CN101117321A - Preparation of N-hydroxyalkyl fluorine aliphatic amine - Google Patents
Preparation of N-hydroxyalkyl fluorine aliphatic amine Download PDFInfo
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- CN101117321A CN101117321A CNA2006101095038A CN200610109503A CN101117321A CN 101117321 A CN101117321 A CN 101117321A CN A2006101095038 A CNA2006101095038 A CN A2006101095038A CN 200610109503 A CN200610109503 A CN 200610109503A CN 101117321 A CN101117321 A CN 101117321A
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Abstract
The invention relates to a preparation process for N-hydroxylalkylation fluorine-containing aliphatic amine shown in general formula (I), which comprises that the alkyl or alcohol halide is made a reaction with the fluorine-containing alicyclic amine in aqueous solution. The invention can improve the yields of N-hydroxylalkylation fluorine-containing aliphatic amine. Additionally, the invention has simple process, is easy to operate and run, and has low cost of raw materials.
Description
Technical field
The present invention relates to the preparation method of fluorine-containing fatty imines, more specifically, relate to the preparation method of N-hydroxyalkyl fluorine aliphatic amine, comprise making halo alkanol and the reaction of fluorine-containing aliphatic amide.
Background technology
The N-hydroxyalkyl fluorine aliphatic amine is important chemical feedstocks, can be used as the intermediate of multiple product, also can be used as the monomeric raw material of preparation fluoropolymer.For example, N-(2-hydroxyethyl)-2 ', 2 '-difluoro propylamine (also being called 2-(2,2-difluoro Propylamino) ethanol) is a kind of important medicine intermediate, can be used for medicines such as synthetic CB1 cannabinoid receptors antagonist.
United States Patent (USP) the 2nd, 585 discloses by the synthetic N-(2-hydroxyethyl)-2 ' of following reaction formula the method for 2 '-difluoro propylamine in No. 230:
Above-mentioned synthesis technique is in autoclave, makes 2, and in 100 ℃ of reactions, rectification process obtains product in the dioxane solvent for 2-difluoro propylamine and oxyethane.
There are 4 deficiencies in this method: 1, react in autoclave, the required equipment relative complex is unfavorable for industrialization; 2, use a large amount of solvent dioxane, raw materials cost is higher; 3, use inflammable, explosive oxyethane, poor stability; 4, reaction conversion ratio is low, and solvent and product boiling point are approaching, and separating difficulty strengthens, so product yield is lower.
Publication number is that the PCT international application of WO 2005/056514 discloses a kind of method for preparing the aliphatics hydramine, comprises making halo alkanol and amine in the aqueous solution, at 20～90 ℃ of reactions, yield 47～75%.
Disclose a kind of method for preparing polyhydric alcohol amine in Chinese patent ZL95112778.0 number, comprised making amine that propylene glycol of chlorine and 3-5 doubly measure in the aqueous solution, at 60～80 ℃ of reactions 2-3 hour, yield 75%.This paper is incorporated herein by reference the reference that all relate in full.
Summary of the invention
In order to overcome deficiency of the prior art, the invention provides the preparation method of the N-hydroxyalkyl fluorine aliphatic amine of general formula (I),
Wherein,
Each R
1And R
2Be hydrogen or alkyl independently of each other;
R
3Be hydrogen or alkyl;
M is 1～4 integer;
N is 2～7 integer;
Described method is included in and makes general formula (II) compound in the aqueous solution,
Wherein X is C1, Br or I, R
1Described as defined above with n;
With the reaction of general formula (III) compound,
R wherein
2, R
3Described as defined above with m.
In the present invention's one preferred embodiment, each R
1And R
2Be hydrogen or C independently
1～C
4Alkyl, more preferably hydrogen.
In another preferred embodiment of the present invention, R
3Be hydrogen or C
1～C
6Alkyl, more preferably hydrogen.
In some preferred embodiment of the present invention, the mol ratio of general formula (II) compound and general formula (III) compound is about 1: 1～1: 4.
In other preferred embodiments of the present invention, described being reflected under the alkali existence carried out.Preferably, the mol ratio of described alkali and general formula (II) compound is about 1: 1～1: 4, more preferably about 1: 1～1: 2.
In other preferred embodiment of the present invention, described being reflected at approximately under-10～60 ℃ the temperature carried out, and more preferably carries out under about 0～25 ℃ temperature, carries out particularly preferably in 0～5 ℃.
Compared with prior art, the inventive method yield is higher, and raw material is relatively inexpensive, so production cost is lower.In addition, the inventive method technology is simple, and easy handling and operation are fit to suitability for industrialized production.
Embodiment
Similar with the ammonolysis reaction of halohydrocarbon, in the present invention, owing to have the part positive charge in the halo alkanol shown in the general formula (II) with on the carbon atom that halogen links to each other, and there are lone-pair electron on the N atom of the fluorine-containing aliphatic amide shown in the general formula (III), therefore nucleophilic substitution reaction can take place in both, obtains N-hydroxyalkyl fluorine aliphatic amine and hydrogen halide.
Consider sterically hindered influence to this reaction, in a preferred embodiment, each R
1And R
2Be hydrogen or C independently
1～C
6Alkyl, more preferably hydrogen or C
1～C
4Alkyl, for example methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, tertiary butyl or the like.Further preferably, each R
1And R
2Be hydrogen or C independently
1～C
4Straight chained alkyl.Particularly preferably, R
1And R
2Be hydrogen.
In another preferred embodiment, R
3Be hydrogen or C
1～C
6Alkyl, more preferably hydrogen or C
1～C
4Alkyl is preferably hydrogen especially.
In a further preferred embodiment, R
1, R
2And R
3Be hydrogen simultaneously.
In another preferred embodiment, n is 2～4 integer.
In the methods of the invention, general formula (I) compound can be further and general formula (III) compound generation nucleophilic substitution reaction, generates N, the fluorine-containing aliphatic amide that the N-dihydroxyalkyl replaces.Therefore, preferably use excessive general formula (III) compound to react.In a preferred embodiment, the mol ratio of general formula (II) compound and general formula (III) compound is about 1: 1～1: 4.
Owing to there is hydrogen halide to generate, so the present invention reacts preferably and carries out in the presence of alkali.Yet because the halo alkanol self substitution reaction takes place easily and cyclisation in alkali (as NaOH) solution, therefore used alkali is unsuitable excessive.Preferably, the mol ratio of described alkali and general formula (II) compound is about 1: 1～1: 4, more preferably about 1: 1～1: 2.
Can be used for alkali of the present invention can be any conventional alkali that uses, and is preferably water-soluble alkali, includes but not limited to alkali metal hydroxide, and alkaline carbonate and alkali metal hydrocarbonate are preferably alkali metal hydroxide, as NaOH.
The present invention will be described in more detail below with reference to embodiment, but the present invention is not limited to these specific embodiments.
Embodiment 1
Adopt method of the present invention to prepare N-(2-hydroxyethyl)-2 ', 2 '-difluoro propylamine, its reaction formula is:
In the 250mL there-necked flask that mechanical stirrer, reflux exchanger, thermometer and low temperature bath refrigerating unit are housed, add 2,2-difluoro propylamine 57.1g (0.6 mole) and 20% sodium hydroxide solution 100g (0.5 mole), be cooled to 0～5 ℃, slowly drip ethylene chlorhydrin 40.3g (0.5 mole).0～5 ℃ of reaction 3 hours.After reaction finishes, with isopropyl acetate extraction 4 times (4 * 50mL).Combining extraction liquid distills, steam unreacted 2,2-difluoro propylamine and isopropyl acetate.(65～66 ℃/1mmHg) obtain product N-(2-hydroxyethyl)-2 ', 2 '-difluoro propylamine 59.1g of underpressure distillation.Yield 85.0%.195～196 ℃ of boiling points.
Mass spectroscopy (m/z): 139,108,88,74,68,64,59,55,45,41,37,30.
Infrared spectroscopy (cm
-1): 3329,3005,2945,2860,1464,1393,1248,1150,1059,976,897,791,606,509,449.
Embodiment 2
In the 250mL there-necked flask that mechanical stirrer, reflux exchanger, thermometer and low temperature bath refrigerating unit are housed, add 2,2-difluoro propylamine 57.1g (0.6 mole) and 20% sodium hydroxide solution 100g (0.5 mole), at 20～25 ℃, slowly drip ethylene chlorhydrin 40.3g (0.5 mole).20～25 ℃ of reactions 3 hours.After reaction finishes, press embodiment 1 and handle, obtain product N-(2-hydroxyethyl)-2 ', 2 '-difluoro propylamine 56.9g with quadrat method.Yield 81.9%.
Embodiment 3
In the 250mL there-necked flask that mechanical stirrer, reflux exchanger, thermometer and low temperature bath refrigerating unit are housed, add 2,2-difluoro propylamine 57.1g (0.6 mole) and 30% sodium hydroxide solution 100g (0.75 mole), be cooled to 0～5 ℃, slowly drip ethylene chlorhydrin 40.3g (0.5 mole).0～5 ℃ of reaction 3 hours.After reaction finishes, press embodiment 1 and handle, obtain product N-(2-hydroxyethyl)-2 ', 2 '-difluoro propylamine 48.6g with quadrat method.Yield 69.9%.
Embodiment 4
In the 250mL there-necked flask that mechanical stirrer, reflux exchanger, thermometer and low temperature bath refrigerating unit are housed, add 2,2-difluoro propylamine 57.1g (0.6 mole) and 20% sodium hydroxide solution 100g (0.5 mole), be cooled to 0～5 ℃, slowly drip ethylene chlorhydrin 48.3g (0.6 mole).0～5 ℃ of reaction 3 hours.After reaction finishes, press embodiment 1 and handle, obtain product N-(2-hydroxyethyl)-2 ', 2 '-difluoro propylamine 60.8g with quadrat method.Yield 72.8%.
Comparing embodiment
In autoclave, drop into 2,2-difluoro propylamine 76g, oxyethane 40g, dioxane 400mL is heated to 100 ℃ of reactions 4 hours with reaction mixture.Obtain N-(2-hydroxyethyl)-2 ' through rectification process, 2 '-difluoro propylamine 34g, yield are 29%.
The result of embodiment and comparing embodiment is compared as can be known, the inventive method mild condition, and product yield significantly improves (29% mentions greater than about 70%).
More than describe and in an exemplary fashion the preferred embodiments of the invention are illustrated.Those skilled in the art should be appreciated that under the condition that does not break away from essence spirit of the present invention and scope can make various modifications or replacement to it, and these deutero-embodiments must be included in the scope of the present invention.
Claims (10)
1. the preparation method of general formula (I) compound,
Wherein,
Each R
1And R
2Be hydrogen or C independently of each other
1-C
4Alkyl;
R
3Be hydrogen or C
1-C
6Alkyl;
M is the integer of 1-4;
N is the integer of 2-7;
Described method is included in and makes general formula (II) compound in the aqueous solution,
Wherein X is Cl, Br or I, R
1Described as defined above with n; With the reaction of general formula (III) compound,
R wherein
2, R
3Described as defined above with m.
2. the method for claim 1, wherein R
1Be hydrogen.
3. method as claimed in claim 1 or 2, wherein R
2Be hydrogen.
4. as the described method of arbitrary claim, wherein R in the claim 1～3
3Be hydrogen.
5. as the described method of arbitrary claim in the claim 1～4, the mol ratio of wherein said general formula (II) compound and general formula (III) compound is about 1: 1～1: 4.
6. as the described method of arbitrary claim in the claim 1～5, wherein said being reflected under the alkali existence carried out.
7. method as claimed in claim 6, wherein said alkali is selected from alkali metal hydroxide, alkaline carbonate and alkali metal hydrocarbonate.
8. method as claimed in claim 7, the mol ratio of wherein said alkali and general formula (II) compound is about 1: 1～1: 4.
9. as each described method in the claim 1～8, carry out under the temperature of wherein said being reflected at-10～60 ℃.
10. method as claimed in claim 9, wherein said being reflected under 0～25 ℃ the temperature carried out.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2006101095038A CN101117321A (en) | 2006-08-02 | 2006-08-02 | Preparation of N-hydroxyalkyl fluorine aliphatic amine |
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|---|---|---|---|
| CNA2006101095038A CN101117321A (en) | 2006-08-02 | 2006-08-02 | Preparation of N-hydroxyalkyl fluorine aliphatic amine |
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|---|---|
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631823A (en) * | 2016-12-20 | 2017-05-10 | 天津泰普制药有限公司 | Preparation method of lorcaserin intermediate |
-
2006
- 2006-08-02 CN CNA2006101095038A patent/CN101117321A/en active Pending
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106631823A (en) * | 2016-12-20 | 2017-05-10 | 天津泰普制药有限公司 | Preparation method of lorcaserin intermediate |
| CN106631823B (en) * | 2016-12-20 | 2022-04-26 | 天津泰普制药有限公司 | Preparation method of lorcaserin intermediate |
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