CN103242212B - A kind of brain histamine H 3precursor of Receptor Radioligand and preparation method thereof - Google Patents
A kind of brain histamine H 3precursor of Receptor Radioligand and preparation method thereof Download PDFInfo
- Publication number
- CN103242212B CN103242212B CN201310176094.3A CN201310176094A CN103242212B CN 103242212 B CN103242212 B CN 103242212B CN 201310176094 A CN201310176094 A CN 201310176094A CN 103242212 B CN103242212 B CN 103242212B
- Authority
- CN
- China
- Prior art keywords
- product
- nitro
- histamine
- acetonitrile
- mol ratio
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Abstract
The invention provides a kind of New Histamine H
3precursor compound of acceptor PET part and preparation method thereof, it is mainly used in carrying out radiation synthesis histamine H in the later stage
3the PET radioligand of acceptor, and be applied to animal brain PET and detect.The present invention has the following advantages: 1. the H in the present invention
3the precursor compound of acceptor PET part, the carbon-chain structure in its structure can rotate more flexibly, and the energy of the Rotation energy barrier of ehter bond is very little in addition, with can regulate during receptors bind self structure with better with receptors bind point coincide, thus improve bonding force.2. synthetic reaction condition is not harsh, and reaction yield is higher, the easily separated purifying of product.
Description
One technical field
The present invention relates to a kind of histamine H
3precursor compound of acceptor PET radioligand and preparation method thereof, particularly a kind of by fluoro or nitro-phenoxy phenol connection carbochain, then react with (R)-2-crassitude, synthesizing new histamine H
3the method of the precursor compound of acceptor PET radioligand.
Two background technologies
Histamine Receptors is a class GPCR acceptor, finds that there is 4 kinds of histamine receptor sub-types (H at present
1, H
2, H
3, H
4), wherein histamine H
3acceptor not only participates in the synthesis of histamine in brain, release and metabolism, also participates in the regulation and control of various neurotransmitters in brain.Histamine H
3acceptor can regulate the multiple neuroethology function of central nervous system, all plays an important role in learning and memory, epilepsy, awakening and sleep etc.Histamine H
3acceptor is widely distributed in mammal brain, and the density especially in central nervous system (CNS) is higher, and also finds that there is expression in peripheral nerve endings and some non-neuronal cells.Result of study shows, H
3receptor antagonist and inverse agonist, may be used for treating different neural system diseases, comprise hyperkinetic syndrome, Alzheimer's disease, lethargy, epilepsy, schizophrenia etc.In order to obtain human histamine H
3the information that acceptor accumulates or consumes in disease incidence mechanism, accelerates the screening process of clinical drug exploitation, design H
3acceptor PET radioligand has very important clinical value.H
3receptor Radioligand, discloses histamine H by positron emission computerized tomography (PET)
3distribution in the process of acceptor neuropsychiatric disorders in human brain and variable density, and guide the consumption of the medicine of above-mentioned disease.
The medicine that present stage Ge great medicament research and development company is developing is mostly histamine H
3receptor antagonist.The H of many initial discoveries
3receptor stimulant antagonist is imidazole ring-containing structure all, as
18f-FUB-272,
11c-UCL-1829, VUF5000,
18f-fluoroproxyfan (Chart1) etc.Imidazoles water-soluble larger, fat-soluble less, is unfavorable for penetrating hemato encephalic barrier, therefore, and current H
3the research of receptor acting medicine is tending towards exploring non-imidazole class medicine.
2006,
11the non-imidazole compounds JNJ-10181457 (Chart1) of C mark is reported as one and has optionally H
3receptor Radioligand, experiment in vitro display result is ideal, but experiment in vivo causes result unsatisfactory due to higher non-specific binding.
2008, Merck laboratory reported non-imidazole compounds merck1b and merck2b, and result all to show in good body high specific and combines, monkey in vivo PET experimental result show, they can be used to measure H
3the density distribution of receptor inverse agonists, but these
18the Radiochemical yield of the methane amide analogue of F mark is very low, reactions steps is many, and containing distillating radioactivity intermediate, is unfavorable for last Fully automated synthesis.
2010,
11c-GSK189254 is a kind of histamine H that researchist uses first in healthy volunteer
3acceptor PET developer, is considered to a kind of human histamine H of very promising energetic production
3the tracer agent of acceptor.Although
11c (t
1/
2=20.3min) mark
11c-GSK189254 radioligand has entered clinical trial rank, scientific research personnel be just devoted to find a kind of more efficient, special and have compared with long half-lift
18f (t
1/
2=109.7min) mark brain histamine H
3acceptor tracer agent.
The H that early stage is reported
3acceptor PET radioligand
(left side one is classified as glyoxaline ligand, and the right one is classified as non-imidazole class part)
At the beginning of 2012, the people such as Bao Xiaofeng by PET research [
18f] the situation discovery of XB-1 after mouse and monkey intravenous injection, [
18f] XB-1 as PET radioligand be used for monkey, brain histamine H
3acceptor has good performance performance, comprises and human histamine H
3the highly selective of acceptor, high affinity (K
i=1.9nM), easily penetrate hemato encephalic barrier, be easy to radiate synthesis, high brain intake and "dead" fluorine dropping situations under larger receptor-specific signal etc.But this compound exists furans ring texture, make to have some limitations when itself and receptors bind.
[
18f] XB-1 structural formula
Three summary of the invention
The object of the present invention is to provide a kind of brain histamine H
3precursor of Receptor Radioligand and preparation method thereof, for carrying out radiation synthesis histamine H in the later stage
3the PET radioligand of acceptor, and be applied to animal brain PET and detect.
The technical scheme realizing the object of the invention is: a kind of brain histamine H
3the precursor of Receptor Radioligand, its general formula is:
Wherein, n is 1 or 2; R is nitro or fluorine, and the position of R is No. 2 positions or No. 4 positions.
A kind of brain histamine H
3the preparation method of the precursor of Receptor Radioligand, concrete steps are as follows:
Step one, joins in acetonitrile organic solvents by fluoro or nitro-phenoxy phenol and 1-bromo-3-chloropropane or the bromo-2-monochloroethane of 1-, stirs lower dissolving, then add Anhydrous potassium carbonate, heating, cooling after backflow, extraction, dry, concentrated, rapid column chromatography, obtains product.
Step 2, product step one obtained, (R)-2-crassitude, potassiumiodide and Anhydrous potassium carbonate join in acetonitrile organic solvents, heating, cooling after backflow, and extraction is dry, concentrated, and rapid column chromatography, obtains final product.
The product structure that wherein step one obtains is:
Its reaction formula is as follows:
1A R=2-NO
2; 2B n=A R=2-NO
2; 2A'n=1R=2-NO
2; 3A n=2R=2-NO
2; 3A'n=1R=2-NO
2;
1B R=4-F; 2E n=B R=4-F; 2B'n=1R=4-F; 3B n=2R=4-F; 3B'n=1R=4-F;
1C R=4-NO
2. 2F n=C R=4-NO
2; 2C'n=1R=4-NO
2. 3C n=2R=4-NO
2; 3C'n=1R=4-NO
2.
Wherein, the i-th step reaction reagent is: 1-bromo-3-chloropropane or the bromo-2-monochloroethane of 1-, salt of wormwood, acetonitrile; I-th i walks reaction reagent: R-2-crassitude, potassiumiodide, salt of wormwood, acetonitrile.Wherein, 1A, 1B, 1C by experiment room synthesis obtain, and namely first by fluoro or nitration chlorobenzene and 4-hydroxyanisol generation nucleophilic substitution reaction, then are hydrolyzed by acetic acid and Hydrogen bromide and obtain 1A, 1B, 1C.
The present invention has the following advantages: 1. the H in the present invention
3the precursor compound of acceptor PET part, the carbon-chain structure in its structure can rotate more flexibly, and the energy of the Rotation energy barrier of ehter bond is very little in addition, with can regulate during receptors bind self structure with better with receptors bind point coincide, thus improve bonding force.2. synthetic reaction condition is not harsh, and reaction yield is higher, the easily separated purifying of product.
Four embodiments
A kind of brain histamine H of the present invention
3the precursor of Receptor Radioligand, its general formula is:
Wherein, n is 1 or 2; R is nitro or fluorine, and the position of R is No. 2 positions or No. 4 positions.Preferred version to be R be No. 2 position nitros or No. 4 position nitros or No. 2 position fluorine.
A kind of brain histamine H of the present invention
3the preparation method of the precursor of Receptor Radioligand, concrete steps are as follows:
Step one, fluoro or nitro-phenoxy phenol and 1-bromo-3-chloropropane or the bromo-2-monochloroethane of 1-are joined in acetonitrile organic solvents, stir lower dissolving, then add Anhydrous potassium carbonate, be heated to 85-90 DEG C, reflux after 24 ~ 48 hours and cool, extraction, dry, concentrated, rapid column chromatography, obtains the 1st step product; Wherein, the mol ratio of fluoro or nitro-phenoxy phenol and 1-bromo-3-chloropropane or the bromo-2-monochloroethane of 1-is 1:1 ~ 2; The mol ratio of fluoro or nitro-phenoxy phenol and salt of wormwood is 1:2 ~ 5; The mol ratio of fluoro or nitro-phenoxy phenol and acetonitrile is 1:0.22 ~ 0.44; The nitro of described fluoro or nitro-phenoxy phenol or fluorine are No. 2 positions or No. 4 positions, preferred version to be R be No. 2 position nitros or No. 4 position nitros or No. 2 position fluorine.
Step 2, joins in acetonitrile organic solvents by the product of step one, (R)-2-crassitude, potassiumiodide and Anhydrous potassium carbonate, is heated to 85-90 DEG C, reflux after 24 ~ 48 hours and cool, extraction, dry, concentrated, rapid column chromatography, obtains final product; Wherein, the product of described step one and the mol ratio of (R)-2-crassitude are 1:1.2 ~ 2; The product of described step one and the mol ratio of potassiumiodide are 1:0.6 ~ 2; The product of described step one and the mol ratio of salt of wormwood are 1:2 ~ 6; The 1st described step product and the mol ratio of acetonitrile are 1:0.2 ~ 0.33.
In present method, the productive rate of step 1 product is 43.8 ~ 97.5%, and the productive rate of step 2 product is 34.9 ~ 77.5%.
Following instance contributes to understanding the present invention, but is not limited to content of the present invention.
Embodiment 1
1. under room temperature, 4-(2-nitro-phenoxy) phenol (500mg is added in 50mL round-bottomed flask, 2.16mmol), salt of wormwood (597mg, 4.32mmol) with 25ml acetonitrile, slowly the bromo-3-chloropropane (0.427mL, 4.32mmol) of 1-is dripped again in stirring.By reaction mixture, be heated to 85 DEG C, condensing reflux stirs 38h (TLC thin-layer chromatography follows the tracks of reaction process).Cooling, acetonitrile is removed in underpressure distillation, and salt of wormwood is fallen in extraction, and concentrated solution, rapid column chromatography, obtain product 1-(4-(3-chlorine propoxy-) phenoxy group)-2-oil of mirbane 573mg, productive rate is 86.1%, and product is yellow oily material.
Carry out hydrogen spectrum, the qualification of carbon spectrum to product, its detected result is as follows:
1HNMR(500MHz,CDCl
3):δ7.94(1H,dd,J
1=1.50Hz,J
1=8.15Hz),7.46(1H,m),7.14(1H,m),7.03(2H,m),6.93(3H,d,J=8.85Hz),4.12(2H,t,J=5.80Hz),3.77(2H,t,J=6.30Hz),2.26(2H,m).
13CNMR(CDCl
3):156.01,151.91,148.87,140.75,134.24,125.74,122.48,121.18,119.13,115.90,64.87,41.64,32.30ppm.
2. under room temperature, 1-(4-(3-chlorine propoxy-) phenoxy group)-2-oil of mirbane (450mg is added in 50mL round-bottomed flask, 1.46mmol), potassiumiodide (145mg, 0.876mmol), salt of wormwood (605mg, 4.38mmol) with 25ml acetonitrile, slowly (R)-2-crassitude (177 μ L, 1.75mmol) is dripped again in stirring.Reaction mixture is heated to 85 DEG C, condensing reflux stirs 48h(TLC thin-layer chromatography and follows the tracks of reaction process).Cooling, acetonitrile is removed in underpressure distillation, salt of wormwood and potassiumiodide are fallen in extraction, concentrated solution, rapid column chromatography, obtain product (R)-2-methyl isophthalic acid-(3-(4-(2-nitro-phenoxy) phenoxy group) propyl group) tetramethyleneimine 237mg, productive rate is 45.5%, and product is pale yellowish oil material.
Carry out hydrogen spectrum, carbon spectrum and Mass Spectrometric Identification to product, its detected result is as follows:
1HNMR(500MHz，CDCl
3):δ7.92(1H,dd,J
1=1.30Hz,J
1=8.15Hz),7.44(1H,m),7.12(1H,m),7.01(2H,m),6.92(3H,m),4.03(2H,m),3.20(1H,m),3.01(1H,m), 2.35(1H,m),2.23(1H,m),2.16(1H,m),2.04(2H,m),1.92(1H,m),1.80(1H,m),1.71(1H,m),1.45(1H,m),1.12(3H,d,J=6.00Hz).
13CNMR(CDCl
3):δ156.35,152.06,148.50,140.66,134.12,125.71,122.27,121.18,118.94,115.8567.00,60.43,54.06,50.85,32.76,28.59,21.73,19.00ppm.
MS,[M+H]
+,357.17;calculated for C
19H
22N
2O
4,[M
++H],357.19.
Embodiment 2
1. under room temperature, 4-(2-nitro-phenoxy) phenol (1g is added in 50mL round-bottomed flask, 4.32mmol), salt of wormwood (4.48g, 21.6mmol) with 30ml acetonitrile, slowly the bromo-2-monochloroethane (0.358mL, 4.32mmol) of 1-is dripped again in stirring.By reaction mixture, be heated to 85 DEG C, condensing reflux stirs 33h (TLC thin-layer chromatography follows the tracks of reaction process).Cooling, acetonitrile is removed in underpressure distillation, and salt of wormwood is fallen in extraction, and concentrated solution, rapid column chromatography, obtain product 1-(4-(2-chloroethoxy) phenoxy group)-2-oil of mirbane 555mg, productive rate is 43.8%, and product is pale yellow oil matter.
Carry out hydrogen spectrum, the qualification of carbon spectrum to product, its detected result is as follows:
1HNMR(CDCl
3):δ7.92(1H,dd,J
1=1.60Hz,J
2=8.15Hz),7.45(1H,m),7.13(1H,m),7.02(2H,m),6.92(3H,m),4.22(2H,t,J=5.80Hz),3.82(2H,t,J=5.85Hz)ppm.
13CNMR(CDCl
3):δ155.44,151.75,149.31,140.78,134.29,125.78,122.62,121.17,119.25,116.21,68.67,42.18ppm.
2. under room temperature, 1-(4-(2-chloroethoxy) phenoxy group)-2-oil of mirbane (300mg is added in 50mL round-bottomed flask, 1.02mmol), potassiumiodide (378mg, 2.04mmol), salt of wormwood (846mg, 7.12mmol) with 20ml acetonitrile, slowly (R)-2-crassitude (206 μ L, 2.04mmol) is dripped again in stirring.Reaction mixture is heated to 90 DEG C, condensing reflux stirs 40h(TLC thin-layer chromatography and follows the tracks of reaction process).Cooling, acetonitrile is removed in underpressure distillation, salt of wormwood and potassiumiodide are fallen in extraction, concentrated solution, rapid column chromatography, obtain product (R)-2-methyl isophthalic acid-(2-(4-(2-nitro-phenoxy) phenoxy group) ethyl) tetramethyleneimine 253mg, productive rate is 72.5%, and product is deep yellow oily mater.
Carry out hydrogen spectrum, carbon spectrum and Mass Spectrometric Identification to product, its detected result is as follows:
1HNMR(CDCl
3):δ7.92(1H,d,J=8.10Hz),7.45(1H,m),7.12(1H,t,J=7.90Hz),6.99(2H,m),6.92(3H,t,J=7.95Hz),4.17(2H,t,J=4.95Hz),3.34(1H,m),3.28(1H,m),2.67(1H,m),2.60(1H,m),2.44(1H,m),2.00(1H,m),1.88(1H,m),1.78(1H,m),1.53(1H,m),1.23(3H,d,J=6.10Hz)ppm.
13CNMR(CDCl
3):δ155.89,151.97,148.80,140.71,134.17,125.75,122.37, 121.19,119.05,115.93,67.10,61.17,54.82,52.71,32.29,21.89,18.62ppm.
MS,[M+H]
+,328.08;calculated for C
19H
22N
2O
4,[M
++H],343.16.
Embodiment 3
1. implement by the method described in embodiment 1 step 1, unlike substrate used and reagent be: 4-(4-fluorophenoxy) phenol (408mg, 2mmol), salt of wormwood (553mg, 4mmol), the bromo-3-chloropropane of 1-(0.396mL, 4mmol), 10ml acetonitrile, temperature of reaction is 87 DEG C, return time is 43h, obtain product 547mg, productive rate is 97.5%, and product 1-(4-(3-chlorine propoxy-) phenoxy group)-4-fluorobenzene is pale yellowish oil material.
Carry out hydrogen spectrum, carbon spectrum and the qualification of fluorine spectrum to product, its detected result is as follows:
1HNMR(500MHz,CDCl
3):δ7.03～6.99(2H,m),6.98～6.89(6H,m),4.11(2H,t,J=5.90Hz),3.78(2H,t,J=6.35Hz),2.25(2H,m)ppm.
13CNMR(CDCl
3):159.41,157.50,155.05,150.96,120.38,119.34,116.37,115.70,64.84,41.66,32.40ppm.
19FNMR(CDCl
3):-121.20ppm.
2. implement by the method described in embodiment 1 step 2, unlike substrate used and reagent be: 1-(4-(3-chlorine propoxy-) phenoxy group)-4-fluorobenzene (500mg, 1.8mmol), potassiumiodide (296mg, 1.8mmol), salt of wormwood (1.480g, 10.8mmol), (R)-2-crassitude (252 μ L, 2.7mmol), 20ml acetonitrile, temperature of reaction is 89 DEG C, return time is 38h, obtain product (R)-1-(3-(4-(4-fluorophenoxy) phenoxy group) propyl group)-2-crassitude 443mg, productive rate is 75.4%, product is pale yellowish oil material.
Carry out hydrogen spectrum, carbon spectrum, fluorine spectrum and Mass Spectrometric Identification to product, its detected result is as follows:
1HNMR(CDCl
3):δ7.00～6.93(2H,m),6.92～6.86(6H,m),4.01(2H,m),3.22(1H,m),3.01(1H,m),2.35(1H,m),2.23(1H,m),2.17(1H,m),2.02(2H,m),1.92(1H,m),1.80(1H,m),1.71(1H,m),1.46(1H,m),1.13(3H,d,J=6.15Hz)ppm.
13CNMR(CDCl
3):δ159.32,157.41,155.34,150.62,120.32,119.19,116.26,115.65,66.99,60.55,54.07,50.94,32.74,28.60,21.72,18.93ppm.
19FNMR(CDCl
3):-121.41ppm.
MS,[M+H]
+,330.07;calculated for C
20H
24FNO
2,[M
++H],330.18.
Embodiment 4
1. implement by the method described in embodiment 1 step 1, unlike substrate used and reagent be: 4-(4-fluorophenoxy) phenol (530mg, 2.6mmol), salt of wormwood (1.078g, 7.8mmol), the bromo-2-monochloroethane of 1-(0.433mL, 5.2mmol), 10ml acetonitrile, temperature of reaction is 87 DEG C, return time is 45h, obtain product 330mg, productive rate is 47.7%, and product 1-(4-(2-chloroethoxy) phenoxy group)-4-fluorobenzene is pale yellowish oil material.
Carry out hydrogen spectrum, carbon spectrum and the qualification of fluorine spectrum to product, its detected result is as follows:
1HNMR(500MHz,CDCl
3):δ7.04～6.99(2H,m),6.97～6.90(6H,m),4.22(2H,t,J=5.85Hz),3.82(2H,t,J=5.85Hz)ppm.
13CNMR(CDCl
3):159.48,157.56,154.45,151.44,120.31,119.49,116.38,116.06,68.72,42.12ppm.
19FNMR(CDCl
3):-120.89ppm.
2. implement by the method described in embodiment 1 step 2, unlike substrate used and reagent be: 1-(4-(2-chloroethoxy) phenoxy group)-4-fluorobenzene (320mg, 1.2mmol), potassiumiodide (199mg, 1.2mmol), salt of wormwood (498mg, 3.6mmol), (R)-2-crassitude (146 μ L, 1.44mmol), 20ml acetonitrile, temperature of reaction is 88 DEG C, return time is 47h, obtain product (R)-1-(2-(4-(4-fluorophenoxy) phenoxy group) ethyl)-2-crassitude 263mg, productive rate is 69.2%, product is greenish orange look oily mater.
Carry out hydrogen spectrum, carbon spectrum, fluorine spectrum and Mass Spectrometric Identification to product, its detected result is as follows:
1HNMR(CDCl
3):δ7.01～6.96(2H,m),6.93～6.87(6H,m),4.09(2H,m),3.24(2H,m),2.53(1H,m),2.43(1H,m),2.29(1H,m),1.92(1H,m),1.81(1H,m),1.71(1H,m),1.42(1H,m),1.15(3H,d,J=6.10Hz)ppm.
13CNMR(CDCl
3):δ159.32,157.44,155.14,150.73,120.27,119.26,116.27,115.67,67.69,60.56,54.07,52.97,32.51,21.99,19.18ppm.
19FNMR(CDCl
3):-121.33ppm.
MS,[M+H]
+,316.06;calculated for C
19H
22N
2O
4,[M
++H],316.16.
Embodiment 5
1. implement by the method described in embodiment 1 step 1, unlike substrate used and reagent be: 4-(4-nitrophenoxy) phenol (500mg, 2.16mmol), salt of wormwood (896mg, 6.48mmol), the bromo-3-chloropropane of 1-(0.427mL, 4.32mmol), 25ml acetonitrile, temperature of reaction is 90 DEG C, return time is 24h, obtain product 1-(4-(3-chlorine propoxy-) phenoxy group)-4-oil of mirbane 563mg, productive rate is 84.7%, and product is light tan solid.
Carry out hydrogen spectrum, the qualification of carbon spectrum to product, its detected result is as follows:
1HNMR(500MHz,CDCl
3):δ8.20(2H,d,J=9.25Hz),7.05(2H,d,J=9.05Hz),6.98(4H,m),4.15(2H,t,J=5.80Hz),3.79(2H,t,J=6.30Hz),2.28(2H,m)ppm.
13CNMR(CDCl
3):δ164.22,156.40,148.02,142.35,126.00,122.00,116.47,116.00,64.83,41.62,32.29ppm.
2. implement by the method described in embodiment 1 step 2, unlike substrate used and reagent be: 1-(4-(3-chlorine propoxy-) phenoxy group)-4-oil of mirbane (450mg, 1.46mmol), potassiumiodide (242mg, 1.46mmol), salt of wormwood (605mg, 4.38mmol), (R)-2-crassitude (R)-2-crassitude (177 μ L, 1.75mmol), 25ml acetonitrile, temperature of reaction is 85 DEG C, return time is 34h, obtain product (R)-2-methyl isophthalic acid-(3)-(4-(4-nitrophenoxy) phenoxy group) propyl group) tetramethyleneimine 182mg, productive rate is 34.9%, product is brown oil material.
Carry out hydrogen spectrum, carbon spectrum and Mass Spectrometric Identification to product, its detected result is as follows:
1HNMR(CDCl
3,500MHz):δ8.17(2H,d,J=9.20Hz),7.00(2H,d,J=9.05Hz),6.94(4H,m),4.03(2H,m),3.21(1H,m),3.01(1H,m),2.35(1H,m),2.23(1H,m),2.16(1H,m),2.02(2H,m),1.93(1H,m),1.80(1H,m),1.71(1H,m),1.45(1H,m),1.12(3H,d,J=6.10Hz).
13CNMR(CDCl
3):δ164.28,156.71,147.70,142.27,125.95,121.88,116.38,115.96,66.99,60.40,54.07,50.85,32.77,28.62,21.73,19.03ppm.
MS,[M+H]
+,357.17;calculated for C
19H
22N
2O
4,[M
++H],357.03.
Embodiment 6
1. implement by the method described in embodiment 1 step 1, unlike substrate used and reagent be: 4-(4-nitrophenoxy) phenol (500mg, 2.16mmol), salt of wormwood (896mg, 6.48mmol), the bromo-2-monochloroethane of 1-(0.358mL, 4.32mmol), 25ml acetonitrile, temperature of reaction is 90 DEG C, return time is 36h, obtain product 1-(4-(2-chloroethoxy) phenoxy group)-4-oil of mirbane 377mg, productive rate is 59.3%, and product is faint yellow solid.
Carry out hydrogen spectrum, the qualification of carbon spectrum to product, its detected result is as follows:
1HNMR(500MHz,CDCl
3):δ8.20(2H,d,J=9.25Hz),7.06(2H,d,J=9.05Hz),6.98(4H,m),4.26(2H,t,J=5.80Hz),3.85(2H,t,J=5.80Hz).
13CNMR(CDCl
3):164.07,155.85,148.51,142.46,126.01,122.03,116.55,116.34,68.67,42.03ppm.
2. implement by the method described in embodiment 1 step 2, unlike substrate used and reagent be: 1-(4-(2-chloroethoxy) phenoxy group)-4-oil of mirbane (300mg, 1mmol), potassiumiodide (169mg, 1mmol), salt of wormwood (423mg, 3mmol), (R)-2-crassitude (123 μ L, 1.2mmol), 20ml acetonitrile, temperature of reaction is 87 DEG C, return time is 37h, obtain product (R)-2-methyl isophthalic acid-(3)-(4-(4-nitrophenoxy) phenoxy group) propyl group) tetramethyleneimine 271mg, productive rate is 77.5%, product is brown wax matter.
Carry out hydrogen spectrum, carbon spectrum and Mass Spectrometric Identification to product, its detected result is as follows:
1HNMR(CDCl
3):δ8.18(2H,d,J=9.30Hz),7.02(2H,d,J=9.1Hz),6.96(4H,m), 4.23(2H,m),3.35(2H,m),2.75(2H,m),2.52(1H,m),2.05(1H,m),1.94(1H,m),1.83(1H,m),1.60(1H,m),1.29(3H,d,J=6.00Hz).
13CNMR(CDCl
3):δ164.17,156.03,148.15,142.36,125.99,121.96,116.49,116.12,66.51,61.85,54.72,52.56,32.09,21.83,18.11ppm.
MS,[M+H]
+,343.05;calculated for C
19H
22N
2O
4,[M
++H],343.16.
Claims (6)
1. a brain histamine H
3the precursor of Receptor Radioligand, is characterized in that, its general formula is:
Wherein, n is 1 or 2; R is nitro or fluorine, and the position of R is No. 2 positions or No. 4 positions.
2. brain histamine H according to claim 1
3the precursor of Receptor Radioligand, is characterized in that, R is No. 2 position nitros or No. 4 position nitros or No. 2 position fluorine.
3. a kind of brain histamine H according to claim 1
3the preparation method of the precursor of Receptor Radioligand, is characterized in that, concrete steps are as follows:
Step one, join in acetonitrile by fluoro or nitro-phenoxy phenol and 1-bromo-3-chloropropane or the bromo-2-monochloroethane of 1-, stir lower dissolving, then add Anhydrous potassium carbonate, heating, cooling after backflow, extraction, dry, concentrated, rapid column chromatography, obtains product
Step 2, product step one obtained, (R)-2-crassitude, potassiumiodide and Anhydrous potassium carbonate join in acetonitrile, heating, cooling after backflow, and extraction is dry, concentrated, and rapid column chromatography, obtains final product
4. brain histamine H according to claim 3
3the preparation method of the precursor of Receptor Radioligand, is characterized in that, the nitro of described fluoro or nitro-phenoxy phenol or fluorine are No. 2 position nitros or No. 4 position nitros or No. 2 position fluorine.
5. brain histamine H according to claim 3
3the preparation method of the precursor of Receptor Radioligand, is characterized in that, in step one, described Heating temperature is 85-90 DEG C, and return time is 24 ~ 48 hours; The mol ratio of described fluoro or nitro-phenoxy phenol and 1-bromo-3-chloropropane or the bromo-2-monochloroethane of 1-is 1:1 ~ 2; The mol ratio of fluoro or nitro-phenoxy phenol and salt of wormwood is 1:2 ~ 5; The mol ratio of fluoro or nitro-phenoxy phenol and acetonitrile is 1:0.22 ~ 0.44.
6. brain histamine H according to claim 3
3the preparation method of the precursor of Receptor Radioligand, is characterized in that, in step 2, described Heating temperature is 85-90 DEG C, and return time is 24 ~ 48 hours; The product of described step one and the mol ratio of (R)-2-crassitude are 1:1.2 ~ 2; The product of step one and the mol ratio of potassiumiodide are 1:0.6 ~ 2; The product of step one and the mol ratio of salt of wormwood are 1:2 ~ 6; The product of step one and the mol ratio of acetonitrile are 1:0.2 ~ 0.33.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310176094.3A CN103242212B (en) | 2013-05-13 | 2013-05-13 | A kind of brain histamine H 3precursor of Receptor Radioligand and preparation method thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310176094.3A CN103242212B (en) | 2013-05-13 | 2013-05-13 | A kind of brain histamine H 3precursor of Receptor Radioligand and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN103242212A CN103242212A (en) | 2013-08-14 |
| CN103242212B true CN103242212B (en) | 2015-11-04 |
Family
ID=48922118
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310176094.3A Expired - Fee Related CN103242212B (en) | 2013-05-13 | 2013-05-13 | A kind of brain histamine H 3precursor of Receptor Radioligand and preparation method thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN103242212B (en) |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5723492A (en) * | 1994-10-11 | 1998-03-03 | G.D. Searle & Co. | LTA4 hydrolase inhibitor pharmaceutical compositions and methods of use |
| US6248765B1 (en) * | 1995-03-21 | 2001-06-19 | Institut National De La Sante Et De La Recherche Medical | Imidazole derivatives as histamine receptor H3 (ANT) agonists |
| US20030013733A1 (en) * | 2000-09-22 | 2003-01-16 | Richard Apodaca | Octahydro-indolizine and quinolizine and hexahydro-pyrrolizine |
| CN101142180A (en) * | 2005-03-17 | 2008-03-12 | 伊莱利利公司 | Pyrrolidine derivatives as histamine h3 receptor antagonists |
-
2013
- 2013-05-13 CN CN201310176094.3A patent/CN103242212B/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5723492A (en) * | 1994-10-11 | 1998-03-03 | G.D. Searle & Co. | LTA4 hydrolase inhibitor pharmaceutical compositions and methods of use |
| US6248765B1 (en) * | 1995-03-21 | 2001-06-19 | Institut National De La Sante Et De La Recherche Medical | Imidazole derivatives as histamine receptor H3 (ANT) agonists |
| US20030013733A1 (en) * | 2000-09-22 | 2003-01-16 | Richard Apodaca | Octahydro-indolizine and quinolizine and hexahydro-pyrrolizine |
| CN101142180A (en) * | 2005-03-17 | 2008-03-12 | 伊莱利利公司 | Pyrrolidine derivatives as histamine h3 receptor antagonists |
Non-Patent Citations (1)
| Title |
|---|
| Radiosynthesis and Evaluation of an 18F-Labeled Positron Emission Tomography (PET) Radioligand for Brain Histamine Subtype-3 Receptors Based on a Nonimidazole 2-Aminoethylbenzofuran Chemotype;Xiaofeng Bao et.al.;《J. Med. Chem.》;20120207;第55卷;第2406-2415页 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN103242212A (en) | 2013-08-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Chun et al. | Rapid and Efficient Radiosyntheses of meta‐Substituted [18F] Fluoroarenes from [18F] Fluoride Ion and Diaryliodonium Tosylates within a Microreactor | |
| CN116194440A (en) | Quinazolinone HSD17B13 inhibitors and uses thereof | |
| CN108997282B (en) | Arylbenzofuran derivatives having alpha-glucosidase inhibitory activity | |
| Takada et al. | Radiosynthesis of [2-11C-carbonyl] dantrolene using [11C] phosgene for PET | |
| CN103242212B (en) | A kind of brain histamine H 3precursor of Receptor Radioligand and preparation method thereof | |
| Li et al. | Rapid incorporation of a difluoroacetate radical into para-quinone methides via radical 1, 6-conjugate addition | |
| Haulotte et al. | Biosynthesis of defensive coccinellidae alkaloids: incorporation of fatty acids in adaline, coccinelline, and harmonine | |
| Nosova et al. | Synthesis and fluorescent properties of 2-styryl-6, 7-difluoro-8-hydroxyquinoline and its Zn (II) complex | |
| CN104098606B (en) | A kind of Phosphorescent ionic type iridium complex and its preparation method and application | |
| Kraus et al. | A three-component reaction between benzynes, the enolate of acetaldehyde, and unsaturated esters and dihydroisoquinolines | |
| Fernandes et al. | Neurotransmitter amino acid—oxobenzo [f] benzopyran conjugates: synthesis and photorelease studies | |
| Shearer et al. | Discovery of a novel class of PPARδ partial agonists | |
| WO2017090631A1 (en) | Fluorescent probe for detecting extracellular metabolite and screening method employing said fluorescent probe | |
| Bauman et al. | Synthesis, labelling and evaluation of hydantoin‐substituted indole carboxylic acids as potential ligands for positron emission tomography imaging of the glycine binding site of the N‐methyl‐D‐aspartate receptor | |
| WO2016097339A1 (en) | Labelled coumarin derivatives | |
| Kuramochi et al. | Synthesis and structure–activity relationships of 6-{4-[(3-fluorobenzyl) oxy] phenoxy} nicotinamide derivatives as a novel class of NCX inhibitors: a QSAR study | |
| Ullah et al. | Bioisosteric synthesis of nitrogen containing derivatives of salicyl alcohol, their in vivo pharmacological studies with molecular modeling | |
| Li et al. | One‐step radiosynthesis of 4‐[18F] flouro‐3‐nitro‐N‐2‐propyn‐1‐yl‐benzamide ([18F] FNPB): a new stable aromatic porosthetic group for efficient labeling of peptides with fluorine‐18 | |
| Somandi et al. | Molecular Docking Studies, Synthesis and Biological Evaluation of Substituted Pyrimidine‐2, 4‐diamines as Inhibitors of Plasmodium falciparum Dihydrofolate Reductase | |
| CN102285993B (en) | Tetrahydropyridine oxapicene derivative as well as preparation method and application thereof | |
| CN103172551A (en) | Precursor compound for PET (Polyethylene Terephthalate) ligand of H3 receptor, and synthesis method of precursor compound | |
| CN114213416B (en) | Irreversible BTK inhibitor with oxazolo [4,5-b ] pyridine structure and application thereof | |
| Giskeødegård | C-5 Alkylidation of hydantoins An overview of three different synthetic approaches | |
| Chong et al. | Synthesis and evaluation of novel 18 F‐labeled quinazoline derivatives with low lipophilicity for tumor PET imaging | |
| Murai et al. | Simple deuterium introduction at α-position of carbonyl in diazirinyl derivatives for photoaffinity labeling |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| CF01 | Termination of patent right due to non-payment of annual fee | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20151104 Termination date: 20170513 |