CN115057847B - Preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine - Google Patents
Preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine Download PDFInfo
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- CN115057847B CN115057847B CN202210887462.4A CN202210887462A CN115057847B CN 115057847 B CN115057847 B CN 115057847B CN 202210887462 A CN202210887462 A CN 202210887462A CN 115057847 B CN115057847 B CN 115057847B
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- KWHOJGMFJHLVNN-UHFFFAOYSA-N CC1=NC(Cl)=C(C2OCCO2)C(Cl)=N1 Chemical compound CC1=NC(Cl)=C(C2OCCO2)C(Cl)=N1 KWHOJGMFJHLVNN-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims abstract description 26
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 claims abstract description 12
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 9
- WCQOBLXWLRDEQA-UHFFFAOYSA-N ethanimidamide;hydrochloride Chemical compound Cl.CC(N)=N WCQOBLXWLRDEQA-UHFFFAOYSA-N 0.000 claims abstract description 8
- 238000006243 chemical reaction Methods 0.000 claims description 43
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 39
- 239000012074 organic phase Substances 0.000 claims description 16
- 238000010992 reflux Methods 0.000 claims description 15
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 13
- 150000001875 compounds Chemical class 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 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 10
- 238000001816 cooling Methods 0.000 claims description 10
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 9
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 8
- LTMHNWPUDSTBKD-UHFFFAOYSA-N diethyl 2-(ethoxymethylidene)propanedioate Chemical compound CCOC=C(C(=O)OCC)C(=O)OCC LTMHNWPUDSTBKD-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 5
- 239000000706 filtrate Substances 0.000 claims description 5
- 239000005457 ice water Substances 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 239000000203 mixture Substances 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 238000005406 washing Methods 0.000 claims description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 2
- 238000000605 extraction Methods 0.000 claims description 2
- 238000002386 leaching Methods 0.000 claims description 2
- 239000002994 raw material Substances 0.000 abstract description 6
- 238000003786 synthesis reaction Methods 0.000 abstract description 5
- 238000000746 purification Methods 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 2
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 0.000 abstract 1
- 125000002777 acetyl group Chemical class [H]C([H])([H])C(*)=O 0.000 abstract 1
- -1 ethoxy methylene diethyl Chemical group 0.000 abstract 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 abstract 1
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 27
- 239000000243 solution Substances 0.000 description 18
- 238000004809 thin layer chromatography Methods 0.000 description 6
- 239000008346 aqueous phase Substances 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000001556 precipitation Methods 0.000 description 3
- 230000002035 prolonged effect Effects 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 230000035484 reaction time Effects 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- DOMBYPXLCGLBRD-UHFFFAOYSA-N 4,6-dichloro-2-methylpyrimidine-5-carbaldehyde Chemical compound CC1=NC(Cl)=C(C=O)C(Cl)=N1 DOMBYPXLCGLBRD-UHFFFAOYSA-N 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000006482 condensation reaction Methods 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 239000012450 pharmaceutical intermediate Substances 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
- C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
- C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- 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
Abstract
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine. The invention takes ethoxy methylene diethyl malonate as a raw material, forms acetal with glycol under the action of p-toluenesulfonic acid, and then reacts with acetamidine hydrochloride and phosphorus oxychloride in sequence to form 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine. The invention provides a new route for synthesizing 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methyl pyrimidine, can synthesize 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methyl pyrimidine with high yield and low cost, simplifies post-treatment operation and purification method, and improves yield.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine.
Background
4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine is an important pharmaceutical intermediate. The existing synthesis method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine is that 2-methyl-4, 6-dichloropyrimidine-5-formaldehyde and ethylene glycol are adopted to generate the catalyst through condensation reaction. U.S. Pat. No. 4, 2019194192 and WO2020254451 report the synthesis of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine, respectively, but the synthesis has high material cost, complex post-treatment and purification and low yield.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methyl pyrimidine, which effectively reduces the synthesis cost, simplifies the post-treatment operation and the purification method and improves the yield.
The preparation method of the 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine comprises the following reaction routes:
the method comprises the following specific steps:
(1) Sequentially adding dimethylbenzene and diethyl ethoxymethylene malonate into a reaction bottle under the protection of Ar; sequentially adding ethylene glycol and PTSA, carrying out reflux reaction, cooling after the reaction is finished, adding water, extracting, washing with saturated saline, drying, and concentrating under reduced pressure to obtain a compound I;
(2) Dissolving acetamidine hydrochloride with methanol under Ar protection, cooling to 0-5 ℃, slowly adding sodium methoxide into the solution, stirring at 0-5 ℃ to generate a large amount of white solid, filtering, dropwise adding a methanol solution of a compound I into the filtrate at 25-30 ℃ after finishing the addition, carrying out reflux reaction, cooling, filtering, and leaching to obtain a compound II;
(3) Under Ar protection, phosphorus oxychloride and a compound II are sequentially added into a reaction bottle, reflux reaction is carried out, after the reaction is finished, the temperature is reduced, the mixture is slowly added into ice water, the temperature is controlled to be no more than 15 ℃, the mixture is stirred for 30 minutes at 20-25 ℃ after the addition is finished, extraction is carried out, saturated sodium bicarbonate solution is washed until the pH value is=6-7, an organic phase is obtained through layering, the organic phase is dried by anhydrous sodium sulfate, and is concentrated until a large amount of solids are separated out, and 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine is obtained through filtering.
Preferably, in the step (1), diethyl ethoxymethylene malonate is used in a molar ratio: ethylene glycol: ptsa=1: 4-6:0.1-0.2.
Preferably, in step (2), compound I: acetamidine hydrochloride: sodium methoxide=1: 1-1.2:1.5-2.
The invention provides a new route for synthesizing 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methyl pyrimidine, can synthesize 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methyl pyrimidine with high yield and low cost, simplifies post-treatment operation and purification method, and improves yield.
Drawings
FIG. 1 is a nuclear magnetic resonance spectrum of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine.
Detailed Description
Example 1
A method for preparing 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine, comprising the following steps:
(1) Xylene (1L) and diethyl ethoxymethylene malonate (200 g) were sequentially added to a reaction flask under Ar protection; ethylene glycol (229.64 g), PTSA (15.93 g) was then added sequentially; reflux reaction for 5h, naturally cooling to 25 ℃, adding water (1L), extracting with dichloromethane (500 ml×2 times), back-extracting aqueous phase with dichloromethane (500 ml), mixing organic phases, washing once with saturated salt water (500 ml), drying the organic phases with anhydrous sodium sulfate, concentrating under reduced pressure to obtain 200.3g of yellowish oily compound I, and obtaining 93.3% yield.
(2) Dissolving acetamidine hydrochloride (67.18 g) with methanol (1.2L) under Ar protection, cooling to 0 ℃, slowly adding sodium methoxide (232.64 g) into the solution, stirring at 0 ℃ for 10min, generating a large amount of white solid, filtering, dropwise adding a methanol (300 ml) solution of a compound I (150 g) into the filtrate at 25 ℃ after filtering, carrying out reflux reaction for 3h after the addition, and detecting by TLC to finish the reaction of the raw materials; the reaction solution was cooled to 25 ℃, filtered, rinsed with methanol (75 ml) to give a white solid, which was dried to give 120.7g of compound II as a white powder, yield: 94.3%.
(3) Phosphorus oxychloride (500 ml) and a compound II (100 g) are sequentially added into a reaction bottle under the protection of Ar, reflux reaction is carried out for 5 hours, and TLC detection is carried out to finish the reaction; the reaction solution was cooled to 25 ℃ and slowly added to ice water (2.5L), the temperature was controlled to not more than 15 ℃, stirred for 30 minutes at 20 ℃ after the addition, extracted with dichloromethane (500 ml×3 times), the organic phases were combined, washed with saturated sodium bicarbonate solution to ph=6, the organic phases were separated by layers, dried over anhydrous sodium sulfate, concentrated to a large amount of solid precipitation, filtered to obtain 109.2g of off-white crystals, yield: 92.1%.
Example 2
A method for preparing 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine, comprising the following steps:
(1) Under Ar protection, sequentially adding dimethylbenzene (1L) and diethyl ethoxymethylene malonate (200 g) into a reaction bottle, and layering; ethylene glycol (344.47 g), PTSA (15.93 g) was then added sequentially; reflux reaction is carried out for 6 hours, the detected raw materials are basically reacted, and the reaction time is prolonged to 10 hours without change; the reaction mixture was cooled to room temperature naturally, water (1L) was added, extracted with dichloromethane (500 ml. Times.2), the aqueous phase was back-extracted with dichloromethane (500 ml), the organic phases were combined, washed once with saturated brine (500 ml), and the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 198.1g of compound I as a yellowish oily substance, yield: 92.2%.
(2) Dissolving acetamidine hydrochloride (73.29 g) with methanol (1.2L) under Ar protection, cooling to 0 ℃, slowly adding sodium methoxide (209.4 g) into the solution, stirring at 0 ℃ for 10min, generating a large amount of white solid, filtering, dropwise adding a methanol (300 ml) solution of a compound I (150 g) into the filtrate at 30 ℃ after filtering, carrying out reflux reaction for 4h after the addition, detecting by TLC, and finishing the reaction of the raw materials; the reaction solution was cooled to 30 ℃, filtered, rinsed with methanol (75 ml) to give a white solid, which was dried to give 119.7g of compound II as a white powder, yield: 93.5%.
(3) Under Ar protection, phosphorus oxychloride (400 ml) and a compound II (100 g) are sequentially added into a reaction bottle, reflux reaction is carried out for 5 hours, and TLC detection is carried out to finish the reaction; the reaction solution was cooled to 20 ℃ and slowly added to ice water (2.5L), the temperature was controlled to not more than 15 ℃, stirred for 30 minutes at 20 ℃ after the addition, extracted with dichloromethane (500 ml×3 times), the organic phases were combined, washed with saturated sodium bicarbonate solution to ph=6, the organic phases were separated by layers, dried over anhydrous sodium sulfate, concentrated to a large amount of solid precipitation, filtered to obtain 107.1g of off-white crystals, yield: 90.3%.
Example 3
A method for preparing 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine, comprising the following steps:
(1) Under Ar protection, sequentially adding dimethylbenzene (1L) and diethyl ethoxymethylene malonate (200 g) into a reaction bottle, and layering; ethylene glycol (287.06 g), PTSA (31.6 g) was then added sequentially; reflux reaction is carried out for 7 hours, the detected raw materials are basically reacted, and the reaction time is prolonged to 10 hours without change; the reaction mixture was cooled to room temperature naturally, water (1L) was added, extracted with dichloromethane (500 ml. Times.2), the aqueous phase was back-extracted with dichloromethane (500 ml), the organic phases were combined, washed once with saturated brine (500 ml), and the organic phases were dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 198.4g of compound I as a yellowish oily substance, yield: 92.4%.
(2) Dissolving acetamidine hydrochloride (67.2 g) with methanol (1.2L) under Ar protection, cooling to 5 ℃, slowly adding sodium methoxide (175 g) into the solution, stirring at 5 ℃ for 10min, generating a large amount of white solid, filtering, then dropwise adding a methanol (300 ml) solution of a compound I (150 g) into the filtrate at 30 ℃, carrying out reflux reaction for 3h after the addition, and detecting by TLC (thin layer chromatography), thus finishing the reaction of the raw materials; the reaction solution was cooled to 25 ℃, filtered, rinsed with methanol (75 ml) to give a white solid, which was dried to give 120.9g of compound II as a white powder, yield: 94.4%.
(3) Under Ar protection, phosphorus oxychloride (600 ml) and a compound II (100 g) are sequentially added into a reaction bottle, reflux reaction is carried out for 6 hours, and TLC detection is carried out to finish the reaction; the reaction solution was cooled to 25 ℃ and slowly added to ice water (2.5L), the temperature was controlled to not more than 15 ℃, stirred for 30 minutes at 25 ℃ after the addition, extracted with dichloromethane (500 ml×3 times), the organic phases were combined, washed with saturated sodium bicarbonate solution to ph=7, the organic phases were separated by layers, dried over anhydrous sodium sulfate, concentrated to a large amount of solid precipitation, filtered to obtain 109.4g of off-white crystals, yield: 92.3%.
Claims (4)
1. A preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine is characterized by comprising the following reaction routes:
2. the preparation method of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine according to claim 1, which is characterized by comprising the following specific steps:
(1) Sequentially adding dimethylbenzene and diethyl ethoxymethylene malonate into a reaction bottle under the protection of Ar; sequentially adding ethylene glycol and PTSA, carrying out reflux reaction, cooling after the reaction is finished, adding water, extracting, washing with saturated saline, drying, and concentrating under reduced pressure to obtain a compound I;
(2) Dissolving acetamidine hydrochloride with methanol under Ar protection, cooling to 0-5 ℃, slowly adding sodium methoxide into the solution, stirring at 0-5 ℃ to generate a large amount of white solid, filtering, dropwise adding a methanol solution of a compound I into the filtrate at 25-30 ℃ after finishing the addition, carrying out reflux reaction, cooling, filtering, and leaching to obtain a compound II;
(3) Under Ar protection, phosphorus oxychloride and a compound II are sequentially added into a reaction bottle, reflux reaction is carried out, after the reaction is finished, the temperature is reduced, the mixture is slowly added into ice water, the temperature is controlled to be no more than 15 ℃, the mixture is stirred for 30 minutes at 20-25 ℃ after the addition is finished, extraction is carried out, saturated sodium bicarbonate solution is washed until the pH value is=6-7, an organic phase is obtained through layering, the organic phase is dried by anhydrous sodium sulfate, and is concentrated until a large amount of solids are separated out, and 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine is obtained through filtering.
3. The process for the preparation of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine according to claim 1, wherein in step (1), diethyl ethoxymethylene malonate is used in a molar ratio: ethylene glycol: ptsa=1: 4-6:0.1-0.2.
4. The process for the preparation of 4, 6-dichloro-5- (1, 3-dioxolan-2-yl) -2-methylpyrimidine according to claim 1, wherein in step (2), compound I: acetamidine hydrochloride: sodium methoxide=1: 1-1.2:1.5-2.
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| CN102432547A (en) * | 2011-11-22 | 2012-05-02 | 太仓市运通化工厂 | Method for synthetizing 4,6-dichloro-2-methyl pyridine |
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| WO2020254451A1 (en) * | 2019-06-19 | 2020-12-24 | Boehringer Ingelheim International Gmbh | Anticancer combination therapy |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| SI3728254T1 (en) * | 2017-12-21 | 2023-06-30 | Boehringer Ingelheim International Gmbh | Benzylamino substituted pyridopyrimidinones and derivatives as sos1 inhibitors |
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| CN101180294A (en) * | 2005-05-25 | 2008-05-14 | 默克专利股份有限公司 | Pyran/dioxan derivatives and use thereof in liquid crystal media |
| CN101180295A (en) * | 2005-05-25 | 2008-05-14 | 默克专利股份有限公司 | Tetrahydropyrane derivatives comprising several rings containing oxygen and method for the production thereof |
| CN102432547A (en) * | 2011-11-22 | 2012-05-02 | 太仓市运通化工厂 | Method for synthetizing 4,6-dichloro-2-methyl pyridine |
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