CN110283059A - A kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method - Google Patents
A kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method Download PDFInfo
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- CN110283059A CN110283059A CN201910490317.0A CN201910490317A CN110283059A CN 110283059 A CN110283059 A CN 110283059A CN 201910490317 A CN201910490317 A CN 201910490317A CN 110283059 A CN110283059 A CN 110283059A
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- compound
- hydrogen
- indanone
- dihydro
- fluoro
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/45—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation
- C07C45/455—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by condensation with carboxylic acids or their derivatives
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
- C07C45/61—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups
- C07C45/64—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by reactions not involving the formation of >C = O groups by introduction of functional groups containing oxygen only in singly bound form
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/36—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by hydrogenation of carbon-to-carbon unsaturated bonds
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
- C07C51/363—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2602/00—Systems containing two condensed rings
- C07C2602/02—Systems containing two condensed rings the rings having only two atoms in common
- C07C2602/04—One of the condensed rings being a six-membered aromatic ring
- C07C2602/08—One of the condensed rings being a six-membered aromatic ring the other ring being five-membered, e.g. indane
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Abstract
The present invention relates to a kind of -1 hydrogen of fluoro- 5- hydroxyl -2, the 3- dihydro of 7- -1-Indanone synthetic methods, the technical issues of mainly solution currently without suitable Industrialized synthesis method.The first step, it is reacted in solvent pyridine by compound 1, malonic acid, piperidines first and obtains compound 2, second step, compound 2 is dissolved in tetrahydrofuran progress hydrogenation under the catalysis of palladium charcoal and obtains compound 3, third step, compound 3 carry out retaining ring under polyphosphoric acids effect and react to obtain compound 4, the 4th step, compound 4 obtains -1 hydrogen of fluoro- 5- hydroxyl -2, the 3- dihydro of 7- -1-Indanone in the case where sodium hydroxide, calcium hydroxide and water do solvent refluxing effect.
Description
Technical field
The present invention relates to -1 hydrogen of the fluoro- 5- hydroxyl -2,3- dihydro of compound 7- -1-Indanone synthetic methods.
Background technique
- 1 hydrogen of the fluoro- 5- hydroxyl -2,3- dihydro of compound 7- -1-Indanone (MFCD09908164) and relevant derivative exist
Have in pharmaceutical chemistry and organic synthesis and is widely applied.- 1 hydrogen of the fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method at present
Rarely has document report.It is easy to operate therefore, it is necessary to develop a raw material to be easy to get, react easily controllable, overall yield is suitble to, and fits
Close the synthetic method of industrialized production.
Summary of the invention
It is easy to operate the purpose of the present invention is developing one kind to be easy to get with raw material, react easily controllable, the higher 7- of yield
- 1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro -1-Indanone synthetic method.It mainly solves currently without suitable Industrialized synthesis method
Technical problem.
Technical solution of the present invention: a kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method, this hair
Bright point of 4 steps, the first step are reacted in solvent pyridine by compound 1, malonic acid, piperidines obtain compound 2 first, second step, are changed
Conjunction object 2 is dissolved in tetrahydrofuran progress hydrogenation under the catalysis of palladium charcoal and obtains compound 3, and third step, compound 3 is in polyphosphoric acids
The lower progress retaining ring of effect reacts to obtain compound 4, the 4th step, and compound 4 does solvent refluxing in sodium hydroxide, calcium hydroxide and water
Final compound 5 is obtained under effect.Reaction equation is as follows:
The first step is 100 DEG C of 2 hours of reaction；Second step, the condition of catalytic hydrogenation are 25 DEG C, 50psi, 16 hours；Third step
Reaction temperature is 80 DEG C, the reaction time 2 hours；4th 100 DEG C of step back flow reaction, 3 hours.
The Chinese paraphrase that the present invention abridges: THF: tetrahydrofuran；PPA: polyphosphoric acids.
Beneficial effects of the present invention: reaction process of the present invention design rationally, which employs be easy to get, can large-scale production original
Expect 3,5- difluorobenzaldehyde, synthesize -1 hydrogen of fluoro- 5- hydroxyl -2, the 3- dihydro of 7- -1-Indanone by 4 steps, this method route is short, receives
Rate may be up to 32%, and reaction is easy to amplify, easy to operate.
Specific embodiment
Reaction equation of the present invention is as follows:
Embodiment 1:
By compound 1(500 g, 3.52 mol), malonic acid (823 g, 7.92 mol) and piperidines (248 g, 2.92
Mol it) is slowly added batch-wise and dissolves in pyridine (5 L), then 100o2 hours, TLC (methylene chloride/methanol body are reacted under C
Product ratio=10/1) display end of reaction.Reaction system is cooled to 25 DEG C, then drying is concentrated to get crude Compound 2
(638 g).
Compound 2 (117 kg, 638 mol) is dissolved in ethyl alcohol (1.2 L), the wet palladium charcoal of water content 50% is then added
(12 g) is passed through hydrogen for system and carries out displacement three times, and Hydrogen Vapor Pressure 50psi, 25 DEG C are reacted 16 hours.TLC (dichloromethane
Alkane/methanol volume ratio=10/1) display end of reaction.Reaction filtering, filtrate are concentrated to get crude Compound 3((692 g).
Polyphosphoric acids (1.00 kg) is added into reaction flask in 80 DEG C of heating, then compound 3 (300 g,
1.61mmol) is added, and waits reactants all to add and finishes, then temperature control is in 80 DEG C of 2 hours of reaction, TLC (methylene chloride/methanol
Volume ratio=20/1) display end of reaction.Reaction system is cooled to 25 DEG C, water (5 L) and tertbutyl methyl is then added
Ether (1.5L*3) is extracted, organic phase 5% potassium hydroxide of mass percentage concentration (2.5 L) water washing, then dry concentration
Obtain crude Compound 4(155 g).
Compound 4 (204 g, 1.21 mol) is dissolved in water (2.2 L), be slowly added into sodium hydroxide (48.5 g,
1.21 mol) and calcium hydroxide (89.8 g, 1.21 mol), in 100 DEG C of 3 hours of reaction, TLC (ethyl acetate) display
Reaction system is cooled to 25 DEG C by end of reaction, and the hydrochloric acid that (100 mL) 4M is added, which is broken, to go out, and concentration removes a large amount of solvents, then
Concentration mixes sample progress column Chromatographic purification and obtains compound 5 (68 g) yield 32.05%, while also obtaining by-product 5A (22 g)
Yield 10.70%.
1 ET12994-21-P1R CDCl3 Varian_Y_400MHz
δ 9.23 (br s, 1H), 6.57 (td, J=0.9, 8.5 Hz, 1H), 6.40 (dd, J=1.8, 10.6
Hz, 1H), 3.08 - 2.98 (m, 1H), 2.71 - 2.63 (m, 1H)。
Claims (5)
1. -1 hydrogen of a kind of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method, it is characterized in that: the following steps are included:
One step, is reacted in solvent pyridine by compound 1, malonic acid, piperidines obtain compound 2, second step first, and compound 2 is dissolved in
Tetrahydrofuran carries out hydrogenation under the catalysis of palladium charcoal and obtains compound 3, third step, compound 3 under polyphosphoric acids effect into
Row retaining ring reacts to obtain compound 4, the 4th step, and compound 4 is obtained in the case where sodium hydroxide, calcium hydroxide and water do solvent refluxing effect
To final compound 5；Reaction equation is as follows:
。
2. a kind of-1 hydrogen of fluoro- 5- hydroxyl-2, the 3- dihydro of 7- according to claim 1-1-Indanone synthetic method, special
Sign is: 100 DEG C of the first step are reacted 2 hours.
3. a kind of-1 hydrogen of fluoro- 5- hydroxyl-2, the 3- dihydro of 7- according to claim 1-1-Indanone synthetic method, special
Sign is: 25 DEG C of second step reaction temperature, pressure 50psi, the reaction time 16 hours.
4. a kind of-1 hydrogen of fluoro- 5- hydroxyl-2, the 3- dihydro of 7- according to claim 1-1-Indanone synthetic method, special
Sign is: 80 DEG C of third step are reacted 2 hours.
5. a kind of-1 hydrogen of fluoro- 5- hydroxyl-2, the 3- dihydro of 7- according to claim 1-1-Indanone synthetic method, special
Sign is: the 4th 100 DEG C of step back flow reaction 3 hours.
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| CN201910490317.0A CN110283059A (en) | 2019-06-06 | 2019-06-06 | A kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method |
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| CN201910490317.0A CN110283059A (en) | 2019-06-06 | 2019-06-06 | A kind of -1 hydrogen of fluoro- 5- hydroxyl -2,3- dihydro of 7- -1-Indanone synthetic method |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114621070A (en) * | 2022-04-02 | 2022-06-14 | 上海陶术生物科技有限公司 | Synthesis method of 3, 4-dihydronaphthalene-1 (2H) -ketone derivative |
Citations (3)
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| JP2915465B2 (en) * | 1990-02-07 | 1999-07-05 | 日本カーバイド工業株式会社 | Process for producing 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid and 2,3,5,6-tetrafluorophenol |
| CN101293820A (en) * | 2007-04-27 | 2008-10-29 | 天津药明康德新药开发有限公司 | Process for synthesizing 5-trifluoromethyl-1-indene ketone |
| CN103012086A (en) * | 2011-09-26 | 2013-04-03 | 江西阿尔法高科药业有限公司 | Method for preparing 2,3-dihydro-1-indanone and derivative thereof |
-
2019
- 2019-06-06 CN CN201910490317.0A patent/CN110283059A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2915465B2 (en) * | 1990-02-07 | 1999-07-05 | 日本カーバイド工業株式会社 | Process for producing 4-hydroxy-2,3,5,6-tetrafluorobenzoic acid and 2,3,5,6-tetrafluorophenol |
| CN101293820A (en) * | 2007-04-27 | 2008-10-29 | 天津药明康德新药开发有限公司 | Process for synthesizing 5-trifluoromethyl-1-indene ketone |
| CN103012086A (en) * | 2011-09-26 | 2013-04-03 | 江西阿尔法高科药业有限公司 | Method for preparing 2,3-dihydro-1-indanone and derivative thereof |
Non-Patent Citations (4)
| Title |
|---|
| DAVID S. BROWN等: "Epoxidation with dioxiranes derived from 2-fluoro-2-substituted-1-tetralones and -1-indanones", 《TETRAHEDRON》 * |
| ZHANG XIAOBO等: "A Practical Synthesis of 2′-Fluoro- 4′- hydroxyacetophenone", 《ORGANIC PREPARATIONS AND PROCEDURES INTERNATIONAL》 * |
| ZIEGLER CB等: "SYNTHESIS AND ANTIBACTERIAL ACTIVITY OF SOME 7-SUBSTITUTED 1-ETHYL-6-FLUORO-1,4-DIHYDRO-4-OXOQUINOLINE-3-CARBOXYLIC ACIDS - ETHERS, SECONDARY-AMINES AND SULFIDES AS C-7 SUBSTITUENTS", 《JOURNAL OF HETEROCYCLIC CHEMISTRY》 * |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114621070A (en) * | 2022-04-02 | 2022-06-14 | 上海陶术生物科技有限公司 | Synthesis method of 3, 4-dihydronaphthalene-1 (2H) -ketone derivative |
| CN114621070B (en) * | 2022-04-02 | 2024-03-19 | 上海陶术生物科技有限公司 | Synthesis method of 3, 4-dihydronaphthalene-1 (2H) -one derivative |
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