixes, and is stirred to react 3h~12h, wherein changes
Close object 2：The molar ratio of methyl-trifluoromethyl sulfonic acid is 1:1~5；It isolates and purifies to obtain midbody compound after the completion of reaction
3。
The application of above-mentioned midbody compound 3：It is synthesized for F-BPA nucleophilic fluorinations.
According to an example, the present invention also provides a kind of midbody compounds 4, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 4 includes the following steps：To K2.2.2, K2CO3And K18In the mixture of F
Dimethyl sulfoxide is added dropwise to be allowed to dissolve, 0.5h or more is stirred to react at 90-160 DEG C；The dimethyl sulfoxide solution of compound 3 is added dropwise,
The back flow reaction 15min or more at 90~160 DEG C；Wherein, compound 3：K2.2.2：K18The molar ratio of F is 1：1~2：1~5；
Then dimethyl sulfoxide is removed, residue is dissolved with methanol, crosses Sep-Pak C18 solid-phase extraction columns；Extracted by Sep-Pak C18 solid phases
Elution on column is taken to isolate midbody compound 4.
The application of above-mentioned midbody compound 4：It is synthesized for F-BPA nucleophilic fluorinations.
According to an example, the present invention also provides a kind of midbody compounds 5, and structural formula is as follows：
The synthetic method of above-mentioned midbody compound 5 includes the following steps：TC18 columns are added after compound 4 is dissolved in water,
Column is rushed with water, then discharge surplus liquid is blown with gas；NaBH is added4Reactant aqueous solution 2min or more rushes column with water, then uses gas
Blow discharge surplus liquid；HI reactant aqueous solutions 2min or more is added, arranges surplus liquid with gas, is afforded dissolved in toluene
The toluene solution of intermediate compounds therefor 5；Wherein, compound 4：NaBH4：The molar ratio of HI is 1：1~5：1~5.
The application of above-mentioned midbody compound 5：It is synthesized for F-BPA nucleophilic fluorinations.
Embodiment 1：
The present embodiment is related to the nucleophilic fluorination synthesis of F-BPA, and building-up process includes the following steps：
(1) synthesis of compound 2
Add 0.84g compounds 1,0.82g dimethyl ammoniums hydrochloride, 0.83g K in three-necked bottle2CO3, add 20mL dimethyl sulfoxides
With the reaction dissolvent of 8mL water composition, back flow reaction 2h, 0.55g K are added in side port2CO3, continue back flow reaction 4h, reaction solution dropped
To room temperature, stop reaction, 40mL, which is added, in reaction solution is saturated K2CO3In aqueous solution, reaction solution is divided into two layers, with separatory funnel point
Go out to use K2CO3Layer, residual reaction liquid add diethyl ether 30mL extractions twice, and combined ether layer, ether layer is washed once with 30mL, adds nothing
Water magnesium sulfate is dried overnight.It is filtered to remove anhydrous magnesium sulfate, ether solution is rotated to faint yellow solid is done to obtain, and is dried in vacuo to obtain chemical combination
Object 2.Compound 2 is in yellow powder, which is 61%,1HNMR、13CNMR spectrograms show that structure is correct.1HNMR
(400MHz, dimethyl sulfoxide) δ (ppm) 2.06 (s, 6H ,-CH3) 2.49 (s, solvent peaks), 2.85 (s, 2H ,-B-OH), 6.80,
6.82,7.68 (3H, fragrant hydrogen), 10.24 (s, 1H ,-CHO).13CNMR (dimethyl sulfoxide):δ(ppm)190.0,
146.2,135.3,131.1,121.2,119.4,114.2,43.6。
(2) synthesis of compound 3
Add 0.97g compounds 2 in three-necked bottle, adds 15mL dichloromethane to dissolve, in N2Under protection, 1.64g methyl-three is added
Methyl fluoride sulfonate is dissolved in 2mL dichloromethane acquired solutions, at room temperature, is stirred to react 3h, reaction solution is gradually become from faint yellow
Green eventually becomes red, occurs a large amount of precipitations in reaction solution.Filtering precipitate, respectively with cold 20mL dichloromethane and
50mL washed with ether precipitates, and sediment gradually becomes white, is dried in vacuo to obtain compound 3.Compound 3 is white powdered, should
It is 88% to walk yield.1HNMR、13CNMR spectrograms show that structure is correct.1HNMR (400MHz, dimethyl sulfoxide) δ (ppm) 2.34 (s,
9H ,-CH3), 3.25 (s, 2H ,-B-OH), 7.19,7.21,7.45, (3H, fragrant hydrogen), 10.31 (s, 1H ,-CHO).13CNMR (two
First sulfoxide):δ(ppm)193.1,149.2,138.6,136.1,130.5,129.0,125.3,62.8,26.8.
(3) synthesis of compound 4
In three-neck flask, 1.67g K2.2.2,0.5g K is added2CO3, 438mg KF, then by dropping funel be added 30mL without
Water dimethyl sulfoxide dissolves, and at 120-130 DEG C of oil bath, heating stirring reacts 1h, and 1.05g compounds 3 are dissolved in 10mL anhydrous dimethyls
Sulfoxide is slowly dropped by dropping funel in reaction solution, becomes deep burnt sugar coloring with the instillation reaction solution of compound 3,120-130 DEG C is returned
Stream is stirred to react 30min, stops reaction, is cooled to room temperature, and vacuum distillation removes solvent dimethyl sulfoxide, and bottoms methanol is molten
Solution crosses Sep-Pak C18 solid-phase extraction columns, uses ether, 0.5mol/L HCl solutions and water elution respectively, finally uses dichloromethane
Anhydrous magnesium sulfate drying, filtering is added in elution, eluent, and filtrate rotates to doing, obtains Tan solid, be dried in vacuo to obtain compound
4.Compound 4 is in pale yellow powder shape, which is 57%.1HNMR、13CNMR spectrograms show that structure is correct.1HNMR
(400MHz, dimethyl sulfoxide):δ (ppm) 2.09 (s, 2H ,-B-OH), 2.51 (s, solvent peaks), 7.49,7.51,8.12 (3H, virtue
Hydrogen), 10.32 (s, 1H ,-CHO).13CNMR (dimethyl sulfoxide):δ(ppm)193.0,163.1,136.2,131.4,
125.8,124.4,116.5。
(4) synthesis of compound 5
1.05g compounds 4 are dissolved in water to 6mL, is added on the tC18 columns handled well in advance, column is rushed with 20mL water, then
Discharge surplus liquid is blown with nitrogen.It is slowly added to 3mL NaBH4Solution (100mg/mL) reacts 2min, adds water to rush column, then use nitrogen
Surplus liquid is discharged in air-blowing 15s.It is slowly added to 1mL HI (57wt%) solution, reacts at room temperature 2min, surplus liquid is arranged with nitrogen,
15mL toluene is added to elute to obtain compound 5.The yield of compound 5 is 77%.1HNMR、13CNMR spectrograms show that structure is correct.1HNMR
(400MHz, dimethyl sulfoxide):δ (ppm) 1.99 (s, 2H ,-B-OH), 4.44 (s, 2H ,-CH2) 7.89,8.14,8.22 (3H, virtue
Hydrogen).13CNMR (dimethyl sulfoxide):δ(ppm)162.3,133.1,129.2,126.4,124.8,116.5.
(5) synthesis of compound 6
Toluene eluent is transferred in reaction bulb, add N- (diphenyl methyl)-glycine t-butyl ester 1.5g,
After Maruoka chiral phase-transfer catalysts 5mg is sufficiently mixed, 5min is reacted at room temperature, adds HI (57wt%) solution 1.50mL,
9mol/LKOH solution 1mL are heated to 180 DEG C of reaction 3min, and solvent is evaporated off in heating, residual with the acetic acid of 50mmol/L
Slag, is added pretreated Silican columns and tC18 columns, the elution of 50mmol/L acetic acid, and eluent is rotated to doing, is dried in vacuo
Compound 6.Compound 6 is white powdered, yield 86%.1HNMR、13CNMR, MS spectrogram show that structure is correct.1HNMR
(400MHz,TFA):δ(ppm)1.98(s,1H,CH),2.34(2H,-CH2),3.32(s,2H,NH2),4.06(s,2H,-B-
), OH 7.32,7.51,8.12 (3H, fragrant hydrogen), 11.13 (s, 1H ,-COOH).13CNMR(TFA):δ(ppm)177.0,162.1,
141.9,130.2,124.4,115.1,112.8,62.5,39.4.So far, by continuous 5 step organic synthesis, with nucleophilic fluorine
Change substitution technique and be prepared F-L-BPA, gross production rate is up to 20%, total reaction time about 2h.
Embodiment 2
The present embodiment is related to18The nucleophilic fluorination of F-BPA synthesizes, and building-up process includes the following steps：
(1) synthesis of compound 2
Add 0.84g compounds 1,0.82g dimethyl ammoniums hydrochloride, 0.83g K in three-necked bottle2CO3, add 20mL dimethyl sulfoxides
With the reaction dissolvent of 8mL water composition, back flow reaction 2h, 0.55g K are added in side port2CO3, continue back flow reaction 4h, reaction solution dropped
To room temperature, stop reaction, 40mL, which is added, in reaction solution is saturated K2CO3In aqueous solution, reaction solution is divided into two layers, with separatory funnel point
Go out to use K2CO3Layer, residual reaction liquid add diethyl ether 30mL extractions twice, and combined ether layer, ether layer is washed once with 30mL, adds nothing
Water magnesium sulfate is dried overnight.It is filtered to remove anhydrous magnesium sulfate, ether solution is rotated to faint yellow solid is done to obtain, and is dried in vacuo to obtain chemical combination
Object 2.Compound 2 is in yellow powder, which is 61%,1HNMR、13CNMR spectrograms show that structure is correct.1HNMR
(400MHz, dimethyl sulfoxide) δ (ppm) 2.06 (s, 6H ,-CH3) 2.49 (s, solvent peaks), 2.85 (s, 2H ,-B-OH), 6.80,
6.82,7.68 (3H, fragrant hydrogen), 10.24 (s, 1H ,-CHO).13CNMR (dimethyl sulfoxide):δ(ppm)190.0,
146.2,135.3,131.1,121.2,119.4,114.2,43.6。
(2) synthesis of compound 3
Add 0.97g compounds 2 in three-necked bottle, adds 15mL dichloromethane to dissolve, in N2Under protection, 1.64g methyl-three is added
Methyl fluoride sulfonate is dissolved in 2mL dichloromethane acquired solutions, at room temperature, is stirred to react 3h, reaction solution is gradually become from faint yellow
Green eventually becomes red, occurs a large amount of precipitations in reaction solution.Filtering precipitate, respectively with cold 20mL dichloromethane and
50mL washed with ether precipitates, and sediment gradually becomes white, is dried in vacuo to obtain compound 3.Compound 3 is white powdered, should
It is 88% to walk yield.1HNMR、13CNMR spectrograms show that structure is correct.1HNMR (400MHz, dimethyl sulfoxide) δ (ppm) 2.34 (s,
9H ,-CH3), 3.25 (s, 2H ,-B-OH), 7.19,7.21,7.45, (3H, fragrant hydrogen), 10.31 (s, 1H ,-CHO).13CNMR (two
First sulfoxide):δ(ppm)193.1,149.2,138.6,136.1,130.5,129.0,125.3,62.8,26.8.
(3) synthesis of compound 4'
Accelerator is produced18F-The QMA columns activated are added in 400 μ L of solution (activity about 25mCi), with preparation
Good K2.2.2/K2CO3500 μ L of solution (K2.2.2 contents are 8.85 μm of ol) are eluted in glass reaction bottle, and reaction bulb is extremely added
It is heated to closely doing for 120 DEG C in heat block, adds 100 μ L acetonitriles and be heated to closely doing (being repeated 3 times).After last time is evaporated, wait for anti-
After answering bottle to cool down, the solution that 2.1mg (6.0 μm of ol) compound 3 is dissolved in 500 μ L anhydrous dimethyl sulfoxides is added into residue, it will
Reaction bulb is heated to 140 DEG C of reaction 10min on heat block and obtains compound 4'.
(4) synthesis of compound 5'
Compound 4' in reaction bulb is diluted with water to 3mL, is added on the tC18 columns handled well in advance, is rushed with 10mL water
Column, then blow 15s with nitrogen and surplus liquid is discharged.It is slowly added to 1mL NaBH4Solution (1mg/mL) reacts 2min, water is added to rush column,
15s is blown with nitrogen surplus liquid is discharged again.10 μ L HI (57wt%) solution are slowly added to, 2min is reacted at room temperature, are arranged with nitrogen more
Extraction raffinate body adds 3mL toluene to elute to obtain compound 5'.
(5) synthesis of compound 6'
Toluene eluent is transferred in reaction bulb, 3mg N- (diphenyl methyl)-glycine t-butyl ester 3mg is added
(10.2
μm ol), after Maruoka chiral phase-transfer catalysts 0.5mg is sufficiently mixed, reacts 5min at room temperature, add HI
150 μ L, 9mol/L KOH solution of (57wt%) solution, 100 μ L, are heated to 180 DEG C of reaction 3min, and heating is evaporated off solvent toluene, uses
The acetic acid residue of 50mmol/L, is added pretreated Silican columns and tC18 columns, and 50mmol/L acetic acid elutes to obtain chemical combination
Object 6', i.e.,18F-L-BPA。
Through multistep organic synthesis,18F-BPA total generated time about 100min, synthesis terminate to obtain 130MBq products (warp
Decay correction), Radiochemical yield about 26%.Product emissions chemical purity is measured by thin-layered chromatography, and point sample is in silica gel thin-layer
On plate, with ammonium acetate solution (a concentration of 10mmolL-1)：Acetonitrile=30:The mixed solution of 70 (volume ratios) is solvent exhibition
It opens, its radiochemistry collection of illustrative plates is measured by mini-scan radio thin layer's scanners after drying, the results show that putting for product is made
Chemical purity is penetrated up to 98%.
Although being shown and having illustrated according to some embodiments of present general inventive concept, however, ordinary skill
Personnel should be understood that in the case of the principle and spirit without departing substantially from the present general inventive concept, can be made to these embodiments
Change, the scope of the present invention is limited with claim and their equivalent.
Claims (6)
1. a kind of midbody compound, it is characterised in that its structural formula is as follows：
2. a kind of synthetic method of midbody compound as described in claim 1, it is characterised in that this approach includes the following steps：
Under inert gas protection, by the dichloromethane solution phase of the dichloromethane solution of compound 2 and methyl-trifluoromethyl sulfonic acid
Mixing, is stirred to react 3h~12h, wherein compound 2：The molar ratio of methyl-trifluoromethyl sulfonic acid is 1:1~5；It has reacted
It isolates and purifies to obtain midbody compound after；The structural formula of the compound 2 is as follows：
3. synthetic method as claimed in claim 2, it is characterised in that：The inert gas is nitrogen, helium or argon gas.
4. synthetic method as claimed in claim 2, it is characterised in that：The dichloromethane is by chloroform, ethyl acetate, third
Ketone or methanol replace.
5. such as claim 2-4 any one of them synthetic methods, it is characterised in that：It is described to isolate and purify to obtain intermediate compound
The method of object is：Sediment obtained by the reaction is removed into impurity elimination with 4 DEG C of dichloromethane below and 4 DEG C of ether cleanings below successively
Matter obtains midbody compound after vacuum drying.
6. a kind of application of midbody compound as described in claim 1, it is characterised in that be applied to F-BPA nucleophilic fluorinations
Synthesis.
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| TW201533013A (en) * | 2014-02-28 | 2015-09-01 | 史鐵勒製藥股份有限公司 | Method for producing 4-borono-L-phenylalanine introduced with 18F atom and a derivative of 4-borono-L-phenylalanine introduced with 18F atom |
| JP2016204314A (en) * | 2015-04-23 | 2016-12-08 | 国立研究開発法人理化学研究所 | Compound and method for producing 4-boronophenylalanine derivative |
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