CN1976728A - Contrast agents for myocardial perfusion imaging. - Google Patents

Contrast agents for myocardial perfusion imaging. Download PDF

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CN1976728A
CN1976728A CN 200580021474 CN200580021474A CN1976728A CN 1976728 A CN1976728 A CN 1976728A CN 200580021474 CN200580021474 CN 200580021474 CN 200580021474 A CN200580021474 A CN 200580021474A CN 1976728 A CN1976728 A CN 1976728A
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contrast agent
imaging moiety
imaging
hydrogen
milliliters
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H·S·拉德克
D·S·卡斯比尔
M·T·阿祖尔
D·D·迪施诺
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Bristol Myers Squibb Pharma Co
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Bristol Myers Squibb Pharma Co
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Abstract

The present disclosure is directed, in part, to compounds and methods for imaging myocardial perfusion, comprising administering to a patient a contrast agent which comprises a compound that binds MC-1, and an imaging moiety, and scanning the patient using diagnostic imaging.

Description

The contrast agent of myocardial perfusion imaging
The disclosure relates to the noval chemical compound that comprises imaging moiety and they are used to diagnose the purposes of some disease of patient.
Mitochondrion is the membrane-enclosed organelle that distributes by most of eukaryotic cytosoles.Especially enrichment in cardiac muscular tissue of mitochondrion.
Complex 1 (" MC-1 ") is film-bonded protein complex with 46 different subunits.This kind of enzyme complex is one that constitutes in the mammal mitochondrion in the three kinds of energy-conversion complex of respiratory chain.This NADH-ubiquinone oxide-reductase enzyme is the inlet point of most of electronics, and it passes respiratory chain, cause at last hydrogen reduction be water (Q.Rev.Biophys.1992,25,253-324).
The inhibitor of known MC-1 comprises deguelin, piericidin A, ubicidin-3, rolliniastatin-1, rolliniastatin-2 (bullatacin), capsaicin, pyridaben (pyridaben), fragrant general demodicid mite (fenpyroximate), amytal, MPP+, (BBA 1998 for quinoline and quinolinones, 1364,222-235).
Disclosure part is based on following understanding: block advantageously some chemical compound of enrichment in mitochondrion of mitochondrial normal function, and these chemical compounds of enrichment in being rich in mitochondrial cardiac muscular tissue thus.If, so just can detect this combination, can provide valuable diagnosis to indicate for myocardial perfusion imaging thus with these chemical compounds of imaging moiety labelling.Concerning this description, when the imaging part was connected with chemical compound, chemical compound was called as " labelling " chemical compound.
In one embodiment, the disclosure provides contrast agent, and it comprises the poly-acetic acid of imaging moiety and annonaceae, and quinone gathers acetic acid, the chromone of replacement and open chain deguelin analog.
In another embodiment, the disclosure provides contrast agent, and it comprises the poly-acetic acid (acetogenin) of imaging moiety and annonaceae.The poly-acetic acid of annonaceae is a compounds that is come representation feature by an end by the functionalized aliphatic chain of furanone.They are isolating from annonaceae (Annonaceae) plant classification at first, it is reported that they have high activity to various tumor cell lines, and compare with MC-1, and its inhibitory action is very high.Such compound-base is divided into three classes usually in the centre of molecule: adjacent double tetrahydrofuran, and non-adjacent double tetrahydrofuran and single oxolane, its relative activity is with these descend in proper order (Nakanishi, 2003).
Experimental evidence shows that the structure of adjacent oxolane ring is not the pivotal role factor (Miyoshi, 1998) of SAR (structure-activity relationship).For example, the IC with MC-I as follows 50The trilobacin of value report and the inhibition activity of bullatacin are mutually the same in the experimental error scope.
Figure A20058002147400141
Other example that has the poly-acetic acid of annonaceae of adjacent oxolane ring comprises:
Figure A20058002147400142
The poly-acetic acid that has the annonaceae of non-adjacent double tetrahydrofuran typically has a pair of oxolane, and its carbochain by C-4 to C-8 length connects.In addition, as if relevant spatial chemistry does not have the huge effect shown in the high activity of following bullatalicin and sylvaticin.These chemical compound difference only are that the THF ring condenses and hydroxyl chirality (trans:threo vs.cis:threo).
Figure A20058002147400151
Although the poly-acetic acid of single oxolane annonaceae tends to less activity, they still have significant activity, and provide and be more prone to synthetic target.The example that has the poly-acetic acid of annonaceae of single oxolane ring comprises:
Except that 4 of furan nucleus or the α position, the replacement that lactone-furan connects base has typically reduced activity.Under the situation of murihexocin, can change the effectiveness of chemical compound up hill and dale:
Recently, the report (Jiang, 2002) of glycol ether as double T HF part alternative disclosed.These chemical compounds have outstanding antitumor performance, but they are not directly tested at MC-1.Infer that they will show good activity, and can very directly synthesize:
Thus, in an embodiment of the present disclosure, contrast agent has general formula (I)
Figure A20058002147400162
Wherein
M is 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14;
N is 0,1,2,3,4,5,6,7 or 8;
O is 0 or 1;
P is 5,6,7,8,9,10,11 or 12;
---expression does not exist or singly-bound;
When--when-expression did not exist, A and B were independently selected from hydrogen and imaging moiety;
When---when being singly-bound, each (C (R naturally of A and B 1) 2) k
K is 1 or 2, and condition is as each (C (R naturally of A and B 1) 2) kThe time, a k is 1, and other is 1 or 2;
R 1, R 2, R 4, R 5, R 7, R 8, R 10, R 15And R 16Be hydrogen, hydroxyl or imaging moiety independently when occurring at every turn;
R 3Be hydrogen, hydroxyl or imaging moiety;
R 3 'Be hydrogen; Or
R 3And R 3 'And form C=O or C=CR with the carbon atom that they are connected 13R 14;
R 6Be hydrogen, hydroxyl or imaging moiety;
R 6 'Be hydrogen; Or
R 6And R 6 'And form C=O or C=CR with the carbon atom that they are connected 13R 14
R 9Be hydrogen, hydroxyl or imaging moiety;
R 9 'Be hydrogen; Or
R 9And R 9 'And form C=O or C=CR with the carbon atom that they are connected 13R 14
R 11Be C 1-C 6Alkyl; With
R 12, R 13And R 14Be hydrogen, the optional C that is replaced by imaging moiety independently 1-C 6Alkyl, aralkyl or imaging moiety;
Condition is that at least one imaging moiety exists in general formula (I).
In another embodiment, R 4It is imaging moiety.
In another embodiment, R 5It is imaging moiety.
In another embodiment, R 8It is imaging moiety.
In another embodiment, R 9It is imaging moiety.
In another embodiment, the disclosure provides contrast agent, and it comprises the poly-acetic acid of imaging moiety and annonaceae, and wherein contrast agent is:
Wherein x is 0,1,2,3,4,5 or 6.
In another embodiment, the disclosure provides contrast agent, and it comprises the poly-acetic acid of imaging moiety annonaceae, and wherein contrast agent is:
Wherein x is 0,1,2,3,4,5 or 6.
In another embodiment, the disclosure provides contrast agent, and it comprises the poly-acetic acid of imaging moiety and annonaceae, and wherein contrast agent is:
Wherein x is 0,1,2,3,4,5,6,7 or 8.
In another embodiment, the disclosure provides contrast agent, and it comprises the poly-acetic acid of imaging moiety and annonaceae, and wherein contrast agent is:
Figure A20058002147400201
Wherein n ' is 0,1,2,3,4,5,6,7,8,9 or 10 when occurring at every turn independently; With
Wherein n " is 2,3,4,5,6,7,8,9 or 10 when occurring at every turn independently.
In another embodiment, the disclosure provides contrast agent, and it comprises that the imaging moiety quinone gathers acetic acid, and wherein contrast agent has general formula (II):
Wherein
Q is 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14;
R is 0,1,2,3,4,5,6,7 or 8;
S is 0 or 1;
T is 5,6,7,8,9,10,11 or 12;
---expression does not exist or singly-bound;
When--when-expression did not exist, D and E were independently selected from hydrogen and imaging moiety;
When---when being singly-bound, each (C (R naturally of D and E 15) 2) u
U is 1 or 2, and condition is as each (C (R naturally of D and E 15) 2) uThe time, a u is 1, and other is 1 or 2;
R 15, R 16, R 18, R 19, R 21And R 22Be hydrogen, hydroxyl or imaging moiety independently when occurring at every turn;
R 17Be hydrogen, hydroxyl or imaging moiety;
R 17 'Be hydrogen; Or
R 17And R 17 'And form C=O or C=CR with the carbon atom that they are connected 27R 28
R 20Be hydrogen, hydroxyl or imaging moiety;
R 20 'Be hydrogen; Or
R 20And R 20 'And form C=O or C=CR with the carbon atom that they are connected 27R 28
R 23Be hydrogen, hydroxyl or imaging moiety;
R 23 'Be hydrogen; Or
R 23And R 23 'And form C=O or C=CR with the carbon atom that they are connected 27R 28
R 24, R 25And R 26Be hydrogen, the optional C that is replaced by imaging moiety independently 1-C 6Alkyl, C 1-C 6Alkoxyl, hydroxyl, halogen or imaging moiety; With
R 27And R 28Be hydrogen, the optional C that is replaced by imaging moiety independently 1-C 6Alkyl, aralkyl, imaging moiety;
Condition is that at least one imaging moiety exists in general formula (II).
In another embodiment, R 18, R 19, R 22Or R 23It is imaging moiety.
In another embodiment, R 22It is imaging moiety.
In another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and the poly-acetic acid of quinone, and wherein contrast agent is:
Figure A20058002147400221
Wherein x is 0,1,2,3,4,5,6,7,8,9 or 10.
In another embodiment, the disclosure provides contrast agent, and it comprises developer and open chain deguelin analog.Recently, Nicoloau and partner (Nicoloau, K.C.; Pfefferkorn, J.A.; Schuler, E.; Roecker, A.J.; Cao, G.-Q.; Casida, J.E.Combinatorial Synthesis of Novel and Potent Inhibitors ofNADH:Ubiquinone Oxidoreductase Chemistry ﹠amp; Biology 2000,7,979-992; Nicoloau, K.C.; Pfefferkorn, J.A.; Roecker, A.J.; Cao, G.-Q.Inhibitors of NADH:Ubiquinone Oxidoreductase PCT WO02/20008A1) based on the overall drug effect layout of deguelin, the inhibitor of some high selectivities of MC-1 has been described.
Use standard screening and optimization method, they can constitute a class and have the active chemical compound of wide scope, and some have suitably low affinity/inhibitory action for MC-1.These chemical compounds help chemoproection/chemotherapy and use.Further example comprises the combination of unstable functional group, and these functional groups can make molecule tachymetabolism from circulating plasma, removes background signal from the perfusion material:
Figure A20058002147400231
Thus, in another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and open chain deguelin analog, and wherein contrast agent has general formula (III):
Wherein
G is-S-,-O-,
Figure A20058002147400233
J is S, C (R 37) 2, or O;
It is single or two key; With
R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R 40, R 41And R 42Be hydrogen, the optional C that is replaced by imaging moiety independently when occurring at every turn 1-C 6Alkyl, the optional C that is replaced by imaging moiety 1-C 6Alkoxyl or imaging moiety; Condition is to work as When being two key, R 31And R 32Be non-existent; With condition be that at least one imaging moiety exists in general formula (III).
In another embodiment, R 36, R 37, R 38Or R 42It is imaging moiety.
In another embodiment, R 38It is imaging moiety.
In another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and open chain deguelin analog, and wherein contrast agent is:
In another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and open chain deguelin analog, and wherein contrast agent is:
Figure A20058002147400242
In another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and open chain deguelin analog, and wherein contrast agent is:
In another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and open chain deguelin analog, and wherein contrast agent is:
Figure A20058002147400252
In another embodiment, the disclosure provides contrast agent, and it comprises the chromone of developing agent and replacement.Recently, and Lindell and partner (Bioorg.Med.Chem.Letters2004,14,511-514) chromone of a series of replacements has been described, it is the high selectivity inhibitor of MC-I.These chemical compounds comprise and known commercial acaricide pyridaben (Sanmite TM) (highly active MC-I inhibitor) similar activity, have the similar side chain SAR essential condition that merges in the molecule.
Thus, in another embodiment, the disclosure provides contrast agent, and it comprises the chromone of imaging moiety and replacement, and wherein contrast agent has general formula (IV):
Figure A20058002147400262
Wherein
N, m and o are 1,2,3 or 4 independently;
Z is O, S, or NR 46
R 45Be imaging moiety or the optional C that is replaced by imaging moiety 1-C 4Alkyl;
R 46Be hydrogen or C 1-C 3Alkyl;
Ar is a phenyl, furyl, thienyl,  azoles quinoline base, different  azoles quinoline base, thiazolyl, isothiazolyl, pyridine radicals, naphthyl, pyrimidine radicals, or pyrazinyl;
G represents not exist or O; With
L is an imaging moiety;
Condition is when G represents not exist, and o is 3.
In another embodiment, the disclosure provides contrast agent, and it comprises the chromone of imaging moiety and replacement, and wherein contrast agent is:
Figure A20058002147400271
In another embodiment, the disclosure provides contrast agent, and it comprises the chromone of imaging moiety and replacement, and wherein contrast agent is:
Figure A20058002147400272
In another embodiment, the disclosure provides contrast agent, comprise imaging moiety and be selected from annonaceae the poly-acetic acid of poly-acetic acid, quinone, replace the chemical compound of chromone and open chain deguelin analog, wherein imaging moiety is radiosiotope, the paramagnetic species that are used for the MRI imaging, the echo entity (echogenicentity) that is used for ultrasonic imaging that are used for nuclear medicine, is used for the fluorescence entity of fluorescence imaging or is used for the optical activity entity of optical imagery.
In another embodiment, imaging moiety is the paramagnetic species that are used for the MRI imaging, and wherein paramagnetic species are Gd 3+, Fe 3+, In 3+, or Mn 2+
In another embodiment, imaging moiety is the echo entity that is used for ultrasonic imaging, and wherein the echo entity is the surfactant microsphere that fluorohydrocarbon is sealed.
In another embodiment, imaging moiety is the radiosiotope that is used for nuclear medicine, and wherein radiosiotope is 11C, 13N, 18F, 123I, 124I, 125I, 99mTc, 95Tc, 111In, 76Br, 62Cu, 64Cu, 67Ga, or 68Ga.In another embodiment, imaging moiety is 18F.In another embodiment, imaging moiety is 99mTc.
In another embodiment, the disclosure provides the method for myocardial perfusion imaging, comprising: give the patient contrast agent, contrast agent comprises imaging moiety and is selected from the chemical compound of the poly-acetic acid of annonaceae, the poly-acetic acid of quinone, replacement chromone and open chain deguelin analog; With use diagnostic imaging scan patients.In another embodiment, imaging moiety is the radiosiotope that is used for nuclear medicine, the paramagnetism species that are used for the MRI imaging, the echo entity that is used for ultrasonic imaging, the fluorescence entity that is used for fluorescence imaging or the optical activity entity that is used for optical imagery.
In another embodiment, the disclosure provides contrast agent, and it comprises imaging moiety and capsaicin or derivatives thereof.
Imaging moiety
Nuclear medicine contrast agent of the present disclosure comprises 11C, 13N, 18F, 123I, 124I, 125I, 99mTc, 95Tc, 111In, 76Br, 62Cu, 64Cu, 67Ga and 68Ga. 11The C-cetylate has been used to survey fatty acid oxidation 11The C-acetas has been used for estimating the oxidative metabolism of cardiac muscle, and (Circulation 1987,76,687-696). 13N-ammonia generally has been used for myocardial perfusion imaging, and (Circulation 1989,80,1328-37).Based on 18The reagent of F as the developer of anoxia and cancer (Drugs of the Future 2002,27,655-667).15-(p-( 123I)-iodine substituted phenyl)-pentadecanoic acid and 15-(p-( 123I)-iodine substituted phenyl)-3 (R, S)-the methyl pentadecanoic acid is two kinds of iodination reagents that are used for the myocardial metabolism imaging.In one embodiment, the imaging moiety that adopts in the contrast agent that provides is 18F.Further, imaging moiety of the present disclosure can by one or more atomic number 20 or bigger absorption X ray or the atom of " weight " form, further be included in parent molecular moiety and X ray and absorb optional coupling part L between the atom.The heavy atom that usually uses in x-ray contrast agent is an iodine.Recently, x-ray contrast agent of being made up of metallo-chelate (United States Patent (USP) 5,417,959) and many chelates (United States Patent (USP) 5,679,810) of being made up of many metal ions are disclosed.Recently, multi-ring bunch of complex disclosed as x-ray contrast agent (United States Patent (USP) 5,804,161, WO 91/14460 and WO 92/17215).In some embodiment of the present disclosure, the special metal that is used for x-ray contrast agent comprises Re, Sm, Ho, Lu, Pm, Y, Bi, Pd, Gd, La, Au, Au, Yb, Dy, Cu, Rh, Ag, and Ir.
MRI contrast agent of the present disclosure can comprise one or more similar portions that is connected with one or more paramagnetic metal ion, further is included in the optional coupling part L between analog part and the paramagnetic metal ion.Paramagnetic metal ion can exist with the form of metallo-chelate or complex or metal oxide particle.United States Patent (USP) 5,412,148 and 5,760,191, the example of the paramagnetic metal ion chelating agen that is used for the MRI contrast agent has been described.United States Patent (USP) 5,801,228, United States Patent (USP) 5,567,411 and United States Patent (USP) 5,281,704, described and can be used for complexation is used for the paramagnetic metal ion of MRI contrast agent more than one Polychelants (polychelate).United States Patent (USP) 5,520,904 has been described the particulate composition of forming by as the paramagnetic metal ion of MRI contrast agent.The example of specific metal comprises Gd 3+, Fe 3+, In 3+, and Mn 2+
Acoustic contrast agent of the present disclosure can comprise be connected with the microvesicle of bio-compatible gas, liquid-carrier and surfactant microsphere or introduce wherein many analog parts, further be included in the optional coupling part L between analog part and the microvesicle.Here, term " liquid-carrier " is meant aqueous solution, and term " surfactant " is meant any amphipathic material, and it can cause the tensile reduction in solution median surface.Some suitable surfactants that are used to form the surfactant microsphere for example are disclosed among the EP0727225A2.Term " surfactant microsphere " comprises microsphere, nanosphere, liposome, folliculus or the like.Biocompatible gas can be the gas that any physiology accepts, and comprises for example air, or fluorohydrocarbon, for example C 3-C 5Perfluoro alkane, it provides the difference of echogenicity (echogenicity), and the contrast of ultrasonic imaging is provided thus.Gas can seal, be included in the microsphere, or otherwise be limited in the microsphere, the analog part is connected with microsphere, chooses wantonly to be connected by connecting base.Connection can be covalency, ion or connect by Van der Waals force.The specific examples of this contrast agent for example comprises, has the perfluoroparaffin that the lipid of many tumor neogenetic vasculature receptors comprises, tumor neogenetic dimension pipe receptors bind peptide, polypeptide or peptide mimics.The example of inflation imaging moiety is included in those of narration in the U.S. Patent Application Serial 09/931,317 of August 16 calendar year 2001 application and the United States Patent(USP) Nos. 5,088,499,5,547,656,5,228,446,5,585,112 and 5,846,517.
Chelating agen
Labelling has 99mMany methods of the chemical compound of Tc are known, comprise direct labelled compound or comprise chelating moiety (" chelating agen ").In one embodiment, chelating agen is DADT, MAG3, MAMA, PAMA, or DOTA.
Chemical compound of the present disclosure can be chosen wantonly and contain chelating agen (" C ").In some embodiment of disclosure chemical compound, chelating agen is to form the lipid ball of echo material filling or the surfactant of microvesicle.In some other embodiment, chelating agen is to have the bonding unit that is selected from following general formula:
Figure A20058002147400301
Wherein
Each A 1Be independently selected from-NR 46R 47,-NHR 53,-SH ,-S (Pg) ,-OH ,-PR 46R 47,-P (O) R 48R 49, with the key that is connected with chemical compound in conjunction with MC-1;
Each A 2Be independently selected from N (R 53), N (R 46), S, O, P (R 46) and-OP (O) (R 48) O-;
A 3Be N;
A 4Be selected from OH and OC (=O) C 1-C 20Alkyl;
A 5Be OC (=O) C 1-C 20Alkyl;
Each E is independently selected from: by 0-3 R 50The C that replaces 1-C 16Alkylidene is by 0-3 R 50The C that replaces 6-C 10Arlydene is by 0-3 R 50The C that replaces 3-C 10The ring alkylidene is by 0-3 R 50Heterocyclic radical-the C that replaces 1-C 10Alkylidene is by 0-3 R 50The C that replaces 6-C 10Aryl-C 1-C 10Alkylidene and by 0-3 R 50The inferior heterocyclic radical that replaces;
E 1Be selected from a key and E;
Each E 2Be independently selected from: by 0-3 R 50The C that replaces 1-C 16Alkyl is by 0-3 R 50The C that replaces 6-C 10Aryl is by 0-3 R 50The C that replaces 3-C 10Cycloalkyl is by 0-3 R 50Heterocyclic radical-the C that replaces 1-C 10Alkyl is by 0-3 R 50The C that replaces 6-C 10Aryl-C 1-C 10Alkyl is by 0-3 R 50The C that replaces 1-C 10Alkyl-C 6-C 10Aryl and by 0-3 R 50The heterocyclic radical that replaces;
E 3By 1-3 R 59The C that replaces 1-C 10Alkylidene;
Pg is the mercaptan protecting group;
R 46And R 47Each is independently selected from: the key that is connected with chemical compound in conjunction with MC-1, hydrogen is by 0-3 R 50The C that replaces 1-C 10Alkyl is by 0-3 R 50The aryl that replaces is by 0-3 R 50The C that replaces 3-C 10Cycloalkyl is by 0-3 R 50Heterocyclic radical-the C that replaces 1-C 10Alkyl is by 0-3 R 50The C that replaces 6-C 10Aryl-C 1-C 10Alkyl and by 0-3 R 50The heterocyclic radical that replaces;
R 48And R 49Each is independently selected from: the key that is connected with chemical compound in conjunction with MC-1 ,-OH is by 0-3 R 50The C that replaces 1-C 10Alkyl is by 0-3 R 50The aryl that replaces is by 0-3 R 50The C that replaces 3-C 10Cycloalkyl is by 0-3 R 50Heterocyclic radical-the C that replaces 1-C 10Alkyl is by 0-3 R 50The C that replaces 6-C 10Aryl-C 1-C 10Alkyl and by 0-3 R 50The heterocyclic radical that replaces;
Each R 50Be independently selected from: the key that is connected with chemical compound ,=O, halogen, trifluoromethyl, cyano group ,-CO in conjunction with MC-1 2R 51,-C (=O) R 51,-C (=O) N (R 51) 2,-CHO ,-CH 2OR 51,-OC (=O) R 51,-OC (=O) OR 51,-OR 51,-OC (=O) N (R 51) 2,-NR 51C (=O) R 51,-NR 51C (=O) OR 51,-NR 51C (=O) N (R 51) 2,-NR 51SO 2N (R 51) 2,-NR 51SO 2R 51,-SO 3H ,-SO 2R 51,-SR 51,-S (=O) R 51,-SO 2N (R 51) 2,-N (R 51) 2,-NHC (=S) NHR 51,=NOR 51, NO 2,-C (=O) NHOR 51,-C (=O) NHN (R 51) 2,-OCH 2CO 2H, 2-(1-morpholino) ethyoxyl, C 1-C 5Alkyl, C 2-C 4Thiazolinyl, C 3-C 6Cycloalkyl, C 3-C 6Methyl cycloalkyl, C 2-C 6Alkoxyalkyl is by 0-2 R 51The aryl that replaces, and heterocyclic radical;
Each R 51Be independently selected from: the key that is connected with chemical compound, hydrogen, C in conjunction with MC-1 1-C 6Alkyl, phenyl, benzyl and C 1-6Alkoxyl;
R 53It is coordinate bond to metal;
Each R 59Be selected from R 61,=O ,-CO 2R 60,-C (=O) R 60,-C (=O) N (R 60) 2,-CH 2OR 60,-OR 60,-N (R 60) 2, and C 2-C 4Thiazolinyl;
Each R 60Be independently selected from R 61, hydrogen, C 1-C 6Alkyl, phenyl, benzyl, and trifluoromethyl; With
R 61It is the key that is connected with chemical compound in conjunction with MC-1;
At least one A wherein 1, R 46, R 47, R 48, R 49, R 50, R 51And R 61It is the key that is connected with chemical compound in conjunction with MC-1.
Preparation method
Generally 18The chemical compound of F labelling is next synthetic by the Sn2 displacement of suitable leaving group.The preferred sulphonic acid ester of these leaving groups for example tosylate (tosylate, TsO), methanesulfonates (methanesulfonates, MsO), or triflate (triflate, TfO).Leaving group can also be a halogenide, phosphine oxide (by the Mitsunobu reaction), or inner leaving group (for example epoxide or cyclic sulfates).These chemical compounds are by K high activityization, dry 18The F preparation, it is by adding for example krytofix[2.2.2 of cryptand] preparation " hotter ".Usually carry out desalination by chromatography (Sep-Pak) in opposite directions and come purification.
The representational method of preparation contrast agent is described in the following embodiments.In case will being conspicuous technology, the instruction that above-mentioned chemical change can use those those of ordinary skills to grasp the application carries out.The representative reactions solvent comprises, for example, and DMF, NMP, DMSO, THF, ethyl acetate, dichloromethane and chloroform.Reaction solution can be by adding amine for example triethylamine or DIEA maintenance neutrality or alkaline.Reaction can ambient temperature and with blanket of nitrogen protection in order to avoid suffer to carry out under the condition of oxygen and water.
Can use interim protecting group to prevent that other reactive functional group from participating in reaction, for example amine, mercaptan, alcohol, phenol and carboxylic acid.Representational amine protecting group comprises, for example, tertbutyloxycarbonyl and trityl (under the acid condition of gentleness, removing), Fmoc (by utilize secondary amine for example piperidines remove), and benzyloxycarbonyl group (removing) by strong acid or by catalytic hydrogenolysis.Can also use trityl as protecting group mercaptan, phenol and alcohol.In certain embodiments, the carboxylic acid protecting group comprises for example tertiary butyl ester (removing by weak acid), and benzyl ester (removing by catalytic hydrogenolysis usually) and Arrcostab be methyl or ethyl (removing by weak base usually) for example.When end of synthesis, can use the condition of above-described individual protect base to remove all protecting groups, in case the instruction that end product can be grasped the application by those those of ordinary skills will be that conspicuous technology is come purification.
The poly-acetic acid of annonaceae can be by quite long path (Naito, 1995; Hoye, 1995,1996,1997), and some non-natural pair-THF analog (Sasaki, 1998; Kuwabara, 2000) come synthetic the preparation.Aforesaid chemical compound can prepare by the nucleophilic ring opening of epoxide.These epoxide can be used for preparing by the intrachain alkene epoxidation of fat easily:
Perhaps, deoxidation derivative can prepare by selective protection and activation:
Purposes
Contrast agent of the present disclosure can be used for formation method, is included in imaging method among the patient, comprises by injection, inculcates or any other known method afford patient contrast agent, and carry out imaging in patient's the people zone that interested phenomenon is positioned at that makes.
Effective dose that is given and the concrete mode that gives will change, this depends on age, weight and the concrete position of being treated and employed concrete contrast agent, included method of diagnosis and the suchlike factors such as form of preparation, the form of preparation is suspension, emulsion, microsphere, liposome or the like for example, and these it will be apparent to those skilled in the art that.
Usually, give dosage, and can improve dosage, until obtaining ideal diagnosis effect with reduced levels.In one embodiment, can give the contrast agent of foregoing description by intravenous injection, common form with saline solution, with about 0.1 dosage (with all combinations and the sub-portfolio of its dosage range and given dose) to about 100mCi/70kg body weight, or preferred with about dosage of 0.5 to about 50mCi.The technology of using those of ordinary skill to know is carried out imaging.
For being used as the nuclear medicine contrast agent, the compositions of the present disclosure, the dosage that give by intravenous injection, generally in the scope (with all combinations and the sub-portfolio of its dosage range and given dose) of about 0.5 μ mol/kg to about 1.5mmol/kg, preferred about 0.8 μ mol/kg is to about 1.2mmol/kg.
For as the MRI contrast agent, can use compositions of the present disclosure by the mode that is similar to other MRI reagent, as described below: United States Patent (USP) 5,155,215; United States Patent (USP) 5,087,440; Magn.Reson.Med.1986,3,808; Radiology 1988,166, and 835; With Radiology 1988,166,693.Usually, can intravenous give the aseptic aqueous solution of patient's contrast agent, dosage range from about 0.01 to about 1.0mmol/kg body weight (with all combinations and the sub-portfolio of its dosage range and given dose).
Acoustic contrast agent of the present disclosure can give by intravenous injection, and quantity is from about 10 to about 30 μ L echo gas/kg body weight (with all combinations and the sub-portfolio of its dosage range and given dose), or inculcates with the speed of about 3 μ L/kg/min and to give.
Another aspect of the present disclosure is the diagnostic kit that is used to prepare the diagnostic reagent that detection, imaging and/or monitoring heart muscle perfusion use.Diagnostic kit of the present disclosure comprises one or more phials, contain preparation aseptic, non-pyrogenicity in the phial, preparation comprises reagent of the present disclosure and optional other component of predetermined quantity, for example for example Wheat flavone and two (3-sulfophenyl) phosphines of 3-[of one or two auxiliary part] benzenesulfonic acid (TPPTS), Reducing agent, transfer ligand, buffer, lyophilization auxiliary agent, stabilizing additive, solubilization auxiliary agent and antibacterial.Test kit can also comprise Reducing agent, for example stannum (II).
The buffer that is used to prepare contrast agent and test kit comprises for example phosphate, citrate, sulfosalicylate and second hydrochloride buffer.More fully detail list can obtain in American Pharmacopeia.
The lyophilization auxiliary agent that is used to prepare contrast agent and test kit comprises for example mannitol, lactose, Sorbitol, dextran, FICOLL Polymer, and polyvinylpyrrolidone/ (PVP).
The stabilizing additive that is used to prepare contrast agent and test kit comprises, for example, and ascorbic acid, cysteine, single thioglycerol, sodium sulfite, sodium pyrosulfite, gentisic acid, and inositol.
The solubilization auxiliary agent that is used to prepare contrast agent and test kit comprises, for example, ethanol, glycerol, Polyethylene Glycol, propylene glycol, the polyethylene glycol oxide sorbitan monooleate, sorbitan monooleate, polysorbate, poly-(oxygen ethylene)-poly-(oxypropylene)-poly-(oxygen ethylene) block copolymer (" pluronic ") and lecithin.In certain embodiments, solubilisation aids is Polyethylene Glycol and pluronic.
The antibacterial that is used to prepare contrast agent and test kit comprises, for example, and benzyl alcohol, benzalkonium chloride, chlorobutanol and P-hydroxybenzoic acid methyl, propyl group or butyl ester.
Component in diagnostic kit can also provide more than one functions.For example, the Reducing agent that is used for radionuclide can also serve as stabilizing additive, or buffer can also serve as transfer ligand, or the lyophilization auxiliary agent can also serve as transfer, auxiliary or common ligands.
The chemical compound of Miao Shuing can have asymmetric center herein.Unless otherwise stated, all chiralitys, diastereomeric and racemic form is included in the disclosure.Many geometric isomers of alkene, the two keys of C=N or the like also may reside in the chemical compound described herein, and all these stable isomers are included in the disclosure scope.Should be understood that chemical compound of the present disclosure can contain the carbon atom of asymmetric replacement, and can separate with optical activity or racemic form.How this area prepares optically active form as everyone knows, for example by paratartarics take apart or by synthetic by optically active initiation material.Two different isomerization bodies (cis and trans) of peptide bond are known existence; Both can also be present in the chemical compound described herein, and all these stable isomers are included in the disclosure scope.Use amino acid whose conventional 3-letter abbreviations to represent concrete amino acid whose D-and L-isomer herein, as represented: D-Leu or L-Leu by following example.
For simplicity, junction point ("-") is not described.When describing atom or chemical compound, should be appreciated that hope substitutes variable in the mode of the valence state that meets atom or chemical compound with the definition variable.For example, if variable A " be confirmed as C (R 80)=C (R 80), in order to meet their corresponding valencys, two carbon atoms are formed the part of chain.
When any variable occurred more than once in any substituent group or any formula, its definition when at every turn occurring was not rely on its definition when every other the appearance.Thus, for example, if show that the perhaps many groups of group are by 0-2 R 80Replace, then described group can be chosen wantonly by two R at the most 80Replace, and the R of each appearance in each group 80Be independently selected from defined suitable R 80Tabulation.Equally, for example, for group-N (R 81) 2, two R on N 81In the substituent group each is independently selected from defined suitable R 81Tabulation.Have only when this combination results stable compound, just allow the combination of substituent group and/or variable.When the key of two atoms intersects in show connecting substituent key and connecting ring, then this substituent group can with any atomic linkage on encircling.
Definition
In some instances, in the group front of enumerating, indicate the carbon atom number in the concrete group.For example, term " C 6-C 10Aryl " expression contains the aryl of six to ten carbon atoms, term " C 6-C 10Aryl-C 1-C 10Alkyl ", the aryl that is meant six to ten carbon atoms is connected with parent molecular moiety by the alkyl of one to ten carbon atom.
Term used herein " thiazolinyl " is meant the straight or branched hydrocarbon that contains at least one carbon-to-carbon double bond.
Term used herein " alkoxyl " is meant the C that is connected with parent molecular moiety by oxygen atom 1-C 6Alkyl.
Term used herein " alkoxyalkyl " is meant the C that is replaced by, two or three alkoxyls 1-C 6Alkyl.
Term used herein " alkyl " is meant derived from a group to the straight or branched saturated hydrocarbons of 20 carbon atoms.
Term used herein " alkylidene " is meant the divalent group derived from the straight or branched saturated hydrocarbons.
Term used herein " analog part " is meant the chemical compound of the present disclosure except that one or more imaging moieties.
Term used herein " aryl " is meant that phenyl or wherein one or more rings are the dicyclo condensed ring systems of phenyl.Dicyclo condensed ring system turnkey is drawn together and monocycle cycloalkenyl group, monocyclic cycloalkyl or the condensed phenyl of another phenyl.Aryl of the present disclosure can be connected with parent molecular moiety by any commutable carbon atom in the group.The representative example of aryl includes, but are not limited to, anthryl, azulene base, fluorenyl, indanyl, indenyl, naphthyl, phenyl, and tetralyl.
Term used herein " aralkyl " is meant the alkyl that is replaced by, two or three aryl.
Term used herein " aryl alkylene " is meant the bivalence aralkyl, wherein with a point of contact of parent molecular moiety on aryl moiety, other point of contact is on moieties.
Term used herein " arlydene " is meant divalent aryl.
Term used herein " is assisted " or " common ligands " is meant and is used for finishing with the radionuclide bonding unit of chelating agen or reagent the part of the coordination sphere of radionuclide.For the radiopharmaceutical that comprises binary ligand system, the radionuclide coordination sphere comprises one or more chelating agen or bonding unit and one or more the auxiliary or common ligands that comes from one or more reagent, and condition is to have part, chelating agen or the bonding unit of two types altogether.For example, comprise the radiopharmaceutical of the identical auxiliary or common ligands in chelating agen coming from a reagent or bonding unit and comprise two chelating agen coming from one or two reagent or bonding unit and one are auxiliary or the radiopharmaceutical of common ligands, think that the both comprises binary ligand system with two.For the radiopharmaceutical that comprises the ternary Fas lignand system, the radionuclide coordination sphere comprises one or more chelating agen or bonding unit and one or more two the dissimilar auxiliary or common ligands that come from one or more reagent, and condition is to have part, chelating agen or the bonding unit of three types altogether.For example, comprise the radiopharmaceutical of the different auxiliary or common ligands in chelating agen coming from a reagent or bonding unit, think that it comprises the ternary Fas lignand system with two.
Be used to prepare radiopharmaceutical and be used to prepare assisting or common ligands of described radiopharmaceutic diagnostic kit, comprise one or more oxygen, nitrogen, carbon, sulfur, phosphorus, arsenic, selenium and tellurium donor atom.Part can be a transfer ligand in radiopharmaceutic synthesizing, and also can serve as auxiliary or common ligands in another radiopharmaceutical.No matter part is called shifts or auxiliary or common ligands, depend on that all part whether is retained in the radionuclide coordination sphere in the radiopharmaceutical, this is by the chelating agen of radionuclide and one or more reagent or the unitary Coordinative Chemistry mensuration of bonding.
" antibacterial " be the lay up period before preparation uses or use after diagnostic kit comes synthesis of radiopharmaceuticals, the vegetative component in can inhibitory preparation.
Term used herein " bubble " or " microvesicle " are meant vesicle, and it is a feature to exist around one or more film or the wall of internal voids usually, internal voids gassy or its precursor.Typically bubble or microvesicle comprise, for example, liposome, micelle, or the like.
Term used herein " chelating agen " and " bonding unit " refer to by part or group on one or more donor atom and the bonded reagent of metal ion.
As seen term used herein " contrast agent " is meant the reagent that is used for outstanding specific surface area, so that organ, blood vessel and/or organize more obvious.By improving the significant degree on the surface of being studied, can measure the existence and the degree of disease and/or damage.
Term used herein " cycloalkenyl group " be meant have three to ten four carbon atoms and the heteroatomic non-aromatization of zero, unsaturated monocyclic, dicyclo, the three-loop system of part.The representative example of cycloalkenyl group includes, but are not limited to, cyclohexenyl group, octahydro naphthyl, and norbornene.
Term used herein " cycloalkyl " is meant to have three to ten four carbon atoms and the heteroatomic saturated monocycle of zero, dicyclo or tricyctic hydrocarbon loop systems.The representative example of cycloalkyl includes, but are not limited to, cyclopropyl, cyclopenta, bicyclo-[3.1.1] heptyl, and adamantyl.
Term " C used herein 3-C 10The ring alkylidene " be meant and contain three divalent cycloalkyls to ten carbon atoms.
Term used herein " diagnostic imaging " is meant the method that is used for contrast agent detection.
" diagnostic kit " or " test kit " is included in the component set that is called preparation in one or more phials, and the end user that they are used is used for the radiopharmaceutical of composite diagnosis in clinical or pharmacy are provided with.Except available usually those for the end user who uses, the preferred reagent box provides all necessary components, with synthetic and use diagnostic medicine, for example water for injection or normal saline, the radioactive nucleus cellulose solution is used to heat the device of test kit between radiopharmaceutic synthesis stage, if necessary, give for example syringe of the necessary device of patient's radiopharmaceutical, isolation cover, imaging device or the like.Final form with preparation provides contrast agent to the end user, and preparation generally is included in the phial, both can be that lyophilized solid also can be an aqueous solution.The end user is generally with freeze dried substance and water or normal saline reorganization, and takes out patient dose from formed preparation aqueous solution, or only takes out dose.
Term used herein " donor atom " is meant by chemical bond and the direct-connected atom of metal.
Term used herein " halogen " is meant F, Cl, Br or I.
Term used herein " heterocyclic radical " be meant contain one, two or three independently are selected from five, six or heptatomic ring of nitrogen, oxygen and sulfur heteroatom.Five-membered ring has zero to two two keys, six and heptatomic ring have zero to three two keys.Term " heterocyclic radical " also comprises such bicyclic radicals, and wherein heterocyclic ring and phenyl, monocyclic cycloalkenyl group, monocyclic cycloalkyl or another monocyclic heterocyclic radical condense.Heterocyclic radical of the present disclosure can be connected with parent molecular moiety by carbon atom in the group or nitrogen-atoms.The example of heterocyclic radical includes, but are not limited to, benzothienyl, furyl, imidazole radicals, indolinyl, indyl, isothiazolyl, different  azoles base, morpholinyl,  azoles base, piperazinyl, piperidyl, pyrazolyl, pyridine radicals, pyrrolidinyl, pyrrolopyridinyl, pyrrole radicals, thiazolyl, thienyl, and thio-morpholinyl.
Term used herein " heterocyclic radical alkyl " is meant the alkyl that is replaced by, two or three heterocyclic radicals.
Term used herein " heterocyclic radical alkylidene " is meant the divalent heterocycle alkyl, wherein with a point of contact of parent molecular moiety on the heterocyclic radical part, other point of contact is on moieties.
Term used herein " inferior heterocyclic radical " is meant divalent heterocycle.
Term used herein " hydroxyl " is meant-OH.
Term used herein " imaging moiety " refers to can detection, one or more parts of the molecule of the existence of imaging and/or monitoring disease, pathology obstacle and/or disease and/or development.
Term used herein " connects base " and is meant the molecular moiety that serves as the interval between two other parts of molecule.Connect base other function of describing herein also can be provided.The example that connects base comprises straight chain, side chain or cyclic alkyl, aryl, ether, polyhydroxy, polyethers, polyamide, heterocycle, aromatic hydrocarbons, hydrazides, peptide, class peptone, or compatible covalent bond or its combination of other physiology.
Term used herein " lipid " is meant synthetic or naturally occurring amphipathic compound, and it comprises hydrophilic component and hydrophobic component.Lipid comprises, for example, and fatty acid, neutral fat, phospholipid, glycolipid, aliphatic alcohol and paraffin, terpenes and steroidal.The exemplary composition that comprises lipoid substance comprises suspension, emulsion and vesicular compositions.
" liposome " is meant the common spheric cluster or the aggregation of the amphipathic compound that comprises lipoid substance, generally is for example double-deck forms of one or more concentric layers.They may also be referred to as the fat vacuole capsule herein.
" lyophilization auxiliary agent " is the component that has favourable physical property for lyophilization, and glass transition temperature for example, and it joins in the preparation usually is with the cryodesiccated physical property of the combination that improves the preparation all components.
Term used herein " open chain deguelin analog " is meant the analog (as follows) of deguelin, and at least one of its medium ring C and D do not exist, and the connection base that promptly is connected residue ring substitutes.
Deguelin
Phrase used herein " pharmacy is acceptable " is meant chemical compound, raw material, compositions and/or the dosage form in reliable medical judgment scope, be suitable for contacting human do not have with tissue animal over-drastic toxicity, stimulation, allergy or with rational benefit/corresponding other problem of dangerous ratio or complication.
Chemical compound of the present disclosure can exist with the form of the acceptable salt of pharmacy.The salt or the zwitterionic form of term used herein " the acceptable salt of pharmacy " expression disclosure chemical compound, it is that water or oil are molten or dispersible, in reliable medical judgment scope, be fit to contact with patient's tissue and do not have excessive toxicity, stimulation, allergy or with reasonable benefit/corresponding other problem of dangerous ratio or complication, and be effective for its target purposes.Salt can prepare during the last separation of chemical compound and purification, or prepares by suitable nitrogen-atoms and suitable acid reaction independently.Representational acid-addition salts comprises second hydrochloric acid, adipate, alginate, citrate, aspartate, benzoate, benzene sulfonate, disulfate, butyrate, camphorate, camsilate; Digluconate, glycerophosphate, Hemisulphate, enanthate, caproate, formates, fumarate, hydrochlorate, hydrobromate, hydriodate, 2-isethionate, lactate, maleate, sym-toluenesulfonic acid salt, mesylate, naphthylene sulfonate, nicotinate, 2-naphthalene sulfonate, oxalates, palmitate (palmoate), pectinic acid salt, persulfate, 3-phenylpropionic acid salt, picrate, Pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, phosphate, glutamate, Glu, bicarbonate, tosilate and hendecane hydrochlorate.The example that can be used to form the acid of pharmacy acceptable addition salt comprises for example for example oxalic acid, maleic acid, succinic acid and citric acid of hydrochloric acid, hydrobromic acid, sulphuric acid and phosphoric acid and organic acid of mineral acid.
" reagent " is meant the chemical compound of the present disclosure that can be converted into metal medicine of the present disclosure.Reagent can directly make and be used for preparing metal medicine of the present disclosure, maybe can be the component in the test kit of the present disclosure.
" Reducing agent " is the chemical compound that reacts with radionuclide, and it generally obtains with form relative inertness, the high oxidation state chemical compound, reduces its oxidation state by metastatic electron to radionuclide, makes it have more reactivity thus.Comprise in radiopharmaceutic preparation and the Reducing agent that uses at the test kit that is used for described radiopharmaceutic preparation, for example, stannous chloride, stannous fluoride, formamidine sulfinic acid, ascorbic acid, cysteine, phosphine and monovalence copper or ferrous salt.Other Reducing agent for example is described in the people PCT application 94/22496 such as Brodack.
" stabilizing additive " is the component that generally joins in metal medicine or the diagnostic kit, can the stable metal medicine or prolong shelf-life before must using of test kit.Stabilizing additive can be antioxidant, Reducing agent or radical scavenger, and can react the stability that raising is provided by preferential species with can degrade other component or metal medicine.
" stable compound " is meant fully firm chemical compound herein, can be separated to useful purity from reactant mixture, and be mixed with effective pharmaceutical agent.
" solubilisation aids " is to improve the deliquescent component of one or more other component in the needed medium of preparation.
Term used herein " mercaptan protecting group " is meant protects mercapto to exempt from the group of undesirable reaction during building-up process.Can use any mercaptan protecting group known in the art.The example of mercaptan protecting group includes, but are not limited to following: acetylamino methyl, benzene carbon amide ylmethyl, 1-ethoxyethyl group, benzoyl, and trityl group.
" transfer ligand " is the part that forms intermediate complex with metal ion, and it is enough stable, can prevent unnecessary side reaction, but enough unstable, can change contrast agent into.The formation of intermediate complex is that kinetics is favourable, is that thermodynamics is favourable and form the metal medicine.Comprise gluconate for example, gluceptate, mannitol in the preparation of contrast agent with at the transfer ligand that the test kit of the preparation that is used for diagnostic radioactive drug uses, glucosaccharic acid salt, N, N, N ', N '-ethylenediaminetetraacetic acid, pyrophosphate and methylene diphosphonate.Usually, transfer ligand comprises oxygen or nitrogen donor atom.
Term used herein " vesicle " is meant globular entity, it is characterized by to have internal voids.In one embodiment, vesicle comprises the various lipids of describing herein by the lipid preparation.In any vesicle that obtains, lipid can be the monolayer or double-deck form, and list or double-deck lipid can be used to form, and one or more is single or double-deck.Under the situation single or double-deck more than, list or bilayer are normally concentric.The fat vacuole capsule of Miao Shuing comprises this entity herein, is commonly referred to liposome, micelle, bubble, microvesicle, microsphere or the like.Thus, lipid can be used to form the vesicle (comprising a monolayer or bilayer) of monolayer, vesicle of low layer (comprising about two or about three monolayers or bilayer) or multiwalled vesicle (comprising about three above monolayers or bilayer).According to requiring, the internal voids of vesicle can full of liquid, for example comprises, and is liquid, aqueous, gas, and gasiform precursor, and/or solid or solute substance for example comprise bioactive agents.
Term used herein " vesicular compositions " is meant compositions, and it is by the lipid preparation, and it comprises vesicle.
Describe the disclosure in conjunction with some embodiment now, these embodiments are not to want to limit the scope of the present disclosure.On the contrary, the disclosure will contain all alternatives, improvement and content of equal value, as comprising within the scope of the claims.Thus, the following example will illustrate a kind of practice of the present disclosure, should be appreciated that embodiment is for some embodiment being described, the most effective embodiment of being thought is provided, and understand the explanation of its method and notion aspect easily.
Embodiment 1
1a.{2R-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-3-{2-[(1, the 1-dimethyl ethyl) diphenylmethyl silanyloxy base]-11-methoxy Oxy-1 1-[octahydro-5 '-(1-(methoxy oxygen base) 11-3-alkynyl) [2.2 '-two furan]-the 5-yl]-6-endecatylene-8-alkynyl }-5-methyl-2-(5H)-furanone
Figure A20058002147400431
At room temperature stir { 2R-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-3-{2-[(1, the 1-dimethyl ethyl) diphenylmethyl silanyloxy base]-11-hydroxyl-11-[octahydro-5 '-(1-hydroxyl 11-3-alkynyl) [2.2 '-two furan]-5-yl]-6-endecatylene-8-alkynyl }-(82.3 milligrams of 5-methyl-2-(5H)-furanone, 0.1mmol, it can be by Hoye and Ye, US5,677,4671 and J.Am.Chem.Soc.1996,118, the path that 1801-1802 describes prepares) diisopropylethylamine (2 milliliters) solution, add methoxy chlorine (24 milligrams, 23 μ l) simultaneously.Mixture is at room temperature stirred four hours, and vacuum concentration.Residue is distributed between water (2ml) and ether (2 milliliters).Water phase separated, and with ether (2mL) extraction, with the organic fraction washing (1 * 5%CuSO that merges 4, 1 * water), dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), form needed product.
1b.{2R-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-3-{2-hydroxyl-11-methoxy Oxy-1 1-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] undecyl }-5-methyl-2-(5H)-furanone
Under nitrogen current, with { 2R-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-3-{2-[(1, the 1-dimethyl ethyl) diphenylmethyl silanyloxy base]-11-methoxy Oxy-1 1-[octahydro-5 '-(1-(methoxy oxygen base) 11-3-alkynyl) [2.2 '-two furan]-5-yl]-6-endecatylene-8-alkynyl }-(64 milligrams of 5-methyl-2-(5H)-furanone, benzene 70umole) (0.5 milliliter) solution at room temperature stirs, add simultaneously three (triphenylphosphine) radium chloride (14 milligrams, 15umole).Mixture is filled hydrogen, and at room temperature stirred two days.Add entry, and separate each layer.(3 * 2mL) extract water layer, and organic fraction of washing (1 * 20 ml water) merging, and dry (saturated NaCl aqueous solution, sodium sulfate) filters, and concentrates with ethyl acetate.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product.
The gained material is dissolved among the THF (2 milliliters), and tetra-n-butyl ammonium (100uL, 1.0M solution is in THF) solution is fluoridized in adding.Mixture is at room temperature stirred 30 minutes, and vacuum concentration.Residue is distributed between water (2ml) and ethyl acetate (2 milliliters).Water phase separated, and with ethyl acetate (2mL) extraction, with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also concentrated.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product.
1c.{2R-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-the 3-{2-[ptoluene-sulfonyl]-11-methoxy Oxy-1 1-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] undecyl }-5-methyl-2-(5H)-furanone
Figure A20058002147400451
With { 2R-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-3-{2-hydroxyl-11-methoxy Oxy-1 1-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] undecyl }-(34 milligrams of 5-methyl-2-(5H)-furanone, pyridine 50umole) (2 milliliters) solution at room temperature stirs, add simultaneously p-toluenesulfonyl chloride (20 milligrams, 60umole).Mixture is at room temperature stirred 15 hours, and vacuum concentration.Residue is distributed between water (2ml) and ethyl acetate (2 milliliters).Water phase separated, and with ethyl acetate (3 * 2mL) extract, with the organic fraction washing (1 * 5%CuSO that merges 4, 1 * water), dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product.
1d.{2S-[2 α [2 ' R *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 11R *]-3-{2-[ 18F] fluoro-11-hydroxyl-11-[octahydro-5 '-(1-hydroxyl undecyl) [2.2 '-two furan]-the 5-yl] undecyl }-5-methyl-2-(5H)-furanone
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the 10 milliliters of thin-walled silanization vacuum test tubes (vacutainer) that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By acetonitrile (3 * 200 μ L) repeat add and evaporation, residue is further dry.The acetonitrile that adds other equal portions, and mixture is concentrated in the vacuum that does not have heating.Except that before desolvating, add { 2R-[2 α [2 ' R fully fast *, 5 ' R *(R *)], 5 β [1 (S *), 2R *, 6E, 11R *]-the 3-{2-[ptoluene-sulfonyl]-11-methoxy Oxy-1 1-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] undecyl }-THF (the 150 μ l) solution of 5-methyl-2-(5H)-furanone (2 milligrams).Phial was heated 30 minutes down at 65 ℃.After the cooling, (30 μ l 6M), are heated to 65 ℃ with phial to the THF solution of adding HCl once more, keep 15 minutes, then cooling.With the dilution of the inclusions water (4mL) in the phial, and by silica gel cylinder (preload Waters Light C-18 Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 2
2a.5-formoxyl-octahydro-5 '-(1-methoxymethoxy undecyl) [2.2 '-two furan]
Figure A20058002147400471
With decyl octahydro-α '-(methylol)-2,2 '-two furan-5,5 '-dimethanol-α-{ [(1, the 1-dimethyl ethyl) dimethyl] silyl ether } (it can pass through United States Patent (USP) 5 for 4.87 grams, 10mmol, 587,491, the path shown in the embodiment 15 prepares) (15mmol) handle with benzaldehyde dimethyl acetal by 2.27 grams in DMF (25 milliliters) and toluenesulfonic acid (30 milligrams) for solution.Mixture is at room temperature stirred 24 hours, and vacuum concentration.Residue is distributed between water (50ml) and ethyl acetate (50 milliliters).Water phase separated, and with ethyl acetate (2 * 50mL) extract, with the organic fraction washing (1 * saturated NaHCO that merges 3Aqueous solution, 1 * water), dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.
Residual oil is dissolved among the THF (20mL), and (1.0M in THF, 10.5 milliliters, 1.05eq.), at room temperature stirred the mixture two hours to add tetrabutylammonium fluoride.Solvent removed in vacuo, and residue distributed between water (50mL) and ethyl acetate (50ml).Water phase separated, and with ethyl acetate (2 * 50mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.
Residual oil is dissolved in the diisopropylethylamine (15mL), and adding chloromethyl methyl ether (880mg, 11mmol).Mixture was at room temperature stirred eight hours solvent removed in vacuo.Residue is distributed between water (40ml) and ethyl acetate (40 milliliters).Water phase separated, and with ethyl acetate (2 * 40mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain acetal oil.
Oil is dissolved in the two  alkane (20 milliliters), and is transferred in the hydrogenation high-pressure bottle.Adding palladium/carbon (5%, 100mg), pressurizeed 45 minutes to device with hydrogen (2atm).Discharge gas,, mixture is passed through kieselguhr (Celite by means of two other  alkane ) filter.Vacuum concentrated filtrate, chromatographic isolation (hexane-2: 1 hexane: the ethyl acetate gradient, through 230-400 order silica gel), glycol oil obtained.
(416mg 1.0mmol) is dissolved among the THF (5mL), and adds the H with ether system with a part of gained oil 5IO 6Saturated solution (16mL, it can be according to J.Org.Chem.1963, the method preparation of describing in 28,23).Sedimentary iodic acid is filtered, the solution that vacuum concentration obtains, chromatographic isolation (hexane-2: 1 hexane: the ethyl acetate gradient, through 230-400 order silica gel), obtain aldehyde oil.
(2b.5-1, the 1-dimethyl ethyl) the dimetylsilyl oxygen base ninth of the ten Heavenly Stems-1, the 8-diine
Figure A20058002147400481
With 1,9-pair-the trimethyl silyl ninth of the ten Heavenly Stems-1,8-diine-5-alcohol (2.80 grams, 10mmol, by Clive, the preparation of the method for D.L.J.; Cole, D.C.JCS, Perkin 1 1991,12, diisopropylethylamine 3263-70) (10 milliliters) solution at room temperature stirs, add simultaneously the chloromethyl methyl ether (880 milligrams, 11mmol).Mixture was stirred four hours, then vacuum concentration.Residue is distributed between ether (100ml) and water (100 milliliters).Water phase separated, and with ether (2 * 100mL) extract, with Organic substance washing (2 * 100mL, the 0.5M NaHSO that merges 4), dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.
Gained oil is dissolved among the THF (10mL), and (1.0M solution is in THF, 21mL) to add TBAF.Mixture is at room temperature stirred one hour, and topple in the entry (100mL).Water phase separated, (2 * 100mL) extract, and with the Organic substance vacuum concentration that merges, utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain diine oil with ether.
(2c.5-1, the 1-dimethyl ethyl) dimetylsilyl Oxy-1 0-methoxymethoxy-10-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] last of the ten Heavenly stems-1, the 8-diine
With 5-(1, the 1-dimethyl ethyl) the dimetylsilyl oxygen base ninth of the ten Heavenly Stems-1, (1.80 grams, THF 10mmol) (10 milliliters) solution is-78 ℃ of stirrings, adds n-butyllithium solution (2.0M, in hexane, 4.95 milliliters) simultaneously for the 8-diine.Stirred the mixture ten minutes at-78 ℃, and the adding etherate of trifluoroboron (9.9mmol, 1.25mL).After-78 ℃ of restir 30 minutes, adding 5-formoxyl-octahydro-5 '-(1-methoxymethoxy undecyl)-[2.2 ']-two furan (1.35 grams, THF 3.5mmol) (8 milliliters) solution.The solution that obtains was stirred four hours down at-78 ℃, pour into NH then 4The Cl aqueous solution (100mL, 2.0M) in.(3 * 100mL) extract mixture, with the organic fraction washing (1 * water) that merges, filter, and dry (saturated NaCl aqueous solution, sodium sulfate) concentrates with ethyl acetate.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, through 230-400 order silica gel), obtain 5-(1, the 1-dimethyl ethyl) dimetylsilyl Oxy-1 0-methoxymethoxy-10-[octahydro-5 '-(1-hydroxyl undecyl) [2.2 '-two furan]-5-yl] last of the ten Heavenly stems-1,8-diine oil.
At room temperature, should oil (1.27g, diisopropylethylamine 2mmol) (6mL) solution chloromethyl methyl ether (201mg, 2.5mmol) processing.Stir after two hours,, and residue distributed between water (50mL) and ethyl acetate (50mL) the mixture vacuum concentration.Water phase separated, and with ethyl acetate (2 * 50mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, through 230-400 order silica gel), obtain 5-(1, the 1-dimethyl ethyl) dimetylsilyl Oxy-1 0-methoxy Oxy-1 0-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] last of the ten Heavenly stems-1,8-diine oil.
2d.3-{2, two (methoxy oxygen the base)-8-[(1 of 13-, the 1-dimethyl ethyl) dimetylsilyl oxygen base]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] 13 carbon-4, the 11-diynyl }-5-methyl-2-(5H)-furanone
With 5-(1, the 1-dimethyl ethyl) dimetylsilyl Oxy-1 0-methoxy Oxy-1 0-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] last of the ten Heavenly stems-1,8-diine (1.035g, 1.5mmol) THF (6 milliliters) solution-78 ℃ of coolings, add n-BuLi/hexane (2.0M, 0.75 milliliter) simultaneously.After stirring 30 minutes, add etherate of trifluoroboron (190ul 1.5mmol), after in addition 15 minutes, adds (5S)-methyl-3-[(2S)-epoxy ethyl methyl]-5H-furan-2-ketone (154 milligrams, THF 1.0mmol) (2 milliliters) solution.Reactant mixture was stirred three hours down at-78 ℃, pour into NH then 4The Cl aqueous solution (100mL, 2.0M) in.(3 * 100mL) extract mixture, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates with ethyl acetate.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, through 230-400 order silica gel), obtain 3-{2-hydroxyl-13-methoxy oxygen base-8-[(1, the 1-dimethyl ethyl) dimetylsilyl oxygen base]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] 13 carbon-4, the 11-diynyl }-5-methyl-2-(5H)-furanone oil.
This oil is dissolved in the diisopropylethylamine (3mL), and adding chloromethyl methyl ether (120mg, 1.5mmol).Mixture was at room temperature stirred eight hours, vacuum concentration, and residue distributed between water (50mL) and ethyl acetate (50mL).Water phase separated, and with ethyl acetate (2 * 50mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product oil.
2e.3-{2, two (methoxy oxygen base)-8-(the ptoluene-sulfonyl)-13-[octahydros-5 of 13-'-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] tridecyl }-5-methyl-2-(5H)-furanone
With 3-{2, two (methoxy oxygen the base)-8-[(1 of 13-, the 1-dimethyl ethyl) dimetylsilyl oxygen base]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] 13 carbon-4, the 11-diynyl }-(87.8 milligrams of 5-methyl-2-(5H)-furanone, 0.10mmol) and right-toluene sulfonyl hydrazide (1.86 grams, dimethoxy-ethane 10mmol) (15 milliliters) solution reflux is simultaneously with three hours adding NaOAc (984 milligrams of 12mmol) aqueous solutions (10 milliliters).With the mixture cool to room temperature, be poured in the water (100 milliliters), and (2 * 30mL) extract with dichloromethane.With the organic layer drying (sodium sulfate) that merges, filter and concentrate.
Residue is dissolved among the THF (5mL), and (1.0M is in THF, 120uL) to add TBAF.Mixture was at room temperature stirred 30 minutes, and concentrate.Residue is distributed between water (50ml) and ethyl acetate (50 milliliters).Water phase separated, and with ethyl acetate (2 * 50mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.
Oil is dissolved in the pyridine (1.0mL), and the adding paratoluensulfonyl chloride (28.5mg, 0.15mmol).Mixture is at room temperature stirred two hours, and vacuum concentration.Residue is distributed between dichloromethane (5 milliliters) and water (5 milliliters).Water phase separated, and with dichloromethane (2 * 5mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product oil.
2f.3-{2, two (methoxy oxygen the base)-8-[of 13- 18F] fluoro-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] tridecyl }-5-methyl-2-(5H)-furanone
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Remove fully desolvate before; add fast 3-{2, two (methoxy oxygen base)-8-(the ptoluene-sulfonyl)-13-[octahydros-5 of 13-'-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] tridecyl }-THF (150ul) solution of 5-methyl-2-(5H)-furanone (1 milligram).Phial was heated 15 minutes down at 65 ℃.After the cooling, add methyl sulfide (100ul), add etherate of trifluoroboron (200uL) subsequently.Phial is heated to 65 ℃ once more, kept 15 minutes, then cooling.With the dilution of the inclusions water (4mL) in the phial, and by silica gel cylinder (preload Waters Light C-18Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 3
(3a.3-{8-ptoluene-sulfonyl)-2, two (methoxy oxygen base)-13-[tetrahydrochysene-5-(the 1-methoxy oxygen base tridecyl) furan-2-yl of 13-] tridecyl }-5-methyl-2-(5H)-furanone
With annonacinone (595 milligrams, diisopropylethylamine 1.0mmol) (7 milliliters) solution at room temperature stirs, add simultaneously the chloromethyl methyl ether (360 milligrams, 4.5mmol).Mixture was at room temperature stirred eight hours, vacuum concentration, and residue distributed between water (50mL) and ethyl acetate (50mL).Water phase separated, and with ethyl acetate (2 * 50mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, through 230-400 order silica gel), obtain 3-{2, two (methoxy oxygen base)-13-[tetrahydrochysene-5-(the 1-methoxy oxygen base tridecyl) furan-2-yl of 13-] tridecane-8-ketone-1-yl }-5-methyl-2-(5H)-furanone.
By means of THF (100uL), the ketone through overprotection of above-mentioned preparation is dissolved in the ethanol (3mL).(76mg 2.0mmol), and at room temperature stirred mixture 30 minutes to add solid sodium borohydride with portion.Reactant mixture water (20 milliliters) is diluted, and (3 * 50ml) extract with ethyl acetate.With the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain alcohol through overprotection.
With part alcohol (365mg 0.5mmol) is dissolved in the pyridine (5mL), and add paratoluensulfonyl chloride (143mg, 0.75mmol).Mixture is at room temperature stirred two hours, and vacuum concentration.Residue is distributed between dichloromethane (5 milliliters) and water (5 milliliters).Water phase separated, and with dichloromethane (2 * 5mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product.
3b.3-{8-[ 18F] fluoro-2,13-dihydroxy-13-[tetrahydrochysene-5-(1-hydroxyl tridecyl) furan-2-yl] tridecyl }-5-methyl-2-(5H)-furanone
Figure A20058002147400541
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Remove fully desolvate before; add fast the 3-{8-(ptoluene-sulfonyl)-2 that obtains, two (methoxy oxygen base)-13-[tetrahydrochysene-5-(the 1-methoxy oxygen base tridecyl) furan-2-yl of 13-] tridecyl }-THF (150ul) solution of 5-methyl-2-(5H)-furanone (1 milligram).Phial was heated 15 minutes down at 65 ℃.After the cooling, add methyl sulfide (100ul), add etherate of trifluoroboron (200uL) subsequently.Phial is heated to 65 ℃ once more, kept 15 minutes, then cooling.With the dilution of the inclusions water (4mL) in the phial, and by silica gel cylinder (preload Waters Light C-18 Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, form needed product.
Embodiment 4
4a.5-methyl isophthalic acid, 2,3,4-tetramethoxy-6-(1-hydroxyl tritriacontyl-12-alkynes-1-yl) benzene
With the 5-methyl isophthalic acid, 2,3,4-tetramethoxy benzene (2.12g, 10mmol, Hansen, C.A.; Dean, A.B.; Draths, K.M.; Frost, J.W.J.Am.Chem.Soc.1999,121 (15), 3799-3800) and tetramethylethylenediamine (TMEDA, 2.96 milliliters, hexane 20mmol) (25 milliliters) solution cools off in 0 ℃ of following ice bath, (2.0M is in hexane, 5mL) to drip n-butyllithium solution simultaneously.This yellow reaction mixture was stirred 30 minutes, use THF (20 milliliters) dilution then.Adding 12-tridecyne aldehyde (tridecynal) (4.27 grams, 22mmol, J.Org.Chem.2001,66 (14), THF 4766-4770) (10 milliliters) solution, and with this mixture stirring two hours.By adding saturated NH 4Cl aqueous solution (20 milliliters) will react quencher.Add entry (30mL), water phase separated, (2 * 50mL) extract with ethyl acetate.With the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), form needed product.
4b.5-methyl isophthalic acid, 2,3,4-tetramethoxy-6-(1-(1, the 1-dimethyl ethyl) dimetylsilyl oxygen base 13 carbon-12-alkynes-1-yl) benzene
Figure A20058002147400561
With imidazoles (1.36g, 20mmol) and the 5-methyl isophthalic acid, 2,3, (6.10 grams 15mmol) are dissolved among the DMF (20 milliliters) 4-tetramethoxy-6-(1-hydroxyl 13 carbon-12-alkynes-1-yl) benzene, and at room temperature stir, add simultaneously the tert-butyldimethylsilyl chloride solid (2.42g, 16mmol).The solution that obtains is at room temperature stirred two hours, and topple in the entry (50mL).Water phase separated, and with ethyl acetate (2 * 100ml) extract.With the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product.
4c.6-{14-methoxy oxygen base-2-[(1, the 1-dimethyl ethyl) dimetylsilyl oxygen base]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] 14 carbon-12-alkynes-1-yl }-the 5-methyl isophthalic acid, 2,3,4-tetramethoxy benzene
Figure A20058002147400562
At-78 ℃, with the 5-methyl isophthalic acid, 2,3,4-tetramethoxy-6-(1-(1, the 1-dimethyl ethyl) dimetylsilyl oxygen base 13 carbon-12-alkynes-1-yl) benzene (4.06 grams, THF 10mmol) (15 milliliters) solution stirring, add n-butyllithium solution (2.0M, in hexane, 4.95 milliliters) simultaneously.Stirred the mixture ten minutes at-78 ℃, and the adding etherate of trifluoroboron (9.9mmol, 1.25mL).After-78 ℃ of restir 30 minutes, adding 5-formoxyl-octahydro-5 '-(1-methoxymethoxy undecyl)-[2.2 ']-two furan (1.35 grams, THF 3.5mmol) (8 milliliters) solution.The solution that obtains was stirred four hours down at-78 ℃, pour into NH then 4The Cl aqueous solution (100mL, 2.0M) in.(3 * 100mL) extract mixture, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters and concentrates with ethyl acetate.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, through 230-400 order silica gel), obtain 6-{14-hydroxyl-2-[(1, the 1-dimethyl ethyl) dimetylsilyl oxygen base]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl)-[2.2 '-two furan]-the 5-yl] 14 carbon-12-alkynes-1-yl }-the 5-methyl isophthalic acid, 2,3,4-tetramethoxy benzene oil.
At room temperature, should oil (1.81g, diisopropylethylamine 2mmol) (6mL) solution chloromethyl methyl ether (201mg, 2.5mmol) processing.Stir after two hours,, and residue distributed between water (50mL) and ethyl acetate (50mL) the mixture vacuum concentration.Water phase separated, and with ethyl acetate (2 * 50mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product oil.
4d.5-{14-methoxy oxygen base-2-[ptoluene-sulfonyl]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] tetradecane-1-yl }-6-methyl-2,3-dimethoxy-1,4-benzoquinone
With 6-{14-methoxy oxygen base-2-[(1, the 1-dimethyl ethyl) dimetylsilyl oxygen base]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] 14 carbon-12-alkynes-1-yl }-the 5-methyl isophthalic acid, 2,3, (95 milligrams of 4-tetramethoxy benzene, 0.10mmol) and right-toluene sulfonyl hydrazide (1.86 grams, dimethoxy-ethane 10mmol) (15 milliliters) solution reflux is simultaneously with three hours adding NaOAc (984 milligrams of 12mmol) water (10 milliliters) solution.With the mixture cool to room temperature, be poured in the water (100 milliliters), and (2 * 30mL) extract with dichloromethane.With the organic layer drying (sodium sulfate) that merges, filter and concentrate.
Residue is dissolved among the THF (5mL), and (1.0M is in THF, 120uL) to add TBAF.Mixture was at room temperature stirred 30 minutes, and concentrate.Residue is distributed between water (50ml) and ethyl acetate (50 milliliters).Water phase separated, (2 * 50mL) extract with ethyl acetate, and organic fraction washing (1 * water) that will merge, dry (saturated NaCl aqueous solution, sodium sulfate), filter, concentrate, obtain 6-{14-methoxy oxygen base-2-hydroxyl-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] tetradecane-1-yl-the 5-methyl isophthalic acid, 2,3,4-tetramethoxy benzene.
At 0 ℃, with 6-{14-methoxy oxygen base-2-hydroxyl-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] tetradecane-1-yl-the 5-methyl isophthalic acid, 2,3, (42 milligrams of 4-tetramethoxy benzene, 0.05mmol) and pyridine-2, and the 6-dicarboxylic acids (83.5 milligrams, acetonitrile 0.5mmol) (6 milliliters) solution stirring, drip ceric ammonium nitrate (CAN simultaneously, 180 milligrams, acetonitrile/water 0.33mmol) (1: 1,5 milliliters) solution.Mixture was stirred five hours at 0 ℃, by adding CHCl 3/ isopropyl alcohol (1: 1, add entry (10mL) 10mL), subsequently and come quencher.Separate each layer, and with water CHCl 3/ isopropyl alcohol (1: 1,3 * 30 milliliters) extracts.The organic fraction that merges is concentrated, and by hurried chromatography (hexane-2: 1 hexane: ethyl acetate gradient, through 230-400 order silica gel) the purification residue, obtain yellow solid: 5-{14-methoxy oxygen base-2-hydroxyl-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] tetradecane-1-yl }-6-methyl-2,3-dimethoxy-1, the 4-benzoquinone.
With 5-{14-methoxy oxygen base-2-hydroxyl-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-5-yl] tetradecane-1-yl-6-methyl-2,3-dimethoxy-1, (84 milligrams of 4-benzoquinone, 0.1mmol) be dissolved in the pyridine (1.0 milliliters), and the adding p-toluenesulfonyl chloride (28.5 milligrams, 0.15mmol).Mixture is at room temperature stirred two hours, and vacuum concentration.Residue is distributed between ethyl acetate (5 milliliters) and water (5 milliliters).Water phase separated, and with ethyl acetate (2 * 5mL) extract, and with the organic fraction washing (1 * water) that merges, dry (saturated NaCl aqueous solution, sodium sulfate) filters also and concentrates.Utilize chromatograph (hexane-2: 1 hexane: ethyl acetate gradient, process 230-400 order silica gel), obtain needed product.
4e.5-{14-methoxy oxygen base-2-[ 18F] fluoro-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] tetradecane-1-yl }-6-methyl-2,3-dimethoxy-1,4-benzoquinone.
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Remove fully desolvate before; add 5-{14-methoxy oxygen base-2-[ptoluene-sulfonyl fast]-13-[octahydro-5 '-(1-(methoxy oxygen base) undecyl) [2.2 '-two furan]-the 5-yl] tetradecane-1-yl }-6-methyl-2; 3-dimethoxy-1, THF (150ul) solution of 4-benzoquinone (1 milligram).Phial was heated 15 minutes down at 65 ℃.After the cooling, add methyl sulfide (100ul), add etherate of trifluoroboron (200uL) subsequently.Phial is heated to 65 ℃ once more, kept 15 minutes, then cooling.With the dilution of the inclusions water (4mL) in the phial, and by silica gel cylinder (preload Waters Light C-18Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 5
5a. succinic acid 4-(4-ketobutyric acid methyl ester) benzyl ester methyl ester
Figure A20058002147400592
Benzyl alcohol (20g, 0.185 mole) is joined in 100 milliliters of round-bottomed flasks that dichloromethane (50ml) is housed.Flask is cooled to 0 ℃.Then aluminum chloride (1.85 moles) and 3-chloro carbonyl propiono methyl ester (0.37mol) are joined in the above-mentioned flask.Stirred the mixture 3 hours, and then at leisure water was joined in the flask.Inclusions is poured in the separatory funnel, and separates each layer.Use the dichloromethane extraction water layer, merge organic layer, and use the salt water washing, use dried over mgso, filter, vacuum concentration obtains the crude product residue, and it can be directly in next step use.
(5b.4-[4-methylol)-phenyl]-4-oxo-methyl butyrate
In 50 milliliters of round-bottomed flasks, (15g 44.6mmol) is dissolved in the methanol benzyl ester methyl ester with succinic acid 4-(4-ketobutyric acid methyl ester).Sodium being joined in the above-mentioned solution then, is 9 until pH value.Agitating solution 2 hours is then removed methanol on rotary evaporator, the crude product residue is carried in the ethyl acetate water and salt water washing, and after drying and filtration.Vacuum is removed organic solvent, and the crude product that will so obtain passes through the hurried chromatography of silica gel, and (ethyl acetate: purification hexane) obtains needed product.
(5c.4-[4-methylol)-phenyl]-methyl butyrate
Figure A20058002147400602
With 4-[4-(methylol)-phenyl]-(8g 36mmol) is dissolved in the methanol 4-oxo-methyl butyrate.Add Pd/C (0.8g, 10%wt, dry basis).Use the rubber septum sealed flask then, and will be full of H 2The balloon of gas is applied thereto.Then this heterogeneous mixture was stirred 4 hours, then remove balloon and stopper, and make the hydrogen loss.Then by kieselguhr (Celite ) the pad filter reaction mixture, and the filtrate vacuum concentration that will so obtain, form needed product.
5d.2-sulfenyl (thio)-3-methyl .alpha.-5:6-benzopyran-4-ketone
C 10H 8O 2S
Accurate mass: 192.02
In 250 milliliters of round-bottomed flasks that potassium tert-butoxide (0.599mmol) is housed, drip 1-(2-hydroxyl-phenyl)-third-1-ketone (30g, 0.199mol mmol) and 75 milliliters of toluene solutions of Carbon bisulfide (0.24mmol), cooling simultaneously is to maintain the temperature between 15-22 ℃.Reactant mixture was at room temperature stirred 4 days, then be poured in the water (250mL).Separating water layer, use washed with dichloromethane, use the acetic acid acidify, is 5 until pH value.It was stirred 2 hours once more, then water layer is poured in the separatory funnel, (3 * 30mL) extract with dichloromethane.Use saturated sodium bicarbonate solution, water washing organic layer then then.With saline, then use the dried over sodium sulfate organic layer, filter then.(ether: purification hexane) obtains pure 2-sulfenyl-3-methyl .alpha.-5:6-benzopyran-4-ketone by hurried chromatography with removing the crude product that obtains after the organic solvent.
(5e.2-4-(butanoic acid methyl ester) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400612
Triphenylphosphine (33.6mmol) and diethylazodicarboxylate (3.6mmol) are packed in 50 milliliters of round-bottomed flasks.Then THF (30ml) is joined in the flask, and flask is cooled to 0 ℃.Said mixture was stirred 30 minutes, then adds 2-sulfenyl-3-methyl .alpha.-5:6-benzopyran-4-ketone (22.4mmol) and 4-[4-(methylol)-phenyl with a collection of form]-methyl butyrate (7g, 33.6mmol).Reactant mixture is warming up to room temperature, and stirred 24 hours.Add 5%NaHCO then 3(10ml), and with mixture be poured in the separatory funnel.Use ethyl acetate (2 * 25 milliliters) to extract water layer then,, then use dried over mgso, filter and vacuum concentration the organic layer salt water washing that merges.(ethyl acetate: purification hexane) obtains above-mentioned product by hurried chromatography with residue.
(5f.2-4-(4-hydroxybutyl) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400621
Lithium aluminium hydride (33.2mmol) is joined in 50 milliliters of round-bottomed flasks, and ether (25 milliliters) is joined wherein, cooling flask to 0 ℃.(7.5g 22.15mmol) joins in the above-mentioned flask by the pressure balance charging hopper sulfenyl-3-methyl .alpha.-5:6-benzopyran-4-ketone at leisure will to be dissolved in 2-(4-(butanoic acid methyl ester) phenyl methyl) in the ether.Stirred reaction mixture 3 hours, then order is to wherein adding entry (1.25mL), 15%NaOH (1.25mL) and water (3.7mL).It was stirred 20 minutes, and the after-filtration inclusions.Water and saline wash filtrate are used dried over sodium sulfate, filter and vacuum concentration, obtain residue, and (ether: purification hexane) obtains above-mentioned product by the hurried chromatography of silica gel with residue.
(5g.2-4-(4-tosyl oxygen Ji Dingji) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone
(6.0 grams 16.9mmol) join in 50 milliliters of round-bottomed flasks, and to wherein adding pyridine (15 milliliters) with 2-(4-(4-hydroxybutyl) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone.Add toluene sulfochloride (25.4mmol) with a collection of form then, stirred this mixture 8 hours, then to wherein adding entry and ethyl acetate.Inclusions is poured in the separatory funnel, and separates each layer.With organic layer 5%CuSO 4(2 * 10mL) water and salt water washings then.Then it is used dried over mgso, filter and vacuum concentration.The residue that obtains is passed through the hurried chromatography of silica gel, and (ethyl acetate: purification hexane) obtains product.
(5h.2-4-(4-fluorine butyl) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone
In 25 milliliters of round-bottomed flasks, sulfenyl 3-methyl .alpha.-5:6-benzopyran-(7.5g 14.7mmol) is dissolved among the THF 4-ketone with 2-(4-(4-tosyl oxygen Ji Dingji) phenyl methyl).Then tetrabutylammonium fluoride (14.7mmol) solution (1M is in THF) is joined wherein, and gained solution is heated to backflow, kept 2 hours.Inclusions is concentrated on rotary evaporator, and the residue that obtains is passed through the hurried chromatography of silica gel (ethyl acetate: purification hexane).
5i.2-(4-(4-[ 18F]-the fluorine butyl) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400632
With moisture 18F (16mCi, 0.1 milliliter) joins in the vacuum test tube that contains 5 μ l tetrabutylammonium hydroxide (40%wt aqueous solution).Under nitrogen atmosphere, in 100 ℃ oil bath, mixture is concentrated, add 250 μ L acetonitriles, and also it is concentrated under nitrogen atmosphere.Repeat this process twice, then 100 μ L acetonitriles are joined wherein, and inclusions is carried out evacuation.Before dryin-up point, add THF, then add 5 milligrams 2-(4-(4-tosyl oxygen Ji Dingji) phenyl methyl) sulfenyl 3-methyl .alpha.-5:6-benzopyran-4-ketone.Then in 70 ℃ oil bath with mixture heated 30 minutes.With its dilute with water, be applied on the C18 Sep-Pak then, the acetonitrile eluting is used in the water flushing, obtains above-claimed cpd.
Embodiment 6
6a.2-ethylmercapto group 3-methyl .alpha.-5:6-benzopyran-4-ketone is synthetic
2-sulfenyl 3-methyl .alpha.-5:6-benzopyran-(10g adds DMF in round-bottomed flask 52mmol) to 4-ketone to containing.Then iodoethane (62.4mmol) and potassium carbonate (62.4mmol) are added in this flask, and stirred this reactant mixture 3 hours.Then to wherein adding entry, and it is poured in the separatory funnel.(2 * 25ml) extract with ethyl acetate with water layer then.With organic layer water and the salt water washing that merges, use dried over mgso, filter and concentrate.(ether: purification hexane) forms needed product by the hurried chromatography of silica gel with concentrating the residue that obtains after the organic layer.
6b.2-ethyl sulfinyl-3-methylol .alpha.-5:6-benzopyran-4-ketone
In 50 milliliters of round-bottomed flasks, add selenium dioxide (13.6mmol) and 90% tert-butyl hydroperoxide (54.5mmol).Then to wherein adding dichloromethane (25 milliliters), and this mixture was at room temperature stirred 30 minutes.(6g 27.2mmol) joins in the flask, and stirred reaction mixture 10 hours with 2-ethylmercapto group-3-methyl .alpha.-5:6-benzopyran-4-ketone.On rotary evaporator, remove dichloromethane, and ether is joined in the residue.Organic facies is washed with 10%KOH, and with the salt water washing once.Remove once more and desolvate, and cold acetic acid and methyl sulfide are joined in the flask.Stir the inclusions several hrs, then with 20%K 2CO 3Join in the flask.With the water ethyl acetate extraction, water and salt water washing, and use dried over sodium sulfate, and filter, concentrate.The residue that obtains after concentrating is passed through the hurried chromatography of silica gel (ether: purification hexane).
6c.2-ethyl sulfinyl-3-((2-THP trtrahydropyranyl oxygen base) methyl) .alpha.-5:6-benzopyran-4-ketone
(5g adds dihydropyran (29.7mmol) and toluenesulfonic acid (0.99 mole) in 19.8mmol) to the 2-ethyl sulfinyl-3-methylol .alpha.-5:6-benzopyran-4-ketone in the dichloromethane (20 milliliters) of being dissolved in 25 milliliters of round-bottomed flasks.Reactant mixture was stirred 3 hours, then be poured in the separatory funnel, add entry.Add ethyl acetate then, and separate each layer.With organic layer water (3 * 10) and salt water washing, and use dried over sodium sulfate, filter.With the filtrate vacuum concentration, and the residue that obtains is passed through the hurried chromatography of silica gel, and (ether: purification hexane) obtains above-mentioned product.
(6d.2-4-tert-butyl group benzyl) sulfenyl-3-((2-THP trtrahydropyranyl oxygen base) methyl) .alpha.-5:6-benzopyran-4-ketone
Adding 2-ethyl sulfinyl-3-((2-THP trtrahydropyranyl oxygen base) methyl) .alpha.-5:6-benzopyran-4-ketone in the 25ml round-bottomed flask (5g, 14.87mmol).To wherein adding acetonitrile, then add 4-tert-butyl group benzyl mercaptan (74.3mmol) then.At room temperature stirred reaction mixture is 10 hours, then solvent removed in vacuo.The crude product residue that obtains is passed through silica gel chromatography, and (ethyl acetate: purification hexane) obtains product.
(6e.2-4-tert-butyl group benzyl) sulfenyl-3-methylol .alpha.-5:6-benzopyran-4-ketone
In 50 milliliters of round-bottomed flasks, (5.5g 12.55mmol) is dissolved in the oxolane .alpha.-5:6-benzopyran-4-ketone with 2-(4-tert-butyl group benzyl) sulfenyl-3-((2-THP trtrahydropyranyl oxygen base) methyl).Add acetic acid and water then, make THF: acetic acid: the ratio of water is 4: 2: 1 (28mL).Flask is warming up to 45 ℃, and stirred the mixture 3 hours.After the cooling flask, inclusions is poured in the separatory funnel, and uses the ethyl acetate extraction water layer.Then with organic layer water and salt water washing, and use dried over sodium sulfate, filter.With the filtrate vacuum concentration, and the residue that obtains is passed through the hurried chromatography of silica gel, and (ethyl acetate: purification hexane) obtains above-mentioned product.
(6f.2-4-tert-butyl group benzyl) sulfenyl-3-tosyl oxygen ylmethyl .alpha.-5:6-benzopyran-4-ketone
(3g 8.47mmol), and is dissolved in dichloromethane (10 milliliters) with it to add 2-(4-tert-butyl group benzyl) sulfenyl-3-methylol .alpha.-5:6-benzopyran-4-ketone in the 25ml round-bottomed flask.Then toluene sulfochloride (12.7mmol) and triethylamine (12.7mmol) are joined wherein, and at room temperature stirred this reactant mixture 4 hours.Solvent removed in vacuo then, and with the residue that obtains (ethyl acetate: purification hexane) obtains above-mentioned product by the hurried chromatography of silica gel.
(6g.2-4-tert-butyl group benzyl) sulfenyl-3-methyl fluoride .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400663
(3g 5.9mmol) joins in 15 milliliters of round-bottomed flasks, and with tetrabutylammonium fluoride solution (5.9mmol with 2-(4-tert-butyl group benzyl) sulfenyl-3-tosyl oxygen ylmethyl .alpha.-5:6-benzopyran-4-ketone; 1M is in THF) join wherein.Solution is heated to the maintenance 3 hours that refluxes, then removes all volatile matters, and the residue that obtains is passed through the hurried chromatography of silica gel (ethyl acetate: purification hexane).
(6h.2-4-tert-butyl group benzyl) sulfenyl-3-[ 18F]-methyl fluoride .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400671
With moisture 18F (16mCi, 0.1 milliliter) joins in the vacuum test tube that contains 5 μ l tetrabutylammonium hydroxide (40%wt aqueous solution).Under nitrogen atmosphere, in 100 ℃ oil bath, mixture is concentrated, add 250 μ L acetonitriles, and also it is concentrated under nitrogen atmosphere.Repeat this process twice, then 100 μ L acetonitriles are joined wherein, and inclusions is carried out evacuation.Before bone dry, add THF, then add 2-(4-tert-butyl group benzyl) sulfenyl-3-tosyl oxygen ylmethyl .alpha.-5:6-benzopyran-4-ketone of 5 milligrams.Then in 70 ℃ oil bath with mixture heated 30 minutes.With its dilute with water, be applied on the C18 Sep-Pak then, the acetonitrile eluting is used in the water flushing, obtains above-claimed cpd.
Embodiment 7
7a.2 '-tert-butoxy-6 '-the hydroxy phenyl ethyl ketone
Figure A20058002147400672
In the 100ml round-bottomed flask, add 2 ', 6 '-dihydroxy benzenes methyl ethyl ketone methyl ketone (25g, 0.15 mole), then to wherein adding dichloromethane (50mL).Then it is cooled to-75 ℃, then adds 2.6 milliliters of H 3PO 4, then add 6.22 milliliters of etherate of trifluoroborons, add isobutene. (125mL) then.To react at-75 ℃ then and stir 1.5 hours, then at room temperature spend the night.Reactant mixture is poured in the 2N Ammonia (200ml), and uses dichloromethane extraction.Then the organic layer water is then used the salt water washing, and use dried over sodium sulfate, filter.The crude product residue that obtains after the concentrated filtrate is passed through the hurried chromatography of silica gel, and (ethyl acetate: purification hexane) obtains above-mentioned product.
7b.5-tert-butoxy-2-sulfenyl-3-methyl .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400681
In 100 milliliters of round-bottomed flasks that potassium tert-butoxide (270mmol) is housed, drip 2 '-tert-butoxy-6 '-hydroxy phenyl ethyl ketone (20g, 90mmol) and 50 milliliters of toluene solutions of Carbon bisulfide (99mmol), cooling simultaneously is to maintain the temperature between 15-22 ℃.Reactant mixture was at room temperature stirred 4 days, then be poured in the water (250mL).Separating water layer, use washed with dichloromethane, use the acetic acid acidify, is 5 up to pH value.It was stirred 2 hours once more, then water layer is poured in the separatory funnel, (3 * 40mL) extract with dichloromethane.Use saturated sodium bicarbonate solution, water washing organic layer then then.With saline, then use the dried over sodium sulfate organic layer, filter then.The crude product that obtains after the concentrated filtrate is passed through hurried chromatography purification, obtain pure 2-sulfenyl-3-methyl .alpha.-5:6-benzopyran-4-ketone.
(7c.2-4-tert-butyl group benzyl sulfydryl)-3-methyl-5-tert-butoxy .alpha.-5:6-benzopyran-4-ketone
Figure A20058002147400682
Triphenylphosphine (37.8mmol) and diethylazodicarboxylate (37.8mmol) are packed in 50 milliliters of round-bottomed flasks.Then THF (20mL) is joined in the flask, and flask is cooled to 0 ℃.Said mixture was stirred 30 minutes, and (10g is 37.8mmol) with 4-tert-butyl benzene methanol (38mmol) then to add 2-sulfenyl-3-methyl 5-tert-butoxy .alpha.-5:6-benzopyran-4-ketone with a collection of form.Reactant mixture is warming up to room temperature, and stirred 24 hours.Add 5%NaHCO then 3, and mixture is poured in the separatory funnel.Use ethyl acetate (2 * 25 milliliters) to extract water layer then,, then use dried over mgso, filter and vacuum concentration the organic layer salt water washing that merges.By hurried chromatography purification residue, obtain above-mentioned product.
(7d.2-4-tert-butyl group benzyl sulfydryl)-3-methyl-5-hydroxy benzo pyrans-4-ketone
In 50 milliliters of round-bottomed flasks, add 2-(4-tert-butyl group benzyl sulfydryl)-3-methyl-5-tert-butoxy .alpha.-5:6-benzopyran-4-ketone (10g, 24.3mmol).Stirred this reactant mixture 8 hours then to wherein adding anhydrous trifluoroacetic acid (15mL), and at 0 ℃.In flask, add dichloromethane then, and mixture is poured in the separatory funnel.Then its water is then used the salt water washing, and use dried over sodium sulfate, filter.Then with the filtrate vacuum concentration, and with the residue that obtains (ethyl acetate: purification hexane) obtains needed product by the hurried chromatography of silica gel.
(7e.2-4-tert-butyl group benzyl sulfydryl)-3-methyl-5-tosyl oxygen base .alpha.-5:6-benzopyran-4-ketone
In 25 milliliters of round-bottomed flasks, with 2-(4-tert-butyl group benzyl sulfydryl)-(5g 14.1mmol) is dissolved in the pyridine 3-methyl-5-hydroxy benzo pyrans-4-ketone, and paratoluensulfonyl chloride (15mmol) is joined wherein.Reactant mixture was stirred 8 hours.In flask, add entry then, and inclusions is poured in the separatory funnel.Add ethyl acetate, and separate each layer.Then with organic layer water and salt water washing, and use dried over sodium sulfate, filter.With the filtrate vacuum concentration, and the residue that obtains is passed through the hurried chromatography of silica gel, and (hexane: ethyl acetate) purification obtains above-mentioned product.
(7f.2-4-tert-butyl group benzyl sulfydryl)-3-methyl-5-fluorobenzene and pyrans-4-ketone
Figure A20058002147400701
In the 15mL round-bottomed flask; with (200 milligrams of 2-(4-tert-butyl group benzyl sulfydryl)-3-methyl-5-tosyl oxygen base .alpha.-5:6-benzopyrans-4-ketone; 0.39mmol) be dissolved among the THF, and potassium fluoride (0.39mmol) and Kryptofix (0.39mmol) are joined wherein.Solution is heated to the maintenance 3 hours that refluxes, then is cooled to room temperature.Concentrated reaction mixture then, and with the crude product residue that obtains by the hurried chromatography purification of silica gel, obtain above-mentioned product.
(7g.2-4-tert-butyl group benzyl sulfydryl)-3-methyl-5-[ 18F]-fluorobenzene and pyrans-4-ketone
Figure A20058002147400702
To containing at 300mg 18100mCi in the O water 18Add 1 ml soln of forming by 10mg Kryptofix, 1mg potassium carbonate, 0.005mL water and 0.95mL acetonitrile in 5 milliliters of reaction phials of F.With the phial heating, remove all solvents, and dry acetonitrile (1mL) is joined in the phial.Also be removed by evaporation.Then to 2-(4-tert-butyl group benzyl sulfydryl)-3-methyl-5-tosyl oxygen base .alpha.-5:6-benzopyran-4-ketone (5 milligrams) that wherein is added in the acetonitrile.With the phial sealing, and 100 ℃ of heating 30 minutes.Mixture is diluted with dichloromethane, and, use the oxolane eluting by Sep-Pak.With solvent evaporation, obtain needed chemical compound.
Embodiment 8
8a.2-bromo-1-(2,2-dimethyl-.alpha.-5:6-benzopyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone
Figure A20058002147400711
To 1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone (37 grams, 0.1mol, Chemistry and Biology 2000,7,979) speed with the continuous variable color that obtains reactant mixture in carbon tetrachloride (300 milliliters) solution adds bromine (16.0g, 0.1 mole).After adding is finished (about 10 minutes), with the reactant mixture reduction vaporization, obtain 2-bromo-1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone, it just need not be further purified can be used for next step.
8b.2-[ 18F] fluoro-1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone
Figure A20058002147400712
To containing at 300mg 1850mCi in the O water 18Add 1 ml soln of forming by 10mg Kryptofix, 1mg potassium carbonate, 0.005mL water and 0.95mL acetonitrile in 5 milliliters of reaction phials of F.With the phial heating, remove all solvents, and dry acetonitrile (1ml) is joined in the phial once more, be removed in a vacuum once more.Then tributyl-[2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-3-(3,4,5-trimethoxy-phenyl)-acrylic]-stannane (5 milligrams) in acetonitrile is joined in the phial.With the phial sealing, and heated 30 minutes, to 100 ℃.Mixture is diluted with dichloromethane, and, use the THF eluting by Sep-Pak.Concentrated filtrate obtains 2-[ 18F] fluoro-1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone.
Embodiment 9
(9a.1-2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-2-hydroxyl-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone
To be dissolved in 1-(2,2-dimethyl-benzodihydropyran-6-the yl)-2-(3,4 among the THF (3 milliliters), 5-trimethoxy-phenyl)-(184.1 milligrams of ethyl ketones, 0.5mmol) be added drop-wise in cold NaHMDS (0.6mL, 1.0M is in THF) THF (3mL) solution of stirring.The reactant mixture that obtains was stirred 30 minutes, then drip (+/-)-camphoryl-sulfonyl oxa-aziridine in THF (3mL) (187mg, 0.75mmol).After 15 minutes, with the saturated NH of reactant mixture 4I (moisture) solution (3mL) cancellation, and dilute with ether.Mixture is warmed to room temperature.With the water layer ether extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters and concentrates.Use silica gel chromatography purification crude product 1-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-2-hydroxyl-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone.
9b. toluene-4-sulfonic acid 2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester
Figure A20058002147400722
To 1-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-2-hydroxyl-2-(3,4,5-trimethoxy-phenyl)-(28 milligrams of ethyl ketones, 0.073mmol) dichloromethane (1.5 milliliters) agitating solution in add (15.3 milligrams of p-toluenesulfonyl chlorides, 0.080mmol) and pyridine (6.47 μ l, 0.080mmol).Reactant mixture is continued at room temperature to stir.Use silica gel chromatography purification crude product.
(9c.1-2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-2-[ 18F] fluoro-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Except that before desolvating, add THF (150ul) all, phial is not compressed, add toluene-4-sulfonic acid 2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester (2 milligrams) with portion.With phial capping again, and 65 ℃ of heating 30 minutes.After the cooling, with phial water (4mL) dilution, and by silica gel cylinder (preload Waters Light C-18Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 10
10a.6-[2-iodo-1-(3,4,5-trimethoxy-benzyl)-vinyl]-2,2-dimethyl-2H-.alpha.-5:6-benzopyran
Figure A20058002147400732
Diiodo-acute pyogenic infection of nails alkane (26.88g, 0.1 mole) and triphenylphosphine (0.1 mole of 26.23 gram) are dissolved in the ether, at room temperature stirred 24 hours.Collect the interior  salt that obtains by filtering, and vacuum drying.Interior  salt is dissolved among the THF (100mL), and is cooled to-78 ℃.(18.34g 0.1mol) is added drop-wise in the reactant mixture of stirring with N-hmds sodium (N-sodium hexamethyldisilazide).Reactant mixture was stirred 30 minutes in addition.(36.82g 0.1mol) joins in the reactant mixture will to be dissolved in ketone among the THF (50mL).Reaction is warming up to 0 ℃.After 2 hours, will react and use saturated NH 4Cl (aqueous solution) cancellation.With the water layer ether extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters, and concentrates, and passes through chromatogram purification.
10b. tributyl-[2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-3-(3,4,5-trimethoxy-phenyl)-acrylic]-stannane
Figure A20058002147400741
To 6-[2-iodo-1-(3,4,5-trimethoxy-benzyl)-and vinyl]-2, (974 milligrams of 2-dimethyl-2H-.alpha.-5:6-benzopyran, 1.98mmol) 1, add in 4-two  alkane (9 milliliters) solution three normal-butyl vinyl-stannanes (650 milligrams, 2.05mmol), LiCl (252 milligrams, 594mmol), Pd (PPh 3) 4(46 milligrams, 0.04mmol) with several 2,6-two-tert-butyl group-4-sylvan crystal.The suspension that obtains be heated to reflux kept 4 hours, be cooled to room temperature, and with pyridine (1mL) and fluoridize pyridine  (2mL, 1.4M solution, in THF, 2.8mmol) processing.The mixture that stirring at room temperature obtains 16 hours is then with the ether dilution, by little kieselguhr (Celite ) the pad filtration.With filtrate water, 10%HCl, water, salt water washing, use dried over sodium sulfate, filter and concentrate.Crude product can be used for next step without being further purified.
10c.6-[2-[ 18F] fluoro-1-(3,4,5-trimethoxy-benzyl)-vinyl]-2,2-dimethyl-2H-.alpha.-5:6-benzopyran
Figure A20058002147400742
To containing at 300mg 1850mCi in the O water 18Add 1 ml soln of forming by 10mg Kryptofix, 1mg potassium carbonate, 0.005mL water and 0.95mL acetonitrile in 5 milliliters of reaction phials of F.With the phial heating, remove all solvents, and dry acetonitrile (1ml) is joined in the phial once more, be removed in a vacuum once more.Then tributyl-[2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-3-(3,4,5-trimethoxy-phenyl)-acrylic]-stannane (5 milligrams) in acetonitrile is joined in the phial.With the phial sealing, and heated 30 minutes, to 100 ℃.Mixture is diluted with dichloromethane, and, use the THF eluting by Sep-Pak.Concentrated filtrate obtains 6-[2-[ 18F] fluoro-1-(3,4,5-trimethoxy-benzyl)-vinyl]-2,2-dimethyl-2H-.alpha.-5:6-benzopyran.
Embodiment 11
11a.4-hydroxyl-2,2-dimethyl-benzodihydropyran-6-carboxylic acid
With 6-bromo-2, anhydrous THF (50 milliliters) solution of 2-dimethyl-chromanol-4-alcohol (2.42 grams, 10mmol, Buckle, people such as D.R., J.Med.Chem.1990,33,3028) is cooled to-78 ℃.(2.5M in hexane, 9.0 milliliters, 22.6mmol) is added drop-wise in this stirred reaction mixture with n-BuLi.Reactant mixture is continued to stir other 15 minutes at-78 ℃.The gaseous carbon dioxide bubbling is passed through reactant mixture, and elevate the temperature to 25 ℃.After 12 hours, remove volatile matter by reduction vaporization, and crude product is carried in the water.With 1N HCl acidify water layer, and use ether extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters and concentrates.Thick product can be used for next step without being further purified.
11b.4-hydroxyl-2,2-dimethyl-benzodihydropyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester
With (3,4, the 5-trimethoxyphenyl) methanol (1.98 grams, 10mmol) and dimethyl aminopyridine (1.47 restrain, and 12mmol) are dissolved in the anhydrous methylene chloride (50 milliliters).Solution is cooled to 0 ℃.(4.31 grams 15mmol) are added dropwise to will to be dissolved in 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide in the dichloromethane (50 milliliters).Reactant mixture is continued to stir other 2 hours at 0 ℃, make it then to room temperature.After 12 hours, use saturated NH 4Cl cancellation reactant mixture.With the water layer dichloromethane extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters and concentrates.Use silica gel chromatography purification crude product 4-hydroxyl-2,2-dimethyl-benzodihydropyran-6-carboxylic acid 3,4,5-trimethoxy benzyl ester.
11c.2,2-dimethyl-4-(toluene-4-sulfonyloxy)-benzodihydropyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester
Figure A20058002147400761
To 4-hydroxyl-2,2-dimethyl-benzodihydropyran-6-carboxylic acid 3,4, (29.4 milligrams of 5-trimethoxy benzyl esters, 0.073mmol) dichloromethane (1.5 milliliters) agitating solution in add TsCl (15.3 milligrams, 0.080mmol) and pyridine (6.47ul, 0.080mmol).Reactant mixture is continued at room temperature to stir.Use silica gel chromatography purification crude product, obtain 2,2-dimethyl-4-(toluene-4-sulfonyloxy)-benzodihydropyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester.
11d.4-[ 18F] fluoro-2,2-dimethyl-benzodihydropyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester
Figure A20058002147400762
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Except that before desolvating, add THF (150ul) all, phial is not compressed, add 2 with portion, 2-dimethyl-4-(toluene-4-sulfonyloxy)-benzodihydropyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester (2 milligrams).With phial capping again, and 65 ℃ of heating 30 minutes.After the cooling, with phial water (4mL) dilution, and by silica gel cylinder (preload Waters Light C-18 Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 12
8-[ 18F] fluoro-2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester synthetic
Figure A20058002147400771
With tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) and 18(10mCi's F-aqueous solution 200uL) packs in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper.With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Except that before desolvating, add THF (150ul) all, phial is not compressed, add the previous Chemistry and Biology2000 of passing through, 2 of 7,979 preparations with portion, 2-dimethyl-8-nitro-2H-.alpha.-5:6-benzopyran-6-carboxylic acid 3,4,5-trimethoxy-benzyl ester (2 milligrams).With phial capping again, and 65 ℃ of heating 30 minutes.Be cooled to after the room temperature, with phial water (4mL) dilution, and by silica gel cylinder (preload Waters Light C-18 Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 13
(13a. 4-hydroxyl-phenyl sulfane base)-(3,4,5-trimethoxy-phenyl)-ethyl acetate
At-78 ℃, will be at (4.52 grams of the trimethylsilyl chloride among the THF (25ml), 14mmol) and in THF (25 milliliters) (3,4,5-trimethoxy-phenyl)-ethyl acetate (2.03g, 8mmol) join successively in THF (25 milliliters) solution of lithium diisopropylamine (by diisopropylamine (8.8mmol) and n-BuLi (1.6N, in hexane, 5.5 milliliters) preparation).Mixture was stirred 1 hour down at-78 ℃.(1.12g 8.4mmol) joins in the agitating solution with a N-chlorosuccinimide.Make reactant mixture be warmed to 0 ℃ with 3 hours, stirred 30 minutes at 0 ℃, then dilute with water.With the water layer dichloromethane extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters and concentrates.With thick product silica gel chromatography purification.
13b.4-hydroxyl-phenyl sulfane base)-(3,4,5-trimethoxy-phenyl)-ethyl acetate
Figure A20058002147400782
To the 4-sulfydryl-phenol that is dissolved in DMF (20 milliliters) (1.26 grams, 10mmol), K 2CO 3(4.14 grams, 30mmol) and tetrabutylammonium iodide (0.74 gram, (2.88 restrain, 10mmol) to drip 4-chloro-(3,4,5-trimethoxy-phenyl)-ethyl acetate in DMF (10 milliliters) in solution 2mmol).Reactant mixture is continued at room temperature to stir.After 12 hours, with 3%HCl (moisture) cancellation reactant mixture.With the water layer ethyl acetate extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters and concentrates.With thick product silica gel chromatography purification.
13c.4-[2-hydroxyl-1-(3,4,5-trimethoxy-phenyl)-ethyl sulfane base]-phenol
To be dissolved in the 4-hydroxyl-phenyl sulfane base among the THF (30 milliliters))-(3,4,5-trimethoxy-phenyl)-(4.8 grams, (3.15 grams are in THF 12.7mmol) (32.7 milliliters) solution 12.7mmol) to join refrigerative (0 ℃) lithium aluminium hydride fast for ethyl acetate.Stirred reaction mixture at room temperature.1.5 after hour, with 2.5N HCl and cancellation reactant mixture.With the water layer ethyl acetate extraction.Dried over sodium sulfate is used in the organic layer water, the salt water washing that merge, filters and concentrates.With thick product silica gel chromatography purification.
13d.2-[4-(1,1-dimethyl-Propargyl oxygen base-phenyl sulfane base]-2-(3,4,5-trimethoxy-phenyl)-ethanol
Figure A20058002147400792
With 3-chloro-3-methyl isophthalic acid-butine (1.72 grams, 16.8mmol) join 4-[2-hydroxyl-1-(3,4,5-trimethoxy-phenyl)-ethyl sulfane base]-phenol (2.83 grams, 8.41mmol), potassium carbonate (2.35 the gram, 16.82mmol), potassium iodide (2.37 the gram, 14.23mmol) and Copper diiodide (33 milligrams, 0.17mmol) in the mixture of dry DMF (10 milliliters).Reactant mixture is heated to 70 ℃ then.After 4 hours, reaction is cooled to room temperature, and concentrating under reduced pressure.Residue is dissolved in the dichloromethane again, water and salt water washing, and use dried over sodium sulfate, and filter, concentrate.With thick product silica gel chromatography purification.
(13e.2-2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-base sulfane base)-2-(3,4,5-trimethoxy-phenyl)-ethanol
With N, N-diethylaniline (9.53 milliliters) is heated to 185 ℃.Dropping 2-[4-(1,1-dimethyl-Propargyl oxygen base-phenyl sulfane base]-2-(3,4,5-trimethoxy-phenyl)-ethanol (16.11 grams, 0.04 mole).Reactant mixture is heated to 195 ℃ then.After 1 hour, reactant mixture is cooled to room temperature, and dilutes with hexane.Extract organic layer with 5%HCl, use dried over sodium sulfate, filter and concentrate, obtain needed product, it just need not be further purified can be used for next step.
13f. toluene-4-sulfonic acid 2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-base sulfane base)-2-(3,4,5-trimethoxy-phenyl)-ethyl ester
Figure A20058002147400802
To 2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-base sulfane base)-2-(3,4,5-trimethoxy-phenyl)-(29.3 milligrams of ethanol, 0.073mmol) dichloromethane (1.5 milliliters) agitating solution in add (15.3 milligrams of p-toluenesulfonyl chlorides, 0.080mmol) and pyridine (6.47ul, 0.080mmol).Reactant mixture is continued at room temperature to stir.Use silica gel chromatography purification crude product, obtain needed product.
13g.6-[2-[ 18F] fluoro-1-(3,4,5-trimethoxy-phenyl)-ethyl sulfane base]-2,2-dimethyl-2H-.alpha.-5:6-benzopyran
Tetrabutylammonium hydroxide (5uL, 40%w/v aqueous solution) is packed in the thin-walled silanization vacuum test tube 10 milliliters, that have the silanization stopper, and add 18The F-aqueous solution (10mCi, 200uL).With the mixture that obtains 100 ℃, under nitrogen current evaporate to dryness.By repeat to add and the evaporation acetonitrile (3 * 200uL), residue is further dry.The acetonitrile that adds other equal portions, and in the vacuum that does not have heating, concentrate.Except that before desolvating, add THF (150ul) all, phial is not compressed, add 2-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-base sulfane base)-2-(3,4,5-trimethoxy-phenyl)-ethyl ester (2 milligrams) with portion.With phial capping again, and 65 ℃ of heating 30 minutes.After the cooling, with phial water (4mL) dilution, and by silica gel cylinder (preload Waters Light C-18 Sep-Pak), with load sample.With cylinder water flushing, and with acetonitrile (2 milliliters) eluting.Evaporate acetonitrile, and residue is passed through the HPLC purification, obtain needed product.
Embodiment 14
Synthesizing of embodiment 14a:4-(4-hydroxyl-Ding-1-alkynyl)-essence of Niobe:
To the 4-methyl-bromobenzoate (13.4 grams, add in diethylamide 0.62mmol) (200 milliliters) agitating solution Palladous chloride. (0.55 gram, 3.06mmol) and triphenylphosphine (0.16 restrains, 0.62mmol).With the solution degassing, and (0.12 gram, 0.62mmol) (4.34 restrain, 62mmol) with 3-butine-1-alcohol to add Copper diiodide.Reactant mixture is continued at room temperature to stir to spend the night.Crossed two days later, added other 0.5mol% Palladous chloride., 1.0mol% triphenylphosphine and 12mol%3-butine-1-alcohol.According to LCMS, finish in case react, concentrated reaction mixture, and crude product is carried in the serosity of silica gel and ethyl acetate.Remove organic solvent, and will remain dry silica gel and be contained in the cellular glass funnel.Use hexane: ethyl acetate mixture (1: 4) washs completely, then use ethyl acetate (100%) washing, (11.9g is 0.58mmol) as needed product (94% productive rate) to obtain needed 4-(4-hydroxyl-Ding-1-alkynyl)-essence of Niobe.
1H(CDCl 3，600MHz)：δ7.95(2H，d，J＝8.4Hz)，7.45(2H，d，J＝8.4Hz)，3.9(s，3H)，3.83(2H，t，J＝6.6Hz)，2.71(2H，t，J＝6.0Hz).
Synthesizing of embodiment 14b:4-(4-hydroxyl-butyl)-essence of Niobe:
In ethanol (60 milliliters) agitating solution of 4-(4-hydroxyl-Ding-1-alkynyl)-essence of Niobe (6.29 gram, 0.031 mole), add palladium/carbon (5 grams, 10%, on carbon), and with reactant mixture in 50psi hydrogenation.After 20 hours, filter reaction mixture is removed catalyst, concentrated filtrate, and (5.67g is 0.027mol) as needed product (89% productive rate) to obtain 4-(4-hydroxyl-butyl)-essence of Niobe.
1H(CDCl 3，600MHz)：δ7.94(2H，d，J＝8.4Hz)，7.24(2H，d，J＝8.4Hz)，3.89(s，3H)，3.65(2H，t，J＝6.6Hz)，2.65(2H，J＝7.8Hz，1.71(2H，m)，1.58(2H，m).
Synthesizing of embodiment 14c:4-(4-methylol-phenyl)-Ding-1-alcohol:
Figure A20058002147400822
In THF (100 milliliters) agitating solution of 4-(4-hydroxyl-butyl)-essence of Niobe (2.24 grams, 0.01 mole), drip lithium aluminium hydride solution (8.0 milliliters, 1M is in THF).After adding finishes, reactant mixture is continued at room temperature to stir.After 6 hours, water cancellation reactant mixture.With the water layer ethyl acetate extraction.Use Na 2SO 4Dry all merging organic layers filter, and concentrate, and obtain 4-(4-methylol-phenyl)-Ding-1-alcohol yellow oil (1.90 grams, 0.01 mole, 98% productive rate).
1H(CDCl 3，600MHz)：δ7.29(2H，d，J＝8.1Hz)，7.16(2H，d，J＝8.1Hz)，4.60(2H，s)，3.60(2H，t，J＝7.5Hz)，2.62(2H，t，J＝7.5Hz)，1.67(2H，m)，1.56(2H，m)； 13C(CDCl 3，150MHz)：δ141.7，138.5，128.5，127.0，65.0，62.5，35.2，32.1，27.5.
Embodiment 14d:4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-essence of Niobe synthetic:
Figure A20058002147400831
To 4-(4-hydroxyl-butyl)-essence of Niobe (300 milligrams, add in DMF 1.44mmol) (4 milliliters) solution imidazoles (147 milligrams, 2.16mmol), then add TBDMS-Cl (324 milligrams, 2.16mmol).At room temperature stirring reaction is 2 hours, and by TLC (3: 1 hexanes: ethyl acetate) monitoring.After raw material exhausts, use the ethyl acetate diluting reaction, water (3x) and saturated sodium bicarbonate (1x) washing.Use the dried over sodium sulfate organic layer, filter and concentrate, obtain yellow oil (360mg, 77% productive rate).This crude product oil just need not be further purified and can be used for next step.
Embodiment 14d:{4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-phenyl }-methanol synthetic:
To 4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-THF (5.5 milliliters) of essence of Niobe (0.80 gram, 2.48 moles) stirs in cooling (0 ℃) solution and drips lithium aluminium hydride solution (4.96 milliliters, 1M is in THF).After adding finishes, reactant mixture is continued at room temperature to stir.After 2 hours, water cancellation reactant mixture.With the water layer ethyl acetate extraction.With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces yellow oil.The use silica gel chromatography (1: 2 ethyl acetate: purification crude product hexane), obtain 4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-phenyl }-methanol (0.65 gram, 2.21 moles, 89% productive rate).
Embodiment 14e:2-[4-(4-hydroxyl-butyl)-dibenzylsulfide. alkyl]-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic:
2-sulfydryl-.alpha.-5:6-benzopyran-4-ketone in being dissolved in anhydrous THF (80 milliliters) (1.52 grams, 7.90mmol) and 4-(4-methylol-phenyl)-Ding-1-alcohol (1.90 grams, 9.90mmol) adding solid PPh in the solution 3(3.11 the gram, 11.90mmol) and DIAD (2.30 milliliters, 11.90mmol).After adding finishes, reactant mixture is continued at room temperature to stir.After 20 hours, with the reactant mixture dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.The use silica gel chromatography (1: 1 pentane: ethyl acetate) purification crude product obtains 2-[4-(4-hydroxyl-butyl)-dibenzylsulfide. alkyl]-3-methyl-.alpha.-5:6-benzopyran-4-ketone (1.29 grams, 3.64mmol), moderate yield (46%).
1H(CDCl 3，600MHz)：δ8.18(1H，dd，J＝7.9，1.3Hz)，7.60(1H，ddd，J＝8.6，7.2，1.7Hz)，7.31(2H，t，J＝8.5Hz)，7.29(2H，d，J＝8.1Hz)，7.12(2H，d，J＝8.1Hz)，4.36(2H，s)，3.62(2H，m)，2.61(2H，t，J＝7.5Hz)，2.00(3H，s)，1.67(2H，m)，1.56(2H，m)； 13C(CDCl 3，150MHz)：δ174.9，161.3，156.0，141.5，133.2，132.3，128.3，128.2，125.7，124.5，122.2，117.2，116.3，62.3，34.7，31.8，29.2，26.9，10.1.；
HRMS C 21H 22O 3The value of calculation of S: 355.1363:, measured value: 355.1364
Embodiment 14f: toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base sulfane ylmethyl)-phenyl]-butyl ester synthetic:
Figure A20058002147400842
To the 2-[4-that is dissolved in anhydrous methylene chloride (8.0 milliliters) (4-hydroxyl-butyl)-dibenzylsulfide. alkyl]-(300 milligrams of 3-methyl-.alpha.-5:6-benzopyrans-4-ketone, 0.85mmol) add (194 milligrams of TsCl in the solution, 1.01mmol), (124 milligrams of DMAP, 1.01mmol) and TEA (0.213 milliliter, 1.52mmol).Reactant mixture is continued at room temperature to stir.After 3 hours, with the reactant mixture dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.The use silica gel chromatography (1: 1 pentane: ethyl acetate) purification crude product obtains toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base sulfane ylmethyl)-phenyl]-butyl ester (280 milligrams, 0.55mmol), moderate yield (65%).
1H(CDCl 3，600MHz)：δ8.18(1H，dd，J＝7.9，1.3Hz)，7.77(2H，d，J＝8.2Hz).7.62(1H，m)，7.39(2H，t，J＝8.0Hz)，7.33(2H，d，J＝8.0Hz)，7.30(2H，d，J＝8.0Hz)，7.07(2H，d，J＝8.0Hz)，4.37(2H，s)，4.02(2H，t，J＝5.8z)，2.55(2H，t，J＝7.3Hz)，2.05(3H，s)，1.65(4H，m)； 13C(CDCl 3，150MHz)：δ175.5，162.2，156.7，144.9，141.5，134.1，133.4，133.0，130.0，129.1，129.0，128.1，126.5?125.3，122.9，117.5，117.0，70.5，35.3，34.9，28.6，27.2，21.8，10.8.；
HRMS C 28H 28O 5S 2Value of calculation: 509.1450:, measured value: 509.1441
Embodiment 14g:2-[4-(4-fluoro-butyl)-dibenzylsulfide. alkyl]-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic
To toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base sulfane ylmethyl)-phenyl]-(10 milligrams of butyl esters, 0.020mmol) anhydrous acetonitrile (0.2 milliliter) solution adding (2.28 milligrams of KF, 0.04mmol) and Kryptofix (14.8 milligrams, 0.04mmol).After adding finishes, reactant mixture is heated to 90 ℃.After 25 minutes, reactant mixture is cooled to room temperature, and dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use reversed phase chromatography (Luna, 10u, C18,10 microns of 250 * 21.2mm, 20% water-90% acetonitrile in water is in two mobile phases, adopt 0.1%TFA as modifier) the purification crude product, obtain 2-[4-(4-fluoro-butyl)-dibenzylsulfide. alkyl]-3-methyl-.alpha.-5:6-benzopyran-4-ketone (3.3 milligrams, 0.01mmol), moderate yield (46%).
19F(CDCl 3，564MHz)：δ-218.67(1F，m). 1H(CDCl 3，600MHz)：δ8.18(1H，dd，J＝7.8，1.8Hz)，7.60(1H，m)，7.36(2H，m)，7.31(2H，d，J＝7.8Hz)，7.13(2H，d，J＝8.0Hz)，4.47(1H，m)，4.39(1H，m)，4.36(2H，s)，2.63(2H，t，J＝6.6Hz)，2.03(3H，s)，1.69(4H，m)； 13C(CDCl 3，150MHz)：δ175.3，162.0，156.5，141.7，133.8，132.7，128.8，126.2125.2，122.6，117.3，116.8，84.4(83.3)，35.1，35.0，29.9(29.8)，26.9，10.5.
Embodiment 15
2-{4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-phenoxy group }-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic:
With solid NaH (37 milligrams 1.5mmol) are placed in the reaction flask, and are cooled to 0 ℃ in ice baths.With 4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-phenyl }-(377 milligrams, dry DMF 1.28mmol) (23 milliliters) drips of solution is added in the reaction flask methanol, stirs simultaneously.After adding finishes, reactant mixture is continued to stir other 1 hour at 0 ℃.(0.92 gram, 3.84mmol) drips of solution is added in this stirred reaction mixture will to be dissolved in 2-mesyl-3-methyl-.alpha.-5:6-benzopyran-4-ketone among the dry DMF (20 milliliters).After adding finishes, reactant mixture is continued at room temperature to stir.Judge according to TLC,, reactant mixture is cooled to 0 ℃ in case reaction is finished, and the water cancellation.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.The use silica gel chromatography (1: 1 hexane: ethyl acetate) purification crude product obtains 2-{4-[4-(tert-butyl group-dimethyl-silanyloxy base)-butyl]-phenoxy group }-3-methyl-.alpha.-5:6-benzopyran-4-ketone (258 milligrams, 0.73 milligram, 49%).HRMS C 27H 36O 4The value of calculation of Si: 453.2455, measured value: 453.2457.
Embodiment 15b:2-[4-(4-hydroxyl-butyl)-benzyloxy]-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic:
Figure A20058002147400871
To the 2-{4-[4-that is dissolved in anhydrous THF (5 milliliters) (tert-butyl group-dimethyl-silanyloxy base)-butyl]-phenoxy group }-(258 milligrams of 3-methyl-.alpha.-5:6-benzopyrans-4-ketone, 0.57mmol) drip TBAF solution (1.0M solution in the solution, in THF, 1.15 milliliters, 1.15mmol).After adding finishes, in stirring at room reaction 1 hour, water cancellation then.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.The use silica gel chromatography (1: 2 hexane: ethyl acetate) purification crude product obtains 2-[4-(4-hydroxyl-butyl)-benzyloxy]-3-methyl-.alpha.-5:6-benzopyran-4-ketone (101 milligrams, 0.30mmol), moderate yield (52%).HRMS C 21H 22O 4Value of calculation: 339.1590:, measured value: 339.1591.
Embodiment 15c: toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base oxygen ylmethyl)-phenyl]-butyl ester synthetic:
2-[4-(4-hydroxyl-butyl)-benzyloxy in being dissolved in anhydrous methylene chloride (3.0 milliliters)]-(101 milligrams of 3-methyl-.alpha.-5:6-benzopyrans-4-ketone, 0.30mmol) add (68 milligrams of TsCl in the solution, 0.36mmol), (55 milligrams of DMAP, 0.45mmol) and TEA (0.050 milliliter, 0.36mmol).Reactant mixture is continued at room temperature to stir.After 20 hours, with the reactant mixture dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.The use silica gel chromatography (4: 1 pentanes: ethyl acetate) purification crude product obtains toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base oxygen ylmethyl)-phenyl]-butyl ester (75.2 milligrams, 0.15mmol), moderate yield (51%).
1H(CDCl 3，600MHz)：δ8.21(1H，dd，J＝8.2，1.5Hz)，7.77(2H，d，J＝8.3Hz).7.60(1H，m)，7.33(2H，d，J＝8.0Hz)，7.36(2H，d，J＝8.0Hz)，7.39(2H，d，J＝8.2Hz)，7.33(2H，d，J＝8.0Hz)，7.99(2H，d，J＝7.9Hz)，5.43(2H，s)，4.04(2H，t，J＝5.9Hz)，2.59(2H，t，J＝7.3Hz)，2.44(3H，s)，1.99(3H，s)，1.68(4H，m)；)；
13C(CDCl 3，150MHz)：δ178.2，161.8，152.2，144.2，141.9，132.7，132.2，131.9，129.3，128.3，127.7，127.4，125.6，127.7，122.1，116.1，70.1，69.8，34.3，27.9，26.5，21.1，6.7.
HRMS C 28H 28O 6The S value of calculation: 545.1498, measured value: 515.1493.
Embodiment 15d:2-[4-(4-fluoro-butyl)-benzyloxy]-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic:
Figure A20058002147400881
To toluene-4-sulfonic acid 4-[4-(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base oxygen ylmethyl)-phenyl]-(20 milligrams of butyl esters, 0.04mmol) anhydrous acetonitrile (0.5 milliliter) solution in add (4.72 milligrams of KF, 0.08mmol) and Kryptofix (30.6 milligrams, 0.08mmol).After adding finishes, reactant mixture is heated to 90 ℃.After 15 minutes, reactant mixture is cooled to room temperature, and dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use reversed phase chromatography (Luna, 10u, C18,10 microns of 250 * 21.2mm, 30% water-90% acetonitrile in water is in two mobile phases, adopt 0.1%TFA as modifier) the purification crude product, obtain 2-[4-(4-fluoro-butyl)-benzyloxy]-3-methyl-.alpha.-5:6-benzopyran-4-ketone (6.8 milligrams, 0.02mmol), low-yield (13.6%). 19F (CDCl 3, 564MHz): δ-218.72 (1F, m) .HRMS C 21H 21FO 3Value of calculation: 341.1547, measured value: 341.1547. 1H(CDCl 3，600MHz)：δ8.21(1H，dd，J＝8.3，1.6Hz)，7.60(1H，m)，7.39(2H，m)，7.22(2H，d，J＝8.0Hz)，7.13(2H，d，J＝8.0Hz)，5.44(2H，s)，4.50(1H，m)，4.41(1H，m)，2.68(2H，t，J＝7.1Hz)，1.99(3H，s)，1.75(4H，m).
Embodiment 16
Embodiment 16a:2-(4 iodos-benzyl)-iso-indoles-1,3-diketone synthetic:
To 4-iodo-benzyl bromide a-bromotoluene (9.04 grams, add in DMF 30.4mmol) (316 milliliters) solution phthalimide (4.47 grams, 30.4mmol) and cesium carbonate (14.86 restrain, 45.6mmol).Under blanket of nitrogen, will react at room temperature to stir and spend the night.Second day, with the cancellation of reactant mixture water.From the reactant mixture of quencher, be settled out product, leach, wash with water, collect white solid (9.5 grams, 86% productive rate).
1H?NMR(600MHz，CDCl 3)：δ7.84(m，2H)，7.71(m，2H)，7.63(d，2H，J＝8.4Hz)，7.17(d，2H，J＝8.4Hz)，4.77(s，2H). 13C?NMR(150MHz，CDCl 3)：δ168.1，138.0，136.2，134.3，132.2，130.8，123.6，93.7，41.3.
Embodiment 16b:2-[4-(4-hydroxyl-Ding-1-alkynyl)-benzyl]-iso-indoles-1,3-diketone synthetic:
Figure A20058002147400901
To 2-(4 iodos-benzyl)-iso-indoles-1,3-diketone (2.0 grams, 5.51mmol), (14.4 milligrams of triphenylphosphines, 0.055mmol) and (5 milligrams of Palladous chloride .s, 0.028mmol) DEA (20 milliliters) serosity in add (11 milligrams of DMF (4 milliliters) and Copper diiodides, 0.055mmol), then add 3-butine-1-alcohol (417 μ L, 5.51mmol).Under blanket of nitrogen, will react at room temperature to stir and spend the night.Second day, reactant mixture is concentrated and (2: 1 hexanes: ethyl acetate) purification obtains yellow solid product (0.76g, 45% productive rate) by hurried column chromatography.
1H?NMR(600MHz，CDCl 3)：δ7.86(m，2H)，7.76(m，2H)，7.36(s，4H)，4.83(s，2H)，3.80(q，2H，J＝6.3Hz)，2.68(t，2H，J＝6.2Hz)，1.80(t，1H，J＝6.4Hz)； 13C?NMR(150MHz，CDCl 3)：δ167.5，135.5，133.6，131.5，131.4，128.0，122.9，122.5，86.3，81.5，60.6，40.8，23.3.
Embodiment 16c:2-[4-(4-hydroxyl-butyl)-benzyl]-iso-indoles-1,3-diketone synthetic:
Figure A20058002147400902
To 2-[4-(4-hydroxyl-Ding-1-alkynyl)-benzyl]-iso-indoles-1, (2.0 grams add palladium/carbon (10wt%, 1.04 grams) to the 3-diketone in ethanol/ethyl acetate 6.55mmol) (3: 1,163 milliliters) solution.Under the hydrogen of 50psi, will react at room temperature to stir and spend the night.By 1H NMR monitoring reaction is seen the conversion to product.When finishing, by kieselguhr (Celite ) filter reaction mixture, with the ethyl acetate washing, concentrate, obtain product yellow oil (1.88g, 93% productive rate).
1H?NMR(600MHz，CDCl 3)：δ7.81(2H，m)，7.67(m，2H)，7.33(d，2H，J＝8.1Hz)，7.10(d，2H，J＝8.1Hz)，4.79(s，2H)，3.69(q，3H，J＝7.0Hz)，3.60(t，2H，J＝6.5Hz)，2.58(t，2H，J＝7.4Hz)，1.64(m，2H)，1.55(m2H)； 13C?NMR(150MHz，CDCl 3)：168.3，142.2，134.1，134.0，132.3，128.8，128.8，123.5，62.9，41.5，35.4，32.4，27.6.
Embodiment 16d:2-[4-(4-hydroxyl-butyl)-benzylamino]-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic:
Figure A20058002147400911
With 2-[4-(4-hydroxyl-butyl)-benzyl]-iso-indoles-1, the 3-diketone (964 milligrams, 3.12mmol) and hydrazine (215 μ L, n-butyl alcohol 6.86mmol) (59 milliliters) solution was placed 1 hour under refluxing.When being cooled to room temperature, form precipitation, it is leached and wash with n-butyl alcohol.Concentrated filtrate obtains the product yellow solid then, and it need not just can be used for next step by any further purification.
1H?NMR(600MHz，DMSO-d6)：δ＝7.22(d，2H，J?＝7.8Hz)，7.11(d，2H，J＝7.8Hz)，3.69(s，2H)，3.39(t，2H，J＝6.6Hz)，2.54(t，2H，J＝7.6Hz)，1.56(m，2H)，1.41(m，2H)； 13C?NMR(150MHz，CDCl 3)：168.3，142.2，134.1，134.0，132.3，128.8，128.8，123.5，62.9，41.5，35.4，32.4，27.6.
To 2-methanesulfinyl-3-methyl-.alpha.-5:6-benzopyran-4-ketone (0.35 gram, add in acetonitrile 1.78mmol) (37 milliliters) solution 4-(4-aminomethyl-phenyl)-Ding-1-alcohol (0.47 gram, 2.13mmol) and DMF (18 milliliters).At N 2Under the atmosphere, will be reflected to stir in 50 ℃ of oil baths and spend the night.Second day, reactant mixture is chilled to room temperature, concentrate, obtain oil.With oily purification, obtain needed white solid product (120mg, 20% productive rate) by hurried column chromatography (100% ethyl acetate).
1H?NMR(600MHz，CDCl 3)：δ8.20(d，1H，J＝7.9Hz)，7.53(t，1H，J＝7.8Hz)，7.35(t，1H，J＝7.6Hz)，7.31(d，1H，J＝8.4Hz)，7.29(d，2H，J＝7.9Hz)，7.21(d，2H，J＝7.9Hz)，4.82(bt，1H，J＝5.9Hz)，4.66(d，2H，J＝5.6Hz)，3.68(m，2H)，2.66(t，2H，J＝7.5Hz)，1.97(s，3H)，?1.70(m，2H)，1.61(m，2H)，1.24(bt，1H，J＝5.3Hz)； 13C?NMR(150MHz，CDCl 3)：δ174.0，160.3，152.2，141.4，135.5，130.7，128.2，126.9，125.0，123.g，122.3，115.8，92.7，61.5，44.6，34.8，31.8，27.2，7.3.
Embodiment 16e: toluene-4-sulfonic acid 4-{4-[(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base is amino)-methyl]-phenyl }-butyl ester synthetic:
Figure A20058002147400921
In 0 ℃ of ice bath, to 2-[4-(4-hydroxyl-butyl)-benzylamino]-(100 milligrams of 3-methyl-.alpha.-5:6-benzopyrans-4-ketone, 0.30mmol) dichloromethane (37 milliliters) solution in add (68 milligrams of p-toluenesulfonyl chlorides, 0.36mmol), (43.4 milligrams of dimethyl aminopyridines, 0.36mmol) and triethylamine (62 μ l, 0.44mmol).At N 2Under the atmosphere, the reacting slurry stirring is spent the night, be warming up to ambient temperature overnight at leisure.Second day, reactant mixture is concentrated and, obtain product oil (45mg, 31% productive rate) by hurried column chromatography (3: 1 → 1: 1 hexane: ethyl acetate → 100% ethyl acetate)) purification.
1H?NMR(600MHz，CDCl 3)：δ8.19(dd，1H，J＝1.5and?7.9Hz)，7.76(d，2H，J＝8.3Hz)，7.76(m，1H)，7.32(d，2H，J＝7.9Hz)，7.29(d，2H，J＝8.1Hz)，7.26(d，2H，J＝8.0Hz)，7.13(d，2H，J＝8.0Hz)，4.90(t，1H，J＝5.1Hz)，4.64(d，2H，J＝5.6Hz)，4.02(t，2H，J＝5.9Hz)，2.57(t，2H，J＝7.3Hz)，2.43(s，3H)，1.96(s，3H)，1.65(m，4H)； 13C?NMR(150MHz，CDCl 3)：δ174.9，160.2，152.8，144.7，141.5，135.4，133.1，131.4，129.8，128.9，127.9，127.7，125.9，124.6，122.8，116.2，93.4，70.3，45.5，34.7，28.4，27.1，21.6，7.6.
Embodiment 16f:2-[4-(4-fluoro-butyl)-benzylamino]-3-methyl-.alpha.-5:6-benzopyran-4-ketone synthetic
Figure A20058002147400931
Amino to toluene-4-sulfonic acid 4-{4-[(3-methyl-4-oxo-4H-.alpha.-5:6-benzopyran-2-base)-methyl]-phenyl }-(24 milligrams of butyl esters, 0.049mmol) ACN (1.1 milliliters) solution in add (37 milligrams of K222,0.098mmol), then add KF (6 milligrams, 0.098mmol).Under blanket of nitrogen, stirring reaction is 30 minutes in 90 ℃ of oil baths, monitors by LC-MS.Then reaction is cooled to room temperature, and directly be injected on the preparation HPLC column chromatography (Luna, 10u, C18,10 microns of 250 * 21.2mm, 60% water-90% acetonitrile in water in two mobile phases, adopts 0.1%TFA as modifier).Collect needed fraction, and be neutralized to pH value 7.6, lyophilizing then.(3: 1 hexanes: ethyl acetate) purification again obtains needed product solid (0.3mg,＜2% productive rate) by hurried column chromatography with material.
1H?NMR(600?MHz，CDCl 3/DMSO-d 6)：δ8.03(m，1H)，7.35(m，1H)，7.16(m，4H)，7.07(m，2H)，4.52(m，2H)，4.35(m，1H)，4.27(m，1H)，2.58(m，2H)，1.75(s，3H)，1.24(m，4H).
Embodiment 17
Synthesizing of embodiment 17a:3-methyl-2-methyl sulfane base-.alpha.-5:6-benzopyran-4-ketone:
To contain 2-sulfydryl-3-methyl-.alpha.-5:6-benzopyran-4-ketone (2.26 grams, 11.76mmol) and potassium carbonate (1.62 restrain, add in acetone 11.76mmol) (120 milliliters) solution iodomethane (807 μ L, 12.93mmol).To be reflected under the blanket of nitrogen, at room temperature stir 16 hours, then concentrate, obtain crude product oil.Residue is carried in the water, and is adjusted to pH value 7 with 5%HCl.The water layer that obtains is washed with ethyl acetate.With organic layer water and salt water washing, use dried over sodium sulfate then, filter, concentrate, obtain needed product yellow solid (1.95g, 80% productive rate), it just need not be further purified can be used for next step.
1H?NMR(600MHz，CDCl 3)：δ8.21(d，1H，J＝6.6Hz)，7.61(m，1H)，7.38(m，2H)，2.66(s，3H)，2.09(s，3H).
Synthesizing of embodiment 17b:2-methanesulfinyl-3-methyl-.alpha.-5:6-benzopyran-4-ketone:
Figure A20058002147400941
At 0 ℃, (1.95 grams, (2 restrain, 11.82mmol) to add mCPBA in dichloromethane 9.45mmol) (75 milliliters) solution to containing 3-methyl-2-methyl sulfane base-.alpha.-5:6-benzopyran-4-ketone.Stirring reaction 2 hours.After raw material exhausts, filter reaction mixture, and the filtrate that obtains with 5% cold sodium carbonate, water and the washing of saturated sodium bisulfate.Use the dried over sodium sulfate organic layer, filter, concentrate, obtain needed product light yellow solid (1.74g, 83% productive rate), it just need not be further purified can be used for next step.
1H?NMR(600MHz，DMSO-d6)：δ8.08(dd，1H，J＝7.8，1.2Hz)，7.88(m，1H)，7.76(d，1H，J＝7.8Hz)，7.55(m，1H)，3.01(s，3H)，2.12(s，3H).
Synthesizing of embodiment 17c:2-mesyl-3-methyl-.alpha.-5:6-benzopyran-4-ketone:
Figure A20058002147400942
At 0 ℃, (2.39 grams, (4 restrain, 11.82mmol) to add mCPBA in dichloromethane 11.6mmol) (75 milliliters) solution to containing 3-methyl-2-methyl sulfane base-.alpha.-5:6-benzopyran-4-ketone.Stirring reaction 2 hours.After raw material exhausts, filter reaction mixture, and the filtrate that obtains with 5% cold sodium carbonate, water and the washing of saturated sodium bisulfate.Use the dried over sodium sulfate organic layer, filter, concentrate, obtain needed product light yellow solid (0.685g, 33% productive rate), it just need not be further purified can be used for next step.
1H?NMR(600MHz，CDCl3)：δ8.22(d，1H，J＝3.0Hz)，7.76(m，1H)，7.52(d，1H，J＝8.4Hz)，7.48(m，1H)，3.31(s，3H)，2.46(s，3H).
Embodiment 18
Embodiment 18a:(4-hydroxyl-3,5-dimethoxy-phenyl)-methyl acetate synthetic:
(9.5 grams 0.042mmol) join in methanol (260 milliliters) and the sulphuric acid (8 milliliters) with (4-hydroxyl-3,5-dimethoxy-phenyl)-acetic acid.After adding finishes, will react reflux and spend the night.Second day, reactant mixture is cooled down, concentrate, obtain crude product oil.Oil is dissolved in the ethyl acetate again, and dried over sodium sulfate is used in water, salt water washing, filters, and concentrates once more.(50%: 50% ethyl acetate: purification crude product pentane) obtains needed product (1.5g, 75% productive rate is based on reclaiming raw material) to use silica gel chromatography.
Embodiment 18b:(4-benzyloxy-3,5-dimethoxy-phenyl)-methyl acetate synthetic:
Figure A20058002147400952
To (4-hydroxyl-3,5-dimethoxy-phenyl)-methyl acetate (4.1 grams, add in acetone 18.1mmol) (50 milliliters) solution potassium carbonate (1.39 grams, 10.1mmol), benzyl chloride (3.58 grams, 28.28mmol) and potassium iodide (catalytic quantity).After adding finishes, reactant mixture is heated to backflow spends the night.Second day, reactant mixture is cooled to room temperature, and dilute with water.With the water layer ethyl acetate extraction.With the organic layer dried over sodium sulfate of all merging, filter and concentrate.Use silica gel chromatography (gradient, 100% pentane to 100% ethyl acetate) purification crude product, obtain needed chemical compound (1.5 grams, 26%).
Embodiment 18c:2-(4-benzyloxy-3,5-dimethoxy-phenyl)-alcoholic acid synthetic:
(3.57 grams 11.3mmol) are dissolved among the THF (113 milliliters) with (4-benzyloxy-3,5-dimethoxy-phenyl)-methyl acetate.LAH solution (1M in THF, 11.3 milliliters) is dropwise joined in the reactant mixture of stirring.After adding finishes, will react and continue at room temperature to stir to spend the night.Second day, will react the water cancellation.With the water layer ethyl acetate extraction.With the organic layer dried over sodium sulfate of all merging, filter and concentrate, obtain crude product (2.89g, 89%), it need not just can be used in next step by any other purification.
Embodiment 18d:(4-benzyloxy-3,5-dimethoxy-phenyl)-acetaldehyde synthetic:
Figure A20058002147400962
To 2-(4-benzyloxy 3,5-dimethoxy-phenyl)-ethanol (1.0 grams, add in dichloromethane 3.3mmol) (25 milliliters) solution Dess-Martin reagent (1.54 grams, 3.6mmol) and water (59 μ l).After adding finishes, will react and continue to stir 6 hours.Leach the precipitation that obtains, and filtrate is concentrated.(gradient was from 1: 2 ethyl acetate: hexane to 1: 1 ethyl acetate: purification crude product hexane) obtains needed chemical compound yellow oil (547 milligrams, 55%) to use silica gel chromatography.
Synthesizing of embodiment 18e:2-(4-benzyloxy-3,5-dimethoxy-phenyl)-1-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-ethyl ketone:
To 6-bromo-2, (it is according to Chemistry andBiology, 2000 to 2-dimethyl-2H-.alpha.-5:6-benzopyran, p.979, Vol.7 prepares) (567.7 milligrams add n-BuLi (2.88M in THF 2.38mmol) (7 milliliters) cooling (78 ℃) agitating solution, 0.94 milliliter, 2.71mmol).After adding finishes, reactant mixture is continued to stir down at-78 ℃.After 25 minutes, will be dissolved in (4-benzyloxy 3,5-dimethoxy-phenyl)-acetaldehyde (619.6 milligrams 2.17mmol) add of THF (7.0 milliliters).After adding finishes, continue stirring reaction 15 minutes, then use the saturated ammonium chloride cancellation.Water layer separated and use ethyl acetate extraction.With the organic layer dried over sodium sulfate of all merging, filter and concentrate, obtain crude product oil.(3: 1 ethyl acetate: purification crude product hexane) obtains needed product (200.5 milligrams, 20% productive rate) by silica gel chromatography.
Embodiment 18f:(4-benzyloxy-3,5-dimethoxy-phenyl)-1-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-ethyl ketone synthetic:
To be dissolved in 2-(the 4-benzyloxy-3 of dichloromethane (2 milliliters), 5-dimethoxy-phenyl)-1-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-ethyl ketone (119.4 milligrams, 0.27mmol) be added drop-wise to PCC (69.2 milligrams, in dichloromethane 0.27mmol) (6.0 milliliters) agitating solution.3.5 after hour, reactant mixture is poured on the pre-saturated silica filler (1: 2 hexane: ethyl acetate), with it with 1: 1 ethyl acetate: the hexanes mixtures washing, collect needed chemical compound yellow oil (167 milligrams, 97% productive rate).
Embodiment 18g:1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(4-hydroxyl-3,5-dimethoxy-phenyl]-ethyl ketone synthetic:
2-(4-benzyloxy 3 in being dissolved in methanol (5.0 milliliters) and hexane (3.3 milliliters), 5-dimethoxy-phenyl)-1-(2,2-dimethyl-2H-.alpha.-5:6-benzopyran-6-yl)-add palladium/carbon (19.13 milligrams, 10%, on carbon) in ethyl ketone (62.8 milligrams) solution.With reactant mixture repeatedly, then contact atmosphere of hydrogen with nitrogen purging.Under room temperature and normal pressure, carry out hydrogenation.After 15 minutes, with the nitrogen purging reaction, filter reaction mixture is removed catalyst once more.Concentrated filtrate obtains needed product.
Embodiment 18h:1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-[4-(2-fluoro-ethyoxyl)-3,5-dimethoxy-phenyl]-ethyl ketone synthetic:
To 1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(4-hydroxyl-3,5-dimethoxy-phenyl]-(5.0 milligrams of ethyl ketones, 0.014mmol) DMF (1.4 milliliters) solution in add potassium carbonate (1N (aqueous solution), 21.1 μ l, 0.021mmol), then add toluenesulfonic acid fluoro ethyl ester (6.12 milligrams, 0.028mmol).After adding finishes, reactant mixture is heated to 90 ℃.After 1 hour, reactant mixture is cooled to room temperature.Water is joined in the refrigerative reactant mixture, and use the ethyl acetate extraction water layer.With the organic layer dried over sodium sulfate of all merging, filter and concentrate, obtain yellow oil.By reversed phase chromatography (Luna, 10u, C18,150 * 21.2mm, 10 microns, solvent system: 70% 90% acetonitrile solution: 30% water, in two mobile phases, use 01% TFA) purification, obtain needed chemical compound (1.05 milligrams, 19% productive rate).
Embodiment 19
Embodiment 19a:[1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyleneoxy]-trimethyl-silane synthetic:
Figure A20058002147400982
The i-Pr that will from CaH, distill out 2(0.556mL 4.04mmol) joins among the THF (7mL) NH, and is cooled to-78 ℃.The dropping n-butyllithium solution (2.59M, in THF, 1.56 milliliters, 4.04mmol).Add finish after ,-30 ℃ of stirred reaction mixtures 35 minutes, then be cooled to-78 ℃ once more.To be dissolved in the TMS-Cl (0.546 milliliter) of THF (25 milliliters) and 1-(2,2-dimethyl-benzodihydropyran-6-yl)-(3,4,5-trimethoxy-phenyl)-(1.20g 3.23mmol) is added drop-wise in the stirred reaction mixture ethyl ketone 2-.After adding finishes, continued stirred reaction mixtures other 30 minutes, then be warmed up to-30 ℃ at-78 ℃.After-30 ℃ are stirred 1 hour, use the ether diluting reaction, and be warmed up to room temperature.Concentrated reaction mixture at room temperature, and (4: 1 pentanes: ethyl acetate to 1: 1 pentane: the ethyl acetate) crude product that obtains of purification obtains needed chemical compound (879.1 milligrams, 74% productive rate is based on reclaiming raw material) to use silica gel chromatography.
Synthesizing of embodiment 19b:[1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone:
Figure A20058002147400991
(13.24 milligrams, 0.113mmol) solution is cooled to-5 ℃ with the Osmic acid. (25%wt, 0.574 milliliter) in water-soluble (0.27 milliliter) and the acetone (0.48 milliliter) and NMO.To be dissolved in [1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyleneoxy]-trimethyl-silane (50 milligrams 0.113mmol) are added drop-wise in this refrigerative agitating solution in the acetone (0.2 milliliter).After adding finishes, will react and continue to stir down at 0 ℃.After 3 hours, with sodium dithionite and florisil cancellation reaction.Filter reaction mixture, and filtrate is concentrated.(4: 1 pentanes: ethyl acetate to 1: 1 pentane: ethyl acetate) purification crude product obtains needed chemical compound (4.3 milligrams, 8%) to use silica gel chromatography.
Embodiment 19c: toluene-4-sulfonic acid 2-(2,2-dimethyl-benzodihydropyran-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-ethyl ester synthetic:
Figure A20058002147400992
In being dissolved in anhydrous methylene chloride (1.0 milliliters) [1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-(3.4 milligrams of ethyl ketones, 0.009mmol) add (1.94 milligrams of TsCl in the solution, 0.011mmol), DMAP (1.24 milligrams, 0.011mmol) and TEA (21.3 μ l, 0.015mmol).Reactant mixture is continued at room temperature to stir to spend the night.Second day, with the reactant mixture dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use silica gel chromatography purification crude product, obtain needed product.
Synthesizing of embodiment 19d:1-(2,2-dimethyl-benzodihydropyran-6-yl)-2-fluoro-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone:
Figure A20058002147401001
To toluene-4-sulfonic acid 2-(2,2-dimethyl-benzodihydropyran-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-(21.6 milligrams of ethyl esters, 0.04mmol) anhydrous ACN (0.5 milliliter) solution in add (4.72 milligrams of KF, 0.08mmol) and Kryptofix (30.6 milligrams, 0.08mmol).After adding finishes, reactant mixture is heated to 90 ℃.After 15 minutes, reactant mixture is cooled to room temperature, and dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use reversed phase chromatography purification crude product, obtain needed chemical compound.
Embodiment 20
Embodiment 20a:7-bromo-3,3-dimethyl-4-Chromanone synthetic:
With 5 '-bromo-2 '-hydroxyacetophenonum is dissolved in acetone (8.45 milliliters) and the toluene (43 milliliters).Pyrrolidine (1.90 milliliters) is added drop-wise in this stirred reaction mixture.After adding finishes, reaction mixture refluxed is heated.Second day, with the reactant mixture cool to room temperature,, use dried over sodium sulfate with 2M HCl (aqueous solution) washing, filter and concentrate.(90: 10 pentanes: purification crude product ether) obtains needed product (3.11g, 53% productive rate) to use silica gel chromatography.
Embodiment 20b:7-bromo-3,3-dimethyl-benzodihydropyran-4-alcohol synthetic:
Figure A20058002147401011
To 7-bromo-3, (1.5g, (0.351 restrains 3-dimethyl-4-Chromanone, 6.5mmol) to add potassium borohydride in methanol 5.91mmol) (17 milliliters) cooling (0 ℃) solution.After adding finished, at room temperature stirring reaction was 2 hours, uses 2M HCl (aqueous solution) cancellation then.With ethyl acetate extraction water layer (3x).With the organic layer dried over sodium sulfate that merges, filter, concentrate, produce the off-white color solid, it just need not be further purified can be used for next step.
Embodiment 20c:(7-bromo-3,3-dimethyl-benzodihydropyran-4-base oxygen base)-tert-butyl group-dimethyl-silane synthetic:
To 7-bromo-3,3-dimethyl-benzodihydropyran-4-alcohol (300 milligrams, add in DMF 1.44mmol) (3.33 milliliters) solution imidazoles (119 milligrams, 1.75mmol), then add TBDMS-Cl (263 milligrams, 1.75mmol).Second day, use the ethyl acetate diluting reaction, water (3x) and saturated sodium bicarbonate (1x) washing.With the organic layer dried over sodium sulfate, filter and concentrate.Use silica gel chromatography (100% pentane is to 50% pentane in ethyl acetate) purification crude product, produce needed product (290g, 65% productive rate).
The embodiment 20d:1-[(4-tert-butyl group-dimethyl-silanyloxy base)-benzyloxy (2,2-dimethyl-2H-benzodihydropyran-6-yl]-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone synthetic:
Figure A20058002147401013
To (7-bromo-3,3-dimethyl-benzodihydropyran-4-base oxygen base)-tert-butyl group-dimethyl-silane (290 milligrams, add in THF 0.78mmol) (3.75 milliliters) cooling (78 ℃) agitating solution n-BuLi (2.11M, 0.42 milliliter, 0.89mmol).After adding finishes, reactant mixture is continued to stir down at-78 ℃.After 25 minutes, will be dissolved in (3,4, the 5-trimethoxyphenyl)-acetaldehyde (149 milligrams 0.71mmol) add among the THF (0.41 milliliter).After adding finishes, continue stirring reaction 15 minutes, then use the saturated ammonium chloride cancellation.Water layer separated and use ethyl acetate extraction.With the organic layer dried over sodium sulfate of all merging, filter and concentrate, obtain crude product oil.(1: 1 ethyl acetate: purification crude product hexane) obtains needed product (50 milligrams, 14% productive rate) by silica gel chromatography.
Embodiment 20e:1-[4-(tert-butyl group-dimethyl-silanyloxy base)-2,2-dimethyl-benzodihydropyran-6-yl]-2-(3,4,5 trimethoxies-phenyl)-ethyl ketone synthetic:
Figure A20058002147401021
To be dissolved in the 1-[(4-tert-butyl group-dimethyl-silanyloxy base in the dichloromethane (2.5 milliliters))-benzyloxy-(2,2-dimethyl-2H-benzodihydropyran-6-yl]-2-(3,4,5-trimethoxy-phenyl)-(50 milligrams of ethyl ketones, 0.01mmol) be added drop-wise to PCC (23.6 milligrams, in dichloromethane 0.11mmol) (2.5 milliliters) agitating solution.After 2 hours, reactant mixture is poured on the pre-saturated silica filler (100% pentane), with it with 1: 1 ethyl acetate: the hexanes mixtures washing, then wash with 100% ethyl acetate, collect needed chemical compound oil.
Synthesizing of embodiment 20f:1-(4-hydroxyl-2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone:
Figure A20058002147401022
1-[4-in being dissolved in anhydrous THF (11 milliliters) (tert-butyl group-dimethyl-silanyloxy base)-2,2-dimethyl-benzodihydropyran-6-yl]-2-(3,4,5 trimethoxies-phenyl)-(54.5 milligrams of ethyl ketones, 1.09 mM) drip TBAF solution (1.0M solution in the solution, in THF, 1.65 milliliters, 1.65 mMs).After adding finishes, in stirring at room reaction 1 hour, water cancellation then.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use silica gel chromatography purification crude product, obtain needed chemical compound.
Embodiment 20g: toluene-4-sulfonic acid 2,2-dimethyl-6-[2-(3,4,5-trimethoxy-phenyl)-acetyl group]-benzodihydropyran-4-base ester synthetic:
Figure A20058002147401031
1-(4-hydroxyl-2 in being dissolved in anhydrous methylene chloride (1.0 milliliters), 2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-(3.5 milligrams of ethyl ketones, 0.009mmol) add (1.94 milligrams of TsCl in the solution, 0.011mmol), DMAP (1.24 milligrams, 0.011mmol) and TEA (21.3 milliliters, 0.015 mM).Reactant mixture is continued at room temperature to stir to spend the night.Second day, with the reactant mixture dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use silica gel chromatography purification crude product, obtain needed product.
Synthesizing of embodiment 20h:1-(4-fluoro-2,2-dimethyl-benzodihydropyran-6-yl)-2-(3,4,5-trimethoxy-phenyl)-ethyl ketone:
Figure A20058002147401032
To toluene-4-sulfonic acid 2-(2,2-dimethyl-benzodihydropyran-6-yl)-2-oxo-1-(3,4,5-trimethoxy-phenyl)-(21.6 milligrams of ethyl esters, 0.04mmol) anhydrous ACN (0.5 milliliter) solution in add (4.72 milligrams of KF, 0.08mmol) and Kryptofix (30.6 milligrams, 0.08mmol).After adding finishes, reactant mixture is heated to 90 ℃.After 15 minutes, reactant mixture is cooled to room temperature, and dilute with water.Separate water layer, and extract with ethyl acetate (3x).With all merging organic layer Na 2SO 4Drying is filtered and is concentrated, and produces oil.Use reversed phase chromatography purification crude product, obtain needed chemical compound.
Synthetic and the purification process of radiation for preparing radiolabeled chromone analog with fluoro-18 radionuclides.
Under study for action the fluoro-18 of Shi Yonging ( 18F) production method comprises: (Woburn, about 10MeV proton MA) is with H by PETnet by using 2 18The enriched in oxygen of O form-18 ( 18O) carry out proton bombardment.The expression formula of this nuclear reaction is:
O 18(p，γ) 18F。
For all radioactivity synthetic reactions, can use similar method.All glass drying ovens are silanizations, to eliminate the adhesion of material and chamber wall, make the transmission optimization.Special-purpose specific HPLC device is used for all chemical compounds of purification.Special-purpose specific HPLC device is used for the radiometric analysis of end product.
18F generally derives from supplier, its be deposited on the processing post that lead screen coats ( 18The F post) on. 18The F post contains and is placed on one of aluminium oxide in the glass column or the two of quaternary ammonium salt coordinate sodium salt.Styletable with have a negative and positive Luer TMThe Tygon of locked joints TMPipe leads to.Use following method from post, to remove 18F.
1. with 15 milligrams of potassium carbonate (K 2CO 3) 1 milliliter of distillation/deionized water (H 2O) solution be dissolved in 4 milliliters of anhydrous acetonitrile (CH 3CN) in 90 milligram 4,7,13,16,21,24-six oxa-s-1,10-diazabicyclo [8.8.8] hexacosane (Kryptofix TMK222) solution merges, and stirs lightly, guarantees that layer does not separate, and forms post elute soln (CES).
2. use 3 milliliters of syringes, from the phial that step 3 is described, extract a ml aliquots sample CES, and with syringe be connected to 18Tygon on the F post TMThe positive Luer of pipe TMLocked joints is connected.
3. narrow footpath is measured syringe needle and is connected to 18Other Tygon on the F post TMThe cloudy Luer of pipe TMSealed joint is connected, and with syringe needle by being contained in 15mL 24/40Pyrex TMRubber septum on the pyriform glass flask inserts.
4. wash flask with the syringe needle emptying of 15mL pyriform flask, and with drying nitrogen.Syringe needle and a vacuum tube of flushing are led to, and regulate liquid stream, CES just can pass through at leisure like this 18The F post is drawn in 15 milliliters of pyriform flasks.
5. regulate vacuum and N 2Air-flow, the inclusions of flask just can be reduced and is drying like this.Use vacuum, drive transmission, by syringe with anhydrous CH 3CN (1mL) joins in the flask.Make vacuum and N 2Air balance is to remove acetonitrile.Repeat this program twice, then remove vacuum.
6. remove the inclusions of flask by syringe, and radioactivity is quantitative.In radioactive label is synthetic, directly use 18F solution.
Subsequent step has been described usefulness 18F carries out radioactive label chromone analog.As mentioned above, these steps are the same to each chemical compound.Following reaction scheme has been described all 18The representative solution of F-chromone analog:
7. at the 5mL Wheaton of the taper silanization that has magnetic stirring bar TMIn the cuvette, the tosylate precursor (2.5mg) for preparing the aim colour keto analog is dissolved in CH 3Among the CN (0.5mL).Phial is immersed in the oil bath, 90 ℃ of heating.With above-described 18F solution joins in the reaction phial, at 90 ℃ with the mixture heated that obtains 30 minutes.
8. inclusions is transferred in 50 milliliters of silanization round-bottomed flasks that contain distillation/deionized water (25mL), the inclusions of removing flask by syringe, and at Waters TMDeposit on OasisHLB (hydrophilic-lipophilic balance (HLB)) post, unreacted fluoride and undesirable salt are flow through with eluent.
9. use dichloromethane (3mL, CH 2Cl 2), from post, organic component is eluted in 5 milliliters of taper phials.By preparation HPLC (Phenomenex LUNA C-18 post 250 * 10mm, 5u granule, 100A hole, gradient elution 90/10H 2O/CH 3CN-CH 3CN) purification eluent.Suitable fraction is concentrated, and analytical radio chemistry productive rate and radiochemical purity (analyzing HPLC).Concentrated solution is extremely done in a vacuum, and is dissolved in the 10% alcoholic acid saline of suitable volumes, is used for injection and/or biological study.
The disclosure is not limited to the example of above-mentioned explanation, and under the condition that does not deviate from its essential feature, can express with other specific forms, and this is tangible for those skilled in the art.Therefore expectation is, consider that embodiment is property as an illustration in all fields, rather than restrictive, restriction referring to additional claim, therefore but not the foregoing description, and change in the equivalents of claim and the institute in the scope and all be included in wherein.

Claims (32)

1. contrast agent, it comprises imaging moiety and is selected from the poly-acetic acid of annonaceae, quinone poly-acetic acid, the chromone of replacement and the chemical compound of open chain deguelin analog.
2. the contrast agent of claim 1 has general formula (I)
Wherein
M is 1,2,3,4,5,6,7,8,9,10,11,12,13, or 14;
N is 0,1,2,3,4,5,6,7 or 8;
O is 0 or 1;
P is 5,6,7,8,9,10,11 or 12;
---expression does not exist or singly-bound;
When--when-expression did not exist, A and B were independently selected from hydrogen and imaging moiety;
When---when being singly-bound, each (C (R naturally of A and B 1) 2) k
K is 1 or 2, and condition is as each (C (R naturally of A and B 1) 2) kThe time, a k is 1, and other is 1 or 2;
R 1, R 2, R 4, R 5, R 7, R 8, R 10, R 15, and R 16Be hydrogen, hydroxyl or imaging moiety independently when occurring at every turn;
R 3Be hydrogen, hydroxyl or imaging moiety;
R 3 'Be hydrogen; Or
R 3And R 3 'And form C=O or C=CR with the carbon atom that they are connected 13R 14
R 6Be hydrogen, hydroxyl or imaging moiety;
R 6 'Be hydrogen; Or
R 6And R 6 'And form C=O or C=CR with the carbon atom that they are connected 13R 14
R 9Be hydrogen, hydroxyl or imaging moiety;
R 9 'Be hydrogen; Or
R 9And R 9 'And form C=O or C=CR with the carbon atom that they are connected 13R 14
R 11Be C 1-C 6Alkyl; With
R 12, R 13And R 14Be hydrogen, the optional C that is replaced by imaging moiety independently 1-C 6Alkyl, aralkyl or imaging moiety;
Condition is that at least one imaging moiety exists in general formula (I).
3. the contrast agent of claim 2, wherein R 4It is imaging moiety.
4. the contrast agent of claim 2, wherein R 5It is imaging moiety.
5. the contrast agent of claim 2, wherein R 8It is imaging moiety.
6. the contrast agent of claim 2, wherein R 9It is imaging moiety.
7. the contrast agent of claim 1, wherein contrast agent is
Wherein x is 0,1,2,3,4,5 or 6.
8. the contrast agent of claim 1, wherein contrast agent is
Figure A2005800214740004C1
Wherein x is 0,1,2,3,4,5 or 6.
9. the contrast agent of claim 1, wherein contrast agent is
Wherein x is 0,1,2,3,4,5,6,7 or 8.
10. the contrast agent of claim 1, wherein contrast agent is
Wherein n ' is 0,1,2,3,4,5,6,7,8,9 or 10 when occurring at every turn independently; With
Wherein n " is 2,3,4,5,6,7,8,9 or 10 when occurring at every turn independently.
11. the contrast agent of claim 1 has general formula (II)
Wherein
Q is 1,2,3,4,5,6,7,8,9,10,11,12,13 or 14;
R is 0,1,2,3,4,5,6,7 or 8;
S is 0 or 1;
T is 5,6,7,8,9,10,11 or 12;
---expression does not exist or singly-bound;
When--when-expression did not exist, D and E were independently selected from hydrogen and imaging moiety;
When---when being singly-bound, each (C (R naturally of D and E 15) 2) u
U is 1 or 2, and condition is as each (C (R naturally of D and E 15) 2) uThe time, a u is 1, and other is 1 or 2;
R 15, R 160, R 18, R 19, R 21And R 22Be hydrogen, hydroxyl or imaging moiety independently when occurring at every turn;
R 17Be hydrogen, hydroxyl or imaging moiety;
R 17 'Be hydrogen; Or
R 17And R 17 'And form C=O or C=CR with the carbon atom that they are connected 27R 28
R 20Be hydrogen, hydroxyl or imaging moiety;
R 20 'Be hydrogen; Or
R 20And R 20 'And form C=O or C=CR with the carbon atom that they are connected 27R 28
R 23Be hydrogen, hydroxyl or imaging moiety;
R 23 'Be hydrogen; Or
R 23And R 23 'And form C=O or C=CR with the carbon atom that they are connected 27R 28
R 24, R 25And R 26Be hydrogen, the optional C that is replaced by imaging moiety independently 1-C 6Alkyl, C 1-C 6Alkoxyl, hydroxyl, halogen or imaging moiety; With
R 27And R 28Be hydrogen, the optional C that is replaced by imaging moiety independently 1-C 6Alkyl, aralkyl, imaging moiety;
Condition is that at least one imaging moiety exists in general formula (II).
12. the contrast agent of claim 11, wherein R 18, R 19, R 22Or R 23It is imaging moiety.
13. the contrast agent of claim 11, wherein R 22It is imaging moiety.
14. the contrast agent of claim 1, wherein contrast agent is
Figure A2005800214740007C1
Wherein x is 0,1,2,3,4,5,6,7,8,9 or 10.
15. the contrast agent of claim 1 has general formula (III)
Wherein
G is-S-,-O-,
Figure A2005800214740008C2
J is S, C (R 37) 2, or O;
It is single or two key; With
R 30, R 31, R 32, R 33, R 34, R 35, R 36, R 37, R 38, R 39, R 40, R 41And R 42Be hydrogen, the optional C that is replaced by imaging moiety independently when occurring at every turn 1-C 6Alkyl, the optional C that is replaced by imaging moiety 1-C 6Alkoxyl or imaging moiety; Condition is to work as
Figure A2005800214740008C4
When being two key, R 31And R 32Be non-existent; With
Condition is that at least one imaging moiety exists in general formula (III).
16. the contrast agent of claim 15, wherein R 36, R 37, R 38Or R 42It is imaging moiety.
17. the contrast agent of claim 15, wherein R 38It is imaging moiety.
18. the contrast agent of claim 1, wherein contrast agent is
19. the contrast agent of claim 1, wherein contrast agent is
20. the contrast agent of claim 1, wherein contrast agent is
Figure A2005800214740010C1
21. the contrast agent of claim 1, wherein contrast agent is
Figure A2005800214740010C2
22. the contrast agent of claim 1 has general formula (IV)
Figure A2005800214740010C3
Wherein
N, m and o are 1,2,3 or 4 independently;
Z is O, S or NR 46
R 45Be imaging moiety or the optional C that is replaced by imaging moiety 1-C 4Alkyl;
R 46Be hydrogen or C 1-C 3Alkyl;
Ar is a phenyl, furyl, thienyl,  azoles quinoline base, different  azoles quinoline base, thiazolyl, isothiazolyl, pyridine radicals, naphthyl, pyrimidine radicals, or pyrazinyl;
G represents not exist or O; With
L is an imaging moiety;
Condition is when G represents not exist, and o is 3.
23. the contrast agent of claim 1, wherein contrast agent is
Figure A2005800214740011C1
24. the contrast agent of claim 1, wherein contrast agent is
Figure A2005800214740011C2
25. the contrast agent of claim 1, wherein imaging moiety is the radiosiotope that is used for nuclear medicine, the paramagnetism species that are used for the MRI imaging, the echo entity that is used for ultrasonic imaging, the fluorescence entity that is used for fluorescence imaging or the optical activity entity that is used for optical imagery.
26. the contrast agent of claim 25, the paramagnetism species that wherein are used for the MRI imaging are Gd 3+, Fe 3+, In 3+, or Mn 2+
27. the contrast agent of claim 25, the echo entity that wherein is used for ultrasonic imaging are the surfactant microspheres that fluorohydrocarbon is sealed.
28. the contrast agent of claim 25, the radiosiotope that wherein is used for nuclear medicine is 11C, 13N, 18F, 123I, 124I, 125I, 99mTc, 95Tc, 111In, 76Br, 62Cu, 64Cu, 67Ga or 68Ga.
29. the contrast agent of claim 28, wherein imaging moiety is 18F.
30. the contrast agent of claim 28, wherein imaging moiety is 99mTc.
31. the method for a myocardial perfusion imaging comprises giving the patient contrast agent, contrast agent comprises imaging moiety and is selected from the chemical compound of the poly-acetic acid of annonaceae, the poly-acetic acid of quinone, replacement chromone and open chain deguelin analog; With use diagnostic imaging scan patients.
32. the method for claim 31, wherein imaging moiety is the radiosiotope that is used for nuclear medicine, the paramagnetism species that are used for the MRI imaging, the echo entity that is used for ultrasonic imaging, the fluorescence entity that is used for fluorescence imaging or the optical activity entity that is used for optical imagery.
CN 200580021474 2004-04-28 2005-04-27 Contrast agents for myocardial perfusion imaging. Pending CN1976728A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102014969B (en) * 2008-02-29 2014-07-09 兰休斯医疗成像公司 Contrast agents for applications including perfusion imaging
CN113416739A (en) * 2021-06-24 2021-09-21 黑龙江八一农垦大学 Application of Saccharomyces rouxii gene in improving yield of HDMF (high-density multi-ferule) produced by microorganisms

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102014969B (en) * 2008-02-29 2014-07-09 兰休斯医疗成像公司 Contrast agents for applications including perfusion imaging
CN113416739A (en) * 2021-06-24 2021-09-21 黑龙江八一农垦大学 Application of Saccharomyces rouxii gene in improving yield of HDMF (high-density multi-ferule) produced by microorganisms

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