CN104478742A - Fluoro compound and preparation method thereof - Google Patents
Fluoro compound and preparation method thereof Download PDFInfo
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- CN104478742A CN104478742A CN201410682225.XA CN201410682225A CN104478742A CN 104478742 A CN104478742 A CN 104478742A CN 201410682225 A CN201410682225 A CN 201410682225A CN 104478742 A CN104478742 A CN 104478742A
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Abstract
The invention provides a fluoro compound with a structural formula. The fluoro compound has a wide application range as a fluoro drug intermediate. In the structural formula, R is selected from C1-C6 alkyl. The invention also provides a preparation method of the fluoro compound. The preparation method at least has the advantages of mild reaction condition, cheap and available raw materials, high reaction yield of each step, simple purification method and the like; and the purity of the product is high.
Description
Technical field
The present invention relates to a kind of fluoric compound and preparation method thereof, belong to medicine intermediate synthesis field.
Background technology
Fluorochemicals is a kind of useful compound, and it is by the characteristic of the excellences such as the volatilizable water-repellancy of fluorine atom, and the raw material always as various Industrial products uses.In addition, in the technical field of fluorine chemical, its application in the transparent resin material of optical communication, optical waveguides, optical recording, liquid-crystal display etc. can be enumerated.Because fluorine is the maximum element of electronegativity, polyfluor organic compound has the features such as chemical stability, surfactivity and excellent heat resistance.
Fluorine medicine has special biological activity and organism adaptability due to fluorinated organic compound, and the curative effect of Drugs Containing Fluorine is than general medicine several times all by force, and its exploitation is the most active.At present commercialization and the fluorine-containing medicines developed have nearly hundred kinds in the world.Part staple product has: tranquilizer droperidol; Antitumour drug Ro 2-9757; Antiphlogistic drug diflorasone; Amcinonide fluohydrocortisone, the resistance to moral of fluorine chlorine, flurrenolone, fluorine ground Kathon CG; Antiarrhythmics flecainide; Antifungal drug fluconazole, flucytosine; Anticarcinogen phosphoric acid NSC-118218; Soporific flumazenil; Antasthmatic flunisolide; Antidepressant fluoxetine (Prozac, antidepressant class world sales volume first); Perfluorodecalin fluorine carbon (artificial blood); Diet pill fluorine Lamine.It can thus be appreciated that fluorochemicals has important use at field of medicaments.
Summary of the invention
The invention provides a kind of fluoric compound with following structural formula, it is as a kind of fluoro pharmaceutical intermediate, and tool has been widely used,
In formula, R is selected from the alkyl of C1 ~ C6.
Preferably, R is selected from methyl, ethyl or sec.-propyl.
The present invention provides a kind of preparation method of above-mentioned fluoric compound simultaneously, and synthetic route is:
In formula, R is selected from the alkyl of C1 ~ C6;
Comprise the following steps:
(1) esterification of raw material 1 pentafluorobenzoic acid is generated compound 2;
(2) fluorine of ester group contraposition on compound 2 amido is replaced generation compound 3;
(3) fluorine at compound 3 ortho position methoxy substitution is generated compound 4;
(4) hydrolysis of ester group of compound 4 is generated compound 5;
(5) compound 5 decarboxylation is generated compound 6;
(6) the amido deprotection of compound 6 is generated compound 7.
Preferably, R
1be selected from the alkyl of C1 ~ C6, R
2be selected from tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz), p-toluenesulfonyl or trifluoroacetyl group.
Preferably, R
1be selected from methyl, ethyl or sec.-propyl.
Preferably, step (1) described enzymatic synthesis condition is that raw material 1 first forms acyl chlorides, then with alcohol reacting generating compound 2.
Preferably, step (1) described enzymatic synthesis condition is that raw material 1 reacts with alcohol and generates ester, and catalyzer is sulfuric acid.
Preferably, step (3) described methoxy substitution fluorine agents useful for same is sodium methylate.
Preferably, step (5) described decarboxylation reaction conditions is decarboxylation at 120 DEG C ~ 130 DEG C in chlorobenzene.
Fluoric compound preparation method provided by the invention at least has the following advantages: reaction conditions is gentle, and raw material is cheap and easy to get, and often walk reaction yield high, purification process is simple, and product purity is high.
Embodiment
Below will describe the present invention.But these embodiments do not limit the present invention, the conversion in the method that those of ordinary skill in the art makes according to these embodiments is all included in protection scope of the present invention.
R in the compounds of this invention 2 ~ 4
1preferably from the alkyl of C1 ~ C6, R
1preferred from methyl, ethyl or sec.-propyl further, R in compound 3 ~ 6
2preferably from tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz), p-toluenesulfonyl or trifluoroacetyl group.
Embodiment 1: prepare compound 2
The preparation of compound 2 can adopt and raw material 1 is first formed acyl chlorides, then with alcohol reacting generating compound 2, or under catalyst sulfuric acid exists will original 1 and alcohol react and generate ester.The present embodiment is with first method and R and R
1being methyl is that example is described.
In there-necked flask, add 50g raw material 1, add 100ml anhydrous methanol, stir, be down to-5 DEG C ~ 5 DEG C, drip 30g thionyl chloride, drip and finish, be warming up to backflow, reaction 12h, cooling, concentrated, add 100mlMTBE, use saturated NaHCO successively
3solution and washing, organic layer is dry, concentrated, obtains 45g compound 2, yield 85%, purity 98.9%.
Embodiment 2: prepare compound 3
R in compound 3
2be described for benzyl, those skilled in the art easily expect R
2also tertbutyloxycarbonyl, carbobenzoxy-(Cbz), p-toluenesulfonyl or trifluoroacetyl group can be selected from.
In there-necked flask, add 50g compound 2 and 40g N-Methyl pyrrolidone, stir, be down to-5 DEG C ~ 5 DEG C, drip 20g benzylamine, drip and finish, drip 30g DIPEA, drip and finish, be heated to 70 DEG C ~ 80 DEG C, reaction 8h, cooling, add MTBE and water, organic layer uses 10% acetic acid and washing successively, organic layer is dry, and concentrated, recrystallization obtains 55g compound 3, yield: 80%, purity: 99.2%.
Embodiment 3: prepare compound 4
In there-necked flask, 50g compound 3 and 60ml methyl alcohol is added under protection of inert gas; stir the lower methanol solution 200ml dripping 45g sodium methylate, drip and finish, be warming up to 60 DEG C ~ 70 DEG C reaction 12h; be cooled to-5 DEG C ~ 5 DEG C; drip 50g acetic acid, add water and MTBE, organic layer is washed with water and saturated sodium bicarbonate solution successively; dry; concentrate and obtain 40g compound 4, yield: 75%, purity: 98.4%.
Embodiment 4: prepare compound 5
In there-necked flask, add 50g compound 4 and 200ml ethanol, stir and be cooled to-5 DEG C ~ 5 DEG C, drip the NaOH aqueous solution of 20ml 0.5mol/L, be warming up to 60 DEG C ~ 70 DEG C, cooling, concentrated, residuum adds water, and aqueous phase MTBE washes, aqueous phase hydrochloric acid adjust pH to 2 ~ 3, add MTBE extraction, organic phase uses salt solution and washing successively, dry, concentrates to obtain 44g compound 5, yield: 92%, purity 98.0%.
Embodiment 5: prepare compound 6
In there-necked flask, add 50g compound 5 and 200ml chlorobenzene, be warming up to 120 DEG C ~ 130 DEG C, reaction 5h, is cooled to room temperature, uses saturated sodium bicarbonate solution and washing successively, dry, concentrates and obtains 36g compound 6, yield: 85%, purity: 98.2%.
Embodiment 6: prepare compound 7
In there-necked flask, add 50g compound 6,300ml THF and 5g palladium hydroxide carbon, pass into H
2, room temperature reaction 3h, suction filtration, concentrated, sherwood oil recrystallization obtains 32g compound 7, yield 96%, purity 99.4%.HNMR(CDCl
3，300MHz)δ:6.13(m,1H),3.80(d,6H)。
Be to be understood that, although this specification sheets is described according to embodiment, but not each embodiment only comprises an independently technical scheme, this narrating mode of specification sheets is only for clarity sake, those skilled in the art should by specification sheets integrally, technical scheme in each embodiment also through appropriately combined, can form other embodiments that it will be appreciated by those skilled in the art that.
A series of detailed description listed is above only illustrating for feasibility embodiment of the present invention; they are also not used to limit the scope of the invention, all do not depart from the skill of the present invention equivalent implementations done of spirit or change all should be included within protection scope of the present invention.
Claims (9)
1. a fluoric compound, has following structural formula:
In formula, R is selected from the alkyl of C1 ~ C6.
2. fluoric compound according to claim 1, is characterized in that, R is selected from methyl, ethyl or sec.-propyl.
3. a preparation method for fluoric compound described in claim 1, is characterized in that, synthetic route is:
In formula, R is selected from the alkyl of C1 ~ C6;
Comprise the following steps:
(1) esterification of raw material 1 pentafluorobenzoic acid is generated compound 2;
(2) fluorine of ester group contraposition on compound 2 amido is replaced generation compound 3;
(3) fluorine at compound 3 ortho position methoxy substitution is generated compound 4;
(4) hydrolysis of ester group of compound 4 is generated compound 5;
(5) compound 5 decarboxylation is generated compound 6;
(6) the amido deprotection of compound 6 is generated compound 7.
4. the preparation method of fluoric compound according to claim 3, is characterized in that, R
1be selected from the alkyl of C1 ~ C6, R
2be selected from tertbutyloxycarbonyl, benzyl, carbobenzoxy-(Cbz), p-toluenesulfonyl or trifluoroacetyl group.
5. the preparation method of fluoric compound according to claim 4, is characterized in that, R
1be selected from methyl, ethyl or sec.-propyl.
6. the preparation method of fluoric compound according to claim 4, is characterized in that, step (1) described enzymatic synthesis condition is that raw material 1 first forms acyl chlorides, then with alcohol reacting generating compound 2.
7. the preparation method of fluoric compound according to claim 4, is characterized in that, step (1) described enzymatic synthesis condition is that raw material 1 reacts with alcohol and generates ester, and catalyzer is sulfuric acid.
8. the preparation method of fluoric compound according to claim 4, is characterized in that, step (3) described methoxy substitution fluorine agents useful for same is sodium methylate.
9. the preparation method of fluoric compound according to claim 4, is characterized in that, step (5) described decarboxylation reaction conditions is decarboxylation at 120 DEG C ~ 130 DEG C in chlorobenzene.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115368219A (en) * | 2022-10-25 | 2022-11-22 | 苏州康纯医药科技有限公司 | Preparation method of FGFR inhibitor key intermediate |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| US20040019210A1 (en) * | 2002-07-25 | 2004-01-29 | Chivikas Connolly Cleo J. | Kinase inhibitors |
| WO2006038112A1 (en) * | 2004-10-01 | 2006-04-13 | Warner-Lambert Company Llc | Use of kinase inhibitors to promote neochondrogenesis |
| CN103265538A (en) * | 2013-02-19 | 2013-08-28 | 中国人民解放军南京军区南京总医院 | Azole antifungal compound and preparation method and application thereof |
-
2014
- 2014-11-24 CN CN201410682225.XA patent/CN104478742A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040019210A1 (en) * | 2002-07-25 | 2004-01-29 | Chivikas Connolly Cleo J. | Kinase inhibitors |
| WO2006038112A1 (en) * | 2004-10-01 | 2006-04-13 | Warner-Lambert Company Llc | Use of kinase inhibitors to promote neochondrogenesis |
| CN103265538A (en) * | 2013-02-19 | 2013-08-28 | 中国人民解放军南京军区南京总医院 | Azole antifungal compound and preparation method and application thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115368219A (en) * | 2022-10-25 | 2022-11-22 | 苏州康纯医药科技有限公司 | Preparation method of FGFR inhibitor key intermediate |
| CN115368219B (en) * | 2022-10-25 | 2022-12-27 | 苏州康纯医药科技有限公司 | Preparation method of FGFR inhibitor key intermediate |
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Application publication date: 20150401 |