CN115141183B - Preparation method and application of myocardial perfusion developer precursor - Google Patents
Preparation method and application of myocardial perfusion developer precursor Download PDFInfo
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- 238000002360 preparation method Methods 0.000 title abstract description 14
- 230000002107 myocardial effect Effects 0.000 title abstract description 13
- 230000010412 perfusion Effects 0.000 title abstract description 13
- 239000002243 precursor Substances 0.000 title abstract description 10
- 238000000034 method Methods 0.000 claims abstract description 45
- 238000004519 manufacturing process Methods 0.000 claims abstract description 13
- 150000001875 compounds Chemical class 0.000 claims description 68
- 238000006243 chemical reaction Methods 0.000 claims description 59
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 claims description 48
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 claims description 31
- 239000002904 solvent Substances 0.000 claims description 29
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 27
- HTSGKJQDMSTCGS-UHFFFAOYSA-N 1,4-bis(4-chlorophenyl)-2-(4-methylphenyl)sulfonylbutane-1,4-dione Chemical compound C1=CC(C)=CC=C1S(=O)(=O)C(C(=O)C=1C=CC(Cl)=CC=1)CC(=O)C1=CC=C(Cl)C=C1 HTSGKJQDMSTCGS-UHFFFAOYSA-N 0.000 claims description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical group CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 21
- FKLJPTJMIBLJAV-UHFFFAOYSA-N Compound IV Chemical compound O1N=C(C)C=C1CCCCCCCOC1=CC=C(C=2OCCN=2)C=C1 FKLJPTJMIBLJAV-UHFFFAOYSA-N 0.000 claims description 20
- 239000002253 acid Substances 0.000 claims description 20
- YWMLORGQOFONNT-UHFFFAOYSA-N [3-(hydroxymethyl)phenyl]methanol Chemical compound OCC1=CC=CC(CO)=C1 YWMLORGQOFONNT-UHFFFAOYSA-N 0.000 claims description 16
- NLFBCYMMUAKCPC-KQQUZDAGSA-N ethyl (e)-3-[3-amino-2-cyano-1-[(e)-3-ethoxy-3-oxoprop-1-enyl]sulfanyl-3-oxoprop-1-enyl]sulfanylprop-2-enoate Chemical compound CCOC(=O)\C=C\SC(=C(C#N)C(N)=O)S\C=C\C(=O)OCC NLFBCYMMUAKCPC-KQQUZDAGSA-N 0.000 claims description 16
- DDPWVABNMBRBFI-UHFFFAOYSA-N tert-butylhydrazine;hydron;chloride Chemical compound Cl.CC(C)(C)NN DDPWVABNMBRBFI-UHFFFAOYSA-N 0.000 claims description 14
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical group C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Natural products CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical group CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical group CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- 239000003054 catalyst Substances 0.000 claims description 7
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 5
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 5
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 5
- 239000012362 glacial acetic acid Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- 239000012312 sodium hydride Substances 0.000 claims description 5
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 5
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical group CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 4
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 3
- 238000010992 reflux Methods 0.000 claims description 3
- 125000003944 tolyl group Chemical group 0.000 claims description 3
- 239000002516 radical scavenger Substances 0.000 claims 2
- 229960000549 4-dimethylaminophenol Drugs 0.000 claims 1
- XTEGARKTQYYJKE-UHFFFAOYSA-N chloric acid Chemical compound OCl(=O)=O XTEGARKTQYYJKE-UHFFFAOYSA-N 0.000 claims 1
- 229940005991 chloric acid Drugs 0.000 claims 1
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 abstract description 10
- 239000000463 material Substances 0.000 abstract description 7
- 239000002360 explosive Substances 0.000 abstract description 5
- 230000015572 biosynthetic process Effects 0.000 abstract description 2
- 238000003786 synthesis reaction Methods 0.000 abstract description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 15
- 239000000243 solution Substances 0.000 description 13
- 239000000706 filtrate Substances 0.000 description 8
- 239000007787 solid Substances 0.000 description 8
- 239000012074 organic phase Substances 0.000 description 7
- 238000003756 stirring Methods 0.000 description 7
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 6
- 238000001816 cooling Methods 0.000 description 6
- 239000012216 imaging agent Substances 0.000 description 6
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 5
- 239000012295 chemical reaction liquid Substances 0.000 description 5
- 238000001914 filtration Methods 0.000 description 5
- 238000010438 heat treatment Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 238000002390 rotary evaporation Methods 0.000 description 5
- -1 (1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazol-4-yl) methoxy Chemical group 0.000 description 4
- 238000001035 drying Methods 0.000 description 4
- 239000012065 filter cake Substances 0.000 description 4
- PSHKMPUSSFXUIA-UHFFFAOYSA-N n,n-dimethylpyridin-2-amine Chemical group CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 4
- 238000005406 washing Methods 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 239000002994 raw material Substances 0.000 description 3
- 238000000967 suction filtration Methods 0.000 description 3
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- KRHYYFGTRYWZRS-BJUDXGSMSA-N ac1l2y5h Chemical compound [18FH] KRHYYFGTRYWZRS-BJUDXGSMSA-N 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 2
- 239000005457 ice water Substances 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 239000011259 mixed solution Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- XTHPWXDJESJLNJ-UHFFFAOYSA-N sulfurochloridic acid Chemical compound OS(Cl)(=O)=O XTHPWXDJESJLNJ-UHFFFAOYSA-N 0.000 description 2
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 238000007664 blowing Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000032798 delamination Effects 0.000 description 1
- CLEYBUZWXNEMSC-UHFFFAOYSA-N furan-2-carboxylic acid;hydrochloride Chemical compound Cl.OC(=O)C1=CC=CO1 CLEYBUZWXNEMSC-UHFFFAOYSA-N 0.000 description 1
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 238000003541 multi-stage reaction Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/041—Heterocyclic compounds
- A61K51/044—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
- A61K51/0459—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two nitrogen atoms as the only ring hetero atoms, e.g. piperazine
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Physics & Mathematics (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
The application provides a preparation method and application of a myocardial perfusion developer precursor. According to the method, by redesigning the synthesis route of the myocardial perfusion developer precursor, the use of explosive sodium azide is avoided, the production safety is improved, and meanwhile, all materials related to the route are commercialized products, so that the price is low, the materials are easy to obtain, and the production cost is reduced.
Description
Technical Field
The application belongs to the field of biomedicine, and particularly relates to a preparation method and application of a myocardial perfusion developer precursor.
Background
A novel fluorine-18 labeled myocardial perfusion imaging agent has the following structural formula:
2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethoxy-4-tosylate, an important intermediate for the preparation of this novel fluoro-18-labeled myocardial perfusion imaging agent the structural formula of 2- (2- ((1- (3- (((((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethoxy-4-tosylate is as follows:
the synthetic routes to date for this precursor are reported as follows: chinese patent CN103113354B discloses a multi-step reaction preparation method of the precursor by using furfural as a starting material. The route is as follows:
the explosive sodium azide is used in the process of constructing the triazole ring in the patent route, so the operation safety is low, and the commercial production is difficult to carry out.
Disclosure of Invention
Aiming at the problems in the prior art, the application provides a preparation method of a myocardial perfusion developer precursor, so as to overcome the defects of high production cost, complex production operation, low safety and the like of products in the prior art.
Specifically, the present application relates to the following aspects:
1. a process for preparing compound VI, characterized in that compound I is reacted with compound V to give compound VI,
wherein compound VI is shown below:
compound I is shown below:
compound V is shown below:
2. the process according to item 1, characterized in that it comprises a step of reacting compound IV with 1H-1,2, 3-thiazole-4-methanol to obtain compound V:
3. the process according to item 2, wherein the compound IV is reacted with 1H-1,2, 3-thiazole-4-methanol in the presence of a base,
preferably, the base used for the reaction of the compound IV with 1H-1,2, 3-thiazole-4-methanol is potassium carbonate, the solvent is acetone,
further preferably, the reaction temperature of the compound IV and 1H-1,2, 3-thiazole-4-methanol is 50 to 60 ℃.
4. Process according to item 2, characterized in that it comprises a step of reacting compound III with phosphorus tribromide, giving compound IV:
preferably, the solvent used for the reaction of the compound III and the phosphorus tribromide is toluene, and the reaction temperature is 80-100 ℃.
5. The process according to item 4, characterized in that it comprises a step of reacting compound II with 1, 3-benzenedimethanol to give compound III:
preferably, compound II is reacted with 1, 3-benzenedimethanol in the presence of a base,
further preferably, the base used for reacting the compound II with 1, 3-benzenedimethanol is cesium carbonate, the solvent is acetonitrile,
even more preferably, the reaction temperature of compound II with 1, 3-benzenedimethanol is from 80 to 90 ℃.
6. The method according to item 5, characterized in that it comprises a step of reacting furoic acid with tert-butylhydrazine hydrochloride to obtain compound II:
preferably, the reaction of the furoic acid and the tert-butyl hydrazine hydrochloride is carried out at the temperature of below 10 ℃, and the obtained product and glacial acetic acid are refluxed and reacted for 4 to 6 hours in dichloromethane to obtain the compound II.
7. The process according to item 1, further comprising the step of reacting diethylene glycol with p-toluenesulfonyl chloride to give compound I:
preferably, diethylene glycol and paratoluensulfonyl chloride react in the presence of an acid-binding agent and a catalyst,
further preferably, the acid-binding agent is triethylamine, the catalyst is DMAP,
more preferably, the solvent used for the reaction of the diethylene glycol and the p-toluenesulfonyl chloride is one or two of dichloromethane and dichloroethane, and the reaction temperature is 20 to 40 ℃.
8. The process according to item 1, wherein the compound I and the compound V are reacted in the presence of a base,
preferably, the base used for the reaction of compound I and compound V is sodium hydride and the solvent is tetrahydrofuran, and further preferably, the reaction temperature of compound I and compound V is 60 to 70 ℃.
9. A compound VI, prepared by the method of any one of items 1 to 8, wherein compound VI is represented by:
10. use of compound VI prepared by the method of any one of items 1 to 8 or compound VI of item 8 for the preparation of a myocardial perfusion imaging agent.
According to the method, by redesigning the synthesis route of the myocardial perfusion developer precursor, the use of explosive sodium azide is avoided, the production safety is improved, and meanwhile, all materials related to the route are commercialized products, so that the price is low, the materials are easy to obtain, and the production cost is reduced.
Detailed Description
The present application is further described below in conjunction with the following examples, which are included merely to further illustrate and explain the present application and are not intended to limit the present application.
Unless defined otherwise, technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. Although methods and materials similar or equivalent to those described herein can be used in experimental or practical applications, the materials and methods are described below. In case of conflict, the present specification, including definitions, will control, and the materials, methods, and examples are illustrative only and not intended to be limiting. The present application is further described with reference to the following specific examples, which should not be construed as limiting the scope of the present application.
The application aims to provide a synthesis method of a novel compound VI, wherein the compound VI is 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazol-4-yl) methoxy) ethoxy-4-tosylate, and is an important intermediate of a novel fluorine-18 labeled myocardial perfusion imaging agent, wherein the structural formula of the compound VI is as follows:
the process of the present application provides compound VI by reacting compound I with compound V, wherein compound I is as follows:
compound V is shown below:
in a particular embodiment, compound I and compound V are reacted in a solvent in the presence of a base. Among them, the base and the solvent may be those well known in the art. Preferably, the base is sodium hydride and the solvent is tetrahydrofuran. More preferably, the reaction temperature is 60 to 70 ℃, for example, 60 ℃, 62 ℃, 65 ℃, 68 ℃, 70 ℃.
In a specific embodiment, the compound I, sodium hydride and anhydrous tetrahydrofuran are mixed and stirred uniformly, and the temperature is raised to 60-70 ℃. Then slowly dripping the mixed solution of the compound V into the reaction system, and reacting for 2 hours at the temperature of between 60 and 70 ℃ after the addition is finished. Cooling the reaction solution to room temperature, adding water, stirring, adding ethyl acetate, extracting twice, drying the organic phase by using anhydrous sodium sulfate, filtering, and spin-drying the filtrate to obtain the compound VI.
Further, the method of the present application may further comprise the step of reacting compound IV with 1H-1,2, 3-thiazole-4-methanol to obtain compound V, as shown below:
in a specific embodiment, compound IV is reacted with 1H-1,2, 3-thiazole-4-methanol in the presence of a base in a solvent. Among them, the base and the solvent may be those well known in the art. Preferably, the base is potassium carbonate and the solvent is acetone. More preferably, the temperature for the reaction is 50 to 60 ℃, for example, 50 ℃, 52 ℃, 55 ℃,58 ℃,60 ℃.
In a specific embodiment, compound IV is mixed with acetone (200 ml) and stirred uniformly, and 1H-1,2, 3-thiazole-4-methanol and potassium carbonate are added. After the addition, the temperature is raised to 50-60 ℃ for reaction for 12 hours. Cooling the reaction liquid to room temperature, filtering, adding water into the filtrate, crystallizing, and filtering to obtain a compound V.
Further, the process of the present application may further comprise the step of reacting compound III with phosphorus tribromide to give compound IV, specifically as follows:
in a specific embodiment, the solvent used for the reaction of compound III with phosphorus tribromide is toluene, and the reaction temperature is 80 to 100 ℃, and may be, for example, 80 ℃, 82 ℃, 85 ℃, 88 ℃, 90 ℃, 92 ℃, 95 ℃, 98 ℃, 100 ℃.
In a specific embodiment, the compound III and toluene are mixed and stirred uniformly, phosphorus tribromide is slowly dropped, and the temperature of a reaction system is raised to 80-100 ℃ after dropping, so that the reaction is carried out for 6 hours. And cooling the reaction liquid to 15-30 ℃, dropwise adding a saturated sodium bicarbonate aqueous solution until the pH of the reaction liquid is 7-8, separating the liquid, washing the organic phase with water, and removing the solvent by rotary evaporation to obtain a compound IV.
Further, the method of the present application may further comprise the step of reacting compound II with 1, 3-benzenedimethanol to obtain compound III, wherein the reaction steps are as follows:
in a specific embodiment, compound II is reacted with 1, 3-benzenedimethanol in the presence of a base in a solvent. Among them, the base and the solvent may be those well known in the art. Preferably, the base is cesium carbonate and the solvent is acetonitrile. More preferably, the reaction temperature is 80 to 90 ℃, for example, 80 ℃, 82 ℃, 85 ℃, 88 ℃, 90 ℃.
In a specific embodiment, the compound II is mixed with acetonitrile (180 ml), stirred uniformly, added with 1, 3-benzenedimethanol and cesium carbonate, and heated to 80-90 ℃ for reaction for 5 hours. Cooling the reaction liquid to room temperature, carrying out suction filtration, washing a filter cake with acetonitrile, combining filtrates, and removing the solvent by rotary evaporation to obtain a compound III.
Further, the method of the present application may further include a step of reacting furoic acid with tert-butyl hydrazine hydrochloride to obtain compound II, wherein the reaction steps are as follows:
in a specific embodiment, furoic acid and tert-butylhydrazine hydrochloride are reacted at 10 ℃ or lower (e.g., 10 ℃,9 ℃, 8 ℃,7 ℃,6 ℃,5 ℃,4 ℃,3 ℃,2 ℃,1 ℃, 0 ℃), and the resulting product is refluxed with glacial acetic acid in dichloromethane for 4 to 6 hours to obtain compound II.
In one embodiment, the furoic acid is mixed with water, anhydrous sodium carbonate is added in portions in an ice-water bath with stirring, and the mixture is stirred until the solution becomes clear. Adding tert-butyl hydrazine hydrochloride in batches, stirring for 4-6 hours, and carrying out suction filtration. Washing the filter cake with cold water, and drying for 12-16 h by blowing at 30-40 ℃ to obtain a yellowish-brown solid. Mixing the obtained solid with dichloromethane, adding glacial acetic acid, and heating and refluxing for 4-6 hours. Cooling to room temperature, washing the reaction solution with water, 1N NaOH solution and water in sequence, and standing for layering. And drying the organic phase by using anhydrous sodium sulfate, filtering, and removing the solvent from the filtrate by rotary evaporation to obtain a compound II.
Further, the method of the present application may further include a step of reacting diethylene glycol with p-toluenesulfonyl chloride to obtain compound I, wherein the reaction steps are as follows:
in a specific embodiment, diethylene glycol is reacted with p-toluenesulfonyl chloride in the presence of an acid-binding agent and a catalyst in a solvent.
The acid-binding agent has the function of absorbing acid in the reaction, so that the reaction is not influenced. Acid scavengers, catalysts and solvents in the present application may be those well known in the art. Preferably, the acid-binding agent is triethylamine, the catalyst is DMAP (dimethyl amino pyridine), namely 4-dimethylamino pyridine, and the solvent is one or two of dichloromethane and dichloroethane. More preferably, the reaction temperature is 20 to 40 ℃, for example, 20 ℃, 22 ℃, 25 ℃, 28 ℃,30 ℃, 32 ℃, 35 ℃, 38 ℃, 40 ℃.
In a preferred embodiment, as shown in the following scheme, the process of the present application for preparing compound VI comprises the steps of:
step 1: reacting diethylene glycol with p-toluenesulfonyl chloride to obtain a compound I,
step 2: reacting the furoic acid with tert-butyl hydrazine hydrochloride to obtain a compound II,
and step 3: reacting compound II with 1, 3-benzenedimethanol to give compound III,
and 4, step 4: reacting the compound III with phosphorus tribromide to obtain a compound IV,
and 5: reacting the compound IV with 1H-1,2, 3-thiazole-4-methanol to obtain a compound V,
step 6: reacting compound I with compound V to obtain compound VI.
Wherein, the specific reaction reagents and reaction conditions of each step are as described above. And step 2, step 3, step 4 and step 5 are sequentially carried out, namely, the step 2 is firstly completed, then the step 3 is carried out, then the step 4 is carried out, and then the step 5 is carried out. And the execution sequence of the step 1 has no precedence relation with the step 2, the step 3, the step 4 and the step 5. For example, step 1 may be performed before step 2, may be performed after step 5, or may be performed at any time between step 2 and step 5.
The application also provides a compound VI, which is prepared by the method,
wherein compound VI is shown below:
the application also provides the compound VI prepared by the method or the application of the compound VI in preparing the myocardial perfusion imaging agent.
The raw materials adopted by the method for preparing the compound VI are diethylene glycol, p-toluenesulfonyl chloride, furoic acid, tert-butylhydrazine hydrochloride, 1, 3-benzenedimethanol, phosphorus tribromide, 1H-1,2, 3-thiazole-4-methanol and the like, and the raw materials are all low-cost, easily-available and common commercially-available products, so that the use of explosive sodium azide is avoided, the production safety is improved, and the production cost is reduced. Meanwhile, the method can obtain the yield of more than 70%.
Examples
Example 1
Preparation of Compound I
The reaction formula is as follows:
the operation steps are as follows:
DMAP (0.72g, 5.9mmol) and diethylene glycol (20g, 188.5mmol) are put into a reaction vessel, 400mL of dichloromethane is added and stirred, then (79.09g, 414.8mmol) of p-toluenesulfonyl chloride is added, moreover (42g, 414.8mmol) of triethylamine is slowly dropped into the reaction vessel, the reaction is stirred for 6 hours at the temperature of 20 ℃ to 40 ℃, the reaction liquid is washed twice by adding 200mL of water, 20g of anhydrous sodium sulfate is added to the organic phase and dried, then the solution is filtered and evaporated to dryness under reduced pressure, and a yellow oily compound I (72.38g, 174.8mmol) is obtained, and the yield is 92.7%.
Preparation of Compound II
The reaction formula is as follows:
the operation steps are as follows:
chlorosulfuric acid (20g, 118mmol) was mixed with water (200 ml), and anhydrous sodium carbonate (6.4g, 60mmol) was added in portions in an ice-water bath (below 10 ℃) with stirring, and the solution was stirred until it became clear. Adding tert-butyl hydrazine hydrochloride (16.8g, 134.8mmol) in batches, stirring for 4-6 h, and carrying out suction filtration. The filter cake is washed by 50ml of cold water and dried by air blast at the temperature of 30-40 ℃ for 12-16 h to obtain 30.12g of earthy yellow solid.
The obtained solid was mixed with methylene chloride (160 ml), and glacial acetic acid (10 ml) was added thereto, followed by heating and refluxing for 4 to 6 hours. The heating was stopped, the reaction mixture was cooled to room temperature, and the reaction mixture was washed with 200ml of water, 200ml of 1N NaOH solution and 200ml of water in this order, and then allowed to stand for delamination. The organic phase was dried over 10g anhydrous sodium sulfate, filtered and the filtrate was rotary evaporated (temperature not higher than 40 ℃) to remove the solvent to give a pale yellow oil which solidified upon cooling to room temperature to give compound ii (21.98g, 99mmol) as a yellow solid in 84% yield.
Preparation of Compound III
The reaction formula is as follows:
the operation steps are as follows:
compound II (17.6g, 79.6mmol) and acetonitrile (180 ml) were mixed and stirred uniformly, 1, 3-benzenedimethanol (22g, 159.3mmol) and cesium carbonate (10g, 122.7mmol) were added, and the temperature was raised to 80-90 ℃ for reaction for 5 hours. The reaction solution was cooled to room temperature, filtered, the filter cake was washed with 40ml of acetonitrile, the filtrates were combined and the solvent was removed by rotary evaporation (temperature not higher than 40 ℃) to give compound iii as a white solid (15.6 g,48.3 mmol) with a yield of 60.7%.
Preparation of Compound IV
The reaction formula is as follows:
the operation steps are as follows:
mixing the compound III (15.6 g,48.3 mmol) with toluene (200 ml), stirring uniformly, slowly and dropwise adding phosphorus tribromide (15.7 g, 58mmol), reacting after dropwise adding, heating to 80-100 ℃ and reacting for 6 hours. The reaction solution was cooled to 15 to 30 ℃ and a saturated aqueous solution of sodium bicarbonate was added dropwise until the pH of the reaction solution became 7 to 8, the reaction solution was separated, the organic phase was washed with 100ml of water, and the solvent was removed by rotary evaporation (temperature not higher than 60 ℃) to obtain a yellow solid compound IV (16.2g, 42mmol) with a yield of 87%.
Preparation of Compound V
The reaction formula is as follows:
the operation steps are as follows:
the compound IV (16.2g, 42mmol) and acetone (200 ml) are mixed and stirred evenly, 1H-1,2, 3-thiazole-4-methanol (5g, 50.4 mmol) and potassium carbonate (6.97g, 50.4 mmol) are added, and the temperature is raised to 50-60 ℃ for reaction for 12 hours after the addition. The reaction solution was cooled to room temperature and filtered, and water (200 ml) was added to the filtrate, followed by crystallization at 5-10 ℃ for 2 hours, followed by filtration to give Compound V (13.4g, 33mmol) as a yellow solid in 79% yield.
Preparation of Compound VI
The reaction formula is as follows:
the operation steps are as follows:
mixing a compound I (12.3g, 29.7 mmol), sodium hydride (1.2 g (60 percent content), 29.7 mmol) and anhydrous tetrahydrofuran (96 ml), stirring uniformly, heating to 60-70 ℃, slowly dripping a mixed solution of a compound V (12g, 29.7 mmol) and the anhydrous tetrahydrofuran (96 ml) into a reaction system, and reacting for 2 hours at 60-70 ℃ after the addition. After the reaction solution was cooled to room temperature and water (100 ml) was added thereto and stirred for 10 minutes, ethyl acetate (100 ml) was added thereto and extracted twice, the organic phase was dried over anhydrous sodium sulfate (10 g), filtered, and the filtrate was spin-dried (temperature not higher than 40 ℃ C.) to obtain a colorless viscous liquid (13.82g, 31.4 mmol) with a yield of 72%.
Examples 2 to 4
Examples 2-4 differ from example 1 in the molar ratio of diethylene glycol to p-toluenesulfonyl chloride, the molar ratio of furoic acid to tert-butylhydrazine hydrochloride, the molar ratio of compound II to 1, 3-benzenedimethanol, the molar ratio of compound III to phosphorus tribromide during the reaction, and other reaction conditions were the same as in example 1.
Specifically, the molar ratio of diethylene glycol to p-toluenesulfonyl chloride in example 2 is 1. In example 3, the molar ratio of diethylene glycol to p-toluenesulfonyl chloride is 1, the molar ratio of furoic acid to tert-butylhydrazine hydrochloride is 1. In example 4, the molar ratio of diethylene glycol to p-toluenesulfonyl chloride is 1.5, the molar ratio of furoic acid to tert-butylhydrazine hydrochloride is 1.
The main reaction conditions of the above examples are shown in table 1, and the yields of the respective compounds in the respective examples are shown in table 2.
TABLE 1
TABLE 2
The myocardial perfusion imaging agent precursor, namely 2- (2- ((1- (3- (((1- (tert-butyl) -5-chloro-6-oxo-1, 6-dihydropyridazin-4-yl) oxy) methyl) benzyl) -1H-1,2, 3-triazole-4-yl) methoxy) ethoxy-4-tosylate, is prepared by a novel method, the method adopts diethylene glycol, p-toluenesulfonyl chloride, furoic acid, tert-butylhydrazine hydrochloride, 1, 3-benzenedimethanol, phosphorus tribromide, 1H-1,2, 3-thiazole-4-methanol and other raw materials, the use of explosive sodium azide is avoided, the production safety is increased, the production cost is reduced, and meanwhile, the method can obtain the yield of the target compound of more than 70 percent and is simple to operate.
Claims (17)
1. A process for preparing compound VI, characterized in that compound I is reacted with compound V to give compound VI,
wherein compound VI is shown below:
compound I is shown below:
compound V is shown below:
the compound I and the compound V react in the presence of sodium hydride, the solvent is tetrahydrofuran, and the reaction temperature is 60-70 ℃.
2. The process according to claim 1, characterized in that it comprises a step of reacting compound IV with 1H-1,2, 3-thiazole-4-methanol to obtain compound V:
3. the process according to claim 2, wherein compound IV is reacted with 1H-1,2, 3-thiazole-4-methanol in the presence of a base.
4. The process according to claim 3, wherein the base used for the reaction of compound IV with 1H-1,2, 3-thiazole-4-methanol is potassium carbonate and the solvent is acetone,
5. the process according to claim 2, wherein the reaction temperature of compound IV with 1H-1,2, 3-thiazole-4-methanol is 50 to 60 ℃.
6. A process according to claim 2, characterized in that it comprises a step of reacting compound III with phosphorus tribromide to give compound IV:
7. the method according to claim 6, wherein the solvent used for the reaction of compound III with phosphorus tribromide is toluene, and the reaction temperature is 80-100 ℃.
8. The process according to claim 6, characterized in that it comprises a step of reacting compound II with 1, 3-benzenedimethanol to give compound III:
9. the process of claim 8, wherein compound II is reacted with 1, 3-benzenedimethanol in the presence of a base.
10. The process of claim 9 wherein the base used to react compound II with 1, 3-benzenedimethanol is cesium carbonate and the solvent is acetonitrile.
11. The process of claim 9, wherein the reaction temperature of compound II with 1, 3-benzenedimethanol is in the range of 80 to 90 ℃.
12. The method according to claim 8, characterized in that it comprises the step of reacting furoic acid with tert-butylhydrazine hydrochloride to obtain compound II:
13. the process of claim 12, wherein furfuryl chloric acid is reacted with t-butyl hydrazine hydrochloride at a temperature below 10 ℃ and the resulting product is reacted with glacial acetic acid in dichloromethane at reflux for 4 to 6 hours to provide compound II.
14. The process according to claim 1, further comprising the step of reacting diethylene glycol with p-toluenesulfonyl chloride to give compound I:
15. the process of claim 14, wherein diethylene glycol is reacted with p-toluenesulfonyl chloride in the presence of an acid scavenger and a catalyst.
16. The method of claim 15, wherein the acid scavenger is triethylamine and the catalyst is DMAP.
17. The method according to claim 15, wherein the solvent used for the reaction of diethylene glycol and p-toluenesulfonyl chloride is one or both of dichloromethane and dichloroethane, and the reaction temperature is 20 to 40 ℃.
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