CN116924924A - Synthetic method of tetracaine - Google Patents
Synthetic method of tetracaine Download PDFInfo
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- CN116924924A CN116924924A CN202310908820.XA CN202310908820A CN116924924A CN 116924924 A CN116924924 A CN 116924924A CN 202310908820 A CN202310908820 A CN 202310908820A CN 116924924 A CN116924924 A CN 116924924A
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- butyl
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- GKCBAIGFKIBETG-UHFFFAOYSA-N tetracaine Chemical compound CCCCNC1=CC=C(C(=O)OCCN(C)C)C=C1 GKCBAIGFKIBETG-UHFFFAOYSA-N 0.000 title claims abstract description 25
- 229960002372 tetracaine Drugs 0.000 title claims abstract description 24
- 238000010189 synthetic method Methods 0.000 title claims description 4
- 238000006243 chemical reaction Methods 0.000 claims abstract description 40
- 238000000034 method Methods 0.000 claims abstract description 13
- ZJDBQMWMDZEONW-UHFFFAOYSA-N 4-[(2-methylpropan-2-yl)oxycarbonylamino]benzoic acid Chemical compound CC(C)(C)OC(=O)NC1=CC=C(C(O)=O)C=C1 ZJDBQMWMDZEONW-UHFFFAOYSA-N 0.000 claims abstract description 9
- UEEJHVSXFDXPFK-UHFFFAOYSA-N N-dimethylaminoethanol Chemical compound CN(C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000002994 raw material Substances 0.000 claims abstract description 8
- MPPPKRYCTPRNTB-UHFFFAOYSA-N 1-bromobutane Chemical compound CCCCBr MPPPKRYCTPRNTB-UHFFFAOYSA-N 0.000 claims abstract description 6
- 239000002253 acid Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 42
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 24
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 23
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 22
- 238000003756 stirring Methods 0.000 claims description 21
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 18
- 239000012074 organic phase Substances 0.000 claims description 16
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 15
- 239000003153 chemical reaction reagent Substances 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 10
- 238000001035 drying Methods 0.000 claims description 10
- 238000001914 filtration Methods 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 10
- 239000007788 liquid Substances 0.000 claims description 10
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 10
- LVTJOONKWUXEFR-FZRMHRINSA-N protoneodioscin Natural products O(C[C@@H](CC[C@]1(O)[C@H](C)[C@@H]2[C@]3(C)[C@H]([C@H]4[C@@H]([C@]5(C)C(=CC4)C[C@@H](O[C@@H]4[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@@H](O)[C@H](O[C@H]6[C@@H](O)[C@@H](O)[C@@H](O)[C@H](C)O6)[C@H](CO)O4)CC5)CC3)C[C@@H]2O1)C)[C@H]1[C@H](O)[C@H](O)[C@H](O)[C@@H](CO)O1 LVTJOONKWUXEFR-FZRMHRINSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 10
- 238000001308 synthesis method Methods 0.000 claims description 10
- 238000010992 reflux Methods 0.000 claims description 9
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 8
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 8
- 150000001875 compounds Chemical class 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 238000001291 vacuum drying Methods 0.000 claims description 8
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 claims description 6
- 238000000605 extraction Methods 0.000 claims description 6
- 239000000243 solution Substances 0.000 claims description 6
- 239000012445 acidic reagent Substances 0.000 claims description 5
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical group COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 4
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 230000015572 biosynthetic process Effects 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 239000012071 phase Substances 0.000 claims description 4
- 125000006239 protecting group Chemical group 0.000 claims description 4
- 238000003786 synthesis reaction Methods 0.000 claims description 4
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 3
- RQXXCWHCUOJQGR-UHFFFAOYSA-N 1,1-dichlorohexane Chemical group CCCCCC(Cl)Cl RQXXCWHCUOJQGR-UHFFFAOYSA-N 0.000 claims description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 2
- 239000011259 mixed solution Substances 0.000 claims description 2
- 238000005191 phase separation Methods 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 125000003944 tolyl group Chemical group 0.000 claims description 2
- -1 N-Boc-N-butyl-4-aminobenzoic acid butyl ester Chemical compound 0.000 abstract description 19
- 239000012535 impurity Substances 0.000 abstract description 5
- UKVIEHSSVKSQBA-UHFFFAOYSA-N methane;palladium Chemical compound C.[Pd] UKVIEHSSVKSQBA-UHFFFAOYSA-N 0.000 abstract description 4
- 230000002194 synthesizing effect Effects 0.000 abstract description 3
- 238000004321 preservation Methods 0.000 abstract description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 abstract 1
- 238000005984 hydrogenation reaction Methods 0.000 abstract 1
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 15
- 239000000047 product Substances 0.000 description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 10
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- 238000002360 preparation method Methods 0.000 description 8
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 6
- 239000012065 filter cake Substances 0.000 description 6
- ALYNCZNDIQEVRV-UHFFFAOYSA-N 4-aminobenzoic acid Chemical compound NC1=CC=C(C(O)=O)C=C1 ALYNCZNDIQEVRV-UHFFFAOYSA-N 0.000 description 5
- 239000000706 filtrate Substances 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 206010002091 Anaesthesia Diseases 0.000 description 4
- ZTQSAGDEMFDKMZ-UHFFFAOYSA-N Butyraldehyde Chemical compound CCCC=O ZTQSAGDEMFDKMZ-UHFFFAOYSA-N 0.000 description 4
- 230000037005 anaesthesia Effects 0.000 description 4
- 230000000052 comparative effect Effects 0.000 description 4
- 229910052739 hydrogen Inorganic materials 0.000 description 4
- 239000001257 hydrogen Substances 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- YCCRFDDXAVMSLM-UHFFFAOYSA-N 4-(butylamino)benzoic acid Chemical compound CCCCNC1=CC=C(C(O)=O)C=C1 YCCRFDDXAVMSLM-UHFFFAOYSA-N 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229960004050 aminobenzoic acid Drugs 0.000 description 3
- 239000007791 liquid phase Substances 0.000 description 3
- 238000010587 phase diagram Methods 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 239000003054 catalyst Substances 0.000 description 2
- 239000012141 concentrate Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000012044 organic layer Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 238000005406 washing Methods 0.000 description 2
- UEEJHVSXFDXPFK-UHFFFAOYSA-O N-dimethylethanolamine Chemical compound C[NH+](C)CCO UEEJHVSXFDXPFK-UHFFFAOYSA-O 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 238000001839 endoscopy Methods 0.000 description 1
- 238000002692 epidural anesthesia Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000002690 local anesthesia Methods 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229910052751 metal Inorganic materials 0.000 description 1
- 239000002184 metal Substances 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 1
- 239000008096 xylene Substances 0.000 description 1
- 238000004383 yellowing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/16—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions not involving the amino or carboxyl groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C227/00—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton
- C07C227/14—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof
- C07C227/18—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters
- C07C227/20—Preparation of compounds containing amino and carboxyl groups bound to the same carbon skeleton from compounds containing already amino and carboxyl groups or derivatives thereof by reactions involving amino or carboxyl groups, e.g. hydrolysis of esters or amides, by formation of halides, salts or esters by hydrolysis of N-acylated amino-acids or derivatives thereof, e.g. hydrolysis of carbamates
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C269/00—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
- C07C269/06—Preparation of derivatives of carbamic acid, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups by reactions not involving the formation of carbamate groups
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a method for synthesizing tetracaine, which comprises the following steps: taking N-Boc-4-aminobenzoic acid (A) as a raw material, and carrying out heat preservation reaction on the raw material and bromon-butane to obtain N-Boc-N-butyl-4-aminobenzoic acid butyl ester (B); removing Boc from N-Boc-N-butyl-4-aminobenzoic acid butyl ester (B) under weak acid to obtain N-butyl-4-aminobenzoic acid butyl ester (C); butyl N-butyl-4-aminobenzoate (C) reacts with N, N-dimethylethanolamine to obtain the tetracaine (I). The method effectively reduces the generation risk of N-disubstituted butyl impurities, does not need palladium-carbon hydrogenation reaction, and the prepared tetracaine has high purity and yield, the purity of the product is more than 99.8%, and the single impurity is less than 0.05%, thereby meeting the requirements of medicinal raw materials.
Description
Technical Field
The invention belongs to the technical field of synthesis processes, and particularly relates to a method for synthesizing tetracaine.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Tetracaine (tetracaine), which is known as 4- (butylamino) -benzoic acid-2- (dimethylamino) ethyl ester, belongs to long-acting ester local anesthetics, has good fat solubility and penetrability, is suitable for carrying out mucosal surface anesthesia, nerve block anesthesia, epidural anesthesia and subarachnoid anesthesia, is commonly used for various detection and diagnosis of ophthalmology or local anesthesia of nose and throat parts, and can also be applied to endoscopy or spinal column and epidural block anesthesia.
At present, a synthetic process of tetracaine is provided in a patent CN201210242596.7, wherein aminobenzoic acid and n-butyraldehyde are adopted to obtain 4- (n-butenylamino) benzoic acid, palladium carbon (10%) is added, and hydrogen is introduced for reduction, so that 4- (n-butylamino) benzoic acid is obtained. The preparation method relates to the addition of hydrogen, the danger coefficient of production personnel is obviously improved, the palladium-carbon catalyst is high in price, and the preparation process cost is high.
Aiming at the current situation, the invention considers that the method for producing the tetracaine has important significance, and the method has the advantages of simple process, low cost and high safety coefficient.
Disclosure of Invention
Based on the technical background, the invention aims to provide the method for preparing the tetracaine, which is mild in reaction conditions and high in product yield. In order to achieve the technical purpose, the invention provides the following scheme:
in a first aspect of the present invention, there is provided a method for synthesizing tetracaine, the synthetic route being as follows:
the synthesis method comprises the following specific steps:
(1) Raw material N-Boc-4-aminobenzoic acid (A) reacts with bromo-N-butane in an alkaline solvent to obtain a compound B;
(2) Removing Boc protecting groups from the compound B in weak acid to prepare a compound C;
(3) And (3) reacting the compound C with N, N-dimethylethanolamine to obtain the tetracaine (I).
In step (1):
the molar ratio of the N-Boc-4-aminobenzoic acid to the bromo-N-butane is 1:2-1:8, and more preferably 1:3-1:5.
The alkaline solvent is a mixed solution of an alkaline reagent and an organic reagent, wherein the alkaline reagent is selected from one or a combination of a plurality of triethylamine, N-diisopropylethylamine, sodium carbonate and potassium carbonate, and is preferably triethylamine or potassium carbonate; the organic reagent is selected from one or more of acetonitrile, toluene, xylene, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide, and is preferably acetonitrile or toluene.
Further, the dosage ratio of the alkaline reagent to the organic reagent is 55-65 g: 90-110 ml.
In one embodiment, the specific synthesis manner of the step (1) is as follows:
adding an alkaline solvent and N-Boc-4-aminobenzoic acid into a reaction vessel, heating to 55-65 ℃, slowly dropwise adding bromon-butane, and reacting for 5-7 h at 65-75 ℃ after dropwise adding; after the reaction is finished, adding 45-55% ethyl acetate solution into the reaction system for liquid separation, preserving the organic phase for partial drying and filtering, adding n-hexane for heating and refluxing for 0.4-0.6 h, stirring and crystallizing for 2h at 10-20 ℃, and vacuum drying for 4-6 h at 40-45 ℃ to obtain the compound B.
In the step (2):
the weak acid is a low concentration of acidic reagent, such as formic acid, glacial acetic acid, trifluoroacetic acid, preferably formic acid, glacial acetic acid, and possible concentrations are, for example, 8-12 g/L.
The reaction temperature is 40-50 ℃ and the reaction is stirred for 5-7 h to remove the Boc protecting group.
In a specific embodiment, the reaction steps are as follows:
adding the compound B into the low-concentration acidic reagent, and stirring and reacting for 5-7 h at 35-45 ℃; adding 45-55% ethyl acetate solution into the reaction system for separating, keeping the organic phase partially dried and concentrated, adding n-hexane for heating and refluxing, stirring and crystallizing at 0-10 ℃ for 2-4 h, and vacuum drying at 40-45 ℃ for 4-6 h to obtain the compound C.
In the step (3):
the molar ratio of the compound C to the N, N-dimethylethanolamine is as follows: 1:2-1:6; preferably 1:3 to 1:5. In a specific embodiment, the compound C and sodium methoxide are put into a solvent, heated to 55-65 ℃ and stirred for 0.4-0.6 h, N-dimethylethanolamine is slowly added, and the temperature is continuously heated to 80-90 ℃ for reaction for 4-6 h; after the reaction is finished, adding dichloromethane and water for extraction, obtaining an organic phase part, adding water, adjusting the pH value to 5-6 for phase separation, obtaining a water phase part, adding dichloromethane, adjusting the pH value to 8-9, retaining the dichlorohexane part for drying and concentrating, adding n-hexane for heating and refluxing, stirring and crystallizing at 30-40 ℃ for 0.4-0.6 h, then preserving heat at 10-15 ℃ for 1-3 h, filtering, and drying at 30-40 ℃ for 5-7 h to obtain the product.
Further, the solvent is selected from toluene, N-dimethylformamide or N, N-dimethylacetamide; further preferred is N, N-dimethylformamide or N, N-dimethylacetamide.
The beneficial effects of the above technical scheme are:
1. in the invention, in the substitution of 4-aminobenzoic acid and bromo-n-butane, the exposure of amino can lead to the generation of dibutyl substituted impurities; aiming at the problems, the invention provides a brand new process route, the amino groups of the raw materials are protected by BOC and react with bromo-N-butane, so that the occurrence of a dibutyl substitution reaction on N is avoided, and the generation of impurities is effectively reduced.
2. The synthesis method provided by the invention does not need to use a high-pressure reaction kettle, does not need high-temperature operation, does not need expensive raw materials such as palladium-carbon metal catalysts and the like, does not need reaction raw materials with high danger coefficients such as hydrogen and the like, and has mild reaction conditions; and the temperature range of the synthesis process is reasonable, and the appearance of the obtained product is white crystalline powder, and the phenomena of darkness and yellowing are avoided.
3. The tetracaine product synthesized by the method has high purity, the purity of the prepared product is more than 99.8%, single impurities are less than 0.05%, and the product yield is more than 60%.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a chromatogram (A) and a partial enlarged view (B) of the tetracaine product in the comparative example;
FIG. 2 is a chromatogram (A) and a partial enlarged view (B) of the tetracaine product in example 1;
FIG. 3 is a chromatogram (A) and a partial enlarged view (B) of the tetracaine product in example 2.
Detailed Description
It should be noted that the following detailed description is exemplary and is intended to provide further explanation of the invention. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present invention. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof.
In order to enable those skilled in the art to more clearly understand the technical scheme of the present invention, the technical scheme of the present invention will be described in detail below with reference to specific examples and comparative examples.
Comparative example
Comparative example: CN102731333B
1. 100ml of anhydrous methanol was added to the reaction flask, 13.7g of p-aminobenzoic acid and 8g of n-butyraldehyde were added to the anhydrous methanol, the temperature was raised to 50℃and the mixture was stirred for 4 hours under heat preservation, and the methanol was concentrated under reduced pressure to give 4- (n-butenylamino) benzoic acid.
2. 4- (n-butenylamino) benzoic acid, 100ml of water and 6g of sodium hydroxide were added to a high-pressure reaction vessel, and 1.0g of 10% palladium on carbon was further added thereto to react at a hydrogen pressure of 1.5MPa and a temperature of 90℃for 4 hours. The filtrate was filtered and ph=2 was adjusted with 10% hydrochloric acid, and the resulting solid was vacuum dried at 50 ℃ for 4h to give 4- (n-butylamino) benzoic acid.
3. 4- (n-butylamino) benzoic acid was added to the reaction flask, 100ml toluene, 10g N, N-dimethylethanolamine and 5g concentrated sulfuric acid were added, and water was separated under reflux. After the reaction, 10% hydrochloric acid is added to adjust the pH to be=2, a water layer is separated and taken, 50ml of dichloromethane is added to the water layer, 20% sodium hydroxide is added to adjust the pH to be=13, an organic layer is separated and taken, the dichloromethane is concentrated to dryness, and the obtained solid is dried to obtain a crude product of tetracaine.
4. The crude tetracaine is dissolved in 100ml of 5% hydrochloric acid, 50ml of dichloromethane is added, 20% sodium hydroxide is added to adjust the pH to be 12, the organic layer is separated, the dichloromethane is concentrated to dryness under reduced pressure, and the obtained solid is dried in vacuum at 35 ℃ for 5 hours, so that 10.0g of off-white tetracaine is obtained.
The total yield is: 37.9%. Purity of finished product: 99.573% and its liquid phase diagram is shown in FIG. 1.
Example 1
Preparation of N-Boc-N-butyl-4-aminobenzoic acid butyl ester:
100ml of acetonitrile, 50g of N-Boc-4-aminobenzoic acid and 61g of potassium carbonate are added into a 1L four-port reaction bottle, the temperature is raised to 60 ℃, 60g of n-butyl bromide is slowly added dropwise, and the reaction is carried out at 70 ℃ for 6 hours after the dropwise addition. Cooling to room temperature, adding 250ml of ethyl acetate and water, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, adding 200ml of N-hexane, heating, refluxing and stirring for 0.5h, stirring and crystallizing at 10-20 ℃ for 2h, filtering, and vacuum drying a filter cake at 40-45 ℃ for 5h to obtain 59.8g of N-Boc-N-butyl-4-aminobenzoic acid butyl ester, wherein the yield is as follows: 81.2%.
Preparation of butyl N-butyl-4-aminobenzoate:
in a 1L four port reaction flask, 50g of N-Boc-N-butyl-4-aminobenzoate, 200ml of acetonitrile and 17g of formic acid were added. The reaction was stirred at 40℃for 6h. 250ml of ethyl acetate and 250ml of water were added, the liquid was separated by extraction, and the organic phase was washed with 200ml of water. The organic phase is dried by anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, 200ml of n-hexane is added, the mixture is heated, refluxed and stirred for 0.5h, stirred and devitrified for 3h at 0-10 ℃, filtered, and the filter cake is dried for 5h at 40-45 ℃ in vacuum, thus obtaining 31.7g of N-butyl-4-aminobenzoic acid butyl ester, the yield is: 88.9%.
3. Preparation of tetracaine:
into a 1L four-port reaction bottle, 30g of butyl N-butyl-4-aminobenzoate, 100ml of N, N-dimethylformamide and 1.2g of sodium methoxide are added, the mixture is stirred for 0.5h after being heated to 60 ℃, 21g of N, N-dimethylethanolamine is slowly added, and the system is continuously heated to 85 ℃ for stirring reaction for 5h. After the reaction was completed, the system was cooled to room temperature, 200ml of each of methylene chloride and water was added, the liquid was separated by extraction, and the organic phase was washed once more with 100ml of water. 150ml of water is added into the organic phase, and the pH value of the system is adjusted to 5-6 by using 2N hydrochloric acid. Stirring the solution for 30min, separating phases, adding 150ml of dichloromethane into the aqueous phase, regulating the pH value to 8-9 by using 10% sodium hydroxide, extracting and separating the liquid, washing the dichloromethane layer by using 50ml of water, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, adding 50ml of n-hexane into the concentrate, stirring at 30-40 ℃ for 0.5h, then preserving heat at 10-15 ℃ and stirring for 2h, filtering, and vacuum drying the filter cake at 35 ℃ for 6h to obtain 27.1g of white crystalline powder, wherein the yield: 85.2%.
The total yield of the three steps is as follows: 61.5 percent of finished product purity: 99.881% and its liquid phase diagram is shown in FIG. 2.
Example 2
Preparation of N-Boc-N-butyl-4-aminobenzoic acid butyl ester:
100ml of toluene, 50g of N-Boc-4-aminobenzoic acid and 61g of triethylamine are added into a 1L four-port reaction bottle, the temperature is raised to 60 ℃, 85g of n-butyl bromide is slowly added dropwise, and the reaction is carried out at 65 ℃ for 6 hours after the dropwise addition. Cooling to room temperature, adding 250ml of ethyl acetate and water, separating liquid, drying an organic phase by using anhydrous sodium sulfate, filtering, concentrating filtrate under reduced pressure, adding 200ml of N-hexane, heating, refluxing and stirring for 0.5h, stirring and crystallizing at 10-20 ℃ for 2h, filtering, and vacuum drying a filter cake at 40-45 ℃ for 5h to obtain 61.1g of N-Boc-N-butyl-4-aminobenzoic acid butyl ester, wherein the yield is: 83.0%.
Preparation of butyl N-butyl-4-aminobenzoate:
into a 1L four-port reaction flask, 50g of N-Boc-N-butyl-4-aminobenzoate, 200ml of N-hexane and 20g of glacial acetic acid were added. The reaction was stirred at 45℃for 6h. 250ml of ethyl acetate and 250ml of water were added, the liquid was separated by extraction, and the organic phase was washed with 200ml of water. The organic phase is dried by anhydrous sodium sulfate, filtered, the filtrate is concentrated under reduced pressure, 200ml of n-hexane is added, the mixture is heated, refluxed and stirred for 0.5h, stirred and devitrified for 3h at 0-10 ℃, filtered, and the filter cake is dried for 5h at 40-45 ℃ in vacuum, thus obtaining 30.9g of N-butyl-4-aminobenzoic acid butyl ester, the yield is: 86.6%.
3. Preparation of tetracaine:
into a 1L four-port reaction bottle, 30g of butyl N-butyl-4-aminobenzoate, 100ml of N, N-dimethylacetamide and 1.5g of sodium methoxide are added, the mixture is stirred for 0.5h after being heated to 70 ℃, 23g of N, N-dimethylethanolamine is slowly added, and the system is continuously heated to 80 ℃ for stirring reaction for 5h. After the reaction was completed, the system was cooled to room temperature, 200ml of each of methylene chloride and water was added, the liquid was separated by extraction, and the organic phase was washed once more with 100ml of water. 150ml of water is added into the organic phase, and the pH value of the system is adjusted to 5-6 by using 2N hydrochloric acid. Stirring the solution for 30min, separating phases, adding 150ml of dichloromethane into the aqueous phase, regulating the pH value to 8-9 by using 10% sodium hydroxide, extracting and separating the liquid, washing the dichloromethane layer by using 50ml of water, drying by using anhydrous sodium sulfate, concentrating under reduced pressure, adding 50ml of n-hexane into the concentrate, stirring at 30-40 ℃ for 0.5h, then preserving heat at 10-15 ℃ and stirring for 2h, filtering, and vacuum drying the filter cake at 35 ℃ for 6h to obtain 28.3g of white crystalline powder, wherein the yield: 89.0%.
Total yield of three steps: 64.0% of finished product purity: 99.858% and its liquid phase diagram is shown in FIG. 3.
The above description is only of the preferred embodiments of the present invention and is not intended to limit the present invention, but various modifications and variations can be made to the present invention by those skilled in the art. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. A synthetic method of tetracaine is characterized by comprising the following synthetic routes:
2. the synthesis method according to claim 1, characterized by the specific steps of:
(1) Raw material N-Boc-4-aminobenzoic acid (A) reacts with bromo-N-butane in an alkaline solvent to obtain a compound B;
(2) Removing Boc protecting groups from the compound B in weak acid to prepare a compound C;
(3) And (3) reacting the compound C with N, N-dimethylethanolamine to obtain the tetracaine (I).
3. The synthesis method according to claim 2, wherein in step (1): the molar ratio of the N-Boc-4-aminobenzoic acid to the bromo-N-butane is 1:2-1:8;
the alkaline solvent is a mixed solution of an alkaline reagent and an organic reagent, wherein the alkaline reagent is selected from one or a combination of a plurality of triethylamine, N-diisopropylethylamine, sodium carbonate and potassium carbonate;
the organic reagent is selected from one or more of acetonitrile, toluene, dimethylbenzene, N-dimethylformamide, N-dimethylacetamide and dimethyl sulfoxide.
4. A method of synthesis according to claim 3, wherein the basic reagent is triethylamine or potassium carbonate and the organic reagent is selected from acetonitrile or toluene, the dosage ratio of basic reagent to organic reagent being 55 to 65g: 90-110 ml.
5. The synthesis method according to claim 2, wherein the specific synthesis method in step (1) is as follows:
adding an alkaline solvent and N-Boc-4-aminobenzoic acid into a reaction vessel, heating to 55-65 ℃, slowly dropwise adding bromon-butane, and reacting for 5-7 h at 65-75 ℃ after dropwise adding; after the reaction is finished, adding 45-55% ethyl acetate solution into the reaction system for liquid separation, preserving the organic phase for partial drying and filtering, adding n-hexane for heating and refluxing for 0.4-0.6 h, stirring and crystallizing for 2h at 10-20 ℃, and vacuum drying for 4-6 h at 40-45 ℃ to obtain the compound B.
6. The synthesis method according to claim 2, wherein in step (2): the weak acid is an acidic reagent with low concentration, the acidic reagent is selected from formic acid, glacial acetic acid and trifluoroacetic acid, and the concentration is 8-12 g/L;
or, the reaction temperature is 40-50 ℃ and stirring reaction is carried out for 5-7 h to remove Boc protecting groups.
7. The synthesis method according to claim 2, wherein the specific embodiment of step (2) is as follows:
adding the compound B into an acidic reagent with low concentration, and stirring and reacting for 5-7 h at 35-45 ℃; adding 45-55% ethyl acetate solution into the reaction system for separating, keeping the organic phase partially dried and concentrated, adding n-hexane for heating and refluxing, stirring and crystallizing at 0-10 ℃ for 2-4 h, and vacuum drying at 40-45 ℃ for 4-6 h to obtain the compound C.
8. The synthesis method according to claim 2, wherein in step (3): the molar ratio of the compound C to the N, N-dimethylethanolamine is as follows: 1:2-1:6.
9. The synthesis method according to claim 2, wherein in the specific embodiment of step (3), the compound C and sodium methoxide are put into solvent, heated to 55-65 ℃ and stirred for 0.4-0.6 h, and N, N-dimethylethanolamine is slowly added, and the temperature is continuously heated to 80-90 ℃ for reaction for 4-6 h; after the reaction is finished, adding dichloromethane and water for extraction, obtaining an organic phase part, adding water, adjusting the pH value to 5-6 for phase separation, obtaining a water phase part, adding dichloromethane, adjusting the pH value to 8-9, retaining the dichlorohexane part for drying and concentrating, adding n-hexane for heating and refluxing, stirring and crystallizing at 30-40 ℃ for 0.4-0.6 h, then preserving heat at 10-15 ℃ for 1-3 h, filtering, and drying at 30-40 ℃ for 5-7 h to obtain the product.
10. The synthetic method of claim 2 wherein the solvent is selected from toluene, N-dimethylformamide or N, N-dimethylacetamide.
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