CN113045477B - Preparation method of fluorine-containing primary amine intermediate - Google Patents
Preparation method of fluorine-containing primary amine intermediate Download PDFInfo
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- C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
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- C07D209/48—Iso-indoles; Hydrogenated iso-indoles with oxygen atoms in positions 1 and 3, e.g. phthalimide
Abstract
The invention discloses a preparation method of a fluorine-containing primary amine intermediate, which takes N-hydroxyalkyl phthalimide compound as a raw material, and directly fluorinates the N-hydroxyalkyl phthalimide compound under the action of an organic solvent and a Lewis acid catalyst to obtain the N-fluoroalkyl phthalimide intermediate, and the intermediate is reduced to obtain the fluorine-containing primary amine. The method has the advantages of cheap and easily-obtained raw materials, simple and easy-controlled process route, capability of effectively promoting the N-hydroxyalkyl phthalimide to generate the corresponding fluoride with high conversion rate, capability of avoiding dehydrofluorination reaction in the fluorination process, yield of the fluoride intermediate of more than 85 percent, purity of more than 97 percent, and suitability for large-scale production.
Description
Technical Field
The invention relates to a preparation method of a fluorine-containing primary amine intermediate, belonging to the technical field of organic fluorine chemistry.
Background
Primary amine containing fluorine is an important chemical raw material, and is widely applied to synthesis and production of fine chemicals such as medicines, pesticides, dyes and the like. Primary monofluoroamines are commonly used in pharmaceutical synthesis, e.g., 2-fluoroethylamine and its hydrochloride salts are useful in the preparation of anti-cancer drugs, 3-fluoropropylamine hydrochloride is useful in the preparation of drugs for modulating dopamine neurotransmission for the treatment of central nervous disorders, and 5-fluoropentylamine is useful in the synthesis of 1H-1,2, 4-triazole-3-carboxamide derivatives having antagonistic effect on the cannabinoid receptor 1 (CB 1).
In the prior art, monofluoro-primary amine can be prepared by using corresponding fluorine-containing alcohol and fluorine-containing amide as starting materials. Document J, med. Chem., 1966, 9 (6) 892-911 and Chinese patent CN104496825A disclose a method for preparing 2-fluoroethanol hydrochloride, which comprises using 2-fluoroethanol as raw material, reacting 2-fluoroethanol with p-toluenesulfonyl chloride to obtain p-toluenesulfonyl fluoroethyl ester, reacting the ester with phthalimide potassium salt to obtain N- (2-fluoroethyl) phthalimide, and reducing concentrated hydrochloric acid with hydrazine hydrate to obtain 2-fluoroethylamine hydrochloride.
The monofluoro primary amine can also be prepared by reducing raw materials such as monofluoro amide or nitrile, for example, 2-fluoroethylamine can be prepared by reducing 2-fluoroacetamide or 2-fluoroacetonitrile, or by converting 1-bromo-2-fluoroethane and 1-chloro-2-fluoroethane functional groups, and related documents can be seen in J.Chem.Soc., 1948, 2174-2177, J.Org.Chem.1964, 29, 2870-2872, J.am.Chem.Soc.1968, 90 (10) 2455-2462 and the like, and the raw materials or intermediates used in the methods are special, difficult to prepare and the yield is also difficult to satisfy. Besides 2-fluoroethylamine and its hydrochloride, few other monofluorinated primary amines such as 3-fluoropropylamine, 4-fluorobutylamine, 5-fluoropentylamine and the like have been reported in the literature.
In conclusion, the main problem that the existing fluorine-containing primary amine, particularly monofluoro-primary amine, can not be prepared on a large scale is that the preparation of an intermediate has a great problem, either raw materials are not easy to obtain and need to be specially prepared, or a route is long and needs multi-step conversion, or the yield is low. Therefore, a synthetic route which is simple to operate, wide in application range, economical and feasible still needs to be found.
Disclosure of Invention
In view of the above, the present invention aims to provide a method for preparing a primary fluorine-containing amine intermediate. The invention takes N-hydroxyalkyl phthalimide compound as raw material, under the action of organic solvent and Lewis acid catalyst, N-fluoroalkyl phthalimide intermediate is obtained by direct fluorination, and primary amine containing fluorine is obtained by reduction of the intermediate. The method has the advantages of cheap and easily-obtained raw materials, simple and easy-controlled process route, capability of effectively promoting the N-hydroxyalkyl phthalimide to generate the corresponding fluoride at high conversion rate, capability of avoiding dehydrofluorination reaction in the fluorination process, fluoride intermediate yield of more than 85 percent and purity of more than 97 percent, and suitability for large-scale production.
The invention is realized by the following technical scheme: a preparation method of a fluorine-containing primary amine intermediate takes N-hydroxyalkyl phthalimide compound as a raw material, and reacts with a fluorinating reagent under the action of a Lewis acid catalyst and an organic solvent to obtain the fluorine-containing primary amine intermediate of N-fluoroalkyl phthalimide, and then the intermediate is reduced to obtain the fluorine-containing primary amine, and the preparation method comprises the following steps:
step 1: taking N-hydroxyalkyl phthalimide compound with the structure shown in the formula (I), adding organic solvent, stirring and dissolving to obtain N-hydroxyalkyl phthalimide compound solution;
(I) In the structure shown, R is a linear or branched alkylene group having 0 to 20 carbon atoms, or a linear or branched substituted alkylene group having 0 to 20 carbon atoms;
and 2, step: adding a Lewis acid catalyst into a fluorination reagent, and stirring and reacting at room temperature for 0.5-2 h under the protection of nitrogen to obtain an activated fluorination reagent;
and 3, step 3: dropwise adding the fluorinated reagent activated in the step (2) into the N-hydroxyalkyl phthalimide compound solution in the step (1) for reaction, wherein in the dropwise adding process, the system temperature is controlled to be 10-30 ℃, the reaction is continued for 1-2 h after the dropwise adding is finished, and then the temperature is increased to 40-80 ℃ for continued reaction for 1-3 h, so as to obtain an N-fluoroalkyl phthalimide fluorine-containing primary amine intermediate;
the intermediate of the fluorine-containing primary amine prepared by the invention has a structure shown in (II), and the fluorine-containing primary amine meets the following formula FCH2-R-CH2NH2Wherein R is a linear or branched alkylene group having 0 to 20 carbon atoms, or a linear or branched substituted alkylene group having 0 to 20 carbon atoms;
and (3) post-treatment of the fluorine-containing primary amine intermediate product: and (4) carrying out reduced pressure separation on the N-fluoroalkyl phthalimide fluorine-containing primary amine intermediate prepared in the step (3) to remove the organic solvent, adding absolute ethyl alcohol to dissolve amide, filtering, dissolving and washing filter residues with the absolute ethyl alcohol, and finally drying the filter residues to constant weight to obtain the N-fluoroalkyl phthalimide product with the purity of over 97 percent.
In the post-treatment process, the reduced pressure separation is carried out at the temperature of 20-40 ℃ and under the condition of 30-60 mmHg; the absolute ethyl alcohol is added according to 40-200% of the mass of the rest materials of the system; dissolving and washing the filter residue for 2-4 times by using absolute ethyl alcohol at the temperature of 0-40 ℃, and drying the washed filter residue in a forced air oven at the temperature of 80 ℃ to constant weight.
In the step 1, the organic solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, chloroform, dichloroethane, trichlorotrifluoroethane, acetonitrile and propionitrile;
further, the organic solvent is used in an amount of 20 to 500%, preferably 50 to 200%, based on the mass of the N-hydroxyalkylphthalimide. The solvent mainly serves to dissolve and disperse the reactants to facilitate heat and mass transfer.
In the step 2, the fluorinating reagent is a fluoric alkylamine fluorinating reagent. The fluorating reagent containing fluoroalkyl amine is a dehydroxylation fluorating reagent with wider application.
The structural formula of the fluorinating reagent containing fluoroalkyl amines is as follows: X-CHF-CF2-NR1R2Wherein X is a fluorine atom, a chlorine atom, a trifluoromethyl group, a trifluoromethoxy group, a pentafluoroethoxy group or a heptafluoropropoxy group; r is1、R2Is C1-3The alkyl groups, which may be the same or different.
For example, CHFClCF2NEt2、CF3CHFCF2NEt2、CHF2CF2NMe2、CF3OCF2CHFNEt2、CHF2CF2NMeEt、CF3CF2CF2OCHFCF2NMeCH(CH3)2Isofluorinating agents, of which, CHFClCF2NEt2Because it is not stable and easy to decompose and deteriorate, it is usually necessary to prepare the raw materials on site, and commercial reagents may be purchased, or dimethylamine, diethylamine, N-ethylmethylamine, N-methylisopropylamine, etc. may be used in combination with chlorotrifluoroethylene, tetrafluoroethylene, hexafluoropropylene, perfluoromethyl vinyl ether, perfluoromethylvinyletherPropyl vinyl ether and the like.
Furthermore, the molar amount of the fluorinated reagent containing fluoroalkyl amine is 1 to 2 times of the molar mass of the N-hydroxyalkyl phthalimide compound.
In the step 2, the Lewis acid catalyst is one or more of aluminum trichloride, ferric trichloride, titanium tetrachloride, stannic tetrachloride and boron trifluoride. Wherein, the aluminum trichloride and the ferric trichloride are solid products; titanium tetrachloride and stannic chloride are liquid products; boron trifluoride is a gaseous product, and a commercially available boron trifluoride diethyl etherate solution is generally used.
Further, the particle size of the Lewis acid catalyst solid product is 50-500 meshes.
Furthermore, the dosage of the Lewis acid catalyst is 0.1-3% of the mass of the fluorination reagent.
In step 3, the system temperature is controlled by the dropping speed of the fluorinating agent.
The intermediate N-fluoroethylphthalimide prepared by the invention can be reduced by hydrazine such as hydrazine hydrate by a conventional method to be converted into primary fluorine-containing amine.
Compared with the prior art, the invention has the following advantages and beneficial effects:
(1) The invention provides a novel preparation method for producing a fluorine-containing primary amine intermediate in a large scale, which is characterized in that under the action of an organic solvent and a Lewis acid catalyst, an N-hydroxyalkyl phthalimide compound is directly fluorinated by using a fluorine-containing alkylamine fluorination reagent to obtain corresponding N-fluoroalkyl phthalimide, the method can effectively promote the N-hydroxyalkyl phthalimide compound to generate the corresponding N-fluoroalkyl phthalimide (the fluorine-containing primary amine intermediate) with high conversion rate, the actual yield can reach more than 85 percent, and the raw materials are cheap and easy to obtain, so that the method is suitable for large-scale production.
(2) The organic solvent adopted by the method can effectively control the material viscosity of a fluorination reaction system, and the ratio of the solvent dosage to the N-hydroxyalkyl phthalimide compound quality is reasonably controlled, so that the fluorination reaction process can be effectively improved, and the N-fluoroalkyl phthalimide is ensured to have higher conversion rate.
(3) The method adopts organic solvents such as diethyl ether, tetrahydrofuran, dichloromethane and the like as solvent systems, the boiling point of the organic solvents is greatly different from that of a target product, so that the later separation and purification are facilitated, and the solvents are easy to obtain, cheap and recyclable.
(4) The method of the invention adopts Lewis acid as the catalyst, which can effectively promote the reaction, shorten the time and improve the yield, when the catalyst is solid, the solid catalyst is crushed in a dry environment in advance to the granularity of 50-500 meshes, and then the solid catalyst is added into the system for reaction, and the promotion effect is particularly obvious.
(5) The method adopts the fluorine-containing alkylamine fluorination reagent with a specific structure, the fluorine-containing alkylamine fluorination reagent can be prepared on site during actual use, the fluorine-containing alkylamine fluorination reagent can be used for reaction after simple low-temperature decompression and purification and then is premixed and activated with the Lewis acid catalyst, the dosage of the Lewis acid catalyst is limited to 0.1-3% of the mass of the fluorination reagent during actual use, and the fluorine-containing alkylamine fluorination reagent and the Lewis acid catalyst which are used in a matching way can effectively ensure that the fluorination reaction is carried out at high efficiency.
(6) The method of the invention adopts the fluorine-containing alkylamine fluorination reagent to cooperate with the Lewis acid catalyst, which can promote the fluorination reaction to be carried out efficiently, quickly and stably, and simultaneously can avoid the dehydrofluorination reaction in the fluorination process, thereby ensuring the higher yield of the fluorine-containing primary amine intermediate N-fluorinated alkyl phthalimide.
(7) The N-fluoroalkyl phthalimide intermediate obtained by the method can be efficiently converted into the fluorine-containing primary amine by using a known reduction method, the process route is simple and easy to control, the production cost of the fluorine-containing primary amine is reduced, and the industrial production of the fluorine-containing primary amine is facilitated.
Detailed Description
The present invention will be described in further detail with reference to examples, but the embodiments of the present invention are not limited thereto.
1. CHFClCF according to the invention referred to in the following examples2NEt2Containing fluorineThe alkylamine fluorination reagent is prepared on site by the following method and then is used:
cleaning the pipelines such as the 5L low-pressure reaction kettle, the feeding pipeline and the like, blowing by using nitrogen to ensure no blockage, and keeping the device dry. And (4) testing leakage of nitrogen at 0.5MPa, and feeding and reacting after no leakage is proved. The charging hole of the kettle is opened, the vacuum pump is used for vacuum pumping, ice water refrigerant is firstly introduced after the vacuum pumping, the temperature of the kettle is reduced to about 5 ℃, and then 200g of diethylamine (2.73 mol) is sucked into the reaction kettle by utilizing the vacuum in the kettle. Then starting stirring, slowly adding 318g of chlorotrifluoroethylene (2.73 mol) when the temperature of the reaction kettle is reduced to below 10 ℃, controlling the temperature of the reaction kettle to be not more than 20 ℃, removing a feeding pipeline after the feeding of the chlorotrifluoroethylene is finished, reacting for about 12 hours, reducing the pressure of the reaction kettle to 0 or negative pressure, supplementing nitrogen to positive pressure, collecting materials, performing reduced pressure refining to obtain 516g of brown yellow liquid product, and analyzing CHFClCF by GC2NEt2The content was 95%, and the yield was 94.5%.
2. CHFClCF removal as referred to in the following examples of the invention2NEt2The external fluorine-containing alkylamine fluorination reagent can be a commercial product or a product similar to CF on the basis of different raw materials3CHFCF2NEt2The fluorizating reagent is prepared by the same method:
CF3CHFCF2NEt2preparation of fluorinating reagent: 105g of diethylamine (1.44 mol) and 200ml of anhydrous ether are put into a three-neck flask with a gas-guide tube and reflux condensation, cooled to 0-5 ℃, cooled by an ice bath, 216g (1.44 mol) of hexafluoropropylene gas is blown into the reaction solution, stirred vigorously and controlled to be lower than 10 ℃, and the hexafluoropropylene is absorbed in about 2 hours. The ice bath was removed, warmed to room temperature and stirred overnight. The solvent was removed by rotary evaporation, and the residue was distilled under reduced pressure to give 260g of a colorless oil in which CF was analyzed by GC3CHFCF2NEt2Content 78% isomer Et2NCF=CFCF3Content 22% and preparation yield 63%.
Example 1
1) Adding 98.5g (0.51 mol) of commercial N-hydroxyethyl phthalimide with the purity of 99 percent and 50ml (about 70 g) of solvent dichloromethane into a 500ml three-necked bottle at room temperature, and starting stirring to completely dissolve the N-hydroxyethyl phthalimide;
2) CF is added into another 250ml three-neck flask3CHFCF2NEt2148g (0.51 mol) of fluorinating agent (GC content is 78%) and 3.0g of crushed aluminum trichloride (50 meshes) catalyst are stirred and reacted for 1h at room temperature under the protection of nitrogen;
3) Dropwise adding the activated fluorination reagent into a dichloromethane solution of N-hydroxyethyl phthalimide under stirring by using a constant-pressure feeding funnel, controlling the dropwise adding speed of the fluorination reagent to maintain the temperature of the system at 30 ℃, continuously reacting for 1h after dropwise adding is finished, heating to 60 ℃ and continuously reacting for 1h, detecting the reaction progress by using a TLC (thin layer chromatography) point plate, and stopping the reaction if the raw materials disappear to obtain the intermediate of the N-fluoroalkyl phthalimide fluorine-containing primary amine.
And (3) post-treatment of the fluorine-containing primary amine intermediate product: separating and removing CH under reduced pressure at 30 deg.C and 60mmHg2Cl2Adding anhydrous ethanol at 25 ℃ according to 80% of the mass of the rest materials in the system to dissolve amide, filtering, dissolving and washing filter residue with the anhydrous ethanol at room temperature for 3 times, and finally drying the filter residue in a forced air oven at 80 ℃ to constant weight to obtain 85.7g of N-fluoroethyl phthalimide, wherein the product purity is 99.2% and the yield is 86.4%. Having a hydrogen spectrum of nuclear magnetic resonance of1H NMR (400 MHz, CDCl3) δ (ppm): 7.71-7.88 (m, 4H,-C6H4), 4.62 (td, 2H, -CH2CH2F), 3.94 (td, 2H, -CH2CH2F) Fluorine spectrum19F NMR (400 MHz, CDCl3) δ (ppm): -224 (m, -CH2CH2F) Further proving that the intermediate of the fluorine-containing primary amine is an N-fluoroethyl phthalimide compound.
Reduction treatment of fluorine-containing primary amine intermediate: adding 80.7g of N-fluoroethylphthalimide with the purity of 99.2 percent and 150g of absolute ethyl alcohol into a 500ml three-neck flask with a mechanical stirring device, a constant-pressure feeding funnel and a thermometer guide pipe, stirring and raising the mixture to the reflux temperature, after the solid is dissolved completely, dropwise adding 30g of 80 percent hydrazine hydrate through the constant-pressure feeding funnel, continuing to react for 3 hours after the dropwise adding is completed, monitoring the reaction progress by using a TLC point plate during the process, and continuing to react for 30 minutes if the raw materials disappear. Work-up gave 25.5g of 99.72% (GC purity) 2-fluoroethylamine, reduction yield 91.6%.
Example 2
193g (1 mol) of commercially available N-hydroxyethylphthalimide having a purity of 99% are weighed into a 1L three-necked flask with mechanical stirring, a constant-pressure addition funnel and a thermometer tube, and 100ml (about 80 g) of dry acetonitrile are added under a nitrogen blanket. The water bath was started and the fluorinating reagent CHFClCF, purified from 375g (1.5 mol) and having a GC content of 95%, was added dropwise with stirring2NEt25g of a mixed solution of boron trifluoride diethyl etherate having a content of 46% and 100ml of acetonitrile. Maintaining the internal temperature at 20-25 ℃ during the dripping period, continuing the reaction for 1h after the dripping is finished, then increasing the temperature to 45 ℃ for continuing the reaction for 1h, monitoring the reaction progress by using a TLC (thin layer chromatography) point plate during the reaction, and stopping the reaction if the raw materials disappear to obtain the N-fluoroalkyl phthalimide fluorine-containing primary amine intermediate.
Post-treatment of intermediate product containing primary fluorine amine: separating under reduced pressure at 20 ℃ and 40mmHg to remove acetonitrile as a solvent, adding 40 ℃ absolute ethyl alcohol according to 60% of the mass of the rest materials of the system to dissolve amide, filtering, dissolving and washing filter residue for 4 times by using 15 ℃ absolute ethyl alcohol, and finally drying the filter residue in a 80 ℃ forced air oven until the weight is constant to obtain 183g of N-fluoroethylphthalimide, wherein the purity of the product is 99.5%, and the yield is 94.3%.
Example 3
With a fluorinating agent CHF of 97%2CF2NMe2The fluorination reagent, catalyst and solvent of example 2 were replaced by (prepared by equimolar reaction of tetrafluoroethylene and dimethylamine), titanium tetrachloride and tetrahydrofuran, wherein the amount of tetrahydrofuran was 96.5g, and the other material ratios and process conditions were the same as those of example 2. 188g of N-fluoroethylphthalimide is finally obtained, the product purity is 99.6 percent, and the yield is 97 percent.
Example 4
1) 200g of N- (3-hydroxypropyl) phthalimide (0.95 mol) having a purity of 97.4% was charged in a 1L three-necked flask at room temperature, 200ml (about 300 g) of dry chloroform was added thereto, and the N- (3-hydroxypropyl) phthalimide was completely dissolved with stirring.
2) Into another 250ml three-necked flask was charged 210g of a fluorinating agent CHFClCF having a GC content of 98% after purification2NEt2(1.08 mol), then 1.2g of crushed aluminum trichloride (250 meshes) is added, and the reaction is stirred for 1h at room temperature under the protection of nitrogen.
3) And (2) dropwise adding the activated fluorination reagent into N- (3-hydroxypropyl) phthalimide through a constant-pressure feeding funnel for reaction, controlling the dropwise adding speed to keep the temperature of the system at 30 ℃, continuing to react for 1h after dropwise adding is finished, then heating to 65 ℃ for continuing to react for 1h, monitoring the reaction progress by using a TLC (thin layer chromatography) point plate, and stopping the reaction if the raw materials disappear to obtain the N- (3-fluoropropyl) phthalimide fluorine-containing primary amine intermediate.
Post-treatment of intermediate product containing primary fluorine amine: and (2) carrying out reduced pressure separation at 40 ℃ and 30mmHg to remove chloroform, adding 10 ℃ absolute ethyl alcohol according to 150% of the mass of the rest materials of the system to dissolve amide, filtering, dissolving and washing filter residues by using the room temperature absolute ethyl alcohol for 3 times, and finally drying the filter residues in a 80 ℃ forced air oven to constant weight to obtain 184g of N- (3-fluoropropyl) phthalimide, wherein the product purity is 99.1%, and the yield is 92.7%. Having a hydrogen spectrum of nuclear magnetic resonance of1H NMR (400 MHz, CDCl3) δ (ppm): 7.75-7.88 (m, 4H, -C6H4), 4.55 (dt, 2H, -CH2CH2CH2F), 4.08 (t, 2H, -CH2CH2CH2F), 2.19 (m, 2H, -CH2CH2CH2F) Fluorine spectrum19F NMR (400 MHz, CDCl3) δ (ppm): -223 (m, -CH2CH2CH2F) The primary fluorine-containing amine intermediate is further proved to be N- (3-fluoropropyl) phthalimide compound.
Reduction treatment of primary fluorine-containing amine intermediate: 3-Fluoropropylamine (FCH) was obtained by reducing N- (3-fluoropropyl) phthalimide with hydrazine hydrate in the same manner as in example 12CH2CH2NH2）。
Example 5
1) 200g of N- (5-hydroxypentyl) phthalimide having a purity of 98.5% (0.845 mol) was charged into a 1L three-necked flask at room temperature, 200ml (about 250 g) of dichloroethane was added, and the N- (5-hydroxypentyl) phthalimide was completely dissolved with stirring.
2) Into another 500ml three-necked flask was charged 335g of a fluorinating agent CF having a GC content of 98% after purification3OCF2CHFNEt2(prepared by equimolar reaction of perfluoromethyl vinyl ether and diethylamine), 2.5g of crushed ferric chloride (500 mesh) was added, and the reaction was stirred at room temperature for 1 hour under nitrogen protection.
3) And (2) dropwise adding the fluorination reagent into the N- (5-hydroxypentyl) phthalimide through a constant-pressure feeding funnel for reaction, controlling the dropwise adding speed to keep the temperature of the system at 30 ℃, continuing to react for 1h after dropwise adding is finished, then heating to 65 ℃ and continuing to react for 2h, monitoring the reaction progress by using a TLC (thin layer chromatography) point plate, and stopping the reaction if the raw materials disappear to obtain the N- (5-fluoropentyl) phthalimide fluorine-containing primary amine intermediate.
Post-treatment of intermediate product containing primary fluorine amine: and (2) separating and removing dichloroethane under the conditions of 25 ℃ and 50mmHg under reduced pressure, adding 0 ℃ absolute ethyl alcohol according to 200% of the mass of the rest materials in the system to dissolve amide, filtering, dissolving and washing the filter residue with the room temperature absolute ethyl alcohol for 2 times, and finally drying the filter residue in a 80 ℃ forced air oven to constant weight to obtain 185g of N- (5-fluoropentyl) phthalimide, wherein the product purity is 98.6%, and the yield is 91.9%. Having a hydrogen spectrum of nuclear magnetic resonance of1H NMR (400 MHz, CDCl3) δ (ppm): 7.74-7.88 (m, 4H, -C6H4), 4.29 (dt, 2H, -CH2CH2CH2CH2CH2F), 3.67 (t, 2H, -CH2CH2CH2CH2CH2F), 1.71 (m, 2H, -CH2CH2CH2CH2CH2F), 1.49 (m, 2H, -CH2CH2CH2CH2CH2F), 1.28 (m, 2H, -CH2CH2CH2CH2CH2F) Fluorine spectrum19F NMR (400 MHz, CDCl3) δ (ppm): -220 (m, -CH2CH2CH2CH2CH2F) Further demonstrating that the primary fluorinated amine intermediate is N- (5-fluoropentyl) phthalimideAn amine compound.
Reduction treatment of fluorine-containing primary amine intermediate: 5-Fluoropentylamine (FCH) was obtained by reducing N- (5-fluoropentyl) phthalimide with hydrazine hydrate in the same manner as in example 12(CH2)3CH2NH2）。
Example 6
1) 100g of 98% N- (8-hydroxyoctyl) phthalimide (0.36 mol) was charged into a three-necked flask at room temperature, 150ml (200 g) of methylene chloride was added thereto, and the N- (8-hydroxyoctyl) phthalimide was completely dissolved with stirring.
2) In a further 250ml three-necked flask, 105g (0.7 mol) of CHF, a purified fluorination reagent having a content of 97% was placed2CF2NMe2And 3g of tin tetrachloride, stirred at room temperature for 1h under nitrogen.
3) And (2) dropwise adding the activated fluorination reagent into N- (8-hydroxyoctyl) phthalimide through a constant-pressure feeding funnel for reaction, controlling the dropwise adding speed to keep the temperature of the system at 30 ℃, continuing to react for 1h after the dropwise adding is finished, then heating to 65 ℃ for continuing to react for 2h, monitoring the reaction progress by using a TLC point plate, and stopping the reaction if the raw materials disappear to obtain the N- (8-fluorooctyl) phthalimide fluorine-containing primary amine intermediate.
The intermediate product containing primary fluorine amine was worked up in the same manner as in example 1 to give 88.5g of N- (8-fluorooctyl) phthalimide, the product purity was 97.2%, and the yield was 86.3%. Having a hydrogen spectrum of nuclear magnetic resonance of1H NMR (400 MHz, CDCl3) δ (ppm): 7.85-7.88 (m, 4H, -C6H4), 4.39 (dt, 2H, -CH2CH2(CH2)4CH2CH2F), 3.76 (t, 2H, -CH2CH2(CH2)4CH2CH2F), 1.70 (m, 2H, -CH2CH2(CH2)4CH2CH2F), 1.58 (m, 2H, -CH2CH2(CH2)4CH2CH2F), 1.29 (m, 8H, -CH2CH2(CH2)4CH2CH2F) Fluorine spectrum19F NMR (400 MHz, CDCl3) δ (ppm): -221 (m, -CH2CH2(CH2)4CH2CH2F) Further proving that the primary fluorine-containing amine intermediate is an N- (8-fluoro octyl) phthalimide compound.
Reduction treatment of primary fluorine-containing amine intermediate: in the same manner as in example 1, N- (8-fluorooctyl) phthalimide was reduced with hydrazine hydrate to obtain 8-Fluorooctylamine (FCH)2(CH2)6CH2NH2）。
Example 7
1) 100g of N- (8-hydroxy-3, 6-dioxaoctyl) phthalimide (0.35 mol) having a content of 97% was charged in a three-necked flask at room temperature, 150ml (about 120 g) of anhydrous propionitrile was added, and N- (8-hydroxy-3, 6-dioxaoctyl) phthalimide was completely dissolved with stirring.
2) In a further 250ml three-necked flask, 105g (0.7 mol) of CHF, a purified fluorination reagent having a content of 97% was placed2CF2NMe2Then, 3g of crushed aluminum trichloride (250 mesh) was added thereto, and the reaction was stirred at room temperature for 1 hour under nitrogen protection.
3) And dropwise adding the activated fluorination reagent into N- (8-hydroxy-3, 6-dioxaoctyl) phthalimide through a constant-pressure feeding funnel for reaction, controlling the dropwise adding speed to keep the temperature of the system at 30 ℃, continuing the reaction for 1h after the dropwise adding is finished, then heating to 75 ℃ for continuing the reaction for 2h, detecting the reaction progress by using a TLC point plate, and stopping the reaction if the raw materials disappear to obtain the N- (8-fluoro-3, 6-dioxaoctyl) phthalimide fluorine-containing primary amine intermediate.
The intermediate product containing a primary fluorine-containing amine was worked up in the same manner as in example 1 to give 88.5g of N- (8-fluoro-3, 6-dioxaoctyl) phthalimide, the product purity was 97.5%, and the yield was 87.7%. Having a hydrogen spectrum of nuclear magnetic resonance of1H NMR (400 MHz, CDCl3) δ (ppm): 7.75-7.88 (m, 4H, -C6H4), 4.26 (dt, 2H, -CH2CH2O(CH2)2OCH2CH2F), 3.83 (t, 2H, -CH2CH2O(CH2)2OCH2CH2F), 3.82 (t, 2H, -CH2CH2O(CH2)2OCH2CH2F), 3.57 (m, 2H, -CH2CH2O(CH2)2OCH2CH2F), 3.54 (m, 4H, -CH2CH2O(CH2)2OCH2CH2F) Fluorine spectrum19F NMR (400 MHz, CDCl3) δ (ppm): -224 (m, -CH2CH2O(CH2)2OCH2CH2F) The primary fluorinated amine intermediate was further demonstrated to be an N- (8-fluoro-3, 6-dioxaoctyl) phthalimide compound.
Reduction treatment of primary fluorine-containing amine intermediate: in the same manner as in example 1, N- (8-fluorooctyl) phthalimide was reduced with hydrazine hydrate to give 8-fluoro-3, 6-dioxaoctylamine (FCH)2CH2OCH2CH2OCH2CH2NH2）。
Example 8
With a fluorinating agent CHF of 98%2CF2NMeEt (prepared by equimolar reaction of tetrafluoroethylene and N-ethylmethylamine), ferric trichloride (300 mesh) and CF3CCl3In place of the fluorinating agent, catalyst and solvent in example 4, wherein CH2ClCH2The process conditions were the same as in example 4 except that the amount of Cl was 40g, the amount of N- (3-hydroxypropyl) phthalimide was 200g, the amount of ferric chloride was 0.21g, and the amount of the fluorinating agent was 210 g. 190g of N- (3-fluoropropyl) phthalimide is finally obtained, the product purity is 99.5 percent, and the yield is 96.1 percent.
Example 9
With a fluorinating agent CF of 98%3CF2CF2OCHFCF2NMeCH(CH3)2(from perfluoropropyl vinyl ether CF)3CF2CF2OCF=CF2Prepared by equimolar reaction with N-methyl isopropyl amine), a catalyst composed of tin tetrachloride and titanium tetrachloride in an equal weight ratio, a mixed solvent of acetonitrile and propionitrile (volume ratio 1: 1) instead of fluorine in example 5The process comprises the following steps of preparing 1000g of a chemical reagent, 200g of N- (5-hydroxypentyl) phthalimide, 10g of a catalyst and 335g of a fluorination reagent by using a mixed solvent, wherein the process conditions are the same as those of example 5. 182g of N- (5-fluoropentyl) phthalimide is finally obtained, the product purity is 98.3 percent, and the yield is 90.1 percent.
Comparative example 1
100g (0.52 mol) of commercial N-hydroxyethylphthalimide with a purity of 99% was weighed into a 500ml three-necked flask with mechanical stirring, a constant pressure addition funnel and a thermometer tube, and 200ml (265 g) of dry dichloromethane was added under nitrogen protection, and N-hydroxyethylphthalimide was completely dissolved with stirring. Then the temperature is reduced to 0 ℃, and 150g (0.78 mol) of fluorizating agent CHFClCF with 98 percent of GC content after purification is added dropwise under stirring2NEt2After the addition, the reaction was continued at 0 ℃ for 24h. Working up in the same manner as in example 1 gave 91g of a product having an N-fluoroethylphthalimide content of 72.2%, a dehydrofluorination product N-vinylphthalimide content of 27.8% and a fluorination yield of 65.5%. ( In experiments, the dehydrofluorination reaction of the product is greatly increased when the reaction is carried out at normal temperature or elevated temperature. In order to reduce the decomposition of the fluorinating agent and the dehydrofluorination of the product, this comparative example employed a method of prolonging the reaction time at a low temperature of 0 deg.C )
As can be seen from the above comparative example 1, starting from an N-hydroxyethylphthalimide compound, CHFClCF which has not been activated with a Lewis acid catalyst is used2NEt2The fluorinating reagent is directly fluorinated to obtain an intermediate containing dehydrofluorination product N-vinyl phthalimide, the product yield and purity are greatly reduced, and the method is not suitable for industrial production.
Claims (9)
1. A preparation method of a fluorine-containing primary amine intermediate is characterized by comprising the following steps:
step 1: taking N-hydroxyalkyl phthalimide compound with the structure shown in the formula (I), adding organic solvent, stirring and dissolving to obtain N-hydroxyalkyl phthalimide compound solution;
(I) In the structure shown, R is a linear or branched alkylene group having 0 to 20 carbon atoms, or a linear or branched substituted alkylene group having 0 to 20 carbon atoms;
step 2: adding a Lewis acid catalyst into a fluorination reagent, and stirring and reacting at room temperature for 0.5-2 h under the protection of nitrogen to obtain an activated fluorination reagent;
the fluorinating reagent is a fluoric alkylamine fluorinating reagent, and the structural formula is as follows: X-CHF-CF2-NR1R2Wherein X is a fluorine atom, a chlorine atom, a trifluoromethyl group, a trifluoromethoxy group, a pentafluoroethoxy group or a heptafluoropropoxy group; r1、R2Is C1-3An alkyl group;
and step 3: dropwise adding the fluorinated reagent activated in the step (2) into the N-hydroxyalkyl phthalimide compound solution in the step (1) for reaction, wherein in the dropwise adding process, the system temperature is controlled to be 10-30 ℃, the reaction is continued for 1-2 h after the dropwise adding is finished, and then the temperature is increased to 40-80 ℃ for continued reaction for 1-3 h, so as to obtain an N-fluoroalkyl phthalimide fluorine-containing primary amine intermediate;
the intermediate of the fluorine-containing primary amine has a structure shown in (II), and the fluorine-containing primary amine satisfies the following formula FCH2-R-CH2NH2Wherein R is a linear or branched alkylene group having 0 to 20 carbon atoms, or a linear or branched substituted alkylene group having 0 to 20 carbon atoms;
2. the method for preparing a primary fluorine-containing amine intermediate according to claim 1, wherein: in the step 1, the organic solvent is one or more of diethyl ether, tetrahydrofuran, dichloromethane, chloroform, dichloroethane, trifluorotrichloroethane, acetonitrile and propionitrile.
3. The method for producing a primary fluorinated amine intermediate according to claim 1 or 2, characterized in that: the dosage of the organic solvent is 20-500% of the mass of the N-hydroxyalkyl phthalimide.
4. The method for preparing a primary fluorine-containing amine intermediate according to claim 1, wherein: the molar amount of the fluorinated reagent containing fluoroalkyl amines is 1-2 times of that of the N-hydroxyalkyl phthalimide compound.
5. The method for preparing a primary fluorine-containing amine intermediate according to claim 1, wherein: in the step 2, the Lewis acid catalyst is one or more of aluminum trichloride, ferric trichloride, titanium tetrachloride, stannic tetrachloride and boron trifluoride.
6. The process for producing a primary fluorinated amine intermediate according to claim 1 or 5, characterized in that: the dosage of the Lewis acid catalyst is 0.1 to 3 percent of the mass of the fluorinating reagent.
7. The method for preparing a primary fluorine-containing amine intermediate according to claim 5, wherein: the Lewis acid catalyst aluminum trichloride and ferric trichloride are solid products, and the granularity is 50-500 meshes.
8. The method for preparing a primary fluorine-containing amine intermediate according to claim 1, wherein: and (4) carrying out reduced pressure separation on the fluorine-containing primary amine intermediate of the N-fluoroalkyl phthalimide prepared in the step (3) to remove the organic solvent, adding absolute ethyl alcohol to dissolve the fluorine-containing primary amine intermediate, filtering, dissolving and washing filter residues by using the absolute ethyl alcohol, and finally drying the filter residues to constant weight to obtain the N-fluoroalkyl phthalimide product with the purity of more than 97%.
9. The method for preparing a primary fluorine-containing amine intermediate according to claim 8, wherein: the reduced pressure separation is carried out at the temperature of 20-40 ℃ and under the condition of 30-60 mmHg; adding the absolute ethyl alcohol according to 40-200% of the mass of the rest materials in the system, dissolving and washing the filter residue for 2-4 times by using the absolute ethyl alcohol at 0-40 ℃, and drying the washed filter residue in a forced air oven at 80 ℃ to constant weight.
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