CN115947768A - Preparation method of azxifuding intermediate - Google Patents
Preparation method of azxifuding intermediate Download PDFInfo
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- CN115947768A CN115947768A CN202310159421.8A CN202310159421A CN115947768A CN 115947768 A CN115947768 A CN 115947768A CN 202310159421 A CN202310159421 A CN 202310159421A CN 115947768 A CN115947768 A CN 115947768A
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- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- 238000006243 chemical reaction Methods 0.000 claims abstract description 35
- 150000001875 compounds Chemical class 0.000 claims abstract description 31
- 238000000034 method Methods 0.000 claims abstract description 13
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 42
- 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 26
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical group ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 12
- 239000000203 mixture Substances 0.000 claims description 10
- CHNLPLHJUPMEOI-UHFFFAOYSA-N oxolane;trifluoroborane Chemical compound FB(F)F.C1CCOC1 CHNLPLHJUPMEOI-UHFFFAOYSA-N 0.000 claims description 10
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 9
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 9
- 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 9
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 150000001347 alkyl bromides Chemical class 0.000 claims description 7
- RDHPKYGYEGBMSE-UHFFFAOYSA-N bromoethane Chemical compound CCBr RDHPKYGYEGBMSE-UHFFFAOYSA-N 0.000 claims description 7
- 230000035484 reaction time Effects 0.000 claims description 7
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 6
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 150000001351 alkyl iodides Chemical class 0.000 claims description 5
- 229910015900 BF3 Inorganic materials 0.000 claims description 4
- 239000004215 Carbon black (E152) Substances 0.000 claims description 4
- 150000001265 acyl fluorides Chemical class 0.000 claims description 4
- DMEGYFMYUHOHGS-UHFFFAOYSA-N cycloheptane Chemical compound C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 4
- 229930195733 hydrocarbon Natural products 0.000 claims description 4
- 150000002430 hydrocarbons Chemical class 0.000 claims description 4
- GDOPTJXRTPNYNR-UHFFFAOYSA-N methylcyclopentane Chemical compound CC1CCCC1 GDOPTJXRTPNYNR-UHFFFAOYSA-N 0.000 claims description 4
- 239000003960 organic solvent Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 3
- 150000001263 acyl chlorides Chemical class 0.000 claims description 3
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 3
- WMFABESKCHGSRC-UHFFFAOYSA-N propanoyl fluoride Chemical compound CCC(F)=O WMFABESKCHGSRC-UHFFFAOYSA-N 0.000 claims description 3
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 2
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 239000000543 intermediate Substances 0.000 claims 9
- 125000000218 acetic acid group Chemical group C(C)(=O)* 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 17
- 230000015572 biosynthetic process Effects 0.000 abstract description 15
- 239000003153 chemical reaction reagent Substances 0.000 abstract description 7
- 239000003814 drug Substances 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 238000011031 large-scale manufacturing process Methods 0.000 abstract description 2
- DMLAVOWQYNRWNQ-UHFFFAOYSA-N azobenzene Chemical compound C1=CC=CC=C1N=NC1=CC=CC=C1 DMLAVOWQYNRWNQ-UHFFFAOYSA-N 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 230000000052 comparative effect Effects 0.000 description 6
- 238000004821 distillation Methods 0.000 description 6
- AOMUALOCHQKUCD-UHFFFAOYSA-N dodecyl 4-chloro-3-[[3-(4-methoxyphenyl)-3-oxopropanoyl]amino]benzoate Chemical group CCCCCCCCCCCCOC(=O)C1=CC=C(Cl)C(NC(=O)CC(=O)C=2C=CC(OC)=CC=2)=C1 AOMUALOCHQKUCD-UHFFFAOYSA-N 0.000 description 6
- 239000012044 organic layer Substances 0.000 description 6
- 239000012074 organic phase Substances 0.000 description 6
- 239000011541 reaction mixture Substances 0.000 description 6
- -1 2-deoxy-2-fluoro-1, 3, 5-tribenzoyl-alpha-D-arabinofuranose Chemical compound 0.000 description 4
- CSJLBAMHHLJAAS-UHFFFAOYSA-N diethylaminosulfur trifluoride Chemical compound CCN(CC)S(F)(F)F CSJLBAMHHLJAAS-UHFFFAOYSA-N 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- KTOLOIKYVCHRJW-XZMZPDFPSA-N 4-amino-1-[(2r,3s,4r,5r)-5-azido-3-fluoro-4-hydroxy-5-(hydroxymethyl)oxolan-2-yl]pyrimidin-2-one Chemical compound O=C1N=C(N)C=CN1[C@H]1[C@@H](F)[C@H](O)[C@](CO)(N=[N+]=[N-])O1 KTOLOIKYVCHRJW-XZMZPDFPSA-N 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000003682 fluorination reaction Methods 0.000 description 3
- 238000009776 industrial production Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- RAHZWNYVWXNFOC-UHFFFAOYSA-N Sulphur dioxide Chemical compound O=S=O RAHZWNYVWXNFOC-UHFFFAOYSA-N 0.000 description 2
- 230000007613 environmental effect Effects 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- RAXXELZNTBOGNW-UHFFFAOYSA-N imidazole Natural products C1=CNC=N1 RAXXELZNTBOGNW-UHFFFAOYSA-N 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 1
- 108010078851 HIV Reverse Transcriptase Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000004334 fluoridation Methods 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000269 nucleophilic effect Effects 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
Classifications
-
- 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
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention belongs to the field of organic synthesis, particularly relates to the technical field of organic drug synthesis, and more particularly relates to a preparation method of an azofume midbody. The method has the advantages of mild reaction conditions, low cost of used reagents, high safety, simple preparation process, high yield of the target compound and high purity, and is suitable for industrial large-scale production.
Description
Technical Field
The invention belongs to the field of organic synthesis, particularly relates to the technical field of organic drug synthesis, and more particularly relates to a preparation method of an azloff midbody.
Background
Azvudine (Azvudine), also known as Azvudine, was invented by professor of junzheng jun and developed jointly by the high and new technology research center of the university of Zheng Zhou, the university of Henan province, and the college of sciences of Henan province. It is an HIV Reverse Transcriptase (RT) inhibitor, belonging to a new generation AIDS treatment drug which is advanced in the world and initiated in China.
2-deoxy-2-fluoro-1, 3, 5-tribenzoyl-alpha-D-arabinofuranose is a key intermediate for synthesizing an azlactone compound, and the chemical structural formula is as follows:
CN 101531695 discloses a preparation method of the compound:
the method comprises the steps of activating hydroxyl at the 2-position of a compound by imidazole sulfonyl, and then carrying out nucleophilic fluorination by using HF or tetrabutylammonium fluoride as a fluorinating reagent to obtain a target compound. The method has the advantages of low yield, more byproducts and difficult purification of the product, and the final product has low purity and is not suitable for industrial production. In addition, HF is used in the reaction, is gas at normal pressure, is extremely toxic and highly corrosive, and simultaneously tetrabutylammonium fluoride is expensive, so that the production cost is high, and the yield of the reaction participating in the fluorination reaction is low.
Another preparation method of the intermediate compound is disclosed in CN 101555267:
in this method, the objective compound can be obtained in one step by a fluoridation reagent DAST (diethylaminosulfur trifluoride). However, the fluoro reagent is liquid and extremely unstable, releases a large amount of highly toxic sulfur dioxide and HF gas after being decomposed in water, has serious environmental pollution, and is very easy to explode when colliding or at high temperature in the production, storage and transportation processes. Meanwhile, the fluoro reagent has strong corrosivity, high requirements on equipment and high difficulty in realizing industrial production, and is expensive in purchase price and high in production cost due to high production difficulty.
In summary, for those skilled in the art, it is a hot and difficult problem to provide a preparation method with low cost, high yield, safety and environmental protection for the fluorination of 2-hydroxyl in the synthesis of 2-deoxy-2-fluoro-1, 3, 5-tribenzoyl- α -D-arabinofuranose.
Disclosure of Invention
The technical problem to be solved by the invention is to provide a preparation method of 2-deoxy-2-fluoro-1, 3, 5-tribenzoyl-alpha-D-arabinofuranose of an azloff midbody, so that the industrial production requirements of low cost, high yield, safety and environmental protection can be met.
In order to solve the technical problems, the invention discloses a preparation method of an azloff midbody, the synthetic route of which is as follows,
wherein R is methyl or ethyl;
the preparation method specifically comprises the following steps:
(a) Adding alkyl bromide or alkyl iodide into a mixture of the compound III, potassium hydroxide and an organic solvent to prepare a compound II; preferably, the organic solvent is dichloromethane, tetrahydrofuran or toluene;
(b) Adding a boron trifluoride coordination compound into a mixture of a compound II, acyl chloride and a hydrocarbon solvent to prepare a compound I;
the potassium hydroxide is solid potassium hydroxide.
Preferably, in step (a), the alkyl bromide is ethyl bromide and the alkyl iodide is methyl iodide.
Further preferably, in step (a), the molar ratio of compound iii, alkyl bromide or iodide, and potassium hydroxide is 1 to 3.
Further preferably, in step (a), the reaction temperature is 40 to 100 ℃, including but not limited to 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃,65 ℃, 70 ℃, 75 ℃, 80 ℃, 85 ℃, 90 ℃, 95 ℃ or 100 ℃, in a preferred embodiment, the reaction temperature is 80 ℃.
Further preferably, in step (a), the reaction time is 4 to 12 hours, including but not limited to 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours or 12 hours, and in a preferred embodiment, the reaction time is 7 hours.
Preferably, in the step (b), the boron trifluoride complex compound is a boron trifluoride tetrahydrofuran complex compound.
More preferably, the molar ratio of the compound ii to the boron trifluoride tetrahydrofuran complex is 1.
Further preferably, in the step (b), the hydrocarbon solvent is one selected from n-hexane, cyclohexane, n-heptane, cycloheptane and methylcyclopentane.
Further preferably, in step (b), the acyl fluoride is acetyl fluoride or propionyl fluoride.
More preferably, the molar ratio of the compound II to the acyl fluoride is 1 to 2.
Further, in step (b), the reaction temperature is-20 to 20 ℃, and may be, but is not limited to, -20 ℃, -15 ℃, -10 ℃, -5 ℃, 0 ℃,5 ℃,10 ℃,15 ℃ or 20 ℃, and in a preferred embodiment, the reaction temperature is-10 ℃.
Further, in the step (b), the reaction time is 8 to 16h, and may be, but is not limited to, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h or 16h, and in a preferred embodiment, the reaction time is 12h.
The invention prepares a target product compound I by reacting a compound III with alkyl bromide or alkyl iodide to form a compound II and then reacting with acyl chloride. The method has the advantages of mild reaction conditions, low cost of used reagents, high safety, simple preparation process, high yield of the target compound and high purity, and is suitable for industrial large-scale production.
Detailed Description
In order that the invention may be better understood, we now provide further explanation of the invention with reference to specific examples.
Unless otherwise specified, the reagents used in the examples of the present invention are all common commercial products.
Example 1
(a) Synthesis of Compound II:
to a reaction vessel were added compound III (50g, 108mmol), solid potassium hydroxide (3.65g, 65mmol) and 100ml dichloromethane, and the mixture was stirred until complete dissolution. Bromoethane (5.88g, 54mmol) was then added and stirred at 80 ℃ for 7h. After completion of the reaction, it was cooled to room temperature (about 25 ℃ C.), filtered, and the organic phase was separated and dried by distillation to obtain 25.38g of compound II in a yield of 95.8% and a purity of 99.6%.
(b) Synthesis of Compound I:
adding the compound II (25g, 51mmol) prepared in the step (a), acetyl fluoride (4.7g, 76.5mmol) and 50ml of n-hexane into a reaction bottle, cooling to-10 ℃, and stirring to dissolve completely. Then, boron trifluoride tetrahydrofuran complex (1.4 g, 10.2mmol) was added by syringe and stirred at-10 ℃ for 12 hours. After the reaction was completed, water was added to the reaction mixture, the organic layer was separated, dried over anhydrous sodium sulfate, and then rectified to obtain 22g of compound I, with a yield of 92.8% and a purity of 99.5%.
Example 2
(a) Synthesis of Compound II:
to a reaction vessel were added compound III (50g, 108mmol), solid potassium hydroxide (6.06g, 108mmol) and 100ml tetrahydrofuran, and the mixture was stirred until completely dissolved. Bromoethane (11.77g, 108mmol) was then added and stirred at 40 ℃ for 12h. After completion of the reaction, it was cooled to room temperature (about 25 ℃ C.), filtered, and the organic phase was separated and dried by distillation to give 48.95g of compound II in 92.4% yield and 99.3% purity.
(b) Synthesis of Compound I:
to a reaction flask were added compound II prepared in step (a) (25g, 51mmol), acetyl fluoride (3.2g, 51mmol) and 50ml cyclohexane, cooled to-20 ℃ and stirred to dissolve completely. Then, boron trifluoride tetrahydrofuran complex (2.1g, 15.3 mmol) was added by syringe and stirred at-20 ℃ for 8 hours. After the reaction was completed, water was added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and then rectified to obtain 21.22g of compound I, the yield was 89.6%, and the purity was 99.4%.
Example 3
(a) Synthesis of Compound II:
to a reaction vessel, compound III (50g, 108mmol), solid potassium hydroxide (3.03g, 54mmol) and 100ml toluene were added and the mixture was stirred until completely dissolved. Methyl iodide (5.11g, 36mmol) was then added and stirred at 100 ℃ for 4h. After completion of the reaction, it was cooled to room temperature (about 25 ℃ C.), filtered, and the organic phase was separated and dried by distillation to obtain 15.49g of compound II, yield 90.3%, purity 99.2%.
(b) Synthesis of Compound I:
to a reaction flask were added compound II prepared in step (a) (24.3g, 51mmol), propionyl fluoride (7.8g, 102mmol) and 50ml n-heptane, cooled to 20 ℃ and stirred for total dissolution. Then, boron trifluoride tetrahydrofuran complex (0.7 g,5.1 mmol) was added by means of a syringe and stirred at 20 ℃ for 16 hours. After the reaction was completed, water was added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and then rectified to obtain 20.8g of compound I, with a yield of 87.8% and a purity of 99.1%.
Comparative example 1
(a) Synthesis of Compound II:
to a reaction vessel, compound III (100g, 216mmol), solid potassium hydroxide (3.65g, 65mmol) and 100ml dichloromethane were added and the mixture was stirred until completely dissolved. Bromoethane (5.88g, 54mmol) was then added and stirred at 80 ℃ for 7h. After completion of the reaction, it was cooled to room temperature (about 25 ℃ C.), filtered, and the organic phase was separated and dried by distillation to give 22.7g of compound II in 85.7% yield and 94.5% purity.
Comparative example 2
(a) Synthesis of Compound II:
to a reaction vessel were added compound III (50g, 108mmol), solid potassium hydroxide (6.06g, 108mmol) and 100ml dichloromethane, and the mixture was stirred until completely dissolved. Bromoethane (5.88g, 54mmol) was then added and stirred at 80 ℃ for 7h. After completion of the reaction, it was cooled to room temperature (about 25 ℃ C.), filtered, and the organic phase was separated and dried by distillation to give 23.18g of Compound II in 87.5% yield with a purity of 96.2%.
Comparative example 3
Synthesis of Compound II:
to a reaction vessel were added compound III (50g, 108mmol), solid potassium hydroxide (3.65g, 65mmol) and 100ml dichloromethane, and the mixture was stirred until complete dissolution. Bromoethane (5.88g, 54mmol) was then added and stirred at 20 ℃ for 7h. After completion of the reaction, it was cooled to room temperature (about 25 ℃ C.), filtered, and the organic phase was separated and dried by distillation to obtain 21.53g of compound II in 81.3% yield and 92.5% purity.
Comparative example 4
Synthesis of Compound I:
to a reaction flask were added compound II (25g, 51mmol) prepared in step (a) of example 1, acetyl fluoride (1.6 g,25.5 mmol) and 50ml of n-hexane, cooled to-10 ℃ and stirred to dissolve completely. Then, boron trifluoride tetrahydrofuran complex (1.4g, 10.2mmol) was added by means of a syringe and stirred at-10 ℃ for 12 hours. After the reaction was completed, water was added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and then rectified to obtain 8g of compound I, with a yield of 67.4% and a purity of 93.6%.
Comparative example 5
Synthesis of Compound I:
to a reaction flask were added compound II (25g, 51mmol) prepared in step (a) of example 1, acetyl fluoride (4.7 g,76.5 mmol) and 50ml of n-hexane, cooled to-10 ℃ and stirred to dissolve completely. Then, boron trifluoride tetrahydrofuran complex (0.36g, 2.55mmol) was added using a syringe and stirred at-10 ℃ for 12 hours. After the reaction was completed, water was added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and then rectified to obtain 17.55g of compound I, with a yield of 74.1% and a purity of 91.5%.
Comparative example 6
Synthesis of Compound I:
to a reaction flask were added compound II (25g, 51mmol) prepared in step (a) of example 1, acetyl fluoride (4.7 g,76.5 mmol) and 50ml of n-hexane, cooled to 30 ℃ and stirred to dissolve completely. Then, boron trifluoride tetrahydrofuran complex (1.4g, 10.2mmol) was added by means of a syringe and stirred at 30 ℃ for 12 hours. After the reaction was completed, water was added to the reaction mixture, and the organic layer was separated, dried over anhydrous sodium sulfate, and then rectified to obtain 19.33g of compound I, with a yield of 81.6% and a purity of 95.2%.
What has been described above is a specific embodiment of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principle of the present invention, and such improvements and modifications are also considered to be within the scope of the present invention.
Claims (10)
1. A preparation method of an Alzheimer intermediate is characterized in that the synthetic route is as follows,
wherein R is methyl or ethyl;
the preparation method specifically comprises the following steps:
(a) Adding alkyl bromide or alkyl iodide into a mixture of the compound III, potassium hydroxide and an organic solvent to prepare a compound II; preferably, the organic solvent is dichloromethane, tetrahydrofuran or toluene;
(b) Adding a boron trifluoride coordination compound into a mixture of a compound II, acyl chloride and a hydrocarbon solvent to prepare a compound I;
the potassium hydroxide is solid potassium hydroxide.
2. The process for the preparation of an azxifuding intermediate according to claim 1, wherein in step (a), the alkyl bromide is preferably ethyl bromide and the alkyl iodide is preferably methyl iodide.
3. The process for preparing an azofumesate intermediate according to claim 1, wherein in step (a), the molar ratio of compound iii, alkyl bromide or iodide, potassium hydroxide is 1 to 3.
4. The process for the preparation of an azxiv intermediate according to claim 1, wherein in step (a), the reaction temperature is 40 to 100 ℃, more preferably 80 ℃.
5. The process for the preparation of an azxiv intermediate according to claim 1, wherein in step (a), the reaction time is between 4 and 12 hours, more preferably the reaction time is 7 hours.
6. The process for producing an azimuths intermediate according to claim 1, wherein in step (b), the boron trifluoride complex compound is a boron trifluoride tetrahydrofuran complex compound; more preferably, the molar ratio of the compound II to the boron trifluoride tetrahydrofuran complex is 1.
7. The method for producing an azxiv intermediate according to claim 1, wherein in step (b), the hydrocarbon-based solvent is one of n-hexane, cyclohexane, n-heptane, cycloheptane or methylcyclopentane.
8. The process for the preparation of azxivudine intermediates of claim 1, wherein in step (b), the acyl fluoride is acetyl or propionyl fluoride; preferably, the molar ratio of the compound II to the acyl fluoride is 1 to 2.
9. The process for the preparation of an azofumesate according to claim 1, characterized in that in step (b) the reaction temperature is between-20 ℃ and 20 ℃, further preferably the reaction temperature is-10 ℃.
10. The process for the preparation of an azxiv intermediate according to claim 1, wherein in step (b), the reaction time is between 8 and 16h, more preferably between 12h.
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| CN101555267A (en) * | 2008-04-09 | 2009-10-14 | 杭州容立医药科技有限公司 | Synthesis method of clofarabine of nucleoside analogues |
| CN102000103A (en) * | 2009-12-21 | 2011-04-06 | 郑州大学 | Medicinal application of 2'-fluoro-4'-nitrine-nucleoside analogues or salt thereof |
| CN102675381A (en) * | 2011-11-17 | 2012-09-19 | 中国药科大学 | Preparation method of 1-brom-2-deoxy-2-fluoro-3, 5-di-oxo-benzoyl-alpha-D-arabinose |
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