CN102241572A - Preparation method and application of aromatic cyclopropyl butanone compound - Google Patents
Preparation method and application of aromatic cyclopropyl butanone compound Download PDFInfo
- Publication number
- CN102241572A CN102241572A CN2010101728484A CN201010172848A CN102241572A CN 102241572 A CN102241572 A CN 102241572A CN 2010101728484 A CN2010101728484 A CN 2010101728484A CN 201010172848 A CN201010172848 A CN 201010172848A CN 102241572 A CN102241572 A CN 102241572A
- Authority
- CN
- China
- Prior art keywords
- compound
- formula
- ethyl ketone
- preparation
- cyclopropyl
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 0 *N(C(C1CC1)=O)O* Chemical compound *N(C(C1CC1)=O)O* 0.000 description 2
Landscapes
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to the chemical technical field of carbocyclic rings, in particular to a preparation method and application of an aromatic cyclopropyl butanone compound. The preparation method comprises the following steps of: making a compound shown as a formula (a) react with a magnesium elementary substance to obtain a Grignard reagent; undergoing a Grignard reaction on a compound shown as a formula (b) to obtain an aromatic cyclopropyl butanone compound, i.e., a compound shown as a formula (c), wherein the aromatic cyclopropyl butanone compound can be used for preparing a tetrahydrothienopyridine derivative; and when R1 is a two-potential fluorine atom, the compound shown as the formula (c) is an important intermediate for preparing Prasugrel. The structural formula of the related compound is shown in the specifications, wherein R1 refers to F, Cl, alkyl with 1-4 carbon atoms or alkoxy with 1-4 carbon atoms; R2 and R3 refer to alkyls; and X refers to Cl or Br.
Description
Technical field
The present invention relates to organic chemistry filed, particularly the carbocyclic ring technical field of chemistry.
Background technology
Aromatic nucleus propyl group ethyl ketone compounds is the important intermediate of tetrahydrobiopterin synthesis thienopyridine derivative, wherein at present more important tetramethylene sulfide and pyridine derivate are prasugrel (Prasugrel) chemistry 2-acetoxyl group-5-(a-cyclopropyl carbonyl-2-luorobenzyl)-4 by name, 5,6,7-tetramethylene sulfide also [3,2-c] pyridine, it is to be developed jointly by Japan three common (sankyo) and Lilly, is used for the treatment of the medicine of thrombus.But by the method referenced patent CN101177430 of aromatic nucleus propyl group ethyl ketone compounds tetrahydrobiopterin synthesis thienopyridine derivative or the method among the patent CN101250193, concrete route is as follows:
This method is to be raw material with 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, carries out bromination reaction with bromine simple substance, obtains the adjacent luorobenzyl cyclopropyl ketone (formula 9 compounds) of a-bromo; then with 2-oxygen-2,4,5; 6,7,7a-six hydrogen thieno-s [3; 2-c] pyridine (formula 10 compounds) reacts under alkaline condition and obtains 5-(a-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5; 6,7,7a-six hydrogen thieno-s [3; 2-c] pyridine (formula 11 compounds); the 5-that obtains (a-cyclopropyl carbonyl-2-luorobenzyl)-2-oxygen-2,4,5; 6; 7,7a-six hydrogen thieno-s [3,2-c] pyridine reacts with acetylation reagent again; obtain 2-acetoxyl group-5-(a-cyclopropyl carbonyl-2-luorobenzyl)-4; 5,6,7-tetramethylene sulfide also [3; 2-c] pyridine, i.e. prasugrel.
At present the synthetic of aromatic nucleus propyl group ethyl ketone compounds can be with reference to following document:
Reference one, patent WO2009122440 (date of publication is on October 8th, 2009, contriver: RAO, people such as A.V.V.Srinivas) announces route:
The reaction process of this route is, 1-(brooethyl)-2-fluorobenzene and reactive magnesium make (2-luorobenzyl) magnesium chloride, and then carry out grignard reaction with the cyclopropyl nitrile, obtain 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone crude product, and yield only is 72.18%, and cost is also higher.And the cyclopropyl nitrile is easy to generate by product prussiate and ethylene-acetic acid in reaction process, and this has also increased the cost and the difficulty of aftertreatment undoubtedly, and solvent for use is an ether in addition, and during technology, especially the high temperature area very easily produces dangerous.
Reference two, patent WO2009068923 (date of publication is on June 4th, 2009, contriver: MEZEI, people such as Tibor), now getting wherein, best results one example is illustrated:
This reaction process is reacted in sulfur oxychloride for encircling third formyl chloride and dimethyl formamide, the Grignard reagent that the diformazan basic ring propyl formamide that makes and 1-(monochloromethyl)-2-fluorobenzene and reactive magnesium make reacts, and promptly obtains preparing intermediate 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone of prasugrel.The double solvent of doing of sulfur oxychloride that this reaction needed is a large amount of, we know that sulfur oxychloride has very big pungency and toxicity, and the aftertreatment more complicated then needs a large amount of alkali to neutralize as industrialization, and produces and also very easily generation danger of last handling process with a large amount of sulfurous gass.Diformazan basic ring propyl formamide is more stable in addition, and amido linkage is easy fracture not, and reaction is carried out not exclusively, and two step total recoverys only are 64.9%.
In view of aromatic nucleus propyl group ethyl ketone class excellent drug prospect, therefore need exploitation a kind of more economical, safety, the preparation method of easy preparation aromatic nucleus propyl group ethyl ketone class.
Summary of the invention
The object of the present invention is to provide a kind of new method that is used to prepare aromatic nucleus propyl group ethyl ketone compounds, this method adopts another kind of cyclopropyl compounds as reactant, and reaction type is simple, and condition relaxes, the product yield height, and cost is low.
To achieve these goals, the present invention adopts following technical scheme:
A kind of preparation method of aromatic nucleus propyl group ethyl ketone compounds, reaction equation is:
R wherein
1Be F, Cl, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; R
2, R
3Be respectively C
1-C
4Alkyl (R
2, R
3Can be C identical or inequality
1-C
4Alkyl); X is Cl or Br.
C
1-C
4Alkyl specifically can be: methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, sec-butyl, the tertiary butyl; C
1-C
4Alkoxyl group specifically can be: methoxyl group, oxyethyl group, positive propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert.-butoxy.
Concrete reaction process is: under the initiator effect, Grignard reagent and formula (b) compound that formula (a) compound and alkali metal base reaction make carry out grignard reaction, obtain formula (c) compound, just aromatic nucleus propyl group ethyl ketone compounds.
Described basic metal is preferably magnesium, zinc.
Described formula (a) compound is 1 with alkali-metal mole dosage ratio: (1～12); Preferred 1: (1～5).
Described formula (a) compound is worked as R
1When being 2 F, when X was Cl or Br, compound (a) was 2-fluorobenzyl chloride or 2-fluoro benzyl bromide, and the Grignard reagent that then preferably makes is (2-luorobenzyl) magnesium chloride or (2-luorobenzyl) magnesium bromide.
The reaction solvent of this reaction process is selected from ethers, substituted benzene, benzene kind solvent, or its any two or more mixed solvent; Be preferably ether, tetrahydrofuran (THF), benzene, toluene, or its any two or more mixed solvent.
Described solvent load is 5～50 times of described formula (c) compound, is preferably 15～30 times.
Temperature of reaction during the preparation Grignard reagent is-10～35 ℃, preferred 0～25 ℃; 0.5～18 hour reaction times, preferred 2～4 hours.
The mole dosage ratio of described Grignard reagent and formula (b) compound is 1: (1～5) is preferably 1: (1.01～2); The temperature of reaction of grignard reaction (preparation of compound c) is-20～35 ℃, preferred 20～30 ℃.0.5～10 hour reaction times.
Wherein said initiator is an iodine, idoalkane, bromo alkane, or its any two or more mixture; Described idoalkane comprises methyl iodide, and described bromo alkane comprises monobromethane, ethylene dibromide.
Wherein work as R
1When being 2 fluorine atoms, formula (c) compound is: 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, it can be used for preparing prasugrel.Formula (b) but method that the synthetic referenced patent US20050197337 of compound provides, concrete route is as follows:
R wherein
2, R
3Definition identical with above-mentioned definition.
Be specially formula (2) compound and cyclopropyl acyl chlorides and under alkaline condition, carry out substitution reaction, obtain formula (b) compound, just N-alkoxyl group-N-alkyl ring propyl formamide.This reaction product can be not treated, is directly used in preparation aromatic nucleus propyl group ethyl ketone compounds.
The method for preparing aromatic nucleus propyl group ethyl ketone compounds that the present invention provides, cheap and the easily preparation of reaction raw materials, be N, O-dialkyl group hydroxylamine hydrochloride and cyclopropyl acyl chlorides carry out simple substitution reaction, and do not need aftertreatment, the N-alkoxyl group that obtains-N-alkyl ring propyl formamide (formula (b) compound) can be directly used in preparation aromatic nucleus propyl group ethyl ketone compounds.What is more important, N-alkoxyl group-N-alkyl ring propyl formamide is active high, its amido linkage easily disconnects for the amido linkage in the ring propyl formamide of identical alkyl (as: the N-dialkyl cyclic propyl formamide that WO2009068923 provides) than two, therefore aspect preparation aromatic nucleus propyl group ethyl ketone compounds, having reaction carries out easily, reaction type is simple and react completely, reaction conditions relaxes, acquisition product yield height, cost is low, be easy to the characteristics of technology, have very high industrial application and economic worth.
Embodiment
Content for a better understanding of the present invention is described further below in conjunction with specific embodiment.
The preparation of embodiment 1:1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone
(2.88g 0.12mol), drops in three mouthfuls of reaction flasks, under the nitrogen protection to take by weighing magnesium; add tetrahydrofuran (THF) 120mL, 25 ℃ down with 0.1mL glycol dibromide activated magnesium, after activation finishes; (18.9g, 0.10mol), interior temperature control is at 20-25 ℃ slowly to drip 1-(brooethyl)-2-fluorobenzene.Dropwise, continue to react about 2 hours under this temperature, the GC monitoring reaction finishes until reaction.Under 0 ℃, (12.9g, 0.10mol) solution dropwise back TLC tracking reaction and finish until reaction to drip the N-methoxyl group-N-methyl ring propyl formamide that is dissolved in the 200ml tetrahydrofuran (THF).Add saturated ammonium chloride, separatory, extraction steams solvent, and the underpressure distillation of gained organic layer liquid obtains colourless liquid 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 16.83g, and yield is 94.5%.
1H?NMR(CDCl
3，Me
4Si)：δ0.86-0.90(m，2H)，1.05-1.08(m，2H)，1.97-2.02(m，1H)，3.87(s，2H)，7.04-7.18(m，2H)，7.18-7.27(m，2H)；MS(EI)：179.1[M+1]。
The preparation of embodiment 2:1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone
(2.88g 0.12mol), drops in three mouthfuls of reaction flasks, under the nitrogen protection to take by weighing the magnesium powder; add tetrahydrofuran (THF) 120mL, 25 ℃ down with 0.1mL glycol dibromide activated magnesium, after activation finishes; (14.46g, 0.10mol), interior temperature control is at 20-25 ℃ slowly to drip 1-(chloromethyl)-2-fluorobenzene.Dropwise, continue to react about 2 hours under this temperature, the GC monitoring reaction finishes until reaction.Under 0 ℃, (12.9g, 0.10mol) solution dropwise back TLC tracking reaction and finish until reaction to drip the N-methoxyl group-N-methyl ring propyl formamide that is dissolved in the 200ml tetrahydrofuran (THF).Add saturated ammonium chloride, separatory, extraction steams solvent, and the underpressure distillation of gained organic layer liquid obtains colourless liquid 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone 16.21g, and yield is 91.0%.The nuclear magnetic spectrogram data are the same.
The preparation of embodiment 3:2-(3-chloro-phenyl-)-1-cyclopropyl ethyl ketone
Method according to embodiment 1 is operated with method, take by weighing 1-chloro-3-(chloromethyl) benzene (16.1g, 0.10mol), under 0 ℃, dropping is dissolved in the N-oxyethyl group-N-sec.-propyl cyclopropane carboxamide (17.1g in the 200ml tetrahydrofuran (THF), 0.10mol) solution, obtaining 2-(3-chloro-phenyl-)-1-cyclopropyl ethyl ketone 16.6g, yield is 85.3%.
The preparation of embodiment 4:1-cyclopropyl-2-(4-fluorophenyl) ethyl ketone
Method according to embodiment 1 is operated with method, take by weighing 1-(brooethyl)-4-fluorobenzene (18.9g, 0.1mol), under 0 ℃, dropping is dissolved in the N-sec-butoxy-N-sec.-propyl cyclopropane carboxamide (19.9g in the 200ml tetrahydrofuran (THF), 0.1mol) solution, obtain 1-cyclopropyl-2-(4-fluorophenyl) ethyl ketone 14.2g, yield 79.8%.
Embodiment 5:1-cyclopropyl-2-is to the preparation of toluene ethyl ketone
Method according to embodiment 1 is operated with method, take by weighing 1-brooethyl-4-toluene (18.5g, 0.1mol), under 0 ℃, dropping is dissolved in the N-oxyethyl group-N-ethyl cyclopropane carboxamide (15.7g in the 200ml tetrahydrofuran (THF), 0.1mol) solution, obtain 1-cyclopropyl-2-to toluene ethyl ketone 14.3g, yield 81.9%.
The preparation of embodiment 6:1-cyclopropyl-2-(2-ethylphenyl) ethyl ketone
Method according to embodiment 1 is operated with method, take by weighing 1-brooethyl-2-ethylbenzene (19.9g, 0.1mol), under 0 ℃, dropping is dissolved in the N-methoxyl group-N-methyl cyclopropane methane amide (12.9g in the 200ml tetrahydrofuran (THF), 0.10mol) solution, obtaining 1-cyclopropyl-2-(2-ethylbenzene) ethyl ketone 14.3g, yield is 76.1%.
The preparation of embodiment 7:1-cyclopropyl-2-(2-p-methoxy-phenyl) ethyl ketone
Method according to embodiment 1 is operated with method, take by weighing 1-chloromethyl-2-anisole (15.7g, 0.1mol), under 0 ℃, dropping is dissolved in the N-methoxyl group-N-ethyl cyclopropane carboxamide (14.3g in the 200ml tetrahydrofuran (THF), 0.1mol), obtaining 14.2g1-cyclopropyl-2-(2-p-methoxy-phenyl) ethyl ketone, yield is 74.7%.
In sum, the present invention relates to the preparation method of aromatic nucleus propyl group ethyl ketone compounds.Above-mentioned preparation method is that Grignard reagent and formula (b) compound that formula (a) compound and basic metal reaction make carries out grignard reaction, obtain aromatic nucleus propyl group ethyl ketone compounds, when 2 of formula (c) compounds are fluorine atom, both be 1-cyclopropyl-2-(2-fluorophenyl) ethyl ketone, it is the important intermediate of preparation prasugrel.
Need to prove that all documents of mentioning in the present invention quote as a reference in this application, just quoted as a reference separately as each piece document.Should understand in addition, above-described is specific embodiments of the invention and the know-why used, after having read foregoing of the present invention, those skilled in the art can make various changes or modifications and not deviate from spirit of the present invention and scope the present invention, and these equivalent form of values fall within the scope of the invention equally.
Claims (5)
1. the preparation method of an aromatic nucleus propyl group ethyl ketone compounds by making Grignard reagent as shown in the formula (a) compound and basic metal reaction, carries out grignard reaction with formula (b) compound then, obtains aromatic nucleus propyl group ethyl ketone class, i.e. formula (c) compound:
R wherein
1Be F, Cl, C
1-C
4Alkyl or C
1-C
4Alkoxyl group; R
2, R
3Be respectively C
1-C
4Alkyl; X is Cl or Br.
2. the preparation method of aromatic nucleus propyl group ethyl ketone compounds according to claim 1, wherein R
1Be 2 fluorine atoms, R
2With R
3Be all methyl, X is the chlorine atom.
3. the preparation method of aromatic nucleus propyl group ethyl ketone compounds according to claim 1, wherein said basic metal is magnesium.
4. the preparation method of aromatic nucleus propyl group ethyl ketone compounds according to claim 1, it is characterized in that: under the initiator effect, Grignard reagent and formula (b) compound that formula (a) compound and basic metal reaction make carry out grignard reaction, obtain formula (c) compound, just aromatic nucleus propyl group ethyl ketone compounds.
5. the purposes of formula according to claim 1 (c) compound is used to prepare tetramethylene sulfide and pyridine derivatives.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010172848.4A CN102241572B (en) | 2010-05-12 | 2010-05-12 | Preparation method and application of aromatic cyclopropyl butanone compound |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201010172848.4A CN102241572B (en) | 2010-05-12 | 2010-05-12 | Preparation method and application of aromatic cyclopropyl butanone compound |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN102241572A true CN102241572A (en) | 2011-11-16 |
| CN102241572B CN102241572B (en) | 2014-07-16 |
Family
ID=44959854
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201010172848.4A Active CN102241572B (en) | 2010-05-12 | 2010-05-12 | Preparation method and application of aromatic cyclopropyl butanone compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN102241572B (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892345A (en) * | 2015-04-20 | 2015-09-09 | 山东东昌精细化工科技有限公司 | Method for synthesizing n-propylbenzene through Grignard reagent method |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009068923A2 (en) * | 2007-11-27 | 2009-06-04 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Process for the preparation of pharmaceutical intermediates |
-
2010
- 2010-05-12 CN CN201010172848.4A patent/CN102241572B/en active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009068923A2 (en) * | 2007-11-27 | 2009-06-04 | Egis Gyógyszergyár Nyilvánosan Működő Részvénytársaság | Process for the preparation of pharmaceutical intermediates |
Non-Patent Citations (1)
| Title |
|---|
| STEVEN NAHM, ET AL.: "N-methoxy-n-methylamides as effective acylating agents", 《TETRAHEDRON LETTERS》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104892345A (en) * | 2015-04-20 | 2015-09-09 | 山东东昌精细化工科技有限公司 | Method for synthesizing n-propylbenzene through Grignard reagent method |
Also Published As
| Publication number | Publication date |
|---|---|
| CN102241572B (en) | 2014-07-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106029658B (en) | The method for preparing Diacloden | |
| Rong et al. | Synthesis of propargylic and allylic trifluoromethyl selenoethers by copper-mediated trifluoromethylselenolation of propargylic chlorides and allylic bromides | |
| JP2012504153A5 (en) | ||
| Zhang et al. | Cu-catalyzed chlorotrifluoromethylation of alkenes with CF3SO2Cl | |
| Yadav et al. | The reductive etherification of carbonyl compounds using polymethylhydrosiloxane activated by molecular iodine | |
| CN107188832A (en) | A kind of method that utilization carbon dioxide synthesizes the carbamate containing trifluoromethyl | |
| CN102241572B (en) | Preparation method and application of aromatic cyclopropyl butanone compound | |
| Mbakidi et al. | Glycerol-based ionic liquids: crucial microwaves-assisted synthetic step for solketal amines | |
| WO2011021492A1 (en) | Process for production of formyl-substituted aromatic compounds | |
| Yang et al. | Reaction of organozinc halides with aryl isocyanates | |
| CN106795070A (en) | Method for preparing halogeno-benzene | |
| CN106866425B (en) | A kind of green synthesis method of bromo aromatic amine and alpha-brominated aromatic ketone | |
| JPWO2010126170A1 (en) | Method for producing isothiazole derivative | |
| CN106045836B (en) | A kind of method of copper catalysis synthesis aromatic hydrocarbons or heterocycle trifluoromethyl ketone | |
| EP2522648B1 (en) | Process for producing difluorocyclopropane compound | |
| CN107400060A (en) | A kind of synthetic method of the bromaniline of 2 chlorine 6 | |
| JP6637880B2 (en) | 5- (trifluoromethyl) pyrimidine derivative and method for producing the same | |
| CN102675036A (en) | Method for preparing 7-bromine-1-heptylene | |
| Komeyama et al. | Three-component coupling of aryl iodides, allenes, and aldehydes catalyzed by a Co/Cr-hybrid catalyst | |
| Dindulkar et al. | An eco-sustainable green approach for the synthesis of propargylamines using LiOTf as a reusable catalyst under solvent-free condition | |
| JP6894608B2 (en) | New Cyclic Urea Derivative-Hydrogen Bromide | |
| CN108715576A (en) | A kind of preparation method of 3- ethyoxyl-4-carboxylphenylaceticacid acids | |
| JP2013124248A (en) | Manufacturing method for 4,4-difluoro-3,4-dihydroisoquinolines | |
| JP6235932B2 (en) | Method for producing 2-cyanophenylboronic acid derivative | |
| CN103641684A (en) | High-purity chlorohydrins and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant |